CN106074414B - A kind of oral disnitegration tablet and preparation method thereof containing Lurasidone - Google Patents

A kind of oral disnitegration tablet and preparation method thereof containing Lurasidone Download PDF

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CN106074414B
CN106074414B CN201610575033.8A CN201610575033A CN106074414B CN 106074414 B CN106074414 B CN 106074414B CN 201610575033 A CN201610575033 A CN 201610575033A CN 106074414 B CN106074414 B CN 106074414B
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oral disnitegration
lurasidone hcl
disnitegration tablet
lactose
lurasidone
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CN106074414A (en
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柯潇
郑强
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CHENGDU KANGHONG PHARMACEUTICALS GROUP Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing

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Abstract

The present invention relates to a kind of oral disnitegration tablet and preparation method thereof containing Lurasidone HCl, oral disnitegration tablet of the invention contains Lurasidone HCl, filler, disintegrating agent, corrigent and lubricant, while controlling the partial size D of Lurasidone HCl90≤ 75 μm, Lurasidone HCl oral disnitegration tablet of the invention has good dissolution in vitro and good mouthfeel；Industrialized production can be realized using conventional granulation and sheeting equipment in orally disintegrating tablet preparation simple process of the invention.

Description

A kind of oral disnitegration tablet and preparation method thereof containing Lurasidone
The application is application No. is CN201210241053.3, and the applying date is on July 12nd, 2012, entitled " one The divisional application of oral disnitegration tablet and preparation method thereof of the kind containing Lurasidone ".
Technical field
The present invention relates to field of pharmaceutical preparations.Contain the oral disnitegration tablet of Lurasidone and its preparation side more particularly to a kind of Method.
Background technique
Schizophrenia (schizophrenia) is a kind of mental disease that the common cause of disease does not illustrate completely, a lot of diseases In person between twenty and fifty, often there is the obstacle of consciousness, thinking, emotion and behavior etc., general unconscious and disturbance of intelligence.The course of disease is moved more Prolong, account for about more than half of inpatients with mental, there is mental disorder in final final result about half patient, for society and Patient and family members bring it is serious burden [Beijing Shu Liang schizophrenia guideline of prevention and treatment [M]: medical publishing society of Peking University, 2009:3.]。
Lurasidone HCl, that is, N- [4- [4- (1,2- benzisothiazole -3- base) -1- piperazinyl]-(2R, 3R) -2,3- four Methylene-butyl]-bicyclic [2,2,1] the heptane imidodicarbonic diamide hydrochloride (Lurasidone of (1 ' R, 2 ' S, 3 ' R, 4 ' S) -2,3- Hydrochloride), belong to benzisothiazole derivatives, for white to off-white powder；It is atomic to be dissolved in water, it is practically insoluble in The hydrochloric acid of 0.1N is slightly soluble in ethyl alcohol, acetone, is practically insoluble in toluene.It is SUMITOMO CHEMICAL pharmacy (Dainippon Sumitomo) the new atypical antipsychotic agents product of one kind of exploitation, ratify in acquisition FDA on October 28th, 2010, for controlling Schizophrenia is treated, it is pending in the recent period for bipolar disease.
Lurasidone is to dopamine D2Receptor, serotonin (5-HT7、5-HT2A、5-HT1A) and а2cReceptor has height parent And property.But to 5-HT2cReceptor, histamine H1Receptor, acetylcholine M1Receptor and adrenaline а1The affinity of receptor is lower.Shandong It draws western ketone compared with other antipsychotic drugs, has the advantage that first, the medicine extrapyramidal symptom (EPS) is smaller, be not required to Other anticholinergic agents are taken simultaneously；Centainly change second, taking the medicine and also having for the cognitive disorder of schizophreniac It is kind.
Currently, the medicine listing dosage form be ordinary tablet, have 20mg, 40mg, tetra- kinds of specifications of 80mg and 120mg.Lurasidone is general Logical piece has the disadvantage in that
1, it due to Lurasidone poorly water-soluble, and is practically insoluble in gastric acid, only 9%~19% is inhaled through stomach and intestine after oral It receives, raw lower [the United States Food and Drug Administration.Label approved of bioavilability on 12/10/2010(PDF)for LATUDA[EB/OL]].
2, the ordinary tablet of antipsychotics can cause esophageal dysmotility and suction, to cause induction type lung Inflammation is the lethal common cause of gerontal patient's especially old dementia patients.[United States Food and Drug Administration.Label approved on 12/10/2010(PDF)for LATUDA[EB/OL]].
3, mental patient there is a problem of when taking ordinary tablet compliance difference, some patients tablet can be hidden in it is sublingual, The phenomenon that spitting after medical staff leaves, causing " vacation medication ", greatly affected the effect of drug therapy.
Oral disnitegration tablet is a kind of tablet for being not required to water in oral cavity and being disintegrated or dissolving, disintegration time general control Within 1 minute, piece is placed in lingual surface when taking, is met by power is swallowed after saliva is disintegrated rapidly, drug can enter stomach action, Overcome the conventional dosage forms such as conventional tablet, capsule dysphagia in use.Oral disnitegration tablet is Recent study exploitation Novel solid preparation, have convenient to take, disintegration rapidly, absorbs fast, the advantages that biological utilisation is high.Because the dosage form can effectively prevent Only " vacation medication " phenomenon of mental patient, so treatment mental disease class drug such as Aripiprazole, Fluvoxamine, Escitalopram is general Orchid, Olanzapine, Mirtazapine, Clozapine, neat western ketone, Mianserin, blonanserin, Lurasidone, Iloperidone etc. are particularly suited for Develop into the dosage form.
The country it is following to the technical requirements of oral disintegrating tablet [Chinese Hospitals medication evaluation and analysis, the 2nd phase of volume 9 in 2009, 159-200]: (1) should in oral cavity rapidly disintegration, without grittiness, good mouthfeel, be easy to swallow, it is nonirritant to mucous membrane of mouth. (2) suitable disintegration time limited is established, and is incorporated into standard.(3) to insoluble drug should establish suitable dissolution determination method and Limit.(4) the general requirement of its tablet should be met, but friability can not be measured.And for utilizing powder in oral disnitegration tablet Main ingredient requires then more stringent in the technique of direct tablet compressing, it is numb with it is refined et al. [medical Leader, the 7th phase of volume 28 in July, 2009, 891-893] direct powder compression is disclosed suitable for main ingredient and the preferable medicine of auxiliary material dissolubility, powder flowbility, compressibility Object, while thinking that sensory issues are also to limit the principal element of this method；Come small pellet et al. [Chinese medicine company, 2009 volume 18 19th phase, 78-79] also disclose oral disnitegration tablet prepared by direct powder compression method, and if think main ingredient good fluidity, Tabletting can directly be carried out；If main ingredient poor fluidity should not use, while think when preparing oral disnitegration tablet, list should be selected The lesser drug of dosage is as model drug；Also think that drug good fluidity can powder when introducing oral disnitegration tablet in middle benefit gas capital et al. Last direct tablet compressing, while thinking that the single dose of main ingredient wants small (general≤60mg), it is more suitable for the method, more preferably to improve patient's Compliance, and think that sensory issues are the following critical issues for needing further to solve.Therefore, it is known that with direct powder compression When method prepares oral disnitegration tablet, it is desirable that main ingredient good fluidity, dosage is small, and can effectively solve its sensory issues, especially bitter The problems such as taste, irritation, grittiness.
Lurasidone HCl not only poor fluidity, and there is bitter taste.Such as exploitation will not only be solved at oral disnitegration tablet When its dissolution in vitro is low and preparations shaping the problem of poor fluidity, while also to solve its bad mouth after intraoral disintegration Sense problem has biggish technical difficulty.In consideration of it, rare Lurasidone oral disnitegration tablet research or development both at home and abroad at present Document and patent report.
Patent WO2002/024166 discloses a kind of oral preparation using Lurasidone as active constituent, said preparation tool There is instant capacity, and when the active component content variation in preparation, said preparation dissolution characteristic still having the same.But it is above-mentioned special Oral preparation involved in benefit still falls within conventional tablet, does not have the characteristic that oral cavity solution piece is disintegrated rapidly in 1 minute, and fail Effectively solve the problems, such as its bad mouthfeel.
Patent CN101868228A disclose it is a kind of have appropriate tablet hardness concurrently and in intraorally rapidly disintegrating, and adding Hardness declines oral disnitegration tablet that is small, can maintaining good intraoral disintegration performance when saving under the conditions of wet.The patent be related to one Lurasidone is referred in serial effective component, but undisclosed result of study the problems such as to its dissolution rate, mouthfeel.The present application People solves piece using auxiliary material used in the patent and technique preparation oral cavity, and discovery is there are still medicinal powder mobility when tabletting is bad, after molding The problem of oral disnitegration tablet serious bitter taste, (is detailed in the embodiment of the present invention five).
In the prior art for the cover of poor taste, the methods of molecule inclusion, fluidized bed coating, ion exchange are commonly used. Wherein molecule inclusion often has strict requirements to the molecular weight of drug and molecular configuration, and that there are inclusion rates is not high, when preparation Between it is long the disadvantages of；Although fluidized bed coating can effectively taste masking, preparation gained particle oral disnitegration tablet is such as made, can mostly generate Apparent grittiness；And ion-exchange has strict demand to the dissolubility and ionization property of main ingredient, by certain on Limitation.
How oral disnitegration tablet containing Lurasidone in good taste, and that be able to satisfy dissolution specification is obtained, to solve The problems such as patient compliance is poor, medication is difficult, becomes particularly significant.
Summary of the invention
In order to solve the problems in the existing technology, the present invention provides a kind of oral cavities containing Lurasidone HCl to collapse Piece is solved, it is poor to efficiently solve dissolution in vitro existing for Lurasidone HCl oral disnitegration tablet, there is the problem of bad mouthfeel.
In order to achieve the object of the present invention, one aspect of the present invention provides a kind of Orally disintegrating containing Lurasidone HCl Piece contains following components in percentage by weight:
The wherein partial size D of Lurasidone HCl90≤75μm。
Filler described in above-mentioned oral disnitegration tablet be selected from sucrose, lactose, glucose, mannitol, sorbierite, lactitol, One of microcrystalline cellulose, starch, pregelatinized starch or dextrin are a variety of；The disintegrating agent is selected from crospovidone, hands over Join one of sodium carboxymethylcellulose or low-substituted hydroxypropyl cellulose or a variety of；The corrigent is selected from citric acid, sweet Careless glucin, Aspartame, maltose, stevioside, Sucralose, magnesia, xanthan gum, saccharin, fructose, glucan, honey element, One of Talin or menthol are a variety of；The lubricant be selected from stearic acid, magnesium stearate, calcium stearate, superfine silica gel powder, Talcum powder, hydrogenated vegetable oil, Macrogol 6000, Macrogol 4000, lauryl sodium sulfate (magnesium), fumaric acid stearic acid Sodium, Compritol 888 ATO are any one or more of, a kind of more preferably in superfine silica gel powder, magnesium stearate or sodium stearyl fumarate Or it is a variety of.
Suitable acrylic resin can also be contained in above-mentioned oral disnitegration tablet.
The present invention still further provides a kind of oral disnitegration tablet containing Lurasidone HCl, by following weight percent Group be grouped as:
The wherein partial size D of Lurasidone HCl90≤75μm；
The filler is one or more in lactose, microcrystalline cellulose, sucrose, starch, pregelatinized starch；It is described to collapse It solves agent and is selected from one of crospovidone, croscarmellose sodium, low-substituted hydroxypropyl cellulose or a variety of；It is described to rectify Taste agent is selected from one of citric acid, menthol, Aspartame, Sucralose or honey element or a variety of.
Invention still further provides a kind of oral disnitegration tablets containing Lurasidone HCl, by following weight percent Group be grouped as:
The wherein partial size D of Lurasidone HCl90≤75μm；
The filler is one or more in lactose, microcrystalline cellulose, sucrose, starch, pregelatinized starch；It is described to collapse It solves agent and is selected from one of crospovidone, croscarmellose sodium, low-substituted hydroxypropyl cellulose or a variety of；It is described to rectify Taste agent is selected from one of citric acid, menthol, Aspartame, Sucralose or honey element or a variety of.
Invention further provides a kind of oral disnitegration tablets containing Lurasidone HCl, by following weight percent Group is grouped as:
The wherein partial size D of Lurasidone HCl90≤75μm。
The preparation method that another aspect of the invention provides the oral disnitegration tablet containing Lurasidone HCl is wet granulation Tabletting preferably takes Lurasidone HCl to be uniformly mixed with partially filled agent, adds 95% second of appropriate 10% acrylate resins Alcoholic solution softwood is pelletized, dry, whole grain；Remaining filler, disintegrating agent, corrigent, superfine silica gel powder and stearic acid is added Magnesium is uniformly mixed, and tabletting to obtain the final product.
The present invention still further provides a kind of oral disnitegration tablet containing Lurasidone HCl, by following weight percent The group of ratio is grouped as:
The wherein partial size D of Lurasidone HCl90≤75μm；
Containing one or two kinds of in spray drying mannitol or particulate lactose in the filler；It is poly- that the disintegrating agent is selected from crosslinking Tie up one of ketone, croscarmellose sodium, low-substituted hydroxypropyl cellulose or a variety of；The corrigent is selected from citron One of acid, Aspartame or Sucralose are a variety of；The lubricant is selected from superfine silica gel powder, magnesium stearate or stearic rich horse It is one or more in sour sodium.
Invention still further provides a kind of oral disnitegration tablets containing Lurasidone HCl, by following weight percent The group of ratio is grouped as:
The wherein partial size D of Lurasidone HCl90≤75μm；
The filler is the mixture or particulate lactose of spray drying mannitol and cornstarch.
The preparation method that another aspect of the present invention provides a kind of oral disnitegration tablet containing Lurasidone HCl is powder Direct tablet compressing；It preferably takes Lurasidone HCl and filler to be sufficiently mixed uniformly, disintegrating agent and lubricant is added, mixing is equal Even, tabletting to obtain the final product.
D of the present invention90A finger of powder diameter is indicated when being using laser granulometry measurement powder diameter Mark, such as D90It≤75 μm, indicates in the powder systems, there is the partial size of 90% powder to be respectively less than 75 μm, this is this field Well known to technical staff.
The pharmaceutical composition of oral disnitegration tablet of the present invention containing Lurasidone HCl, the advantage is that:
The present invention solves the problems, such as Lurasidone HCl poor fluidity and poor taste, obtain dissolution in vitro it is good, And taste is well and the fast oral disnitegration tablet of disintegration rate, provides one kind newly for the exploitation of the novel form of Lurasidone HCl Selection, also improves the compliance of clinical application, and can effectively avoid " vacation medication " phenomenon of mental patient.The oral cavity collapses simultaneously The preparation process for solving piece is simple, and industrialized production can be realized using conventional granulation and sheeting equipment.
Specific embodiment
Above content of the invention is described in further detail by the following examples.But this should not be interpreted as to this The range for inventing above-mentioned theme is only limitted to example below.Without departing from the idea case in the present invention described above, according to this The various replacements or change that field ordinary technical knowledge and customary means are made, should all be included within the scope of the invention.
To the evaluation of mouthfeel and mobility, disintegration time limited, dissolution rate in embodiment of the present invention or specific embodiment Detection method is as follows:
Mouthfeel: it by 6 healthy volunteer's buccal administrations, evaluates its bitter taste and grittiness intensity, bitter taste is divided into: "+ ++ " bitter taste is strong；" ++ " bitter taste is obvious, can endure；The slight bitter taste of "+"；"-" is without obvious bitter taste.Grittiness is divided into: " +++ " is husky Gravel sense is strong；" ++ " grittiness is obvious, can endure；The slight grittiness of "+"；"-" is without obvious grittiness.
Dissolution rate: taking this product, according to dissolution method (two annex of Chinese Pharmacopoeia version in 2010, Ⅹ the second method of C), with PH3.8 buffer 900ml is dissolution medium, 50 revs/min of revolving speed, operates according to methods, takes dissolution fluid 10ml after a certain period of time, is filtered, Take subsequent filtrate as test solution；Lurasidone HCl reference substance separately is taken, adds a small amount of methanol to make to dissolve, then dilute with dissolution medium It is interpreted into 44 μ g/mL reference substance solutions.Above two solution is taken, according to UV-VIS spectrophotometry (Chinese Pharmacopoeia version two in 2010 IV A of portion's annex), absorbance is measured at the wavelength of 315nm, calculates every the amount of dissolution.Limit is the 85% of labelled amount, is answered Meet regulation.
Mobility: it is evaluated with angle of repose.Using fixed conical bottom method, a certain amount of powder to be measured is taken, under vibration It flows out powder uniformly by funnel, until obtaining highest circular cone body position, measures the angle on cone inclined-plane and plane, weight Again three times, it is averaged.Angle of repose is less than 40 °, the good fluidity of material.
Disintegration time limited: taking teat glass, the water that 2mL is preheated to 37 DEG C is added, then wherein by oral disnitegration tablet investment, quiet It sets, calculates the time required to from the contact water surface to completion disintegration.Tablet after disintegration should be completely (available a small amount of by No. 2 pharmacopeia sieves Water rinses).
Overall merit: when angle of repose≤40 °, mouthfeel is no more than "+", and dissolution rate >=85% is determined as qualification；When stopping 40 ° of angle > or mouthfeel are determined as unqualified more than "+" or dissolution rate < 85%.
The mobility-detected of one Lurasidone HCl of embodiment
According to above-mentioned mobility detection method, the mobility of Lurasidone HCl is measured, as a result as follows:
39.7 ° of the angle of repose of D90≤250um powder；
The angle of repose of D90≤75um powder is greater than 60 °, and about 60~80 °, as a result poor repeatability；
D90≤30um powder cannot can not be detected by funnel, angle of repose.
Embodiment two-way crosses wet granulation technology and prepares oral disnitegration tablet
Lurasidone HCl is white or off-white powder, poor fluidity, and has bitter taste, it is difficult to be prepared into good mouthfeel Oral disnitegration tablet.Inventor is by a large number of experiments, it has surprisingly been found that when selecting pH dependent form dissolubility material such as acrylic resin Lurasidone HCl first individually or with partial supplementary material is pelletized, can be solved well as adhesive by E100, Eudragit E PO The certainly mobility and bitterness problem of this product.And conventional adhesive material is used, such as povidone k30, hydroxypropyl methylcellulose, ethyl It, cannot be effective although the problem of can solve its poor fluidity when cellulose, 70% ethyl alcohol etc. are as adhesive of the invention Cover the bitter taste of disintegrated tablet.
This experiment uses prescription: Lurasidone HCl (D90≤75um) 26.7%, mannitol 53.0%, microcrystalline cellulose 12%, croscarmellose sodium 5.3%, citric acid 0.5%, Aspartame 0.5%, superfine silica gel powder 1.5%, magnesium stearate 0.5%.
Different adhesive formulas number are respectively 95% ethanol solution of 1. 10% Eudragit E 100；2. 10% acrylic acid 95% ethanol solution of resin EPO；3. 95% ethanol solution of 5% povidone k30；4. 70% second of 5% hydroxypropyl methylcellulose Alcoholic solution；5. 95% ethanol solution of 2% ethyl cellulose 6. 70% ethyl alcohol.
Preparation method: it takes Lurasidone HCl to be first uniformly mixed with part mannitol, adds above-mentioned adhesive and make in right amount Softwood is pelletized, dry, whole grain；Be added remaining mannitol, microcrystalline cellulose, croscarmellose sodium, citric acid, Ah This Ba Tian, superfine silica gel powder and magnesium stearate, be uniformly mixed, tabletting to obtain the final product, every hydrochloric Lurasidone 80mg, slice weight 300mg/ Piece.
By bitter taste, grittiness and the disintegration time limited for stopping angle and oral disnitegration tablet of preceding method measurement total mixed drug powder, as a result It is shown in Table 1.
The total mixed drug powder of the different adhesive preparations of table 1 and the testing result of oral disnitegration tablet
Embodiment three prepares oral disnitegration tablet using direct powder compression
Direct powder compression has technical process simple, and it is excellent to be conducive to serialization and automated production etc. for energy- and time-economizing Point.But the technique has higher requirement to the mobility, compressibility, lubricity of material.It is complied with to meet Orally disintegrating and improvement The requirement of property, material must also have good disintegration or solubility property and good mouthfeel.It is challenging to be: salt Sour Lurasidone bulk pharmaceutical chemicals poor fluidity, is insoluble in water, it is necessary to can just be improved using a large amount of filler, it thus can energy band Come piece is great, take the piece number more than consequence, and this point and improve mental patient's Compliance demand run counter to.
For inventor by the research to a large amount of fillers, that investigates the direct powder compression of Lurasidone HCl oral disintegrating tablet can Row, specific formula are shown in Table 2-3.
2 technique of direct powder compression formula (by weight percentage) of table
Remarks: the manufacturer of particles used lactose TABLETTOSE 80, spray drying lactose FLOWLAC 100 in this experiment For happy (MEGGLE) company of U.S. agent；Spray drying PEARLITOL 100SD EARLITOL 200SD, melt poly- PEARLITOL 100SD EARLITOL 300DC, speed collapses The manufacturer of PEARLITOL 100SD EARLITOL FLASH is Luo Gaite (ROQUETTE) company.
3 technique of direct powder compression formula (by weight percentage) of table
The preparation method of above-mentioned formula: it takes Lurasidone HCl (D90≤75um) and filler to be sufficiently mixed uniformly, is added Disintegrating agent and lubricant are uniformly mixed, and tabletting to obtain the final product.
By the grittiness for stopping angle and oral disnitegration tablet of preceding method measurement total mixed drug powder, it the results are shown in Table 4.
The selective mechanisms result of 4 technique of direct powder compression filler of table
Above-mentioned experimental result is shown, it is poor that the medicinal powder mobility that conventional fillers are prepared is used alone.When sweet using spray drying Reveal one or two kinds of in alcohol PEARLITOL 200SD or particulate lactose TABLETTOSE 80；One of or both (or jointly) with When other auxiliary materials are used in mixed way, medicinal powder mobility is obviously improved, and direct powder compression may be implemented.
Influence of the example IV Lurasidone HCl partial size for oral disnitegration tablet
With the difference of Lurasidone HCl partial size, various physical properties have certain change, such as mobility, heap Density, dissolution rate etc., thus compressibility and the dissolution rate of finished product etc. when influencing preparation mass production.Select suitable main ingredient grain Diameter range is the key that solution Lurasidone HCl dissolution in vitro is low.In order to determine suitable main ingredient particle size range, inventor It is found by many experiments: the partial size D of main ingredient90At≤75 μm, Orally disintegrating tablet dissolution obtained is preferable；Main ingredient partial size D90 At≤25 μm, Orally disintegrating tablet dissolution obtained is more preferable；And when being further reduced partial size, the increase of dissolution rate is unobvious.Cause This comprehensively considers production cost, and preferred main ingredient partial size is D90≤75μm。
This experiment uses prescription: Lurasidone HCl 26.7%, lactose 53.0%, microcrystalline cellulose 12%, crosslinking carboxylic first Base sodium cellulosate 5.3%, citric acid 0.5%, Aspartame 0.5%, Ah's superfine silica gel powder 1.5%, magnesium stearate 0.5%.
The Lurasidone HCl formula number of different-grain diameter range are as follows: 1. D90≤125μm；②D90≤75μm；③D90≤50μ m；④D90≤25μm。
Preparation method one: taking Lurasidone HCl to be uniformly mixed with portion of Lactose, with 10% Eudragit E 100 95% ethanol solution is adhesive softwood processed in right amount, is pelletized, dry, whole grain；Remaining lactose, microcrystalline cellulose, crosslinking is added Sodium carboxymethylcellulose, citric acid, Aspartame, superfine silica gel powder and magnesium stearate, be uniformly mixed, tabletting to obtain the final product, every saliferous Sour Lurasidone 80mg, slice weight 300mg/ piece.
Preparation method two: it takes Lurasidone HCl and lactose (particulate lactose TABLETTOSE 80) to be sufficiently mixed uniformly, adds Enter microcrystalline cellulose, croscarmellose sodium, citric acid, Aspartame, superfine silica gel powder and magnesium stearate, be uniformly mixed, Tabletting to obtain the final product, every hydrochloric Lurasidone 80mg, slice weight 300mg/ piece.
By dissolution rate, mouthfeel and the disintegration time limited of preceding method measurement oral disnitegration tablet, it the results are shown in Table 5,6.
The testing result of the oral disnitegration tablet (preparation method one) of 5 different-grain diameter main ingredient of table
The testing result of the oral disnitegration tablet (preparation method two) of 6 different-grain diameter main ingredient of table
Five comparative study of embodiment
The original for preparing identical slice weight grinds piece, patent CN101868228A addresses the oral disnitegration tablet of two kinds of technique of the invention It compares, formula is shown in Table 7.
7 original of table grinds piece, patent CN101868228A addresses Orally disintegrating slice prescription (by weight percentage) of the present invention
* Lurasidone HCl partial size D90≤75μm
Comparative example 1 (original grinds piece) preparation method: according to patent CN101184489B method by Lurasidone HCl and mannitol, Part pre-gelatinized starch, croscarmellose sodium are uniformly mixed, using 5% hydroxypropyl methylcellulose aqueous solution as adhesive, stream Change bed granulation, be added magnesium stearate, mix 5 minutes, tabletting, slice weight 320mg/ piece, film coating to get.
Comparative example 2 (described in patent CN101868228A) preparation method: Lurasidone HCl and cornstarch is sufficiently mixed Close uniformly, add microcrystalline cellulose, calcium phosphate dibasic anhydrous, magnesium stearate be uniformly mixed, tabletting, slice weight 320mg/ piece to get.
Comparative example 3 (oral disnitegration tablet of the present invention) preparation method: Lurasidone HCl and lactose are sufficiently mixed uniformly, then Microcrystalline cellulose, Crospovidone, citric acid, Sucralose, magnesium stearate, superfine silica gel powder is added to be uniformly mixed, tabletting, slice weight 320mg/ piece to get.
Comparative example 4 (oral disnitegration tablet of the present invention) preparation method: Lurasidone HCl is uniformly mixed with portion of Lactose, with 95% ethanol solution of 10% Eudragit E 100 is adhesive, and granulation adds remaining lactose, microcrystalline cellulose, friendship Povidone, citric acid, Sucralose, magnesium stearate, superfine silica gel powder be uniformly mixed, tabletting, slice weight 320mg/ piece to get.
The disintegration time limited of the angle of repose of total mix powder and piece made from each comparative example, mouthfeel and dissolution rate are measured in accordance with the law, as a result It is shown in Table 8.
Each comparative example total mixed drug powder of table 8 and piece testing result
Conclusion: Lurasidone HCl oral disnitegration tablet prepared by the present invention dissolution rate at 15 minutes reach 85% with On, and mouthfeel is without bitter taste, hence it is evident that better than common Orally disintegrating described in Lurasidone HCl ordinary tablet and patent CN101868228A Piece.
Six wet granule compression tablet of embodiment
The formula of experiment 1-6 is shown in Table 9:
The formula (by weight percentage) of the experiment of table 9 1-6
* Lurasidone HCl partial size D90≤75μm
It tests the preparation method of 1-3: with 95% ethanol solution of 10% Eudragit E PO being viscous by Lurasidone HCl Mixture, granulation, it is uniform to add filler, disintegrating agent, corrigent and mix lubricant, tabletting to get.
It tests the preparation method of 4-6: Lurasidone HCl being uniformly mixed with partially filled agent, with 10% acrylic resin 95% ethanol solution of E100 is adhesive, and it is equal to add remaining filler, disintegrating agent, corrigent and mix lubricant for granulation It is even, tabletting to get.
Disintegration time limited, mouthfeel and the dissolution rate for measuring oral disnitegration tablet made from each experimental formula in accordance with the law, the results are shown in Table 10.
Table 10 tests 1-6 oral disnitegration tablet testing result
Seven direct powder compression of embodiment
The formula of experiment 1-9 is shown in Table 11.
The pharmaceutical formulation (by weight percentage) of the experiment of table 11 1-9
It tests the preparation method of 1-9: taking Lurasidone HCl and filler to be sufficiently mixed uniformly, disintegrating agent and lubrication is added Agent is uniformly mixed, and tabletting to obtain the final product.
Disintegration time limited, the mouthfeel of total mixed drug powder angle of repose made from the formula of measurement experiment 1-9 and oral disnitegration tablet in accordance with the law And dissolution rate, it the results are shown in Table 12.
The testing result of the experiment of table 12 1-9
The pharmaceutical formulation of experiment 10-17 is shown in Table 13.
Table 13 tests 10-17 (by weight percentage)
It tests the preparation method of 10-17: taking Lurasidone HCl and filler to be sufficiently mixed uniformly, disintegrating agent and profit is added Lubrication prescription is uniformly mixed, and tabletting to obtain the final product.
The disintegration time limited of total mixed drug powder angle of repose and oral disnitegration tablet made from each experimental formula, mouthfeel and molten are measured in accordance with the law Out-degree the results are shown in Table 14.
Table 14 tests 10-17 and is formulated testing result

Claims (13)

1. a kind of oral disnitegration tablet containing Lurasidone HCl, it is characterised in that consist of the following components in percentage by weight:
Wherein the oral disnitegration tablet is prepared using direct powder compression；
Partial size D90≤75 μm of the Lurasidone HCl；
It is that speed collapses PEARLITOL 100SD EARLITOL FLASH that the speed, which collapses mannitol, and particulate lactose is particulate lactose TABLETTOSE 80.
2. a kind of oral disnitegration tablet containing Lurasidone HCl, it is characterised in that consist of the following components in percentage by weight:
Wherein the oral disnitegration tablet is prepared using direct powder compression；
Partial size D90≤75 μm of the Lurasidone HCl；
The spray drying mannitol is spray drying PEARLITOL 100SD EARLITOL 200SD, and it is that speed collapses PEARLITOL 100SD EARLITOL that speed, which collapses mannitol, FLASH。
3. a kind of oral disnitegration tablet containing Lurasidone HCl, it is characterised in that consist of the following components in percentage by weight:
Wherein the oral disnitegration tablet is prepared using direct powder compression；
Partial size D90≤75 μm of the Lurasidone HCl；
The particulate lactose is particulate lactose TABLETTOSE 70, and lactose starch is lactose starch StarLac.
4. a kind of oral disnitegration tablet containing Lurasidone HCl, it is characterised in that consist of the following components in percentage by weight:
Wherein, it is that speed collapses PEARLITOL 100SD EARLITOL FLASH that speed, which collapses mannitol, and particulate lactose is particulate lactose TABLETTOSE 80.
5. a kind of oral disnitegration tablet containing Lurasidone HCl, it is characterised in that consist of the following components in percentage by weight:
Wherein the oral disnitegration tablet is prepared using direct powder compression；
Partial size D90≤75 μm of the Lurasidone HCl；
The spray drying lactose is spray drying lactose FLOWLAC 100, and particulate lactose is particulate lactose TABLETTOSE 80.
6. a kind of oral disnitegration tablet containing Lurasidone HCl, it is characterised in that consist of the following components in percentage by weight:
Wherein the oral disnitegration tablet is prepared using direct powder compression；
Partial size D90≤75 μm of the Lurasidone HCl；
Described to melt poly- mannitol to melt poly- PEARLITOL 100SD EARLITOL 300DC, spray drying mannitol is spray drying mannitol PEARLITOL200SD。
7. a kind of oral disnitegration tablet containing Lurasidone HCl, it is characterised in that consist of the following components in percentage by weight:
Wherein the oral disnitegration tablet is prepared using direct powder compression；
Partial size D90≤75 μm of the Lurasidone HCl；
The particulate lactose is particulate lactose TABLETTOSE 70.
8. a kind of oral disnitegration tablet containing Lurasidone HCl, it is characterised in that consist of the following components in percentage by weight:
Wherein the oral disnitegration tablet is prepared using direct powder compression；
Partial size D90≤75 μm of the Lurasidone HCl；
The particulate lactose is particulate lactose TABLETTOSE 70.
9. a kind of oral disnitegration tablet containing Lurasidone HCl, it is characterised in that consist of the following components in percentage by weight:
Wherein the oral disnitegration tablet is prepared using direct powder compression；
Partial size D90≤75 μm of the Lurasidone HCl；
The particulate lactose is particulate lactose TABLETTOSE 70, and microcrystalline cellulose is microcrystalline cellulose PH101.
10. a kind of oral disnitegration tablet containing Lurasidone HCl, it is characterised in that consist of the following components in percentage by weight:
Wherein the oral disnitegration tablet is prepared using direct powder compression；
Partial size D90≤75 μm of the Lurasidone HCl；
The filler is the mixture of spray drying mannitol and cornstarch；
The spray drying mannitol is spray drying PEARLITOL 100SD EARLITOL 200SD.
11. the oral disnitegration tablet of Lurasidone HCl according to claim 10, it is characterised in that by following weight percent The group of ratio is grouped as:
12. a kind of oral disnitegration tablet containing Lurasidone HCl, it is characterised in that consist of the following components in percentage by weight:
Wherein the oral disnitegration tablet is prepared using direct powder compression；
Partial size D90≤75 μm of the Lurasidone HCl；
The spray drying mannitol is spray drying PEARLITOL 100SD EARLITOL 200SD, and particulate lactose is particulate lactose TABLETTOSE 80。
13. containing the oral disnitegration tablet of Lurasidone HCl described in any one of -12 according to claim 1, it is characterised in that When direct powder compression, Lurasidone HCl and filler is taken to be sufficiently mixed uniformly, disintegrating agent and lubricant is added, mixing is equal Even, tabletting to obtain the final product.
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