WO2011121823A1 - Particulate pharmaceutical composition for oral administration - Google Patents
Particulate pharmaceutical composition for oral administration Download PDFInfo
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- WO2011121823A1 WO2011121823A1 PCT/JP2010/067039 JP2010067039W WO2011121823A1 WO 2011121823 A1 WO2011121823 A1 WO 2011121823A1 JP 2010067039 W JP2010067039 W JP 2010067039W WO 2011121823 A1 WO2011121823 A1 WO 2011121823A1
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- pharmaceutical composition
- oral administration
- particulate pharmaceutical
- particulate
- drug
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
- A61K9/2081—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
- A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
Definitions
- the present invention relates to a particulate pharmaceutical composition for oral administration comprising atorvastatin.
- the present invention relates to a particulate pharmaceutical composition for oral administration, wherein a core containing atorvastatin and sodium lauryl sulfate is coated with a coating material containing polyvinyl acetal diethylaminoacetate and a water-soluble polymer substance, and
- the present invention relates to an orally disintegrating tablet containing a particulate pharmaceutical composition for oral administration.
- the present invention also relates to the use of polyvinyl acetal diethylaminoacetate and a water-soluble polymer substance for producing a granular pharmaceutical composition for oral administration which is coated with atorvastatin-containing particles and reduces the change in dissolution rate after compression molding. Is. Furthermore, this invention relates to the manufacturing method of the granular pharmaceutical composition for oral administration which coat
- HMG-CoA 3-hydroxy-3-methylglutaryl-coenzyme A
- atorvastatin calcium hydrate is sold as Lipitor®, which has the chemical name [R- (R *, R *)]-2- (4-fluorophenyl) - ⁇ , ⁇ -dihydroxy- 5- (1-methylethyl) -3-phenyl-4-[(phenylamino) carbonyl] -1H-pyrrole-1-heptanoic acid calcium salt (2: 1) trihydrate and has the following formula:
- Atorvastatin and its pharmaceutically acceptable salts are selective and competitive inhibitors of HMG-CoA reductase.
- Atorvastatin calcium is a potent lipid-lowering compound and is therefore useful as a lipid-lowering agent and / or cholesterol-lowering agent, and at the same time useful for the treatment of osteoporosis, benign prostatic hypertrophy (BPH), and Alzheimer's disease. is there.
- atorvastatin or a pharmaceutically acceptable salt thereof in a pure crystalline form so that a formulation containing atorvastatin or a pharmaceutically acceptable salt thereof can meet strict pharmaceutical requirements and standards There is a need. Furthermore, the process for producing atorvastatin or a pharmaceutically acceptable salt thereof is required to follow a large scale production. It is also desirable that the product be in a form that can be quickly filtered and easily dried. Ultimately, it is economically desirable for the product to be stable for long periods of time without requiring special storage conditions. So far, various crystal forms of atorvastatin or a pharmaceutically acceptable salt thereof have been disclosed (Patent Documents 1 and 2).
- atorvastatin is a poorly soluble drug, its in-vitro dispersibility and dissolution properties are poor, resulting in a problem of reduced bioavailability.
- a method of changing a crystal to an amorphous form there is a method of changing a crystal to an amorphous form.
- atorvastatin and optionally excipients are dissolved in a non-hydroxyl solvent to form a solution, and the solvent is lyophilized to provide an amorphous
- a method for producing amorphous atorvastatin (Patent Document 4), which comprises producing quality atorvastatin.
- a solid pharmaceutical composition comprising a solid dispersion with a pharmaceutically acceptable excipient which is a larger optional ingredient, comprising amorphous atorvastatin or a pharmaceutically acceptable complex, salt,
- a solid pharmaceutical composition comprising a solvate or hydrate and a melt processable polymer is disclosed (Patent Document 5).
- Patent Document 6 a method of heat treatment at a specific temperature is disclosed.
- atorvastatin or a pharmaceutically acceptable salt thereof is a drug having a strong bitter taste.
- the drug or the composition comprising the drug may be treated with a coating that suppresses the drug release for a certain period of time in the oral cavity. is there. Since the coating generally uses a water-insoluble polymer or the like, there is a problem that the dispersibility / elution property of the drug is lowered.
- oral particulate pharmaceutical compositions such as granules, fine granules, and powders are smaller in size than tablets and capsules, so that they are easy to take even for patients who have difficulty swallowing tablets and capsules.
- the particulate pharmaceutical composition for oral administration is small in size, the specific surface area increases, so that the drug is rapidly released in the oral cavity after taking it, causing various problems. For example, if the drug has an unpleasant taste, the drug quickly released in the oral cavity may cause a strong discomfort to the patient and significantly reduce dosage compliance.
- a saccharide having a low moldability is sprayed with a high moldability saccharide as a binder and coated and / or granulated, and when tablet strength is further required
- Orally disintegrating tablet humidity-dried tablet
- drug, diluent, and saccharide having a melting point relatively lower than that of the drug and diluent, and the saccharide having a low melting point is uniformly contained in the tablet
- An orally disintegrating tablet (Patent Document 8) containing a drug and / or diluent particles, which is blended with a melt-solidified product of a saccharide having a low melting point, and a drug, the degree of gelatinization of 30% or more and 60% Processed starches which are the following, orally disintegrating tablets containing sugars (Patent Document 9) and the like are known.
- a drug having a bitter taste when applied to these orally disintegrating tablets, for example, a drug solution is sprayed onto a core made of crystalline cellulose to prepare drug-containing particles, and then a polymer suitable for the particles is prepared.
- a method of applying a film coating with a substance is employed.
- the film tears and the drug leaks out so it is technically very difficult to suppress the bitter taste of the drug in the oral cavity.
- tableting is performed at a low pressure in order to avoid breakage of the coated film due to tableting, there is a concern that tablet hardness suitable for handling in the production process and transportation process cannot be obtained.
- an acrylic polymer As a method for suppressing an unpleasant taste, use of an acrylic polymer is known. Oral administration containing a drug-containing core, an intermediate layer containing two types of water-soluble components, an insolubilization accelerator and an insolubilizing substance, and a water infiltration control layer that controls the rate of water intrusion into the outermost layer A time-release particulate pharmaceutical composition for use is known, and an acrylic acid polymer is exemplified as a material used for a water infiltration control layer (Patent Document 10). However, depending on the drug or base selected, there is room for further improvement to reduce initial drug elution and to achieve subsequent rapid drug release.
- Patent Document 11 An invention relating to a taste-masked pharmaceutical composition comprising a polymer mixture is known (Patent Document 11).
- Patent Document 12 a film coating agent that conceals an unpleasant taste such as a bitter taste of a solid preparation by a film coat containing methyl cellulose and an acrylic acid-based polymer containing a methacrylic acid ester and / or an acrylic acid ester in a monomer unit, and having an excellent dissolution property.
- Patent Document 12 neither of Patent Documents 11 and 12 describes an elution change when compression-molding the coated granule, and there is a concern about a change in elution rate due to compression molding.
- Patent Document 13 A method for regenerating the elution control function inside a compression molded product is disclosed (Patent Document 13). Furthermore, as a method of compressing together with an excipient that absorbs impact due to compression, a preparation is described in which a film-protecting agent having an average particle diameter of 20 ⁇ m or less is physically mixed with a drug-containing film particle and then compression-molded.
- Patent Document 14 In order to provide a compression-molded preparation with reduced coating damage during compression molding of drug-containing coated particles, a substance containing drug-containing coated particles and having an average particle diameter of about 50 ⁇ m or more and an initial dissolution rate ratio of 4 or more An invention relating to a compression molding preparation containing fine particles as a film protective agent is disclosed (Patent Document 14).
- Patent Documents 13 and 14 depending on the selected drug or base, even if the initial drug elution is reduced, subsequent rapid drug release is not achieved, and a special device capable of alcohol treatment is used. There is a problem that needs to be used.
- Patent Document 15 an atorvastatin preparation containing a mixture containing atorvastatin and sodium lauryl sulfate is disclosed in Patent Document 15 (Example 3).
- Patent document 15 makes it a subject to stabilize atorvastatin, and a technical idea differs from this invention.
- a particulate pharmaceutical composition for oral administration that can reduce or reduce the change in drug elution rate even after compression molding while reducing the initial drug elution amount of atorvastatin and maintaining rapid drug release thereafter. That is, a particulate pharmaceutical composition for oral administration that achieves rapid dispersibility and dissolution in the digestive tract when concealing an unpleasant taste in the oral cavity (compliance compliance), and an oral cavity containing the composition Technology development regarding disintegrating tablets is necessary.
- Japanese Patent No. 3296564 specification (I, II, IV type), Japanese Patent No. 3965155 (V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, and XIX types)
- International Publication No. WO2006 / 046109 Pamphlet International Publication No. WO2004 / 110407 Pamphlet International Publication No. WO2006 / 059224 Pamphlet International Publication No. WO2007 / 034316 Pamphlet International Publication No. WO95 / 20380 (corresponding to US Pat. No. 5,576,014) International Publication No. WO02 / 92057 (corresponding US Pat. No.
- the present invention relates to a particulate pharmaceutical composition for oral administration that can reduce or reduce a change in drug elution rate even after compression molding while reducing the initial drug elution amount of atorvastatin and maintaining rapid drug release thereafter. And an orally disintegrating tablet containing the composition.
- the present invention also provides a particulate pharmaceutical composition for oral administration which achieves rapid dispersibility and dissolution in the digestive tract when atorvastatin is used to conceal an unpleasant taste in the mouth (compliance compliance), and An orally disintegrating tablet containing the composition is provided.
- the present inventors can reduce or reduce the initial drug elution amount of atorvastatin, and suppress or reduce the change in drug elution rate even after compression molding while maintaining rapid drug release thereafter.
- the particulate pharmaceutical composition for oral administration in which particles containing atorvastatin and sodium lauryl sulfate are coated with a coating material containing polyvinyl acetal diethylaminoacetate and a water-soluble polymer substance, the desired effect of the present invention described in detail below
- a drug based on the interaction between atorvastatin and a specific base The delayed elution induces a decrease in bioavailability, and the desired effect of the present invention is achieved by the selection and use of a specific polymer substance;
- the pharmaceutical composition for oral administration described above By confirming that the or
- the present invention [1] Particulate pharmaceutical for oral administration in which particles containing atorvastatin or a pharmaceutically acceptable salt thereof and sodium lauryl sulfate are coated with a coating substance containing polyvinyl acetal diethylaminoacetate and a water-soluble polymer substance Composition, [2]
- the water-soluble polymer substance is selected from the group consisting of hydroxypropylcellulose, hypromellose, methylcellulose, hydroxyethylcellulose, povidone, copolyvidone, polyvinyl alcohol-polyethylene glycol graft copolymer, polyvinyl alcohol, macrogol, and polyethylene oxide 1
- the water-soluble polymer substance is selected from the group consisting of hydroxypropylcellulose, hypromellose, methylcellulose, hydroxyethylcellulose, povidone, copolyvidone, polyvinyl alcohol-polyethylene glycol graft copolymer, polyvinyl alcohol, macrogol, and polyethylene oxide.
- a method for producing a particulate pharmaceutical composition for oral administration according to [9], which is a species or two or more species [11] The method for producing a granular pharmaceutical composition for oral administration according to [9], wherein the water-soluble polymer substance is hypromellose.
- the fluidizing agent is talc, kaolin, calcium silicate, magnesium silicate, light anhydrous silicic acid, magnesium stearate, calcium stearate, iron oxide, titanium oxide, calcium carbonate, calcium phosphate, gypsum, magnesium carbonate, hydroxide
- atorvastatin it is possible to reduce the release of atorvastatin from the core of the particulate pharmaceutical composition after compression molding for a certain period of time during which particles are present in the oral cavity, and (2) atorvastatin is rapidly released after a certain period of time. (3) It is possible to express sufficient efficacy by being released in the upper part of the digestive tract. (3) About atorvastatin having an unpleasant taste, in the digestive tract when concealing an unpleasant taste in the oral cavity It is possible to achieve quick elution in the case of (4) taking compliance and preventing delay in absorption, and the like.
- Example 3 water, Japanese Pharmacopoeia dissolution test 1st liquid (JP1), and Japanese Pharmacopoeia dissolution test 2nd liquid (JP2) were used as test solutions. It is the elution profile obtained in this way.
- Example 5 water, Japanese Pharmacopoeia dissolution test 1st liquid (JP1), and Japanese Pharmacopoeia dissolution test 2nd liquid (JP2) were used as test solutions. It is the elution profile obtained in this way.
- Example 2 is an elution profile obtained by conducting a liquid displacement elution test on the particulate pharmaceutical compositions (masking particles before tableting) prepared in Example 3 and Comparative Examples 2 to 4. It is a graph which shows the collection
- SLS sodium lauryl sulfate
- AEA polyvinyl acetal diethylaminoacetate
- the term “particulate pharmaceutical composition” refers to a drug-containing particulate composition that is smaller than the following fixed value and is orally administered in various forms together with one or more pharmaceutical additives. means.
- the size of the particulate pharmaceutical composition is defined as an average particle diameter of 2 mm or less.
- the shape of the particulate pharmaceutical composition is a shape other than a sphere, the size of the particulate pharmaceutical composition is defined as having an average longest diameter of 2 mm or less.
- the lower limit value is not particularly limited as long as it is a pharmaceutically acceptable range, and for example, 1 ⁇ m or more, another embodiment is 10 ⁇ m or more, and a further embodiment is 20 ⁇ m or more.
- Examples of the method for measuring the particle diameter include the microscopy described in the Fifteenth Revised Japanese Pharmacopoeia General Test Method. Microscopy is a method of directly observing the appearance and shape of individual particles with the naked eye or micrographs using an optical microscope, and measuring their sizes. The major axis average diameter, the triaxial average diameter, and the biaxial average The diameter can be used as the particle diameter.
- the “core” is not particularly limited as long as it can be a pharmaceutically acceptable grain. It is a group for constituting the particulate pharmaceutical composition of the present invention and for coating the intermediate layer and the coating material used in the present invention.
- the core is composed of the drug itself or pharmaceutically acceptable additives. Particles [eg, crystalline cellulose (grains) (may be described as microcrystalline cellulose), lactose, starch, etc.] can also be used. It is also possible to use a drug alone or a mixture of a drug and a pharmaceutically acceptable additive. You may manufacture the particle
- additives and sodium lauryl sulfate and a binder for example, water-soluble polymer: for example, hypromellose (also known as hydroxypropylmethylcellulose) (TC-5, Shin-Etsu Chemical), hydroxypropylcellulose ( Nisso HPC, Nippon Soda Co., Ltd.), methyl methacrylate / butyl methacrylate containing an acidic substance in an amount that neutralizes 10% or more of the basic group described in Japanese Patent No.
- water-soluble polymer for example, hypromellose (also known as hydroxypropylmethylcellulose) (TC-5, Shin-Etsu Chemical), hydroxypropylcellulose ( Nisso HPC, Nippon Soda Co., Ltd.), methyl methacrylate / butyl methacrylate containing an acidic substance in an amount that neutralizes 10% or more of the basic group described in Japanese Patent No.
- dimethylaminoethyl methacrylate copolymer [aminoalkyl methacrylate copolymer E (trade name; Eudragit E100, Evonik Degussa GmbH)], povidone (Collidon, BASF), methylcellulose (METOLOSE, Shin-Etsu Chemical) etc.)
- the dispersed liquid may be sprayed.
- the core can be coated with sodium lauryl sulfate and a water-soluble polymer.
- Examples of the size of the nucleus include, for example, 1 ⁇ m or more and 1000 ⁇ m or less, other embodiments include 5 ⁇ m or more and 500 ⁇ m or less, and further embodiments include 10 ⁇ m or more and 200 ⁇ m or less.
- “rapid dispersibility / dissolution” means that when a test is performed using 900 mL of Japanese Pharmacopoeia Dissolution Test Solution 1 (JP1) according to the 15th revised Japanese Pharmacopoeia Dissolution Test Method 2, It means that the elution rate at 15 minutes is 50% or more. In another embodiment, it means that the dissolution rate in 15 minutes is 60% or more.
- “suppressing drug release for a certain period of time” or “suppressing initial drug dissolution” means that the dissolution rate of a drug is suppressed to 0 to 3% in a dissolution test assuming the oral cavity.
- the “lag time” means the “time when the drug dissolution rate is suppressed to 0 to 3%”.
- the “lag time” is used for the purpose of shielding the unpleasant taste of the drug in the oral cavity, and the characteristics and purpose of the drug / formulation (for example, the type and degree of the unpleasant taste of the drug, the duration of the taste, the oral cavity of the formulation It is appropriately set in consideration of the internal residence time, etc., but is defined as, for example, 2 minutes or more, for example, “lag time” is, for example, “intermediate layer” component in the composition, its blending ratio / coating amount, water It can be arbitrarily adjusted by designing such as appropriately increasing / decreasing the components of the infiltration amount control layer and the blending ratio / coating amount thereof.
- unpleasant taste means a taste that causes unpleasant feeling when taken, and specifically includes bitterness, astringency, gummy taste, acidity, pungent taste, astringent taste, and the like.
- insolubilization means a phenomenon in which the solubility in water or the dissolution rate is lowered.
- insolubilize”, “insolubilize”, and “promoting insolubilization” means that a dissolved substance is phase-separated from water, precipitated, precipitated, precipitated, or dissolved in water. Indicates blocking.
- the “test solution assuming the oral cavity” means a pH 6.8 phosphate buffer solution (the 15th revised Japanese Pharmacopoeia dissolution test method second solution).
- the particulate pharmaceutical composition for oral administration according to the present invention is such that particles containing atorvastatin or a pharmaceutically acceptable salt thereof and sodium lauryl sulfate are coated with a coating substance containing polyvinyl acetal diethylaminoacetate and a water-soluble polymer substance. It is a particulate pharmaceutical composition for oral administration.
- the orally disintegrating tablet of the present invention is an orally disintegrating tablet comprising the particulate pharmaceutical composition for oral administration of the present invention.
- Atorvastatin or a pharmaceutically acceptable salt thereof used in the present invention is atorvastatin calcium hydrate, chemical name [R- (R *, R *)] disclosed in US Pat. No. 5,273,995. -2- (4-Fluorophenyl) - ⁇ , ⁇ -dihydroxy-5- (1-methylethyl) -3-phenyl-4-[(phenylamino) carbonyl] -1H-pyrrole-1-heptanoic acid calcium salt 2: 1) Trihydrate is included. Atorvastatin calcium hydrate has the following formula: Currently marketed as Lipitor®. Atorvastatin or a pharmaceutically acceptable salt thereof is a selective and competitive inhibitor of HMG-CoA reductase.
- Examples of pharmaceutically acceptable salts include metal salts such as alkali metals and alkaline earth metals, or amine salts such as organic amines.
- a salt with sodium, potassium, lithium, calcium, magnesium, aluminum, iron, zinc, calcium carbonate, calcium hydroxide, magnesium carbonate, magnesium hydroxide, magnesium silicate, magnesium aluminate, magnesium aluminum hydroxide is used.
- a salt with calcium can be mentioned.
- Atorvastatin calcium is a potent lipid-lowering compound and is therefore useful as a lipid-lowering agent and / or cholesterol-lowering agent, and at the same time useful for the treatment of osteoporosis, benign prostatic hypertrophy (BPH), and Alzheimer's disease. is there.
- atorvastatin examples include, for example, types I, II, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, and XIX.
- type I may be mentioned.
- "Type I crystal” is crystalline Form I atorvastatin hydrate disclosed in Japanese Patent No. 3,296,564.
- the amount of atorvastatin or a pharmaceutically acceptable salt thereof is not particularly limited as long as it is a pharmaceutically preventive or therapeutically effective amount.
- it is about 2.5 mg to about 80 mg per day. It is about 5 mg or more and about 500 mg or less, and as a further aspect, it is about 2.5 mg or more and about 80 mg or less.
- it is administered to a patient at an adult dosage level of about 0.1 mg to about 8.0 mg / kg body weight per day.
- the daily dose is in the range of about 0.1 mg / kg to about 2.0 mg / kg.
- the blending amount can be changed or adjusted to 5 mg or more and 80 mg or less, and in another embodiment, 5 mg or more and 100 mg or less depending on efficacy or application.
- the dosage is increased gradually until the optimum effect is reached according to the circumstances.
- the total dose per day can be divided and administered several times a day.
- the proportion of the drug is usually appropriately selected according to the type, use (indication), and age (or body weight) of the drug, as long as it is a therapeutically effective amount or a prophylactically effective amount.
- it is 0.5 wt% or more and 90 wt% or less per "particulate pharmaceutical composition" or pharmaceutical preparation of the present invention, and in another embodiment, 0.5 wt% or more and 80 wt% or less. As 0.5 to 70% by weight.
- the sodium lauryl sulfate used in the present invention is not particularly limited as long as it has a function of improving dispersibility of atorvastatin or a pharmaceutically acceptable salt thereof. Moreover, sodium lauryl sulfate will not be specifically limited if it has a function which improves the solubility of polyvinyl acetal diethylamino acetate. Examples of sodium lauryl sulfate include trade names NIKKOL SLS (Nikko Chemicals), Emar 0 (Kao), TEXAPON K12 P PH (Cognis Japan), and TEXAPON K12 G PH (Cognis Japan).
- the amount of sodium lauryl sulfate is not particularly limited as long as it is pharmaceutically acceptable and improves the dispersibility of atorvastatin or a pharmaceutically acceptable salt thereof. , Atorvastatin or a pharmaceutically acceptable salt thereof, 30 wt% or more and 200 wt% or less, in another embodiment, 40 wt% or more and 100 wt% or less, and in another embodiment, atorvastatin or a pharmaceutical product thereof It can be 60 wt% or more and 100 wt% or less based on the amount of salt allowed.
- the amount of sodium lauryl sulfate is not particularly limited as long as it is an amount that improves the solubility of polyvinyl acetal diethylaminoacetate.
- the aspect is 50% by weight to 200% by weight with respect to polyvinyl acetal diethylaminoacetate.
- the aspect may be 100% by weight or more and 200% by weight or less, still another aspect may be 120% by weight or more and 200% by weight or less, and still another aspect may be 130% by weight or more and 200% by weight or less.
- Polyvinyl acetal diethylaminoacetate (hereinafter sometimes abbreviated as AEA) used in the present invention is an acetal obtained by dehydration condensation of polyvinyl alcohol and acetaldehyde, and a part of the remaining hydroxyl groups and diethylaminoacetic acid It is an ester bond and is not particularly limited as long as it is pharmaceutically acceptable. Specific examples include those commercially available under the trade name “AEA (registered trademark)” (for example, average molecular weight 65000) as gastric coating agents (Pharmaceutical Additive Standards, pp. 634-635, 2003, Yakuji Nipposha).
- AEA registered trademark
- the blending amount of polyvinyl acetal diethylaminoacetate is, for example, 1% by weight or more and 500% by weight or less with respect to the drug-containing particles, and in another aspect, 5% by weight or more and 300% by weight or less, and in another aspect, 10% by weight. % Or more and 150% by weight or less.
- it is 1% by weight or more and 300% by weight or less with respect to the intermediate layer-coated particles.
- it is 5% by weight or more and 200% by weight or less, and in another embodiment, it is 5% by weight or more and 150% by weight or less. be able to.
- the ratio of the coating amount in the particulate pharmaceutical composition is, for example, 1% by weight or more and 200% by weight or less, and in another embodiment, 5% by weight or more and 100% by weight or less, and in another embodiment, 5% by weight or more and 50% by weight or less. It can be up to wt%.
- the “water-soluble polymer substance” used in the present invention is not particularly limited as long as it is pharmaceutically acceptable.
- the polymer substance constitutes a coating component together with polyvinyl acetal diethylaminoacetate, and the “particulate pharmaceutical composition” is coated with the coating substance, so that the drug substance from the “particulate pharmaceutical composition” is compressed after compression molding.
- polymer substance examples include gum arabic, sodium alginate, pregelatinized starch, casein sodium, carrageenan, carboxyvinyl polymer, sodium carboxymethyl starch, carmellose sodium, xanthan gum, dextran, dextrin, hydroxypropylcellulose, hypromellose, methylcellulose. , Hydroxyethyl cellulose, pullulan, povidone, copolyvidone, polyoxyethylene-polyoxypropylene glycol, polyvinyl acetal diethylaminoacetate, polyvinyl alcohol-polyethylene glycol graft copolymer, polyvinyl alcohol, macrogol, and polyethylene oxide.
- Further embodiments include hydroxypropylcellulose, hypromellose, methylcellulose, hydroxyethylcellulose and the like.
- Still other embodiments include hydroxypropylcellulose, hypromellose, hydroxyethylcellulose and the like.
- hypromellose examples include a high-molecular substance (indicated viscosity of 3 mPa ⁇ s to 15 mPa ⁇ s) marketed under the trade name of the 15th revised Japanese Pharmacopoeia Hypromellose (Shin-Etsu Chemical). These water-soluble polymer substances can be used alone or in combination of two or more.
- composition ratio (mixing ratio) of polyvinyl acetal diethylaminoacetate and water-soluble polymer substance used in the present invention, usually depending on purposes such as physical properties of the drug, stability, absorption site, type and use of dosage form, An appropriate blending amount is appropriately selected.
- the amount of the water-soluble polymer substance is, for example, from 1% by weight to 30% by weight with respect to polyvinyl acetal diethylaminoacetate. In another embodiment, the amount is from 5% by weight to 20% by weight, and in a further embodiment, from 5% by weight to 15%. % By weight or less.
- an appropriate ratio is appropriately selected for the coating amount of the coating material containing the polyvinyl acetal diethylaminoacetate and the water-soluble polymer material in the present invention.
- the content is 1% by weight or more and 500% by weight or less with respect to the core containing the drug. In another embodiment, it is 5 wt% or more and 300 wt% or less, and in a further embodiment, it is 10 wt% or more and 150 wt% or less.
- the coating amount is lower than 1% by weight, the surface of the particulate pharmaceutical composition is not uniformly coated and the coating layer is extremely thin, so that the drug elution from the particulate pharmaceutical composition by compression molding There is concern about an increase in speed.
- intermediate layer coated particles when the particles containing drug-containing particles are coated with an intermediate layer (which will be described later and may be abbreviated as “intermediate layer” coated particles hereinafter), 1 wt% or more and 500 wt% or less. In another embodiment, it is 5% by weight or more and 200% by weight or less, and in a further embodiment, it is 10% by weight or more and 150% by weight or less.
- the ratio of the coating amount in the particulate pharmaceutical composition is, for example, 1% by weight or more and 200% by weight or less. In another embodiment, it is 5% by weight or more and 100% by weight or less, and in another embodiment, it is 5% by weight or more and 50% by weight or less.
- the particulate pharmaceutical composition of the present invention can employ an embodiment in which a “fluidizing agent” is blended as desired.
- a “fluidizing agent” is blended as desired.
- the blending of the fluidizing agent is not particularly limited during a specific production method.
- the “particulate pharmaceutical composition” of the present invention is produced by a fluidized bed granulation method, mixing of the components and particles As the material dries, static electricity is generated, which may hinder fluidization.
- the fluidizing agent has a function of neutralizing generated static electricity and the like, and is not particularly limited as long as it improves fluidization during coating.
- the fluidizing agent examples include metal silicates, silicon dioxides, higher fatty acid metal salts, metal oxides, alkaline earth metal salts, metal hydroxides, and other embodiments include talc, kaolin, Calcium silicate, magnesium silicate, light anhydrous silicic acid, magnesium stearate, calcium stearate, iron oxide, titanium oxide, calcium carbonate, calcium phosphate, gypsum, magnesium carbonate, aluminum hydroxide, hydrous silicon dioxide, crystalline cellulose, synthetic silicic acid Aluminum, heavy anhydrous silicic acid, magnesium alumina hydroxide, stearic acid, corn starch, magnesium aluminate metasilicate, calcium hydrogen phosphate granulate, and glyceryl monostearate, further embodiments include talc, Kaolin, silicate Siumu, magnesium silicate, light anhydrous silicic acid, magnesium stearate, and glyceryl monostearate.
- One or more fluidizing agents can be added in appropriate combination.
- the blending amount of the fluidizing agent is, for example, 1% by weight to 500% by weight with respect to the drug-containing particles. In another embodiment, it is 1% by weight or more and 200% by weight or less, and in a further embodiment, it is 5% by weight or more and 100% by weight or less. With respect to polyvinyl acetal diethylaminoacetate, it is, for example, 1% by weight or more and 200% by weight or less, and in another aspect, it is 5% by weight or more and 100% by weight or less, and in a further aspect, it is 20% by weight or more and 60% by weight or less.
- grains of an intermediate body other than an orally disintegrating tablet can be mix
- pharmaceutical preparations other than orally disintegrating tablets include powders, fine granules, dry syrups, tablets and the like.
- the orally disintegrating tablet of the present invention will be described, but the pharmaceutical preparation of the present invention is not limited thereto.
- the “orally disintegrating tablet” means that when taking a tablet without ingesting water, the oral cavity is substantially within 2 minutes only by saliva, as another aspect within 1 minute, as a further aspect It means tablets that disintegrate within 45 seconds and other preparations similar to tablets.
- the particulate pharmaceutical composition of the present invention can be contained in such an orally disintegrating tablet.
- International Publication No. WO95 / 20380 US Patent No. 5576014
- International Publication No. WO2002 / 92057 Pamphlet U.S. Patent Application Publication No. 2003/099701
- U.S. Pat. No. 4,305,502 U.S. Pat. No. 4,371,516, U.S. Pat. No.
- orally disintegrating tablets containing the particulate pharmaceutical composition As such orally disintegrating tablets containing the particulate pharmaceutical composition, the orally disintegrating tablets described in Japanese Patent No. 3412694 (US Patent No. 5223264) and Japanese Patent Application Laid-Open No. 2003-55197 are disclosed.
- the particulate pharmaceutical composition of the present invention can be contained in these orally disintegrating tablets.
- Orally disintegrating tablets are generally classified into a mold type, a moist type, and a normal tableting type, and the particulate pharmaceutical composition of the present invention may be contained in any type of orally disintegrating tablet.
- the mold-type orally disintegrating tablet is prepared by filling a mold with a solution or suspension such as an excipient as disclosed in, for example, Japanese Patent No. 2807346 (US Pat. No. 5,466,464). It is made by drying.
- the mold-type orally disintegrating tablet containing the particulate pharmaceutical composition of the present invention is, for example, a solution or suspension of the particulate pharmaceutical composition of the present invention, excipients such as sugars, and binders such as gelatin and agar.
- the PTP pocket After filling the PTP pocket with the liquid, it can be produced by removing moisture by a method such as freeze drying, drying under reduced pressure, or low temperature drying.
- Wet type orally disintegrating tablets are moistened with excipients such as saccharides as shown in Patent No. 3069458 (U.S. Pat. No. 5,018,618, U.S. Pat. No. 5,720,974).
- the product After tableting under low pressure, the product is dried. Therefore, for example, the particulate pharmaceutical composition of the present invention, an excipient such as a saccharide can be wetted with a small amount of water or a mixture of water and alcohol, and the wet mixture can be molded at a low pressure and dried.
- the granulated product can be compression-molded to form a compressed molded product, or the compressed molded product can be humidified and dried to produce an orally disintegrating tablet.
- a normal tablet type orally disintegrating tablet as shown in International Publication No. WO99 / 47124 Pamphlet (US Patent No. 6658554)
- the particulate pharmaceutical composition of the present invention is used.
- An orally disintegrating tablet can be produced by compression molding using an amorphous sugar and an excipient such as a product and a crystalline saccharide, followed by humidification and drying.
- a normal tablet type orally disintegrating tablet as disclosed in International Publication No.
- WO2002 / 92057 pamphlet (US Patent Application Publication No. 2003/099701 specification), for example, A mixture of a particulate pharmaceutical composition, an excipient, and a saccharide having a melting point lower than that of the excipient is compression-molded and heated to form a crosslink by melting and solidifying the saccharide having a lower melting point.
- Orally disintegrating tablets can be prepared. By such humidification drying or heat treatment, the tablet strength of the orally disintegrating tablet can be improved.
- Orally disintegrating tablets can be prepared by compression-molding a mixture of the particulate pharmaceutical composition and excipients and processed starches having a pregelatinization degree of 30% to 60%.
- a general excipient can be used, but it is particularly preferable to use a pharmaceutically acceptable saccharide, and a technique utilizing the moldability of the saccharide.
- a pharmaceutically acceptable saccharide In the case of using saccharides with low moldability, crystalline / amorphous saccharides, and tablet strength improvement technology by humidification drying, it is common to use cross-linking technology with crystalline saccharides and saccharide melt-solidified products.
- high melting point saccharides can be used.
- the saccharide having low moldability means, for example, when tableting 150 mg of saccharide with a punch having a diameter of 8 mm at a tableting pressure of 10 kg / cm 2 or more and 50 kg / cm 2 or less, the hardness of the tablet is 0 kp or more and 2 kp or less.
- the term “highly moldable saccharide” means that the hardness by the same method is 2 kp or more.
- Saccharides with low moldability are pharmaceutically acceptable, and examples thereof include lactose, mannitol, glucose, sucrose, xylitol, and erythritol. One or two or more of these may be used in appropriate combination.
- Highly moldable saccharides are pharmaceutically acceptable, and examples thereof include maltose, maltitol, sorbitol, trehalose, lactitol and the like. These saccharides can also be used alone or in combination of two or more.
- “Crystalline saccharide” is pharmaceutically acceptable, and examples thereof include mannitol, maltitol, erythritol, xylitol and the like. These may be used alone or in combination of two or more. “Amorphous saccharides” are pharmaceutically acceptable and include, for example, lactose, sucrose, glucose, sorbitol, maltose, trehalose, etc., and these saccharides may be used alone or in combination of two or more. It is also possible to use it.
- the “saccharide having a high melting point” is pharmaceutically acceptable, and examples thereof include xylitol, trehalose, maltose, sorbitol, erythritol, glucose, sucrose, maltitol, mannitol and the like. One or two or more of these may be used in appropriate combination.
- the “sugar having a low melting point” is pharmaceutically acceptable, and examples thereof include xylitol, trehalose, maltose, sorbitol, erythritol, glucose, sucrose, maltitol, mannitol and the like. These saccharides can also be used alone or in combination of two or more.
- binders for orally disintegrating tablets include maltitol and copolyvidone. Also about this binder, it is also possible to use 1 type or in combination of 2 or more types as appropriate.
- a water-soluble polymer for example, hydroxypropylcellulose, hypromellose, povidone, polyvinyl alcohol, gum arabic powder, gelatin, pullulan and the like are suitable.
- ⁇ -ized means that when physical treatment is applied to starch, water enters between the molecules and swells (gelatinizes). Become.
- processed starch include corn starch, wheat starch, potato starch, rice starch, tapioca starch and the like.
- the blending amount of the excipient used for the orally disintegrating tablet containing the particulate pharmaceutical composition of the present invention, or the total amount of the excipient in the whole preparation is the blending amount of the particulate pharmaceutical composition of the present invention and / or Or it is suitably adjusted according to the size of the tablet and the like, but usually 20 mg or more and 1000 mg or less per tablet is preferable, 50 mg or more and 900 mg or less is preferable as another aspect, and 50 mg or more and 800 mg or less is preferable as a further aspect.
- the blending amount of highly moldable saccharides, water-soluble polymers, amorphous saccharides, and saccharides with a low melting point is 0.5 wt. % Or more and 50% by weight or less is preferable, and in another embodiment, it is 1% by weight or more and 40% by weight or less, and in a further embodiment, it is 2% by weight or more and 30% by weight or less, or 1% by weight or more and 20% by weight or less % Or less is preferred.
- the orally disintegrating tablet contains the particulate pharmaceutical composition of the present invention
- a particulate pharmaceutical composition equivalent to 0.5% by weight or more and 90% by weight or less of the whole orally disintegrating tablet can be contained.
- it is 0.5 wt% or more and 80 wt% or less, and in another embodiment, it corresponds to 1 wt% or more and 60 wt% or less.
- various pharmaceutical excipients are appropriately used as necessary, and formulated.
- a pharmaceutical excipient is not particularly limited as long as it is pharmaceutically acceptable and pharmacologically acceptable.
- binders, disintegrants, acidulants, foaming agents, artificial sweeteners, fragrances, lubricants, colorants, stabilizers, buffers, antioxidants, surfactants, and the like are used.
- binder examples include hypromellose and gum arabic.
- disintegrant examples include corn starch, potato starch, carmellose calcium, and carmellose sodium.
- sour agent examples include citric acid, tartaric acid, malic acid and the like.
- foaming agent examples include baking soda.
- artificial sweetener examples include saccharin sodium, dipotassium glycyrrhizin, aspartame, stevia and thaumatin.
- fragrances include lemon, lemon lime, orange and menthol.
- the lubricant examples include magnesium stearate, calcium stearate, sucrose fatty acid ester, polyethylene glycol, talc, stearic acid and the like.
- Examples of the colorant include yellow ferric oxide, red ferric oxide, edible yellow No. 4, No. 5, edible red No. 3, No. 102, and edible blue No. 3.
- Buffers include citric acid, succinic acid, fumaric acid, tartaric acid, ascorbic acid or salts thereof, glutamic acid, glutamine, glycine, aspartic acid, alanine, arginine or salts thereof, magnesium oxide, zinc oxide, magnesium hydroxide, phosphoric acid Boric acid or a salt thereof.
- Examples of the antioxidant include ascorbic acid, dibutylhydroxytoluene, propyl gallate and the like.
- surfactant examples include polysorbate 80, sodium lauryl sulfate, polyoxyethylene hydrogenated castor oil, and the like.
- the pharmaceutical excipient one or a combination of two or more can be added as appropriate.
- the compounding amount of these various pharmaceutical excipients is, for example, 1% by weight or more and 100% by weight or less with respect to the drug-containing particles, and in another aspect, 5% by weight or more and 80% by weight or less, and 10% as a further aspect. % By weight to 50% by weight.
- the core containing the drug and sodium lauryl sulfate may be coated with a coating material containing atorvastatin, sodium lauryl sulfate, and a water-soluble polymer. it can.
- a coating material containing atorvastatin, sodium lauryl sulfate, and a water-soluble polymer it can.
- the drug-containing nucleus particles made of only a drug can be used.
- particles comprising a drug and one or more additives may be produced and used.
- the drug and a suitable excipient for example, microcrystalline cellulose, lactose, corn starch, etc.
- a binder for example, a water-soluble polymer: For example, hydroxypropyl methylcellulose (also known as hypromellose) (TC-5, Shin-Etsu Chemical), hydroxypropyl cellulose (Nisso HPC, Nippon Soda Co., Ltd.), 10% or more of the basic group described in Japanese Patent No.
- a solution in which a drug and a binder are dissolved or dispersed may be sprayed on additive particles [for example, crystalline cellulose (grains), purified white sucrose spherical granules, white sucrose / starch spherical granules, etc.] serving as an appropriate core.
- additive particles for example, crystalline cellulose (grains), purified white sucrose spherical granules, white sucrose / starch spherical granules, etc.
- These particles can be further coated with a coating material containing sodium lauryl sulfate and a water-soluble polymer.
- the coating substance containing polyvinyl acetal diethylaminoacetate and the water-soluble polymer substance may be directly coated on the core containing the drug, or one layer or two or more layers. It may be coated after coating.
- an “intermediate layer” is formed between a coating substance containing polyvinyl acetal diethylaminoacetate and a water-soluble polymer substance and a nucleus containing a drug. It may be arranged.
- the “intermediate layer” means a coating layer containing one or more water-soluble insolubilizers and one or more water-soluble insolubilizers.
- the intermediate layer can be directly coated on the core containing the drug. Further, the intermediate layer may be coated after the drug-containing core is coated in advance as a coating layer of one layer or two or more components that do not prevent the formation of lag time and subsequent rapid drug release.
- the intermediate layer contains two or more kinds of essential components (insolubilization accelerator and insolubilizing substance), and these plural essential components can be contained in one layer and covered. May be uniform or unevenly distributed.
- the intermediate layer can cover two or more essential components (insolubilization accelerator and insolubilizing substance) by dividing them into two or more layers, and in that case, how to divide the components Any arrangement may be used. Even in the case of a plurality of layers, the coating layers containing a plurality of essential components are collectively referred to as an intermediate layer.
- the “insolubilization accelerator” used in the “intermediate layer” is not particularly limited as long as it is a pharmaceutically acceptable water-soluble substance and has a property to promote insolubilization of the “insolubilized substance” described later.
- “insolubilization accelerator” is “extremely soluble”, “easily soluble” in the definition / measurement method of “solubility” described in the general rules of the 15th revision Japanese Pharmacopoeia, It is a substance with solubility that is “slightly soluble”, “slightly difficult to dissolve”, and “hardly soluble”.
- examples of the “insolubilization accelerator” include sodium carbonate, potassium carbonate, sodium dihydrogen phosphate, dipotassium phosphate, disodium hydrogen phosphate, sodium metaphosphate, trisodium phosphate, and phosphoric acid.
- Embodiments include sodium carbonate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium metaphosphate, trisodium phosphate, potassium bicarbonate, sodium bicarbonate, sodium polyphosphate, sodium pyrophosphate, sodium chloride, chloride Potassium, sodium sulfate, sodium sulfite, sodium citrate, disodium citrate, sodium glutamate, disodium succinate, glycine, alanine, sorbitol, xylitol, inositol, sucrose, glucose, or fructose or their hydrates
- further Embodiments include sodium carbonate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium citrate, disodium citrate or hydrates thereof.
- One or two or more insolubilizers can be used in appropriate combination.
- the “insolubilizing substance” used in the “intermediate layer” is not particularly limited as long as it is a pharmaceutically acceptable water-soluble substance and insolubilized by the “insolubilization accelerator”. Specifically, for example, in the provisions and measurement methods for “solubility” described in the 15th revised Japanese Pharmacopoeia General Rules, “very soluble”, “easy to dissolve”, “slightly soluble”, “ It is a substance with solubility that is said to be “slightly insoluble” or “hard to dissolve”.
- examples of the “insolubilizing substance” include hypromellose, hydroxypropylcellulose, methylcellulose, polyvinyl alcohol-polyethylene glycol graft copolymer, carboxyvinyl polymer, polyvinyl alcohol, polyethylene oxide, povidone, copolyvidone, polyoxyethylene cured Castor oil, N-isopropylacrylamide, and polymers containing a hydrophobic group introduced at the N-position of acrylamide, polyoxyethylene-polyoxypropylene glycol, macrogol (molecular weight 6000 or more), hydroxyethyl cellulose, etc. .
- hypromellose hydroxypropylcellulose, methylcellulose, polyvinyl alcohol-polyethylene glycol graft copolymer, carboxyvinyl polymer, polyvinyl alcohol, polyethylene oxide, povidone, copolyvidone, polyoxyethylene hydrogenated castor oil, N-isopropylacrylamide and acrylamide
- a polymer or a polyoxyethylene-polyoxypropylene glycol containing a derivative having a hydrophobic group introduced at the N-position thereof and as further embodiments, hypromellose, methylcellulose, polyvinyl alcohol-polyethylene glycol graft copolymer, N-isopropylacrylamide
- a polymer containing a derivative having a hydrophobic group introduced at the N-position of acrylamide One or more insolubilizing substances can be used in appropriate combination.
- the ratio of the insolubilization accelerator to the weight of the intermediate layer is not particularly limited as long as it is a ratio suitable for achieving the object of the present invention.
- the content is 20% by weight or more and less than 95% by weight, as another aspect, 30% by weight or more and less than 90% by weight, and as another aspect, 40% by weight or more and less than 80% by weight.
- the coating amount of the intermediate layer is not particularly limited as long as it is an amount suitable for achieving the object of the present invention.
- the content is 1% by weight or more and 500% by weight or less with respect to the core particles containing the drug.
- it is 1% by weight or more and 300% by weight or less.
- it is 20% by weight or more and 200% by weight or less, and in another embodiment, it is 30% by weight or more and 100% by weight or less.
- the coating amount is lower than 1% by weight, there is a concern that a sufficiently long lag time cannot be formed. Considering the efficiency in production, if the coating amount is too large, the production time is long and inefficient.
- the ratio of the intermediate layer to the total weight of the particulate composition is not particularly limited as long as it is a ratio suitable for achieving the object of the present invention. Specifically, for example, 0.1 wt% or more and 95 wt% or less, as another embodiment, 1 wt% or more and 85 wt% or less, and as another embodiment, 3 wt% or more and 80 wt% or less, 5 wt% More than 70% by weight, and still another embodiment is 10% by weight to 60% by weight.
- an embodiment in which the above-mentioned pharmaceutical excipient is further coated on the outside of the coating layer containing polyvinyl acetal diethylaminoacetate and a water-soluble polymer substance can be employed.
- coating additives include amino acids such as glycine and alanine, sweeteners such as glycyrrhizic acid, sugars such as sucrose, fructose, maltose, glucose, and cyclodextrin, and sugar alcohols such as mannitol, xylitol, maltitol, and sorbitol. Is mentioned.
- An appropriate amount of one or more kinds of pharmaceutical excipients can be appropriately added to the coating layer (outer layer) made of the pharmaceutical excipient.
- the coating amount of the outer layer is, for example, 1% by weight or more and 200% by weight or less with respect to the drug-containing particles, in another aspect, 1% by weight or more and 100% by weight or less, and in a further aspect, 5% by weight or more and 40% by weight or less. is there.
- the ratio of the outer layer to the total weight of the particulate composition is, for example, 1% by weight or more and 50% by weight or less, in another embodiment 1% by weight or more and 25% by weight or less, and in a further embodiment 5% by weight or more and 10% by weight or less. It is as follows.
- the particulate pharmaceutical composition of the present invention can be produced by a method known per se, such as coating, drying, heat treatment, tableting and the like.
- the core containing the drug is coated with the coating substance of the present invention.
- the drug-containing nucleus particles made of only a drug can be used.
- particles comprising a drug and one or more additives may be produced and used.
- the drug and an appropriate excipient for example, crystalline cellulose, lactose, corn starch, etc.
- a binder for example, hydroxypropyl cellulose
- the drug and the binder are dissolved in additive particles (for example, crystalline cellulose (granule) (may be described as microcrystalline cellulose), purified white sucrose spherical granules, white sucrose / starch spherical granules, etc.) that serve as an appropriate core.
- additive particles for example, crystalline cellulose (granule) (may be described as microcrystalline cellulose), purified white sucrose spherical granules, white sucrose / starch spherical granules, etc.
- the dispersed liquid may be sprayed.
- a particulate pharmaceutical composition such as a fluidized bed coating apparatus, a rolling coating apparatus, or a centrifugal rolling coating apparatus. Any method may be used.
- a fluidized bed side spray type coating apparatus a necessary amount of liquid containing a coating component may be sprayed with a spray gun while a core containing a drug is flowed with warm air.
- the liquid containing the coating component is prepared by dissolving or dispersing essential components in a solvent such as water, ethanol, methanol or the like. Further, these solvents can be appropriately mixed and used.
- the intermediate layer may be coated on the outer side of the core containing the drug, or the particulate pharmaceutical composition of the present invention may be further coated with a pharmaceutical excipient and then coated with the coating substance of the present invention.
- a method for coating the intermediate layer on the core particles containing the drug it is produced by a method known per se.
- any method capable of coating the particulate pharmaceutical composition such as a fluidized bed coating apparatus, a rolling coating apparatus, or a centrifugal rolling coating apparatus, may be used.
- a necessary amount of a liquid containing a coating component may be sprayed with a spray gun while flowing the core particles containing the drug with warm air.
- the liquid containing the coating component is prepared by dissolving or dispersing essential components in a solvent such as water, ethanol, methanol or the like. Further, these solvents can be appropriately mixed and used.
- the preferred spraying speed of the coating varies depending on the production method or the scale to be produced, but when produced on a 1 kg scale by the fluidized bed granulation method, it is 2 g / min or more and 8 g / min or less, and in another embodiment, 5 g / min or more. 7 g / min or less.
- a preferable product temperature when the intermediate layer or the water infiltration control layer is coated on the drug-containing core is 15 ° C. or more and 60 ° C. or less, and in another embodiment, 15 ° C. or more and 45 ° C. or less.
- the particulate pharmaceutical composition coated with the drug-containing particles may be subjected to drying, heat treatment and the like.
- This coating film can also be processed by adjusting the temperature and humidity.
- the temperature can be 40 to 80 ° C. and the humidity can be 10 to 60 RH%.
- the particle size of the particulate pharmaceutical composition in the present invention is not particularly limited as long as the longest diameter is 2 mm or less.
- the case where it is contained in the orally disintegrating tablet is not particularly limited as long as it does not give an unpleasant feeling of roughness such as sand when taken, but the average particle diameter is preferably adjusted to 350 ⁇ m or less.
- the average particle diameter is 1 ⁇ m or more and 350 ⁇ m or less, and in a further embodiment, it is 20 ⁇ m or more and 350 ⁇ m or less.
- a tableting method a direct tableting method in which a tablet is obtained by mixing a drug-containing particle and an appropriate additive and then compression-molded, a wet granulation in which a binder liquid is sprayed and granulated after mixing the drug-containing particle and the additive
- the method include tableting after melt granulation in which drug-containing particles and an appropriate low-melting substance are mixed and then heated and granulated.
- the tableting device include a rotary tableting machine and a single-shot tableting machine.
- the tableting device is not particularly limited as long as it is a method for producing a compression-molded product (preferably a tablet) pharmaceutically. .
- polyvinyl acetal diethylaminoacetate and the water-soluble polymer substance of the present invention a granular pharmaceutical composition for oral administration is produced in which drug-containing particles having a bitter taste are coated and the change in release rate is reduced even after compression molding.
- the use of polyvinyl acetal diethylaminoacetate and a water-soluble polymeric substance for the purpose of this invention is referred to the description of the particulate pharmaceutical composition of the present invention for a detailed description of the invention.
- the manufacturing method of the orally disintegrating tablet containing the particulate pharmaceutical composition of the present invention will be described below.
- the particulate pharmaceutical composition of the present invention and a saccharide having low moldability are mixed.
- humidification and drying processes can be employed.
- “Humidification” is determined by the apparent critical relative humidity of the saccharides contained, but usually humidifies above its critical relative humidity.
- the humidity is 30 RH% or more and 100 RH% or less, and in another aspect, it is 50 RH% or more and 90 RH% or less.
- the temperature at this time is preferably 15 ° C. or more and 50 ° C. or less, and in another embodiment, it is 20 ° C. or more and 40 ° C. or less.
- the treatment time is 1 hour or more and 36 hours or less, and in another aspect, it is 12 hours or more and 24 hours or less.
- “Drying” is not particularly limited as long as it is a step of removing moisture absorbed by humidification.
- the drying temperature condition can be set to 10 ° C.
- the treatment time can be 0.5 hours or more and 6 hours or less, and in another aspect, it can be 1 hour or more and 4 hours or less.
- the particulate pharmaceutical composition of the present invention melting point A high-excipient excipient and a saccharide with a low melting point are mixed, and the mixture is sprayed with a binder for orally disintegrating tablets to coat and / or granulate, and the granulated product can be compression-molded.
- a heating step can be employed to increase the hardness of the prepared molded product.
- Heating is determined by the melting point of the saccharide having a low melting point, and is usually heated to a temperature not lower than the melting point of the low saccharide and lower than the melting point of the high excipient.
- the treatment time can be 0.5 minutes or more and 120 minutes or less, and in another aspect, it can be 1 minute or more and 60 minutes or less.
- the prepared dispersion is sprayed onto 5.42 kg of crystalline cellulose (grain) (Asahi Kasei Chemicals, product name CP-102Y, the same shall apply hereinafter) to prepare particles covering the first layer. did.
- atorvastatin calcium trihydrate was added with stirring to 300.0 g of sodium lauryl sulfate and 120.0 g of hypromellose in 2880.0 g of purified water to prepare a dispersion.
- the prepared dispersion was sprayed onto 300.0 g of crystalline cellulose (grains) using a fluidized bed granulator to prepare particles covering the first layer.
- orally disintegrating tablet 229.6 mg of the granulated product for orally disintegrating tablet prepared in Example 1 and 70.4 mg of the granular pharmaceutical composition (masking particle) of the present invention were mixed, and the mixture was mixed with a diameter. After filling a 9.5 mm mortar, the tablet is tableted at various pressures (2.0 kN and 3.0 kN) using an autograph to produce an orally disintegrating tablet containing the particulate pharmaceutical composition of the present invention.
- T 10% of the oral disintegrating tablet calculated from the elution profile, and the rate of change with respect to T 10% of the particulate pharmaceutical composition of the tableting shown in Tables 9 to 13.
- T 10% represents the time to elution rate of 10%, and the change rate with respect to T 10% was calculated from the following equation.
- T 10% change rate (%) T 10% (after tableting) / T 10% (before tableting)
- Experimental Example 2 Dissolution test of particulate pharmaceutical composition Japanese Pharmacopoeia dissolution of particulate pharmaceutical compositions of Comparative Examples 2 to 4 and Examples 3 and 5 (masking particles before tableting) using an automatic 6-series dissolution tester The dissolution test was performed according to Test Method No. 2. The drug content was 10 mg, and 900 mL each of water, Japanese Pharmacopoeia dissolution test 1st liquid (JP1), and Japanese Pharmacopoeia dissolution test 2nd liquid (JP2) were used (paddle rotation speed: 100 rotations / minute). The elution profiles obtained as a result of the test are shown in FIGS.
- Example 3 masking particles provided with a third film made of polyvinyl acetal diethylaminoacetate, talc, and hypromellose (TC-5E)
- TC-5E hypromellose
- Example 3 Liquid Displacement Dissolution Test of Particulate Pharmaceutical Composition Dissolution of Example 3 or Comparative Examples 2 to 4 (masking particles before tableting) reflecting vivo using an automatic 6-series dissolution tester The test was conducted. 30 minutes after adding a particulate pharmaceutical composition containing 10 mg of drug to JP1 300 mL, 600 mL of 5-fold concentrated JP2 was added thereto, and dissolution of the drug from the preparation was measured (paddle rotation speed: 50 rotations / Min). In addition, the drug dissolution rate from the preparation after 45 minutes obtained in this test correlates with Cmax and AUC in the dog oral administration test. The obtained elution profile is shown in FIG.
- the particulate pharmaceutical composition coated with polyvinyl acetal diethylaminoacetate (Example 3) has a higher D45min (drug elution rate after 45 minutes) than the particulate pharmaceutical composition coated with a film comprising other components in the liquid replacement test. showed that.
- the particulate pharmaceutical composition of the present invention has a drug dispersibility and dissolution property equal to or higher than that of a solid preparation containing atorvastatin or a pharmaceutically acceptable salt thereof currently provided in the medical field. It is useful as a pharmaceutical composition that can achieve rapid dispersibility and dissolution in the digestive tract even when an unpleasant taste is masked in the oral cavity.
- atorvastatin or a pharmaceutically acceptable salt thereof currently provided in the medical field.
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Abstract
Disclosed is a particulate pharmaceutical composition for oral administration, which is obtained by coating particles, which contain atorvastatin or a pharmaceutically acceptable salt thereof and sodium lauryl sulfate, with a coating material that contains a polyvinyl acetal diethylamino acetate and a water-soluble polymer material.
Description
本発明は、アトルバスタチンを含有してなる経口投与用粒子状医薬組成物に関する。
詳細には、本発明は、アトルバスタチンおよびラウリル硫酸ナトリウムを含有する核が、ポリビニルアセタールジエチルアミノアセテートおよび水溶性高分子物質を含む被膜物質により被覆されてなる、経口投与用粒子状医薬組成物、および該経口投与用粒子状医薬組成物を含有してなる口腔内崩壊錠に関するものである。
また、本発明は、アトルバスタチン含有粒子に被覆し、圧縮成形後も溶出速度の変化を低減する経口投与用粒子状医薬組成物を製造するためのポリビニルアセタールジエチルアミノアセテートおよび水溶性高分子物質の使用に関するものである。
更に、本発明は、アトルバスタチン含有粒子に被覆し、圧縮成形後も溶出速度の変化を低減する経口投与用粒子状医薬組成物の製造方法に関するものである。 The present invention relates to a particulate pharmaceutical composition for oral administration comprising atorvastatin.
Specifically, the present invention relates to a particulate pharmaceutical composition for oral administration, wherein a core containing atorvastatin and sodium lauryl sulfate is coated with a coating material containing polyvinyl acetal diethylaminoacetate and a water-soluble polymer substance, and The present invention relates to an orally disintegrating tablet containing a particulate pharmaceutical composition for oral administration.
The present invention also relates to the use of polyvinyl acetal diethylaminoacetate and a water-soluble polymer substance for producing a granular pharmaceutical composition for oral administration which is coated with atorvastatin-containing particles and reduces the change in dissolution rate after compression molding. Is.
Furthermore, this invention relates to the manufacturing method of the granular pharmaceutical composition for oral administration which coat | covers atorvastatin containing particle | grains and reduces the change of an elution rate after compression molding.
詳細には、本発明は、アトルバスタチンおよびラウリル硫酸ナトリウムを含有する核が、ポリビニルアセタールジエチルアミノアセテートおよび水溶性高分子物質を含む被膜物質により被覆されてなる、経口投与用粒子状医薬組成物、および該経口投与用粒子状医薬組成物を含有してなる口腔内崩壊錠に関するものである。
また、本発明は、アトルバスタチン含有粒子に被覆し、圧縮成形後も溶出速度の変化を低減する経口投与用粒子状医薬組成物を製造するためのポリビニルアセタールジエチルアミノアセテートおよび水溶性高分子物質の使用に関するものである。
更に、本発明は、アトルバスタチン含有粒子に被覆し、圧縮成形後も溶出速度の変化を低減する経口投与用粒子状医薬組成物の製造方法に関するものである。 The present invention relates to a particulate pharmaceutical composition for oral administration comprising atorvastatin.
Specifically, the present invention relates to a particulate pharmaceutical composition for oral administration, wherein a core containing atorvastatin and sodium lauryl sulfate is coated with a coating material containing polyvinyl acetal diethylaminoacetate and a water-soluble polymer substance, and The present invention relates to an orally disintegrating tablet containing a particulate pharmaceutical composition for oral administration.
The present invention also relates to the use of polyvinyl acetal diethylaminoacetate and a water-soluble polymer substance for producing a granular pharmaceutical composition for oral administration which is coated with atorvastatin-containing particles and reduces the change in dissolution rate after compression molding. Is.
Furthermore, this invention relates to the manufacturing method of the granular pharmaceutical composition for oral administration which coat | covers atorvastatin containing particle | grains and reduces the change of an elution rate after compression molding.
3-ヒドロキシ-3-メチルグルタリル-コエンザイムA(HMG-CoA)のメバロン酸塩への転化は、コレステロールの生合成経路における早期の律速過程である。この過程は、酵素のHMG-CoAレダクターゼによって触媒される。スタチンは、HMG-CoAレダクターゼがこの転化を触媒するのを抑制する。したがって、スタチンは総じて強力な脂質低下剤である。
The conversion of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) to mevalonate is an early rate-limiting process in the biosynthetic pathway of cholesterol. This process is catalyzed by the enzyme HMG-CoA reductase. Statins inhibit HMG-CoA reductase from catalyzing this conversion. Statins are therefore generally potent lipid lowering agents.
現在、アトルバスタチンカルシウム水和物はLipitor(登録商標)として販売されており、これは化学名[R-(R*,R*)]-2-(4-フルオロフェニル)-β,δ-ジヒドロキシ-5-(1-メチルエチル)-3-フェニル-4-[(フェニルアミノ)カルボニル]-1H-ピロール-1-ヘプタン酸カルシウム塩(2:1)三水和物と次式を有する。
Currently, atorvastatin calcium hydrate is sold as Lipitor®, which has the chemical name [R- (R *, R *)]-2- (4-fluorophenyl) -β, δ-dihydroxy- 5- (1-methylethyl) -3-phenyl-4-[(phenylamino) carbonyl] -1H-pyrrole-1-heptanoic acid calcium salt (2: 1) trihydrate and has the following formula:
アトルバスタチンとその製薬学的に許容される塩は、HMG-CoAレダクターゼの選択的で競合的な抑制剤である。アトルバスタチンカルシウムは、強力な脂質低下化合物であり、このため脂質低下剤及び/又はコレステロール低下剤として有用であり、同時に、骨粗しょう症、良性の前立腺肥大(BPH)、及びアルツハイマー病の治療に有用である。
Atorvastatin and its pharmaceutically acceptable salts are selective and competitive inhibitors of HMG-CoA reductase. Atorvastatin calcium is a potent lipid-lowering compound and is therefore useful as a lipid-lowering agent and / or cholesterol-lowering agent, and at the same time useful for the treatment of osteoporosis, benign prostatic hypertrophy (BPH), and Alzheimer's disease. is there.
アトルバスタチン又はその製薬学的に許容される塩を含有する製剤を厳格な製薬要件および規格に適合できるようにするために、アトルバスタチン又はその製薬学的に許容される塩を純粋な結晶型で製造する必要がある。更に、アトルバスタチン又はその製薬学的に許容される塩の製造方法は、大規模生産に従うものであることが必要とされる。また、製品が敏速に濾過でき、そして容易に乾燥される形態であることが望ましい。最終的には、製品が特殊な保存条件を必要とせずに長期間安定であることが経済的に望ましい。これまでにアトルバスタチン又はその製薬学的に許容される塩の様々な結晶型が開示されている(特許文献1、2)。
Manufacture atorvastatin or a pharmaceutically acceptable salt thereof in a pure crystalline form so that a formulation containing atorvastatin or a pharmaceutically acceptable salt thereof can meet strict pharmaceutical requirements and standards There is a need. Furthermore, the process for producing atorvastatin or a pharmaceutically acceptable salt thereof is required to follow a large scale production. It is also desirable that the product be in a form that can be quickly filtered and easily dried. Ultimately, it is economically desirable for the product to be stable for long periods of time without requiring special storage conditions. So far, various crystal forms of atorvastatin or a pharmaceutically acceptable salt thereof have been disclosed (Patent Documents 1 and 2).
一方で、アトルバスタチンは難溶性の薬物であることから、イン・ビトロにおける分散性・溶出性が悪くバイオアベイラビリティ低下の問題となる。このような問題を改善させるための手段として、結晶を非晶質形態に変化させる方法が挙げられる。
On the other hand, since atorvastatin is a poorly soluble drug, its in-vitro dispersibility and dissolution properties are poor, resulting in a problem of reduced bioavailability. As a means for improving such a problem, there is a method of changing a crystal to an amorphous form.
例えば、非晶質アトルバスタチンの改良された製造方法を提供することを目的に、アトルバスタチン及び場合により賦形剤を非ヒドロキシル溶媒に溶解して溶液を形成し、そして溶媒を凍結乾燥して、アモルファスのアトルバスタチンを得ることを含むアモルファスのアトルバスタチンを形成する方法(特許文献3)や、ヒドロキシル基含有溶媒を含む溶液中にアトルバスタチンを溶解させ、該溶液から該ヒドロキシル基含有溶媒を急速に蒸発させて非晶質アトルバスタチンを生成させることを含む、非晶質アトルバスタチンの製造方法(特許文献4)が開示されている。
For example, with the aim of providing an improved process for producing amorphous atorvastatin, atorvastatin and optionally excipients are dissolved in a non-hydroxyl solvent to form a solution, and the solvent is lyophilized to provide an amorphous A method of forming amorphous atorvastatin including obtaining atorvastatin (Patent Document 3), or dissolving atorvastatin in a solution containing a hydroxyl group-containing solvent, and rapidly evaporating the hydroxyl group-containing solvent from the solution to produce amorphous Disclosed is a method for producing amorphous atorvastatin (Patent Document 4), which comprises producing quality atorvastatin.
また、揮発性有機溶媒の使用を含まない非晶質アトルバスタチンを製造するための方法、及び非晶質アトルバスタチンを含有する安定な医薬組成物を得ることを目的に、非晶質アトルバスタチンと一つ又はそれより多い任意成分である医薬的に需要可能な賦形剤との固体分散物を含んでなる固体医薬組成物であって、非晶質アトルバスタチン或いはその医薬的に需要可能な複合体、塩、溶媒和物又は水和物及び溶融加工可能なポリマーを含んでなる固体医薬組成物が開示されている(特許文献5)。
In addition, for the purpose of obtaining a method for producing amorphous atorvastatin that does not involve the use of a volatile organic solvent and a stable pharmaceutical composition containing amorphous atorvastatin, A solid pharmaceutical composition comprising a solid dispersion with a pharmaceutically acceptable excipient which is a larger optional ingredient, comprising amorphous atorvastatin or a pharmaceutically acceptable complex, salt, A solid pharmaceutical composition comprising a solvate or hydrate and a melt processable polymer is disclosed (Patent Document 5).
更に、非晶質体のアトルバスタチンを安定化させるために、ある特定の温度で熱処理する方法が開示されている(特許文献6)。
Furthermore, in order to stabilize amorphous atorvastatin, a method of heat treatment at a specific temperature is disclosed (Patent Document 6).
また、アトルバスタチン又はその製薬学的に許容される塩は強い苦味を有する薬物である。薬物の不快な味の隠蔽、口腔内での吸収回避などの目的のために、薬物或いは薬物を含んでなる組成物に口腔内で一定時間薬物放出を抑制するコーティングなどの処理がなされる場合がある。コーティングは一般的に水不溶性の高分子等を用いるため、薬物の分散性・溶出性は低下する問題がある。
In addition, atorvastatin or a pharmaceutically acceptable salt thereof is a drug having a strong bitter taste. For the purpose of concealing the unpleasant taste of the drug and avoiding absorption in the oral cavity, the drug or the composition comprising the drug may be treated with a coating that suppresses the drug release for a certain period of time in the oral cavity. is there. Since the coating generally uses a water-insoluble polymer or the like, there is a problem that the dispersibility / elution property of the drug is lowered.
一方、顆粒剤、細粒剤、散剤等の経口粒子状医薬組成物は、錠剤やカプセル剤よりもサイズが小さいため、錠剤、カプセル剤の嚥下が困難な患者でも服用が容易な剤形である。しかし、経口投与用粒子状医薬組成物は、そのサイズが小さいため比表面積が増加することにより、服用後薬物が口腔内で速やかに放出されてしまい、種々の問題を引き起こす。例えば、薬物が不快な味を有する場合、口腔内で速やかに放出された薬物が患者に強い不快感を与え、服用コンプライアンスを著しく低下させることがある。
On the other hand, oral particulate pharmaceutical compositions such as granules, fine granules, and powders are smaller in size than tablets and capsules, so that they are easy to take even for patients who have difficulty swallowing tablets and capsules. . However, since the particulate pharmaceutical composition for oral administration is small in size, the specific surface area increases, so that the drug is rapidly released in the oral cavity after taking it, causing various problems. For example, if the drug has an unpleasant taste, the drug quickly released in the oral cavity may cause a strong discomfort to the patient and significantly reduce dosage compliance.
当該問題を回避するため、経口粒子状医薬組成物においては、一定時間口腔内で薬物放出を抑制あるいは低減することが必要となる。例えば、薬物が不快な味を有する場合には、口腔内に経口粒子状医薬組成物が存在する一定時間の間、薬物の放出を低減する手段等を採用することができる。
In order to avoid this problem, it is necessary to suppress or reduce drug release in the oral cavity for a certain period of time in the oral particulate pharmaceutical composition. For example, when the drug has an unpleasant taste, means for reducing the release of the drug for a certain period of time when the oral particulate pharmaceutical composition is present in the oral cavity can be employed.
一方近年、口腔内崩壊錠は水なしでも服用することが出来、かつ嚥下困難な患者でも服用が比較的容易になることから、患者が薬を服用する際の利便性を高めた剤形として注目されている。
On the other hand, in recent years, orally disintegrating tablets can be taken without water and are relatively easy to take even for patients who have difficulty swallowing. Has been.
該口腔内崩壊錠に関する技術として、例えば、成形性の低い糖類に対し、成形性の高い糖類を結合剤として噴霧し被覆および/または造粒することを特徴とし、錠剤強度をさらに必要とするときには、加湿乾燥されてなる口腔内崩壊錠(特許文献7)、薬物、稀釈剤、および薬物と稀釈剤より相対的に融点の低い糖類を含有してなり、融点の低い糖類が錠剤中に均一に配合され、薬物および/または稀釈剤粒子を、融点の低い糖類の溶融固化物により架橋を形成してなる口腔内崩壊錠(特許文献8)、また、薬物、α化度が30%以上60%以下である加工したデンプン類、及び糖類を含有してなる口腔内崩壊錠(特許文献9)等が知られている。
As a technique relating to the orally disintegrating tablet, for example, a saccharide having a low moldability is sprayed with a high moldability saccharide as a binder and coated and / or granulated, and when tablet strength is further required Orally disintegrating tablet (humidity-dried tablet) (Patent Document 7), drug, diluent, and saccharide having a melting point relatively lower than that of the drug and diluent, and the saccharide having a low melting point is uniformly contained in the tablet An orally disintegrating tablet (Patent Document 8) containing a drug and / or diluent particles, which is blended with a melt-solidified product of a saccharide having a low melting point, and a drug, the degree of gelatinization of 30% or more and 60% Processed starches which are the following, orally disintegrating tablets containing sugars (Patent Document 9) and the like are known.
これらの口腔内崩壊錠に、例えば苦味を有する薬物が適用される場合、例えば、結晶セルロースからなる核に対し、薬物溶液を噴霧して薬物含有粒子を調製した後、該粒子に適切な高分子物質でフィルムコーティングを施す方法が採用される。被覆する高分子物質の種類や打錠する際の圧力によっては、フィルムが断裂し、薬物が漏出するため、口腔内における薬物の苦味を抑制することは技術的に非常に難しい。逆に、被覆されたフィルムの打錠による破断を回避するために低圧で打錠した際には、製造工程、輸送工程におけるハンドリングに適した錠剤硬度が得られないなどの問題が懸念される。
For example, when a drug having a bitter taste is applied to these orally disintegrating tablets, for example, a drug solution is sprayed onto a core made of crystalline cellulose to prepare drug-containing particles, and then a polymer suitable for the particles is prepared. A method of applying a film coating with a substance is employed. Depending on the type of polymer substance to be coated and the pressure at the time of tableting, the film tears and the drug leaks out, so it is technically very difficult to suppress the bitter taste of the drug in the oral cavity. Conversely, when tableting is performed at a low pressure in order to avoid breakage of the coated film due to tableting, there is a concern that tablet hardness suitable for handling in the production process and transportation process cannot be obtained.
不快な味を抑制する方法としてアクリル酸系高分子の使用が知られている。
薬物を含有する核と、2種類の水溶性成分である、不溶化促進剤および不溶化物質を含有する中間層と、最外層に内部への水浸入速度を制御する水浸入制御層を含有する経口投与用時限放出型粒子状医薬組成物が知られており、水浸入制御層に用いる素材としてアクリル酸系高分子が例示されている(特許文献10)。しかしながら、選択される薬物または基剤によっては、初期薬物溶出を低減し、かつその後の速やかな薬物放出性を達成するためには更なる改善の余地がある。 As a method for suppressing an unpleasant taste, use of an acrylic polymer is known.
Oral administration containing a drug-containing core, an intermediate layer containing two types of water-soluble components, an insolubilization accelerator and an insolubilizing substance, and a water infiltration control layer that controls the rate of water intrusion into the outermost layer A time-release particulate pharmaceutical composition for use is known, and an acrylic acid polymer is exemplified as a material used for a water infiltration control layer (Patent Document 10). However, depending on the drug or base selected, there is room for further improvement to reduce initial drug elution and to achieve subsequent rapid drug release.
薬物を含有する核と、2種類の水溶性成分である、不溶化促進剤および不溶化物質を含有する中間層と、最外層に内部への水浸入速度を制御する水浸入制御層を含有する経口投与用時限放出型粒子状医薬組成物が知られており、水浸入制御層に用いる素材としてアクリル酸系高分子が例示されている(特許文献10)。しかしながら、選択される薬物または基剤によっては、初期薬物溶出を低減し、かつその後の速やかな薬物放出性を達成するためには更なる改善の余地がある。 As a method for suppressing an unpleasant taste, use of an acrylic polymer is known.
Oral administration containing a drug-containing core, an intermediate layer containing two types of water-soluble components, an insolubilization accelerator and an insolubilizing substance, and a water infiltration control layer that controls the rate of water intrusion into the outermost layer A time-release particulate pharmaceutical composition for use is known, and an acrylic acid polymer is exemplified as a material used for a water infiltration control layer (Patent Document 10). However, depending on the drug or base selected, there is room for further improvement to reduce initial drug elution and to achieve subsequent rapid drug release.
また、噛む事が出来、味がマスクされている製剤を調製するため、薬物、並びに少なくとも5重量%の高温フィルム形成ポリマー及び少なくとも5重量%の低温フィルム形成ポリマーの混合物を含んでなるコアをコートするポリマー混合物を含んで成る味がマスクされた医薬組成物に関する発明が知られている(特許文献11)。
また、メチルセルロースとモノマー単位にメタクリル酸エステルおよび/又はアクリル酸エステルを含むアクリル酸系ポリマーとを含むフィルムコートにより固形製剤の苦味などの不快な味を隠蔽し、かつ溶出性に優れるフィルムコーティング剤が開示されている(特許文献12)。
しかしながら、特許文献11又は12のいずれもコーティング顆粒を圧縮成形する際の溶出変化については記載されておらず、圧縮成形による溶出速度の変化が懸念される。 Also coated with a core comprising a drug and a mixture of at least 5 wt% hot film forming polymer and at least 5 wt% cold film forming polymer to prepare a chewable and taste masked formulation An invention relating to a taste-masked pharmaceutical composition comprising a polymer mixture is known (Patent Document 11).
In addition, a film coating agent that conceals an unpleasant taste such as a bitter taste of a solid preparation by a film coat containing methyl cellulose and an acrylic acid-based polymer containing a methacrylic acid ester and / or an acrylic acid ester in a monomer unit, and having an excellent dissolution property (Patent Document 12).
However, neither of Patent Documents 11 and 12 describes an elution change when compression-molding the coated granule, and there is a concern about a change in elution rate due to compression molding.
また、メチルセルロースとモノマー単位にメタクリル酸エステルおよび/又はアクリル酸エステルを含むアクリル酸系ポリマーとを含むフィルムコートにより固形製剤の苦味などの不快な味を隠蔽し、かつ溶出性に優れるフィルムコーティング剤が開示されている(特許文献12)。
しかしながら、特許文献11又は12のいずれもコーティング顆粒を圧縮成形する際の溶出変化については記載されておらず、圧縮成形による溶出速度の変化が懸念される。 Also coated with a core comprising a drug and a mixture of at least 5 wt% hot film forming polymer and at least 5 wt% cold film forming polymer to prepare a chewable and taste masked formulation An invention relating to a taste-masked pharmaceutical composition comprising a polymer mixture is known (Patent Document 11).
In addition, a film coating agent that conceals an unpleasant taste such as a bitter taste of a solid preparation by a film coat containing methyl cellulose and an acrylic acid-based polymer containing a methacrylic acid ester and / or an acrylic acid ester in a monomer unit, and having an excellent dissolution property (Patent Document 12).
However, neither of Patent Documents 11 and 12 describes an elution change when compression-molding the coated granule, and there is a concern about a change in elution rate due to compression molding.
一方、メタアクリル酸メチル・メタアクリル酸ブチル・メタアクリル酸ジメチルアミノエチル共重合体を被覆した粒子状組成物を圧縮した際に溶出制御機能が失われるが、アルコール系溶媒で処理することにより、圧縮成形物の内部で溶出制御機能を再生させる方法が開示されている(特許文献13)。
さらに、圧縮による衝撃を吸収する賦形剤とともに圧縮する方法として、薬物含有被膜粒子に、平均粒子径20μm以下の被膜保護剤を物理混合し、圧縮成形した製剤が記載されている。薬物含有被覆粒子の圧縮成形時における被膜の損傷を低減した圧縮成形製剤を提供するため、薬物含有被膜粒子を含み、かつ平均粒子径が約50μm以上で初期溶出速度比が4以上を示す物質の微粒子を被膜保護剤として含む圧縮成形製剤に関する発明が開示されている(特許文献14)。
しかしながら、特許文献13又は14のいずれも、選択された薬物または基剤によっては、初期薬物溶出を低減しても、その後の速やかな薬物放出が達成されない、また、アルコール処理が可能な特別な装置の使用が必要とされる課題が考えられる。 On the other hand, the elution control function is lost when the particulate composition coated with methyl methacrylate / butyl methacrylate / dimethylaminoethyl methacrylate copolymer is compressed, but by treating with an alcohol solvent, A method for regenerating the elution control function inside a compression molded product is disclosed (Patent Document 13).
Furthermore, as a method of compressing together with an excipient that absorbs impact due to compression, a preparation is described in which a film-protecting agent having an average particle diameter of 20 μm or less is physically mixed with a drug-containing film particle and then compression-molded. In order to provide a compression-molded preparation with reduced coating damage during compression molding of drug-containing coated particles, a substance containing drug-containing coated particles and having an average particle diameter of about 50 μm or more and an initial dissolution rate ratio of 4 or more An invention relating to a compression molding preparation containing fine particles as a film protective agent is disclosed (Patent Document 14).
However, in either of Patent Documents 13 and 14, depending on the selected drug or base, even if the initial drug elution is reduced, subsequent rapid drug release is not achieved, and a special device capable of alcohol treatment is used. There is a problem that needs to be used.
さらに、圧縮による衝撃を吸収する賦形剤とともに圧縮する方法として、薬物含有被膜粒子に、平均粒子径20μm以下の被膜保護剤を物理混合し、圧縮成形した製剤が記載されている。薬物含有被覆粒子の圧縮成形時における被膜の損傷を低減した圧縮成形製剤を提供するため、薬物含有被膜粒子を含み、かつ平均粒子径が約50μm以上で初期溶出速度比が4以上を示す物質の微粒子を被膜保護剤として含む圧縮成形製剤に関する発明が開示されている(特許文献14)。
しかしながら、特許文献13又は14のいずれも、選択された薬物または基剤によっては、初期薬物溶出を低減しても、その後の速やかな薬物放出が達成されない、また、アルコール処理が可能な特別な装置の使用が必要とされる課題が考えられる。 On the other hand, the elution control function is lost when the particulate composition coated with methyl methacrylate / butyl methacrylate / dimethylaminoethyl methacrylate copolymer is compressed, but by treating with an alcohol solvent, A method for regenerating the elution control function inside a compression molded product is disclosed (Patent Document 13).
Furthermore, as a method of compressing together with an excipient that absorbs impact due to compression, a preparation is described in which a film-protecting agent having an average particle diameter of 20 μm or less is physically mixed with a drug-containing film particle and then compression-molded. In order to provide a compression-molded preparation with reduced coating damage during compression molding of drug-containing coated particles, a substance containing drug-containing coated particles and having an average particle diameter of about 50 μm or more and an initial dissolution rate ratio of 4 or more An invention relating to a compression molding preparation containing fine particles as a film protective agent is disclosed (Patent Document 14).
However, in either of Patent Documents 13 and 14, depending on the selected drug or base, even if the initial drug elution is reduced, subsequent rapid drug release is not achieved, and a special device capable of alcohol treatment is used. There is a problem that needs to be used.
また、アトルバスタチン及びラウリル硫酸ナトリウムを含有する混合物を含むアトルバスタチン製剤が特許文献15(実施例3)に開示されている。特許文献15は、アトルバスタチンの安定化を課題としており、本発明とは技術的思想が異なる。
In addition, an atorvastatin preparation containing a mixture containing atorvastatin and sodium lauryl sulfate is disclosed in Patent Document 15 (Example 3). Patent document 15 makes it a subject to stabilize atorvastatin, and a technical idea differs from this invention.
上記状況下、アトルバスタチンの初期薬物溶出量を低減し、その後の速やかな薬物放出を維持しつつ、圧縮成形後も薬物溶出速度の変化を抑制または低減可能な、経口投与用粒子状医薬組成物、すなわち口腔内における不快な味の隠蔽(服用コンプライアンス)を施した際の、消化管内における速やかな分散性・溶出性を達成する経口投与用粒子状医薬組成物、及び該組成物を含有する口腔内崩壊錠に関する技術開発が必要である。
Under the above circumstances, a particulate pharmaceutical composition for oral administration that can reduce or reduce the change in drug elution rate even after compression molding while reducing the initial drug elution amount of atorvastatin and maintaining rapid drug release thereafter. That is, a particulate pharmaceutical composition for oral administration that achieves rapid dispersibility and dissolution in the digestive tract when concealing an unpleasant taste in the oral cavity (compliance compliance), and an oral cavity containing the composition Technology development regarding disintegrating tablets is necessary.
本発明は、アトルバスタチンの初期薬物溶出量を低減し、その後の速やかな薬物放出を維持しつつ、圧縮成形後も薬物溶出速度の変化を抑制または低減可能な、経口投与用粒子状医薬組成物、及び該組成物を含有する口腔内崩壊錠を提供するものである。
また、本発明は、アトルバスタチンの口腔内における不快な味の隠蔽(服用コンプライアンス)を施した際の、消化管内における速やかな分散性・溶出性を達成する経口投与用粒子状医薬組成物、及び該組成物を含有する口腔内崩壊錠を提供するものである。 The present invention relates to a particulate pharmaceutical composition for oral administration that can reduce or reduce a change in drug elution rate even after compression molding while reducing the initial drug elution amount of atorvastatin and maintaining rapid drug release thereafter. And an orally disintegrating tablet containing the composition.
The present invention also provides a particulate pharmaceutical composition for oral administration which achieves rapid dispersibility and dissolution in the digestive tract when atorvastatin is used to conceal an unpleasant taste in the mouth (compliance compliance), and An orally disintegrating tablet containing the composition is provided.
また、本発明は、アトルバスタチンの口腔内における不快な味の隠蔽(服用コンプライアンス)を施した際の、消化管内における速やかな分散性・溶出性を達成する経口投与用粒子状医薬組成物、及び該組成物を含有する口腔内崩壊錠を提供するものである。 The present invention relates to a particulate pharmaceutical composition for oral administration that can reduce or reduce a change in drug elution rate even after compression molding while reducing the initial drug elution amount of atorvastatin and maintaining rapid drug release thereafter. And an orally disintegrating tablet containing the composition.
The present invention also provides a particulate pharmaceutical composition for oral administration which achieves rapid dispersibility and dissolution in the digestive tract when atorvastatin is used to conceal an unpleasant taste in the mouth (compliance compliance), and An orally disintegrating tablet containing the composition is provided.
上記状況下、本発明者らは、アトルバスタチンの初期薬物溶出量を低減し、その後の速やかな薬物放出を維持しつつ、圧縮成形後も薬物溶出速度の変化を抑制または低減可能であり、アトルバスタチンの口腔内における不快な味の隠蔽(服用コンプライアンス)を施した際の、消化管内における速やかな分散性・溶出性を達成する経口投与用粒子状医薬組成物の創製に鋭意検討した結果、(1)アトルバスタチンおよびラウリル硫酸ナトリウムを含有する粒子がポリビニルアセタールジエチルアミノアセテートおよび水溶性高分子物質を含む被膜物質により被覆されてなる経口投与用粒子状医薬組成物が、以下に詳述する本発明の所望の効果を有すること、また該検討において、(2)アトルバスタチンと特定基剤との相互作用に基づく薬物溶出の遅延が生物学的利用率の低下を誘発すること、そして、特定の高分子物質の選択・使用により、本発明の所望の効果を有すること、(3)上記経口投与用医薬組成物を含有する口腔内崩壊錠が本発明の所望の効果を有すること等を確認することにより、本発明を完成させるに至った。
Under the circumstances described above, the present inventors can reduce or reduce the initial drug elution amount of atorvastatin, and suppress or reduce the change in drug elution rate even after compression molding while maintaining rapid drug release thereafter. As a result of intensive investigations into the creation of a granular pharmaceutical composition for oral administration that achieves rapid dispersibility and dissolution in the digestive tract when concealing an unpleasant taste in the mouth (compliance compliance), (1) The particulate pharmaceutical composition for oral administration, in which particles containing atorvastatin and sodium lauryl sulfate are coated with a coating material containing polyvinyl acetal diethylaminoacetate and a water-soluble polymer substance, the desired effect of the present invention described in detail below (2) a drug based on the interaction between atorvastatin and a specific base The delayed elution induces a decrease in bioavailability, and the desired effect of the present invention is achieved by the selection and use of a specific polymer substance; (3) the pharmaceutical composition for oral administration described above; By confirming that the orally disintegrating tablet contained has the desired effects of the present invention, the present invention has been completed.
すなわち、本発明は、
[1]アトルバスタチン又はその製薬学的に許容される塩およびラウリル硫酸ナトリウムを含有する粒子が、ポリビニルアセタールジエチルアミノアセテートおよび水溶性高分子物質を含む被膜物質により被覆されてなる、経口投与用粒子状医薬組成物、
[2]水溶性高分子物質が、ヒドロキシプロピルセルロース、ヒプロメロース、メチルセルロース、ヒドロキシエチルセルロース、ポビドン、コポリビドン、ポリビニルアルコール-ポリエチレングリコールグラフトコポリマー、ポリビニルアルコール、マクロゴール、およびポリエチレンオキサイドからなる群より選択される1種または2種以上である、[1]の経口投与用粒子状医薬組成物、
[3]水溶性高分子物質がヒプロメロースである、[1]の経口投与用粒子状医薬組成物、
[4]さらに被膜物質に流動化剤を含有する、[1]~[3]のいずれかの経口投与用粒子状医薬組成物、
[5]流動化剤が、ケイ酸金属類、二酸化ケイ素類、高級脂肪酸金属塩類、金属酸化物類、アルカリ土類金属塩、および金属水酸化物からなる群より選択される1種または2種以上である、[4]の経口投与用粒子状医薬組成物、
[6]流動化剤が、タルク、カオリン、ケイ酸カルシウム、ケイ酸マグネシウム、軽質無水ケイ酸、ステアリン酸マグネシウム、ステアリン酸カルシウム、酸化鉄、酸化チタン、炭酸カルシウム、リン酸カルシウム、セッコウ、炭酸マグネシウム、水酸化アルミニウム、含水二酸化ケイ素、結晶セルロース、合成ケイ酸アルミニウム、重質無水ケイ酸、水酸化アルミナマグネシウム、ステアリン酸、トウモロコシデンプン、メタケイ酸アルミン酸マグネシウム、リン酸水素カルシウム造粒物、およびグリセリルモノステアレートからなる群より選択される1種または2種以上である、[4]の経口投与用粒子状医薬組成物、
[7]流動化剤がタルクである、[4]の経口投与用粒子状医薬組成物、
[8][1]~[7]のいずれかの経口投与用粒子状医薬組成物を含有してなる口腔内崩壊錠、
[9]アトルバスタチン又はその製薬学的に許容される塩およびラウリル硫酸ナトリウムを含有する粒子を、ポリビニルアセタールジエチルアミノアセテートおよび水溶性高分子物質を含む被膜物質により被覆する、経口投与用粒子状医薬組成物の製造方法、
[10]水溶性高分子物質が、ヒドロキシプロピルセルロース、ヒプロメロース、メチルセルロース、ヒドロキシエチルセルロース、ポビドン、コポリビドン、ポリビニルアルコール-ポリエチレングリコールグラフトコポリマー、ポリビニルアルコール、マクロゴール、およびポリエチレンオキサイドからなる群より選択される1種または2種以上である、[9]の経口投与用粒子状医薬組成物の製造方法、
[11]水溶性高分子物質がヒプロメロースである、[9]の経口投与用粒子状医薬組成物の製造方法、
[12]さらに被膜物質に流動化剤を含有する、[9]~[11]のいずれかの経口投与用粒子状医薬組成物の製造方法、
[13]流動化剤が、ケイ酸金属類、二酸化ケイ素類、高級脂肪酸金属塩類、金属酸化物類、アルカリ土類金属塩、および金属水酸化物からなる群より選択される1種または2種以上である、[12]の経口投与用粒子状医薬組成物の製造方法、
[14]流動化剤が、タルク、カオリン、ケイ酸カルシウム、ケイ酸マグネシウム、軽質無水ケイ酸、ステアリン酸マグネシウム、ステアリン酸カルシウム、酸化鉄、酸化チタン、炭酸カルシウム、リン酸カルシウム、セッコウ、炭酸マグネシウム、水酸化アルミニウム、含水二酸化ケイ素、結晶セルロース、合成ケイ酸アルミニウム、重質無水ケイ酸、水酸化アルミナマグネシウム、ステアリン酸、トウモロコシデンプン、メタケイ酸アルミン酸マグネシウム、リン酸水素カルシウム造粒物、およびグリセリルモノステアレートからなる群より選択される1種または2種以上である、[12]の経口投与用粒子状医薬組成物の製造方法、
[15]流動化剤がタルクである、[12]の経口投与用粒子状医薬組成物の製造方法、
[16]アトルバスタチン又はその製薬学的に許容される塩を含有する粒子を被覆し、圧縮成形後も放出速度の変化を低減する経口投与用粒子状医薬組成物を製造するための、ポリビニルアセタールジエチルアミノアセテートおよび水溶性高分子物質の使用
に関する。 That is, the present invention
[1] Particulate pharmaceutical for oral administration in which particles containing atorvastatin or a pharmaceutically acceptable salt thereof and sodium lauryl sulfate are coated with a coating substance containing polyvinyl acetal diethylaminoacetate and a water-soluble polymer substance Composition,
[2] The water-soluble polymer substance is selected from the group consisting of hydroxypropylcellulose, hypromellose, methylcellulose, hydroxyethylcellulose, povidone, copolyvidone, polyvinyl alcohol-polyethylene glycol graft copolymer, polyvinyl alcohol, macrogol, and polyethylene oxide 1 A particulate pharmaceutical composition for oral administration according to [1], which is a species or two or more species,
[3] The particulate pharmaceutical composition for oral administration according to [1], wherein the water-soluble polymer substance is hypromellose,
[4] A particulate pharmaceutical composition for oral administration according to any one of [1] to [3], further comprising a fluidizing agent in the coating substance,
[5] One or two fluidizing agents selected from the group consisting of metal silicates, silicon dioxides, higher fatty acid metal salts, metal oxides, alkaline earth metal salts, and metal hydroxides The above-mentioned particulate pharmaceutical composition for oral administration according to [4],
[6] The fluidizing agent is talc, kaolin, calcium silicate, magnesium silicate, light anhydrous silicic acid, magnesium stearate, calcium stearate, iron oxide, titanium oxide, calcium carbonate, calcium phosphate, gypsum, magnesium carbonate, hydroxide Aluminum, hydrous silicon dioxide, crystalline cellulose, synthetic aluminum silicate, heavy anhydrous silicic acid, magnesium alumina hydroxide, stearic acid, corn starch, magnesium aluminate metasilicate, calcium hydrogen phosphate granules, and glyceryl monostearate [1] a particulate pharmaceutical composition for oral administration, which is one or more selected from the group consisting of:
[7] The particulate pharmaceutical composition for oral administration according to [4], wherein the fluidizing agent is talc,
[8] An orally disintegrating tablet comprising the particulate pharmaceutical composition for oral administration according to any one of [1] to [7],
[9] A granular pharmaceutical composition for oral administration, in which particles containing atorvastatin or a pharmaceutically acceptable salt thereof and sodium lauryl sulfate are coated with a coating substance containing polyvinyl acetal diethylaminoacetate and a water-soluble polymer substance. Manufacturing method,
[10] The water-soluble polymer substance is selected from the group consisting of hydroxypropylcellulose, hypromellose, methylcellulose, hydroxyethylcellulose, povidone, copolyvidone, polyvinyl alcohol-polyethylene glycol graft copolymer, polyvinyl alcohol, macrogol, and polyethylene oxide. A method for producing a particulate pharmaceutical composition for oral administration according to [9], which is a species or two or more species,
[11] The method for producing a granular pharmaceutical composition for oral administration according to [9], wherein the water-soluble polymer substance is hypromellose.
[12] The method for producing a granular pharmaceutical composition for oral administration according to any one of [9] to [11], further comprising a fluidizing agent in the coating substance,
[13] One or two fluidizing agents selected from the group consisting of metal silicates, silicon dioxides, higher fatty acid metal salts, metal oxides, alkaline earth metal salts, and metal hydroxides [12] The method for producing a particulate pharmaceutical composition for oral administration according to the above,
[14] The fluidizing agent is talc, kaolin, calcium silicate, magnesium silicate, light anhydrous silicic acid, magnesium stearate, calcium stearate, iron oxide, titanium oxide, calcium carbonate, calcium phosphate, gypsum, magnesium carbonate, hydroxide Aluminum, hydrous silicon dioxide, crystalline cellulose, synthetic aluminum silicate, heavy anhydrous silicic acid, magnesium alumina hydroxide, stearic acid, corn starch, magnesium aluminate metasilicate, calcium hydrogen phosphate granules, and glyceryl monostearate [12] A method for producing a particulate pharmaceutical composition for oral administration according to [12], which is one or more selected from the group consisting of
[15] The method for producing a granular pharmaceutical composition for oral administration according to [12], wherein the fluidizing agent is talc,
[16] Polyvinyl acetal diethylamino for producing a granular pharmaceutical composition for oral administration which is coated with particles containing atorvastatin or a pharmaceutically acceptable salt thereof and reduces the change in release rate even after compression molding The use of acetate and water-soluble polymeric substances.
[1]アトルバスタチン又はその製薬学的に許容される塩およびラウリル硫酸ナトリウムを含有する粒子が、ポリビニルアセタールジエチルアミノアセテートおよび水溶性高分子物質を含む被膜物質により被覆されてなる、経口投与用粒子状医薬組成物、
[2]水溶性高分子物質が、ヒドロキシプロピルセルロース、ヒプロメロース、メチルセルロース、ヒドロキシエチルセルロース、ポビドン、コポリビドン、ポリビニルアルコール-ポリエチレングリコールグラフトコポリマー、ポリビニルアルコール、マクロゴール、およびポリエチレンオキサイドからなる群より選択される1種または2種以上である、[1]の経口投与用粒子状医薬組成物、
[3]水溶性高分子物質がヒプロメロースである、[1]の経口投与用粒子状医薬組成物、
[4]さらに被膜物質に流動化剤を含有する、[1]~[3]のいずれかの経口投与用粒子状医薬組成物、
[5]流動化剤が、ケイ酸金属類、二酸化ケイ素類、高級脂肪酸金属塩類、金属酸化物類、アルカリ土類金属塩、および金属水酸化物からなる群より選択される1種または2種以上である、[4]の経口投与用粒子状医薬組成物、
[6]流動化剤が、タルク、カオリン、ケイ酸カルシウム、ケイ酸マグネシウム、軽質無水ケイ酸、ステアリン酸マグネシウム、ステアリン酸カルシウム、酸化鉄、酸化チタン、炭酸カルシウム、リン酸カルシウム、セッコウ、炭酸マグネシウム、水酸化アルミニウム、含水二酸化ケイ素、結晶セルロース、合成ケイ酸アルミニウム、重質無水ケイ酸、水酸化アルミナマグネシウム、ステアリン酸、トウモロコシデンプン、メタケイ酸アルミン酸マグネシウム、リン酸水素カルシウム造粒物、およびグリセリルモノステアレートからなる群より選択される1種または2種以上である、[4]の経口投与用粒子状医薬組成物、
[7]流動化剤がタルクである、[4]の経口投与用粒子状医薬組成物、
[8][1]~[7]のいずれかの経口投与用粒子状医薬組成物を含有してなる口腔内崩壊錠、
[9]アトルバスタチン又はその製薬学的に許容される塩およびラウリル硫酸ナトリウムを含有する粒子を、ポリビニルアセタールジエチルアミノアセテートおよび水溶性高分子物質を含む被膜物質により被覆する、経口投与用粒子状医薬組成物の製造方法、
[10]水溶性高分子物質が、ヒドロキシプロピルセルロース、ヒプロメロース、メチルセルロース、ヒドロキシエチルセルロース、ポビドン、コポリビドン、ポリビニルアルコール-ポリエチレングリコールグラフトコポリマー、ポリビニルアルコール、マクロゴール、およびポリエチレンオキサイドからなる群より選択される1種または2種以上である、[9]の経口投与用粒子状医薬組成物の製造方法、
[11]水溶性高分子物質がヒプロメロースである、[9]の経口投与用粒子状医薬組成物の製造方法、
[12]さらに被膜物質に流動化剤を含有する、[9]~[11]のいずれかの経口投与用粒子状医薬組成物の製造方法、
[13]流動化剤が、ケイ酸金属類、二酸化ケイ素類、高級脂肪酸金属塩類、金属酸化物類、アルカリ土類金属塩、および金属水酸化物からなる群より選択される1種または2種以上である、[12]の経口投与用粒子状医薬組成物の製造方法、
[14]流動化剤が、タルク、カオリン、ケイ酸カルシウム、ケイ酸マグネシウム、軽質無水ケイ酸、ステアリン酸マグネシウム、ステアリン酸カルシウム、酸化鉄、酸化チタン、炭酸カルシウム、リン酸カルシウム、セッコウ、炭酸マグネシウム、水酸化アルミニウム、含水二酸化ケイ素、結晶セルロース、合成ケイ酸アルミニウム、重質無水ケイ酸、水酸化アルミナマグネシウム、ステアリン酸、トウモロコシデンプン、メタケイ酸アルミン酸マグネシウム、リン酸水素カルシウム造粒物、およびグリセリルモノステアレートからなる群より選択される1種または2種以上である、[12]の経口投与用粒子状医薬組成物の製造方法、
[15]流動化剤がタルクである、[12]の経口投与用粒子状医薬組成物の製造方法、
[16]アトルバスタチン又はその製薬学的に許容される塩を含有する粒子を被覆し、圧縮成形後も放出速度の変化を低減する経口投与用粒子状医薬組成物を製造するための、ポリビニルアセタールジエチルアミノアセテートおよび水溶性高分子物質の使用
に関する。 That is, the present invention
[1] Particulate pharmaceutical for oral administration in which particles containing atorvastatin or a pharmaceutically acceptable salt thereof and sodium lauryl sulfate are coated with a coating substance containing polyvinyl acetal diethylaminoacetate and a water-soluble polymer substance Composition,
[2] The water-soluble polymer substance is selected from the group consisting of hydroxypropylcellulose, hypromellose, methylcellulose, hydroxyethylcellulose, povidone, copolyvidone, polyvinyl alcohol-polyethylene glycol graft copolymer, polyvinyl alcohol, macrogol, and polyethylene oxide 1 A particulate pharmaceutical composition for oral administration according to [1], which is a species or two or more species,
[3] The particulate pharmaceutical composition for oral administration according to [1], wherein the water-soluble polymer substance is hypromellose,
[4] A particulate pharmaceutical composition for oral administration according to any one of [1] to [3], further comprising a fluidizing agent in the coating substance,
[5] One or two fluidizing agents selected from the group consisting of metal silicates, silicon dioxides, higher fatty acid metal salts, metal oxides, alkaline earth metal salts, and metal hydroxides The above-mentioned particulate pharmaceutical composition for oral administration according to [4],
[6] The fluidizing agent is talc, kaolin, calcium silicate, magnesium silicate, light anhydrous silicic acid, magnesium stearate, calcium stearate, iron oxide, titanium oxide, calcium carbonate, calcium phosphate, gypsum, magnesium carbonate, hydroxide Aluminum, hydrous silicon dioxide, crystalline cellulose, synthetic aluminum silicate, heavy anhydrous silicic acid, magnesium alumina hydroxide, stearic acid, corn starch, magnesium aluminate metasilicate, calcium hydrogen phosphate granules, and glyceryl monostearate [1] a particulate pharmaceutical composition for oral administration, which is one or more selected from the group consisting of:
[7] The particulate pharmaceutical composition for oral administration according to [4], wherein the fluidizing agent is talc,
[8] An orally disintegrating tablet comprising the particulate pharmaceutical composition for oral administration according to any one of [1] to [7],
[9] A granular pharmaceutical composition for oral administration, in which particles containing atorvastatin or a pharmaceutically acceptable salt thereof and sodium lauryl sulfate are coated with a coating substance containing polyvinyl acetal diethylaminoacetate and a water-soluble polymer substance. Manufacturing method,
[10] The water-soluble polymer substance is selected from the group consisting of hydroxypropylcellulose, hypromellose, methylcellulose, hydroxyethylcellulose, povidone, copolyvidone, polyvinyl alcohol-polyethylene glycol graft copolymer, polyvinyl alcohol, macrogol, and polyethylene oxide. A method for producing a particulate pharmaceutical composition for oral administration according to [9], which is a species or two or more species,
[11] The method for producing a granular pharmaceutical composition for oral administration according to [9], wherein the water-soluble polymer substance is hypromellose.
[12] The method for producing a granular pharmaceutical composition for oral administration according to any one of [9] to [11], further comprising a fluidizing agent in the coating substance,
[13] One or two fluidizing agents selected from the group consisting of metal silicates, silicon dioxides, higher fatty acid metal salts, metal oxides, alkaline earth metal salts, and metal hydroxides [12] The method for producing a particulate pharmaceutical composition for oral administration according to the above,
[14] The fluidizing agent is talc, kaolin, calcium silicate, magnesium silicate, light anhydrous silicic acid, magnesium stearate, calcium stearate, iron oxide, titanium oxide, calcium carbonate, calcium phosphate, gypsum, magnesium carbonate, hydroxide Aluminum, hydrous silicon dioxide, crystalline cellulose, synthetic aluminum silicate, heavy anhydrous silicic acid, magnesium alumina hydroxide, stearic acid, corn starch, magnesium aluminate metasilicate, calcium hydrogen phosphate granules, and glyceryl monostearate [12] A method for producing a particulate pharmaceutical composition for oral administration according to [12], which is one or more selected from the group consisting of
[15] The method for producing a granular pharmaceutical composition for oral administration according to [12], wherein the fluidizing agent is talc,
[16] Polyvinyl acetal diethylamino for producing a granular pharmaceutical composition for oral administration which is coated with particles containing atorvastatin or a pharmaceutically acceptable salt thereof and reduces the change in release rate even after compression molding The use of acetate and water-soluble polymeric substances.
本発明によれば、(1)圧縮成形後に粒子状医薬組成物の核からアトルバスタチンの放出を口腔内に粒子が存在する一定時間低減することができる、(2)一定時間後にアトルバスタチンが速やかに放出(薬物が消化管上部において放出)されることにより十分な薬効を発現することができる、(3)不快な味を有するアトルバスタチンについて、口腔内における不快な味の隠蔽を施した際の、消化管内における速やかな溶出性を達成することができる、(4)服用コンプライアンスと吸収の遅延の防止を達成することができる、などの効果が得られる。
According to the present invention, (1) it is possible to reduce the release of atorvastatin from the core of the particulate pharmaceutical composition after compression molding for a certain period of time during which particles are present in the oral cavity, and (2) atorvastatin is rapidly released after a certain period of time. (3) It is possible to express sufficient efficacy by being released in the upper part of the digestive tract. (3) About atorvastatin having an unpleasant taste, in the digestive tract when concealing an unpleasant taste in the oral cavity It is possible to achieve quick elution in the case of (4) taking compliance and preventing delay in absorption, and the like.
以下、本発明の経口投与用粒子状医薬組成物を説明する。
本明細書における「粒子状医薬組成物」とは、サイズが下記の一定値より小さく、1種または2種以上の医薬添加剤と共に、種々の形態として経口投与を行う薬物含有粒子状組成物を意味する。粒子状組成物の形状が球に近似できる場合、粒子状医薬組成物のサイズは平均粒子径が2mm以下であると規定する。また、粒子状医薬組成物の形状が球以外の形状の場合、粒子状医薬組成物のサイズは平均最長径が2mm以下であると規定する。
なお、下限数値は製薬学的に許容される範囲であれば特に制限されないが、例えば1μm以上、他の態様として10μm以上、更なる態様として20μm以上が挙げられる。
粒子径の測定法としては、第十五改正日本薬局方一般試験法に記載されている顕微鏡法が挙げられる。顕微鏡法は光学顕微鏡を用いて肉眼又は顕微鏡写真によって直接に個々の粒子の外観および形状を観察し、その大きさを測定する方法であり、長軸平均径、三軸平均径や、二軸平均径を粒子径として用いることができる。 Hereinafter, the particulate pharmaceutical composition for oral administration of the present invention will be described.
As used herein, the term “particulate pharmaceutical composition” refers to a drug-containing particulate composition that is smaller than the following fixed value and is orally administered in various forms together with one or more pharmaceutical additives. means. When the shape of the particulate composition can approximate a sphere, the size of the particulate pharmaceutical composition is defined as an average particle diameter of 2 mm or less. Moreover, when the shape of the particulate pharmaceutical composition is a shape other than a sphere, the size of the particulate pharmaceutical composition is defined as having an average longest diameter of 2 mm or less.
The lower limit value is not particularly limited as long as it is a pharmaceutically acceptable range, and for example, 1 μm or more, another embodiment is 10 μm or more, and a further embodiment is 20 μm or more.
Examples of the method for measuring the particle diameter include the microscopy described in the Fifteenth Revised Japanese Pharmacopoeia General Test Method. Microscopy is a method of directly observing the appearance and shape of individual particles with the naked eye or micrographs using an optical microscope, and measuring their sizes. The major axis average diameter, the triaxial average diameter, and the biaxial average The diameter can be used as the particle diameter.
本明細書における「粒子状医薬組成物」とは、サイズが下記の一定値より小さく、1種または2種以上の医薬添加剤と共に、種々の形態として経口投与を行う薬物含有粒子状組成物を意味する。粒子状組成物の形状が球に近似できる場合、粒子状医薬組成物のサイズは平均粒子径が2mm以下であると規定する。また、粒子状医薬組成物の形状が球以外の形状の場合、粒子状医薬組成物のサイズは平均最長径が2mm以下であると規定する。
なお、下限数値は製薬学的に許容される範囲であれば特に制限されないが、例えば1μm以上、他の態様として10μm以上、更なる態様として20μm以上が挙げられる。
粒子径の測定法としては、第十五改正日本薬局方一般試験法に記載されている顕微鏡法が挙げられる。顕微鏡法は光学顕微鏡を用いて肉眼又は顕微鏡写真によって直接に個々の粒子の外観および形状を観察し、その大きさを測定する方法であり、長軸平均径、三軸平均径や、二軸平均径を粒子径として用いることができる。 Hereinafter, the particulate pharmaceutical composition for oral administration of the present invention will be described.
As used herein, the term “particulate pharmaceutical composition” refers to a drug-containing particulate composition that is smaller than the following fixed value and is orally administered in various forms together with one or more pharmaceutical additives. means. When the shape of the particulate composition can approximate a sphere, the size of the particulate pharmaceutical composition is defined as an average particle diameter of 2 mm or less. Moreover, when the shape of the particulate pharmaceutical composition is a shape other than a sphere, the size of the particulate pharmaceutical composition is defined as having an average longest diameter of 2 mm or less.
The lower limit value is not particularly limited as long as it is a pharmaceutically acceptable range, and for example, 1 μm or more, another embodiment is 10 μm or more, and a further embodiment is 20 μm or more.
Examples of the method for measuring the particle diameter include the microscopy described in the Fifteenth Revised Japanese Pharmacopoeia General Test Method. Microscopy is a method of directly observing the appearance and shape of individual particles with the naked eye or micrographs using an optical microscope, and measuring their sizes. The major axis average diameter, the triaxial average diameter, and the biaxial average The diameter can be used as the particle diameter.
「核」は、製薬学的に許容される粒となり得る基になるものであれば特に限定されない。本発明の粒子状医薬組成物を構成し、中間層および本発明で用いられる被膜物質を被覆するための基である。核は、薬物それ自体から構成されたり、また製薬学的に許容される添加物から構成される。粒子[例えば結晶セルロース(粒)(微結晶セルロースとして記載している場合がある)、乳糖・デンプン等]を用いることも出来る。薬物のみや薬物と製薬学的に許容される添加物との混合物を用いることも出来る。公知の技術を用いて1種または2種以上の添加物からなる粒子を製造し、それを用いても良い。また、適当な核となる添加物粒子に、薬物及びラウリル硫酸ナトリウムと結合剤(例えば、水溶性高分子:例えば、ヒプロメロース(別称ヒドロキシプロピルメチルセルロース)(TC-5、信越化学)、ヒドロキシプロピルセルロース(日曹HPC、日本曹達株式会社)、特許第3563070号明細書で記載されている塩基性基の10%以上を中和する量の酸性物質を含んでなるメタアクリル酸メチル・メタアクリル酸ブチル・メタアクリル酸ジメチルアミノエチル共重合体[アミノアルキルメタクリレートコポリマーE(商品名;オイドラギットE100、エボニックデグザGmbH社)]、ポビドン(コリドン、BASF)、メチルセルロース(METOLOSE、信越化学)等)とを溶解または分散した液を噴霧しても良い。更に、所望により、核に対し、ラウリル硫酸ナトリウム及び水溶性高分子で被覆することもできる。核の大きさとして、例えば1μm以上1000μm以下、他の態様として5μm以上500μm以下、更なる態様として10μm以上200μm以下を挙げることができる。
The “core” is not particularly limited as long as it can be a pharmaceutically acceptable grain. It is a group for constituting the particulate pharmaceutical composition of the present invention and for coating the intermediate layer and the coating material used in the present invention. The core is composed of the drug itself or pharmaceutically acceptable additives. Particles [eg, crystalline cellulose (grains) (may be described as microcrystalline cellulose), lactose, starch, etc.] can also be used. It is also possible to use a drug alone or a mixture of a drug and a pharmaceutically acceptable additive. You may manufacture the particle | grains which consist of 1 type, or 2 or more types of additives using a well-known technique, and may use it. In addition, additives and sodium lauryl sulfate and a binder (for example, water-soluble polymer: for example, hypromellose (also known as hydroxypropylmethylcellulose) (TC-5, Shin-Etsu Chemical), hydroxypropylcellulose ( Nisso HPC, Nippon Soda Co., Ltd.), methyl methacrylate / butyl methacrylate containing an acidic substance in an amount that neutralizes 10% or more of the basic group described in Japanese Patent No. 3356730 Dimethylaminoethyl methacrylate copolymer [aminoalkyl methacrylate copolymer E (trade name; Eudragit E100, Evonik Degussa GmbH)], povidone (Collidon, BASF), methylcellulose (METOLOSE, Shin-Etsu Chemical) etc.) The dispersed liquid may be sprayed. Furthermore, if desired, the core can be coated with sodium lauryl sulfate and a water-soluble polymer. Examples of the size of the nucleus include, for example, 1 μm or more and 1000 μm or less, other embodiments include 5 μm or more and 500 μm or less, and further embodiments include 10 μm or more and 200 μm or less.
本明細書では、「圧縮成形後の放出速度の変化」に関して、打錠前のマスキング粒子からアトルバスタチンが10%溶出されるときの時間を「T10%(打錠前)」、2~3kNで製したマスキング粒子を含有する口腔内崩壊錠からのアトルバスタチンが10%溶出する時間を「T10%(打錠後)」とする時、T10%(打錠後)/T10%(打錠前)で定義されるT10%に対する変化率が30~100%、更なる態様として50~100%、更なる態様として70~100%である時、打錠による溶出促進を低減したと規定する。
In this specification, regarding “change in release rate after compression molding”, the time when 10% of atorvastatin is eluted from the masking particles before tableting is made as “T 10% (before tableting)” at 2-3 kN. When the time for 10% dissolution of atorvastatin from the orally disintegrating tablet containing masking particles is “T 10% (after tableting)”, T 10% (after tableting) / T 10% (before tableting) When the rate of change with respect to the defined T of 10% is 30 to 100%, a further embodiment is 50 to 100%, and a further embodiment is 70 to 100%, it is defined that the dissolution enhancement by tableting is reduced.
本発明における「速やかな分散性・溶出性」とは、第十五改正日本薬局方溶出試験法第2法に従い日本薬局方溶出試験液第1液(JP1)900mLを用いて試験を行うとき、15分での溶出率が50%以上を示すことを意味する。他の態様として、15分での溶出率が60%以上を示すことを意味する。
In the present invention, “rapid dispersibility / dissolution” means that when a test is performed using 900 mL of Japanese Pharmacopoeia Dissolution Test Solution 1 (JP1) according to the 15th revised Japanese Pharmacopoeia Dissolution Test Method 2, It means that the elution rate at 15 minutes is 50% or more. In another embodiment, it means that the dissolution rate in 15 minutes is 60% or more.
本明細書において「一定時間薬物放出を抑制する」あるいは「初期薬物溶出抑制」とは、口腔内を想定した溶出試験において、薬物の溶出率を0乃至3%に抑制することを意味する。
本明細書において「ラグタイム」とは、上記「薬物の溶出率が0~3%に抑制された時間」を意味する。該「ラグタイム」は、口腔内における薬物の不快な味の遮蔽等を目的として、薬物・製剤の特性・目的(例えば、薬物の不快な味の種類や程度、味の持続時間、製剤の口腔内滞留時間等を考慮して適宜設定されるが、例えば2分以上と規定される。「ラグタイム」は、例えば、組成物中の「中間層」の成分とその配合割合・被覆量、水浸入量制御層の成分とその配合割合・被覆量を適宜増減する等の設計を行うことにより、任意に調整することができる。
本明細書において「不快な味」とは、服用時に不快感をもたらす味を意味し、具体的には苦味、渋味、えぐ味、酸味、辛味、収斂味等が挙げられる。
本明細書において「不溶化」とは、水に対する溶解度、あるいは溶解速度を低下させる現象を意味する。また、「不溶化する」「不溶化させる」「不溶化を促す」とは、溶解した物質を水と相分離させる、あるいは析出させる、沈殿させる、あるいは未だ溶解していない固体物質が水に溶解することを妨げることを示す。
本明細書において「口腔内を想定した試験液」とは、pH6.8リン酸緩衝液(第十五改正日本薬局方溶出試験法第2液)を意味する。 In the present specification, “suppressing drug release for a certain period of time” or “suppressing initial drug dissolution” means that the dissolution rate of a drug is suppressed to 0 to 3% in a dissolution test assuming the oral cavity.
In the present specification, the “lag time” means the “time when the drug dissolution rate is suppressed to 0 to 3%”. The “lag time” is used for the purpose of shielding the unpleasant taste of the drug in the oral cavity, and the characteristics and purpose of the drug / formulation (for example, the type and degree of the unpleasant taste of the drug, the duration of the taste, the oral cavity of the formulation It is appropriately set in consideration of the internal residence time, etc., but is defined as, for example, 2 minutes or more, for example, “lag time” is, for example, “intermediate layer” component in the composition, its blending ratio / coating amount, water It can be arbitrarily adjusted by designing such as appropriately increasing / decreasing the components of the infiltration amount control layer and the blending ratio / coating amount thereof.
In the present specification, “unpleasant taste” means a taste that causes unpleasant feeling when taken, and specifically includes bitterness, astringency, gummy taste, acidity, pungent taste, astringent taste, and the like.
In the present specification, “insolubilization” means a phenomenon in which the solubility in water or the dissolution rate is lowered. In addition, “insolubilize”, “insolubilize”, and “promoting insolubilization” means that a dissolved substance is phase-separated from water, precipitated, precipitated, precipitated, or dissolved in water. Indicates blocking.
In the present specification, the “test solution assuming the oral cavity” means a pH 6.8 phosphate buffer solution (the 15th revised Japanese Pharmacopoeia dissolution test method second solution).
本明細書において「ラグタイム」とは、上記「薬物の溶出率が0~3%に抑制された時間」を意味する。該「ラグタイム」は、口腔内における薬物の不快な味の遮蔽等を目的として、薬物・製剤の特性・目的(例えば、薬物の不快な味の種類や程度、味の持続時間、製剤の口腔内滞留時間等を考慮して適宜設定されるが、例えば2分以上と規定される。「ラグタイム」は、例えば、組成物中の「中間層」の成分とその配合割合・被覆量、水浸入量制御層の成分とその配合割合・被覆量を適宜増減する等の設計を行うことにより、任意に調整することができる。
本明細書において「不快な味」とは、服用時に不快感をもたらす味を意味し、具体的には苦味、渋味、えぐ味、酸味、辛味、収斂味等が挙げられる。
本明細書において「不溶化」とは、水に対する溶解度、あるいは溶解速度を低下させる現象を意味する。また、「不溶化する」「不溶化させる」「不溶化を促す」とは、溶解した物質を水と相分離させる、あるいは析出させる、沈殿させる、あるいは未だ溶解していない固体物質が水に溶解することを妨げることを示す。
本明細書において「口腔内を想定した試験液」とは、pH6.8リン酸緩衝液(第十五改正日本薬局方溶出試験法第2液)を意味する。 In the present specification, “suppressing drug release for a certain period of time” or “suppressing initial drug dissolution” means that the dissolution rate of a drug is suppressed to 0 to 3% in a dissolution test assuming the oral cavity.
In the present specification, the “lag time” means the “time when the drug dissolution rate is suppressed to 0 to 3%”. The “lag time” is used for the purpose of shielding the unpleasant taste of the drug in the oral cavity, and the characteristics and purpose of the drug / formulation (for example, the type and degree of the unpleasant taste of the drug, the duration of the taste, the oral cavity of the formulation It is appropriately set in consideration of the internal residence time, etc., but is defined as, for example, 2 minutes or more, for example, “lag time” is, for example, “intermediate layer” component in the composition, its blending ratio / coating amount, water It can be arbitrarily adjusted by designing such as appropriately increasing / decreasing the components of the infiltration amount control layer and the blending ratio / coating amount thereof.
In the present specification, “unpleasant taste” means a taste that causes unpleasant feeling when taken, and specifically includes bitterness, astringency, gummy taste, acidity, pungent taste, astringent taste, and the like.
In the present specification, “insolubilization” means a phenomenon in which the solubility in water or the dissolution rate is lowered. In addition, “insolubilize”, “insolubilize”, and “promoting insolubilization” means that a dissolved substance is phase-separated from water, precipitated, precipitated, precipitated, or dissolved in water. Indicates blocking.
In the present specification, the “test solution assuming the oral cavity” means a pH 6.8 phosphate buffer solution (the 15th revised Japanese Pharmacopoeia dissolution test method second solution).
本発明の経口投与用粒子状医薬組成物は、アトルバスタチン又はその製薬学的に許容される塩およびラウリル硫酸ナトリウムを含有する粒子が、ポリビニルアセタールジエチルアミノアセテートおよび水溶性高分子物質を含む被膜物質により被覆されてなる、経口投与用粒子状医薬組成物である。
本発明の口腔内崩壊錠は、本発明の経口投与用粒子状医薬組成物を含有してなる口腔内崩壊錠である。 The particulate pharmaceutical composition for oral administration according to the present invention is such that particles containing atorvastatin or a pharmaceutically acceptable salt thereof and sodium lauryl sulfate are coated with a coating substance containing polyvinyl acetal diethylaminoacetate and a water-soluble polymer substance. It is a particulate pharmaceutical composition for oral administration.
The orally disintegrating tablet of the present invention is an orally disintegrating tablet comprising the particulate pharmaceutical composition for oral administration of the present invention.
本発明の口腔内崩壊錠は、本発明の経口投与用粒子状医薬組成物を含有してなる口腔内崩壊錠である。 The particulate pharmaceutical composition for oral administration according to the present invention is such that particles containing atorvastatin or a pharmaceutically acceptable salt thereof and sodium lauryl sulfate are coated with a coating substance containing polyvinyl acetal diethylaminoacetate and a water-soluble polymer substance. It is a particulate pharmaceutical composition for oral administration.
The orally disintegrating tablet of the present invention is an orally disintegrating tablet comprising the particulate pharmaceutical composition for oral administration of the present invention.
本発明に用いられるアトルバスタチン又はその製薬学的に許容される塩は、米国特許第5,273,995号に開示されたアトルバスタチンカルシウム水和物、化学名[R-(R*,R*)]-2-(4-フルオロフェニル)-β,δ-ジヒドロキシ-5-(1-メチルエチル)-3-フェニル-4-[(フェニルアミノ)カルボニル]-1H-ピロール-1-ヘプタン酸カルシウム塩(2:1)3水和物が含まれる。アトルバスタチンカルシウム水和物は、以下の式:
により表される、リピトール(Lipitor)(登録商標)として現在販売されている。アトルバスタチン又はその製薬学的に許容される塩は、HMG-CoAレダクターゼの選択的で競合的な阻害剤である。製薬学的に許容される塩としては、例えばアルカリ金属及びアルカリ土類金属のような金属塩、又は有機アミンのようなアミン塩を挙げることができる。他の態様として、ナトリウム、カリウム、リチウム、カルシウム、マグネシウム、アルミニウム、鉄、亜鉛、炭酸カルシウム、水酸化カルシウム、炭酸マグネシウム、水酸化マグネシウム、珪酸マグネシウム、アルミン酸マグネシウム、水酸化マグネシウムアルミニウムとの塩を挙げることができる。更なる態様として、カルシウムとの塩を挙げることができる。アトルバスタチンカルシウムは、強力な脂質低下性化合物であり、このため脂質低下剤及び/又はコレステロール低下剤として有用であり、同時に、骨粗鬆症、良性の前立腺肥大症(BPH)、及びアルツハイマー病の治療に有用である。また、結晶性形態のアトルバスタチンは、例えばI、II、IV、V、VI、VII、VIII、IX、X、XI、XII、XIII、XIV、XV、XVI、XVII、XVIII、およびXIX型が挙げられ、他の態様としてI型が挙げられる。「I型結晶」は、日本特許第3296564号に開示された結晶性形態Iのアトルバスタチン水和物である。
Atorvastatin or a pharmaceutically acceptable salt thereof used in the present invention is atorvastatin calcium hydrate, chemical name [R- (R *, R *)] disclosed in US Pat. No. 5,273,995. -2- (4-Fluorophenyl) -β, δ-dihydroxy-5- (1-methylethyl) -3-phenyl-4-[(phenylamino) carbonyl] -1H-pyrrole-1-heptanoic acid calcium salt 2: 1) Trihydrate is included. Atorvastatin calcium hydrate has the following formula:
Currently marketed as Lipitor®. Atorvastatin or a pharmaceutically acceptable salt thereof is a selective and competitive inhibitor of HMG-CoA reductase. Examples of pharmaceutically acceptable salts include metal salts such as alkali metals and alkaline earth metals, or amine salts such as organic amines. As another embodiment, a salt with sodium, potassium, lithium, calcium, magnesium, aluminum, iron, zinc, calcium carbonate, calcium hydroxide, magnesium carbonate, magnesium hydroxide, magnesium silicate, magnesium aluminate, magnesium aluminum hydroxide is used. Can be mentioned. As a further embodiment, a salt with calcium can be mentioned. Atorvastatin calcium is a potent lipid-lowering compound and is therefore useful as a lipid-lowering agent and / or cholesterol-lowering agent, and at the same time useful for the treatment of osteoporosis, benign prostatic hypertrophy (BPH), and Alzheimer's disease. is there. The crystalline forms of atorvastatin include, for example, types I, II, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, and XIX. As another embodiment, type I may be mentioned. "Type I crystal" is crystalline Form I atorvastatin hydrate disclosed in Japanese Patent No. 3,296,564.
アトルバスタチン又はその製薬学的に許容される塩の配合量は、医薬的に予防または治療上有効な量であれば特に制限されないが、例えば1日当たり約2.5mg以上約80mg以下、他の態様として約5mg以上約500mg以下、更なる態様として約2.5mg以上約80mg以下である。又は1日につき体重1kg当たり約0.1mg以上約8.0mg以下の成人投与レベルで患者に投与される。他の態様としては1日当たりの投与量は、約0.1mg/kg以上約2.0mg/kg以下の範囲にある。配合量は、効力又は適用によって、5mg以上80mg以下、他の態様としては5mg以上100mg以下に変化又は調節することが出来る。一般に、治療は化合物の最適の投与量より低い量で開始される。その後、投与量は、状況に応じて最適の作用に達するまで漸増される。必要に応じて、1日当たりの全投与量を分割して1日複数回投与することも出来る。
また、薬物の配合割合は、通常薬物の種類、用途(適応症)、年齢(又は体重)に応じ適宜選択されるが、治療学的に有効な量あるいは予防学的に有効な量であれば特に制限されない。例えば、本発明の「粒子状医薬組成物」又は医薬品製剤当たり0.5重量%以上90重量%以下であり、他の態様としては0.5重量%以上80重量%以下であり、更なる態様としては0.5重量%以上70重量%以下である。 The amount of atorvastatin or a pharmaceutically acceptable salt thereof is not particularly limited as long as it is a pharmaceutically preventive or therapeutically effective amount. For example, it is about 2.5 mg to about 80 mg per day. It is about 5 mg or more and about 500 mg or less, and as a further aspect, it is about 2.5 mg or more and about 80 mg or less. Alternatively, it is administered to a patient at an adult dosage level of about 0.1 mg to about 8.0 mg / kg body weight per day. In another embodiment, the daily dose is in the range of about 0.1 mg / kg to about 2.0 mg / kg. The blending amount can be changed or adjusted to 5 mg or more and 80 mg or less, and in another embodiment, 5 mg or more and 100 mg or less depending on efficacy or application. Generally, treatment is initiated with an amount lower than the optimum dose of the compound. Thereafter, the dosage is increased gradually until the optimum effect is reached according to the circumstances. If necessary, the total dose per day can be divided and administered several times a day.
In addition, the proportion of the drug is usually appropriately selected according to the type, use (indication), and age (or body weight) of the drug, as long as it is a therapeutically effective amount or a prophylactically effective amount. There is no particular limitation. For example, it is 0.5 wt% or more and 90 wt% or less per "particulate pharmaceutical composition" or pharmaceutical preparation of the present invention, and in another embodiment, 0.5 wt% or more and 80 wt% or less. As 0.5 to 70% by weight.
また、薬物の配合割合は、通常薬物の種類、用途(適応症)、年齢(又は体重)に応じ適宜選択されるが、治療学的に有効な量あるいは予防学的に有効な量であれば特に制限されない。例えば、本発明の「粒子状医薬組成物」又は医薬品製剤当たり0.5重量%以上90重量%以下であり、他の態様としては0.5重量%以上80重量%以下であり、更なる態様としては0.5重量%以上70重量%以下である。 The amount of atorvastatin or a pharmaceutically acceptable salt thereof is not particularly limited as long as it is a pharmaceutically preventive or therapeutically effective amount. For example, it is about 2.5 mg to about 80 mg per day. It is about 5 mg or more and about 500 mg or less, and as a further aspect, it is about 2.5 mg or more and about 80 mg or less. Alternatively, it is administered to a patient at an adult dosage level of about 0.1 mg to about 8.0 mg / kg body weight per day. In another embodiment, the daily dose is in the range of about 0.1 mg / kg to about 2.0 mg / kg. The blending amount can be changed or adjusted to 5 mg or more and 80 mg or less, and in another embodiment, 5 mg or more and 100 mg or less depending on efficacy or application. Generally, treatment is initiated with an amount lower than the optimum dose of the compound. Thereafter, the dosage is increased gradually until the optimum effect is reached according to the circumstances. If necessary, the total dose per day can be divided and administered several times a day.
In addition, the proportion of the drug is usually appropriately selected according to the type, use (indication), and age (or body weight) of the drug, as long as it is a therapeutically effective amount or a prophylactically effective amount. There is no particular limitation. For example, it is 0.5 wt% or more and 90 wt% or less per "particulate pharmaceutical composition" or pharmaceutical preparation of the present invention, and in another embodiment, 0.5 wt% or more and 80 wt% or less. As 0.5 to 70% by weight.
本発明で用いられるラウリル硫酸ナトリウムは、アトルバスタチン又はその製薬学的に許容される塩の分散性を改善する機能を有するものであれば特に限定されるものではない。また、ラウリル硫酸ナトリウムは、ポリビニルアセタールジエチルアミノアセテートの溶解性を向上させる機能を有するものであれば特に限定されるものではない。ラウリル硫酸ナトリウムとしては、例えば、商品名 NIKKOL SLS(日光ケミカルズ)、エマール0(花王)、TEXAPON K12 P PH(コグニスジャパン)、TEXAPON K12 G PH(コグニスジャパン)を挙げることができる。
The sodium lauryl sulfate used in the present invention is not particularly limited as long as it has a function of improving dispersibility of atorvastatin or a pharmaceutically acceptable salt thereof. Moreover, sodium lauryl sulfate will not be specifically limited if it has a function which improves the solubility of polyvinyl acetal diethylamino acetate. Examples of sodium lauryl sulfate include trade names NIKKOL SLS (Nikko Chemicals), Emar 0 (Kao), TEXAPON K12 P PH (Cognis Japan), and TEXAPON K12 G PH (Cognis Japan).
ラウリル硫酸ナトリウムの配合量は、製薬学的に許容され、かつアトルバスタチン又はその製薬学的に許容される塩の分散性を改善する量であれば特に制限はされないが、それらの合計量として、例えば、アトルバスタチン又はその製薬学的に許容される塩の量に対して30重量%以上200重量%以下、他の態様として、40重量%以上100重量%以下、更に他の態様としてアトルバスタチン又はその製薬学的に許容される塩の量に対して60重量%以上100重量%以下であることができる。
また、ラウリル硫酸ナトリウムの配合量は、ポリビニルアセタールジエチルアミノアセテートの溶解性を向上させる量であれば特に制限はないが、ポリビニルアセタールジエチルアミノアセテートに対し、例えば、50重量%以上200重量%以下、他の態様として100重量%以上200重量%以下、更に他の態様として120重量%以上200重量%以下、更に他の態様として130重量%以上200重量%以下であることができる。 The amount of sodium lauryl sulfate is not particularly limited as long as it is pharmaceutically acceptable and improves the dispersibility of atorvastatin or a pharmaceutically acceptable salt thereof. , Atorvastatin or a pharmaceutically acceptable salt thereof, 30 wt% or more and 200 wt% or less, in another embodiment, 40 wt% or more and 100 wt% or less, and in another embodiment, atorvastatin or a pharmaceutical product thereof It can be 60 wt% or more and 100 wt% or less based on the amount of salt allowed.
The amount of sodium lauryl sulfate is not particularly limited as long as it is an amount that improves the solubility of polyvinyl acetal diethylaminoacetate. For example, it is 50% by weight to 200% by weight with respect to polyvinyl acetal diethylaminoacetate. The aspect may be 100% by weight or more and 200% by weight or less, still another aspect may be 120% by weight or more and 200% by weight or less, and still another aspect may be 130% by weight or more and 200% by weight or less.
また、ラウリル硫酸ナトリウムの配合量は、ポリビニルアセタールジエチルアミノアセテートの溶解性を向上させる量であれば特に制限はないが、ポリビニルアセタールジエチルアミノアセテートに対し、例えば、50重量%以上200重量%以下、他の態様として100重量%以上200重量%以下、更に他の態様として120重量%以上200重量%以下、更に他の態様として130重量%以上200重量%以下であることができる。 The amount of sodium lauryl sulfate is not particularly limited as long as it is pharmaceutically acceptable and improves the dispersibility of atorvastatin or a pharmaceutically acceptable salt thereof. , Atorvastatin or a pharmaceutically acceptable salt thereof, 30 wt% or more and 200 wt% or less, in another embodiment, 40 wt% or more and 100 wt% or less, and in another embodiment, atorvastatin or a pharmaceutical product thereof It can be 60 wt% or more and 100 wt% or less based on the amount of salt allowed.
The amount of sodium lauryl sulfate is not particularly limited as long as it is an amount that improves the solubility of polyvinyl acetal diethylaminoacetate. For example, it is 50% by weight to 200% by weight with respect to polyvinyl acetal diethylaminoacetate. The aspect may be 100% by weight or more and 200% by weight or less, still another aspect may be 120% by weight or more and 200% by weight or less, and still another aspect may be 130% by weight or more and 200% by weight or less.
本発明に用いられる「ポリビニルアセタールジエチルアミノアセテート」(以下、AEAと略記することがある)とは、ポリビニルアルコールとアセトアルデヒドが脱水縮合して得たアセタール、また、残りの水酸基の一部とジエチルアミノ酢酸がエステル結合したものであり、製薬学的に許容されるものであれば特に制限されない。具体的には、例えば、胃溶性コーティング剤として「AEA(登録商標)」の商品名で市販されているもの(例えば、平均分子量65000)が挙げられる(医薬品添加物規格、pp. 634-635、2003年、薬事日報社)。
“Polyvinyl acetal diethylaminoacetate” (hereinafter sometimes abbreviated as AEA) used in the present invention is an acetal obtained by dehydration condensation of polyvinyl alcohol and acetaldehyde, and a part of the remaining hydroxyl groups and diethylaminoacetic acid It is an ester bond and is not particularly limited as long as it is pharmaceutically acceptable. Specific examples include those commercially available under the trade name “AEA (registered trademark)” (for example, average molecular weight 65000) as gastric coating agents (Pharmaceutical Additive Standards, pp. 634-635, 2003, Yakuji Nipposha).
ポリビニルアセタールジエチルアミノアセテートの配合量は、薬物含有粒子に対して、例えば1重量%以上500重量%以下であり、他の態様として5重量%以上300重量%以下であり、更に他の態様として10重量%以上150重量%以下であることができる。中間層被覆粒子に対して、例えば1重量%以上300重量%以下であり、他の態様として5重量%以上200重量%以下であり、更に他の態様として5重量%以上150重量%以下であることができる。粒子状医薬組成物中の被覆量の割合が、例えば1重量%以上200重量%以下であり、他の態様として5重量%以上100重量%以下であり、更に他の態様として5重量%以上50重量%以下であることができる。
The blending amount of polyvinyl acetal diethylaminoacetate is, for example, 1% by weight or more and 500% by weight or less with respect to the drug-containing particles, and in another aspect, 5% by weight or more and 300% by weight or less, and in another aspect, 10% by weight. % Or more and 150% by weight or less. For example, it is 1% by weight or more and 300% by weight or less with respect to the intermediate layer-coated particles. In another embodiment, it is 5% by weight or more and 200% by weight or less, and in another embodiment, it is 5% by weight or more and 150% by weight or less. be able to. The ratio of the coating amount in the particulate pharmaceutical composition is, for example, 1% by weight or more and 200% by weight or less, and in another embodiment, 5% by weight or more and 100% by weight or less, and in another embodiment, 5% by weight or more and 50% by weight or less. It can be up to wt%.
本発明に用いられる「水溶性高分子物質」としては、製薬学的に許容されるものであれば特に制限されない。また、当該高分子物質は、ポリビニルアセタールジエチルアミノアセテートとともに被膜成分を構成し、当該被膜物質により「粒子状医薬組成物」が被覆されることにより、圧縮成形後に「粒子状医薬組成物」から薬物の溶出を低減する機能を有するものであれば特に制限されない。
前記高分子物質としては、例えば、アラビアゴム、アルギン酸ナトリウム、α化デンプン、カゼインナトリウム、カラギーナン、カルボキシビニルポリマー、カルボキシメチルスターチナトリウム、カルメロースナトリウム、キサンタンガム、デキストラン、デキストリン、ヒドロキシプロピルセルロース、ヒプロメロース、メチルセルロース、ヒドロキシエチルセルロース、プルラン、ポビドン、コポリビドン、ポリオキシエチレン-ポリオキシプロピレングリコール、ポリビニルアセタールジエチルアミノアセテート、ポリビニルアルコール-ポリエチレングリコールグラフトコポリマー、ポリビニルアルコール、マクロゴール、ポリエチレンオキサイドが挙げられ、他の態様として、ヒドロキシプロピルセルロース、ヒプロメロース、メチルセルロース、ヒドロキシエチルセルロース、ポビドン、コポリビドン、ポリビニルアルコール-ポリエチレングリコールグラフトコポリマー、ポリビニルアルコール、マクロゴール、ポリエチレンオキサイド等が挙げられる。更なる態様としてヒドロキシプロピルセルロース、ヒプロメロース、メチルセルロース、ヒドロキシエチルセルロース等が挙げられる。更に他の態様としてヒドロキシプロピルセルロース、ヒプロメロース、ヒドロキシエチルセルロース等が挙げられる。ヒプロメロースとしては、第十五改正日本薬局方ヒプロメロース(信越化学)の商品名で市販されている高分子物質(表示粘度3mPa・s以上15mPa・s以下)を挙げることができる。
これらの水溶性高分子物質は1種または2種以上を適宜組み合わせて使用することができる。 The “water-soluble polymer substance” used in the present invention is not particularly limited as long as it is pharmaceutically acceptable. In addition, the polymer substance constitutes a coating component together with polyvinyl acetal diethylaminoacetate, and the “particulate pharmaceutical composition” is coated with the coating substance, so that the drug substance from the “particulate pharmaceutical composition” is compressed after compression molding. There is no particular limitation as long as it has a function of reducing elution.
Examples of the polymer substance include gum arabic, sodium alginate, pregelatinized starch, casein sodium, carrageenan, carboxyvinyl polymer, sodium carboxymethyl starch, carmellose sodium, xanthan gum, dextran, dextrin, hydroxypropylcellulose, hypromellose, methylcellulose. , Hydroxyethyl cellulose, pullulan, povidone, copolyvidone, polyoxyethylene-polyoxypropylene glycol, polyvinyl acetal diethylaminoacetate, polyvinyl alcohol-polyethylene glycol graft copolymer, polyvinyl alcohol, macrogol, and polyethylene oxide. Propylcellulose, hypromellose, Chill cellulose, hydroxyethyl cellulose, povidone, copolyvidone, polyvinyl alcohol - polyethylene glycol graft copolymer, polyvinyl alcohol, macrogol, polyethylene oxide, and the like. Further embodiments include hydroxypropylcellulose, hypromellose, methylcellulose, hydroxyethylcellulose and the like. Still other embodiments include hydroxypropylcellulose, hypromellose, hydroxyethylcellulose and the like. Examples of hypromellose include a high-molecular substance (indicated viscosity of 3 mPa · s to 15 mPa · s) marketed under the trade name of the 15th revised Japanese Pharmacopoeia Hypromellose (Shin-Etsu Chemical).
These water-soluble polymer substances can be used alone or in combination of two or more.
前記高分子物質としては、例えば、アラビアゴム、アルギン酸ナトリウム、α化デンプン、カゼインナトリウム、カラギーナン、カルボキシビニルポリマー、カルボキシメチルスターチナトリウム、カルメロースナトリウム、キサンタンガム、デキストラン、デキストリン、ヒドロキシプロピルセルロース、ヒプロメロース、メチルセルロース、ヒドロキシエチルセルロース、プルラン、ポビドン、コポリビドン、ポリオキシエチレン-ポリオキシプロピレングリコール、ポリビニルアセタールジエチルアミノアセテート、ポリビニルアルコール-ポリエチレングリコールグラフトコポリマー、ポリビニルアルコール、マクロゴール、ポリエチレンオキサイドが挙げられ、他の態様として、ヒドロキシプロピルセルロース、ヒプロメロース、メチルセルロース、ヒドロキシエチルセルロース、ポビドン、コポリビドン、ポリビニルアルコール-ポリエチレングリコールグラフトコポリマー、ポリビニルアルコール、マクロゴール、ポリエチレンオキサイド等が挙げられる。更なる態様としてヒドロキシプロピルセルロース、ヒプロメロース、メチルセルロース、ヒドロキシエチルセルロース等が挙げられる。更に他の態様としてヒドロキシプロピルセルロース、ヒプロメロース、ヒドロキシエチルセルロース等が挙げられる。ヒプロメロースとしては、第十五改正日本薬局方ヒプロメロース(信越化学)の商品名で市販されている高分子物質(表示粘度3mPa・s以上15mPa・s以下)を挙げることができる。
これらの水溶性高分子物質は1種または2種以上を適宜組み合わせて使用することができる。 The “water-soluble polymer substance” used in the present invention is not particularly limited as long as it is pharmaceutically acceptable. In addition, the polymer substance constitutes a coating component together with polyvinyl acetal diethylaminoacetate, and the “particulate pharmaceutical composition” is coated with the coating substance, so that the drug substance from the “particulate pharmaceutical composition” is compressed after compression molding. There is no particular limitation as long as it has a function of reducing elution.
Examples of the polymer substance include gum arabic, sodium alginate, pregelatinized starch, casein sodium, carrageenan, carboxyvinyl polymer, sodium carboxymethyl starch, carmellose sodium, xanthan gum, dextran, dextrin, hydroxypropylcellulose, hypromellose, methylcellulose. , Hydroxyethyl cellulose, pullulan, povidone, copolyvidone, polyoxyethylene-polyoxypropylene glycol, polyvinyl acetal diethylaminoacetate, polyvinyl alcohol-polyethylene glycol graft copolymer, polyvinyl alcohol, macrogol, and polyethylene oxide. Propylcellulose, hypromellose, Chill cellulose, hydroxyethyl cellulose, povidone, copolyvidone, polyvinyl alcohol - polyethylene glycol graft copolymer, polyvinyl alcohol, macrogol, polyethylene oxide, and the like. Further embodiments include hydroxypropylcellulose, hypromellose, methylcellulose, hydroxyethylcellulose and the like. Still other embodiments include hydroxypropylcellulose, hypromellose, hydroxyethylcellulose and the like. Examples of hypromellose include a high-molecular substance (indicated viscosity of 3 mPa · s to 15 mPa · s) marketed under the trade name of the 15th revised Japanese Pharmacopoeia Hypromellose (Shin-Etsu Chemical).
These water-soluble polymer substances can be used alone or in combination of two or more.
本発明に用いられるポリビニルアセタールジエチルアミノアセテートと水溶性高分子物質との組成比(配合割合)としては、通常薬物の物性、安定性、吸収部位、剤形の種類・用途等の目的に応じて、適宜適当な配合量が選択される。水溶性高分子物質の量はポリビニルアセタールジエチルアミノアセテートに対して、例えば1重量%以上30重量%以下であり、他の態様として5重量%以上20重量%以下、更なる態様として5重量%以上15重量%以下である。
As a composition ratio (mixing ratio) of polyvinyl acetal diethylaminoacetate and water-soluble polymer substance used in the present invention, usually depending on purposes such as physical properties of the drug, stability, absorption site, type and use of dosage form, An appropriate blending amount is appropriately selected. The amount of the water-soluble polymer substance is, for example, from 1% by weight to 30% by weight with respect to polyvinyl acetal diethylaminoacetate. In another embodiment, the amount is from 5% by weight to 20% by weight, and in a further embodiment, from 5% by weight to 15%. % By weight or less.
本発明におけるポリビニルアセタールジエチルアミノアセテートと水溶性高分子物質とを含む被膜物質の被覆量についても、適宜適当な割合が選択される。例えば、薬物を含有する核に対して、1重量%以上500重量%以下である。他の態様として5重量%以上300重量%以下であり、更なる態様として10重量%以上150重量%以下である。被覆量が1重量%より低い場合には、粒子状医薬組成物表面への被覆が均一に行われず、かつ被覆層の厚さが極めて薄いため、圧縮成形による粒子状医薬組成物からの薬物溶出速度の変化の増大が懸念される。
また、所望により、薬物含有粒子を中間層により被覆した粒子(後記説明することとし、以下「中間層」被覆粒子と略記することもある)とする場合、該中間層被覆粒子に対して、例えば1重量%以上500重量%以下である。他の態様として5重量%以上200重量%以下であり、更なる態様として10重量%以上150重量%以下である。粒子状医薬組成物中の被覆量の割合が、例えば1重量%以上200重量%以下である。他の態様として5重量%以上100重量%以下であり、更に他の態様として5重量%以上50重量%以下である。 An appropriate ratio is appropriately selected for the coating amount of the coating material containing the polyvinyl acetal diethylaminoacetate and the water-soluble polymer material in the present invention. For example, the content is 1% by weight or more and 500% by weight or less with respect to the core containing the drug. In another embodiment, it is 5 wt% or more and 300 wt% or less, and in a further embodiment, it is 10 wt% or more and 150 wt% or less. When the coating amount is lower than 1% by weight, the surface of the particulate pharmaceutical composition is not uniformly coated and the coating layer is extremely thin, so that the drug elution from the particulate pharmaceutical composition by compression molding There is concern about an increase in speed.
In addition, if desired, when the particles containing drug-containing particles are coated with an intermediate layer (which will be described later and may be abbreviated as “intermediate layer” coated particles hereinafter), 1 wt% or more and 500 wt% or less. In another embodiment, it is 5% by weight or more and 200% by weight or less, and in a further embodiment, it is 10% by weight or more and 150% by weight or less. The ratio of the coating amount in the particulate pharmaceutical composition is, for example, 1% by weight or more and 200% by weight or less. In another embodiment, it is 5% by weight or more and 100% by weight or less, and in another embodiment, it is 5% by weight or more and 50% by weight or less.
また、所望により、薬物含有粒子を中間層により被覆した粒子(後記説明することとし、以下「中間層」被覆粒子と略記することもある)とする場合、該中間層被覆粒子に対して、例えば1重量%以上500重量%以下である。他の態様として5重量%以上200重量%以下であり、更なる態様として10重量%以上150重量%以下である。粒子状医薬組成物中の被覆量の割合が、例えば1重量%以上200重量%以下である。他の態様として5重量%以上100重量%以下であり、更に他の態様として5重量%以上50重量%以下である。 An appropriate ratio is appropriately selected for the coating amount of the coating material containing the polyvinyl acetal diethylaminoacetate and the water-soluble polymer material in the present invention. For example, the content is 1% by weight or more and 500% by weight or less with respect to the core containing the drug. In another embodiment, it is 5 wt% or more and 300 wt% or less, and in a further embodiment, it is 10 wt% or more and 150 wt% or less. When the coating amount is lower than 1% by weight, the surface of the particulate pharmaceutical composition is not uniformly coated and the coating layer is extremely thin, so that the drug elution from the particulate pharmaceutical composition by compression molding There is concern about an increase in speed.
In addition, if desired, when the particles containing drug-containing particles are coated with an intermediate layer (which will be described later and may be abbreviated as “intermediate layer” coated particles hereinafter), 1 wt% or more and 500 wt% or less. In another embodiment, it is 5% by weight or more and 200% by weight or less, and in a further embodiment, it is 10% by weight or more and 150% by weight or less. The ratio of the coating amount in the particulate pharmaceutical composition is, for example, 1% by weight or more and 200% by weight or less. In another embodiment, it is 5% by weight or more and 100% by weight or less, and in another embodiment, it is 5% by weight or more and 50% by weight or less.
本発明の粒子状医薬組成物には、所望により「流動化剤」を配合する態様を採用することができる。流動化剤の配合は、特定の製造方法時に特に限定されるものではないが、例えば、流動層造粒法により本発明の「粒子状医薬組成物」を製造する場合、各成分の混合や粒子の乾燥に伴い、静電気が発生し、流動化の障害となることがある。流動化剤は、発生した静電気を中和する機能等を有するものであり、コーティング時の流動化を改善するものであれば特に限定されない。かかる流動化剤としては、例えば、ケイ酸金属類、二酸化ケイ素類、高級脂肪酸金属塩、金属酸化物、アルカリ土類金属塩、金属水酸化物が挙げられ、他の態様として、タルク、カオリン、ケイ酸カルシウム、ケイ酸マグネシウム、軽質無水ケイ酸、ステアリン酸マグネシウム、ステアリン酸カルシウム、酸化鉄、酸化チタン、炭酸カルシウム、リン酸カルシウム、セッコウ、炭酸マグネシウム、水酸化アルミニウム、含水二酸化ケイ素、結晶セルロース、合成ケイ酸アルミニウム、重質無水ケイ酸、水酸化アルミナマグネシウム、ステアリン酸、トウモロコシデンプン、メタケイ酸アルミン酸マグネシウム、リン酸水素カルシウム造粒物、およびグリセリルモノステアレートが挙げられ、更なる態様としては、タルク、カオリン、ケイ酸カルシウム、ケイ酸マグネシウム、軽質無水ケイ酸、ステアリン酸マグネシウム、およびグリセリルモノステアレートが挙げられる。流動化剤は1種または2種以上適宜組み合わせて添加することができる。
The particulate pharmaceutical composition of the present invention can employ an embodiment in which a “fluidizing agent” is blended as desired. The blending of the fluidizing agent is not particularly limited during a specific production method. For example, when the “particulate pharmaceutical composition” of the present invention is produced by a fluidized bed granulation method, mixing of the components and particles As the material dries, static electricity is generated, which may hinder fluidization. The fluidizing agent has a function of neutralizing generated static electricity and the like, and is not particularly limited as long as it improves fluidization during coating. Examples of the fluidizing agent include metal silicates, silicon dioxides, higher fatty acid metal salts, metal oxides, alkaline earth metal salts, metal hydroxides, and other embodiments include talc, kaolin, Calcium silicate, magnesium silicate, light anhydrous silicic acid, magnesium stearate, calcium stearate, iron oxide, titanium oxide, calcium carbonate, calcium phosphate, gypsum, magnesium carbonate, aluminum hydroxide, hydrous silicon dioxide, crystalline cellulose, synthetic silicic acid Aluminum, heavy anhydrous silicic acid, magnesium alumina hydroxide, stearic acid, corn starch, magnesium aluminate metasilicate, calcium hydrogen phosphate granulate, and glyceryl monostearate, further embodiments include talc, Kaolin, silicate Siumu, magnesium silicate, light anhydrous silicic acid, magnesium stearate, and glyceryl monostearate. One or more fluidizing agents can be added in appropriate combination.
流動化剤の配合量は、薬物含有粒子に対して、例えば1重量%以上500重量%以下である。他の態様として1重量%以上200重量%以下であり、更なる態様として5重量%以上100重量%以下である。ポリビニルアセタールジエチルアミノアセテートに対して、例えば1重量%以上200重量%以下であり、他の態様として5重量%以上100重量%以下であり、更なる態様として20重量%以上60重量%以下である。
The blending amount of the fluidizing agent is, for example, 1% by weight to 500% by weight with respect to the drug-containing particles. In another embodiment, it is 1% by weight or more and 200% by weight or less, and in a further embodiment, it is 5% by weight or more and 100% by weight or less. With respect to polyvinyl acetal diethylaminoacetate, it is, for example, 1% by weight or more and 200% by weight or less, and in another aspect, it is 5% by weight or more and 100% by weight or less, and in a further aspect, it is 20% by weight or more and 60% by weight or less.
本発明の医薬品製剤については、口腔内崩壊錠の他、中間体の粒子を配合して、各種医薬品製剤とすることができる。口腔内崩壊錠以外の医薬品製剤としては、例えば、散剤、細粒剤、ドライシロップ剤、錠剤等が挙げられる。
以下に本発明の口腔内崩壊錠に関して説明するが、本発明の医薬品製剤を限定するものではない。 About the pharmaceutical formulation of this invention, the particle | grains of an intermediate body other than an orally disintegrating tablet can be mix | blended, and it can be set as various pharmaceutical formulations. Examples of pharmaceutical preparations other than orally disintegrating tablets include powders, fine granules, dry syrups, tablets and the like.
Hereinafter, the orally disintegrating tablet of the present invention will be described, but the pharmaceutical preparation of the present invention is not limited thereto.
以下に本発明の口腔内崩壊錠に関して説明するが、本発明の医薬品製剤を限定するものではない。 About the pharmaceutical formulation of this invention, the particle | grains of an intermediate body other than an orally disintegrating tablet can be mix | blended, and it can be set as various pharmaceutical formulations. Examples of pharmaceutical preparations other than orally disintegrating tablets include powders, fine granules, dry syrups, tablets and the like.
Hereinafter, the orally disintegrating tablet of the present invention will be described, but the pharmaceutical preparation of the present invention is not limited thereto.
本発明において、「口腔内崩壊錠」とは、水を摂取せずに錠剤を服用した場合、口腔内で実質的に唾液のみにより2分以内、他の態様として1分以内、更なる態様として45秒以内に崩壊する錠剤、その他錠剤に類する製剤を意味する。
本発明の粒子状医薬組成物はこのような口腔内崩壊錠に含有させることができ、例えば、国際公開第WO95/20380号パンフレット(米国対応特許第5576014号明細書)、国際公開第WO2002/92057号パンフレット(米国対応特許出願公開第2003/099701号明細書)、米国特許第4305502号明細書、米国特許第4371516号明細書、特許第2807346号(米国対応特許第5466464号明細書)、特開平5-271054号公報(欧州対応特許第553777号明細書)、特開平10-182436号公報(米国対応特許第5958453号明細書)、特許第3412694号(米国対応特許第5223264号明細書)、国際公開WO98/02185パンフレット(米国対応特許第6287596号明細書)、及び国際公開第WO2008/032767号パンフレット(米国対応特許出願公開第2008/0085309号明細書)に記載の公知の口腔内崩壊錠の薬物として該粒子状医薬組成物を適用し、該公報に記載の口腔内崩壊錠基剤を用い、該公報記載の方法に従い、口腔内崩壊錠とすることができる。このように粒子状医薬組成物を含有する口腔内崩壊錠としては、特許第3412694号明細書(米国対応特許第5223264号明細書)、特開2003-55197号公報に記載された口腔内崩壊錠が挙げられ、本発明の粒子状医薬組成物はこれらの口腔内崩壊錠に含有させることができる。 In the present invention, the “orally disintegrating tablet” means that when taking a tablet without ingesting water, the oral cavity is substantially within 2 minutes only by saliva, as another aspect within 1 minute, as a further aspect It means tablets that disintegrate within 45 seconds and other preparations similar to tablets.
The particulate pharmaceutical composition of the present invention can be contained in such an orally disintegrating tablet. For example, International Publication No. WO95 / 20380 (US Patent No. 5576014), International Publication No. WO2002 / 92057 Pamphlet (U.S. Patent Application Publication No. 2003/099701), U.S. Pat. No. 4,305,502, U.S. Pat. No. 4,371,516, U.S. Pat. No. 2,807,346 (U.S. Pat. Publication No. 5-271054 (European Patent No. 553777), Japanese Patent Application Laid-Open No. 10-182436 (U.S. Patent No. 5958543), Patent No. 3412694 (U.S. Patent No. 5223264), International Drugs of known orally disintegrating tablets described in published WO98 / 02185 pamphlet (US patent 6287596) and international published WO2008 / 032767 pamphlet (US published patent application 2008/0085309) The particulate pharmaceutical composition is applied as An orally disintegrating tablet base described in the report can be used to make an orally disintegrating tablet according to the method described in the publication. As such orally disintegrating tablets containing the particulate pharmaceutical composition, the orally disintegrating tablets described in Japanese Patent No. 3412694 (US Patent No. 5223264) and Japanese Patent Application Laid-Open No. 2003-55197 are disclosed. The particulate pharmaceutical composition of the present invention can be contained in these orally disintegrating tablets.
本発明の粒子状医薬組成物はこのような口腔内崩壊錠に含有させることができ、例えば、国際公開第WO95/20380号パンフレット(米国対応特許第5576014号明細書)、国際公開第WO2002/92057号パンフレット(米国対応特許出願公開第2003/099701号明細書)、米国特許第4305502号明細書、米国特許第4371516号明細書、特許第2807346号(米国対応特許第5466464号明細書)、特開平5-271054号公報(欧州対応特許第553777号明細書)、特開平10-182436号公報(米国対応特許第5958453号明細書)、特許第3412694号(米国対応特許第5223264号明細書)、国際公開WO98/02185パンフレット(米国対応特許第6287596号明細書)、及び国際公開第WO2008/032767号パンフレット(米国対応特許出願公開第2008/0085309号明細書)に記載の公知の口腔内崩壊錠の薬物として該粒子状医薬組成物を適用し、該公報に記載の口腔内崩壊錠基剤を用い、該公報記載の方法に従い、口腔内崩壊錠とすることができる。このように粒子状医薬組成物を含有する口腔内崩壊錠としては、特許第3412694号明細書(米国対応特許第5223264号明細書)、特開2003-55197号公報に記載された口腔内崩壊錠が挙げられ、本発明の粒子状医薬組成物はこれらの口腔内崩壊錠に含有させることができる。 In the present invention, the “orally disintegrating tablet” means that when taking a tablet without ingesting water, the oral cavity is substantially within 2 minutes only by saliva, as another aspect within 1 minute, as a further aspect It means tablets that disintegrate within 45 seconds and other preparations similar to tablets.
The particulate pharmaceutical composition of the present invention can be contained in such an orally disintegrating tablet. For example, International Publication No. WO95 / 20380 (US Patent No. 5576014), International Publication No. WO2002 / 92057 Pamphlet (U.S. Patent Application Publication No. 2003/099701), U.S. Pat. No. 4,305,502, U.S. Pat. No. 4,371,516, U.S. Pat. No. 2,807,346 (U.S. Pat. Publication No. 5-271054 (European Patent No. 553777), Japanese Patent Application Laid-Open No. 10-182436 (U.S. Patent No. 5958543), Patent No. 3412694 (U.S. Patent No. 5223264), International Drugs of known orally disintegrating tablets described in published WO98 / 02185 pamphlet (US patent 6287596) and international published WO2008 / 032767 pamphlet (US published patent application 2008/0085309) The particulate pharmaceutical composition is applied as An orally disintegrating tablet base described in the report can be used to make an orally disintegrating tablet according to the method described in the publication. As such orally disintegrating tablets containing the particulate pharmaceutical composition, the orally disintegrating tablets described in Japanese Patent No. 3412694 (US Patent No. 5223264) and Japanese Patent Application Laid-Open No. 2003-55197 are disclosed. The particulate pharmaceutical composition of the present invention can be contained in these orally disintegrating tablets.
口腔内崩壊錠は、一般に鋳型タイプ、湿製タイプ、通常打錠タイプに大別され、本発明の粒子状医薬組成物はいずれのタイプの口腔内崩壊錠に含有させてもよい。鋳型タイプの口腔内崩壊錠は、例えば特許第2807346号明細書(米国対応特許第5466464号明細書)にも開示されているように、賦形剤等の溶液又は懸濁液を鋳型に充填し、乾燥して製するものである。本発明の粒子状医薬組成物を含有する鋳型タイプの口腔内崩壊錠は、例えば本発明の粒子状医薬組成物、糖類などの賦形剤、及びゼラチン、寒天などの結合剤の溶液又は懸濁液をPTPポケットに充填後、凍結乾燥、減圧乾燥、低温乾燥などの方法により水分を除去して製することができる。湿製タイプの口腔内崩壊錠は特許3069458号明細書(米国対応特許第5501861号明細書、米国対応特許第5720974号明細書)に示されているように、糖類等の賦形剤を湿潤させ、低圧で打錠した後、乾燥して製するものである。従って、例えば本発明の粒子状医薬組成物、糖類などの賦形剤を少量の水あるいは水とアルコールの混液で湿潤させ、この湿潤混合物を低い圧力で成形後、乾燥させ製することができる。
Orally disintegrating tablets are generally classified into a mold type, a moist type, and a normal tableting type, and the particulate pharmaceutical composition of the present invention may be contained in any type of orally disintegrating tablet. The mold-type orally disintegrating tablet is prepared by filling a mold with a solution or suspension such as an excipient as disclosed in, for example, Japanese Patent No. 2807346 (US Pat. No. 5,466,464). It is made by drying. The mold-type orally disintegrating tablet containing the particulate pharmaceutical composition of the present invention is, for example, a solution or suspension of the particulate pharmaceutical composition of the present invention, excipients such as sugars, and binders such as gelatin and agar. After filling the PTP pocket with the liquid, it can be produced by removing moisture by a method such as freeze drying, drying under reduced pressure, or low temperature drying. Wet type orally disintegrating tablets are moistened with excipients such as saccharides as shown in Patent No. 3069458 (U.S. Pat. No. 5,018,618, U.S. Pat. No. 5,720,974). After tableting under low pressure, the product is dried. Therefore, for example, the particulate pharmaceutical composition of the present invention, an excipient such as a saccharide can be wetted with a small amount of water or a mixture of water and alcohol, and the wet mixture can be molded at a low pressure and dried.
通常打錠タイプの場合は、国際公開第WO95/20380号パンフレット(米国対応特許第5576014号明細書)、国際公開第WO2002/92057号パンフレット(米国対応特許出願公開第2003/099701号明細書)、特開平10-182436号公報(米国対応特許第5958453号明細書)、特開平9-48726号公報、特開平8-19589号公報(米国対応特許第5672364号明細書)、特許2919771号、特許3069458号(米国対応特許第5501861号明細書、米国対応特許第5720974号明細書)、国際公開第WO2008/032767号パンフレット(米国対応特許出願公開第2008/0085309号明細書)に開示されているように、通常の打錠工程を経て調製するものである。本発明の粒子状医薬組成物を含有する通常打錠タイプの口腔内崩壊錠を調製するには、例えば国際公開第WO95/20380号パンフレット(米国対応特許第5576014号明細書)、特許2919771号明細書に開示されているように、本発明の粒子状医薬組成物と成形性の低い糖類などの賦形剤とを、成形性の高い糖類又は水溶性高分子の溶液又は懸濁液を用いて造粒後、この造粒物を圧縮成形して圧縮成形物とするか、さらに該圧縮成形物を加湿乾燥して口腔内崩壊錠を製することができる。また、国際公開第WO99/47124号パンフレット(米国対応特許第6589554号明細書)に示されているような通常打錠タイプの口腔内崩壊錠を調製するには、例えば本発明の粒子状医薬組成物と結晶性の糖類などの賦形剤と、非晶質の糖類を用いて圧縮成形後、加湿乾燥して口腔内崩壊錠を製することができる。さらに、国際公開第WO2002/92057号パンフレット(米国対応特許出願公開第2003/099701号明細書)に開示されているような通常打錠タイプの口腔内崩壊錠を調製するには、例えば本発明の粒子状医薬組成物と賦形剤と、前記賦形剤よりも融点の低い糖類との混合物を圧縮成形後、加熱して、融点の低い糖類が溶融して固化することにより架橋を形成して口腔内崩壊錠を調製することができる。このような加湿乾燥あるいは加熱処理により、口腔内崩壊錠の錠剤強度を向上させることができる。さらに、国際公開第WO2008/032767号パンフレット(米国対応特許出願公開第2008/0085309号明細書)に開示されているような通常打錠タイプの口腔内崩壊錠を調製するには、例えば、本発明の粒子状医薬組成物と賦形剤と、α化度が30%以上60%以下である加工したデンプン類との混合物を圧縮成形して口腔内崩壊錠を調製することが出来る。
In the case of a normal tableting type, International Publication No. WO95 / 20380 pamphlet (US corresponding patent No. 5576014 specification), International Publication No. WO2002 / 92057 pamphlet (US corresponding patent application No. 2003/099701 specification), Japanese Patent Application Laid-Open No. 10-182436 (US Patent No. 5958543), Japanese Patent Application Laid-Open No. 9-48726, Japanese Patent Application Laid-Open No. 8-19589 (US Patent No. 5672364), Patent 2919771, Patent No. 3069458 As disclosed in US Pat. No. 5,018,861 (corresponding to US Pat. No. 5,018,974, US Pat. No. 5,720,974), WO 2008/032767 pamphlet (US-patent published application No. 2008/0085309). It is prepared through a normal tableting process. In order to prepare a normal tablet type orally disintegrating tablet containing the particulate pharmaceutical composition of the present invention, for example, International Publication No. WO95 / 20380 (US Patent No. 5576014), Patent No. 2919771 As described in the document, the particulate pharmaceutical composition of the present invention and an excipient such as a saccharide having a low moldability are mixed with a solution or suspension of a saccharide or a water-soluble polymer having a high moldability. After granulation, the granulated product can be compression-molded to form a compressed molded product, or the compressed molded product can be humidified and dried to produce an orally disintegrating tablet. In order to prepare a normal tablet type orally disintegrating tablet as shown in International Publication No. WO99 / 47124 Pamphlet (US Patent No. 6658554), for example, the particulate pharmaceutical composition of the present invention is used. An orally disintegrating tablet can be produced by compression molding using an amorphous sugar and an excipient such as a product and a crystalline saccharide, followed by humidification and drying. Furthermore, in order to prepare a normal tablet type orally disintegrating tablet as disclosed in International Publication No. WO2002 / 92057 pamphlet (US Patent Application Publication No. 2003/099701 specification), for example, A mixture of a particulate pharmaceutical composition, an excipient, and a saccharide having a melting point lower than that of the excipient is compression-molded and heated to form a crosslink by melting and solidifying the saccharide having a lower melting point. Orally disintegrating tablets can be prepared. By such humidification drying or heat treatment, the tablet strength of the orally disintegrating tablet can be improved. Furthermore, in order to prepare a normal tablet type orally disintegrating tablet as disclosed in International Publication No. WO2008 / 032767 (US Patent Application Publication No. 2008/0085309), for example, the present invention Orally disintegrating tablets can be prepared by compression-molding a mixture of the particulate pharmaceutical composition and excipients and processed starches having a pregelatinization degree of 30% to 60%.
本発明の口腔内崩壊錠に用いられる賦形剤としては、一般的な賦形剤も使用できるが、特に製薬学的に許容される糖類を用いるのが好ましく、糖類の成形性を利用する技術においては成形性の低い糖類、糖類の結晶/非晶質性と加湿乾燥による錠剤強度の向上技術を用いるときは結晶性の糖類、糖類の溶融固化物による架橋化技術を使用する場合は、一般的な賦形剤の他、融点の高い糖類が使用することができる。
As the excipient used in the orally disintegrating tablet of the present invention, a general excipient can be used, but it is particularly preferable to use a pharmaceutically acceptable saccharide, and a technique utilizing the moldability of the saccharide. In the case of using saccharides with low moldability, crystalline / amorphous saccharides, and tablet strength improvement technology by humidification drying, it is common to use cross-linking technology with crystalline saccharides and saccharide melt-solidified products. In addition to typical excipients, high melting point saccharides can be used.
ここで「成形性の低い糖類」とは、例えば糖類150mgを直径8mmの杵を用いて打錠圧10kg/cm2以上50kg/cm2以下で打錠したとき、錠剤の硬度が0kp以上2kp以下を示すものを意味し、また「成形性の高い糖類」とは同様の方法による硬度が、2kp以上を示すものを意味する。成形性の低い糖類は、医薬的に許容されるものであり、例えば乳糖、マンニトール、ブドウ糖、白糖、キシリトール、エリスリトール等を挙げることが出来る。これらの1種又は2種以上を適宜組み合わせて用いることも可能である。成形性の高い糖類は、医薬的に許容されるものであり、例えばマルトース、マルチトール、ソルビトール、トレハロース、ラクチトール等を挙げることが出来る。かかる糖類についても、1種又は2種以上を適宜組み合わせて用いることも可能である。
Here, “the saccharide having low moldability” means, for example, when tableting 150 mg of saccharide with a punch having a diameter of 8 mm at a tableting pressure of 10 kg / cm 2 or more and 50 kg / cm 2 or less, the hardness of the tablet is 0 kp or more and 2 kp or less. In addition, the term “highly moldable saccharide” means that the hardness by the same method is 2 kp or more. Saccharides with low moldability are pharmaceutically acceptable, and examples thereof include lactose, mannitol, glucose, sucrose, xylitol, and erythritol. One or two or more of these may be used in appropriate combination. Highly moldable saccharides are pharmaceutically acceptable, and examples thereof include maltose, maltitol, sorbitol, trehalose, lactitol and the like. These saccharides can also be used alone or in combination of two or more.
「結晶性の糖類」は医薬的に許容されるものであり、例えばマンニトール、マルチトール、エリスリトール、キシリトール等が挙げられる。これらは1種又は2種以上を適宜組み合わせて用いることも可能である。「非晶質の糖類」は、医薬的に許容されるものであり、例えばラクトース、白糖、ブドウ糖、ソルビトール、マルトース、トレハロース等が挙げられ、これらの糖類も1種又は2種以上を適宜組み合わせて用いることも可能である。
“Crystalline saccharide” is pharmaceutically acceptable, and examples thereof include mannitol, maltitol, erythritol, xylitol and the like. These may be used alone or in combination of two or more. “Amorphous saccharides” are pharmaceutically acceptable and include, for example, lactose, sucrose, glucose, sorbitol, maltose, trehalose, etc., and these saccharides may be used alone or in combination of two or more. It is also possible to use it.
また、「融点の高い糖類」は、医薬的に許容されるものであり、例えばキシリトール、トレハロース、マルトース、ソルビトール、エリスリトール、ブドウ糖、白糖、マルチトール、マンニトール等を挙げることが出来る。これらの1種又は2種以上を適宜組み合わせて用いることも可能である。「融点の低い糖類」は、医薬的に許容されるものであり、例えばキシリトール、トレハロース、マルトース、ソルビトール、エリスリトール、ブドウ糖、白糖、マルチトール、マンニトール等を挙げることが出来る。かかる糖類についても、1種又は2種以上を適宜組み合わせて用いることも可能である。口腔内崩壊錠用結合剤としては、マルチトール、コポリビドン等を挙げることが出来る。かかる結合剤についても、1種又は2種以上を適宜組み合わせて用いることも可能である。
In addition, the “saccharide having a high melting point” is pharmaceutically acceptable, and examples thereof include xylitol, trehalose, maltose, sorbitol, erythritol, glucose, sucrose, maltitol, mannitol and the like. One or two or more of these may be used in appropriate combination. The “sugar having a low melting point” is pharmaceutically acceptable, and examples thereof include xylitol, trehalose, maltose, sorbitol, erythritol, glucose, sucrose, maltitol, mannitol and the like. These saccharides can also be used alone or in combination of two or more. Examples of binders for orally disintegrating tablets include maltitol and copolyvidone. Also about this binder, it is also possible to use 1 type or in combination of 2 or more types as appropriate.
成形性の高い糖類に代えて水溶性高分子を使用するときは、例えばヒドロキシプロピルセルロース、ヒプロメロース、ポビドン、ポリビニルアルコール、アラビアゴム末、ゼラチン、プルランなどが好適である。
When a water-soluble polymer is used instead of a highly moldable saccharide, for example, hydroxypropylcellulose, hypromellose, povidone, polyvinyl alcohol, gum arabic powder, gelatin, pullulan and the like are suitable.
また、「α化」とは、デンプンに物理的処理を加えることで分子間に水が入り込んで膨潤化(糊化)することを意味し、α化度が増加するとα化が進んだことになる。加工したデンプンとして、例えばトウモロコシデンプン、コムギデンプン、バレイショデンプン、コメデンプン、タピオカデンプン等を挙げることができる。
In addition, “α-ized” means that when physical treatment is applied to starch, water enters between the molecules and swells (gelatinizes). Become. Examples of the processed starch include corn starch, wheat starch, potato starch, rice starch, tapioca starch and the like.
本発明の粒子状医薬組成物を含有させた口腔内崩壊錠に用いられる賦形剤の配合量、又は製剤全体における賦形剤の総量は、本発明の粒子状医薬組成物の配合量及び/又は錠剤の大きさ等に応じて適宜調整されるが、通常1錠当たり20mg以上1000mg以下が好ましく、他の態様として50mg以上900mg以下であり、更なる態様として50mg以上800mg以下が好適である。
The blending amount of the excipient used for the orally disintegrating tablet containing the particulate pharmaceutical composition of the present invention, or the total amount of the excipient in the whole preparation is the blending amount of the particulate pharmaceutical composition of the present invention and / or Or it is suitably adjusted according to the size of the tablet and the like, but usually 20 mg or more and 1000 mg or less per tablet is preferable, 50 mg or more and 900 mg or less is preferable as another aspect, and 50 mg or more and 800 mg or less is preferable as a further aspect.
また、成形性の高い糖類、水溶性高分子、非晶質の糖類、融点の低い糖類の配合量は、個々の技術によって相違点はあるが、賦形剤の重量に対して0.5重量%以上50重量%以下が好ましく、他の態様として1重量%以上40重量%以下であり、更なる態様として2重量%以上30重量%以下であるか、製剤全体に対し1重量%以上20重量%以下が好適である。
The blending amount of highly moldable saccharides, water-soluble polymers, amorphous saccharides, and saccharides with a low melting point is 0.5 wt. % Or more and 50% by weight or less is preferable, and in another embodiment, it is 1% by weight or more and 40% by weight or less, and in a further embodiment, it is 2% by weight or more and 30% by weight or less, or 1% by weight or more and 20% by weight or less % Or less is preferred.
その他の任意の添加剤の種類、その配合や配合量等については、前記口腔内崩壊錠の特許文献の記載が本明細書の記述として引用される。
The description of the patent document of the orally disintegrating tablet is cited as the description of the present specification for the types of other optional additives, their blending and blending amounts, and the like.
また口腔内崩壊錠に本発明の粒子状医薬組成物を含有させる場合、口腔内崩壊錠全体の0.5重量%以上90重量%以下相当の粒子状医薬組成物を含有させることができる。好ましくは0.5重量%以上80重量%以下であり、他の態様として1重量%以上60重量%以下相当である。
In addition, when the orally disintegrating tablet contains the particulate pharmaceutical composition of the present invention, a particulate pharmaceutical composition equivalent to 0.5% by weight or more and 90% by weight or less of the whole orally disintegrating tablet can be contained. Preferably, it is 0.5 wt% or more and 80 wt% or less, and in another embodiment, it corresponds to 1 wt% or more and 60 wt% or less.
本発明の経口投与用粒子状医薬組成物には、所望によりさらに各種医薬賦形剤が適宜使用され、製剤化される。かかる医薬賦形剤としては、製薬的に許容され、かつ薬理的に許容されるものであれば特に制限されない。例えば、結合剤、崩壊剤、酸味料、発泡剤、人工甘味料、香料、滑沢剤、着色剤、安定化剤、緩衝剤、抗酸化剤、界面活性剤などが使用される。
In the particulate pharmaceutical composition for oral administration of the present invention, various pharmaceutical excipients are appropriately used as necessary, and formulated. Such a pharmaceutical excipient is not particularly limited as long as it is pharmaceutically acceptable and pharmacologically acceptable. For example, binders, disintegrants, acidulants, foaming agents, artificial sweeteners, fragrances, lubricants, colorants, stabilizers, buffers, antioxidants, surfactants, and the like are used.
結合剤としては、例えばヒプロメロース、アラビアゴムなどが挙げられる。
崩壊剤としては、例えばトウモロコシデンプン、バレイショデンプン、カルメロースカルシウム、カルメロースナトリウムなどが挙げられる。
酸味料としては、例えばクエン酸、酒石酸、リンゴ酸などが挙げられる。
発泡剤としては、例えば重曹などが挙げられる。
人工甘味料としては、例えばサッカリンナトリウム、グリチルリチン二カリウム、アスパルテーム、ステビア、ソーマチンなどが挙げられる。
香料としては、例えばレモン、レモンライム、オレンジ、メントールなどが挙げられる。
滑沢剤としては、例えばステアリン酸マグネシウム、ステアリン酸カルシウム、ショ糖脂肪酸エステル、ポリエチレングリコール、タルク、ステアリン酸などが挙げられる。
着色剤としては、例えば黄色三二酸化鉄、赤色三二酸化鉄、食用黄色4号、5号、食用赤色3号、102号、食用青色3号などが挙げられる。
緩衝剤としては、クエン酸、コハク酸、フマル酸、酒石酸、アスコルビン酸またはその塩類、グルタミン酸、グルタミン、グリシン、アスパラギン酸、アラニン、アルギニンまたはその塩類、酸化マグネシウム、酸化亜鉛、水酸化マグネシウム、リン酸、ホウ酸またはその塩類などが挙げられる。
抗酸化剤としては、例えばアスコルビン酸、ジブチルヒドロキシトルエン、没食子酸プロピルなどが挙げられる。
界面活性剤としては、例えばポリソルベート80、ラウリル硫酸ナトリウム、ポリオキシエチレン硬化ヒマシ油などが挙げられる。医薬賦形剤としては、1種または2種以上組み合わせて適宜適量添加することができる。
これらの各種医薬賦形剤の配合量は、薬物含有粒子に対して、例えば1重量%以上100重量%以下であり、他の態様として、5重量%以上80重量%以下、更なる態様として10重量%以上50重量%以下である。 Examples of the binder include hypromellose and gum arabic.
Examples of the disintegrant include corn starch, potato starch, carmellose calcium, and carmellose sodium.
Examples of the sour agent include citric acid, tartaric acid, malic acid and the like.
Examples of the foaming agent include baking soda.
Examples of the artificial sweetener include saccharin sodium, dipotassium glycyrrhizin, aspartame, stevia and thaumatin.
Examples of the fragrances include lemon, lemon lime, orange and menthol.
Examples of the lubricant include magnesium stearate, calcium stearate, sucrose fatty acid ester, polyethylene glycol, talc, stearic acid and the like.
Examples of the colorant include yellow ferric oxide, red ferric oxide, edible yellow No. 4, No. 5, edible red No. 3, No. 102, and edible blue No. 3.
Buffers include citric acid, succinic acid, fumaric acid, tartaric acid, ascorbic acid or salts thereof, glutamic acid, glutamine, glycine, aspartic acid, alanine, arginine or salts thereof, magnesium oxide, zinc oxide, magnesium hydroxide, phosphoric acid Boric acid or a salt thereof.
Examples of the antioxidant include ascorbic acid, dibutylhydroxytoluene, propyl gallate and the like.
Examples of the surfactant includepolysorbate 80, sodium lauryl sulfate, polyoxyethylene hydrogenated castor oil, and the like. As the pharmaceutical excipient, one or a combination of two or more can be added as appropriate.
The compounding amount of these various pharmaceutical excipients is, for example, 1% by weight or more and 100% by weight or less with respect to the drug-containing particles, and in another aspect, 5% by weight or more and 80% by weight or less, and 10% as a further aspect. % By weight to 50% by weight.
崩壊剤としては、例えばトウモロコシデンプン、バレイショデンプン、カルメロースカルシウム、カルメロースナトリウムなどが挙げられる。
酸味料としては、例えばクエン酸、酒石酸、リンゴ酸などが挙げられる。
発泡剤としては、例えば重曹などが挙げられる。
人工甘味料としては、例えばサッカリンナトリウム、グリチルリチン二カリウム、アスパルテーム、ステビア、ソーマチンなどが挙げられる。
香料としては、例えばレモン、レモンライム、オレンジ、メントールなどが挙げられる。
滑沢剤としては、例えばステアリン酸マグネシウム、ステアリン酸カルシウム、ショ糖脂肪酸エステル、ポリエチレングリコール、タルク、ステアリン酸などが挙げられる。
着色剤としては、例えば黄色三二酸化鉄、赤色三二酸化鉄、食用黄色4号、5号、食用赤色3号、102号、食用青色3号などが挙げられる。
緩衝剤としては、クエン酸、コハク酸、フマル酸、酒石酸、アスコルビン酸またはその塩類、グルタミン酸、グルタミン、グリシン、アスパラギン酸、アラニン、アルギニンまたはその塩類、酸化マグネシウム、酸化亜鉛、水酸化マグネシウム、リン酸、ホウ酸またはその塩類などが挙げられる。
抗酸化剤としては、例えばアスコルビン酸、ジブチルヒドロキシトルエン、没食子酸プロピルなどが挙げられる。
界面活性剤としては、例えばポリソルベート80、ラウリル硫酸ナトリウム、ポリオキシエチレン硬化ヒマシ油などが挙げられる。医薬賦形剤としては、1種または2種以上組み合わせて適宜適量添加することができる。
これらの各種医薬賦形剤の配合量は、薬物含有粒子に対して、例えば1重量%以上100重量%以下であり、他の態様として、5重量%以上80重量%以下、更なる態様として10重量%以上50重量%以下である。 Examples of the binder include hypromellose and gum arabic.
Examples of the disintegrant include corn starch, potato starch, carmellose calcium, and carmellose sodium.
Examples of the sour agent include citric acid, tartaric acid, malic acid and the like.
Examples of the foaming agent include baking soda.
Examples of the artificial sweetener include saccharin sodium, dipotassium glycyrrhizin, aspartame, stevia and thaumatin.
Examples of the fragrances include lemon, lemon lime, orange and menthol.
Examples of the lubricant include magnesium stearate, calcium stearate, sucrose fatty acid ester, polyethylene glycol, talc, stearic acid and the like.
Examples of the colorant include yellow ferric oxide, red ferric oxide, edible yellow No. 4, No. 5, edible red No. 3, No. 102, and edible blue No. 3.
Buffers include citric acid, succinic acid, fumaric acid, tartaric acid, ascorbic acid or salts thereof, glutamic acid, glutamine, glycine, aspartic acid, alanine, arginine or salts thereof, magnesium oxide, zinc oxide, magnesium hydroxide, phosphoric acid Boric acid or a salt thereof.
Examples of the antioxidant include ascorbic acid, dibutylhydroxytoluene, propyl gallate and the like.
Examples of the surfactant include
The compounding amount of these various pharmaceutical excipients is, for example, 1% by weight or more and 100% by weight or less with respect to the drug-containing particles, and in another aspect, 5% by weight or more and 80% by weight or less, and 10% as a further aspect. % By weight to 50% by weight.
本発明の経口投与用粒子状医薬組成物において、薬物およびラウリル硫酸ナトリウムを含有する核については、核に対して、アトルバスタチン、ラウリル硫酸ナトリウム、および水溶性高分子を含む被膜物質で被覆することができる。薬物を含有する核としては、薬物のみからなる粒子を用いることもできる。また公知の技術を用いて、薬物と1種または2種以上の添加物からなる粒子を製造し、それを用いてもよい。薬物と添加物からなる粒子の製造は、例えば薬物と適当な賦形剤(例えば微結晶セルロース、乳糖、トウモロコシデンプン等)とを混合し、必要に応じて結合剤(例えば、水溶性高分子:例えば、ヒドロキシプロピルメチルセルロース(別称ヒプロメロース)(TC-5、信越化学)、ヒドロキシプロピルセルロース(日曹HPC、日本曹達株式会社)、特許第3563070号明細書で記載されている塩基性基の10%以上を中和する量の酸性物質を含んでなるメタアクリル酸メチル・メタアクリル酸ブチル・メタアクリル酸ジメチルアミノエチル共重合体[アミノアルキルメタクリレートコポリマーE(商品名;オイドラギットE100、エボニックデグザGmbH社)]、ポビドン(コリドン、BASF)、メチルセルロース(METOLOSE、信越化学)等)を加えて、造粒し、整粒、乾燥してもよい。また適当な核となる添加物粒子[例えば結晶セルロース(粒)、精製白糖球状顆粒、白糖・デンプン球状顆粒等]に薬物と結合剤を溶解または分散した液を噴霧してもよい。これらの粒子に対し、更に、ラウリル硫酸ナトリウム及び水溶性高分子を含む被膜物質で被覆することができる。
In the particulate pharmaceutical composition for oral administration of the present invention, the core containing the drug and sodium lauryl sulfate may be coated with a coating material containing atorvastatin, sodium lauryl sulfate, and a water-soluble polymer. it can. As the drug-containing nucleus, particles made of only a drug can be used. In addition, using a known technique, particles comprising a drug and one or more additives may be produced and used. For the production of particles composed of a drug and an additive, for example, the drug and a suitable excipient (for example, microcrystalline cellulose, lactose, corn starch, etc.) are mixed, and a binder (for example, a water-soluble polymer: For example, hydroxypropyl methylcellulose (also known as hypromellose) (TC-5, Shin-Etsu Chemical), hydroxypropyl cellulose (Nisso HPC, Nippon Soda Co., Ltd.), 10% or more of the basic group described in Japanese Patent No. 3356730 Methyl methacrylate / Butyl methacrylate / Dimethylaminoethyl methacrylate copolymer [aminoalkyl methacrylate copolymer E (trade name; Eudragit E100, Evonik Degussa GmbH) ], Povidone (Kollidon, BASF), methylcellulose (METOLOSE, Shin-Etsu Chemical), etc.) The grains may be dried. Further, a solution in which a drug and a binder are dissolved or dispersed may be sprayed on additive particles [for example, crystalline cellulose (grains), purified white sucrose spherical granules, white sucrose / starch spherical granules, etc.] serving as an appropriate core. These particles can be further coated with a coating material containing sodium lauryl sulfate and a water-soluble polymer.
本発明の経口投与用粒子状医薬組成物において、ポリビニルアセタールジエチルアミノアセテートおよび水溶性高分子物質を含む被膜物質は、薬物を含有する核に直接被覆しても、また1層または2層以上の層を被覆した後に被覆してもよい。1層または2層以上の層を被覆した後に被覆する場合には、例えば、ポリビニルアセタールジエチルアミノアセテートおよび水溶性高分子物質を含む被膜物質と、薬物を含有する核との間に「中間層」を配置させてもよい。「中間層」とは、1種または2種以上の水溶性の不溶化促進剤と、1種または2種以上の水溶性の不溶化物質を含有する被覆層を意味する。中間層は、直接薬物を含有する核に被覆することが可能である。またラグタイム形成及びその後の速やかな薬物放出を妨げない成分を、1層または2層以上の被覆層として、予め薬物を含有する核に被覆した後、中間層を被覆してもよい。中間層は、2種類以上の必須成分(不溶化促進剤及び不溶化物質)を含有するが、これらの複数の必須成分は、1層中に全て含有させて被覆することが可能であり、1層中に均一であってもよく、偏在してあってもよい。また、中間層は、2種類以上の必須成分(不溶化促進剤及び不溶化物質)を2層以上の複数層にそれぞれ分割して被覆することも可能であり、その場合は、成分をどのように分割してもよく、どのような配置にしてもよい。複数層からなる場合でも、複数の必須成分を含有する被覆層をまとめて中間層とよぶ。
In the particulate pharmaceutical composition for oral administration according to the present invention, the coating substance containing polyvinyl acetal diethylaminoacetate and the water-soluble polymer substance may be directly coated on the core containing the drug, or one layer or two or more layers. It may be coated after coating. In the case of coating after coating one layer or two or more layers, for example, an “intermediate layer” is formed between a coating substance containing polyvinyl acetal diethylaminoacetate and a water-soluble polymer substance and a nucleus containing a drug. It may be arranged. The “intermediate layer” means a coating layer containing one or more water-soluble insolubilizers and one or more water-soluble insolubilizers. The intermediate layer can be directly coated on the core containing the drug. Further, the intermediate layer may be coated after the drug-containing core is coated in advance as a coating layer of one layer or two or more components that do not prevent the formation of lag time and subsequent rapid drug release. The intermediate layer contains two or more kinds of essential components (insolubilization accelerator and insolubilizing substance), and these plural essential components can be contained in one layer and covered. May be uniform or unevenly distributed. In addition, the intermediate layer can cover two or more essential components (insolubilization accelerator and insolubilizing substance) by dividing them into two or more layers, and in that case, how to divide the components Any arrangement may be used. Even in the case of a plurality of layers, the coating layers containing a plurality of essential components are collectively referred to as an intermediate layer.
「中間層」に用いられる「不溶化促進剤」としては、製薬学的に許容される水溶性の物質であり、かつ後記「不溶化物質」の不溶化を促す性質を有する物質であれば特に限定されない。具体的には、例えば、「不溶化促進剤」は、第十五改正日本薬局方の通則に記載されている「溶解性」の規定・測定法において、「極めて溶けやすい」、「溶けやすい」、「やや溶けやすい」、「やや溶けにくい」、「溶けにくい」とされる溶解性を有する物質である。
The “insolubilization accelerator” used in the “intermediate layer” is not particularly limited as long as it is a pharmaceutically acceptable water-soluble substance and has a property to promote insolubilization of the “insolubilized substance” described later. Specifically, for example, “insolubilization accelerator” is “extremely soluble”, “easily soluble” in the definition / measurement method of “solubility” described in the general rules of the 15th revision Japanese Pharmacopoeia, It is a substance with solubility that is “slightly soluble”, “slightly difficult to dissolve”, and “hardly soluble”.
更に具体的には、「不溶化促進剤」としては、例えば、炭酸ナトリウム、炭酸カリウム、リン酸二水素ナトリウム、リン酸二カリウム、リン酸水素二ナトリウム、メタリン酸ナトリウム、リン酸三ナトリウム、リン酸二水素カリウム、炭酸水素カリウム、炭酸水素ナトリウム、炭酸アンモニウム、ポリリン酸ナトリウム、ピロリン酸ナトリウム、塩化ナトリウム、塩化カリウム、塩化カルシウム、塩化マグネウム、硫酸ナトリウム、亜硫酸ナトリウム、亜硫酸水素ナトリウム、水酸化ナトリウム、クエン酸ナトリウム、クエン酸二ナトリウム、グルタミン酸ナトリウム、グルタミン酸アルギニン、コハク酸二ナトリウム、酢酸カルシウム、グリシン、アラニン、ソルビトール、キシリトール、イノシトール、白糖、ブドウ糖、果糖又はそれらの水和物などが挙げられる。他の態様としては、炭酸ナトリウム、リン酸二水素ナトリウム、リン酸水素二ナトリウム、メタリン酸ナトリウム、リン酸三ナトリウム、炭酸水素カリウム、炭酸水素ナトリウム、ポリリン酸ナトリウム、ピロリン酸ナトリウム、塩化ナトリウム、塩化カリウム、硫酸ナトリウム、亜硫酸ナトリウム、クエン酸ナトリウム、クエン酸二ナトリウム、グルタミン酸ナトリウム、コハク酸二ナトリウム、グリシン、アラニン、ソルビトール、キシリトール、イノシトール、白糖、ブドウ糖、若しくは果糖又はそれらの水和物、更なる態様としては炭酸ナトリウム、リン酸二水素ナトリウム、リン酸水素二ナトリウム、クエン酸ナトリウム、クエン酸二ナトリウム又はそれらの水和物が挙げられる。不溶化促進剤は1種または2種以上を適宜組み合わせて使用することができる。
More specifically, examples of the “insolubilization accelerator” include sodium carbonate, potassium carbonate, sodium dihydrogen phosphate, dipotassium phosphate, disodium hydrogen phosphate, sodium metaphosphate, trisodium phosphate, and phosphoric acid. Potassium dihydrogen, potassium bicarbonate, sodium bicarbonate, ammonium carbonate, sodium polyphosphate, sodium pyrophosphate, sodium chloride, potassium chloride, calcium chloride, magnesium chloride, sodium sulfate, sodium sulfite, sodium hydrogen sulfite, sodium hydroxide, citric acid Sodium acetate, disodium citrate, sodium glutamate, arginine glutamate, disodium succinate, calcium acetate, glycine, alanine, sorbitol, xylitol, inositol, sucrose, glucose, fructose or it Such as hydrates, and the like. Other embodiments include sodium carbonate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium metaphosphate, trisodium phosphate, potassium bicarbonate, sodium bicarbonate, sodium polyphosphate, sodium pyrophosphate, sodium chloride, chloride Potassium, sodium sulfate, sodium sulfite, sodium citrate, disodium citrate, sodium glutamate, disodium succinate, glycine, alanine, sorbitol, xylitol, inositol, sucrose, glucose, or fructose or their hydrates, further Embodiments include sodium carbonate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium citrate, disodium citrate or hydrates thereof. One or two or more insolubilizers can be used in appropriate combination.
「中間層」に用いられる「不溶化物質」としては、製薬学的に許容される水溶性の物質であり、かつ前記「不溶化促進剤」により不溶化が促される物質であれば特に限定されない。具体的には、例えば、第十五改正日本薬局方の通則に記載されている「溶解性」の規定・測定法において、「極めて溶けやすい」、「溶けやすい」、「やや溶けやすい」、「やや溶けにくい」、「溶けにくい」とされる溶解性を有する物質である。
The “insolubilizing substance” used in the “intermediate layer” is not particularly limited as long as it is a pharmaceutically acceptable water-soluble substance and insolubilized by the “insolubilization accelerator”. Specifically, for example, in the provisions and measurement methods for “solubility” described in the 15th revised Japanese Pharmacopoeia General Rules, “very soluble”, “easy to dissolve”, “slightly soluble”, “ It is a substance with solubility that is said to be “slightly insoluble” or “hard to dissolve”.
更に具体的には、「不溶化物質」としては、例えば、ヒプロメロース、ヒドロキシプロピルセルロース、メチルセルロース、ポリビニルアルコール-ポリエチレングリコール移植片コポリマー、カルボキシビニルポリマー、ポリビニルアルコール、ポリエチレンオキサイド、ポビドン、コポリビドン、ポリオキシエチレン硬化ヒマシ油、N-イソプロピルアクリルアミド及びアクリルアミドのN位に疎水性を有する基を導入した誘導体を含む高分子、ポリオキシエチレン-ポリオキシプロピレングリコール、マクロゴール(分子量6000以上)、ヒドロキシエチルセルロースなどが挙げられる。他の態様としては、ヒプロメロース、ヒドロキシプロピルセルロース、メチルセルロース、ポリビニルアルコール-ポリエチレングリコール移植片コポリマー、カルボキシビニルポリマー、ポリビニルアルコール、ポリエチレンオキサイド、ポビドン、コポリビドン、ポリオキシエチレン硬化ヒマシ油、N-イソプロピルアクリルアミド及びアクリルアミドのN位に疎水性を有する基を導入した誘導体を含む高分子又はポリオキシエチレン-ポリオキシプロピレングリコール、更なる態様としては、ヒプロメロース、メチルセルロース、ポリビニルアルコール-ポリエチレングリコール移植片コポリマー、N-イソプロピルアクリルアミド及びアクリルアミドのN位に疎水性を有する基を導入した誘導体を含む高分子が挙げられる。不溶化物質は1種または2種以上を適宜組み合わせて使用することができる。
More specifically, examples of the “insolubilizing substance” include hypromellose, hydroxypropylcellulose, methylcellulose, polyvinyl alcohol-polyethylene glycol graft copolymer, carboxyvinyl polymer, polyvinyl alcohol, polyethylene oxide, povidone, copolyvidone, polyoxyethylene cured Castor oil, N-isopropylacrylamide, and polymers containing a hydrophobic group introduced at the N-position of acrylamide, polyoxyethylene-polyoxypropylene glycol, macrogol (molecular weight 6000 or more), hydroxyethyl cellulose, etc. . Other embodiments include hypromellose, hydroxypropylcellulose, methylcellulose, polyvinyl alcohol-polyethylene glycol graft copolymer, carboxyvinyl polymer, polyvinyl alcohol, polyethylene oxide, povidone, copolyvidone, polyoxyethylene hydrogenated castor oil, N-isopropylacrylamide and acrylamide A polymer or a polyoxyethylene-polyoxypropylene glycol containing a derivative having a hydrophobic group introduced at the N-position thereof, and as further embodiments, hypromellose, methylcellulose, polyvinyl alcohol-polyethylene glycol graft copolymer, N-isopropylacrylamide And a polymer containing a derivative having a hydrophobic group introduced at the N-position of acrylamide. One or more insolubilizing substances can be used in appropriate combination.
中間層の重量に対する不溶化促進剤の比率としては、本発明の目的を達成するのに適した比率であれば特に限定されない。具体的には、例えば、20重量%以上95重量%未満であり、他の態様としては30重量%以上90重量%未満、更に他の態様としては40重量%以上80重量%未満が挙げられる。
The ratio of the insolubilization accelerator to the weight of the intermediate layer is not particularly limited as long as it is a ratio suitable for achieving the object of the present invention. Specifically, for example, the content is 20% by weight or more and less than 95% by weight, as another aspect, 30% by weight or more and less than 90% by weight, and as another aspect, 40% by weight or more and less than 80% by weight.
中間層の被覆量については、本発明の目的を達成するのに適した量であれば特に限定されない。具体的には、例えば、薬物を含有する核粒子に対して、1重量%以上500重量%以下である。他の態様としては1重量%以上300重量%以下であり、更に他の態様としては、20重量%以上200重量%以下、更にまた他の態様としては30重量%以上100重量%以下である。被覆量が1重量%より低い場合には、十分な長さのラグタイムを形成することができないことが懸念される。また製造における効率性を考慮すると、被覆量が多すぎる場合には製造時間が長く、非効率である。また粒子状組成物の全体の重量に対する中間層の割合は、本発明の目的を達成するのに適した割合であれば特に限定されない。具体的には、例えば、0.1重量%以上95重量%以下、他の態様としては1重量%以上85重量%以下、更に他の態様としては3重量%以上80重量%以下、5重量%以上70重量%以下、更にまた他の態様としては10重量%以上60重量%以下である。
The coating amount of the intermediate layer is not particularly limited as long as it is an amount suitable for achieving the object of the present invention. Specifically, for example, the content is 1% by weight or more and 500% by weight or less with respect to the core particles containing the drug. In another embodiment, it is 1% by weight or more and 300% by weight or less. In still another embodiment, it is 20% by weight or more and 200% by weight or less, and in another embodiment, it is 30% by weight or more and 100% by weight or less. When the coating amount is lower than 1% by weight, there is a concern that a sufficiently long lag time cannot be formed. Considering the efficiency in production, if the coating amount is too large, the production time is long and inefficient. In addition, the ratio of the intermediate layer to the total weight of the particulate composition is not particularly limited as long as it is a ratio suitable for achieving the object of the present invention. Specifically, for example, 0.1 wt% or more and 95 wt% or less, as another embodiment, 1 wt% or more and 85 wt% or less, and as another embodiment, 3 wt% or more and 80 wt% or less, 5 wt% More than 70% by weight, and still another embodiment is 10% by weight to 60% by weight.
本発明の粒子状医薬組成物には、ポリビニルアセタールジエチルアミノアセテートおよび水溶性高分子物質を含む被覆層の外側に、上記医薬賦形剤を更にコーティングする態様も採用することができる。コーティングする添加剤としては、例えば、グリシンやアラニンなどのアミノ酸、グリチルリチン酸などの甘味剤、白糖や果糖やマルトースやブドウ糖やシクロデキストリンなどの糖、マンニトールやキシリトールやマルチトールやソルビトールなどの糖アルコールなどが挙げられる。医薬賦形剤からなる前記被覆層(外層)には1種または2種以上の医薬賦形剤を適宜適量添加することができる。
In the particulate pharmaceutical composition of the present invention, an embodiment in which the above-mentioned pharmaceutical excipient is further coated on the outside of the coating layer containing polyvinyl acetal diethylaminoacetate and a water-soluble polymer substance can be employed. Examples of coating additives include amino acids such as glycine and alanine, sweeteners such as glycyrrhizic acid, sugars such as sucrose, fructose, maltose, glucose, and cyclodextrin, and sugar alcohols such as mannitol, xylitol, maltitol, and sorbitol. Is mentioned. An appropriate amount of one or more kinds of pharmaceutical excipients can be appropriately added to the coating layer (outer layer) made of the pharmaceutical excipient.
前記外層の被覆量は、薬物含有粒子に対して、例えば1重量%以上200重量%以下、他の態様として1重量%以上100重量%以下、更なる態様として5重量%以上40重量%以下である。また、粒子状組成物の全体の重量に対する外層の割合は、例えば1重量%以上50重量%以下、他の態様として1重量%以上25重量%以下、更なる態様として5重量%以上10重量%以下である。
The coating amount of the outer layer is, for example, 1% by weight or more and 200% by weight or less with respect to the drug-containing particles, in another aspect, 1% by weight or more and 100% by weight or less, and in a further aspect, 5% by weight or more and 40% by weight or less. is there. The ratio of the outer layer to the total weight of the particulate composition is, for example, 1% by weight or more and 50% by weight or less, in another embodiment 1% by weight or more and 25% by weight or less, and in a further embodiment 5% by weight or more and 10% by weight or less. It is as follows.
以下に本発明の粒子状医薬組成物の製造法を説明するが、これらは本発明を限定するものではない。
本発明の粒子状医薬組成物は、例えば、コーティング、乾燥、熱処理、打錠等、自体公知の方法により製造可能である。
本発明の粒子状医薬組成物を得るには、薬物を含有する核に対して本発明における被膜物質を被覆する。薬物を含有する核としては、薬物のみからなる粒子を用いることもできる。また公知の技術を用いて、薬物と1種または2種以上の添加物からなる粒子を製造し、それを用いてもよい。薬物と添加物からなる粒子の製造は、例えば薬物と適当な賦形剤(例えば結晶セルロース、乳糖、トウモロコシデンプン等)とを混合し、必要に応じて結合剤(例えばヒドロキシプロピルセルロース等)を加えて、造粒し、整粒、乾燥してもよい。また適当な核となる添加物粒子(例えば結晶セルロース(粒)(微結晶セルロースとして記載している場合がある)、精製白糖球状顆粒、白糖・デンプン球状顆粒等)に薬物と結合剤を溶解または分散した液を噴霧してもよい。 Although the manufacturing method of the particulate pharmaceutical composition of this invention is demonstrated below, these do not limit this invention.
The particulate pharmaceutical composition of the present invention can be produced by a method known per se, such as coating, drying, heat treatment, tableting and the like.
In order to obtain the particulate pharmaceutical composition of the present invention, the core containing the drug is coated with the coating substance of the present invention. As the drug-containing nucleus, particles made of only a drug can be used. In addition, using a known technique, particles comprising a drug and one or more additives may be produced and used. For the production of particles consisting of a drug and an additive, for example, the drug and an appropriate excipient (for example, crystalline cellulose, lactose, corn starch, etc.) are mixed, and a binder (for example, hydroxypropyl cellulose) is added as necessary. Then, it may be granulated, sized and dried. In addition, the drug and the binder are dissolved in additive particles (for example, crystalline cellulose (granule) (may be described as microcrystalline cellulose), purified white sucrose spherical granules, white sucrose / starch spherical granules, etc.) that serve as an appropriate core. The dispersed liquid may be sprayed.
本発明の粒子状医薬組成物は、例えば、コーティング、乾燥、熱処理、打錠等、自体公知の方法により製造可能である。
本発明の粒子状医薬組成物を得るには、薬物を含有する核に対して本発明における被膜物質を被覆する。薬物を含有する核としては、薬物のみからなる粒子を用いることもできる。また公知の技術を用いて、薬物と1種または2種以上の添加物からなる粒子を製造し、それを用いてもよい。薬物と添加物からなる粒子の製造は、例えば薬物と適当な賦形剤(例えば結晶セルロース、乳糖、トウモロコシデンプン等)とを混合し、必要に応じて結合剤(例えばヒドロキシプロピルセルロース等)を加えて、造粒し、整粒、乾燥してもよい。また適当な核となる添加物粒子(例えば結晶セルロース(粒)(微結晶セルロースとして記載している場合がある)、精製白糖球状顆粒、白糖・デンプン球状顆粒等)に薬物と結合剤を溶解または分散した液を噴霧してもよい。 Although the manufacturing method of the particulate pharmaceutical composition of this invention is demonstrated below, these do not limit this invention.
The particulate pharmaceutical composition of the present invention can be produced by a method known per se, such as coating, drying, heat treatment, tableting and the like.
In order to obtain the particulate pharmaceutical composition of the present invention, the core containing the drug is coated with the coating substance of the present invention. As the drug-containing nucleus, particles made of only a drug can be used. In addition, using a known technique, particles comprising a drug and one or more additives may be produced and used. For the production of particles consisting of a drug and an additive, for example, the drug and an appropriate excipient (for example, crystalline cellulose, lactose, corn starch, etc.) are mixed, and a binder (for example, hydroxypropyl cellulose) is added as necessary. Then, it may be granulated, sized and dried. In addition, the drug and the binder are dissolved in additive particles (for example, crystalline cellulose (granule) (may be described as microcrystalline cellulose), purified white sucrose spherical granules, white sucrose / starch spherical granules, etc.) that serve as an appropriate core. The dispersed liquid may be sprayed.
薬物を含有する核の外側に、本発明における被膜物質を被覆する方法としては、流動層コーティング装置、転動コーティング装置、遠心転動コーティング装置など、粒子状医薬組成物に被覆することが可能ないずれの方法を用いてもよい。例えば、流動層側方噴霧式コーティング装置中で、薬物を含有する核を温風で流動させながら、スプレーガンにて被覆成分を含有する液を必要量噴霧すればよい。この被膜成分を含有する液は、必須成分を水、エタノール、メタノール等の溶媒に溶解または分散して調製される。またこれらの溶媒を適宜混合し用いることも可能である。
また、薬物を含有する核の外側に中間層を被覆、あるいは本発明の粒子状医薬組成物に更に医薬賦形剤をコーティング後、本発明における被膜物質を被覆してもよい。 As a method of coating the coating substance in the present invention on the outer side of the drug-containing core, it is possible to coat a particulate pharmaceutical composition such as a fluidized bed coating apparatus, a rolling coating apparatus, or a centrifugal rolling coating apparatus. Any method may be used. For example, in a fluidized bed side spray type coating apparatus, a necessary amount of liquid containing a coating component may be sprayed with a spray gun while a core containing a drug is flowed with warm air. The liquid containing the coating component is prepared by dissolving or dispersing essential components in a solvent such as water, ethanol, methanol or the like. Further, these solvents can be appropriately mixed and used.
Alternatively, the intermediate layer may be coated on the outer side of the core containing the drug, or the particulate pharmaceutical composition of the present invention may be further coated with a pharmaceutical excipient and then coated with the coating substance of the present invention.
また、薬物を含有する核の外側に中間層を被覆、あるいは本発明の粒子状医薬組成物に更に医薬賦形剤をコーティング後、本発明における被膜物質を被覆してもよい。 As a method of coating the coating substance in the present invention on the outer side of the drug-containing core, it is possible to coat a particulate pharmaceutical composition such as a fluidized bed coating apparatus, a rolling coating apparatus, or a centrifugal rolling coating apparatus. Any method may be used. For example, in a fluidized bed side spray type coating apparatus, a necessary amount of liquid containing a coating component may be sprayed with a spray gun while a core containing a drug is flowed with warm air. The liquid containing the coating component is prepared by dissolving or dispersing essential components in a solvent such as water, ethanol, methanol or the like. Further, these solvents can be appropriately mixed and used.
Alternatively, the intermediate layer may be coated on the outer side of the core containing the drug, or the particulate pharmaceutical composition of the present invention may be further coated with a pharmaceutical excipient and then coated with the coating substance of the present invention.
薬物を含有する核粒子に対して、中間層を被覆する方法としては、自体公知の方法により製造される。例えば、流動層コーティング装置、転動コーティング装置、遠心転動コーティング装置など、粒子状医薬組成物に被覆することが可能ないずれの方法を用いてもよい。例えば、流動層側方噴霧式コーティング装置中で、薬物を含有する核粒子を温風で流動させながら、スプレーガンにて被覆成分を含有する液を必要量噴霧すればよい。この被覆成分を含有する液は、必須成分を水、エタノール、メタノール等の溶媒に溶解または分散して調製される。またこれらの溶媒を適宜混合し用いることも可能である。
As a method for coating the intermediate layer on the core particles containing the drug, it is produced by a method known per se. For example, any method capable of coating the particulate pharmaceutical composition, such as a fluidized bed coating apparatus, a rolling coating apparatus, or a centrifugal rolling coating apparatus, may be used. For example, in a fluidized bed side spray type coating apparatus, a necessary amount of a liquid containing a coating component may be sprayed with a spray gun while flowing the core particles containing the drug with warm air. The liquid containing the coating component is prepared by dissolving or dispersing essential components in a solvent such as water, ethanol, methanol or the like. Further, these solvents can be appropriately mixed and used.
好ましいコーティングの噴霧速度は、製造方法または製造するスケールにより異なるが、流動層造粒法により1kgスケールで製造するとき、2g/min以上8g/min以下であり、他の態様として、5g/min以上7g/min以下である。
薬物を含有する核に対して、中間層あるいは水浸入量制御層を被覆する際の好ましい品温は15℃以上60℃以下であり、他の態様として15℃以上45℃以下である。
薬物含有粒子に被覆した粒子状医薬組成物は、乾燥、熱処理などを施しても良い。このコーティング膜は、調温調湿により処理することもできる。例えば、温度は40~80℃であり、湿度は10~60RH%であることができる。 The preferred spraying speed of the coating varies depending on the production method or the scale to be produced, but when produced on a 1 kg scale by the fluidized bed granulation method, it is 2 g / min or more and 8 g / min or less, and in another embodiment, 5 g / min or more. 7 g / min or less.
A preferable product temperature when the intermediate layer or the water infiltration control layer is coated on the drug-containing core is 15 ° C. or more and 60 ° C. or less, and in another embodiment, 15 ° C. or more and 45 ° C. or less.
The particulate pharmaceutical composition coated with the drug-containing particles may be subjected to drying, heat treatment and the like. This coating film can also be processed by adjusting the temperature and humidity. For example, the temperature can be 40 to 80 ° C. and the humidity can be 10 to 60 RH%.
薬物を含有する核に対して、中間層あるいは水浸入量制御層を被覆する際の好ましい品温は15℃以上60℃以下であり、他の態様として15℃以上45℃以下である。
薬物含有粒子に被覆した粒子状医薬組成物は、乾燥、熱処理などを施しても良い。このコーティング膜は、調温調湿により処理することもできる。例えば、温度は40~80℃であり、湿度は10~60RH%であることができる。 The preferred spraying speed of the coating varies depending on the production method or the scale to be produced, but when produced on a 1 kg scale by the fluidized bed granulation method, it is 2 g / min or more and 8 g / min or less, and in another embodiment, 5 g / min or more. 7 g / min or less.
A preferable product temperature when the intermediate layer or the water infiltration control layer is coated on the drug-containing core is 15 ° C. or more and 60 ° C. or less, and in another embodiment, 15 ° C. or more and 45 ° C. or less.
The particulate pharmaceutical composition coated with the drug-containing particles may be subjected to drying, heat treatment and the like. This coating film can also be processed by adjusting the temperature and humidity. For example, the temperature can be 40 to 80 ° C. and the humidity can be 10 to 60 RH%.
本発明における粒子状医薬組成物の粒径は、最長径が2mm以下であれば特に制限されない。口腔内崩壊錠に含有させる場合に関しては、服用時に砂のようなザラツキ感を不快に感じなければ特に限定されないが、好ましくは平均粒子径は350μm以下に調製される。他の態様として平均粒子径は1μm以上350μm以下であり、更なる態様として20μm以上350μm以下である。
The particle size of the particulate pharmaceutical composition in the present invention is not particularly limited as long as the longest diameter is 2 mm or less. The case where it is contained in the orally disintegrating tablet is not particularly limited as long as it does not give an unpleasant feeling of roughness such as sand when taken, but the average particle diameter is preferably adjusted to 350 μm or less. In another embodiment, the average particle diameter is 1 μm or more and 350 μm or less, and in a further embodiment, it is 20 μm or more and 350 μm or less.
打錠方法としては、薬物含有粒子と適当な添加剤を混合後に圧縮成形し錠剤を得る直接打錠法、薬物含有粒子と添加剤を混合後に結合剤液を噴霧し造粒する湿式造粒や薬物含有粒子と適当な低融点物質を混合後に加温し造粒する溶融造粒などの後に打錠する方法が挙げられる。
打錠装置としては、例えばロータリー打錠機、単発打錠機などが挙げられるが、通常製薬学的に圧縮成形物(好適には錠剤)が製造される方法であれば、装置とも特に限定されない。 As a tableting method, a direct tableting method in which a tablet is obtained by mixing a drug-containing particle and an appropriate additive and then compression-molded, a wet granulation in which a binder liquid is sprayed and granulated after mixing the drug-containing particle and the additive, Examples of the method include tableting after melt granulation in which drug-containing particles and an appropriate low-melting substance are mixed and then heated and granulated.
Examples of the tableting device include a rotary tableting machine and a single-shot tableting machine. However, the tableting device is not particularly limited as long as it is a method for producing a compression-molded product (preferably a tablet) pharmaceutically. .
打錠装置としては、例えばロータリー打錠機、単発打錠機などが挙げられるが、通常製薬学的に圧縮成形物(好適には錠剤)が製造される方法であれば、装置とも特に限定されない。 As a tableting method, a direct tableting method in which a tablet is obtained by mixing a drug-containing particle and an appropriate additive and then compression-molded, a wet granulation in which a binder liquid is sprayed and granulated after mixing the drug-containing particle and the additive, Examples of the method include tableting after melt granulation in which drug-containing particles and an appropriate low-melting substance are mixed and then heated and granulated.
Examples of the tableting device include a rotary tableting machine and a single-shot tableting machine. However, the tableting device is not particularly limited as long as it is a method for producing a compression-molded product (preferably a tablet) pharmaceutically. .
本発明のポリビニルアセタールジエチルアミノアセテートおよび水溶性高分子物質の使用としては、苦味を有する薬物含有粒子に被覆し、圧縮成形後も放出速度の変化を低減する経口投与用粒子状医薬組成物を製造するためのポリビニルアセタールジエチルアミノアセテートおよび水溶性高分子物質の使用であり、発明の詳細な説明については本発明の粒子状医薬組成物の説明を引用する。
As the use of the polyvinyl acetal diethylaminoacetate and the water-soluble polymer substance of the present invention, a granular pharmaceutical composition for oral administration is produced in which drug-containing particles having a bitter taste are coated and the change in release rate is reduced even after compression molding. The use of polyvinyl acetal diethylaminoacetate and a water-soluble polymeric substance for the purpose of this invention is referred to the description of the particulate pharmaceutical composition of the present invention for a detailed description of the invention.
以下に本発明の粒子状医薬組成物を含有する口腔内崩壊錠の製造法を説明する。
一例として国際公開第WO95/20380号パンフレット(米国対応特許第5576014号明細書)に記載された口腔内崩壊錠の場合を挙げると、本発明の粒子状医薬組成物と成形性の低い糖類を混合して、かかる混合物を成形性の高い糖類を結合剤として噴霧して被覆及び/または造粒して、該造粒物を圧縮成形する工程を採用することが出来る。さらに調製した成形物の硬度を高めるために、加湿、乾燥の工程を採用することが出来る。「加湿」は、含まれる糖類の見かけの臨界相対湿度により決定されるが、通常その臨界相対湿度以上に加湿する。例えば、湿度として30RH%以上100RH%以下であり、他の態様として50RH%以上90RH%以下である。このときの温度は15℃以上50℃以下であることが好ましく、他の態様として20℃以上40℃以下である。処理時間は1時間以上36時間以下であり、他の態様として12時間以上24時間以下である。「乾燥」は、加湿により吸収した水分を除去する工程であれば特に限定されない。例えば乾燥の温度条件として、10℃以上100℃以下を設定でき、他の態様として20℃以上60℃以下、更なる態様として25℃以上40℃以下を設定することができる。処理時間は、0.5時間以上6時間以下とすることができ、他の態様として1時間以上4時間以下とすることができる。 The manufacturing method of the orally disintegrating tablet containing the particulate pharmaceutical composition of the present invention will be described below.
As an example, in the case of an orally disintegrating tablet described in the pamphlet of International Publication No. WO95 / 20380 (US Patent No. 5576014), the particulate pharmaceutical composition of the present invention and a saccharide having low moldability are mixed. Then, it is possible to employ a step of compressing and molding the granulated product by spraying the mixture with a highly moldable saccharide as a binder and coating and / or granulating the mixture. Furthermore, in order to increase the hardness of the prepared molded product, humidification and drying processes can be employed. “Humidification” is determined by the apparent critical relative humidity of the saccharides contained, but usually humidifies above its critical relative humidity. For example, the humidity is 30 RH% or more and 100 RH% or less, and in another aspect, it is 50 RH% or more and 90 RH% or less. The temperature at this time is preferably 15 ° C. or more and 50 ° C. or less, and in another embodiment, it is 20 ° C. or more and 40 ° C. or less. The treatment time is 1 hour or more and 36 hours or less, and in another aspect, it is 12 hours or more and 24 hours or less. “Drying” is not particularly limited as long as it is a step of removing moisture absorbed by humidification. For example, the drying temperature condition can be set to 10 ° C. or more and 100 ° C. or less, and in another embodiment, 20 ° C. or more and 60 ° C. or less can be set. The treatment time can be 0.5 hours or more and 6 hours or less, and in another aspect, it can be 1 hour or more and 4 hours or less.
一例として国際公開第WO95/20380号パンフレット(米国対応特許第5576014号明細書)に記載された口腔内崩壊錠の場合を挙げると、本発明の粒子状医薬組成物と成形性の低い糖類を混合して、かかる混合物を成形性の高い糖類を結合剤として噴霧して被覆及び/または造粒して、該造粒物を圧縮成形する工程を採用することが出来る。さらに調製した成形物の硬度を高めるために、加湿、乾燥の工程を採用することが出来る。「加湿」は、含まれる糖類の見かけの臨界相対湿度により決定されるが、通常その臨界相対湿度以上に加湿する。例えば、湿度として30RH%以上100RH%以下であり、他の態様として50RH%以上90RH%以下である。このときの温度は15℃以上50℃以下であることが好ましく、他の態様として20℃以上40℃以下である。処理時間は1時間以上36時間以下であり、他の態様として12時間以上24時間以下である。「乾燥」は、加湿により吸収した水分を除去する工程であれば特に限定されない。例えば乾燥の温度条件として、10℃以上100℃以下を設定でき、他の態様として20℃以上60℃以下、更なる態様として25℃以上40℃以下を設定することができる。処理時間は、0.5時間以上6時間以下とすることができ、他の態様として1時間以上4時間以下とすることができる。 The manufacturing method of the orally disintegrating tablet containing the particulate pharmaceutical composition of the present invention will be described below.
As an example, in the case of an orally disintegrating tablet described in the pamphlet of International Publication No. WO95 / 20380 (US Patent No. 5576014), the particulate pharmaceutical composition of the present invention and a saccharide having low moldability are mixed. Then, it is possible to employ a step of compressing and molding the granulated product by spraying the mixture with a highly moldable saccharide as a binder and coating and / or granulating the mixture. Furthermore, in order to increase the hardness of the prepared molded product, humidification and drying processes can be employed. “Humidification” is determined by the apparent critical relative humidity of the saccharides contained, but usually humidifies above its critical relative humidity. For example, the humidity is 30 RH% or more and 100 RH% or less, and in another aspect, it is 50 RH% or more and 90 RH% or less. The temperature at this time is preferably 15 ° C. or more and 50 ° C. or less, and in another embodiment, it is 20 ° C. or more and 40 ° C. or less. The treatment time is 1 hour or more and 36 hours or less, and in another aspect, it is 12 hours or more and 24 hours or less. “Drying” is not particularly limited as long as it is a step of removing moisture absorbed by humidification. For example, the drying temperature condition can be set to 10 ° C. or more and 100 ° C. or less, and in another embodiment, 20 ° C. or more and 60 ° C. or less can be set. The treatment time can be 0.5 hours or more and 6 hours or less, and in another aspect, it can be 1 hour or more and 4 hours or less.
加えて一例として国際公開第WO2002/92057号パンフレット(米国対応特許出願公開第2003/099701号明細書)に記載された口腔内崩壊錠の場合を挙げると、本発明の粒子状医薬組成物、融点の高い賦形剤、融点の低い糖類を混合して、かかる混合物を口腔内崩壊錠用結合剤で噴霧して被覆及び/または造粒して、該造粒物を圧縮成形することも出来る。融点の高い賦形剤と低い糖類を組み合わせる場合、調製した成形物の硬度を高めるために、加熱の工程を採用することも出来る。「加熱」は、含まれる融点の低い糖類の融点により決定されるが、通常低い糖類の融点以上で高い賦形剤の融点未満の温度に加熱する。処理時間は、0.5分以上120分以下とすることが出来、他の態様として1分以上60分以下とすることができる。
In addition, as an example, in the case of an orally disintegrating tablet described in International Publication No. WO2002 / 92057 pamphlet (US patent application publication No. 2003/099701 specification), the particulate pharmaceutical composition of the present invention, melting point A high-excipient excipient and a saccharide with a low melting point are mixed, and the mixture is sprayed with a binder for orally disintegrating tablets to coat and / or granulate, and the granulated product can be compression-molded. When combining an excipient with a high melting point and a saccharide with a low melting point, a heating step can be employed to increase the hardness of the prepared molded product. “Heating” is determined by the melting point of the saccharide having a low melting point, and is usually heated to a temperature not lower than the melting point of the low saccharide and lower than the melting point of the high excipient. The treatment time can be 0.5 minutes or more and 120 minutes or less, and in another aspect, it can be 1 minute or more and 60 minutes or less.
以下、実施例によって本発明を具体的に説明するが、これらは本発明の範囲を限定するものではない。また、各層に番号をつけているが、この番号は本発明を制限するものではない。
Hereinafter, the present invention will be specifically described by way of examples, but these do not limit the scope of the present invention. Each layer is numbered, but this number does not limit the present invention.
参考例:
アトルバスタチンカルシウム三水和物は、日本特許第3296564号明細書(WO97/03959)の実施例に従って製造された結晶性形態Iのアトルバスタチンを用いた。 Reference example:
As atorvastatin calcium trihydrate, crystalline Form I atorvastatin produced according to the example of Japanese Patent No. 3296564 (WO97 / 03959) was used.
アトルバスタチンカルシウム三水和物は、日本特許第3296564号明細書(WO97/03959)の実施例に従って製造された結晶性形態Iのアトルバスタチンを用いた。 Reference example:
As atorvastatin calcium trihydrate, crystalline Form I atorvastatin produced according to the example of Japanese Patent No. 3296564 (WO97 / 03959) was used.
(1)第1層の調製
ラウリル硫酸ナトリウム(日光ケミカルズ社製、製品名ニッコールSLS、以下同じ)3.25kgおよびヒプロメロース(HPMC)(信越化学工業社製、製品名TC-5E、以下記載の無い場合同じ)2.17kgを精製水43.36kgに溶解した液に、アトルバスタチンカルシウム三水和物(ファイザー社製、以下同じ)5.42kgを攪拌下添加し、分散液を調製した。調製した分散液を、流動層造粒装置を用いて、結晶セルロース(粒)(旭化成ケミカルズ社製;製品名CP-102Y、以下同じ)5.42kgに噴霧し、第1層を被覆した粒子を調製した。 (1) Preparation of the first layer Sodium lauryl sulfate (product of Nikko Chemicals, product name Nikkor SLS, hereinafter the same) 3.25 kg and hypromellose (HPMC) (product of Shin-Etsu Chemical Co., product name TC-5E, unless otherwise specified) The same) 5.42 kg of atorvastatin calcium trihydrate (manufactured by Pfizer Inc., the same hereinafter) was added to a solution obtained by dissolving 2.17 kg in 43.36 kg of purified water to prepare a dispersion. Using a fluidized bed granulator, the prepared dispersion is sprayed onto 5.42 kg of crystalline cellulose (grain) (Asahi Kasei Chemicals, product name CP-102Y, the same shall apply hereinafter) to prepare particles covering the first layer. did.
ラウリル硫酸ナトリウム(日光ケミカルズ社製、製品名ニッコールSLS、以下同じ)3.25kgおよびヒプロメロース(HPMC)(信越化学工業社製、製品名TC-5E、以下記載の無い場合同じ)2.17kgを精製水43.36kgに溶解した液に、アトルバスタチンカルシウム三水和物(ファイザー社製、以下同じ)5.42kgを攪拌下添加し、分散液を調製した。調製した分散液を、流動層造粒装置を用いて、結晶セルロース(粒)(旭化成ケミカルズ社製;製品名CP-102Y、以下同じ)5.42kgに噴霧し、第1層を被覆した粒子を調製した。 (1) Preparation of the first layer Sodium lauryl sulfate (product of Nikko Chemicals, product name Nikkor SLS, hereinafter the same) 3.25 kg and hypromellose (HPMC) (product of Shin-Etsu Chemical Co., product name TC-5E, unless otherwise specified) The same) 5.42 kg of atorvastatin calcium trihydrate (manufactured by Pfizer Inc., the same hereinafter) was added to a solution obtained by dissolving 2.17 kg in 43.36 kg of purified water to prepare a dispersion. Using a fluidized bed granulator, the prepared dispersion is sprayed onto 5.42 kg of crystalline cellulose (grain) (Asahi Kasei Chemicals, product name CP-102Y, the same shall apply hereinafter) to prepare particles covering the first layer. did.
(2)第2層の調製
第1層を被覆した粒子7.8kgに対し、クエン酸ナトリウム二水和物(和光純薬社製、以下同じ)1.33kgおよびメチルセルロース(信越化学工業社製、製品名 SM-4、以下同じ)1.17kgを精製水30.96kgに溶解した液を、流動層造粒装置を用いて噴霧し、第2層を被覆した粒子を調製した。 (2) Preparation of the second layer For 7.8 kg of particles coated with the first layer, 1.33 kg of sodium citrate dihydrate (manufactured by Wako Pure Chemical Industries, the same shall apply hereinafter) and methylcellulose (manufactured by Shin-Etsu Chemical Co., Ltd., product name) A solution in which 1.17 kg of SM-4 (same below) was dissolved in 30.96 kg of purified water was sprayed using a fluidized bed granulator to prepare particles coated with the second layer.
第1層を被覆した粒子7.8kgに対し、クエン酸ナトリウム二水和物(和光純薬社製、以下同じ)1.33kgおよびメチルセルロース(信越化学工業社製、製品名 SM-4、以下同じ)1.17kgを精製水30.96kgに溶解した液を、流動層造粒装置を用いて噴霧し、第2層を被覆した粒子を調製した。 (2) Preparation of the second layer For 7.8 kg of particles coated with the first layer, 1.33 kg of sodium citrate dihydrate (manufactured by Wako Pure Chemical Industries, the same shall apply hereinafter) and methylcellulose (manufactured by Shin-Etsu Chemical Co., Ltd., product name) A solution in which 1.17 kg of SM-4 (same below) was dissolved in 30.96 kg of purified water was sprayed using a fluidized bed granulator to prepare particles coated with the second layer.
(3)第3層の調製
第2層を被覆した粒子600.0gに対して、メチルセルロース30.0gを精製水720.0gに溶解した液を、流動層造粒装置を用いて噴霧し、第3層を被覆した粒子を調製した。 (3) Preparation of third layer For 600.0 g of particles coated with the second layer, a solution obtained by dissolving 30.0 g of methylcellulose in 720.0 g of purified water is sprayed using a fluidized bed granulator, and the third layer is sprayed. Coated particles were prepared.
第2層を被覆した粒子600.0gに対して、メチルセルロース30.0gを精製水720.0gに溶解した液を、流動層造粒装置を用いて噴霧し、第3層を被覆した粒子を調製した。 (3) Preparation of third layer For 600.0 g of particles coated with the second layer, a solution obtained by dissolving 30.0 g of methylcellulose in 720.0 g of purified water is sprayed using a fluidized bed granulator, and the third layer is sprayed. Coated particles were prepared.
(4)第4層の調製
ヒプロメロース7.5gを精製水342.0gに溶解した液にメタノール1368.0gを添加・混合し、ヒプロメロース液(水・アルコール混液)を調製した。このヒプロメロース液に、続いてポリビニルアセタールジエチルアミノアセテート(AEA)(三菱化学フーズ製、製品名AEA、以下同じ)52.5gを添加し溶解させ、タルク(松村産業社製、製品名ハイフィラー、以下同じ)30.0gを添加し分散させた。この分散液を、流動層造粒装置を用いて、第3層を被覆した粒子300.0gに対して噴霧し、本発明の粒子状医薬組成物(マスキング粒子)を製造した。 (4) Preparation of Fourth Layer 1368.0 g of methanol was added to and mixed with a solution of 7.5 g of hypromellose in 342.0 g of purified water to prepare a hypromellose solution (water / alcohol mixture). To this hypromellose solution, 52.5 g of polyvinyl acetal diethylaminoacetate (AEA) (Mitsubishi Chemical Foods, product name AEA, the same below) is added and dissolved, and talc (Matsumura Sangyo Co., Ltd., product name High Filler, same below) is dissolved. 30.0 g was added and dispersed. This dispersion was sprayed onto 300.0 g of particles coated with the third layer using a fluidized bed granulator to produce a particulate pharmaceutical composition (masking particles) of the present invention.
ヒプロメロース7.5gを精製水342.0gに溶解した液にメタノール1368.0gを添加・混合し、ヒプロメロース液(水・アルコール混液)を調製した。このヒプロメロース液に、続いてポリビニルアセタールジエチルアミノアセテート(AEA)(三菱化学フーズ製、製品名AEA、以下同じ)52.5gを添加し溶解させ、タルク(松村産業社製、製品名ハイフィラー、以下同じ)30.0gを添加し分散させた。この分散液を、流動層造粒装置を用いて、第3層を被覆した粒子300.0gに対して噴霧し、本発明の粒子状医薬組成物(マスキング粒子)を製造した。 (4) Preparation of Fourth Layer 1368.0 g of methanol was added to and mixed with a solution of 7.5 g of hypromellose in 342.0 g of purified water to prepare a hypromellose solution (water / alcohol mixture). To this hypromellose solution, 52.5 g of polyvinyl acetal diethylaminoacetate (AEA) (Mitsubishi Chemical Foods, product name AEA, the same below) is added and dissolved, and talc (Matsumura Sangyo Co., Ltd., product name High Filler, same below) is dissolved. 30.0 g was added and dispersed. This dispersion was sprayed onto 300.0 g of particles coated with the third layer using a fluidized bed granulator to produce a particulate pharmaceutical composition (masking particles) of the present invention.
(5)口腔内崩壊錠の調製
マンニトール(ROQUETTE社製、製品名PEARLITOL 50C)557.8gおよびマルトース(林原商事製、製品名サンマルトS)6.5gの混合物を、流動層造粒装置を用いて、マルトース水溶液(マルトース51.6gを含む)258gで造粒し、口腔内崩壊錠用の造粒物を調製した。この造粒物234.56mgと本発明の粒子状医薬組成物(マスキング粒子)58.6mgとを混合し、この混合物を直径9.5mmの臼に充填した後、オートグラフ(島津製作所製、AGS-20KNG、以下同じ)を用いて、各種圧力(2.0kNおよび3.0kN)で打錠して、本発明の粒子状医薬組成物を含有する口腔内崩壊錠を製造した。 (5) Preparation of orally disintegrating tablets Maltose using a fluidized bed granulator, a mixture of 557.8 g of mannitol (ROQUETTE, product name PEARLITOL 50C) and 6.5 g of maltose (product name: San Malto S, product of Hayashibara Shoji) Granulation was performed with 258 g of an aqueous solution (including 51.6 g of maltose) to prepare a granulated product for orally disintegrating tablets. After mixing this granulated material 234.56 mg and the particulate pharmaceutical composition (masking particles) 58.6 mg of the present invention, and filling this mixture into a 9.5 mm diameter mortar, Autograph (manufactured by Shimadzu Corporation, AGS-20KNG, The same applies hereinafter) and tableting was carried out at various pressures (2.0 kN and 3.0 kN) to produce an orally disintegrating tablet containing the particulate pharmaceutical composition of the present invention.
マンニトール(ROQUETTE社製、製品名PEARLITOL 50C)557.8gおよびマルトース(林原商事製、製品名サンマルトS)6.5gの混合物を、流動層造粒装置を用いて、マルトース水溶液(マルトース51.6gを含む)258gで造粒し、口腔内崩壊錠用の造粒物を調製した。この造粒物234.56mgと本発明の粒子状医薬組成物(マスキング粒子)58.6mgとを混合し、この混合物を直径9.5mmの臼に充填した後、オートグラフ(島津製作所製、AGS-20KNG、以下同じ)を用いて、各種圧力(2.0kNおよび3.0kN)で打錠して、本発明の粒子状医薬組成物を含有する口腔内崩壊錠を製造した。 (5) Preparation of orally disintegrating tablets Maltose using a fluidized bed granulator, a mixture of 557.8 g of mannitol (ROQUETTE, product name PEARLITOL 50C) and 6.5 g of maltose (product name: San Malto S, product of Hayashibara Shoji) Granulation was performed with 258 g of an aqueous solution (including 51.6 g of maltose) to prepare a granulated product for orally disintegrating tablets. After mixing this granulated material 234.56 mg and the particulate pharmaceutical composition (masking particles) 58.6 mg of the present invention, and filling this mixture into a 9.5 mm diameter mortar, Autograph (manufactured by Shimadzu Corporation, AGS-20KNG, The same applies hereinafter) and tableting was carried out at various pressures (2.0 kN and 3.0 kN) to produce an orally disintegrating tablet containing the particulate pharmaceutical composition of the present invention.
(1)第2層の調製
実施例1で調製した第1層を被覆した粒子300.0gに対し、ラウリル硫酸ナトリウム51.3gおよびメチルセルロース45.1gを精製水688.6gに溶解した液を、流動層造粒装置を用いて噴霧し、第2層を被覆した粒子を調製した。 (1) Preparation of second layer Fluidized bed granulation of a solution obtained by dissolving 51.3 g of sodium lauryl sulfate and 45.1 g of methylcellulose in 688.6 g of purified water with respect to 300.0 g of particles coated with the first layer prepared in Example 1 The particles coated with the second layer were prepared by spraying using the apparatus.
実施例1で調製した第1層を被覆した粒子300.0gに対し、ラウリル硫酸ナトリウム51.3gおよびメチルセルロース45.1gを精製水688.6gに溶解した液を、流動層造粒装置を用いて噴霧し、第2層を被覆した粒子を調製した。 (1) Preparation of second layer Fluidized bed granulation of a solution obtained by dissolving 51.3 g of sodium lauryl sulfate and 45.1 g of methylcellulose in 688.6 g of purified water with respect to 300.0 g of particles coated with the first layer prepared in Example 1 The particles coated with the second layer were prepared by spraying using the apparatus.
(2)第3層の調製
第2層を被覆した粒子300.0gに対し、メチルセルロース15.0gを精製水360.0gに溶解した液を、流動層造粒装置を用いて噴霧し、第3層を被覆した粒子を調製した。 (2) Preparation of the third layer For 300.0 g of particles coated with the second layer, a solution obtained by dissolving 15.0 g of methylcellulose in 360.0 g of purified water is sprayed using a fluidized bed granulator to cover the third layer. Particles were prepared.
第2層を被覆した粒子300.0gに対し、メチルセルロース15.0gを精製水360.0gに溶解した液を、流動層造粒装置を用いて噴霧し、第3層を被覆した粒子を調製した。 (2) Preparation of the third layer For 300.0 g of particles coated with the second layer, a solution obtained by dissolving 15.0 g of methylcellulose in 360.0 g of purified water is sprayed using a fluidized bed granulator to cover the third layer. Particles were prepared.
(3)第4層の調製
ヒプロメロース8.1gを精製水456.0gに溶解した液に、メタノール1824.0gを添加・混合し、ヒプロメロース液(水・アルコール混液)を調製した。このヒプロメロース液に、続いてポリビニルアセタールジエチルアミノアセテート71.2gを添加し溶解させ、タルク40.7gを添加し分散させた。この分散液を、流動層造粒装置を用いて第3層を被覆した粒子300.0gに対して噴霧し、本発明の粒子状医薬組成物(マスキング粒子)を製造した。 (3) Preparation of the fourth layer To a solution obtained by dissolving 8.1 g of hypromellose in 456.0 g of purified water, 1824.0 g of methanol was added and mixed to prepare a hypromellose solution (water / alcohol mixture). Subsequently, 71.2 g of polyvinyl acetal diethylaminoacetate was added and dissolved in this hypromellose solution, and 40.7 g of talc was added and dispersed. This dispersion was sprayed onto 300.0 g of particles coated with the third layer using a fluidized bed granulator to produce a particulate pharmaceutical composition (masking particles) of the present invention.
ヒプロメロース8.1gを精製水456.0gに溶解した液に、メタノール1824.0gを添加・混合し、ヒプロメロース液(水・アルコール混液)を調製した。このヒプロメロース液に、続いてポリビニルアセタールジエチルアミノアセテート71.2gを添加し溶解させ、タルク40.7gを添加し分散させた。この分散液を、流動層造粒装置を用いて第3層を被覆した粒子300.0gに対して噴霧し、本発明の粒子状医薬組成物(マスキング粒子)を製造した。 (3) Preparation of the fourth layer To a solution obtained by dissolving 8.1 g of hypromellose in 456.0 g of purified water, 1824.0 g of methanol was added and mixed to prepare a hypromellose solution (water / alcohol mixture). Subsequently, 71.2 g of polyvinyl acetal diethylaminoacetate was added and dissolved in this hypromellose solution, and 40.7 g of talc was added and dispersed. This dispersion was sprayed onto 300.0 g of particles coated with the third layer using a fluidized bed granulator to produce a particulate pharmaceutical composition (masking particles) of the present invention.
(4)口腔内崩壊錠の調製
実施例1で調製した口腔内崩壊錠用の造粒物252.6mgと本発明の粒子状医薬組成物(マスキング粒子)63.2mgとを混合し、この混合物を直径9.5mmの臼に充填した後、オートグラフを用いて、各種圧力(2.0kNおよび3.0kN)で打錠して、本発明の粒子状医薬組成物を含有する口腔内崩壊錠を製造した。 (4) Preparation of orally disintegrating tablet The granulated product 252.6 mg for the orally disintegrating tablet prepared in Example 1 and 63.2 mg of the granular pharmaceutical composition (masking particle) of the present invention were mixed, and the mixture was mixed with a diameter. After filling a 9.5 mm mortar, the tablet was tableted with various pressures (2.0 kN and 3.0 kN) using an autograph to produce an orally disintegrating tablet containing the particulate pharmaceutical composition of the present invention.
実施例1で調製した口腔内崩壊錠用の造粒物252.6mgと本発明の粒子状医薬組成物(マスキング粒子)63.2mgとを混合し、この混合物を直径9.5mmの臼に充填した後、オートグラフを用いて、各種圧力(2.0kNおよび3.0kN)で打錠して、本発明の粒子状医薬組成物を含有する口腔内崩壊錠を製造した。 (4) Preparation of orally disintegrating tablet The granulated product 252.6 mg for the orally disintegrating tablet prepared in Example 1 and 63.2 mg of the granular pharmaceutical composition (masking particle) of the present invention were mixed, and the mixture was mixed with a diameter. After filling a 9.5 mm mortar, the tablet was tableted with various pressures (2.0 kN and 3.0 kN) using an autograph to produce an orally disintegrating tablet containing the particulate pharmaceutical composition of the present invention.
(1)第3層の調製
ヒプロメロース8.1gを精製水456.0gに溶解した液にメタノール1824.0gを添加・混合し、ヒプロメロース液(水・アルコール混液)を調製した。このヒプロメロース液に、続いてポリビニルアセタールジエチルアミノアセテート71.2gを添加し溶解させ、タルク40.7gを添加し分散させた。この分散液を、流動層造粒装置を用いて、実施例1で調製した第2層を被覆した粒子300.0gに対して噴霧し、本発明の粒子状医薬組成物(マスキング粒子)を製造した。 (1) Preparation of the third layer 1824.0 g of methanol was added to and mixed with a solution obtained by dissolving 8.1 g of hypromellose in 456.0 g of purified water to prepare a hypromellose solution (water / alcohol mixture). Subsequently, 71.2 g of polyvinyl acetal diethylaminoacetate was added and dissolved in this hypromellose solution, and 40.7 g of talc was added and dispersed. This dispersion was sprayed onto 300.0 g of particles coated with the second layer prepared in Example 1 using a fluidized bed granulator to produce the particulate pharmaceutical composition (masking particles) of the present invention. .
ヒプロメロース8.1gを精製水456.0gに溶解した液にメタノール1824.0gを添加・混合し、ヒプロメロース液(水・アルコール混液)を調製した。このヒプロメロース液に、続いてポリビニルアセタールジエチルアミノアセテート71.2gを添加し溶解させ、タルク40.7gを添加し分散させた。この分散液を、流動層造粒装置を用いて、実施例1で調製した第2層を被覆した粒子300.0gに対して噴霧し、本発明の粒子状医薬組成物(マスキング粒子)を製造した。 (1) Preparation of the third layer 1824.0 g of methanol was added to and mixed with a solution obtained by dissolving 8.1 g of hypromellose in 456.0 g of purified water to prepare a hypromellose solution (water / alcohol mixture). Subsequently, 71.2 g of polyvinyl acetal diethylaminoacetate was added and dissolved in this hypromellose solution, and 40.7 g of talc was added and dispersed. This dispersion was sprayed onto 300.0 g of particles coated with the second layer prepared in Example 1 using a fluidized bed granulator to produce the particulate pharmaceutical composition (masking particles) of the present invention. .
(2)口腔内崩壊錠の調製
実施例1で調製した口腔内崩壊錠用の造粒物240.6mgと本発明の粒子状医薬組成物(マスキング粒子)60.2mgとを混合し、この混合物を直径9.5mmの臼に充填した後、オートグラフを用いて各種圧力(2.0kNおよび3.0kN)で打錠して、本発明の粒子状医薬組成物を含有する口腔内崩壊錠を製造した。 (2) Preparation of Orally Disintegrating Tablets 240.6 mg of the granulated product for orally disintegrating tablets prepared in Example 1 and 60.2 mg of the granular pharmaceutical composition (masking particles) of the present invention were mixed, and this mixture was mixed with a diameter. After filling a 9.5 mm mortar, the tablet was tableted with various pressures (2.0 kN and 3.0 kN) using an autograph to produce an orally disintegrating tablet containing the particulate pharmaceutical composition of the present invention.
実施例1で調製した口腔内崩壊錠用の造粒物240.6mgと本発明の粒子状医薬組成物(マスキング粒子)60.2mgとを混合し、この混合物を直径9.5mmの臼に充填した後、オートグラフを用いて各種圧力(2.0kNおよび3.0kN)で打錠して、本発明の粒子状医薬組成物を含有する口腔内崩壊錠を製造した。 (2) Preparation of Orally Disintegrating Tablets 240.6 mg of the granulated product for orally disintegrating tablets prepared in Example 1 and 60.2 mg of the granular pharmaceutical composition (masking particles) of the present invention were mixed, and this mixture was mixed with a diameter. After filling a 9.5 mm mortar, the tablet was tableted with various pressures (2.0 kN and 3.0 kN) using an autograph to produce an orally disintegrating tablet containing the particulate pharmaceutical composition of the present invention.
(1)第4層の調製
ヒプロメロース13.1gを精製水741.0gに溶解した液に、メタノール2964.0gを添加・混合し、ヒプロメロース液(水・アルコール混液)を調製した。このヒプロメロース液に、続いてポリビニルアセタールジエチルアミノアセテート141.5gを添加し溶解させ、タルク40.4gを添加し分散させた。この分散液を、流動層造粒装置を用いて、実施例2で調製した第3層を被覆した粒子300.0gに対して噴霧し、第4層を被覆した粒子を製造した。 (1) Preparation of fourth layer 2964.0 g of methanol was added to and mixed with a solution obtained by dissolving 13.1 g of hypromellose in 741.0 g of purified water to prepare a hypromellose solution (water / alcohol mixed solution). Subsequently, 141.5 g of polyvinyl acetal diethylaminoacetate was added and dissolved in this hypromellose solution, and 40.4 g of talc was added and dispersed. This dispersion was sprayed onto 300.0 g of particles coated with the third layer prepared in Example 2 using a fluidized bed granulator to produce particles coated with the fourth layer.
ヒプロメロース13.1gを精製水741.0gに溶解した液に、メタノール2964.0gを添加・混合し、ヒプロメロース液(水・アルコール混液)を調製した。このヒプロメロース液に、続いてポリビニルアセタールジエチルアミノアセテート141.5gを添加し溶解させ、タルク40.4gを添加し分散させた。この分散液を、流動層造粒装置を用いて、実施例2で調製した第3層を被覆した粒子300.0gに対して噴霧し、第4層を被覆した粒子を製造した。 (1) Preparation of fourth layer 2964.0 g of methanol was added to and mixed with a solution obtained by dissolving 13.1 g of hypromellose in 741.0 g of purified water to prepare a hypromellose solution (water / alcohol mixed solution). Subsequently, 141.5 g of polyvinyl acetal diethylaminoacetate was added and dissolved in this hypromellose solution, and 40.4 g of talc was added and dispersed. This dispersion was sprayed onto 300.0 g of particles coated with the third layer prepared in Example 2 using a fluidized bed granulator to produce particles coated with the fourth layer.
(2)第5層の調製
マンニトール15.5gを精製水139.5gに溶解した。このマンニトール溶液を、流動層造粒装置を用いて、第4層を被覆した粒子310.0gに対して噴霧し、本発明の粒子状医薬組成物(マスキング粒子)を製造した。 (2) Preparation of the fifth layer 15.5 g of mannitol was dissolved in 139.5 g of purified water. This mannitol solution was sprayed onto 310.0 g of the particles coated with the fourth layer using a fluidized bed granulator to produce the particulate pharmaceutical composition (masking particles) of the present invention.
マンニトール15.5gを精製水139.5gに溶解した。このマンニトール溶液を、流動層造粒装置を用いて、第4層を被覆した粒子310.0gに対して噴霧し、本発明の粒子状医薬組成物(マスキング粒子)を製造した。 (2) Preparation of the fifth layer 15.5 g of mannitol was dissolved in 139.5 g of purified water. This mannitol solution was sprayed onto 310.0 g of the particles coated with the fourth layer using a fluidized bed granulator to produce the particulate pharmaceutical composition (masking particles) of the present invention.
(3)口腔内崩壊錠の調製
実施例1で調製した口腔内崩壊錠用の造粒物251.0mgと本発明の粒子状医薬組成物(マスキング粒子)62.8mgとを混合し、この混合物を直径9.5mmの臼に充填した後、オートグラフを用いて各種圧力(2.0kNおよび3.0kN)で打錠して、本発明の粒子状医薬組成物を含有する口腔内崩壊錠を製造した。 (3) Preparation of Orally Disintegrating Tablets 251.0 mg of the granulated product for orally disintegrating tablets prepared in Example 1 and 62.8 mg of the granular pharmaceutical composition (masking particles) of the present invention were mixed, and this mixture was mixed with a diameter. After filling a 9.5 mm mortar, the tablet was tableted with various pressures (2.0 kN and 3.0 kN) using an autograph to produce an orally disintegrating tablet containing the particulate pharmaceutical composition of the present invention.
実施例1で調製した口腔内崩壊錠用の造粒物251.0mgと本発明の粒子状医薬組成物(マスキング粒子)62.8mgとを混合し、この混合物を直径9.5mmの臼に充填した後、オートグラフを用いて各種圧力(2.0kNおよび3.0kN)で打錠して、本発明の粒子状医薬組成物を含有する口腔内崩壊錠を製造した。 (3) Preparation of Orally Disintegrating Tablets 251.0 mg of the granulated product for orally disintegrating tablets prepared in Example 1 and 62.8 mg of the granular pharmaceutical composition (masking particles) of the present invention were mixed, and this mixture was mixed with a diameter. After filling a 9.5 mm mortar, the tablet was tableted with various pressures (2.0 kN and 3.0 kN) using an autograph to produce an orally disintegrating tablet containing the particulate pharmaceutical composition of the present invention.
(1)第1層の調製
ラウリル硫酸ナトリウム300.0gおよびヒプロメロース120.0gを精製水2880.0gに溶解した液に、アトルバスタチンカルシウム三水和物300.0gを攪拌下添加し、分散液を調製した。調製した分散液を、流動層造粒装置を用いて、結晶セルロース(粒)300.0gに噴霧し、第1層を被覆した粒子を調製した。 (1) Preparation of the first layer 300.0 g of atorvastatin calcium trihydrate was added with stirring to 300.0 g of sodium lauryl sulfate and 120.0 g of hypromellose in 2880.0 g of purified water to prepare a dispersion. The prepared dispersion was sprayed onto 300.0 g of crystalline cellulose (grains) using a fluidized bed granulator to prepare particles covering the first layer.
ラウリル硫酸ナトリウム300.0gおよびヒプロメロース120.0gを精製水2880.0gに溶解した液に、アトルバスタチンカルシウム三水和物300.0gを攪拌下添加し、分散液を調製した。調製した分散液を、流動層造粒装置を用いて、結晶セルロース(粒)300.0gに噴霧し、第1層を被覆した粒子を調製した。 (1) Preparation of the first layer 300.0 g of atorvastatin calcium trihydrate was added with stirring to 300.0 g of sodium lauryl sulfate and 120.0 g of hypromellose in 2880.0 g of purified water to prepare a dispersion. The prepared dispersion was sprayed onto 300.0 g of crystalline cellulose (grains) using a fluidized bed granulator to prepare particles covering the first layer.
(2)第2層の調製
第1層を被覆した粒子300.0gに対し、ラウリル硫酸ナトリウム64.3gおよびメチルセルロース25.7gを精製水1195.7gに溶解した液を、流動層造粒装置を用いて噴霧し、第2層を被覆した粒子を調製した。 (2) Preparation of the second layer To 300.0 g of particles coated with the first layer, a solution obtained by dissolving 64.3 g of sodium lauryl sulfate and 25.7 g of methylcellulose in 1195.7 g of purified water is sprayed using a fluidized bed granulator. Then, particles coated with the second layer were prepared.
第1層を被覆した粒子300.0gに対し、ラウリル硫酸ナトリウム64.3gおよびメチルセルロース25.7gを精製水1195.7gに溶解した液を、流動層造粒装置を用いて噴霧し、第2層を被覆した粒子を調製した。 (2) Preparation of the second layer To 300.0 g of particles coated with the first layer, a solution obtained by dissolving 64.3 g of sodium lauryl sulfate and 25.7 g of methylcellulose in 1195.7 g of purified water is sprayed using a fluidized bed granulator. Then, particles coated with the second layer were prepared.
(3)第3層の調製
第2層を被覆した粒子300.0gに対して、メチルセルロース15.0gを精製水360.0gに溶解した液を、流動層造粒装置を用いて噴霧し、第3層を被覆した粒子を調製した。 (3) Preparation of third layer For 300.0 g of particles coated with the second layer, a solution obtained by dissolving 15.0 g of methylcellulose in 360.0 g of purified water is sprayed using a fluidized bed granulator, and the third layer is sprayed. Coated particles were prepared.
第2層を被覆した粒子300.0gに対して、メチルセルロース15.0gを精製水360.0gに溶解した液を、流動層造粒装置を用いて噴霧し、第3層を被覆した粒子を調製した。 (3) Preparation of third layer For 300.0 g of particles coated with the second layer, a solution obtained by dissolving 15.0 g of methylcellulose in 360.0 g of purified water is sprayed using a fluidized bed granulator, and the third layer is sprayed. Coated particles were prepared.
(4)第4層の調製
ヒプロメロース8.1gを精製水456.0gに溶解した液にメタノール1824.0gを添加・混合し、ヒプロメロース液(水・アルコール混液)を調製した。このヒプロメロース液に、続いてポリビニルアセタールジエチルアミノアセテート71.2gを添加し溶解させ、タルク40.7gを添加し分散させた。この分散液を、流動層造粒装置を用いて、第3層を被覆した粒子300.0gに対して噴霧し、本発明の粒子状医薬組成物(マスキング粒子)を製造した。 (4) Preparation of the fourth layer 1824.0 g of methanol was added to and mixed with 8.1 g of hypromellose dissolved in 456.0 g of purified water to prepare a hypromellose solution (water / alcohol mixture). Subsequently, 71.2 g of polyvinyl acetal diethylaminoacetate was added and dissolved in this hypromellose solution, and 40.7 g of talc was added and dispersed. This dispersion was sprayed onto 300.0 g of particles coated with the third layer using a fluidized bed granulator to produce a particulate pharmaceutical composition (masking particles) of the present invention.
ヒプロメロース8.1gを精製水456.0gに溶解した液にメタノール1824.0gを添加・混合し、ヒプロメロース液(水・アルコール混液)を調製した。このヒプロメロース液に、続いてポリビニルアセタールジエチルアミノアセテート71.2gを添加し溶解させ、タルク40.7gを添加し分散させた。この分散液を、流動層造粒装置を用いて、第3層を被覆した粒子300.0gに対して噴霧し、本発明の粒子状医薬組成物(マスキング粒子)を製造した。 (4) Preparation of the fourth layer 1824.0 g of methanol was added to and mixed with 8.1 g of hypromellose dissolved in 456.0 g of purified water to prepare a hypromellose solution (water / alcohol mixture). Subsequently, 71.2 g of polyvinyl acetal diethylaminoacetate was added and dissolved in this hypromellose solution, and 40.7 g of talc was added and dispersed. This dispersion was sprayed onto 300.0 g of particles coated with the third layer using a fluidized bed granulator to produce a particulate pharmaceutical composition (masking particles) of the present invention.
(5)口腔内崩壊錠の調製
実施例1で調製した口腔内崩壊錠用の造粒物229.6mgと本発明の粒子状医薬組成物(マスキング粒子)70.4mgとを混合し、この混合物を直径9.5mmの臼に充填した後、オートグラフを用いて各種圧力(2.0kNおよび3.0kN)で打錠して、本発明の粒子状医薬組成物を含有する口腔内崩壊錠を製造する。 (5) Preparation of orally disintegrating tablet 229.6 mg of the granulated product for orally disintegrating tablet prepared in Example 1 and 70.4 mg of the granular pharmaceutical composition (masking particle) of the present invention were mixed, and the mixture was mixed with a diameter. After filling a 9.5 mm mortar, the tablet is tableted at various pressures (2.0 kN and 3.0 kN) using an autograph to produce an orally disintegrating tablet containing the particulate pharmaceutical composition of the present invention.
実施例1で調製した口腔内崩壊錠用の造粒物229.6mgと本発明の粒子状医薬組成物(マスキング粒子)70.4mgとを混合し、この混合物を直径9.5mmの臼に充填した後、オートグラフを用いて各種圧力(2.0kNおよび3.0kN)で打錠して、本発明の粒子状医薬組成物を含有する口腔内崩壊錠を製造する。 (5) Preparation of orally disintegrating tablet 229.6 mg of the granulated product for orally disintegrating tablet prepared in Example 1 and 70.4 mg of the granular pharmaceutical composition (masking particle) of the present invention were mixed, and the mixture was mixed with a diameter. After filling a 9.5 mm mortar, the tablet is tableted at various pressures (2.0 kN and 3.0 kN) using an autograph to produce an orally disintegrating tablet containing the particulate pharmaceutical composition of the present invention.
(1)第4層の調製
ポリビニルアセタールジエチルアミノアセテート57.3gを精製水342.0gおよびメタノール1368.0gの混液に溶解させ、タルク32.7gを添加し分散させた。この分散液を、流動層造粒装置を用いて、実施例1で調製した第3層を被覆した粒子300.0gに対して噴霧し、比較例1の粒子状医薬組成物(マスキング粒子)を製造した。 (1) Preparation of Fourth Layer 57.3 g of polyvinyl acetal diethylaminoacetate was dissolved in a mixed solution of 342.0 g of purified water and 1368.0 g of methanol, and 32.7 g of talc was added and dispersed. This dispersion is sprayed onto 300.0 g of particles coated with the third layer prepared in Example 1 using a fluidized bed granulator to produce a particulate pharmaceutical composition (masking particles) of Comparative Example 1. did.
ポリビニルアセタールジエチルアミノアセテート57.3gを精製水342.0gおよびメタノール1368.0gの混液に溶解させ、タルク32.7gを添加し分散させた。この分散液を、流動層造粒装置を用いて、実施例1で調製した第3層を被覆した粒子300.0gに対して噴霧し、比較例1の粒子状医薬組成物(マスキング粒子)を製造した。 (1) Preparation of Fourth Layer 57.3 g of polyvinyl acetal diethylaminoacetate was dissolved in a mixed solution of 342.0 g of purified water and 1368.0 g of methanol, and 32.7 g of talc was added and dispersed. This dispersion is sprayed onto 300.0 g of particles coated with the third layer prepared in Example 1 using a fluidized bed granulator to produce a particulate pharmaceutical composition (masking particles) of Comparative Example 1. did.
(2)口腔内崩壊錠の調製
実施例1で調製した口腔内崩壊錠用の造粒物234.6mgと比較例1の粒子状医薬組成物(マスキング粒子)58.6mgとを混合し、この混合物を直径9.5mmの臼に充填した後、オートグラフを用いて各種圧力(2.0kNおよび3.0kN)で打錠して、比較例1の粒子状医薬組成物を含有する口腔内崩壊錠を製造した。 (2) Preparation of orally disintegrating tablet 234.6 mg of granulated product for orally disintegrating tablet prepared in Example 1 and 58.6 mg of particulate pharmaceutical composition (masking particle) of Comparative Example 1 were mixed. After filling a 9.5 mm diameter mortar, the tablet was tableted with various pressures (2.0 kN and 3.0 kN) using an autograph to produce an orally disintegrating tablet containing the particulate pharmaceutical composition of Comparative Example 1.
実施例1で調製した口腔内崩壊錠用の造粒物234.6mgと比較例1の粒子状医薬組成物(マスキング粒子)58.6mgとを混合し、この混合物を直径9.5mmの臼に充填した後、オートグラフを用いて各種圧力(2.0kNおよび3.0kN)で打錠して、比較例1の粒子状医薬組成物を含有する口腔内崩壊錠を製造した。 (2) Preparation of orally disintegrating tablet 234.6 mg of granulated product for orally disintegrating tablet prepared in Example 1 and 58.6 mg of particulate pharmaceutical composition (masking particle) of Comparative Example 1 were mixed. After filling a 9.5 mm diameter mortar, the tablet was tableted with various pressures (2.0 kN and 3.0 kN) using an autograph to produce an orally disintegrating tablet containing the particulate pharmaceutical composition of Comparative Example 1.
(1)第3層の調製
ポリソルベート80(Tween 80)(メルク製;製品名Tween 80)2.3gを精製水138.0gに溶解した液をアミノアルキルメタクリレートコポリマー水分散液(エボニックデグザGmbH社製、製品名オイドラギットRS30D)173.0gに添加しオイドラギットRS溶液を調製した。ヒプロメロース5.8gを精製水880.9gに溶解したヒプロメロース液を、上記調製したオイドラギットRS溶液に添加しコート液とした。流動層造粒装置を用いて、実施例1で調製した第2層を被覆した粒子300.0gに対して噴霧し、比較例2の粒子状医薬組成物(マスキング粒子)を製造した。 (1) Preparation of third layer A solution obtained by dissolving 2.3 g of polysorbate 80 (Tween 80) (product of Merck; product name Tween 80) in 138.0 g of purified water was used as an aminoalkyl methacrylate copolymer aqueous dispersion (Evonik Degussa GmbH, Product name Eudragit RS30D) was added to 173.0 g to prepare Eudragit RS solution. A hypromellose solution prepared by dissolving 5.8 g of hypromellose in 880.9 g of purified water was added to the Eudragit RS solution prepared above to prepare a coating solution. Using a fluidized bed granulator, the particles coated with 300.0 g of the second layer prepared in Example 1 were sprayed to produce the particulate pharmaceutical composition (masking particles) of Comparative Example 2.
ポリソルベート80(Tween 80)(メルク製;製品名Tween 80)2.3gを精製水138.0gに溶解した液をアミノアルキルメタクリレートコポリマー水分散液(エボニックデグザGmbH社製、製品名オイドラギットRS30D)173.0gに添加しオイドラギットRS溶液を調製した。ヒプロメロース5.8gを精製水880.9gに溶解したヒプロメロース液を、上記調製したオイドラギットRS溶液に添加しコート液とした。流動層造粒装置を用いて、実施例1で調製した第2層を被覆した粒子300.0gに対して噴霧し、比較例2の粒子状医薬組成物(マスキング粒子)を製造した。 (1) Preparation of third layer A solution obtained by dissolving 2.3 g of polysorbate 80 (Tween 80) (product of Merck; product name Tween 80) in 138.0 g of purified water was used as an aminoalkyl methacrylate copolymer aqueous dispersion (Evonik Degussa GmbH, Product name Eudragit RS30D) was added to 173.0 g to prepare Eudragit RS solution. A hypromellose solution prepared by dissolving 5.8 g of hypromellose in 880.9 g of purified water was added to the Eudragit RS solution prepared above to prepare a coating solution. Using a fluidized bed granulator, the particles coated with 300.0 g of the second layer prepared in Example 1 were sprayed to produce the particulate pharmaceutical composition (masking particles) of Comparative Example 2.
ヒプロメロースアセテートサクシネート(信越化学工業社製、製品名HPMC-AS HF)76.4gを精製水570.0gおよびエタノール2280.0gからなる混液に溶解させ、タルク43.6gを添加し分散させた。この分散液を、流動層造粒装置を用いて、実施例1で調製した第2層を被覆した粒子300.0gに対して噴霧し、比較例3の粒子状医薬組成物(マスキング粒子)を製造した。
76.4 g of hypromellose acetate succinate (manufactured by Shin-Etsu Chemical Co., Ltd., product name HPMC-AS HF) was dissolved in a mixed solution consisting of 570.0 g of purified water and 2280.0 g of ethanol, and 43.6 g of talc was added and dispersed. This dispersion is sprayed onto 300.0 g of particles coated with the second layer prepared in Example 1 using a fluidized bed granulator to produce a particulate pharmaceutical composition (masking particles) of Comparative Example 3. did.
ヒドロキシプロピルセルロース(日本曹達製、製品名HPC-SL)84.0gおよびエチルセルロース(ダウケミカル製、エトセルSTD10)36gをメタノール1080.0gに溶解させ、コート液を調製した。このコート液を、流動層造粒装置を用いて、実施例1で調製した第2層を被覆した粒子300.0gに対して噴霧し、比較例4の粒子状医薬組成物(マスキング粒子)を製造した。
Hydroxylcellulose (manufactured by Nippon Soda Co., Ltd., product name HPC-SL) 84.0 g and ethylcellulose (Dow Chemical Co., Ltd., Etocel STD10) 36 g were dissolved in methanol 1080.0 g to prepare a coating solution. This coating solution is sprayed onto 300.0 g of particles coated with the second layer prepared in Example 1 using a fluidized bed granulator to produce a particulate pharmaceutical composition (masking particles) of Comparative Example 4. did.
実験例1:粒子状医薬組成物および口腔内崩壊錠の溶出試験
実施例1~4または比較例1で調製した粒子状医薬組成物(打錠前マスキング粒子(表中、「0kN」と記載))及びそれらを含有する口腔内崩壊錠(打錠後、表中「2kN」、「3kN」と記載)について自動6連溶出試験機を用いて、日本薬局方溶出試験法第2法に従い溶出試験を行った。薬物含量は10mgとし、試験液は日本薬局方溶出試験第2液(JP2)900mLを用いた(パドル回転数:100回転/分)。
試験の結果得られた溶出プロファイルを図1~図5に示す。また、溶出プロファイルから算出した口腔内崩壊錠のT10%、および打錠前の粒子状医薬組成物のT10%に対する変化率を表9~表13に示す。T10%は溶出率10%までの時間を表し、T10%に対する変化率については以下の式から算出した。
T10%変化率(%)=T10%(打錠後)/T10%(打錠前) Experimental Example 1: Dissolution test of particulate pharmaceutical composition and orally disintegrating tablet Particulate pharmaceutical composition prepared in Examples 1 to 4 or Comparative Example 1 (masking particles before tableting (described as “0 kN” in the table)) And orally disintegrating tablets containing them (after tableting, described as “2 kN” and “3 kN” in the table), using an automatic 6-dissolution tester, perform dissolution test according to Japanese PharmacopoeiaDissolution Test Method 2 went. The drug content was 10 mg, and 900 mL of Japanese Pharmacopoeia dissolution test second liquid (JP2) was used as the test solution (paddle rotation speed: 100 rotations / minute).
The elution profiles obtained as a result of the test are shown in FIGS. Further, T 10% of the oral disintegrating tablet calculated from the elution profile, and the rate of change with respect to T 10% of the particulate pharmaceutical composition of the tableting shown in Tables 9 to 13. T 10% represents the time to elution rate of 10%, and the change rate with respect to T 10% was calculated from the following equation.
T 10% change rate (%) = T 10% (after tableting) / T 10% (before tableting)
実施例1~4または比較例1で調製した粒子状医薬組成物(打錠前マスキング粒子(表中、「0kN」と記載))及びそれらを含有する口腔内崩壊錠(打錠後、表中「2kN」、「3kN」と記載)について自動6連溶出試験機を用いて、日本薬局方溶出試験法第2法に従い溶出試験を行った。薬物含量は10mgとし、試験液は日本薬局方溶出試験第2液(JP2)900mLを用いた(パドル回転数:100回転/分)。
試験の結果得られた溶出プロファイルを図1~図5に示す。また、溶出プロファイルから算出した口腔内崩壊錠のT10%、および打錠前の粒子状医薬組成物のT10%に対する変化率を表9~表13に示す。T10%は溶出率10%までの時間を表し、T10%に対する変化率については以下の式から算出した。
T10%変化率(%)=T10%(打錠後)/T10%(打錠前) Experimental Example 1: Dissolution test of particulate pharmaceutical composition and orally disintegrating tablet Particulate pharmaceutical composition prepared in Examples 1 to 4 or Comparative Example 1 (masking particles before tableting (described as “0 kN” in the table)) And orally disintegrating tablets containing them (after tableting, described as “2 kN” and “3 kN” in the table), using an automatic 6-dissolution tester, perform dissolution test according to Japanese Pharmacopoeia
The elution profiles obtained as a result of the test are shown in FIGS. Further, T 10% of the oral disintegrating tablet calculated from the elution profile, and the rate of change with respect to T 10% of the particulate pharmaceutical composition of the tableting shown in Tables 9 to 13. T 10% represents the time to elution rate of 10%, and the change rate with respect to T 10% was calculated from the following equation.
T 10% change rate (%) = T 10% (after tableting) / T 10% (before tableting)
実験例2:粒子状医薬組成物の溶出試験
比較例2~4並びに実施例3及び5の粒子状医薬組成物(打錠前マスキング粒子)について自動6連溶出試験機を用いて、日本薬局方溶出試験法第2法に従い溶出試験を行った。薬物含量は10mgとし、試験液は水、日本薬局方溶出試験第1液(JP1)、日本薬局方溶出試験第2液(JP2)をそれぞれ900mL用いた(パドル回転数:100回転/分)。試験の結果得られた溶出プロファイルを図6~図10に示す。 Experimental Example 2: Dissolution test of particulate pharmaceutical composition Japanese Pharmacopoeia dissolution of particulate pharmaceutical compositions of Comparative Examples 2 to 4 and Examples 3 and 5 (masking particles before tableting) using an automatic 6-series dissolution tester The dissolution test was performed according to Test Method No. 2. The drug content was 10 mg, and 900 mL each of water, Japanese Pharmacopoeia dissolution test 1st liquid (JP1), and Japanese Pharmacopoeia dissolution test 2nd liquid (JP2) were used (paddle rotation speed: 100 rotations / minute). The elution profiles obtained as a result of the test are shown in FIGS.
比較例2~4並びに実施例3及び5の粒子状医薬組成物(打錠前マスキング粒子)について自動6連溶出試験機を用いて、日本薬局方溶出試験法第2法に従い溶出試験を行った。薬物含量は10mgとし、試験液は水、日本薬局方溶出試験第1液(JP1)、日本薬局方溶出試験第2液(JP2)をそれぞれ900mL用いた(パドル回転数:100回転/分)。試験の結果得られた溶出プロファイルを図6~図10に示す。 Experimental Example 2: Dissolution test of particulate pharmaceutical composition Japanese Pharmacopoeia dissolution of particulate pharmaceutical compositions of Comparative Examples 2 to 4 and Examples 3 and 5 (masking particles before tableting) using an automatic 6-series dissolution tester The dissolution test was performed according to Test Method No. 2. The drug content was 10 mg, and 900 mL each of water, Japanese Pharmacopoeia dissolution test 1st liquid (JP1), and Japanese Pharmacopoeia dissolution test 2nd liquid (JP2) were used (paddle rotation speed: 100 rotations / minute). The elution profiles obtained as a result of the test are shown in FIGS.
比較例2(アミノアルキルメタクリレートコポリマーRS、ヒプロメロース(TC-5E)、ポリソルベート80からなる第3膜を被覆したマスキング粒子)では、JP1での溶出が不十分であった(図6)。
比較例3(ヒプロメロースアセテートサクシネート、タルクからなる第3膜を被覆したマスキング粒子)では、JP1での溶出が不十分であり、さらにラグタイムの長さも不十分であった(図7)。
比較例4(エチルセルロース、ヒドロキシプロピルセルロースからなる第3膜を被覆したマスキング粒子)では、ラグタイムは形成するもののJP1での溶出が不十分であった(図8)。
実施例3(ポリビニルアセタールジエチルアミノアセテート、タルク、ヒプロメロース(TC-5E)からなる第3膜を施したマスキング粒子)では、十分なラグタイムとJP1での高い溶出を達成した(図9)。
実施例5(ラウリル硫酸ナトリウム/ポリビニルアセタールジエチルアミノアセテート=1.57)では、実施例3(ラウリル硫酸ナトリウム/ポリビニルアセタールジエチルアミノアセテート=0.63)に比較してJP1での高い溶出を達成した(図10)。 In Comparative Example 2 (masking particles coated with a third film comprising aminoalkyl methacrylate copolymer RS, hypromellose (TC-5E), polysorbate 80), elution with JP1 was insufficient (FIG. 6).
In Comparative Example 3 (masking particles coated with a third membrane composed of hypromellose acetate succinate and talc), elution with JP1 was insufficient and the length of lag time was also insufficient (FIG. 7). .
In Comparative Example 4 (masking particles coated with a third film composed of ethyl cellulose and hydroxypropyl cellulose), although lag time was formed, elution with JP1 was insufficient (FIG. 8).
In Example 3 (masking particles provided with a third film made of polyvinyl acetal diethylaminoacetate, talc, and hypromellose (TC-5E)), sufficient lag time and high elution with JP1 were achieved (FIG. 9).
In Example 5 (sodium lauryl sulfate / polyvinyl acetal diethylaminoacetate = 1.57), higher elution with JP1 was achieved compared to Example 3 (sodium lauryl sulfate / polyvinyl acetal diethylaminoacetate = 0.63) (FIG. 10).
比較例3(ヒプロメロースアセテートサクシネート、タルクからなる第3膜を被覆したマスキング粒子)では、JP1での溶出が不十分であり、さらにラグタイムの長さも不十分であった(図7)。
比較例4(エチルセルロース、ヒドロキシプロピルセルロースからなる第3膜を被覆したマスキング粒子)では、ラグタイムは形成するもののJP1での溶出が不十分であった(図8)。
実施例3(ポリビニルアセタールジエチルアミノアセテート、タルク、ヒプロメロース(TC-5E)からなる第3膜を施したマスキング粒子)では、十分なラグタイムとJP1での高い溶出を達成した(図9)。
実施例5(ラウリル硫酸ナトリウム/ポリビニルアセタールジエチルアミノアセテート=1.57)では、実施例3(ラウリル硫酸ナトリウム/ポリビニルアセタールジエチルアミノアセテート=0.63)に比較してJP1での高い溶出を達成した(図10)。 In Comparative Example 2 (masking particles coated with a third film comprising aminoalkyl methacrylate copolymer RS, hypromellose (TC-5E), polysorbate 80), elution with JP1 was insufficient (FIG. 6).
In Comparative Example 3 (masking particles coated with a third membrane composed of hypromellose acetate succinate and talc), elution with JP1 was insufficient and the length of lag time was also insufficient (FIG. 7). .
In Comparative Example 4 (masking particles coated with a third film composed of ethyl cellulose and hydroxypropyl cellulose), although lag time was formed, elution with JP1 was insufficient (FIG. 8).
In Example 3 (masking particles provided with a third film made of polyvinyl acetal diethylaminoacetate, talc, and hypromellose (TC-5E)), sufficient lag time and high elution with JP1 were achieved (FIG. 9).
In Example 5 (sodium lauryl sulfate / polyvinyl acetal diethylaminoacetate = 1.57), higher elution with JP1 was achieved compared to Example 3 (sodium lauryl sulfate / polyvinyl acetal diethylaminoacetate = 0.63) (FIG. 10).
実験例3:粒子状医薬組成物の液置換溶出試験
実施例3または比較例2~4の粒子状医薬組成物(打錠前マスキング粒子)について自動6連溶出試験機を用いてvivoを反映した溶出試験を実施した。薬物を10mg含有する粒子状医薬組成物をJP1 300mLに投入し30分後、これに5倍に濃縮したJP2を600mL添加し、製剤からの薬物の溶出を測定した(パドル回転数:50回転/分)。
なお、本試験で得られた45分後の製剤からの薬物溶出率はイヌ経口投与試験において、CmaxおよびAUCに相関するものである。
得られた溶出プロファイルを図11に示す。ポリビニルアセタールジエチルアミノアセテートを被膜した粒子状医薬組成物(実施例3)は、液置換試験でも他の成分からなる膜を施した粒子状医薬組成物よりも高いD45min(45分後の薬物溶出率)を示した。 Experimental Example 3: Liquid Displacement Dissolution Test of Particulate Pharmaceutical Composition Dissolution of Example 3 or Comparative Examples 2 to 4 (masking particles before tableting) reflecting vivo using an automatic 6-series dissolution tester The test was conducted. 30 minutes after adding a particulate pharmaceutical composition containing 10 mg of drug to JP1 300 mL, 600 mL of 5-fold concentrated JP2 was added thereto, and dissolution of the drug from the preparation was measured (paddle rotation speed: 50 rotations / Min).
In addition, the drug dissolution rate from the preparation after 45 minutes obtained in this test correlates with Cmax and AUC in the dog oral administration test.
The obtained elution profile is shown in FIG. The particulate pharmaceutical composition coated with polyvinyl acetal diethylaminoacetate (Example 3) has a higher D45min (drug elution rate after 45 minutes) than the particulate pharmaceutical composition coated with a film comprising other components in the liquid replacement test. showed that.
実施例3または比較例2~4の粒子状医薬組成物(打錠前マスキング粒子)について自動6連溶出試験機を用いてvivoを反映した溶出試験を実施した。薬物を10mg含有する粒子状医薬組成物をJP1 300mLに投入し30分後、これに5倍に濃縮したJP2を600mL添加し、製剤からの薬物の溶出を測定した(パドル回転数:50回転/分)。
なお、本試験で得られた45分後の製剤からの薬物溶出率はイヌ経口投与試験において、CmaxおよびAUCに相関するものである。
得られた溶出プロファイルを図11に示す。ポリビニルアセタールジエチルアミノアセテートを被膜した粒子状医薬組成物(実施例3)は、液置換試験でも他の成分からなる膜を施した粒子状医薬組成物よりも高いD45min(45分後の薬物溶出率)を示した。 Experimental Example 3: Liquid Displacement Dissolution Test of Particulate Pharmaceutical Composition Dissolution of Example 3 or Comparative Examples 2 to 4 (masking particles before tableting) reflecting vivo using an automatic 6-series dissolution tester The test was conducted. 30 minutes after adding a particulate pharmaceutical composition containing 10 mg of drug to JP1 300 mL, 600 mL of 5-fold concentrated JP2 was added thereto, and dissolution of the drug from the preparation was measured (paddle rotation speed: 50 rotations / Min).
In addition, the drug dissolution rate from the preparation after 45 minutes obtained in this test correlates with Cmax and AUC in the dog oral administration test.
The obtained elution profile is shown in FIG. The particulate pharmaceutical composition coated with polyvinyl acetal diethylaminoacetate (Example 3) has a higher D45min (drug elution rate after 45 minutes) than the particulate pharmaceutical composition coated with a film comprising other components in the liquid replacement test. showed that.
実験例4:
0.1Nおよび0.01N塩酸30mLにポリビニルアセタールジエチルアミノアセテート(AEA)10mgを溶解させ、ラウリル硫酸ナトリウム(SLS)をポリビニルアセタールジエチルアミノアセテートに対する重量比で0.01~2となるように容器へ添加し密栓した。30分間振とう後、3000回転にて15分遠心分離することで析出画分を分離し、乾燥後その重量を測定した。
結果を図12に示す。SLS/AEA比率が小さい範囲ではイオンコンプレックスによると考えられる析出物が認められたが、SLS/AEA比率を大きくするとポリビニルアセタールジエチルアミノアセテートが溶解した。 Experimental Example 4:
10 mg of polyvinyl acetal diethylaminoacetate (AEA) was dissolved in 30 mL of 0.1N and 0.01N hydrochloric acid, and sodium lauryl sulfate (SLS) was added to the container so that the weight ratio with respect to polyvinyl acetal diethylaminoacetate was 0.01 to 2, and the container was sealed. After shaking for 30 minutes, the precipitated fraction was separated by centrifuging at 3000 rpm for 15 minutes, dried and then weighed.
The results are shown in FIG. In the range where the SLS / AEA ratio was small, precipitates thought to be due to the ion complex were observed, but when the SLS / AEA ratio was increased, polyvinyl acetal diethylaminoacetate was dissolved.
0.1Nおよび0.01N塩酸30mLにポリビニルアセタールジエチルアミノアセテート(AEA)10mgを溶解させ、ラウリル硫酸ナトリウム(SLS)をポリビニルアセタールジエチルアミノアセテートに対する重量比で0.01~2となるように容器へ添加し密栓した。30分間振とう後、3000回転にて15分遠心分離することで析出画分を分離し、乾燥後その重量を測定した。
結果を図12に示す。SLS/AEA比率が小さい範囲ではイオンコンプレックスによると考えられる析出物が認められたが、SLS/AEA比率を大きくするとポリビニルアセタールジエチルアミノアセテートが溶解した。 Experimental Example 4:
10 mg of polyvinyl acetal diethylaminoacetate (AEA) was dissolved in 30 mL of 0.1N and 0.01N hydrochloric acid, and sodium lauryl sulfate (SLS) was added to the container so that the weight ratio with respect to polyvinyl acetal diethylaminoacetate was 0.01 to 2, and the container was sealed. After shaking for 30 minutes, the precipitated fraction was separated by centrifuging at 3000 rpm for 15 minutes, dried and then weighed.
The results are shown in FIG. In the range where the SLS / AEA ratio was small, precipitates thought to be due to the ion complex were observed, but when the SLS / AEA ratio was increased, polyvinyl acetal diethylaminoacetate was dissolved.
本発明の粒子状医薬組成物は、現在医療の現場に提供されているアトルバスタチン又はその製薬学的に許容される塩を含有してなる固形製剤に比し、同等以上の薬物分散性・溶出性を示しており、口腔内における不快な味の隠蔽を施しても消化管内における速やかな分散性・溶出性を達成できる医薬組成物として有用である。
以上、本発明を特定の態様に沿って説明したが、当業者に自明の変形や改良は本発明の範囲に含まれる。 The particulate pharmaceutical composition of the present invention has a drug dispersibility and dissolution property equal to or higher than that of a solid preparation containing atorvastatin or a pharmaceutically acceptable salt thereof currently provided in the medical field. It is useful as a pharmaceutical composition that can achieve rapid dispersibility and dissolution in the digestive tract even when an unpleasant taste is masked in the oral cavity.
As mentioned above, although this invention was demonstrated along the specific aspect, the deformation | transformation and improvement obvious to those skilled in the art are included in the scope of the present invention.
以上、本発明を特定の態様に沿って説明したが、当業者に自明の変形や改良は本発明の範囲に含まれる。 The particulate pharmaceutical composition of the present invention has a drug dispersibility and dissolution property equal to or higher than that of a solid preparation containing atorvastatin or a pharmaceutically acceptable salt thereof currently provided in the medical field. It is useful as a pharmaceutical composition that can achieve rapid dispersibility and dissolution in the digestive tract even when an unpleasant taste is masked in the oral cavity.
As mentioned above, although this invention was demonstrated along the specific aspect, the deformation | transformation and improvement obvious to those skilled in the art are included in the scope of the present invention.
Claims (16)
- アトルバスタチン又はその製薬学的に許容される塩およびラウリル硫酸ナトリウムを含有する粒子が、ポリビニルアセタールジエチルアミノアセテートおよび水溶性高分子物質を含む被膜物質により被覆されてなる、経口投与用粒子状医薬組成物。 A particulate pharmaceutical composition for oral administration, wherein particles containing atorvastatin or a pharmaceutically acceptable salt thereof and sodium lauryl sulfate are coated with a coating substance containing polyvinyl acetal diethylaminoacetate and a water-soluble polymer substance.
- 水溶性高分子物質が、ヒドロキシプロピルセルロース、ヒプロメロース、メチルセルロース、ヒドロキシエチルセルロース、ポビドン、コポリビドン、ポリビニルアルコール-ポリエチレングリコールグラフトコポリマー、ポリビニルアルコール、マクロゴール、およびポリエチレンオキサイドからなる群より選択される1種または2種以上である、請求項1に記載の経口投与用粒子状医薬組成物。 The water-soluble polymer substance is one or two selected from the group consisting of hydroxypropylcellulose, hypromellose, methylcellulose, hydroxyethylcellulose, povidone, copolyvidone, polyvinyl alcohol-polyethylene glycol graft copolymer, polyvinyl alcohol, macrogol, and polyethylene oxide The particulate pharmaceutical composition for oral administration according to claim 1, which is a species or more.
- 水溶性高分子物質がヒプロメロースである、請求項1に記載の経口投与用粒子状医薬組成物。 The particulate pharmaceutical composition for oral administration according to claim 1, wherein the water-soluble polymer substance is hypromellose.
- さらに被膜物質に流動化剤を含有する、請求項1~3のいずれか一項に記載の経口投与用粒子状医薬組成物。 The particulate pharmaceutical composition for oral administration according to any one of claims 1 to 3, further comprising a fluidizing agent in the coating substance.
- 流動化剤が、ケイ酸金属類、二酸化ケイ素類、高級脂肪酸金属塩類、金属酸化物類、アルカリ土類金属塩、および金属水酸化物からなる群より選択される1種または2種以上である、請求項4に記載の経口投与用粒子状医薬組成物。 The fluidizing agent is one or more selected from the group consisting of metal silicates, silicon dioxide, higher fatty acid metal salts, metal oxides, alkaline earth metal salts, and metal hydroxides. The particulate pharmaceutical composition for oral administration according to claim 4.
- 流動化剤が、タルク、カオリン、ケイ酸カルシウム、ケイ酸マグネシウム、軽質無水ケイ酸、ステアリン酸マグネシウム、ステアリン酸カルシウム、酸化鉄、酸化チタン、炭酸カルシウム、リン酸カルシウム、セッコウ、炭酸マグネシウム、水酸化アルミニウム、含水二酸化ケイ素、結晶セルロース、合成ケイ酸アルミニウム、重質無水ケイ酸、水酸化アルミナマグネシウム、ステアリン酸、トウモロコシデンプン、メタケイ酸アルミン酸マグネシウム、リン酸水素カルシウム造粒物、およびグリセリルモノステアレートからなる群より選択される1種または2種以上である、請求項4に記載の経口投与用粒子状医薬組成物。 Fluidizers include talc, kaolin, calcium silicate, magnesium silicate, light anhydrous silicic acid, magnesium stearate, calcium stearate, iron oxide, titanium oxide, calcium carbonate, calcium phosphate, gypsum, magnesium carbonate, aluminum hydroxide, water content Group consisting of silicon dioxide, crystalline cellulose, synthetic aluminum silicate, heavy anhydrous silicic acid, magnesium alumina hydroxide, stearic acid, corn starch, magnesium aluminate metasilicate, calcium hydrogen phosphate granule, and glyceryl monostearate The particulate pharmaceutical composition for oral administration according to claim 4, which is one or more selected from the above.
- 流動化剤がタルクである、請求項4に記載の経口投与用粒子状医薬組成物。 The particulate pharmaceutical composition for oral administration according to claim 4, wherein the fluidizing agent is talc.
- 請求項1~7のいずれか一項に記載の経口投与用粒子状医薬組成物を含有してなる口腔内崩壊錠。 An orally disintegrating tablet comprising the particulate pharmaceutical composition for oral administration according to any one of claims 1 to 7.
- アトルバスタチン又はその製薬学的に許容される塩およびラウリル硫酸ナトリウムを含有する粒子を、ポリビニルアセタールジエチルアミノアセテートおよび水溶性高分子物質を含む被膜物質により被覆する、経口投与用粒子状医薬組成物の製造方法。 A method for producing a granular pharmaceutical composition for oral administration, comprising coating particles containing atorvastatin or a pharmaceutically acceptable salt thereof and sodium lauryl sulfate with a coating material containing polyvinyl acetal diethylaminoacetate and a water-soluble polymer substance. .
- 水溶性高分子物質が、ヒドロキシプロピルセルロース、ヒプロメロース、メチルセルロース、ヒドロキシエチルセルロース、ポビドン、コポリビドン、ポリビニルアルコール-ポリエチレングリコールグラフトコポリマー、ポリビニルアルコール、マクロゴール、およびポリエチレンオキサイドからなる群より選択される1種または2種以上である、請求項9に記載の経口投与用粒子状医薬組成物の製造方法。 The water-soluble polymer substance is one or two selected from the group consisting of hydroxypropylcellulose, hypromellose, methylcellulose, hydroxyethylcellulose, povidone, copolyvidone, polyvinyl alcohol-polyethylene glycol graft copolymer, polyvinyl alcohol, macrogol, and polyethylene oxide The manufacturing method of the particulate-form pharmaceutical composition for oral administration of Claim 9 which is a seed | species or more.
- 水溶性高分子物質がヒプロメロースである、請求項9に記載の経口投与用粒子状医薬組成物の製造方法。 The method for producing a granular pharmaceutical composition for oral administration according to claim 9, wherein the water-soluble polymer substance is hypromellose.
- さらに被膜物質に流動化剤を含有する、請求項9~11のいずれか一項に記載の経口投与用粒子状医薬組成物の製造方法。 The method for producing a granular pharmaceutical composition for oral administration according to any one of claims 9 to 11, further comprising a fluidizing agent in the coating substance.
- 流動化剤が、ケイ酸金属類、二酸化ケイ素類、高級脂肪酸金属塩類、金属酸化物類、アルカリ土類金属塩、および金属水酸化物からなる群より選択される1種または2種以上である、請求項12に記載の経口投与用粒子状医薬組成物の製造方法。 The fluidizing agent is one or more selected from the group consisting of metal silicates, silicon dioxide, higher fatty acid metal salts, metal oxides, alkaline earth metal salts, and metal hydroxides. The manufacturing method of the particulate-form pharmaceutical composition for oral administration of Claim 12.
- 流動化剤が、タルク、カオリン、ケイ酸カルシウム、ケイ酸マグネシウム、軽質無水ケイ酸、ステアリン酸マグネシウム、ステアリン酸カルシウム、酸化鉄、酸化チタン、炭酸カルシウム、リン酸カルシウム、セッコウ、炭酸マグネシウム、水酸化アルミニウム、含水二酸化ケイ素、結晶セルロース、合成ケイ酸アルミニウム、重質無水ケイ酸、水酸化アルミナマグネシウム、ステアリン酸、トウモロコシデンプン、メタケイ酸アルミン酸マグネシウム、リン酸水素カルシウム造粒物、およびグリセリルモノステアレートからなる群より選択される1種または2種以上である、請求項12に記載の経口投与用粒子状医薬組成物の製造方法。 Fluidizers include talc, kaolin, calcium silicate, magnesium silicate, light anhydrous silicic acid, magnesium stearate, calcium stearate, iron oxide, titanium oxide, calcium carbonate, calcium phosphate, gypsum, magnesium carbonate, aluminum hydroxide, water content Group consisting of silicon dioxide, crystalline cellulose, synthetic aluminum silicate, heavy anhydrous silicic acid, magnesium alumina hydroxide, stearic acid, corn starch, magnesium aluminate metasilicate, calcium hydrogen phosphate granule, and glyceryl monostearate The manufacturing method of the granular pharmaceutical composition for oral administration of Claim 12 which is 1 type, or 2 or more types selected from more.
- 流動化剤がタルクである、請求項12に記載の経口投与用粒子状医薬組成物の製造方法。 The method for producing a granular pharmaceutical composition for oral administration according to claim 12, wherein the fluidizing agent is talc.
- アトルバスタチン又はその製薬学的に許容される塩を含有する粒子を被覆し、圧縮成形後も放出速度の変化を低減する経口投与用粒子状医薬組成物を製造するための、ポリビニルアセタールジエチルアミノアセテートおよび水溶性高分子物質の使用。 Polyvinyl acetal diethylaminoacetate and aqueous solution for producing a granular pharmaceutical composition for oral administration that coats particles containing atorvastatin or a pharmaceutically acceptable salt thereof and reduces the change in release rate even after compression molding Use of functional polymer substances.
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Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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PCT/JP2010/067039 WO2011121823A1 (en) | 2010-03-29 | 2010-09-30 | Particulate pharmaceutical composition for oral administration |
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JP (1) | JP5614445B2 (en) |
WO (1) | WO2011121823A1 (en) |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2013125497A1 (en) * | 2012-02-20 | 2013-08-29 | ニプロ株式会社 | Method for manufacturing orally disintegrating tablet |
JP2013231011A (en) * | 2012-05-01 | 2013-11-14 | Sawai Pharmaceutical Co Ltd | Atorvastatin-containing pharmaceutical composition and orally disintegrating tablet using the same |
WO2014207162A1 (en) * | 2013-06-27 | 2014-12-31 | Assistance Publique - Hopitaux De Paris | Pharmaceutical composition in the form of granules for treating metabolic disorders in children |
JP2015040206A (en) * | 2013-08-23 | 2015-03-02 | 高田製薬株式会社 | Oral fast-disintegrating tablet containing irritative (astringency, acidity, bitterness) drug and method for producing the same |
GB2624171A (en) * | 2022-11-08 | 2024-05-15 | Novumgen Ltd | An orally disintegrating tablet containing atorvastatin and process of preparing the same |
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WO2001076565A1 (en) * | 2000-04-12 | 2001-10-18 | Banyu Pharmaceutical Co., Ltd. | Compositions disintegrating in oral cavity and preparations disintegrating in oral cavity |
JP2004175796A (en) * | 2002-11-13 | 2004-06-24 | Asahi Kasei Pharma Kk | Intraoral disintegrating preparation for treating dysuria |
JP2005522444A (en) * | 2002-02-14 | 2005-07-28 | ランバクシー ラボラトリーズ リミテッド | Atovastatin formulation stabilized by addition of alkali metal |
WO2005105045A1 (en) * | 2004-04-30 | 2005-11-10 | Astellas Pharma Inc. | Time-limited release type granular pharmaceutical composition for oral administration and intraoral rapid disintegration tablet containing the composition |
JP2006327943A (en) * | 2005-05-23 | 2006-12-07 | Towa Yakuhin Kk | Taste-masked tablet suppressed with delay of elution over time |
WO2008018371A1 (en) * | 2006-08-08 | 2008-02-14 | Kissei Pharmaceutical Co., Ltd. | Oral disintegrating tablet having masked bitter taste and method for production thereof |
JP2008044870A (en) * | 2006-08-11 | 2008-02-28 | Elmed Eisai Kk | Pharmaceutical composition and its production method |
WO2008081891A1 (en) * | 2006-12-28 | 2008-07-10 | Takeda Pharmaceutical Company Limited | Orally disintegrating solid preparation |
JP2008531681A (en) * | 2005-03-02 | 2008-08-14 | アクタヴィス・グループ・エイチエフ | Fast disintegrating preparation containing magnesium carbonate heavy |
JP2009114113A (en) * | 2007-11-06 | 2009-05-28 | Nipro Corp | Intraorally disintegrable tablet and method for producing the same |
JP2009534294A (en) * | 2006-04-27 | 2009-09-24 | 武田薬品工業株式会社 | Solid preparation |
WO2010038691A1 (en) * | 2008-09-30 | 2010-04-08 | アステラス製薬株式会社 | Particulate pharmaceutical composition for oral administration |
WO2010038688A1 (en) * | 2008-09-30 | 2010-04-08 | アステラス製薬株式会社 | Particulate pharmaceutical composition for oral administration of atorvastatin |
-
2010
- 2010-09-30 WO PCT/JP2010/067039 patent/WO2011121823A1/en active Application Filing
- 2010-09-30 JP JP2012508015A patent/JP5614445B2/en not_active Expired - Fee Related
Patent Citations (14)
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WO2001076565A1 (en) * | 2000-04-12 | 2001-10-18 | Banyu Pharmaceutical Co., Ltd. | Compositions disintegrating in oral cavity and preparations disintegrating in oral cavity |
JP2005522444A (en) * | 2002-02-14 | 2005-07-28 | ランバクシー ラボラトリーズ リミテッド | Atovastatin formulation stabilized by addition of alkali metal |
JP2004175796A (en) * | 2002-11-13 | 2004-06-24 | Asahi Kasei Pharma Kk | Intraoral disintegrating preparation for treating dysuria |
WO2005105045A1 (en) * | 2004-04-30 | 2005-11-10 | Astellas Pharma Inc. | Time-limited release type granular pharmaceutical composition for oral administration and intraoral rapid disintegration tablet containing the composition |
JP2008531681A (en) * | 2005-03-02 | 2008-08-14 | アクタヴィス・グループ・エイチエフ | Fast disintegrating preparation containing magnesium carbonate heavy |
JP2006327943A (en) * | 2005-05-23 | 2006-12-07 | Towa Yakuhin Kk | Taste-masked tablet suppressed with delay of elution over time |
JP2009534294A (en) * | 2006-04-27 | 2009-09-24 | 武田薬品工業株式会社 | Solid preparation |
WO2008018371A1 (en) * | 2006-08-08 | 2008-02-14 | Kissei Pharmaceutical Co., Ltd. | Oral disintegrating tablet having masked bitter taste and method for production thereof |
JP2008044870A (en) * | 2006-08-11 | 2008-02-28 | Elmed Eisai Kk | Pharmaceutical composition and its production method |
WO2008081891A1 (en) * | 2006-12-28 | 2008-07-10 | Takeda Pharmaceutical Company Limited | Orally disintegrating solid preparation |
JP2009114113A (en) * | 2007-11-06 | 2009-05-28 | Nipro Corp | Intraorally disintegrable tablet and method for producing the same |
WO2010038691A1 (en) * | 2008-09-30 | 2010-04-08 | アステラス製薬株式会社 | Particulate pharmaceutical composition for oral administration |
WO2010038688A1 (en) * | 2008-09-30 | 2010-04-08 | アステラス製薬株式会社 | Particulate pharmaceutical composition for oral administration of atorvastatin |
JP2010083886A (en) * | 2008-09-30 | 2010-04-15 | Astellas Pharma Inc | Granular pharmaceutical composition for oral administration |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2013125497A1 (en) * | 2012-02-20 | 2013-08-29 | ニプロ株式会社 | Method for manufacturing orally disintegrating tablet |
JPWO2013125497A1 (en) * | 2012-02-20 | 2015-07-30 | ニプロ株式会社 | Method for producing orally disintegrating tablets |
JP2013231011A (en) * | 2012-05-01 | 2013-11-14 | Sawai Pharmaceutical Co Ltd | Atorvastatin-containing pharmaceutical composition and orally disintegrating tablet using the same |
WO2014207162A1 (en) * | 2013-06-27 | 2014-12-31 | Assistance Publique - Hopitaux De Paris | Pharmaceutical composition in the form of granules for treating metabolic disorders in children |
JP2015040206A (en) * | 2013-08-23 | 2015-03-02 | 高田製薬株式会社 | Oral fast-disintegrating tablet containing irritative (astringency, acidity, bitterness) drug and method for producing the same |
GB2624171A (en) * | 2022-11-08 | 2024-05-15 | Novumgen Ltd | An orally disintegrating tablet containing atorvastatin and process of preparing the same |
Also Published As
Publication number | Publication date |
---|---|
JPWO2011121823A1 (en) | 2013-07-04 |
JP5614445B2 (en) | 2014-10-29 |
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