WO2017188361A1 - Tablet containing tosufloxacin tosilate - Google Patents

Tablet containing tosufloxacin tosilate Download PDF

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Publication number
WO2017188361A1
WO2017188361A1 PCT/JP2017/016681 JP2017016681W WO2017188361A1 WO 2017188361 A1 WO2017188361 A1 WO 2017188361A1 JP 2017016681 W JP2017016681 W JP 2017016681W WO 2017188361 A1 WO2017188361 A1 WO 2017188361A1
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Prior art keywords
tablet
powder
sieve
opening
granulated
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PCT/JP2017/016681
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French (fr)
Japanese (ja)
Inventor
一美 田谷
侑輝 粕谷
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富山化学工業株式会社
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Priority to JP2018514690A priority Critical patent/JP6647395B2/en
Publication of WO2017188361A1 publication Critical patent/WO2017188361A1/en

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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
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein

Definitions

  • the present invention relates to a tablet containing tosufloxacin tosylate which exhibits rapid dissolution and does not cause tableting troubles and is excellent in manufacturability.
  • Tosfloxacin is a new quinolone antibacterial agent having a broad antibacterial spectrum against Gram positive bacteria, Gram negative bacteria and anaerobic bacteria (Patent Document 1).
  • Patent Document 1 As a prescription and production method of a solid preparation containing tosufloxacin, it is known to prepare a preparation by mixing tosufloxacin tosylate hydrate, an organic acid having 2 to 6 carbon atoms and a general medical carrier ( Patent Document 2).
  • Patent Document 3 Also known is a granular solid preparation comprising tosufloxacin tosylate, sugar or sugar alcohol and a nonionic water-soluble cellulose derivative or polyvinyl alcohol (Patent Document 3).
  • tablets containing tosufloxacin tosylate are commercially available.
  • granular solid preparations and tablets are known.
  • a granular solid formulation is preferred.
  • the swallowing function develops like an elementary school student and the taste becomes clearer, tablets tend to be preferred.
  • the size of tablets greatly affects compliance. If it is too large, the child will not be able to swallow and compliance will be reduced. Since tablets for adults have a tablet diameter of 7.5 to 8.5 mm, which is large for children, there is a concern that the compliance of children will be reduced. Fine granules have been marketed as pediatric preparations containing tosufloxacin tosylate, but pediatric tablets have not been developed.
  • the dissolution rate after 5 minutes of the commercially available tablet containing tosufloxacin tosylate is 24%.
  • Tosufloxacin tosylate has a metal adhesion property, and when it is tableted, serious tableting failure (sticking) occurs in which the drug substance is fixed to the bag.
  • sticking serious tableting failure
  • An object of the present invention is to provide a tablet containing tosufloxacin tosylate which exhibits rapid dissolution, does not cause tableting troubles such as sticking, and is excellent in manufacturability.
  • the present inventors conducted intensive research. As a result, the tablet containing (1) tosufloxacin tosylate salt, (2) binder, and (3) acidic amino acid exhibits rapid dissolution, And it discovered that it was excellent in manufacturability, without causing a tableting trouble, and completed this invention.
  • the present invention provides the following.
  • a tablet comprising (1) tosufloxacin tosylate, (2) a binder, and (3) an acidic amino acid; the binder is selected from water-soluble polyvinyl polymers and gelatins Two or more tablets, wherein the content of the binder is less than 5% based on the tablet mass.
  • the acidic amino acid is L-aspartic acid.
  • the binder is a water-soluble polyvinyl polymer.
  • the disintegrant is one or more selected from carmellose, carmellose calcium, croscarmellose sodium, low-substituted hydroxypropyl cellulose, crospovidone, sodium carboxymethyl starch and partially pregelatinized starch.
  • the tablet of description The tablet of description.
  • the present invention further provides the following.
  • [A] The tablet according to any one of [1] to [8], further comprising a fluidizing agent.
  • E The tablet according to [C] or [D], wherein the gelatin content is 0.1 to 4% based on the tablet mass.
  • a tablet comprising (1) tosufloxacin tosylate, (2) a binder, and (3) an acidic amino acid; the binder is a water-soluble polyvinyl polymer; the acidic amino acid is L
  • [G] A tablet comprising (1) tosufloxacin tosylate, (2) a binder, and (3) an acidic amino acid; the binder is polyvinyl alcohol; the acidic amino acid is L-aspartic acid Yes; The tablet according to [1], wherein the content of polyvinyl alcohol is 0.1 to 4% based on the weight of the tablet.
  • the tablet of the present invention is a tablet containing tosufloxacin tosylate which is easy to be taken by children and the like, exhibits quick dissolution, does not cause tableting troubles such as sticking, and is excellent in manufacturability.
  • the tablet of the present invention can also be a tablet having a secant for dose adjustment, and is useful as an antibacterial agent for children with improved compliance in children and the like.
  • the present invention is described in detail below. Unless otherwise specified,% used in the present specification means mass%.
  • the content rate of each component used in the present specification means the total content rate of a plurality of substances corresponding to each component unless there is a specific case when there are a plurality of substances corresponding to each component.
  • the “dissolution rate” used in the present specification means the dissolution rate measured according to the 16th revised Japanese Pharmacopoeia dissolution test method 2 (paddle method) unless otherwise specified.
  • the term “fast dissolution” used in the present specification means that the dissolution rate after 5 minutes from the start of the dissolution test is 60% or more.
  • the value of “60% or more” was obtained from tosufloxacin tosylate pediatric fine granules using the f2 function, which is an index of similarity of dissolution behavior.
  • it is more preferable that the dissolution rate 5 minutes after the start of the dissolution test is 73% or more.
  • the tablet of the present invention comprises tosufloxacin tosylate, a binder and an acidic amino acid.
  • the tablet of the present invention means an uncoated tablet and a film-coated tablet.
  • the film-coated tablet means a tablet obtained by coating a base tablet with a coating agent such as a polymer compound.
  • a film-coated tablet is preferable.
  • the tablet diameter is preferably 5.0 to 7.0 mm.
  • the dose and the number of doses can be appropriately selected according to the age, weight and symptoms of the patient, but the amount capable of exerting the drug effect is usually divided from once to several times a day. Can be administered. In general, 30 to 2000 mg of tosufloxacin may be administered in 1 to several divided doses a day.
  • Tosfloxacin tosylate used in the present invention can be produced, for example, by the method described in JP-B-63-020828.
  • Tosfloxacin tosylate used in the present invention includes hydrates, solvates and various forms of crystals and amorphous solids.
  • the tosufloxacin tosylate used in the present invention is preferably a hydrate.
  • the content of tosufloxacin tosylate is preferably 70% or less, more preferably 40 to 60%, relative to the tablet mass.
  • Examples of the binder used in the present invention include one or more selected from water-soluble polyvinyl polymers and gelatins, and water-soluble polyvinyl polymers are preferred.
  • the binder content may be less than 5%.
  • Examples of the water-soluble polyvinyl polymer include one or more selected from polyvinyl alcohol, polyvinyl pyrrolidone, and polyvinyl alcohol / polyethylene glycol / graft copolymer, preferably polyvinyl alcohol and polyvinyl pyrrolidone, and more preferably polyvinyl alcohol.
  • Examples of the polyvinyl alcohol include fully saponified polyvinyl alcohol and partially saponified polyvinyl alcohol, and partially saponified polyvinyl alcohol is preferred.
  • the content of the water-soluble polyvinyl polymer is preferably 0.01 to 4.5%, more preferably 0.05 to 4%, still more preferably 0.1 to 3% with respect to the tablet mass.
  • gelatins include one or two selected from alkali-treated gelatin and acid-treated gelatin, and alkali-treated gelatin is preferred.
  • the content of gelatin is preferably 0.1 to 4%, more preferably 0.3 to 4%, still more preferably 0.5 to 2% based on the tablet mass.
  • the acidic amino acid used in the present invention means an amino acid having two or more carboxyl groups in the molecule.
  • Examples of the acidic amino acid used in the present invention include one or two selected from aspartic acid and glutamic acid.
  • Preferable acidic amino acids include aspartic acid, and L-aspartic acid is more preferable.
  • the content of acidic amino acids is preferably 5 to 50%, more preferably 5 to 30%, still more preferably 10 to 20% based on the tablet mass.
  • the tablet of the present invention preferably further contains a disintegrant.
  • the disintegrant used in the present invention include one or two selected from carmellose, carmellose calcium, croscarmellose sodium, low-substituted hydroxypropylcellulose, crospovidone, sodium carboxymethyl starch, and partially pregelatinized starch. More than species.
  • Preferred disintegrants include one or more selected from carmellose, carmellose calcium, croscarmellose sodium, low-substituted hydroxypropylcellulose, crospovidone and carboxymethyl starch sodium.
  • Carmellose, low-substituted hydroxypropyl One or more selected from cellulose, crospovidone and sodium carboxymethyl starch are more preferred, and a combination of low-substituted hydroxypropylcellulose and crospovidone is more preferred.
  • Low-substituted hydroxypropyl cellulose is a low-substituted hydroxypropyl ether of cellulose, and the dried product contains hydroxypropoxy groups (—OC 3 H 6 OH: 75.09) 5.0 to 16.0% when quantified. .
  • the content of the disintegrant is preferably 5 to 50%, more preferably 5 to 30%, still more preferably 8 to 15% based on the tablet mass.
  • the tablet of the present invention preferably further contains a fluidizing agent.
  • the fluidizing agent include one or more selected from synthetic aluminum silicate, hydrous silicon dioxide, light anhydrous silicic acid, and the like, and one or two selected from hydrous silicon dioxide and light anhydrous silicic acid.
  • light anhydrous silicic acid is more preferable.
  • additives generally used for drugs can be used as long as the effects of the present invention are not impaired.
  • examples of the additive include excipients, lubricants, sweeteners, coloring agents, flavoring agents, surfactants, plasticizers and coating agents.
  • excipient examples include sugar alcohols such as erythritol, mannitol, xylitol and sorbitol; sugars such as sucrose, powdered sugar, lactose and glucose; ⁇ -cyclodextrin, ⁇ -cyclodextrin, ⁇ -cyclodextrin, hydroxypropyl Cyclodextrins such as ⁇ -cyclodextrin and sulfobutyl ether ⁇ -cyclodextrin sodium; celluloses such as crystalline cellulose and microcrystalline cellulose; starches such as corn starch, potato starch and pregelatinized starch; malonic acid and fumaric acid, etc.
  • sugar alcohols such as erythritol, mannitol, xylitol and sorbitol
  • sugars such as sucrose, powdered sugar, lactose and glucose
  • dicarboxylic acids One kind selected from dicarboxylic acids; oxycarboxylic acids such as glycolic acid, gluconic acid, tartaric acid, malic acid and citric acid; and organic acids having 2 to 6 carbon atoms such as ascorbic acid Others include two or more thereof.
  • Preferred excipients include sugar alcohols, and erythritol is more preferred.
  • the amount of the excipient used is not particularly limited, and an amount corresponding to the dosage form may be used.
  • Examples of the lubricant include one or more selected from stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, talc, sucrose fatty acid ester, and the like.
  • Examples of the sweetener include one or more selected from aspartame, saccharin, stevia, sucralose, thaumatin, and acesulfame potassium.
  • Examples of the colorant include one or more selected from titanium dioxide, iron sesquioxide, yellow iron sesquioxide, black iron oxide, edible red No. 102, edible yellow No. 4, edible yellow No. 5, and the like.
  • flavoring agents include essential oils such as orange oil, lemon oil, peppermint oil and pine oil; essences such as orange essence and peppermint essence; flavors such as cherry flavor, vanilla flavor and fruit flavor; apple micron, banana micron, One or two or more kinds selected from powder flavors such as peach micron, strawberry micron, and orange micron; vanillin; and ethyl vanillin.
  • the surfactant include one or more selected from sodium lauryl sulfate, dioctyl sodium sulfosuccinate, polysorbate, and polyoxyethylene hydrogenated castor oil.
  • plasticizer examples include one or more selected from triethyl citrate, dibutyl phthalate, macrogol (polyethylene glycol), triacetin, glycerol monocaprycaprate, lecithin, propylene glycol, and the like.
  • Examples of the coating agent include one or more selected from polymer compounds, plasticizers, colorants, lubricants, brighteners, and the like.
  • Examples of the polymer compound include one or more selected from hypromellose, hydroxypropyl cellulose, polyvinyl alcohol, polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, polyvinyl alcohol / polyethylene glycol / graft copolymer, and the like.
  • Examples of the lubricant used as the coating agent include talc.
  • Examples of the brightening agent include one or more selected from carnauba wax, white beeswax, beeswax and the like.
  • the amount of the polymer compound, plasticizer, colorant, lubricant and brightening agent used is not particularly limited, and a necessary amount may be appropriately blended depending on the purpose. These additives may be added either alone or in combination of two or more. The addition amount is not particularly limited, and an amount corresponding to the dosage form may be added.
  • a preferred tablet of the present invention is a tablet comprising (1) tosufloxacin tosylate, (2) a binder, and (3) an acidic amino acid; the binder is a water-soluble polyvinyl polymer; acidic An amino acid is L-aspartic acid; a tablet having a water-soluble polyvinyl polymer content of 0.01 to 4.5% based on the tablet mass.
  • Preferred water-soluble polyvinyl polymers are the same as described above.
  • a further preferred tablet of the present invention is a tablet comprising (1) tosufloxacin tosylate, (2) a binder, and (3) an acidic amino acid; the binder is polyvinyl alcohol; L-aspartic acid; a tablet having a polyvinyl alcohol content of 0.1 to 4% based on the tablet weight.
  • Preferred polyvinyl alcohol is the same as described above.
  • a preferred tablet of the present invention is a tablet comprising (1) tosufloxacin tosylate, (2) a binder, (3) an acidic amino acid, (4) a disintegrant, and (5) a fluidizing agent.
  • the binder is one or more selected from water-soluble polyvinyl polymers and gelatins; the acidic amino acid is L-aspartic acid; the disintegrant is crospovidone and / or carboxymethyl One or more containing sodium starch; the fluidizing agent is hydrous silicon dioxide or light anhydrous silicic acid; and the content of the binder is 0.1 to 3% of the tablet mass. .
  • binders selected from water-soluble polyvinyl polymers or gelatins and acidic amino acids are added to tosufloxacin tosylate, and further, an excipient, a fluid
  • a granulating powder is produced by a wet granulation method or a dry granulation method by adding an agent, a disintegrant and / or a sweetener. Subsequently, if necessary, an excipient, a fluidizing agent, a disintegrant and / or a lubricant can be added to the granulated powder to obtain a mixed powder for tableting, and tableting can be performed.
  • a film-coated tablet can be produced by a conventional method.
  • a preferable granulation method in the method for producing a granulated powder of the present invention includes a wet granulation method.
  • the wet granulation method include fluidized bed granulation method, rolling fluidized granulation method, centrifugal rolling granulation method, mixed stirring granulation method, high speed mixed stirring granulation method, rolling granulation method, wet crushing method Examples thereof include a granulation method and an extrusion granulation method.
  • Preferable wet granulation methods include fluidized bed granulation method, rolling fluidized granulation method, high speed mixing and stirring granulation method and wet crushing granulation method.
  • Fluidized bed granulation method and rolling fluidized granulation method include More preferred.
  • Alpha starch SWELSTAR WB-1 (Asahi Kasei Chemicals)
  • L-aspartic acid L-aspartic acid (Kyowa Hakko Bio)
  • Erythritol Erythritol T fine powder (Mitsubishi Chemical Foods)
  • Hydrous silicon dioxide Carplex # 80 (DSL.
  • Croscarmellose sodium Kikkolate (Asahi Kasei Chemicals) Crospovidone: Polyplusdon XL-10 (ISP) Light anhydrous silicic acid: Aerosil 200 (Japan Aerosil) Sucralose: Sucralose (P) (San-Eigen F.F.I.) Magnesium stearate: Magnesium stearate vegetable (Taihei Chemical Industry) Gelatin: Gelatin # 150 (Nitta Gelatin) Low-substituted hydroxypropyl cellulose: L-HPC LH-21 (Shin-Etsu Chemical) Hydroxypropyl cellulose: HPC-SL (Nippon Soda) Hydroxypropyl methylcellulose: TC-5E (Shin-Etsu Chemical) Polyvinyl alcohol (partially saponified product): EG-05PW (Nippon Synthetic Chemical Industry) Polyvinyl alcohol / polyethylene glycol / graft copolymer: Kolli
  • Tableting machine Tabflex TAB10 (Okada Seiko)
  • Rolling fluid granulating dryer Multiplex MP-01 (Paurek)
  • Test example 1 The uncoated tablets of Examples 1 to 25 and Comparative Examples 1 to 5 were used as test preparations.
  • (1) Dissolution test of preparation The standard value of dissolution is the dissolution rate 5 minutes after the start of dissolution test, which is similar to that of fast-dissolving children's fine granules, and the similarity of dissolution behavior. It was determined from the f2 function as an index, and was set based on the dissolution rate ⁇ 60% 5 minutes after the start of the dissolution test.
  • the dissolution test was conducted according to Method 16 (Paddle Method) of the 16th revised Japanese Pharmacopoeia. One tablet of each test preparation was added to 900 mL of water and stirred at 50 rpm.
  • the eluate was collected by an automatic sampling device and filtered through a filter having a pore size of 35 ⁇ m.
  • the concentration of tosufloxacin tosylate was measured according to UV-Vis absorbance measurement method ⁇ Japanese Pharmacopoeia General Test Method 2.24>.
  • Table 1 shows the formulation of the tablets with different binder types, the dissolution rate after 5 minutes, and the presence or absence of sticking.
  • the tablets of Examples 1 to 4 containing water-soluble polyvinyl polymer polyvinyl alcohol, polyvinyl pyrrolidone or polyvinyl alcohol / polyethylene glycol / graft copolymer (PVA / PEG graft copolymer) or gelatin as a binder are dissolved after 5 minutes. The rate was 75-82%, indicating rapid dissolution, and there was no sticking.
  • Comparative Examples 1 and 2 the tablets of Comparative Examples 1 and 2 containing hydroxypropylcellulose or hydroxypropylmethylcellulose as a binder had a dissolution rate of 82% and 80% after 5 minutes, respectively. As shown, it was a tablet whose score line and marking were unclear due to the occurrence of sticking.
  • the tablet of Comparative Example 3 containing pregelatinized starch as a binder was an uncoated tablet with a dissolution rate of 55% after 5 minutes and no fast dissolution, and the dividing line and markings were unclear due to the occurrence of sticking. Tablets containing a water-soluble polyvinyl polymer as a binder were excellent in dissolution and manufacturability.
  • Tables 2, 3 and 4 show the tablet formulations with varying amounts of binder used, the dissolution rate after 5 minutes and the presence or absence of sticking.
  • the tablets of Examples 5 to 13 containing polyvinyl alcohol as a binder showed fast dissolution with a dissolution rate of 63 to 84% after 5 minutes even when the amount of the binder was changed to 0.1 to 4%, and sticking There was no tablet, and the scored line and the engraved mark were clear tablets.
  • the binder is added at around 3%, but in the case of polyvinyl alcohol, excellent effects were observed in rapid dissolution and manufacturability even with a very small addition amount.
  • the tablet of Comparative Example 5 to which no binder was added showed a fast dissolution property with an elution rate of 82% after 5 minutes, but only tablets with unclear secant lines and markings were obtained due to the occurrence of sticking.
  • the tablets of Examples 2 and 14 containing polyvinyl pyrrolidone as the binder and the tablets of Examples 3 and 15 containing polyvinyl alcohol / polyethylene glycol / graft copolymer (PVA / PEG graft copolymer) as the binder are both Even when the amount was changed to 1% and 2%, the tablet showed quick dissolution, no sticking, and a tablet with clear score lines and markings.
  • Table 5 shows the formulation of the tablets with different amounts of gelatin used as the binder, the dissolution rate after 5 minutes, and the presence or absence of sticking.
  • the tablets of Examples 4, 16 and 17 having an amount of gelatin of 0.5 to 2% exhibit a fast dissolution property with a dissolution rate of 75 to 79% after 5 minutes, have no sticking, and have a clear dividing line and marking. Met.
  • Table 6 shows the formulations of tablets using polyvinyl alcohol as a binder and various disintegrants, the dissolution rate after 5 minutes, and the presence or absence of sticking.
  • the tablets of Examples 18 to 23 had a dissolution rate as fast as 62 to 80% after 5 minutes, had no sticking, and had clear dividing lines and markings.
  • the tablet of the present invention was excellent in rapid dissolution and manufacturability regardless of the type and combination of disintegrants.
  • Table 7 shows the formulation of the tablet using polyvinyl alcohol as a binder and changing the type or amount of the fluidizing agent, the dissolution rate after 5 minutes, and the presence or absence of sticking.
  • the tablet of Example 24 containing no fluidizing agent and the tablet of Example 25 containing hydrous silicon dioxide as the fluidizing agent showed fast dissolution properties of 62% and 74% after 5 minutes and no sticking
  • the score line and engraved mark were clear uncoated tablets. Since the preparation containing the fluidizing agent exhibits faster dissolution than the preparation containing no fluidizing agent, it is more preferable to include the fluidizing agent.
  • Example 1 Tosfloxacin tosylate hydrate 100.0 g, L-aspartic acid 30.0 g, erythritol 33.0 g, light anhydrous silicic acid 8.0 g, low substituted hydroxypropylcellulose 12.0 g, crospovidone 8.0 g and sucralose 1.0 g were weighed. After passing through a sieve having an opening of 500 ⁇ m, the mixture was charged into a tumbling fluidized granulator and mixed. Thereafter, 200.0 g of a 1% polyvinyl alcohol (partially saponified product) aqueous solution was sprayed and granulated, dried and granulated to obtain a granulated powder.
  • a 1% polyvinyl alcohol partially saponified product
  • Example 2 Tosfloxacin tosylate hydrate 100.0 g, L-aspartic acid 30.0 g, erythritol 33.0 g, light anhydrous silicic acid 8.0 g, low substituted hydroxypropylcellulose 12.0 g, crospovidone 8.0 g and sucralose 1.0 g were weighed. After passing through a sieve having an opening of 500 ⁇ m, the mixture was charged into a tumbling fluidized granulator and mixed. Thereafter, 200.0 g of a 1% polyvinylpyrrolidone aqueous solution was sprayed for granulation, dried and sized to obtain a granulated powder.
  • Example 3 Tosfloxacin tosylate hydrate 100.0 g, L-aspartic acid 30.0 g, erythritol 33.0 g, light anhydrous silicic acid 8.0 g, low substituted hydroxypropylcellulose 12.0 g, crospovidone 8.0 g and sucralose 1.0 g were weighed. After passing through a sieve having an opening of 500 ⁇ m, the mixture was charged into a tumbling fluidized granulator and mixed. Thereafter, 200.0 g of a 1% polyvinyl alcohol / polyethylene glycol / graft copolymer aqueous solution was sprayed and granulated, dried and sized to obtain a granulated powder.
  • Example 4 Tosfloxacin tosylate hydrate 100.0 g, L-aspartic acid 30.0 g, erythritol 33.0 g, light anhydrous silicic acid 8.0 g, low substituted hydroxypropylcellulose 12.0 g, crospovidone 8.0 g and sucralose 1.0 g were weighed. After passing through a sieve having an opening of 500 ⁇ m, the mixture was charged into a tumbling fluidized granulator and mixed. Thereafter, 200.0 g of a 1% gelatin aqueous solution was sprayed to granulate, dried and sized to obtain a granulated powder.
  • Example 5 Tosfloxacin tosylate hydrate 100.0 g, L-aspartic acid 30.0 g, erythritol 34.8 g, light anhydrous silicic acid 8.0 g, low substituted hydroxypropylcellulose 12.0 g, crospovidone 8.0 g and sucralose 1.0 g were weighed. After passing through a sieve having an opening of 500 ⁇ m, the mixture was charged into a tumbling fluidized granulator and mixed. Thereafter, 200.0 g of 0.1% polyvinyl alcohol (partially saponified product) aqueous solution was sprayed and granulated, dried and granulated to obtain a granulated powder.
  • 0.1% polyvinyl alcohol (partially saponified product) aqueous solution was sprayed and granulated, dried and granulated to obtain a granulated powder.
  • Example 6 Tosfloxacin tosylate hydrate 100.0 g, L-aspartic acid 30.0 g, erythritol 34.6 g, light anhydrous silicic acid 8.0 g, low substituted hydroxypropylcellulose 12.0 g, crospovidone 8.0 g and sucralose 1.0 g were weighed. After passing through a sieve having an opening of 500 ⁇ m, the mixture was charged into a tumbling fluidized granulator and mixed. Thereafter, 200.0 g of 0.2% polyvinyl alcohol (partially saponified product) aqueous solution was sprayed and granulated, dried and granulated to obtain a granulated powder.
  • polyvinyl alcohol partially saponified product
  • Example 7 Tosfloxacin tosylate hydrate 100.0 g, L-aspartic acid 30.0 g, erythritol 34.0 g, light anhydrous silicic acid 8.0 g, low substituted hydroxypropylcellulose 12.0 g, crospovidone 8.0 g and sucralose 1.0 g were weighed. After passing through a sieve having an opening of 500 ⁇ m, the mixture was charged into a tumbling fluidized granulator and mixed. Thereafter, 200.0 g of 0.5% polyvinyl alcohol (partially saponified product) aqueous solution was sprayed and granulated, dried and granulated to obtain a granulated powder.
  • polyvinyl alcohol partially saponified product
  • Example 8 Tosfloxacin tosylate hydrate 7.50 g, L-aspartic acid 2.25 g, erythritol 2.50 g, hydrous silicon dioxide 0.30 g, low-substituted hydroxypropylcellulose 1.50 g and polyvinyl alcohol (partially saponified product) 0.29 g were weighed. After sieving with an opening 500 ⁇ m sieve, they were mixed. The powder was put in a mortar, granulated while adding water, sized with a sieve having an opening of 850 ⁇ m, dried, and further sized with a sieve having an opening of 500 ⁇ m to obtain a granulated powder.
  • This tableting powder was compression-molded with a tableting machine using a tablet with a tablet diameter of 6.5 mm and a round uncoated tablet having a score line and a stamp of 117 mg per tablet.
  • Example 9 Tosfloxacin tosylate hydrate 7.50 g, L-aspartic acid 2.25 g, erythritol 2.50 g, hydrous silicon dioxide 0.30 g, low-substituted hydroxypropylcellulose 1.50 g and polyvinyl alcohol (partially saponified product) 0.44 g were weighed. After sieving with an opening 500 ⁇ m sieve, they were mixed. The powder was put in a mortar, granulated while adding water, sized with a sieve having an opening of 850 ⁇ m, dried, and further sized with a sieve having an opening of 500 ⁇ m to obtain a granulated powder.
  • This tableting powder was compression-molded with a tableting machine using a tablet with a tablet diameter of 6.5 mm and a round uncoated tablet having a score line and an inscription of 118 mg per tablet.
  • Example 10 Tosfloxacin tosylate hydrate 7.50 g, L-aspartic acid 2.25 g, erythritol 2.50 g, hydrous silicon dioxide 0.30 g, low substituted hydroxypropylcellulose 1.50 g and polyvinyl alcohol (partially saponified product) 0.59 g were weighed. After sieving with an opening 500 ⁇ m sieve, they were mixed. The powder was put in a mortar, granulated while adding water, sized with a sieve having an opening of 850 ⁇ m, dried, and further sized with a sieve having an opening of 500 ⁇ m to obtain a granulated powder.
  • This tableting powder was compression-molded with a tableting machine using a tablet with a tablet diameter of 6.5 mm, and a round uncoated tablet having a score line of 120 mg per tablet and an inscription was obtained.
  • Example 11 Tosfloxacin tosylate hydrate 7.50 g, L-aspartic acid 2.25 g, erythritol 2.33 g, light anhydrous silicic acid 0.6 g, low substituted hydroxypropylcellulose 0.9 g, crospovidone 0.6 g, polyvinyl alcohol (partially saponified product) 0.3 g And 0.075 g of sucralose was weighed, sieved with a sieve having an opening of 500 ⁇ m, and mixed.
  • the powder was put in a mortar, granulated while adding water, sized with a sieve having an opening of 850 ⁇ m, dried, and further sized with a sieve having an opening of 500 ⁇ m to obtain a granulated powder.
  • 0.5% equivalent of light anhydrous silicic acid and 2.5% equivalent of magnesium stearate were added through a sieve having an opening of 500 ⁇ m and mixed to obtain a tableted powder.
  • This tableting powder was compression-molded with a tableting machine using a tablet with a tablet diameter of 6.5 mm, and a round uncoated tablet having a score line of 120 mg per tablet and an inscription was obtained.
  • Example 12 Tosfloxacin tosylate hydrate 7.50g, L-aspartic acid 2.25g, erythritol 2.18g, light anhydrous silicic acid 0.6g, low substituted hydroxypropylcellulose 0.9g, crospovidone 0.6g, polyvinyl alcohol (partially saponified product) 0.45g And 0.075 g of sucralose was weighed, sieved with a sieve having an opening of 500 ⁇ m, and mixed. The powder was put in a mortar, granulated while adding water, sized with a sieve having an opening of 850 ⁇ m, dried, and further sized with a sieve having an opening of 500 ⁇ m to obtain a granulated powder.
  • Example 13 Tosfloxacin tosylate hydrate 100.0 g, L-aspartic acid 30.0 g, erythritol 27.0 g, light anhydrous silicic acid 8.0 g, low substituted hydroxypropylcellulose 12.0 g, crospovidone 8.0 g and sucralose 1.0 g were weighed. After passing through a sieve having an opening of 500 ⁇ m, the mixture was charged into a tumbling fluidized granulator and mixed. Thereafter, 200.0 g of a 4% polyvinyl alcohol (partially saponified product) aqueous solution was sprayed and granulated, dried and sized to obtain a granulated powder.
  • a 4% polyvinyl alcohol (partially saponified product) aqueous solution was sprayed and granulated, dried and sized to obtain a granulated powder.
  • Example 14 Tosfloxacin tosylate hydrate 7.50 g, L-aspartic acid 2.25 g, erythritol 2.50 g, hydrous silicon dioxide 0.30 g, low-substituted hydroxypropylcellulose 1.50 g, polyvinylpyrrolidone 0.29 g were weighed and sieved with 500 ⁇ m mesh After sieving, they were mixed. The powder was put in a mortar, granulated while adding water, sized with a sieve having an opening of 850 ⁇ m, dried, and further sized with a sieve having an opening of 500 ⁇ m to obtain a granulated powder.
  • This tableting powder was compression-molded with a tableting machine using a tablet with a tablet diameter of 6.5 mm and a round uncoated tablet having a score line and a stamp of 117 mg per tablet.
  • Example 15 Tosfloxacin tosylate hydrate 7.50 g, L-aspartic acid 2.25 g, erythritol 2.50 g, hydrous silicon dioxide 0.30 g, low substituted hydroxypropylcellulose 1.50 g, polyvinyl alcohol / polyethylene glycol / graft copolymer 0.29 g, The mixture was sieved with a sieve having an opening of 500 ⁇ m and mixed. The powder was put in a mortar, granulated while adding water, sized with a sieve having an opening of 850 ⁇ m, dried, and further sized with a sieve having an opening of 500 ⁇ m to obtain a granulated powder.
  • This tableting powder was compression-molded with a tableting machine using a tablet with a tablet diameter of 6.5 mm and a round uncoated tablet having a score line and a stamp of 117 mg per tablet.
  • Example 16 Tosfloxacin tosylate hydrate 100.0 g, L-aspartic acid 30.0 g, erythritol 34.0 g, light anhydrous silicic acid 8.0 g, low substituted hydroxypropylcellulose 12.0 g, crospovidone 8.0 g and sucralose 1.0 g were weighed. After passing through a sieve having an opening of 500 ⁇ m, the mixture was charged into a tumbling fluidized granulator and mixed. Thereafter, 200.0 g of 0.5% gelatin aqueous solution was sprayed to granulate, dried and sized to obtain a granulated powder.
  • Example 17 Tosfloxacin tosylate hydrate 100.0 g, L-aspartic acid 30.0 g, erythritol 31.0 g, light anhydrous silicic acid 8.0 g, low substituted hydroxypropylcellulose 12.0 g, crospovidone 8.0 g and sucralose 1.0 g were weighed. After passing through a sieve having an opening of 500 ⁇ m, the mixture was charged into a tumbling fluidized granulator and mixed. Thereafter, 200.0 g of a 2% gelatin aqueous solution was sprayed to granulate, dried and sized to obtain a granulated powder.
  • Example 18 Weigh 100.0 g of tosufloxacin tosylate hydrate, 30.0 g of L-aspartic acid, 32.0 g of erythritol, 10.0 g of light anhydrous silicic acid, 10.0 g of carmellose and 10.0 g of low-substituted hydroxypropylcellulose, and use a sieve with an opening of 500 ⁇ m. After sieving, it was charged into a rolling fluidized granulator and mixed. Thereafter, 300.0 g of 0.67% polyvinyl alcohol (partially saponified product) aqueous solution was sprayed and granulated, dried and sized to obtain a granulated powder.
  • polyvinyl alcohol partially saponified product
  • magnesium stearate equivalent to 3.0% relative to the weight of the uncoated tablet was added through a sieve having an opening of 180 ⁇ m and mixed to obtain a tableted powder.
  • This tableting powder was compression-molded with a tableting machine using a tablet with a tablet diameter of 6.5 mm, and a round uncoated tablet having a score line of 120 mg per tablet and an inscription was obtained.
  • Example 19 Tosufloxacin tosylate hydrate 100.0 g, L-aspartic acid 30.0 g, erythritol 32.0 g, light anhydrous silicic acid 10.0 g, carmellose 10.0 g and crospovidone 10.0 g were weighed, sieved with a sieve with an opening of 500 ⁇ m, The mixture was charged into a dynamic fluidized granulator and mixed. Thereafter, 300.0 g of 0.67% polyvinyl alcohol (partially saponified product) aqueous solution was sprayed and granulated, dried and sized to obtain a granulated powder.
  • polyvinyl alcohol partially saponified product
  • magnesium stearate equivalent to 3.0% relative to the weight of the uncoated tablet was added through a sieve having an opening of 180 ⁇ m and mixed to obtain a tableted powder.
  • This tableting powder was compression-molded with a tableting machine using a tablet with a tablet diameter of 6.5 mm, and a round uncoated tablet having a score line of 120 mg per tablet and an inscription was obtained.
  • Example 20 Tosfloxacin tosylate hydrate 100.0 g, L-aspartic acid 30.0 g, erythritol 32.0 g, light anhydrous silicic acid 10.0 g, low-substituted hydroxypropylcellulose 10.0 g and crospovidone 10.0 g were weighed and sieved with an opening of 500 ⁇ m After sieving, it was charged into a rolling fluidized granulator and mixed. Thereafter, 300.0 g of 0.67% polyvinyl alcohol (partially saponified product) aqueous solution was sprayed and granulated, dried and sized to obtain a granulated powder.
  • polyvinyl alcohol partially saponified product
  • magnesium stearate equivalent to 3.0% relative to the weight of the uncoated tablet was added through a sieve having an opening of 180 ⁇ m and mixed to obtain a tableted powder.
  • This tableting powder was compression-molded with a tableting machine using a tablet with a tablet diameter of 6.5 mm, and a round uncoated tablet having a score line of 120 mg per tablet and an inscription was obtained.
  • Example 21 Tosufloxacin tosylate hydrate 100.0 g, L-aspartic acid 30.0 g, erythritol 32.0 g, light anhydrous silicic acid 10.0 g and low-substituted hydroxypropylcellulose 20.0 g were weighed, sieved with a sieve having an opening of 500 ⁇ m, The mixture was charged into a dynamic fluidized granulator and mixed. Thereafter, 200.0 g of a 1% polyvinyl alcohol (partially saponified product) aqueous solution was sprayed and granulated, dried and granulated to obtain a granulated powder.
  • a 1% polyvinyl alcohol partially saponified product
  • magnesium stearate equivalent to 3.0% relative to the weight of the uncoated tablet was added through a sieve having an opening of 180 ⁇ m and mixed to obtain a tableted powder.
  • This tableting powder was compression-molded with a tableting machine using a tablet with a tablet diameter of 6.5 mm, and a round uncoated tablet having a score line of 120 mg per tablet and an inscription was obtained.
  • Example 22 Tosufloxacin tosylate hydrate 100.0 g, L-aspartic acid 30.0 g, erythritol 32.0 g, light anhydrous silicic acid 10.0 g and croscarmellose sodium 20.0 g were weighed, passed through a sieve with an opening of 500 ⁇ m, and tumbling flow Charged into a granulator and mixed. Thereafter, 200.0 g of a 1% polyvinyl alcohol (partially saponified product) aqueous solution was sprayed and granulated, dried and granulated to obtain a granulated powder.
  • a 1% polyvinyl alcohol (partially saponified product) aqueous solution was sprayed and granulated, dried and granulated to obtain a granulated powder.
  • magnesium stearate equivalent to 3.0% relative to the weight of the uncoated tablet was added through a sieve having an opening of 180 ⁇ m and mixed to obtain a tableted powder.
  • This tableting powder was compression-molded with a tableting machine using a tablet with a tablet diameter of 6.5 mm, and a round uncoated tablet having a score line of 120 mg per tablet and an inscription was obtained.
  • Example 23 Tosfloxacin tosylate hydrate 100.0 g, L-aspartic acid 30.0 g, erythritol 32.0 g, light anhydrous silicic acid 10.0 g and carboxymethyl starch sodium 20.0 g were weighed, sieved through a sieve with an opening of 500 ⁇ m, and tumbling flow Charged into a granulator and mixed. Thereafter, 200.0 g of a 1% polyvinyl alcohol (partially saponified product) aqueous solution was sprayed and granulated, dried and granulated to obtain a granulated powder.
  • a 1% polyvinyl alcohol (partially saponified product) aqueous solution was sprayed and granulated, dried and granulated to obtain a granulated powder.
  • magnesium stearate equivalent to 3.0% relative to the weight of the uncoated tablet was added through a sieve having an opening of 180 ⁇ m and mixed to obtain a tableted powder.
  • This tableting powder was compression-molded with a tableting machine using a tablet with a tablet diameter of 6.5 mm, and a round uncoated tablet having a score line of 120 mg per tablet and an inscription was obtained.
  • Example 24 Tosfloxacin tosylate hydrate 100.0 g, L-aspartic acid 30.0 g, erythritol 43.3 g, carmellose 10.0 g, and crospovidone 10.0 g were weighed, passed through a sieve with an opening of 500 ⁇ m, and then put into a tumbling fluid granulator and dryer. Charged and mixed. Thereafter, 200.0 g of a 1% polyvinyl alcohol (partially saponified product) aqueous solution was sprayed and granulated, dried and granulated to obtain a granulated powder.
  • a 1% polyvinyl alcohol (partially saponified product) aqueous solution was sprayed and granulated, dried and granulated to obtain a granulated powder.
  • Example 25 Tosfloxacin tosylate hydrate 100.0 g, L-aspartic acid 30.0 g, erythritol 33.3 g, hydrous silicon dioxide 10.0 g, carmellose 10.0 g and crospovidone 10.0 g were weighed, sieved with a sieve with an opening of 500 ⁇ m, and rolled. The mixture was charged into a fluidized granulator and mixed. Thereafter, 200.0 g of a 1% polyvinyl alcohol (partially saponified product) aqueous solution was sprayed and granulated, dried and granulated to obtain a granulated powder.
  • a 1% polyvinyl alcohol partially saponified product
  • Example 26 On the uncoated tablet of Example 5, using a tablet coating machine (DRC-200, manufactured by Paulek), a coating agent (OPADRY 00F440000, Nippon Colorcon GK: Hypromellose 2910 71.500%, Macrogol 6000 14.166%, Talc 7.167%, Titanium oxide 7.067%, ferric sesquioxide 0.100% dispersed in water) was coated at a rate of 4 mg per tablet to obtain 124 mg film-coated tablets per tablet.
  • DRC-200 tablet coating machine
  • a coating agent OPC-200, manufactured by Paulek
  • Example 27 The uncoated tablets of Example 6 were coated in the same manner as in Example 26 to obtain 124 mg of film-coated tablets per tablet.
  • Example 28 The uncoated tablets of Example 7 were coated in the same manner as in Example 26 to obtain 124 mg of film-coated tablets per tablet.
  • Example 29 The uncoated tablets of Example 1 were coated in the same manner as in Example 26 to obtain 124 mg film-coated tablets per tablet.
  • Example 30 The uncoated tablets of Example 13 were coated in the same manner as in Example 26 to obtain 124 mg film-coated tablets per tablet.
  • a light silicic acid equivalent to 0.5% of the uncoated tablet mass is added to the granulated powder through a sieve having an opening of 500 ⁇ m, and magnesium stearate equivalent to 2.5% of the uncoated tablet mass is added to a sieve having an opening of 180 ⁇ m. And mixed to obtain a tableting powder.
  • This tableting powder was compression-molded with a tableting machine using a tablet with a tablet diameter of 6.5 mm, and a round uncoated tablet having a score line of 120 mg per tablet and an inscription was obtained.
  • the tablet of the present invention is useful as an antibacterial agent for children with improved compliance for children.

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Abstract

This tablet contains, (1) tosufloxacin tosilate, (2) a binder, and (3) an acidic amino acid. The tablet contains one or more types of binder selected from water-soluble polyvinyl polymers and gelatins, and is useful as a tablet containing tosufloxacin tosilate that exhibits rapid dissolution, is not subject to tableting problems, and can be manufactured stably.

Description

トスフロキサシントシル酸塩を含む錠剤Tablets containing tosufloxacin tosylate
　本発明は、速溶出性を示し、かつ打錠障害を起こさず、製造性に優れたトスフロキサシントシル酸塩を含む錠剤に関する。 The present invention relates to a tablet containing tosufloxacin tosylate which exhibits rapid dissolution and does not cause tableting troubles and is excellent in manufacturability.
　トスフロキサシンは、グラム陽性菌をはじめグラム陰性菌、嫌気性菌に対し広範囲な抗菌スペクトルを有するニューキノロン系の抗菌薬である（特許文献１）。トスフロキサシンを含む固形製剤の処方・製法としては、トスフロキサシントシル酸塩水和物、炭素数２～６の有機酸および一般的な医療用の担体とを混合して製剤化することが知られている（特許文献２）。また、トスフロキサシントシル酸塩、糖または糖アルコールおよび非イオン性水溶性セルロース誘導体またはポリビニルアルコールからなる粒状固形製剤が知られている（特許文献３）。さらに、トスフロキサシントシル酸塩を含む錠剤が市販されている。 Tosfloxacin is a new quinolone antibacterial agent having a broad antibacterial spectrum against Gram positive bacteria, Gram negative bacteria and anaerobic bacteria (Patent Document 1). As a prescription and production method of a solid preparation containing tosufloxacin, it is known to prepare a preparation by mixing tosufloxacin tosylate hydrate, an organic acid having 2 to 6 carbon atoms and a general medical carrier ( Patent Document 2). Also known is a granular solid preparation comprising tosufloxacin tosylate, sugar or sugar alcohol and a nonionic water-soluble cellulose derivative or polyvinyl alcohol (Patent Document 3). In addition, tablets containing tosufloxacin tosylate are commercially available.
特公昭６３－０２０８２８号公報Japanese Examined Patent Publication No. 63-020828 特公平０２－０３４３２４号公報Japanese Patent Publication No. 02-034324 特許第５２０２８５６号公報Japanese Patent No. 5202856
　小児用固形製剤として、たとえば、粒状固形製剤および錠剤が知られている。嚥下機能の未発達な乳幼児には、粒状固形製剤が好ましい。しかし、小学生のように嚥下機能も発達し、さらに味覚がはっきりしてくると、錠剤が好まれる傾向にある。
　錠剤は、その大きさが服薬コンプライアンスに大きく影響する。大きすぎる場合は、小児が嚥下できず、服薬コンプライアンスが低下する。成人用錠剤は、錠剤径が7.5～8.5mmと小児には大きいため、小児の服薬コンプライアンスの低下が懸念される。
　トスフロキサシントシル酸塩を含む小児用製剤として、細粒剤が市販されているが、小児用錠剤は開発されていない。
　市販されているトスフロキサシントシル酸塩を含む錠剤の5分後の溶出率は24％である。小児において安定した薬剤吸収を得るためには、細粒剤と同等の速溶出性を示す錠剤の開発が望まれている。
　さらに、トスフロキサシントシル酸塩は金属付着性があり、そのものを打錠した場合、原薬が杵に固着するという深刻な打錠障害（スティッキング）が生じる。特に、小児用錠に必要な割線を有する錠剤の安定製造には課題があった。
　本発明の課題は、速やかな溶出性を示し、スティッキングなどの打錠障害を起こさず、製造性に優れたトスフロキサシントシル酸塩を含む錠剤を提供することである。 As solid preparations for children, for example, granular solid preparations and tablets are known. For infants with an undeveloped swallowing function, a granular solid formulation is preferred. However, if the swallowing function develops like an elementary school student and the taste becomes clearer, tablets tend to be preferred.
The size of tablets greatly affects compliance. If it is too large, the child will not be able to swallow and compliance will be reduced. Since tablets for adults have a tablet diameter of 7.5 to 8.5 mm, which is large for children, there is a concern that the compliance of children will be reduced.
Fine granules have been marketed as pediatric preparations containing tosufloxacin tosylate, but pediatric tablets have not been developed.
The dissolution rate after 5 minutes of the commercially available tablet containing tosufloxacin tosylate is 24%. In order to obtain stable drug absorption in children, it is desired to develop a tablet that exhibits the same rapid dissolution properties as fine granules.
Furthermore, tosufloxacin tosylate has a metal adhesion property, and when it is tableted, serious tableting failure (sticking) occurs in which the drug substance is fixed to the bag. In particular, there was a problem in the stable production of tablets having a secant line necessary for pediatric tablets.
An object of the present invention is to provide a tablet containing tosufloxacin tosylate which exhibits rapid dissolution, does not cause tableting troubles such as sticking, and is excellent in manufacturability.
　このような状況下、本発明者らは鋭意研究を行った結果、（１）トスフロキサシントシル酸塩、（２）結合剤、および、（３）酸性アミノ酸を含む錠剤が、速溶出性を示し、かつ打錠障害を起こさず、製造性に優れることを見出し、本発明を完成させた。
　本発明は、以下を提供する。 Under such circumstances, the present inventors conducted intensive research. As a result, the tablet containing (1) tosufloxacin tosylate salt, (2) binder, and (3) acidic amino acid exhibits rapid dissolution, And it discovered that it was excellent in manufacturability, without causing a tableting trouble, and completed this invention.
The present invention provides the following.
［１］　（１）トスフロキサシントシル酸塩、（２）結合剤、および、（３）酸性アミノ酸、を含む錠剤であって；結合剤が、水溶性ポリビニル系高分子およびゼラチン類から選ばれる一種または二種以上であり、結合剤の含有率が、錠剤質量に対して５％未満である、錠剤。
［２］　酸性アミノ酸が、Ｌ－アスパラギン酸である、［１］に記載の錠剤。
［３］　結合剤が、水溶性ポリビニル系高分子である、［１］または［２］に記載の錠剤。
［４］　水溶性ポリビニル系高分子が、ポリビニルアルコールおよびポリビニルピロリドンから選ばれる一種または二種以上である、［１］～［３］のいずれか一に記載の錠剤。
［５］　水溶性ポリビニル系高分子が、ポリビニルアルコールである、［１］～［３］のいずれか一に記載の錠剤。
［６］　水溶性ポリビニル系高分子の含有率が、錠剤質量に対して０．０１～４．５％である、［１］～［５］のいずれか一に記載の錠剤。
［７］　さらに崩壊剤を含む、［１］～［６］のいずれか一に記載の錠剤。
［８］　崩壊剤が、カルメロース、カルメロースカルシウム、クロスカルメロースナトリウム、低置換度ヒドロキシプロピルセルロース、クロスポビドン、カルボキシメチルスターチナトリウムおよび部分α化デンプンから選ばれる一種または二種以上である、［７］に記載の錠剤。 [1] A tablet comprising (1) tosufloxacin tosylate, (2) a binder, and (3) an acidic amino acid; the binder is selected from water-soluble polyvinyl polymers and gelatins Two or more tablets, wherein the content of the binder is less than 5% based on the tablet mass.
[2] The tablet according to [1], wherein the acidic amino acid is L-aspartic acid.
[3] The tablet according to [1] or [2], wherein the binder is a water-soluble polyvinyl polymer.
[4] The tablet according to any one of [1] to [3], wherein the water-soluble polyvinyl polymer is one or more selected from polyvinyl alcohol and polyvinylpyrrolidone.
[5] The tablet according to any one of [1] to [3], wherein the water-soluble polyvinyl polymer is polyvinyl alcohol.
[6] The tablet according to any one of [1] to [5], wherein the content of the water-soluble polyvinyl polymer is 0.01 to 4.5% with respect to the tablet mass.
[7] The tablet according to any one of [1] to [6], further comprising a disintegrant.
[8] The disintegrant is one or more selected from carmellose, carmellose calcium, croscarmellose sodium, low-substituted hydroxypropyl cellulose, crospovidone, sodium carboxymethyl starch and partially pregelatinized starch. [7 ] The tablet of description.
　本発明は、さらに以下を提供する。
［Ａ］　さらに流動化剤を含む、［１］～［８］のいずれか一に記載の錠剤。
［Ｂ］　流動化剤が、含水二酸化ケイ素または軽質無水ケイ酸である、［Ａ］に記載の錠剤。
［Ｃ］　結合剤が、ゼラチン類である、［１］または［２］に記載の錠剤。
［Ｄ］　ゼラチン類が、アルカリ処理ゼラチンである、［Ｃ］に記載の錠剤。
［Ｅ］　ゼラチン類の含有率が、錠剤質量に対して０．１～４％である、［Ｃ］または［Ｄ］に記載の錠剤。 The present invention further provides the following.
[A] The tablet according to any one of [1] to [8], further comprising a fluidizing agent.
[B] The tablet according to [A], wherein the fluidizing agent is hydrous silicon dioxide or light anhydrous silicic acid.
[C] The tablet according to [1] or [2], wherein the binder is gelatin.
[D] The tablet according to [C], wherein the gelatin is alkali-treated gelatin.
[E] The tablet according to [C] or [D], wherein the gelatin content is 0.1 to 4% based on the tablet mass.
［Ｆ］　（１）トスフロキサシントシル酸塩、（２）結合剤、および、（３）酸性アミノ酸、を含む錠剤であって；結合剤が、水溶性ポリビニル系高分子であり；酸性アミノ酸が、Ｌ－アスパラギン酸であり；水溶性ポリビニル系高分子の含有率が、錠剤質量に対して０．０１～４．５％である、［１］に記載の錠剤。
［Ｇ］　（１）トスフロキサシントシル酸塩、（２）結合剤、および、（３）酸性アミノ酸、を含む錠剤であって；結合剤が、ポリビニルアルコールであり；酸性アミノ酸が、Ｌ－アスパラギン酸であり；ポリビニルアルコールの含有率が、錠剤質量に対して０．１～４％である、［１］に記載の錠剤。 [F] A tablet comprising (1) tosufloxacin tosylate, (2) a binder, and (3) an acidic amino acid; the binder is a water-soluble polyvinyl polymer; the acidic amino acid is L The tablet according to [1], which is aspartic acid; the content of the water-soluble polyvinyl polymer is 0.01 to 4.5% with respect to the tablet mass.
[G] A tablet comprising (1) tosufloxacin tosylate, (2) a binder, and (3) an acidic amino acid; the binder is polyvinyl alcohol; the acidic amino acid is L-aspartic acid Yes; The tablet according to [1], wherein the content of polyvinyl alcohol is 0.1 to 4% based on the weight of the tablet.
　本発明の錠剤は、小児等が服用し易く、速溶出性を示し、スティッキングなどの打錠障害を起こさず、製造性に優れたトスフロキサシントシル酸塩を含む錠剤である。
　本発明の錠剤は、用量調節のための割線を有する錠剤とすることもでき、小児等の服薬コンプライアンスの向上した小児用の抗菌剤として有用である。 The tablet of the present invention is a tablet containing tosufloxacin tosylate which is easy to be taken by children and the like, exhibits quick dissolution, does not cause tableting troubles such as sticking, and is excellent in manufacturability.
The tablet of the present invention can also be a tablet having a secant for dose adjustment, and is useful as an antibacterial agent for children with improved compliance in children and the like.
　本発明について以下に詳述する。
　本明細書中に使用される％は、特に断りのない限り、質量％を意味する。
　本明細書中に使用される各成分の含有率は、各成分に該当する物質が複数存在する場合、特に断らない限り、各成分に該当する複数の物質の合計の含有率を意味する。 The present invention is described in detail below.
Unless otherwise specified,% used in the present specification means mass%.
The content rate of each component used in the present specification means the total content rate of a plurality of substances corresponding to each component unless there is a specific case when there are a plurality of substances corresponding to each component.
　本明細書中に使用される「溶出率」は、特に断りのない限り、第16改正日本薬局方の溶出試験法第2法（パドル法）に従って測定される溶出率を意味する。
　本明細書中に使用される「速溶出性」とは、溶出試験開始5分後の溶出率が60％以上であることを意味する。「60％以上」の値は、トスフロキサシントシル酸塩小児用細粒剤から、溶出挙動の類似性の指標であるf2関数を用いて求めた。
　さらに、溶出試験開始5分後の溶出率が73%以上であることが、より好ましい。 The “dissolution rate” used in the present specification means the dissolution rate measured according to the 16th revised Japanese Pharmacopoeia dissolution test method 2 (paddle method) unless otherwise specified.
The term “fast dissolution” used in the present specification means that the dissolution rate after 5 minutes from the start of the dissolution test is 60% or more. The value of “60% or more” was obtained from tosufloxacin tosylate pediatric fine granules using the f2 function, which is an index of similarity of dissolution behavior.
Furthermore, it is more preferable that the dissolution rate 5 minutes after the start of the dissolution test is 73% or more.
＜錠剤＞
　本発明の錠剤は、トスフロキサシントシル酸塩、結合剤および酸性アミノ酸を含む。
　本発明の錠剤とは、素錠およびフィルムコーティング錠を意味する。
　フィルムコーティング錠とは、素錠に高分子化合物などのコーティング剤で剤皮を施した錠剤を意味する。
　錠剤としては、フィルムコーティング錠が好ましい。
　本発明の錠剤は、円形錠の場合、錠剤径が5.0～7.0mmであることが好ましい。
　本発明の錠剤を投与する場合、投与量および投与回数は、患者の年齢、体重および症状に応じて適宜選択できるが、通常、薬効を発揮しうる量を１日、１回から数回に分割して投与すればよい。通常、トスフロキサシンとして、１日、30～2000mgを１回から数回に分割して投与すればよい。 <Tablets>
The tablet of the present invention comprises tosufloxacin tosylate, a binder and an acidic amino acid.
The tablet of the present invention means an uncoated tablet and a film-coated tablet.
The film-coated tablet means a tablet obtained by coating a base tablet with a coating agent such as a polymer compound.
As the tablet, a film-coated tablet is preferable.
When the tablet of the present invention is a round tablet, the tablet diameter is preferably 5.0 to 7.0 mm.
When administering the tablet of the present invention, the dose and the number of doses can be appropriately selected according to the age, weight and symptoms of the patient, but the amount capable of exerting the drug effect is usually divided from once to several times a day. Can be administered. In general, 30 to 2000 mg of tosufloxacin may be administered in 1 to several divided doses a day.
＜トスフロキサシントシル酸塩＞
　本発明に使用されるトスフロキサシントシル酸塩は、たとえば、特公昭６３－０２０８２８号公報に記載の方法により製造することができる。
　本発明に使用されるトスフロキサシントシル酸塩は、水和物、溶媒和物および種々の形状の結晶ならびに非晶質固体を包含する。
　本発明に使用されるトスフロキサシントシル酸塩は、水和物であることが好ましい。
　トスフロキサシントシル酸塩の含有率は、錠剤質量に対して70％以下であることが好ましく、40～60％であることがより好ましい。 <Tosfloxacin tosylate>
Tosfloxacin tosylate used in the present invention can be produced, for example, by the method described in JP-B-63-020828.
Tosfloxacin tosylate used in the present invention includes hydrates, solvates and various forms of crystals and amorphous solids.
The tosufloxacin tosylate used in the present invention is preferably a hydrate.
The content of tosufloxacin tosylate is preferably 70% or less, more preferably 40 to 60%, relative to the tablet mass.
＜結合剤＞
　本発明に使用される結合剤としては、水溶性ポリビニル系高分子およびゼラチン類から選ばれる一種または二種以上が挙げられ、水溶性ポリビニル系高分子が好ましい。
　結合剤の含有率は、5％未満であればよい。
　水溶性ポリビニル系高分子としては、たとえば、ポリビニルアルコール、ポリビニルピロリドンおよび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から選ばれる一種または二種以上が挙げられ、ポリビニルアルコールおよびポリビニルピロリドンが好ましく、ポリビニルアルコールがより好ましい。
　ポリビニルアルコールとしては、完全けん化ポリビニルアルコールおよび部分けん化ポリビニルアルコールが挙げられ、部分けん化ポリビニルアルコールが好ましい。
　水溶性ポリビニル系高分子の含有率は、錠剤質量に対して0.01～4.5％が好ましく、0.05～4％がより好ましく、0.1～3％がさらに好ましい。 <Binder>
Examples of the binder used in the present invention include one or more selected from water-soluble polyvinyl polymers and gelatins, and water-soluble polyvinyl polymers are preferred.
The binder content may be less than 5%.
Examples of the water-soluble polyvinyl polymer include one or more selected from polyvinyl alcohol, polyvinyl pyrrolidone, and polyvinyl alcohol / polyethylene glycol / graft copolymer, preferably polyvinyl alcohol and polyvinyl pyrrolidone, and more preferably polyvinyl alcohol. .
Examples of the polyvinyl alcohol include fully saponified polyvinyl alcohol and partially saponified polyvinyl alcohol, and partially saponified polyvinyl alcohol is preferred.
The content of the water-soluble polyvinyl polymer is preferably 0.01 to 4.5%, more preferably 0.05 to 4%, still more preferably 0.1 to 3% with respect to the tablet mass.
　ゼラチン類としては、アルカリ処理ゼラチンおよび酸処理ゼラチンから選ばれる一種または二種が挙げられ、アルカリ処理ゼラチンが好ましい。
　ゼラチン類の含有率は、錠剤質量に対して0.1～4％が好ましく、0.3～4％がより好ましく、0.5～2％がさらに好ましい。 Examples of gelatins include one or two selected from alkali-treated gelatin and acid-treated gelatin, and alkali-treated gelatin is preferred.
The content of gelatin is preferably 0.1 to 4%, more preferably 0.3 to 4%, still more preferably 0.5 to 2% based on the tablet mass.
＜酸性アミノ酸＞
　本発明に使用される酸性アミノ酸とは、分子内に二つ以上のカルボキシル基を有するアミノ酸を意味する。
　本発明に使用される酸性アミノ酸としては、たとえば、アスパラギン酸およびグルタミン酸から選ばれる一種または二種が挙げられる。好ましい酸性アミノ酸としては、アスパラギン酸が挙げられ、Ｌ－アスパラギン酸がより好ましい。
　酸性アミノ酸の含有率は、錠剤質量に対して5～50％が好ましく、5～30％がより好ましく、10～20％がさらに好ましい。 <Acid amino acid>
The acidic amino acid used in the present invention means an amino acid having two or more carboxyl groups in the molecule.
Examples of the acidic amino acid used in the present invention include one or two selected from aspartic acid and glutamic acid. Preferable acidic amino acids include aspartic acid, and L-aspartic acid is more preferable.
The content of acidic amino acids is preferably 5 to 50%, more preferably 5 to 30%, still more preferably 10 to 20% based on the tablet mass.
＜崩壊剤＞
　本発明の錠剤は、さらに崩壊剤を含むことが好ましい。
　本発明に使用される崩壊剤としては、たとえば、カルメロース、カルメロースカルシウム、クロスカルメロースナトリウム、低置換度ヒドロキシプロピルセルロース、クロスポビドン、カルボキシメチルスターチナトリウムおよび部分α化デンプンなどから選ばれる一種または二種以上が挙げられる。
　好ましい崩壊剤としては、カルメロース、カルメロースカルシウム、クロスカルメロースナトリウム、低置換度ヒドロキシプロピルセルロース、クロスポビドンおよびカルボキシメチルスターチナトリウムから選ばれる一種または二種以上が挙げられ、カルメロース、低置換度ヒドロキシプロピルセルロース、クロスポビドンおよびカルボキシメチルスターチナトリウムから選ばれる一種または二種以上がより好ましく、低置換度ヒドロキシプロピルセルロースおよびクロスポビドンを組み合せることが、さらに好ましい。
　低置換度ヒドロキシプロピルセルロースとは、セルロースの低置換度ヒドロキシプロピルエーテルであり、本品を乾燥したものは定量するとき、ヒドロキシプロポキシ基(－ＯＣ3Ｈ6ＯＨ：75.09) 5.0～16.0％を含む。
　崩壊剤の含有率は、錠剤質量に対して5～50％が好ましく、5～30％がより好ましく、8～15％がさらに好ましい。 <Disintegrant>
The tablet of the present invention preferably further contains a disintegrant.
Examples of the disintegrant used in the present invention include one or two selected from carmellose, carmellose calcium, croscarmellose sodium, low-substituted hydroxypropylcellulose, crospovidone, sodium carboxymethyl starch, and partially pregelatinized starch. More than species.
Preferred disintegrants include one or more selected from carmellose, carmellose calcium, croscarmellose sodium, low-substituted hydroxypropylcellulose, crospovidone and carboxymethyl starch sodium. Carmellose, low-substituted hydroxypropyl One or more selected from cellulose, crospovidone and sodium carboxymethyl starch are more preferred, and a combination of low-substituted hydroxypropylcellulose and crospovidone is more preferred.
Low-substituted hydroxypropyl cellulose is a low-substituted hydroxypropyl ether of cellulose, and the dried product contains hydroxypropoxy groups (—OC 3 H 6 OH: 75.09) 5.0 to 16.0% when quantified. .
The content of the disintegrant is preferably 5 to 50%, more preferably 5 to 30%, still more preferably 8 to 15% based on the tablet mass.
＜流動化剤＞
　本発明の錠剤は、さらに流動化剤を含むことが好ましい。
　流動化剤としては、たとえば、合成ケイ酸アルミニウム、含水二酸化ケイ素および軽質無水ケイ酸などから選ばれる一種または二種以上が挙げられ、含水二酸化ケイ素および軽質無水ケイ酸から選ばれる一種または二種が好ましく、軽質無水ケイ酸がより好ましい。 <Fluidizer>
The tablet of the present invention preferably further contains a fluidizing agent.
Examples of the fluidizing agent include one or more selected from synthetic aluminum silicate, hydrous silicon dioxide, light anhydrous silicic acid, and the like, and one or two selected from hydrous silicon dioxide and light anhydrous silicic acid. Preferably, light anhydrous silicic acid is more preferable.
＜添加物＞
　本発明の錠剤には、本発明の効果を害さない範囲で、通常、薬剤に用いられる添加物を使用することができる。
　添加物としては、賦形剤、滑沢剤、甘味剤、着色剤、着香剤、界面活性剤、可塑剤およびコーティング剤などが挙げられる。
　賦形剤としては、たとえば、エリスリトール、マンニトール、キシリトールおよびソルビトールなどの糖アルコール類；白糖、粉糖、乳糖およびブドウ糖などの糖類；α－シクロデキストリン、β－シクロデキストリン、γ－シクロデキストリン、ヒドロキシプロピルβ－シクロデキストリンおよびスルホブチルエーテルβ－シクロデキストリンナトリウムなどのシクロデキストリン類；結晶セルロースおよび微結晶セルロースなどのセルロース類；トウモロコシデンプン、バレイショデンプンおよびα化デンプンなどのでんぷん類；マロン酸およびフマル酸などのジカルボン酸；グリコール酸、グルコン酸、酒石酸、リンゴ酸およびクエン酸などのオキシカルボン酸；ならびにアスコルビン酸などの炭素数２～６の有機酸などから選ばれる一種または二種以上が挙げられる。好ましい賦形剤としては、糖アルコール類が挙げられ、エリスリトールがより好ましい。賦形剤の使用量は特に限定されず、剤型に応じた量を使用すればよい。 <Additives>
In the tablet of the present invention, additives generally used for drugs can be used as long as the effects of the present invention are not impaired.
Examples of the additive include excipients, lubricants, sweeteners, coloring agents, flavoring agents, surfactants, plasticizers and coating agents.
Examples of the excipient include sugar alcohols such as erythritol, mannitol, xylitol and sorbitol; sugars such as sucrose, powdered sugar, lactose and glucose; α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, hydroxypropyl Cyclodextrins such as β-cyclodextrin and sulfobutyl ether β-cyclodextrin sodium; celluloses such as crystalline cellulose and microcrystalline cellulose; starches such as corn starch, potato starch and pregelatinized starch; malonic acid and fumaric acid, etc. One kind selected from dicarboxylic acids; oxycarboxylic acids such as glycolic acid, gluconic acid, tartaric acid, malic acid and citric acid; and organic acids having 2 to 6 carbon atoms such as ascorbic acid Others include two or more thereof. Preferred excipients include sugar alcohols, and erythritol is more preferred. The amount of the excipient used is not particularly limited, and an amount corresponding to the dosage form may be used.
　滑沢剤としては、たとえば、ステアリン酸、ステアリン酸マグネシウム、ステアリン酸カルシウム、フマル酸ステアリルナトリウム、タルクおよびショ糖脂肪酸エステルなどから選ばれる一種または二種以上が挙げられる。
　甘味剤としては、たとえば、アスパルテーム、サッカリン、ステビア、スクラロース、ソーマチンおよびアセスルファムカリウムなどから選ばれる一種または二種以上が挙げられる。
　着色剤としては、たとえば、二酸化チタン、三二酸化鉄、黄色三二酸化鉄、黒酸化鉄、食用赤色１０２号、食用黄色４号および食用黄色５号などから選ばれる一種または二種以上が挙げられる。
　着香剤としては、たとえば、オレンジ油、レモン油、ハッカ油およびパインオイルなどの精油；オレンジエッセンスおよびペパーミントエッセンスなどのエッセンス；チェリーフレーバー、バニラフレーバーおよびフルーツフレーバーなどのフレーバー；アップルミクロン、バナナミクロン、ピーチミクロン、ストロベリーミクロンおよびオレンジミクロンなどの粉末香料；バニリン；ならびにエチルバニリンなどから選ばれる一種または二種以上が挙げられる。
　界面活性剤としては、たとえば、ラウリル硫酸ナトリウム、スルホコハク酸ジオクチルナトリウム、ポリソルベートおよびポリオキシエチレン硬化ヒマシ油から選ばれる一種または二種以上が挙げられる。
　可塑剤としては、たとえば、クエン酸トリエチル、フタル酸ジブチル、マクロゴール（ポリエチレングリコール）、トリアセチン、グリセロールモノカプリルカプレート、レシチンおよびプロピレングリコールなどから選ばれる一種または二種以上が挙げられる。 Examples of the lubricant include one or more selected from stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, talc, sucrose fatty acid ester, and the like.
Examples of the sweetener include one or more selected from aspartame, saccharin, stevia, sucralose, thaumatin, and acesulfame potassium.
Examples of the colorant include one or more selected from titanium dioxide, iron sesquioxide, yellow iron sesquioxide, black iron oxide, edible red No. 102, edible yellow No. 4, edible yellow No. 5, and the like.
Examples of flavoring agents include essential oils such as orange oil, lemon oil, peppermint oil and pine oil; essences such as orange essence and peppermint essence; flavors such as cherry flavor, vanilla flavor and fruit flavor; apple micron, banana micron, One or two or more kinds selected from powder flavors such as peach micron, strawberry micron, and orange micron; vanillin; and ethyl vanillin.
Examples of the surfactant include one or more selected from sodium lauryl sulfate, dioctyl sodium sulfosuccinate, polysorbate, and polyoxyethylene hydrogenated castor oil.
Examples of the plasticizer include one or more selected from triethyl citrate, dibutyl phthalate, macrogol (polyethylene glycol), triacetin, glycerol monocaprycaprate, lecithin, propylene glycol, and the like.
　コーティング剤としては、たとえば、高分子化合物、可塑剤、着色剤、滑沢剤および光沢化剤などから選ばれる一種または二種以上が挙げられる。
　高分子化合物としては、たとえば、ヒプロメロース、ヒドロキシプロピルセルロース、ポリビニルアルコール、ポリビニルアルコール・アクリル酸・メタクリル酸メチル共重合体および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などから選ばれる一種または二種以上が挙げられる。
　コーティング剤として使用される滑沢剤としては、たとえば、タルクなどが挙げられる。
　光沢化剤としては、たとえば、カルナウバロウ、サラシミツロウおよびミツロウなどから選ばれる一種または二種以上が挙げられる。
　高分子化合物、可塑剤、着色剤、滑沢剤および光沢化剤の使用量は、特に限定されず、目的に応じて必要な量を適宜配合すればよい。
　これらの添加物は、いずれか一種または二種以上を組み合わせて添加してよく、添加量も特に限定されず、剤型に応じた量を添加すればよい。 Examples of the coating agent include one or more selected from polymer compounds, plasticizers, colorants, lubricants, brighteners, and the like.
Examples of the polymer compound include one or more selected from hypromellose, hydroxypropyl cellulose, polyvinyl alcohol, polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, polyvinyl alcohol / polyethylene glycol / graft copolymer, and the like. .
Examples of the lubricant used as the coating agent include talc.
Examples of the brightening agent include one or more selected from carnauba wax, white beeswax, beeswax and the like.
The amount of the polymer compound, plasticizer, colorant, lubricant and brightening agent used is not particularly limited, and a necessary amount may be appropriately blended depending on the purpose.
These additives may be added either alone or in combination of two or more. The addition amount is not particularly limited, and an amount corresponding to the dosage form may be added.
　本発明の好ましい錠剤は、（１）トスフロキサシントシル酸塩、（２）結合剤、および、（３）酸性アミノ酸、を含む錠剤であって；結合剤が、水溶性ポリビニル系高分子であり；酸性アミノ酸が、Ｌ－アスパラギン酸であり；水溶性ポリビニル系高分子の含有率が、錠剤質量に対して0.01～4.5％である、錠剤である。
　好ましい水溶性ポリビニル系高分子は、前記と同様である。 A preferred tablet of the present invention is a tablet comprising (1) tosufloxacin tosylate, (2) a binder, and (3) an acidic amino acid; the binder is a water-soluble polyvinyl polymer; acidic An amino acid is L-aspartic acid; a tablet having a water-soluble polyvinyl polymer content of 0.01 to 4.5% based on the tablet mass.
Preferred water-soluble polyvinyl polymers are the same as described above.
　本発明のさらに好ましい錠剤は、（１）トスフロキサシントシル酸塩、（２）結合剤、および、（３）酸性アミノ酸、を含む錠剤であって；結合剤が、ポリビニルアルコールであり；酸性アミノ酸が、Ｌ－アスパラギン酸であり；ポリビニルアルコールの含有率が、錠剤質量に対して0.1～4％である、錠剤である。
　好ましいポリビニルアルコールは、前記と同様である。 A further preferred tablet of the present invention is a tablet comprising (1) tosufloxacin tosylate, (2) a binder, and (3) an acidic amino acid; the binder is polyvinyl alcohol; L-aspartic acid; a tablet having a polyvinyl alcohol content of 0.1 to 4% based on the tablet weight.
Preferred polyvinyl alcohol is the same as described above.
　別の態様として、本発明の好ましい錠剤は、（１）トスフロキサシントシル酸塩、（２）結合剤、（３）酸性アミノ酸、（４）崩壊剤、および、（５）流動化剤、を含む錠剤であって；結合剤が、水溶性ポリビニル系高分子およびゼラチン類から選ばれる一種または二種以上であり；酸性アミノ酸が、Ｌ－アスパラギン酸であり；崩壊剤が、クロスポピドンおよび／またはカルボキシメチルスターチナトリウムを含む一種または二種以上であり；流動化剤が、含水二酸化ケイ素または軽質無水ケイ酸であり；結合剤の含有率が、錠剤質量に対して0.1～3％である、錠剤である。 In another aspect, a preferred tablet of the present invention is a tablet comprising (1) tosufloxacin tosylate, (2) a binder, (3) an acidic amino acid, (4) a disintegrant, and (5) a fluidizing agent. The binder is one or more selected from water-soluble polyvinyl polymers and gelatins; the acidic amino acid is L-aspartic acid; the disintegrant is crospovidone and / or carboxymethyl One or more containing sodium starch; the fluidizing agent is hydrous silicon dioxide or light anhydrous silicic acid; and the content of the binder is 0.1 to 3% of the tablet mass. .
＜製造方法＞
　本発明の錠剤は、たとえば、トスフロキサシントシル酸塩に水溶性ポリビニル系高分子またはゼラチン類から選ばれる一種または二種以上の結合剤および酸性アミノ酸を添加し、さらに必要に応じて賦形剤、流動化剤、崩壊剤および／または甘味剤を添加し、湿式造粒法または乾式造粒法により造粒末を製造する。次いで、必要に応じて、賦形剤、流動化剤、崩壊剤および／または滑沢剤などを造粒末に加え、打錠用混合末とし、打錠することにより製造することができる。さらに常法により、フィルムコーティング錠を製造することができる。 <Manufacturing method>
In the tablet of the present invention, for example, one or two or more binders selected from water-soluble polyvinyl polymers or gelatins and acidic amino acids are added to tosufloxacin tosylate, and further, an excipient, a fluid A granulating powder is produced by a wet granulation method or a dry granulation method by adding an agent, a disintegrant and / or a sweetener. Subsequently, if necessary, an excipient, a fluidizing agent, a disintegrant and / or a lubricant can be added to the granulated powder to obtain a mixed powder for tableting, and tableting can be performed. Furthermore, a film-coated tablet can be produced by a conventional method.
　本発明の造粒末の製造方法において好ましい造粒方法としては、湿式造粒法が挙げられる。
　湿式造粒法としては、たとえば、流動層造粒法、転動流動造粒法、遠心転動造粒法、混合撹拌造粒法、高速混合撹拌造粒法、転動造粒法、湿式破砕造粒法および押出造粒法などが挙げられる。好ましい湿式造粒法としては、流動層造粒法、転動流動造粒法、高速混合撹拌造粒法および湿式破砕造粒法が挙げられ、流動層造粒法および転動流動造粒法がより好ましい。 A preferable granulation method in the method for producing a granulated powder of the present invention includes a wet granulation method.
Examples of the wet granulation method include fluidized bed granulation method, rolling fluidized granulation method, centrifugal rolling granulation method, mixed stirring granulation method, high speed mixed stirring granulation method, rolling granulation method, wet crushing method Examples thereof include a granulation method and an extrusion granulation method. Preferable wet granulation methods include fluidized bed granulation method, rolling fluidized granulation method, high speed mixing and stirring granulation method and wet crushing granulation method. Fluidized bed granulation method and rolling fluidized granulation method include More preferred.
　次に、本発明の錠剤の有用性を試験例、実施例および比較例で説明するが、本発明はこれらにより、限定されるものではない。
　各試験例において各略号は、以下の意味を有する。
　ＨＰＣ：ヒドロキシプロピルセルロース
　ＨＰＭＣ：ヒドロキシプロピルメチルセルロース
　Ｌ－ＨＰＣ：低置換度ヒドロキシプロピルセルロース
　ＰＥＧ：ポリエチレングリコール
　ＰＶＡ：ポリビニルアルコール
　ＴＦＬＸ：トスフロキサシン
　トスフロキサシントシル酸塩として、トスフロキサシントシル酸塩水和物を用いた。
　カルボキシメチルスターチNa:カルボキシメチルスターチナトリウム
　クロスカルメロースNa:クロスカルメロースナトリウム
　ステアリン酸Mg:ステアリン酸マグネシウム Next, although the usefulness of the tablet of this invention is demonstrated by a test example, an Example, and a comparative example, this invention is not limited by these.
In each test example, each abbreviation has the following meaning.
HPC: hydroxypropylcellulose HPMC: hydroxypropylmethylcellulose L-HPC: low-substituted hydroxypropylcellulose PEG: polyethylene glycol PVA: polyvinyl alcohol TFLX: tosufloxacin Tosufloxacin tosylate hydrate was used as tosufloxacin tosylate.
Carboxymethyl starch Na: Carboxymethyl starch sodium Croscarmellose Na: Croscarmellose sodium Stearic acid Mg: Magnesium stearate
　特に断らない限り、各成分は、以下のものを使用した。
　α化デンプン：SWELSTAR WB-1（旭化成ケミカルズ）
　Ｌ－アスパラギン酸：Ｌ－アスパラギン酸（協和発酵バイオ）
　エリスリトール：エリスリトールT微粉（三菱化学フーズ）
　カルボキシメチルスターチナトリウム：Primojel（DMV）
　カルメロース：NS-300（五徳薬品）
　含水二酸化ケイ素：カープレックス＃80（DSL.ジャパン）
　クロスカルメロースナトリウム：キッコレート（旭化成ケミカルズ）
　クロスポビドン：ポリプラスドンXL-10（ISP）
　軽質無水ケイ酸：アエロジル200（日本アエロジル）
　スクラロース：スクラロース（P）（三栄源エフ・エフ・アイ）
　ステアリン酸マグネシウム：ステアリン酸マグネシウム　植物性（太平化学産業）
　ゼラチン：ゼラチン#150（新田ゼラチン）
　低置換度ヒドロキシプロピルセルロース：L-HPC LH-21（信越化学工業）
　ヒドロキシプロピルセルロース：HPC-SL（日本曹達）
　ヒドロキシプロピルメチルセルロース：TC-5E（信越化学工業）
　ポリビニルアルコール（部分けん化物）：EG-05PW（日本合成化学工業）
　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：コリコートIR（BASF）
　ポリビニルピロリドン：K29/32（ISP） Unless otherwise specified, the following components were used.
Alpha starch: SWELSTAR WB-1 (Asahi Kasei Chemicals)
L-aspartic acid: L-aspartic acid (Kyowa Hakko Bio)
Erythritol: Erythritol T fine powder (Mitsubishi Chemical Foods)
Carboxymethyl starch sodium: Primojel (DMV)
Carmellose: NS-300 (Gotoku Pharmaceutical)
Hydrous silicon dioxide: Carplex # 80 (DSL. Japan)
Croscarmellose sodium: Kikkolate (Asahi Kasei Chemicals)
Crospovidone: Polyplusdon XL-10 (ISP)
Light anhydrous silicic acid: Aerosil 200 (Japan Aerosil)
Sucralose: Sucralose (P) (San-Eigen F.F.I.)
Magnesium stearate: Magnesium stearate vegetable (Taihei Chemical Industry)
Gelatin: Gelatin # 150 (Nitta Gelatin)
Low-substituted hydroxypropyl cellulose: L-HPC LH-21 (Shin-Etsu Chemical)
Hydroxypropyl cellulose: HPC-SL (Nippon Soda)
Hydroxypropyl methylcellulose: TC-5E (Shin-Etsu Chemical)
Polyvinyl alcohol (partially saponified product): EG-05PW (Nippon Synthetic Chemical Industry)
Polyvinyl alcohol / polyethylene glycol / graft copolymer: Kollicoat IR (BASF)
Polyvinylpyrrolidone: K29 / 32 (ISP)
　特に断らない限り、各装置は、以下のものを使用した。錠剤は、硬度が50～70Nになるように打錠した。
　打錠機：タブフレックスTAB10（岡田精工）
　転動流動造粒乾燥機：マルチプレックスMP-01（パウレック） Unless otherwise specified, the following devices were used. The tablets were compressed so that the hardness was 50 to 70N.
Tableting machine: Tabflex TAB10 (Okada Seiko)
Rolling fluid granulating dryer: Multiplex MP-01 (Paurek)
試験例１
　試験製剤として、実施例１～２５および比較例１～５の素錠を用いた。
（１）製剤の溶出試験
　溶出性の基準値は、速溶出性の小児用細粒剤と類似の溶出性となるような、溶出試験開始5分後の溶出率を、溶出挙動の類似性の指標であるf2関数から求め、溶出試験開始5分後の溶出率≧60％を基準として設定した。
　溶出試験は、第16改正日本薬局方の溶出試験法第2法（パドル法）によって行った。各試験製剤1錠を、水900mLに添加し、毎分50回転で撹拌した。溶出試験開始5分後に自動サンプリング装置により溶出液を採取し、孔径35μmのフィルターでろ過した。紫外可視吸光度測定法＜日本薬局方一般試験法2.24＞に従い、トスフロキサシントシル酸塩の濃度を測定した。 Test example 1
The uncoated tablets of Examples 1 to 25 and Comparative Examples 1 to 5 were used as test preparations.
(1) Dissolution test of preparation The standard value of dissolution is the dissolution rate 5 minutes after the start of dissolution test, which is similar to that of fast-dissolving children's fine granules, and the similarity of dissolution behavior. It was determined from the f2 function as an index, and was set based on the dissolution rate ≧ 60% 5 minutes after the start of the dissolution test.
The dissolution test was conducted according to Method 16 (Paddle Method) of the 16th revised Japanese Pharmacopoeia. One tablet of each test preparation was added to 900 mL of water and stirred at 50 rpm. Five minutes after the start of the dissolution test, the eluate was collected by an automatic sampling device and filtered through a filter having a pore size of 35 μm. The concentration of tosufloxacin tosylate was measured according to UV-Vis absorbance measurement method <Japanese Pharmacopoeia General Test Method 2.24>.
（２）製剤の打錠性
　打錠時のスティッキングの有無を評価した。
　素錠の割線および刻印面の肉眼観察により、スティッキングの有無を評価した。
　結果を以下に示す。 (2) Tabletability of the preparation The presence or absence of sticking during tableting was evaluated.
The presence or absence of sticking was evaluated by visual observation of the score line of the uncoated tablet and the marking surface.
The results are shown below.
Figure JPOXMLDOC01-appb-T000001
Figure JPOXMLDOC01-appb-T000001
　表１に結合剤の種類を変えた錠剤の処方、５分後溶出率およびスティッキングの有無を示す。
　結合剤として水溶性ポリビニル系高分子である、ポリビニルアルコール、ポリビニルピロリドンもしくは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（PVA・PEGグラフトコポリマー）またはゼラチンを含む実施例１～４の錠剤は、５分後溶出率が75～82％と速溶出性を示し、かつスティッキングの無い、割線および刻印が鮮明な錠剤であった。
　一方、比較例１および２に示すように、結合剤としてヒドロキシプロピルセルロースまたはヒドロキシプロピルメチルセルロースを含む比較例１および２の錠剤は、５分後溶出率がそれぞれ82％および80％と速溶出性を示したが、スティッキングの発生により割線および刻印が不鮮明な錠剤であった。また、結合剤としてα化デンプンを含む比較例３の錠剤は、５分後溶出率が55％と速溶出性を示さず、かつスティッキングの発生により割線および刻印が不鮮明な素錠であった。結合剤として水溶性ポリビニル系高分子を含む錠剤は溶出性および製造性に優れたものであった。 Table 1 shows the formulation of the tablets with different binder types, the dissolution rate after 5 minutes, and the presence or absence of sticking.
The tablets of Examples 1 to 4 containing water-soluble polyvinyl polymer polyvinyl alcohol, polyvinyl pyrrolidone or polyvinyl alcohol / polyethylene glycol / graft copolymer (PVA / PEG graft copolymer) or gelatin as a binder are dissolved after 5 minutes. The rate was 75-82%, indicating rapid dissolution, and there was no sticking.
On the other hand, as shown in Comparative Examples 1 and 2, the tablets of Comparative Examples 1 and 2 containing hydroxypropylcellulose or hydroxypropylmethylcellulose as a binder had a dissolution rate of 82% and 80% after 5 minutes, respectively. As shown, it was a tablet whose score line and marking were unclear due to the occurrence of sticking. In addition, the tablet of Comparative Example 3 containing pregelatinized starch as a binder was an uncoated tablet with a dissolution rate of 55% after 5 minutes and no fast dissolution, and the dividing line and markings were unclear due to the occurrence of sticking. Tablets containing a water-soluble polyvinyl polymer as a binder were excellent in dissolution and manufacturability.
Figure JPOXMLDOC01-appb-T000002
Figure JPOXMLDOC01-appb-T000002
Figure JPOXMLDOC01-appb-T000003
Figure JPOXMLDOC01-appb-T000003
Figure JPOXMLDOC01-appb-T000004
Figure JPOXMLDOC01-appb-T000004
　表２、３および４に、使用する結合剤の量を変えた錠剤の処方、５分後溶出率およびスティッキングの有無を示す。
　結合剤としてポリビニルアルコールを含む実施例５～１３の錠剤は、結合剤の量が0.1～4％に変化しても、５分後溶出率は63～84％と速溶出性を示し、かつスティッキングが無く、割線および刻印が鮮明な錠剤であった。通常、打錠用顆粒を製造する際、結合剤は3％前後添加するが、ポリビニルアルコールの場合、非常に少ない添加量でも速溶出性および製造性において優れた効果がみられた。
　なお、結合剤を添加しなかった比較例５の錠剤は、５分後溶出率が82％と速溶出性を示したが、スティッキングの発生により割線および刻印が不鮮明な錠剤しか得られなかった。
　また、結合剤としてポリビニルピロリドンを含む実施例２および１４の錠剤ならびに結合剤として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（PVA・PEGグラフトコポリマー）を含む実施例３および１５の錠剤は、共に結合剤の量が1％および2％に変化しても速溶出性を示し、かつスティッキングが無く、割線および刻印が鮮明な錠剤であった。 Tables 2, 3 and 4 show the tablet formulations with varying amounts of binder used, the dissolution rate after 5 minutes and the presence or absence of sticking.
The tablets of Examples 5 to 13 containing polyvinyl alcohol as a binder showed fast dissolution with a dissolution rate of 63 to 84% after 5 minutes even when the amount of the binder was changed to 0.1 to 4%, and sticking There was no tablet, and the scored line and the engraved mark were clear tablets. Usually, when producing granules for tableting, the binder is added at around 3%, but in the case of polyvinyl alcohol, excellent effects were observed in rapid dissolution and manufacturability even with a very small addition amount.
Note that the tablet of Comparative Example 5 to which no binder was added showed a fast dissolution property with an elution rate of 82% after 5 minutes, but only tablets with unclear secant lines and markings were obtained due to the occurrence of sticking.
The tablets of Examples 2 and 14 containing polyvinyl pyrrolidone as the binder and the tablets of Examples 3 and 15 containing polyvinyl alcohol / polyethylene glycol / graft copolymer (PVA / PEG graft copolymer) as the binder are both Even when the amount was changed to 1% and 2%, the tablet showed quick dissolution, no sticking, and a tablet with clear score lines and markings.
Figure JPOXMLDOC01-appb-T000005
Figure JPOXMLDOC01-appb-T000005
　表５に結合剤として使用するゼラチンの量を変えた錠剤の処方、５分後溶出率およびスティッキングの有無を示す。
　ゼラチンの量が0.5～2％である実施例４、１６および１７の錠剤は、５分後溶出率が75～79％と速溶出性を示し、かつスティッキングが無く、割線および刻印が鮮明な錠剤であった。 Table 5 shows the formulation of the tablets with different amounts of gelatin used as the binder, the dissolution rate after 5 minutes, and the presence or absence of sticking.
The tablets of Examples 4, 16 and 17 having an amount of gelatin of 0.5 to 2% exhibit a fast dissolution property with a dissolution rate of 75 to 79% after 5 minutes, have no sticking, and have a clear dividing line and marking. Met.
Figure JPOXMLDOC01-appb-T000006
Figure JPOXMLDOC01-appb-T000006
　表６に結合剤としてポリビニルアルコールを使用し、崩壊剤を種々変えた錠剤の処方、５分後溶出率およびスティッキングの有無を示す。
　実施例１８～２３の錠剤は、５分後溶出率が62～80％と速溶出性を示し、かつスティッキングが無く、割線および刻印が鮮明な錠剤であった。本発明の錠剤は崩壊剤の種類および組み合わせによらず、速溶出性と製造性に優れたものであった。 Table 6 shows the formulations of tablets using polyvinyl alcohol as a binder and various disintegrants, the dissolution rate after 5 minutes, and the presence or absence of sticking.
The tablets of Examples 18 to 23 had a dissolution rate as fast as 62 to 80% after 5 minutes, had no sticking, and had clear dividing lines and markings. The tablet of the present invention was excellent in rapid dissolution and manufacturability regardless of the type and combination of disintegrants.
Figure JPOXMLDOC01-appb-T000007
Figure JPOXMLDOC01-appb-T000007
　表７に結合剤としてポリビニルアルコールを使用し、流動化剤の種類または量を変えた錠剤の処方、５分後溶出率およびスティッキングの有無を示す。
　流動化剤を含まない実施例２４の錠剤および流動化剤として含水二酸化ケイ素を含む実施例２５の錠剤は、５分後溶出率が62％および74％と速溶出性を示し、かつスティッキングが無く、割線および刻印が鮮明な素錠であった。
　流動化剤を含む製剤は、含まない製剤よりも優れた速溶出性を示したことから、流動化剤を含むことがより好ましい。 Table 7 shows the formulation of the tablet using polyvinyl alcohol as a binder and changing the type or amount of the fluidizing agent, the dissolution rate after 5 minutes, and the presence or absence of sticking.
The tablet of Example 24 containing no fluidizing agent and the tablet of Example 25 containing hydrous silicon dioxide as the fluidizing agent showed fast dissolution properties of 62% and 74% after 5 minutes and no sticking The score line and engraved mark were clear uncoated tablets.
Since the preparation containing the fluidizing agent exhibits faster dissolution than the preparation containing no fluidizing agent, it is more preferable to include the fluidizing agent.
実施例１
　トスフロキサシントシル酸塩水和物100.0g、Ｌ－アスパラギン酸30.0g、エリスリトール33.0g、軽質無水ケイ酸8.0g、低置換度ヒドロキシプロピルセルロース12.0g、クロスポビドン8.0gおよびスクラロース1.0ｇを秤取し、目開き500μmの篩で篩過後、転動流動造粒乾燥機に仕込み、混合した。その後、1％ポリビニルアルコール（部分けん化物）水溶液200.0gを噴霧して造粒し、乾燥および整粒して造粒末を得た。この造粒末に素錠質量に対して0.5％相当量の軽質無水ケイ酸を目開き500μmの篩を通して加え、また素錠質量に対して2.5％相当量のステアリン酸マグネシウムを目開き180μmの篩を通して加え、混合し打錠末を得た。この打錠末を、錠剤径6.5mmで碁石面の杵を用い、打錠機で圧縮成型し、1錠あたり120mgの割線および刻印を有する円形の素錠を得た。 Example 1
Tosfloxacin tosylate hydrate 100.0 g, L-aspartic acid 30.0 g, erythritol 33.0 g, light anhydrous silicic acid 8.0 g, low substituted hydroxypropylcellulose 12.0 g, crospovidone 8.0 g and sucralose 1.0 g were weighed. After passing through a sieve having an opening of 500 μm, the mixture was charged into a tumbling fluidized granulator and mixed. Thereafter, 200.0 g of a 1% polyvinyl alcohol (partially saponified product) aqueous solution was sprayed and granulated, dried and granulated to obtain a granulated powder. To this granulated powder, light anhydrous silicic acid equivalent to 0.5% with respect to the weight of the uncoated tablet is added through a sieve having an opening of 500 μm, and magnesium stearate equivalent to 2.5% of the weight of the uncoated tablet is added to a sieve with an opening of 180 μm. And mixed to obtain a tableting powder. This tableting powder was compression-molded with a tableting machine using a tablet with a tablet diameter of 6.5 mm, and a round uncoated tablet having a score line of 120 mg per tablet and an inscription was obtained.
実施例２
　トスフロキサシントシル酸塩水和物100.0g、Ｌ－アスパラギン酸30.0g、エリスリトール33.0g、軽質無水ケイ酸8.0g、低置換度ヒドロキシプロピルセルロース12.0g、クロスポビドン8.0gおよびスクラロース1.0ｇを秤取し、目開き500μmの篩で篩過後、転動流動造粒乾燥機に仕込み、混合した。その後、1％ポリビニルピロリドン水溶液200.0gを噴霧して造粒し、乾燥および整粒して造粒末を得た。この造粒末に素錠質量に対して0.5％相当量の軽質無水ケイ酸を目開き500μmの篩を通して加え、また素錠質量に対して2.5％相当量のステアリン酸マグネシウムを目開き180μmの篩を通して加え、混合し打錠末を得た。この打錠末を、錠剤径6.5mmで碁石面の杵を用い、打錠機で圧縮成型し、1錠あたり120mgの割線および刻印を有する円形の素錠を得た。 Example 2
Tosfloxacin tosylate hydrate 100.0 g, L-aspartic acid 30.0 g, erythritol 33.0 g, light anhydrous silicic acid 8.0 g, low substituted hydroxypropylcellulose 12.0 g, crospovidone 8.0 g and sucralose 1.0 g were weighed. After passing through a sieve having an opening of 500 μm, the mixture was charged into a tumbling fluidized granulator and mixed. Thereafter, 200.0 g of a 1% polyvinylpyrrolidone aqueous solution was sprayed for granulation, dried and sized to obtain a granulated powder. To this granulated powder, light anhydrous silicic acid equivalent to 0.5% with respect to the weight of the uncoated tablet is added through a sieve having an opening of 500 μm, and magnesium stearate equivalent to 2.5% of the weight of the uncoated tablet is added to a sieve with an opening of 180 μm. And mixed to obtain a tableting powder. This tableting powder was compression-molded with a tableting machine using a tablet with a tablet diameter of 6.5 mm, and a round uncoated tablet having a score line of 120 mg per tablet and an inscription was obtained.
実施例３
　トスフロキサシントシル酸塩水和物100.0g、Ｌ－アスパラギン酸30.0g、エリスリトール33.0g、軽質無水ケイ酸8.0g、低置換度ヒドロキシプロピルセルロース12.0g、クロスポビドン8.0gおよびスクラロース1.0ｇを秤取し、目開き500μmの篩で篩過後、転動流動造粒乾燥機に仕込み、混合した。その後、1％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水溶液200.0gを噴霧して造粒し、乾燥および整粒して造粒末を得た。この造粒末に素錠質量に対して0.5％相当量の軽質無水ケイ酸を目開き500μmの篩を通して加え、また素錠質量に対して2.5％相当量のステアリン酸マグネシウムを目開き180μmの篩を通して加え、混合し打錠末を得た。この打錠末を、錠剤径6.5mmで碁石面の杵を用い、打錠機で圧縮成型し、1錠あたり120mgの割線および刻印を有する円形の素錠を得た。 Example 3
Tosfloxacin tosylate hydrate 100.0 g, L-aspartic acid 30.0 g, erythritol 33.0 g, light anhydrous silicic acid 8.0 g, low substituted hydroxypropylcellulose 12.0 g, crospovidone 8.0 g and sucralose 1.0 g were weighed. After passing through a sieve having an opening of 500 μm, the mixture was charged into a tumbling fluidized granulator and mixed. Thereafter, 200.0 g of a 1% polyvinyl alcohol / polyethylene glycol / graft copolymer aqueous solution was sprayed and granulated, dried and sized to obtain a granulated powder. To this granulated powder, light anhydrous silicic acid equivalent to 0.5% with respect to the weight of the uncoated tablet is added through a sieve having an opening of 500 μm, and magnesium stearate equivalent to 2.5% of the weight of the uncoated tablet is added to a sieve with an opening of 180 μm. And mixed to obtain a tableting powder. This tableting powder was compression-molded with a tableting machine using a tablet with a tablet diameter of 6.5 mm, and a round uncoated tablet having a score line of 120 mg per tablet and an inscription was obtained.
実施例４
　トスフロキサシントシル酸塩水和物100.0g、Ｌ－アスパラギン酸30.0g、エリスリトール33.0g、軽質無水ケイ酸8.0g、低置換度ヒドロキシプロピルセルロース12.0g、クロスポビドン8.0gおよびスクラロース1.0ｇを秤取し、目開き500μmの篩で篩過後、転動流動造粒乾燥機に仕込み、混合した。その後、1％ゼラチン水溶液200.0gを噴霧して造粒し、乾燥および整粒して造粒末を得た。この造粒末に素錠質量に対して0.5％相当量の軽質無水ケイ酸を目開き500μmの篩を通して加え、また素錠質量に対して2.5％相当量のステアリン酸マグネシウムを目開き180μmの篩を通して加え、混合し打錠末を得た。この打錠末を、錠剤径6.5mmで碁石面の杵を用い、打錠機で圧縮成型し、1錠あたり120mgの割線および刻印を有する円形の素錠を得た。 Example 4
Tosfloxacin tosylate hydrate 100.0 g, L-aspartic acid 30.0 g, erythritol 33.0 g, light anhydrous silicic acid 8.0 g, low substituted hydroxypropylcellulose 12.0 g, crospovidone 8.0 g and sucralose 1.0 g were weighed. After passing through a sieve having an opening of 500 μm, the mixture was charged into a tumbling fluidized granulator and mixed. Thereafter, 200.0 g of a 1% gelatin aqueous solution was sprayed to granulate, dried and sized to obtain a granulated powder. To this granulated powder, light anhydrous silicic acid equivalent to 0.5% with respect to the weight of the uncoated tablet is added through a sieve having an opening of 500 μm, and magnesium stearate equivalent to 2.5% of the weight of the uncoated tablet is added to a sieve with an opening of 180 μm. And mixed to obtain a tableting powder. This tableting powder was compression-molded with a tableting machine using a tablet with a tablet diameter of 6.5 mm, and a round uncoated tablet having a score line of 120 mg per tablet and an inscription was obtained.
実施例５
　トスフロキサシントシル酸塩水和物100.0g、Ｌ－アスパラギン酸30.0g、エリスリトール34.8g、軽質無水ケイ酸8.0g、低置換度ヒドロキシプロピルセルロース12.0g、クロスポビドン8.0gおよびスクラロース1.0ｇを秤取し、目開き500μmの篩で篩過後、転動流動造粒乾燥機に仕込み、混合した。その後、0.1％ポリビニルアルコール（部分けん化物）水溶液200.0gを噴霧して造粒し、乾燥および整粒して造粒末を得た。この造粒末に素錠質量に対して0.5％相当量の軽質無水ケイ酸を目開き500μmの篩を通して加え、また素錠質量に対して2.5％相当量のステアリン酸マグネシウムを目開き180μmの篩を通して加え、混合し打錠末を得た。この打錠末を、錠剤径6.5mmで碁石面の杵を用い、打錠機で圧縮成型し、1錠あたり120mgの割線および刻印を有する円形の素錠を得た。 Example 5
Tosfloxacin tosylate hydrate 100.0 g, L-aspartic acid 30.0 g, erythritol 34.8 g, light anhydrous silicic acid 8.0 g, low substituted hydroxypropylcellulose 12.0 g, crospovidone 8.0 g and sucralose 1.0 g were weighed. After passing through a sieve having an opening of 500 μm, the mixture was charged into a tumbling fluidized granulator and mixed. Thereafter, 200.0 g of 0.1% polyvinyl alcohol (partially saponified product) aqueous solution was sprayed and granulated, dried and granulated to obtain a granulated powder. To this granulated powder, light anhydrous silicic acid equivalent to 0.5% with respect to the weight of the uncoated tablet is added through a sieve having an opening of 500 μm, and magnesium stearate equivalent to 2.5% of the weight of the uncoated tablet is added to a sieve with an opening of 180 μm. And mixed to obtain a tableting powder. This tableting powder was compression-molded with a tableting machine using a tablet with a tablet diameter of 6.5 mm, and a round uncoated tablet having a score line of 120 mg per tablet and an inscription was obtained.
実施例６
　トスフロキサシントシル酸塩水和物100.0g、Ｌ－アスパラギン酸30.0g、エリスリトール34.6g、軽質無水ケイ酸8.0g、低置換度ヒドロキシプロピルセルロース12.0g、クロスポビドン8.0gおよびスクラロース1.0ｇを秤取し、目開き500μmの篩で篩過後、転動流動造粒乾燥機に仕込み、混合した。その後、0.2％ポリビニルアルコール（部分けん化物）水溶液200.0gを噴霧して造粒し、乾燥および整粒して造粒末を得た。この造粒末に素錠質量に対して0.5％相当量の軽質無水ケイ酸を目開き500μmの篩を通して加え、また素錠質量に対して2.5％相当量のステアリン酸マグネシウムを目開き180μmの篩を通して加え、混合し打錠末を得た。この打錠末を、錠剤径6.5mmで碁石面の杵を用い、打錠機で圧縮成型し、1錠あたり120mgの割線および刻印を有する円形の素錠を得た。 Example 6
Tosfloxacin tosylate hydrate 100.0 g, L-aspartic acid 30.0 g, erythritol 34.6 g, light anhydrous silicic acid 8.0 g, low substituted hydroxypropylcellulose 12.0 g, crospovidone 8.0 g and sucralose 1.0 g were weighed. After passing through a sieve having an opening of 500 μm, the mixture was charged into a tumbling fluidized granulator and mixed. Thereafter, 200.0 g of 0.2% polyvinyl alcohol (partially saponified product) aqueous solution was sprayed and granulated, dried and granulated to obtain a granulated powder. To this granulated powder, light anhydrous silicic acid equivalent to 0.5% with respect to the weight of the uncoated tablet is added through a sieve having an opening of 500 μm, and magnesium stearate equivalent to 2.5% of the weight of the uncoated tablet is added to a sieve with an opening of 180 μm. And mixed to obtain a tableting powder. This tableting powder was compression-molded with a tableting machine using a tablet with a tablet diameter of 6.5 mm, and a round uncoated tablet having a score line of 120 mg per tablet and an inscription was obtained.
実施例７
　トスフロキサシントシル酸塩水和物100.0g、Ｌ－アスパラギン酸30.0g、エリスリトール34.0g、軽質無水ケイ酸8.0g、低置換度ヒドロキシプロピルセルロース12.0g、クロスポビドン8.0gおよびスクラロース1.0ｇを秤取し、目開き500μmの篩で篩過後、転動流動造粒乾燥機に仕込み、混合した。その後、0.5％ポリビニルアルコール（部分けん化物）水溶液200.0gを噴霧して造粒し、乾燥および整粒して造粒末を得た。この造粒末に素錠質量に対して0.5％相当量の軽質無水ケイ酸を目開き500μmの篩を通して加え、また素錠質量に対して2.5％相当量のステアリン酸マグネシウムを目開き180μmの篩を通して加え、混合し打錠末を得た。この打錠末を、錠剤径6.5mmで碁石面の杵を用い、打錠機で圧縮成型し、1錠あたり120mgの割線および刻印を有する円形の素錠を得た。 Example 7
Tosfloxacin tosylate hydrate 100.0 g, L-aspartic acid 30.0 g, erythritol 34.0 g, light anhydrous silicic acid 8.0 g, low substituted hydroxypropylcellulose 12.0 g, crospovidone 8.0 g and sucralose 1.0 g were weighed. After passing through a sieve having an opening of 500 μm, the mixture was charged into a tumbling fluidized granulator and mixed. Thereafter, 200.0 g of 0.5% polyvinyl alcohol (partially saponified product) aqueous solution was sprayed and granulated, dried and granulated to obtain a granulated powder. To this granulated powder, light anhydrous silicic acid equivalent to 0.5% with respect to the weight of the uncoated tablet is added through a sieve having an opening of 500 μm, and magnesium stearate equivalent to 2.5% of the weight of the uncoated tablet is added to a sieve with an opening of 180 μm. And mixed to obtain a tableting powder. This tableting powder was compression-molded with a tableting machine using a tablet with a tablet diameter of 6.5 mm, and a round uncoated tablet having a score line of 120 mg per tablet and an inscription was obtained.
実施例８
　トスフロキサシントシル酸塩水和物7.50g、Ｌ－アスパラギン酸2.25g、エリスリトール2.50g、含水二酸化ケイ素0.30g、低置換度ヒドロキシプロピルセルロース1.50gおよびポリビニルアルコール（部分けん化物）0.29gを秤取し、目開き500μmの篩で篩過後、混合した。その末を乳鉢に入れ、水を添加しながら造粒し、目開き850μmの篩で整粒後乾燥し、さらに、目開き500μmの篩で整粒して造粒末を得た。この造粒末に2％相当量のステアリン酸マグネシウムを目開き500μmの篩を通して加え、混合し打錠末を得た。この打錠末を、錠剤径6.5mmで碁石面の杵を用い、打錠機で圧縮成型し、1錠あたり117mgの割線および刻印を有する円形の素錠を得た。 Example 8
Tosfloxacin tosylate hydrate 7.50 g, L-aspartic acid 2.25 g, erythritol 2.50 g, hydrous silicon dioxide 0.30 g, low-substituted hydroxypropylcellulose 1.50 g and polyvinyl alcohol (partially saponified product) 0.29 g were weighed. After sieving with an opening 500 μm sieve, they were mixed. The powder was put in a mortar, granulated while adding water, sized with a sieve having an opening of 850 μm, dried, and further sized with a sieve having an opening of 500 μm to obtain a granulated powder. To this granulated powder, 2% equivalent amount of magnesium stearate was added through a sieve having an opening of 500 μm and mixed to obtain a tableted powder. This tableting powder was compression-molded with a tableting machine using a tablet with a tablet diameter of 6.5 mm and a round uncoated tablet having a score line and a stamp of 117 mg per tablet.
実施例９
　トスフロキサシントシル酸塩水和物7.50g、Ｌ－アスパラギン酸2.25g、エリスリトール2.50g、含水二酸化ケイ素0.30g、低置換度ヒドロキシプロピルセルロース1.50gおよびポリビニルアルコール（部分けん化物）0.44gを秤取し、目開き500μmの篩で篩過後、混合した。その末を乳鉢に入れ、水を添加しながら造粒し、目開き850μmの篩で整粒後乾燥し、さらに、目開き500μmの篩で整粒して造粒末を得た。この造粒末に2％相当量のステアリン酸マグネシウムを目開き500μmの篩を通して加え、混合し打錠末を得た。この打錠末を、錠剤径6.5mmで碁石面の杵を用い、打錠機で圧縮成型し、1錠あたり118mgの割線および刻印を有する円形の素錠を得た。 Example 9
Tosfloxacin tosylate hydrate 7.50 g, L-aspartic acid 2.25 g, erythritol 2.50 g, hydrous silicon dioxide 0.30 g, low-substituted hydroxypropylcellulose 1.50 g and polyvinyl alcohol (partially saponified product) 0.44 g were weighed. After sieving with an opening 500 μm sieve, they were mixed. The powder was put in a mortar, granulated while adding water, sized with a sieve having an opening of 850 μm, dried, and further sized with a sieve having an opening of 500 μm to obtain a granulated powder. To this granulated powder, 2% equivalent amount of magnesium stearate was added through a sieve having an opening of 500 μm and mixed to obtain a tableted powder. This tableting powder was compression-molded with a tableting machine using a tablet with a tablet diameter of 6.5 mm and a round uncoated tablet having a score line and an inscription of 118 mg per tablet.
実施例１０
　トスフロキサシントシル酸塩水和物7.50g、Ｌ－アスパラギン酸2.25g、エリスリトール2.50g、含水二酸化ケイ素0.30g、低置換度ヒドロキシプロピルセルロース1.50gおよびポリビニルアルコール（部分けん化物）0.59gを秤取し、目開き500μmの篩で篩過後、混合した。その末を乳鉢に入れ、水を添加しながら造粒し、目開き850μmの篩で整粒後乾燥し、さらに、目開き500μmの篩で整粒して造粒末を得た。この造粒末に2％相当量のステアリン酸マグネシウムを目開き500μmの篩を通して加え、混合し打錠末を得た。この打錠末を、錠剤径6.5mmで碁石面の杵を用い、打錠機で圧縮成型し、1錠あたり120mgの割線および刻印を有する円形の素錠を得た。 Example 10
Tosfloxacin tosylate hydrate 7.50 g, L-aspartic acid 2.25 g, erythritol 2.50 g, hydrous silicon dioxide 0.30 g, low substituted hydroxypropylcellulose 1.50 g and polyvinyl alcohol (partially saponified product) 0.59 g were weighed. After sieving with an opening 500 μm sieve, they were mixed. The powder was put in a mortar, granulated while adding water, sized with a sieve having an opening of 850 μm, dried, and further sized with a sieve having an opening of 500 μm to obtain a granulated powder. To this granulated powder, 2% equivalent amount of magnesium stearate was added through a sieve having an opening of 500 μm and mixed to obtain a tableted powder. This tableting powder was compression-molded with a tableting machine using a tablet with a tablet diameter of 6.5 mm, and a round uncoated tablet having a score line of 120 mg per tablet and an inscription was obtained.
実施例１１
　トスフロキサシントシル酸塩水和物7.50g、Ｌ－アスパラギン酸2.25g、エリスリトール2.33g、軽質無水ケイ酸0.6g、低置換度ヒドロキシプロピルセルロース0.9g、クロスポビドン0.6g、ポリビニルアルコール（部分けん化物）0.3gおよびスクラロース0.075gを秤取し、目開き500μmの篩で篩過後、混合した。その末を乳鉢に入れ、水を添加しながら造粒し、目開き850μmの篩で整粒後乾燥し、さらに、目開き500μmの篩で整粒して造粒末を得た。この造粒末に素錠質量に対して0.5%相当量の軽質無水ケイ酸および2.5％相当量のステアリン酸マグネシウムを目開き500μmの篩を通して加え、混合し打錠末を得た。この打錠末を、錠剤径6.5mmで碁石面の杵を用い、打錠機で圧縮成型し、1錠あたり120mgの割線および刻印を有する円形の素錠を得た。 Example 11
Tosfloxacin tosylate hydrate 7.50 g, L-aspartic acid 2.25 g, erythritol 2.33 g, light anhydrous silicic acid 0.6 g, low substituted hydroxypropylcellulose 0.9 g, crospovidone 0.6 g, polyvinyl alcohol (partially saponified product) 0.3 g And 0.075 g of sucralose was weighed, sieved with a sieve having an opening of 500 μm, and mixed. The powder was put in a mortar, granulated while adding water, sized with a sieve having an opening of 850 μm, dried, and further sized with a sieve having an opening of 500 μm to obtain a granulated powder. To this granulated powder, 0.5% equivalent of light anhydrous silicic acid and 2.5% equivalent of magnesium stearate were added through a sieve having an opening of 500 μm and mixed to obtain a tableted powder. This tableting powder was compression-molded with a tableting machine using a tablet with a tablet diameter of 6.5 mm, and a round uncoated tablet having a score line of 120 mg per tablet and an inscription was obtained.
実施例１２
　トスフロキサシントシル酸塩水和物7.50g、Ｌ－アスパラギン酸2.25g、エリスリトール2.18g、軽質無水ケイ酸0.6g、低置換度ヒドロキシプロピルセルロース0.9g、クロスポビドン0.6g、ポリビニルアルコール（部分けん化物）0.45gおよびスクラロース0.075gを秤取し、目開き500μmの篩で篩過後、混合した。その末を乳鉢に入れ、水を添加しながら造粒し、目開き850μmの篩で整粒後乾燥し、さらに、目開き500μmの篩で整粒して造粒末を得た。この造粒末に素錠質量に対して0.5%相当量の軽質無水ケイ酸および2.5％相当量のステアリン酸マグネシウムを目開き500μmの篩を通して加え、混合し打錠末を得た。この打錠末を、錠剤径6.5mmで碁石面の杵を用い、打錠機で圧縮成型し、1錠あたり120mgの割線および刻印を有する円形の素錠を得た。 Example 12
Tosfloxacin tosylate hydrate 7.50g, L-aspartic acid 2.25g, erythritol 2.18g, light anhydrous silicic acid 0.6g, low substituted hydroxypropylcellulose 0.9g, crospovidone 0.6g, polyvinyl alcohol (partially saponified product) 0.45g And 0.075 g of sucralose was weighed, sieved with a sieve having an opening of 500 μm, and mixed. The powder was put in a mortar, granulated while adding water, sized with a sieve having an opening of 850 μm, dried, and further sized with a sieve having an opening of 500 μm to obtain a granulated powder. To this granulated powder, 0.5% equivalent of light anhydrous silicic acid and 2.5% equivalent of magnesium stearate were added through a sieve having an opening of 500 μm and mixed to obtain a tableted powder. This tableting powder was compression-molded with a tableting machine using a tablet with a tablet diameter of 6.5 mm, and a round uncoated tablet having a score line of 120 mg per tablet and an inscription was obtained.
実施例１３
　トスフロキサシントシル酸塩水和物100.0g、Ｌ－アスパラギン酸30.0g、エリスリトール27.0g、軽質無水ケイ酸8.0g、低置換度ヒドロキシプロピルセルロース12.0g、クロスポビドン8.0gおよびスクラロース1.0ｇを秤取し、目開き500μmの篩で篩過後、転動流動造粒乾燥機に仕込み、混合した。その後、4％ポリビニルアルコール（部分けん化物）水溶液200.0gを噴霧して造粒し、乾燥および整粒して造粒末を得た。この造粒末に素錠質量に対して0.5％相当量の軽質無水ケイ酸を目開き500μmの篩を通して加え、また素錠質量に対して2.5％相当量のステアリン酸マグネシウムを目開き180μmの篩を通して加え、混合し打錠末を得た。この打錠末を、錠剤径6.5mmで碁石面の杵を用い、打錠機で圧縮成型し、1錠あたり120mgの割線および刻印を有する円形の素錠を得た。 Example 13
Tosfloxacin tosylate hydrate 100.0 g, L-aspartic acid 30.0 g, erythritol 27.0 g, light anhydrous silicic acid 8.0 g, low substituted hydroxypropylcellulose 12.0 g, crospovidone 8.0 g and sucralose 1.0 g were weighed. After passing through a sieve having an opening of 500 μm, the mixture was charged into a tumbling fluidized granulator and mixed. Thereafter, 200.0 g of a 4% polyvinyl alcohol (partially saponified product) aqueous solution was sprayed and granulated, dried and sized to obtain a granulated powder. To this granulated powder, light anhydrous silicic acid equivalent to 0.5% with respect to the weight of the uncoated tablet is added through a sieve having an opening of 500 μm, and magnesium stearate equivalent to 2.5% of the weight of the uncoated tablet is added to a sieve with an opening of 180 μm. And mixed to obtain a tableting powder. This tableting powder was compression-molded with a tableting machine using a tablet with a tablet diameter of 6.5 mm, and a round uncoated tablet having a score line of 120 mg per tablet and an inscription was obtained.
実施例１４
　トスフロキサシントシル酸塩水和物7.50g、Ｌ－アスパラギン酸2.25g、エリスリトール2.50g、含水二酸化ケイ素0.30g、低置換度ヒドロキシプロピルセルロース1.50g、ポリビニルピロリドン0.29gを秤取し、目開き500μmの篩で篩過後、混合した。その末を乳鉢に入れ、水を添加しながら造粒し、目開き850μmの篩で整粒後乾燥し、さらに、目開き500μmの篩で整粒して造粒末を得た。この造粒末に2％相当量のステアリン酸マグネシウムを目開き500μmの篩を通して加え、混合し打錠末を得た。この打錠末を、錠剤径6.5mmで碁石面の杵を用い、打錠機で圧縮成型し、1錠あたり117mgの割線および刻印を有する円形の素錠を得た。 Example 14
Tosfloxacin tosylate hydrate 7.50 g, L-aspartic acid 2.25 g, erythritol 2.50 g, hydrous silicon dioxide 0.30 g, low-substituted hydroxypropylcellulose 1.50 g, polyvinylpyrrolidone 0.29 g were weighed and sieved with 500 μm mesh After sieving, they were mixed. The powder was put in a mortar, granulated while adding water, sized with a sieve having an opening of 850 μm, dried, and further sized with a sieve having an opening of 500 μm to obtain a granulated powder. To this granulated powder, 2% equivalent amount of magnesium stearate was added through a sieve having an opening of 500 μm and mixed to obtain a tableted powder. This tableting powder was compression-molded with a tableting machine using a tablet with a tablet diameter of 6.5 mm and a round uncoated tablet having a score line and a stamp of 117 mg per tablet.
実施例１５
　トスフロキサシントシル酸塩水和物7.50g、Ｌ－アスパラギン酸2.25g、エリスリトール2.50g、含水二酸化ケイ素0.30g、低置換度ヒドロキシプロピルセルロース1.50g、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0.29gを秤取し、目開き500μmの篩で篩過後、混合した。その末を乳鉢に入れ、水を添加しながら造粒し、目開き850μmの篩で整粒後乾燥し、さらに、目開き500μmの篩で整粒して造粒末を得た。この造粒末に2％相当量のステアリン酸マグネシウムを目開き500μmの篩を通して加え、混合し打錠末を得た。この打錠末を、錠剤径6.5mmで碁石面の杵を用い、打錠機で圧縮成型し、1錠あたり117mgの割線および刻印を有する円形の素錠を得た。 Example 15
Tosfloxacin tosylate hydrate 7.50 g, L-aspartic acid 2.25 g, erythritol 2.50 g, hydrous silicon dioxide 0.30 g, low substituted hydroxypropylcellulose 1.50 g, polyvinyl alcohol / polyethylene glycol / graft copolymer 0.29 g, The mixture was sieved with a sieve having an opening of 500 μm and mixed. The powder was put in a mortar, granulated while adding water, sized with a sieve having an opening of 850 μm, dried, and further sized with a sieve having an opening of 500 μm to obtain a granulated powder. To this granulated powder, 2% equivalent amount of magnesium stearate was added through a sieve having an opening of 500 μm and mixed to obtain a tableted powder. This tableting powder was compression-molded with a tableting machine using a tablet with a tablet diameter of 6.5 mm and a round uncoated tablet having a score line and a stamp of 117 mg per tablet.
実施例１６
　トスフロキサシントシル酸塩水和物100.0g、Ｌ－アスパラギン酸30.0g、エリスリトール34.0g、軽質無水ケイ酸8.0g、低置換度ヒドロキシプロピルセルロース12.0g、クロスポビドン8.0gおよびスクラロース1.0ｇを秤取し、目開き500μmの篩で篩過後、転動流動造粒乾燥機に仕込み、混合した。その後、0.5％ゼラチン水溶液200.0gを噴霧して造粒し、乾燥および整粒して造粒末を得た。この造粒末に素錠質量に対して0.5％相当量の軽質無水ケイ酸を目開き500μmの篩を通して加え、また素錠質量に対して2.5％相当量のステアリン酸マグネシウムを目開き180μmの篩を通して加え、混合し打錠末を得た。この打錠末を、錠剤径6.5mmで碁石面の杵を用い、打錠機で圧縮成型し、1錠あたり120mgの割線および刻印を有する円形の素錠を得た。 Example 16
Tosfloxacin tosylate hydrate 100.0 g, L-aspartic acid 30.0 g, erythritol 34.0 g, light anhydrous silicic acid 8.0 g, low substituted hydroxypropylcellulose 12.0 g, crospovidone 8.0 g and sucralose 1.0 g were weighed. After passing through a sieve having an opening of 500 μm, the mixture was charged into a tumbling fluidized granulator and mixed. Thereafter, 200.0 g of 0.5% gelatin aqueous solution was sprayed to granulate, dried and sized to obtain a granulated powder. To this granulated powder, light anhydrous silicic acid equivalent to 0.5% with respect to the weight of the uncoated tablet is added through a sieve having an opening of 500 μm, and magnesium stearate equivalent to 2.5% of the weight of the uncoated tablet is added to a sieve with an opening of 180 μm. And mixed to obtain a tableting powder. This tableting powder was compression-molded with a tableting machine using a tablet with a tablet diameter of 6.5 mm, and a round uncoated tablet having a score line of 120 mg per tablet and an inscription was obtained.
実施例１７
　トスフロキサシントシル酸塩水和物100.0g、Ｌ－アスパラギン酸30.0g、エリスリトール31.0g、軽質無水ケイ酸8.0g、低置換度ヒドロキシプロピルセルロース12.0g、クロスポビドン8.0gおよびスクラロース1.0ｇを秤取し、目開き500μmの篩で篩過後、転動流動造粒乾燥機に仕込み、混合した。その後、2％ゼラチン水溶液200.0gを噴霧して造粒し、乾燥および整粒して造粒末を得た。この造粒末に素錠質量に対して0.5％相当量の軽質無水ケイ酸を目開き500μmの篩を通して加え、また素錠質量に対して2.5％相当量のステアリン酸マグネシウムを目開き180μmの篩を通して加え、混合し打錠末を得た。この打錠末を、錠剤径6.5mmで碁石面の杵を用い、打錠機で圧縮成型し、1錠あたり120mgの割線および刻印を有する円形の素錠を得た。 Example 17
Tosfloxacin tosylate hydrate 100.0 g, L-aspartic acid 30.0 g, erythritol 31.0 g, light anhydrous silicic acid 8.0 g, low substituted hydroxypropylcellulose 12.0 g, crospovidone 8.0 g and sucralose 1.0 g were weighed. After passing through a sieve having an opening of 500 μm, the mixture was charged into a tumbling fluidized granulator and mixed. Thereafter, 200.0 g of a 2% gelatin aqueous solution was sprayed to granulate, dried and sized to obtain a granulated powder. To this granulated powder, light anhydrous silicic acid equivalent to 0.5% with respect to the weight of the uncoated tablet is added through a sieve having an opening of 500 μm, and magnesium stearate equivalent to 2.5% of the weight of the uncoated tablet is added to a sieve with an opening of 180 μm. And mixed to obtain a tableting powder. This tableting powder was compression-molded with a tableting machine using a tablet with a tablet diameter of 6.5 mm, and a round uncoated tablet having a score line of 120 mg per tablet and an inscription was obtained.
実施例１８
　トスフロキサシントシル酸塩水和物100.0g、Ｌ－アスパラギン酸30.0g、エリスリトール32.0g、軽質無水ケイ酸10.0g、カルメロース10.0gおよび低置換度ヒドロキシプロピルセルロース10.0gを秤取し、目開き500μmの篩で篩過後、転動流動造粒乾燥機に仕込み、混合した。その後、0.67％ポリビニルアルコール（部分けん化物）水溶液300.0gを噴霧して造粒し、乾燥および整粒して造粒末を得た。この造粒末に素錠質量に対して3.0％相当量のステアリン酸マグネシウムを目開き180μmの篩を通して加え、混合し打錠末を得た。この打錠末を、錠剤径6.5mmで碁石面の杵を用い、打錠機で圧縮成型し、1錠あたり120mgの割線および刻印を有する円形の素錠を得た。 Example 18
Weigh 100.0 g of tosufloxacin tosylate hydrate, 30.0 g of L-aspartic acid, 32.0 g of erythritol, 10.0 g of light anhydrous silicic acid, 10.0 g of carmellose and 10.0 g of low-substituted hydroxypropylcellulose, and use a sieve with an opening of 500 μm. After sieving, it was charged into a rolling fluidized granulator and mixed. Thereafter, 300.0 g of 0.67% polyvinyl alcohol (partially saponified product) aqueous solution was sprayed and granulated, dried and sized to obtain a granulated powder. To this granulated powder, magnesium stearate equivalent to 3.0% relative to the weight of the uncoated tablet was added through a sieve having an opening of 180 μm and mixed to obtain a tableted powder. This tableting powder was compression-molded with a tableting machine using a tablet with a tablet diameter of 6.5 mm, and a round uncoated tablet having a score line of 120 mg per tablet and an inscription was obtained.
実施例１９
　トスフロキサシントシル酸塩水和物100.0g、Ｌ－アスパラギン酸30.0g、エリスリトール32.0g、軽質無水ケイ酸10.0g、カルメロース10.0gおよびクロスポビドン10.0gを秤取し、目開き500μmの篩で篩過後、転動流動造粒乾燥機に仕込み、混合した。その後、0.67％ポリビニルアルコール（部分けん化物）水溶液300.0gを噴霧して造粒し、乾燥および整粒して造粒末を得た。この造粒末に素錠質量に対して3.0％相当量のステアリン酸マグネシウムを目開き180μmの篩を通して加え、混合し打錠末を得た。この打錠末を、錠剤径6.5mmで碁石面の杵を用い、打錠機で圧縮成型し、1錠あたり120mgの割線および刻印を有する円形の素錠を得た。 Example 19
Tosufloxacin tosylate hydrate 100.0 g, L-aspartic acid 30.0 g, erythritol 32.0 g, light anhydrous silicic acid 10.0 g, carmellose 10.0 g and crospovidone 10.0 g were weighed, sieved with a sieve with an opening of 500 μm, The mixture was charged into a dynamic fluidized granulator and mixed. Thereafter, 300.0 g of 0.67% polyvinyl alcohol (partially saponified product) aqueous solution was sprayed and granulated, dried and sized to obtain a granulated powder. To this granulated powder, magnesium stearate equivalent to 3.0% relative to the weight of the uncoated tablet was added through a sieve having an opening of 180 μm and mixed to obtain a tableted powder. This tableting powder was compression-molded with a tableting machine using a tablet with a tablet diameter of 6.5 mm, and a round uncoated tablet having a score line of 120 mg per tablet and an inscription was obtained.
実施例２０
　トスフロキサシントシル酸塩水和物100.0g、Ｌ－アスパラギン酸30.0g、エリスリトール32.0g、軽質無水ケイ酸10.0g、低置換度ヒドロキシプロピルセルロース10.0gおよびクロスポビドン10.0gを秤取し、目開き500μmの篩で篩過後、転動流動造粒乾燥機に仕込み、混合した。その後、0.67％ポリビニルアルコール（部分けん化物）水溶液300.0gを噴霧して造粒し、乾燥および整粒して造粒末を得た。この造粒末に素錠質量に対して3.0％相当量のステアリン酸マグネシウムを目開き180μmの篩を通して加え、混合し打錠末を得た。この打錠末を、錠剤径6.5mmで碁石面の杵を用い、打錠機で圧縮成型し、1錠あたり120mgの割線および刻印を有する円形の素錠を得た。 Example 20
Tosfloxacin tosylate hydrate 100.0 g, L-aspartic acid 30.0 g, erythritol 32.0 g, light anhydrous silicic acid 10.0 g, low-substituted hydroxypropylcellulose 10.0 g and crospovidone 10.0 g were weighed and sieved with an opening of 500 μm After sieving, it was charged into a rolling fluidized granulator and mixed. Thereafter, 300.0 g of 0.67% polyvinyl alcohol (partially saponified product) aqueous solution was sprayed and granulated, dried and sized to obtain a granulated powder. To this granulated powder, magnesium stearate equivalent to 3.0% relative to the weight of the uncoated tablet was added through a sieve having an opening of 180 μm and mixed to obtain a tableted powder. This tableting powder was compression-molded with a tableting machine using a tablet with a tablet diameter of 6.5 mm, and a round uncoated tablet having a score line of 120 mg per tablet and an inscription was obtained.
実施例２１
　トスフロキサシントシル酸塩水和物100.0g、Ｌ－アスパラギン酸30.0g、エリスリトール32.0g、軽質無水ケイ酸10.0gおよび低置換度ヒドロキシプロピルセルロース20.0gを秤取し、目開き500μmの篩で篩過後、転動流動造粒乾燥機に仕込み、混合した。その後、1％ポリビニルアルコール（部分けん化物）水溶液200.0gを噴霧して造粒し、乾燥および整粒して造粒末を得た。この造粒末に素錠質量に対して3.0％相当量のステアリン酸マグネシウムを目開き180μmの篩を通して加え、混合し打錠末を得た。この打錠末を、錠剤径6.5mmで碁石面の杵を用い、打錠機で圧縮成型し、1錠あたり120mgの割線および刻印を有する円形の素錠を得た。 Example 21
Tosufloxacin tosylate hydrate 100.0 g, L-aspartic acid 30.0 g, erythritol 32.0 g, light anhydrous silicic acid 10.0 g and low-substituted hydroxypropylcellulose 20.0 g were weighed, sieved with a sieve having an opening of 500 μm, The mixture was charged into a dynamic fluidized granulator and mixed. Thereafter, 200.0 g of a 1% polyvinyl alcohol (partially saponified product) aqueous solution was sprayed and granulated, dried and granulated to obtain a granulated powder. To this granulated powder, magnesium stearate equivalent to 3.0% relative to the weight of the uncoated tablet was added through a sieve having an opening of 180 μm and mixed to obtain a tableted powder. This tableting powder was compression-molded with a tableting machine using a tablet with a tablet diameter of 6.5 mm, and a round uncoated tablet having a score line of 120 mg per tablet and an inscription was obtained.
実施例２２
　トスフロキサシントシル酸塩水和物100.0g、Ｌ－アスパラギン酸30.0g、エリスリトール32.0g、軽質無水ケイ酸10.0gおよびクロスカルメロースナトリウム20.0gを秤取し、目開き500μmの篩で篩過後、転動流動造粒乾燥機に仕込み、混合した。その後、1％ポリビニルアルコール（部分けん化物）水溶液200.0gを噴霧して造粒し、乾燥および整粒して造粒末を得た。この造粒末に素錠質量に対して3.0％相当量のステアリン酸マグネシウムを目開き180μmの篩を通して加え、混合し打錠末を得た。この打錠末を、錠剤径6.5mmで碁石面の杵を用い、打錠機で圧縮成型し、1錠あたり120mgの割線および刻印を有する円形の素錠を得た。 Example 22
Tosufloxacin tosylate hydrate 100.0 g, L-aspartic acid 30.0 g, erythritol 32.0 g, light anhydrous silicic acid 10.0 g and croscarmellose sodium 20.0 g were weighed, passed through a sieve with an opening of 500 μm, and tumbling flow Charged into a granulator and mixed. Thereafter, 200.0 g of a 1% polyvinyl alcohol (partially saponified product) aqueous solution was sprayed and granulated, dried and granulated to obtain a granulated powder. To this granulated powder, magnesium stearate equivalent to 3.0% relative to the weight of the uncoated tablet was added through a sieve having an opening of 180 μm and mixed to obtain a tableted powder. This tableting powder was compression-molded with a tableting machine using a tablet with a tablet diameter of 6.5 mm, and a round uncoated tablet having a score line of 120 mg per tablet and an inscription was obtained.
実施例２３
　トスフロキサシントシル酸塩水和物100.0g、Ｌ－アスパラギン酸30.0g、エリスリトール32.0g、軽質無水ケイ酸10.0gおよびカルボキシメチルスターチナトリウム20.0gを秤取し、目開き500μmの篩で篩過後、転動流動造粒乾燥機に仕込み、混合した。その後、1％ポリビニルアルコール（部分けん化物）水溶液200.0gを噴霧して造粒し、乾燥および整粒して造粒末を得た。この造粒末に素錠質量に対して3.0％相当量のステアリン酸マグネシウムを目開き180μmの篩を通して加え、混合し打錠末を得た。この打錠末を、錠剤径6.5mmで碁石面の杵を用い、打錠機で圧縮成型し、1錠あたり120mgの割線および刻印を有する円形の素錠を得た。 Example 23
Tosfloxacin tosylate hydrate 100.0 g, L-aspartic acid 30.0 g, erythritol 32.0 g, light anhydrous silicic acid 10.0 g and carboxymethyl starch sodium 20.0 g were weighed, sieved through a sieve with an opening of 500 μm, and tumbling flow Charged into a granulator and mixed. Thereafter, 200.0 g of a 1% polyvinyl alcohol (partially saponified product) aqueous solution was sprayed and granulated, dried and granulated to obtain a granulated powder. To this granulated powder, magnesium stearate equivalent to 3.0% relative to the weight of the uncoated tablet was added through a sieve having an opening of 180 μm and mixed to obtain a tableted powder. This tableting powder was compression-molded with a tableting machine using a tablet with a tablet diameter of 6.5 mm, and a round uncoated tablet having a score line of 120 mg per tablet and an inscription was obtained.
実施例２４
　トスフロキサシントシル酸塩水和物100.0g、Ｌ－アスパラギン酸30.0g、エリスリトール43.3g、カルメロース10.0gおよびクロスポビドン10.0gを秤取し、目開き500μmの篩で篩過後、転動流動造粒乾燥機に仕込み、混合した。その後、1％ポリビニルアルコール（部分けん化物）水溶液200.0gを噴霧して造粒し、乾燥および整粒して造粒末を得た。この造粒末に素錠質量に対して2.0％相当量のステアリン酸マグネシウムを目開き180μmの篩を通して加え、混合し打錠末を得た。この打錠末を、錠剤径6.5mmで碁石面の杵を用い、打錠機で圧縮成型し、1錠あたり120mgの割線および刻印を有する円形の素錠を得た。 Example 24
Tosfloxacin tosylate hydrate 100.0 g, L-aspartic acid 30.0 g, erythritol 43.3 g, carmellose 10.0 g, and crospovidone 10.0 g were weighed, passed through a sieve with an opening of 500 μm, and then put into a tumbling fluid granulator and dryer. Charged and mixed. Thereafter, 200.0 g of a 1% polyvinyl alcohol (partially saponified product) aqueous solution was sprayed and granulated, dried and granulated to obtain a granulated powder. To this granulated powder, 2.0% of magnesium stearate with respect to the weight of the uncoated tablet was added through a sieve having an opening of 180 μm and mixed to obtain a tableted powder. This tableting powder was compression-molded with a tableting machine using a tablet with a tablet diameter of 6.5 mm, and a round uncoated tablet having a score line of 120 mg per tablet and an inscription was obtained.
実施例２５
　トスフロキサシントシル酸塩水和物100.0g、Ｌ－アスパラギン酸30.0g、エリスリトール33.3g、含水二酸化ケイ素10.0g、カルメロース10.0gおよびクロスポビドン10.0gを秤取し、目開き500μmの篩で篩過後、転動流動造粒乾燥機に仕込み、混合した。その後、1％ポリビニルアルコール（部分けん化物）水溶液200.0gを噴霧して造粒し、乾燥および整粒して造粒末を得た。この造粒末に素錠質量に対して2.0％相当量のステアリン酸マグネシウムを目開き180μmの篩を通して加え、混合し打錠末を得た。この打錠末を、錠剤径6.5mmで碁石面の杵を用い、打錠機で圧縮成型し、1錠あたり120mgの割線および刻印を有する円形の素錠を得た。 Example 25
Tosfloxacin tosylate hydrate 100.0 g, L-aspartic acid 30.0 g, erythritol 33.3 g, hydrous silicon dioxide 10.0 g, carmellose 10.0 g and crospovidone 10.0 g were weighed, sieved with a sieve with an opening of 500 μm, and rolled. The mixture was charged into a fluidized granulator and mixed. Thereafter, 200.0 g of a 1% polyvinyl alcohol (partially saponified product) aqueous solution was sprayed and granulated, dried and granulated to obtain a granulated powder. To this granulated powder, 2.0% of magnesium stearate with respect to the weight of the uncoated tablet was added through a sieve having an opening of 180 μm and mixed to obtain a tableted powder. This tableting powder was compression-molded with a tableting machine using a tablet with a tablet diameter of 6.5 mm, and a round uncoated tablet having a score line of 120 mg per tablet and an inscription was obtained.
実施例２６
　実施例５の素錠に、錠剤コーティング機（DRC-200、パウレック製）にて、コーティング剤（OPADRY 00F440000、日本カラコン合同会社：ヒプロメロース2910 71.500％、マクロゴール6000 14.166％、タルク7.167％、酸化チタン7.067％、三二酸化鉄 0.100％を水に分散したもの）を1錠あたり4mgの割合でコーティングし、1錠あたり124mgのフィルムコーティング錠を得た。 Example 26
On the uncoated tablet of Example 5, using a tablet coating machine (DRC-200, manufactured by Paulek), a coating agent (OPADRY 00F440000, Nippon Colorcon GK: Hypromellose 2910 71.500%, Macrogol 6000 14.166%, Talc 7.167%, Titanium oxide 7.067%, ferric sesquioxide 0.100% dispersed in water) was coated at a rate of 4 mg per tablet to obtain 124 mg film-coated tablets per tablet.
実施例２７
　実施例６の素錠に、実施例２６と同様にコーティングし、1錠あたり124mgのフィルムコーティング錠を得た。 Example 27
The uncoated tablets of Example 6 were coated in the same manner as in Example 26 to obtain 124 mg of film-coated tablets per tablet.
実施例２８
　実施例７の素錠に、実施例２６と同様にコーティングし、1錠あたり124mgのフィルムコーティング錠を得た。 Example 28
The uncoated tablets of Example 7 were coated in the same manner as in Example 26 to obtain 124 mg of film-coated tablets per tablet.
実施例２９
　実施例１の素錠に、実施例２６と同様にコーティングし、1錠あたり124mgのフィルムコーティング錠を得た。 Example 29
The uncoated tablets of Example 1 were coated in the same manner as in Example 26 to obtain 124 mg film-coated tablets per tablet.
実施例３０
　実施例１３の素錠に、実施例２６と同様にコーティングし、1錠あたり124mgのフィルムコーティング錠を得た。 Example 30
The uncoated tablets of Example 13 were coated in the same manner as in Example 26 to obtain 124 mg film-coated tablets per tablet.
比較例１
　トスフロキサシントシル酸塩水和物100.0g、Ｌ－アスパラギン酸30.0g、エリスリトール33.0g、軽質無水ケイ酸8.0g、低置換度ヒドロキシプロピルセルロース12.0g、クロスポビドン8.0gおよびスクラロース1.0ｇを秤取し、目開き500μmの篩で篩過後、転動流動造粒乾燥機に仕込み、混合した。その後、1％ヒドロキシプロピルセルロース水溶液200.0gを噴霧して造粒し、乾燥および整粒して造粒末を得た。この造粒末に素錠質量に対して0.5％相当量の軽質無水ケイ酸を目開き500μmの篩を通して加え、また素錠質量に対して2.5％相当量のステアリン酸マグネシウムを目開き180μmの篩を通して加え、混合し打錠末を得た。この打錠末を、錠剤径6.5mmで碁石面の杵を用い、打錠機で圧縮成型し、1錠あたり120mgの割線および刻印を有する円形の素錠を得た。 Comparative Example 1
Tosfloxacin tosylate hydrate 100.0 g, L-aspartic acid 30.0 g, erythritol 33.0 g, light anhydrous silicic acid 8.0 g, low substituted hydroxypropylcellulose 12.0 g, crospovidone 8.0 g and sucralose 1.0 g were weighed. After passing through a sieve having an opening of 500 μm, the mixture was charged into a tumbling fluidized granulator and mixed. Thereafter, 200.0 g of a 1% hydroxypropylcellulose aqueous solution was sprayed to granulate, dried and granulated to obtain a granulated powder. To this granulated powder, light anhydrous silicic acid equivalent to 0.5% with respect to the weight of the uncoated tablet is added through a sieve having an opening of 500 μm, and magnesium stearate equivalent to 2.5% of the weight of the uncoated tablet is added to a sieve with an opening of 180 μm. And mixed to obtain a tableting powder. This tableting powder was compression-molded with a tableting machine using a tablet with a tablet diameter of 6.5 mm, and a round uncoated tablet having a score line of 120 mg per tablet and an inscription was obtained.
比較例２
　トスフロキサシントシル酸塩水和物100.0g、Ｌ－アスパラギン酸30.0g、エリスリトール33.0g、軽質無水ケイ酸8.0g、低置換度ヒドロキシプロピルセルロース12.0g、クロスポビドン8.0gおよびスクラロース1.0ｇを秤取し、目開き500μmの篩で篩過後、転動流動造粒乾燥機に仕込み、混合した。その後、1％ヒドロキシプロピルメチルセルロース水溶液200.0gを噴霧して造粒し、乾燥および整粒して造粒末を得た。この造粒末に素錠質量に対して0.5％相当量の軽質無水ケイ酸を目開き500μmの篩を通して加え、また素錠質量に対して2.5％相当量のステアリン酸マグネシウムを目開き180μmの篩を通して加え、混合し打錠末を得た。この打錠末を、錠剤径6.5mmで碁石面の杵を用い、打錠機で圧縮成型し、1錠あたり120mgの割線および刻印を有する円形の素錠を得た。 Comparative Example 2
Tosfloxacin tosylate hydrate 100.0 g, L-aspartic acid 30.0 g, erythritol 33.0 g, light anhydrous silicic acid 8.0 g, low substituted hydroxypropylcellulose 12.0 g, crospovidone 8.0 g and sucralose 1.0 g were weighed. After passing through a sieve having an opening of 500 μm, the mixture was charged into a tumbling fluidized granulator and mixed. Thereafter, 200.0 g of a 1% hydroxypropylmethylcellulose aqueous solution was sprayed to granulate, dried and sized to obtain a granulated powder. To this granulated powder, light anhydrous silicic acid equivalent to 0.5% with respect to the weight of the uncoated tablet is added through a sieve having an opening of 500 μm, and magnesium stearate equivalent to 2.5% of the weight of the uncoated tablet is added to a sieve with an opening of 180 μm. And mixed to obtain a tableting powder. This tableting powder was compression-molded with a tableting machine using a tablet with a tablet diameter of 6.5 mm, and a round uncoated tablet having a score line of 120 mg per tablet and an inscription was obtained.
比較例３
　トスフロキサシントシル酸塩水和物100.0g、Ｌ－アスパラギン酸30.0g、エリスリトール33.0g、軽質無水ケイ酸8.0g、低置換度ヒドロキシプロピルセルロース12.0g、クロスポビドン8.0gおよびスクラロース1.0ｇを秤取し、目開き500μmの篩で篩過後、転動流動造粒乾燥機に仕込み、混合した。その後、1％α化デンプン水溶液200.0gを噴霧して造粒し、乾燥および整粒して造粒末を得た。この造粒末に素錠質量に対して0.5％相当量の軽質無水ケイ酸を目開き500μmの篩を通して加え、また素錠質量に対して2.5％相当量のステアリン酸マグネシウムを目開き180μmの篩を通して加え、混合し打錠末を得た。この打錠末を、錠剤径6.5mmで碁石面の杵を用い、打錠機で圧縮成型し、1錠あたり120mgの割線および刻印を有する円形の素錠を得た。 Comparative Example 3
Tosfloxacin tosylate hydrate 100.0 g, L-aspartic acid 30.0 g, erythritol 33.0 g, light anhydrous silicic acid 8.0 g, low substituted hydroxypropylcellulose 12.0 g, crospovidone 8.0 g and sucralose 1.0 g were weighed. After passing through a sieve having an opening of 500 μm, the mixture was charged into a tumbling fluidized granulator and mixed. Thereafter, 200.0 g of 1% pregelatinized starch aqueous solution was sprayed for granulation, dried and granulated to obtain a granulated powder. To this granulated powder, light anhydrous silicic acid equivalent to 0.5% with respect to the weight of the uncoated tablet is added through a sieve having an opening of 500 μm, and magnesium stearate equivalent to 2.5% of the weight of the uncoated tablet is added to a sieve with an opening of 180 μm. And mixed to obtain a tableting powder. This tableting powder was compression-molded with a tableting machine using a tablet with a tablet diameter of 6.5 mm, and a round uncoated tablet having a score line of 120 mg per tablet and an inscription was obtained.
比較例４
　トスフロキサシントシル酸塩水和物100.0g、Ｌ－アスパラギン酸30.0g、エリスリトール25.0g、軽質無水ケイ酸8.0g、低置換度ヒドロキシプロピルセルロース12.0g、クロスポビドン8.0ｇおよびスクラロース1.0gを秤取し、目開き500μmの篩で篩過後、転動流動造粒乾燥機に仕込み、混合した。その後、5%ポリビニルアルコール（部分けん化物）水溶液200gを噴霧して造粒し、乾燥および整粒して造粒末を得た。この造粒末に素錠質量に対して0.5%相当量の軽質無水ケイ酸を目開き500μmの篩を通して加え、また素錠質量に対して2.5％相当量のステアリン酸マグネシウムを目開き180μmの篩を通して加え、混合し打錠末を得た。この打錠末を、錠剤径6.5mmで碁石面の杵を用い、打錠機で圧縮成型し、1錠あたり120mgの割線および刻印を有する円形の素錠を得た。 Comparative Example 4
Tosfloxacin tosylate hydrate 100.0 g, L-aspartic acid 30.0 g, erythritol 25.0 g, light anhydrous silicic acid 8.0 g, low substituted hydroxypropylcellulose 12.0 g, crospovidone 8.0 g and sucralose 1.0 g were weighed. After passing through a sieve having an opening of 500 μm, the mixture was charged into a tumbling fluidized granulator and mixed. Thereafter, 200 g of a 5% polyvinyl alcohol (partially saponified product) aqueous solution was sprayed and granulated, dried and sized to obtain a granulated powder. A light silicic acid equivalent to 0.5% of the uncoated tablet mass is added to the granulated powder through a sieve having an opening of 500 μm, and magnesium stearate equivalent to 2.5% of the uncoated tablet mass is added to a sieve having an opening of 180 μm. And mixed to obtain a tableting powder. This tableting powder was compression-molded with a tableting machine using a tablet with a tablet diameter of 6.5 mm, and a round uncoated tablet having a score line of 120 mg per tablet and an inscription was obtained.
比較例５
　トスフロキサシントシル酸塩水和物100.0g、Ｌ－アスパラギン酸30.0g、エリスリトール35.0g、軽質無水ケイ酸8.0g、低置換度ヒドロキシプロピルセルロース12.0g、クロスポビドン8.0gおよびスクラロース1.0ｇを秤取し、目開き500μmの篩で篩過後、転動流動造粒乾燥機に仕込み、混合した。その後、水200.0gを噴霧して造粒し、乾燥および整粒して造粒末を得た。この造粒末に素錠質量に対して0.5％相当量の軽質無水ケイ酸を目開き500μmの篩を通して加え、また素錠質量に対して2.5％相当量のステアリン酸マグネシウムを目開き180μmの篩を通して加え、混合し打錠末を得た。この打錠末を、錠剤径6.5mmで碁石面の杵を用い、打錠機で圧縮成型し、1錠あたり120mgの割線および刻印を有する円形の素錠を得た。 Comparative Example 5
Tosfloxacin tosylate hydrate 100.0 g, L-aspartic acid 30.0 g, erythritol 35.0 g, light anhydrous silicic acid 8.0 g, low substituted hydroxypropylcellulose 12.0 g, crospovidone 8.0 g and sucralose 1.0 g were weighed. After passing through a sieve having an opening of 500 μm, the mixture was charged into a tumbling fluidized granulator and mixed. Thereafter, 200.0 g of water was sprayed to granulate, dried and granulated to obtain a granulated powder. To this granulated powder, light anhydrous silicic acid equivalent to 0.5% with respect to the weight of the uncoated tablet is added through a sieve having an opening of 500 μm, and magnesium stearate equivalent to 2.5% of the weight of the uncoated tablet is added to a sieve with an opening of 180 μm. And mixed to obtain a tableting powder. This tableting powder was compression-molded with a tableting machine using a tablet with a tablet diameter of 6.5 mm, and a round uncoated tablet having a score line of 120 mg per tablet and an inscription was obtained.
　本発明の錠剤は、小児等の服薬コンプライアンスを向上した小児用の抗菌剤として有用である。 The tablet of the present invention is useful as an antibacterial agent for children with improved compliance for children.

Claims (8)

  1. （１）トスフロキサシントシル酸塩、（２）結合剤、および、（３）酸性アミノ酸、を含む錠剤であって；
    結合剤が、水溶性ポリビニル系高分子およびゼラチン類から選ばれる一種または二種以上であり、結合剤の含有率が、錠剤質量に対して５％未満である、錠剤。     A tablet comprising (1) tosufloxacin tosylate, (2) a binder, and (3) an acidic amino acid;
    A tablet wherein the binder is one or more selected from water-soluble polyvinyl polymers and gelatins, and the binder content is less than 5% based on the tablet mass.
  2. 酸性アミノ酸が、Ｌ－アスパラギン酸である、請求項１に記載の錠剤。 The tablet according to claim 1, wherein the acidic amino acid is L-aspartic acid.
  3. 結合剤が、水溶性ポリビニル系高分子である、請求項１または２に記載の錠剤。 The tablet according to claim 1 or 2, wherein the binder is a water-soluble polyvinyl polymer.
  4. 水溶性ポリビニル系高分子が、ポリビニルアルコールおよびポリビニルピロリドンから選ばれる一種または二種以上である、請求項１～３のいずれか一項に記載の錠剤。 The tablet according to any one of claims 1 to 3, wherein the water-soluble polyvinyl polymer is one or more selected from polyvinyl alcohol and polyvinyl pyrrolidone.
  5. 水溶性ポリビニル系高分子が、ポリビニルアルコールである、請求項１～３のいずれか一項に記載の錠剤。 The tablet according to any one of claims 1 to 3, wherein the water-soluble polyvinyl polymer is polyvinyl alcohol.
  6. 水溶性ポリビニル系高分子の含有率が、錠剤質量に対して０．０１～４．５％である、請求項１～５のいずれか一項に記載の錠剤。 The tablet according to any one of claims 1 to 5, wherein the content of the water-soluble polyvinyl polymer is 0.01 to 4.5% with respect to the tablet mass.
  7. さらに崩壊剤を含む、請求項１～６のいずれか一項に記載の錠剤。 The tablet according to any one of claims 1 to 6, further comprising a disintegrant.
  8. 崩壊剤が、カルメロース、カルメロースカルシウム、クロスカルメロースナトリウム、低置換度ヒドロキシプロピルセルロース、クロスポビドン、カルボキシメチルスターチナトリウムおよび部分α化デンプンから選ばれる一種または二種以上である、請求項７に記載の錠剤。 The disintegrant is one or more selected from carmellose, carmellose calcium, croscarmellose sodium, low-substituted hydroxypropylcellulose, crospovidone, sodium carboxymethyl starch and partially pregelatinized starch. Tablets.
PCT/JP2017/016681 2016-04-27 2017-04-27 Tablet containing tosufloxacin tosilate WO2017188361A1 (en)

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