WO2019098327A1 - Comprimé orodispersible présentant un goût amer de médicament rapidement soluble inhibé - Google Patents

Comprimé orodispersible présentant un goût amer de médicament rapidement soluble inhibé Download PDF

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Publication number
WO2019098327A1
WO2019098327A1 PCT/JP2018/042487 JP2018042487W WO2019098327A1 WO 2019098327 A1 WO2019098327 A1 WO 2019098327A1 JP 2018042487 W JP2018042487 W JP 2018042487W WO 2019098327 A1 WO2019098327 A1 WO 2019098327A1
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Prior art keywords
drug
orally disintegrating
disintegrating tablet
tablet
dissolution test
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PCT/JP2018/042487
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English (en)
Japanese (ja)
Inventor
浩人 寺田
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大原薬品工業株式会社
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Priority claimed from JP2018209960A external-priority patent/JP7308022B2/ja
Application filed by 大原薬品工業株式会社 filed Critical 大原薬品工業株式会社
Publication of WO2019098327A1 publication Critical patent/WO2019098327A1/fr

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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
    • A61K31/13—Amines
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • 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
    • A61K47/38—Cellulose; Derivatives thereof
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • the present invention relates to an orally disintegrating tablet containing a drug having a high dissolution rate (in particular, memantine hydrochloride).
  • Memantine hydrochloride is a compound (drug) that has antagonism to NMDA receptor, which is a subtype of glutamate receptor, and is used as a therapeutic agent for Alzheimer's disease (see Non-patent Document 1).
  • Examples of compounds pharmacologically related to memantine hydrochloride include donepezil hydrochloride, galantamine hydrobromide, rivastigmine and the like.
  • memantine hydrochloride is provided to medical practice in the form of a tablet.
  • the formulation and manufacturing method of a preparation containing memantine hydrochloride are introduced in the following Patent Documents 1 to 3, and the like.
  • Patent Documents 1 to 3 an orally disintegrating tablet containing granules (including the case of coated granules) containing memantine hydrochloride obtained by fluid bed granulation is described and patented
  • Examples 18 and 19 of Document 2 describe tablets containing granules containing memantine hydrochloride obtained by agitation granulation
  • Patent Document 3 describes coated tablets containing memantine hydrochloride and the like.
  • the technique for improving the bitter taste of memantine hydrochloride for orally disintegrating tablets containing memantine hydrochloride has not been disclosed sufficient information in the prior art.
  • the improvement of the bitter taste of the drug in the orally disintegrating tablet is an important issue in improving the feeling of taking the tablet by the patient. Therefore, the present inventor aimed to develop a new technical means capable of remarkably improving the bitter taste of a drug having a fast dissolution rate such as memantine hydrochloride in an orally disintegrating tablet.
  • the problem to be solved by the present invention is to significantly improve the bitter taste of the drug which is felt in the oral cavity when the orally disintegrating tablet containing a drug having a high dissolution rate (especially memantine hydrochloride) is taken.
  • the inventor of the present invention conducted intensive studies on formulation and manufacturing method of chewing to improve the bitter taste of memantine hydrochloride in the orally disintegrating tablet. As a result, it was discovered that suppressing the initial dissolution rate of memantine hydrochloride to a certain range of values significantly improves the bitter taste of the chewing felt when taking the orally disintegrating tablet. Based on the findings, the inventor further intensively studied and completed the following invention.
  • the bitter taste which is felt when the drug is present in the oral cavity is surprisingly significantly suppressed by adjusting the dissolution rate of the sputum immediately after the orally disintegrating tablet disintegrates and the drug elutes to a certain range.
  • the dissolution rate of the drug is about 80.0% or less at 5 minutes after the start of the dissolution test conducted using the second dissolution test according to the 17th Amended Japanese Pharmacopoeia Dissolution Test (Paddle Method)
  • Dissolution test liquid 2 liquid volume of pH 6.8 phosphate buffer plus 1 volume of water Japanese Pharmacopoeia Dissolution test liquid 2 (2) Drug at time 5 minutes after the start of the dissolution test An orally disintegrating tablet, wherein the dissolution rate of is about 70.0% or less. (3) The orally disintegrating tablet according to the above (1) or (2), wherein the drug is selected from memantine, sitagliptin, solifenacin, pregabalin and any of the aforementioned salts.
  • a drug (memantine hydrochloride, solifenacin succinate etc.) is contained in a granule, and the granule is a water-insoluble polymer which is an ethyl acrylate / methyl methacrylate copolymer and an enteric polymer which is a methacrylic acid copolymer
  • the dissolution rate of the drug at about 5 minutes after the start of the dissolution test conducted using the first dissolution test according to the 17th Amended Japanese Pharmacopoeia Dissolution Test Method (Paddle Method) is about 5.0% or more ( An orally disintegrating tablet, which is preferably a non-enteric preparation exhibiting about 10.0 to about 100.0%).
  • Dissolution test liquid 1 The coating liquid in which the drug was dissolved or suspended was prepared by adding 1000 mL of water to 2.0 g of sodium chloride and 7.0 ml of hydrochloric acid to prepare a solution according to the Japanese Pharmacopoeia Dissolution Test liquid 1 (8), A method for producing the orally disintegrating tablet according to any one of the above (1) to (7), which comprises the step of spraying the fluidized core particles to perform wet granulation (example: fine particle coating method). (9) The oral cavity according to the above (8), wherein the coating liquid in which the enteric polymer is dissolved is sprayed onto the fluidized drug-containing granules to perform wet granulation (eg, fine particle coating method). Method of producing an internally disintegrating tablet.
  • a method for treating Alzheimer's disease which is produced by the tablet according to any one of the above (1) to (7) (orally disintegrating tablet) or the method according to the above (8) to (9) Administering the pilled tablet (orally disintegrating tablet).
  • the bitter taste of a drug felt in the oral cavity when taking an orally disintegrating tablet containing a drug having a high dissolution rate is significantly improved.
  • the orally disintegrating tablet of the present invention is preferably a plain tablet (a tablet which is not covered with a film coating layer, a sugar coating layer or the like, as it is molded by tableting etc. hereinafter the same). It is also possible to make a film coated tablet by applying a film coating layer to the film.
  • An orally disintegrating tablet is provided as a tablet that disintegrates rapidly in the oral cavity, as distinguished from ordinary tablets, and it is particularly preferred that the oral disintegration time is less than about 60 seconds, and less than about 40 seconds.
  • the disintegration time in the oral cavity can be determined, for example, by measuring the time it takes for the sputum to collapse when the tablet is placed on the tongue and infiltrated with saliva, or an orally disintegrating tablet tester (eg, OD-mate) Test time: may be determined by measuring the time for the tablet to disintegrate in the test liquid: water (37.degree. C.) condition, and the person skilled in the art to which the present invention belongs may disintegrate in the oral cavity. It may be determined by a method that can generally be performed to measure time.
  • the shape of the orally disintegrating tablet of the present invention is not particularly limited, and may be, for example, a circular tablet ⁇ a circular flat tablet (including a corner tablet, etc.), a circular R tablet (including a corner tablet, a two-stage R tablet, etc.), etc. Although any shape such as a lock may be used, a circular lock is particularly preferable.
  • the pressure for compression molding the orally disintegrating tablet of the present invention by tableting is preferably in the range of about 300 to about 1500 kgf.
  • the drug contained in the orally disintegrating tablet of the present invention include memantine, sitagliptin, solifelipacin, pregabalin and any of the above-mentioned fast-dissolving drugs, preferably memantine hydrochloride or solifenacin It is preferably a succinate salt, particularly memantine hydrochloride, and preferably a single agent containing only one drug.
  • the median diameter (d 50 ) of the drug used for producing the orally disintegrating tablet of the present invention is preferably about 25.0 ⁇ m or less, more preferably about 10.0 ⁇ m or less. It is also possible to adjust to any particle size by dry or wet grinding as appropriate.
  • the drug is at least about 3.0% by weight, preferably about 5.0 to about 20.0% by weight, more preferably about 8.0 to about the total weight of the uncoated tablet. It is contained in uncoated tablets in the range of about 13.0% by weight. It is desirable that memantine hydrochloride be contained in any one of about 5 mg, about 10 mg or about 20 mg in one tablet, and it is desirable that pregabalin be contained in any one of about 25 mg, about 75 mg or about 150 mg in one tablet.
  • the orally disintegrating tablet of the present invention is a drug at a time point 5 minutes after the start of the dissolution test conducted using the dissolution test second solution (pH 6.8) according to the 17th revised Japanese Pharmacopoeia Dissolution Test Method (paddle method) Is preferably about 80.0% or less (preferably about 30.0% or more, more preferably about 40.0% or more, and still more preferably about 50.0% or more). It is less than or equal to about 70.0%, and even more preferably less than or equal to about 65.0%.
  • Dissolution rate of the drug at 10 minutes after the start of the dissolution test is about 70.0% or more (desirably about 98.0% or less, more desirably about 95.0% or less), preferably about 80.0% It is possible to do more than.
  • Dissolution test liquid 2 is the Japanese Pharmacopoeia Dissolution Test Liquid 2 which is one volume of pH 6.8 phosphate buffer solution plus 1 volume of water. The detailed conditions of the dissolution test can be based on that described in Test Example 1 (paddle rotation number: 50 rpm).
  • the orally disintegrating tablet of the present invention can be a non-enteric preparation, and according to the 17th Amended Japanese Pharmacopoeia Dissolution Test Method (Paddle Method), using Dissolution Test Solution 1 (pH 1.2) For example, about 5.0% or more (preferably about 10.0 to about 100.0%, more preferably about 20.0 to about 100.0) of dissolution rate of the drug at 5 minutes after initiation of the dissolution test conducted. %) Is possible.
  • Dissolution test liquid 1 is the Japanese Pharmacopoeia Dissolution Test Liquid 1 (pH 1.2) obtained by adding water to 2.0 g of sodium chloride and 7.0 ml of hydrochloric acid to make it 1000 ml. The detailed conditions of the dissolution test can depend on those described in Test Example 3 (paddle rotation number: 50 rpm).
  • the sustained release coating and the drug are preferably contained in the same granule, and it is desirable that the periphery of the drug be coated with the sustained release coating.
  • the sustained release coating agent is at least about 1.0% by weight, preferably about 2.0 to about 40.0% by weight, more preferably about 5.0 to about 15.0% by weight based on the total weight of the uncoated tablet. % In the uncoated tablet.
  • the sustained release coating agent for example, water insoluble polymers, gastric soluble polymers, enteric polymers etc. may be mentioned, preferably water insoluble polymers or enteric polymers, more preferably water insoluble high. It is a molecule (preferably with an enteric polymer).
  • a water-insoluble polymer is substantially or completely not soluble in a water solvent (consisting essentially of water) (the detailed definition shows the solubility described in the 17th Amended Japanese Pharmacopoeia)
  • a water solvent consisting essentially of water
  • mostly insoluble it has a high molecular weight of about 10000 or more, which is characterized as "the amount of solvent required to dissolve 1 g of solute is 10000 mL or more". It is desirable to be a molecule.
  • water-insoluble polymer examples include cellulose acetate, ethyl cellulose, aminoalkyl methacrylate copolymer, vinyl acetate resin, ethyl acrylate / methyl methacrylate copolymer and the like, preferably ethyl acrylate / methyl methacrylate copolymer is there.
  • stomach-soluble polymer examples include polyvinyl acetal diethylaminoacetate, methyl methacrylate / butyl methacrylate / dimethylaminoethyl methacrylate copolymer and the like.
  • Enteric polymers include, for example, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, hydroxymethylethyl cellulose phthalate, carboxymethyl ethyl cellulose, methacrylic acid / methyl methacrylate copolymer, methacrylic acid / ethyl acrylate copolymer (Methacrylic acid copolymer) and the like can be mentioned, with preference being given to methacrylic acid / ethyl acrylate copolymer.
  • the enteric polymer when the water-insoluble polymer and the enteric polymer are contained (preferably, they are contained in the same granule together with the drug), the enteric polymer
  • the water-insoluble polymer is preferably about 12.0 to about 120.0 parts by weight, more preferably about 18.0 to about 80.0 parts by weight, and still more preferably about 20.
  • the tablet is contained in the range of 0 to about 48.0 parts by weight.
  • additives that can be used to produce the orally disintegrating tablet of the present invention excipients, binders, disintegrants, lubricants, and flavoring agents generally used other than the above-mentioned additives And coating agents, plasticizers, light shielding agents, surfactants and the like.
  • excipients include lactose, microcrystalline cellulose, D-mannitol, erythritol, xylitol, sorbitol, isomalt, maltitol, sucrose, glucose, corn starch, potato starch, rice starch, wheat starch, partial alpha Starch, low substituted hydroxypropyl cellulose and the like can be mentioned, with preference given to D-mannitol.
  • the excipient is contained in the uncoated tablet preferably in the range of about 40.0 to about 95.0% by weight based on the total weight of the uncoated tablet.
  • binders include hydroxypropyl cellulose, hypromellose, methylcellulose, povidone, ethylcellulose, polyvinyl alcohol, polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, starch (corn starch, potato starch, rice starch, wheat starch etc. And polyethylene glycol etc., preferably hydroxypropyl cellulose.
  • the binder is preferably contained in the uncoated tablet in the range of about 0.01 to about 5.0% by weight based on the total weight of the uncoated tablet.
  • the disintegrant examples include low substituted hydroxypropyl cellulose, carmellose, carmellose calcium, carmellose sodium, hydroxypropyl starch, carboxymethyl starch sodium, crospovidone, agar powder and the like, preferably crospovidone. It is.
  • the disintegrant is preferably contained in the uncoated tablet in the range of about 2.0 to about 20.0% by weight based on the total weight of the uncoated tablet.
  • the lubricant include light anhydrous silicic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, talc, hydrogenated oil and the like, with preference given to magnesium stearate.
  • the lubricant is preferably contained in the uncoated tablet in the range of about 0.1 to about 3.0% by weight based on the total weight of the uncoated tablet.
  • flavoring agent examples include ascorbic acid, L-aspartic acid, aspartame, sucralose, acesulfame potassium, thaumatin, l-menthol and the like.
  • the flavoring agent is preferably contained in the uncoated tablet in the range of about 1.0 to about 5.0% by weight based on the total weight of the uncoated tablet.
  • Specific coating agents include hydroxypropyl cellulose, hypromellose, methylcellulose, povidone, polyvinyl alcohol, polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, starch (corn starch, potato starch, rice starch, wheat starch etc.), A wide variety of polyethylene glycols, talcs, etc. may be mentioned, in addition to the sustained release coatings specifically listed above.
  • the coating agent is contained in the tablet preferably in the range of about 2.0 to about 40.0% by weight based on the total weight of the uncoated tablet.
  • plasticizers include sesame oil, castor oil, cotton seed oil / soybean oil mixture, dimethylpolysiloxane / silicon dioxide mixture, medium-chain fatty acid triglyceride, triethyl citrate, tributyl citrate, triacetin, diethyl phthalate, dibutyl phthalate, Examples include butyl phthalyl butyl glycolate, glycerin, glycerin fatty acid ester, polyethylene glycol, propylene glycol, stearic acid and the like, with preference given to triethyl citrate.
  • the plasticizer is preferably contained in the uncoated tablet in the range of about 0.01 to about 2.0% by weight based on the total weight of the uncoated tablet.
  • Specific light shielding agents include titanium oxide, yellow iron oxide, yellow ferric oxide, brown iron oxide, ferric oxide, food yellow No. 4, food yellow No. 5, food yellow No. 4 aluminum lake, food red No. 2, Food red No. 3 and food red No. 102 can be mentioned.
  • the light shielding agent is preferably contained in the tablet in the range of about 0.01 to about 2.0% by weight based on the total weight of the uncoated tablet.
  • the orally disintegrating tablet of the present invention preferably contains a drug-containing granule which is coated with a coating layer (hereinafter referred to as "coated granules according to the present invention").
  • a coating layer hereinafter referred to as "coated granules according to the present invention”
  • the sustained release coating is preferably about 5.0 to about 80 parts by weight based on 100.0 parts by weight of the coated granules according to the present invention. It is contained in the coated granules according to the present invention in the range of 0 parts by weight, more preferably about 10.0 to about 50.0 parts by weight, and still more preferably about 15.0 to about 30.0 parts by weight.
  • the coating layer is preferably about 15.0 to about 90.0 parts by weight, more preferably about 20.0 to about 70.0 parts by weight, per 100.0 parts by weight of the coated granules according to the present invention. More preferably, it is contained in the coated granules according to the present invention in the range of about 25.0 to about 55.0 parts by weight.
  • a fine particle coating method is mentioned as a specific example of the manufacturing method of granulated materials (granules), such as a coated granule concerning the present invention.
  • granulated materials such as a coated granule concerning the present invention.
  • the desired granulated product can be easily produced according to a conventional method.
  • a fluid bed granulator an excipient serving as core particles is allowed to flow, and a coating liquid containing a drug and a binder is spray-dried and coated (coated) to form granules containing a drug. Is obtained.
  • the coated granules according to the present invention can be obtained by coating.
  • the coated granules according to the present invention can be mixed with excipients and lubricants and compressed to produce the orally disintegrating tablet (uncoated tablet) of the present invention.
  • a PTP sheet product including the orally disintegrating tablet of the present invention by sandwiching and covering the tablet with a sheet for packaging and aluminum foil or the like and heat sealing.
  • materials used for packaging sheets of straw include polyvinyl chloride, polypropylene, polyvinylidene chloride, polychlorotrifluoroethylene and the like.
  • a PTP sheet product is produced using a material having a drying function, an aluminum pillow package of the PTP sheet product, a desiccant It is possible to carry out known methods, such as sealing the bottle with a tablet in a bottle.
  • "about” refers to a tolerance of up to ⁇ 10% of the indicated value. Where a range of two values is recited herein, the range of ⁇ ⁇ also includes the two values themselves.
  • 240 g of the core granules obtained above are fluidized in a jet fluidized bed granulator, and 300 g of a methacrylic acid copolymer LD (Eudragit L30D55 / Evonik Japan, solid content 30%), ethyl acrylate / methyl methacrylate Copolymer dispersion (Eudragit NE30D / Evonik Japan: 30% solids) 100 g, Triethyl citrate (Citroflex 2 SC-60 / Morimura Shoji Co., Ltd.) 9.0 g, light anhydrous silica (Aerosil 300 / Evonik Japan) )
  • a solution of 3.0 g of 60 g of talc Victrilite SK-C / manufactured by Kakoyama Mining Co., Ltd.
  • 600 g of purified water is sprayed and dried, and sifted through a 30-mesh sieve (sized) Granules (coated granul
  • This mixture is compression molded using a rotary tableting machine (Vera 5 / manufactured by Kikusui Seisakusho Ltd.) with a striking pressure of 1000 kgf, and a single tablet of 190.0 mg, a diameter of 8.0 mm and a plain tablet of 3.4 mm in thickness (circular shape R tablets).
  • PEARLITOL Flash® is an additive consisting of mannitol and corn starch.
  • This mixture is compression molded using a rotary tableting machine (Vera 5 / Kikusui Seisakusho Co., Ltd.) with a striking pressure of 1000 kgf, and a single tablet mass of 150.0 mg, diameter 7.5 mm, thickness 3.4 mm uncoated tablet (circular shape R tablets).
  • Comparative Example 2 165 g of the core granules obtained in Comparative Example 1 were fluidized in a spouted fluid bed granulator, and hydroxypropyl methylcellulose acetate succinate (Shin-Etsu AQ OAT AS-LG (registered trademark) / Shin-Etsu Chemical Co., Ltd.) 89 .1 g, 9.9 g of methylcellulose (SM-4 / Shin-Etsu Chemical Co., Ltd.), 33 g of talc (Victrilite SK-C / Kakomitsu San Mining Co., Ltd.) and 24 g of 10% ammonia water are suspended and dispersed in 1500 g of purified water The solution obtained was sprayed, dried and sieved (sorted) with a 30-mesh sieve to obtain granules (coated granules).
  • hydroxypropyl methylcellulose acetate succinate Shin-Etsu AQ OAT AS-LG (registered trademark) / Shin
  • This mixture is compression molded using a rotary tableting machine (Vera 5 / Kikusui Seisakusho Co., Ltd.) with a striking pressure of 1000 kgf, and a single tablet mass of 150.0 mg, diameter 7.5 mm, thickness 3.4 mm uncoated tablet (circular shape R tablets).
  • Comparative Example 3 165 g of the core granules obtained in Comparative Example 1 are fluidized in a jet fluid bed granulator, to which 82.5 g of aminoalkyl methacrylate copolymer E (Eudragit EPO / Evonik Japan), 8.25 g of sodium lauryl sulfate, A solution of 12.38 g of stearic acid (manufactured by Merck) and 28.88 g of talc (Victrilite SK-C / Kakomitsu Sangyo Shoji Co., Ltd.) suspended and dispersed in 750 g of purified water is sprayed and dried, and a 30-mesh sieve is used.
  • E aminoalkyl methacrylate copolymer
  • talc Victrilite SK-C / Kakomitsu Sangyo Shoji Co., Ltd.
  • the mixture was sieved (sorted) in the above to obtain granules (coated granules).
  • 11.88 g of the coated granules obtained above 30.69 g of PEARLITOLFLASH (registered trademark) (manufactured by Rocket Japan), 1.5 g of crospovidone (manufactured by Kollidon CL-F / BASF), and aspartame (manufactured by Ajinomoto Co.) 0.
  • This mixture is compression molded using a rotary tableting machine (Vera 5 / Kikusui Seisakusho Co., Ltd.) with a striking pressure of 1000 kgf, and a single tablet mass of 150.0 mg, diameter 7.5 mm, thickness 3.4 mm uncoated tablet (circular shape R tablets).
  • Example 1 Dissolution test of sustained release coated drug
  • the tablets prepared in Example 1 and Comparative Examples 2 and 3 (wherein the drug granules were coated with the sustained release coating agent) are frequently the 17th revised Japanese pharmacy.
  • the dissolution rate (%) of memantine 5 and 10 minutes after the start of the test was determined by the dissolution test method (paddle method) of the general test method (using LC / MS).
  • Example 2 Sensory test of orally disintegrating tablet For each of three subjects who are adult males, each of the orally disintegrating tablets described in Example 1 and Comparative Examples 1 and 2 was used in the oral cavity 1 I was allowed to disintegrate in the oral cavity while gently moving the tongue while including only the lock. At that time, the above-mentioned subjects evaluated the bitter taste of each orally disintegrating tablet felt in the oral cavity, and the average evaluation results of chewing were shown in Table 1 below. The above evaluation by each subject is about having the subject select the most appropriate numerical item from 0: not bitter, 1: slightly bitter, 2: bitter, 3: very bitter, for bitterness. went.
  • Example 3 the bitter taste is significantly reduced in Example 1 in which the dissolution rate at 5 minutes after the start of the dissolution test is lower than in Comparative Examples 2 and 3 in which the dissolution rate at 5 minutes after the dissolution start is higher.
  • the orally disintegrating tablet of the present invention is capable of surprisingly significantly suppressing its bitter taste which is felt when the drug is present in the oral cavity.
  • D-mannitol (PEARLITOL 100SD, manufactured by Rocket Japan Co., Ltd.) is introduced into a jet fluid bed granulator (MP-01-SPC type, manufactured by Powrex Co., Ltd.) to be fluidized, and methyl cellulose (Metolose SM-15)
  • MP-01-SPC type manufactured by Powrex Co., Ltd.
  • methyl cellulose (Metolose SM-15)
  • This mixture is compression molded at a striking pressure of 800 kgf using a rotary tableting machine (Vera5 / manufactured by Kikusui Seisakusho Co., Ltd.), and an orally disintegrating tablet having a mass of 170.0 mg per tablet, a diameter of 8.0 mm and a thickness of 4.0 mm. (Unlock, round R lock) was obtained.
  • the above-mentioned drug substance and each additive were used in the above-mentioned production in such an amount that the formulation of tablets shown in Table 4 below.
  • a solution of tocopherol in ethanol is sprayed and dried on hydrous silicon dioxide fluidized and fluidized, and then solifenacin succinate A suspension of light anhydrous silicic acid suspended in an aqueous solution of methyl cellulose and water in methyl cellulose was sprayed and dried to obtain coated granules A containing amorphous solifenacin succinate.
  • the coated granules B obtained above are charged into a fluidized bed granulating and drying coating machine and fluidized, and a methacrylic acid copolymer LD (Eudragit L30D55 / Evonik Japan Co., Ltd .: solid content 30%), acrylic acid A liquid obtained by suspending and dispersing ethyl methyl methacrylate copolymer dispersion (Eudragit NE30D / Evonik Japan: solid content 30%), triethyl citrate, glycerin monostearate and polysorbate 80 in purified water is sprayed and dried. Thus, coated granules C were obtained.
  • a methacrylic acid copolymer LD Eudragit L30D55 / Evonik Japan Co., Ltd .: solid content 30%
  • acrylic acid A liquid obtained by suspending and dispersing ethyl methyl methacrylate copolymer dispersion (Eudragit NE30D / Evonik Japan: solid content
  • This mixture is compression molded at a batting pressure of 750 kgf using a rotary type tableting machine (Vera 5 / manufactured by Kikusui Seisakusho Co., Ltd.), and an orally disintegrating tablet having a weight of 150.0 mg, a diameter of 7.5 mm and a thickness of 3.9 mm. (Unlock, round R lock) was obtained.
  • Example 2 drug: memantine hydrochloride
  • Example 3 drug: solifenacin succinate
  • the tablets of Examples 2 and 3 in which the bitter taste of the drug was significantly improved had a low dissolution rate at 5 minutes, etc. at which the dissolution test (test liquid: NIED "Dissolution test liquid 2") started. confirmed.
  • the tablets of Examples 2 and 3 show a dissolution of 5% or more in a dissolution test (test liquid: "Dissolution test first liquid” of JP). Therefore, the tablet of the present invention is shown to be a non-enteric preparation.
  • an orally disintegrating tablet containing a drug having a high dissolution rate particularly, memantine hydrochloride
  • a drug having a high dissolution rate particularly, memantine hydrochloride

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  • Organic Chemistry (AREA)
  • Medicinal Preparation (AREA)

Abstract

Selon l'invention, le goût amer d'un médicament ressenti à l'intérieur de la bouche, est considérablement amélioré, lors de la prise d'un comprimé orodispersible comprenant un médicament à élution rapide. Plus précisément, l'invention fournit un comprimé orodispersible qui, selon le test d'élution de la dix-septième édition de la Pharmacopée japonaise (méthode de la palette), présente un taux d'élution du médicament à un instant suivant de 5 minutes le test d'élution, compris dans une plage de ４０,０ à ７０,０％. De préférence, le médicament consiste en un hydrochlorure de mémantine, et un succinate de solifénacine.
PCT/JP2018/042487 2017-11-17 2018-11-16 Comprimé orodispersible présentant un goût amer de médicament rapidement soluble inhibé WO2019098327A1 (fr)

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JP2017-222234 2017-11-17
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JP2018-139892 2018-07-26
JP2018139892 2018-07-26
JP2018-209960 2018-11-07
JP2018209960A JP7308022B2 (ja) 2017-11-17 2018-11-07 速溶性薬物の苦味が抑制された口腔内崩壊錠

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WO2005039542A1 (fr) * 2003-10-27 2005-05-06 Yamanouchi Pharmaceutical Co., Ltd. Microparticule enrobee contenant un medicament pour comprime a dissolution orale
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JP2010280589A (ja) * 2009-06-03 2010-12-16 Ohara Yakuhin Kogyo Kk 生理活性物質含有粒子の製造方法
JP2014167031A (ja) * 2014-06-18 2014-09-11 Otsuka Pharmaceut Co Ltd 固形製剤
WO2014189034A1 (fr) * 2013-05-21 2014-11-27 武田薬品工業株式会社 Comprimé à délitement oral
US20170172942A1 (en) * 2006-07-06 2017-06-22 Forest Laboratories Holdings Limited Orally dissolving formulations of memantine
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JP2018065776A (ja) * 2016-10-21 2018-04-26 ニプロ株式会社 医薬組成物粒子とそれを含む口腔内崩壊製剤、医薬組成物粒子の製造方法
CN108066305A (zh) * 2016-11-16 2018-05-25 深圳万和制药有限公司 改善口崩片硬度和崩解的方法和定位释放口腔崩解片
CN108066297A (zh) * 2016-11-16 2018-05-25 深圳万和制药有限公司 治疗老年痴呆症的定位释放美金刚口腔崩解片组合物
JP2018172363A (ja) * 2017-03-31 2018-11-08 大原薬品工業株式会社 腸溶性組成物中に含まれる薬物塩の溶出性を改善する方法

Patent Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005039542A1 (fr) * 2003-10-27 2005-05-06 Yamanouchi Pharmaceutical Co., Ltd. Microparticule enrobee contenant un medicament pour comprime a dissolution orale
WO2005105045A1 (fr) * 2004-04-30 2005-11-10 Astellas Pharma Inc. Composition pharmaceutique granulaire du type à libération limitée dans le temps en vue d'une administration orale et comprimé à désintégration rapide intra orale contenant la composition
US20170172942A1 (en) * 2006-07-06 2017-06-22 Forest Laboratories Holdings Limited Orally dissolving formulations of memantine
JP2010280589A (ja) * 2009-06-03 2010-12-16 Ohara Yakuhin Kogyo Kk 生理活性物質含有粒子の製造方法
WO2014189034A1 (fr) * 2013-05-21 2014-11-27 武田薬品工業株式会社 Comprimé à délitement oral
JP2014167031A (ja) * 2014-06-18 2014-09-11 Otsuka Pharmaceut Co Ltd 固形製剤
WO2017146053A1 (fr) * 2016-02-23 2017-08-31 ニプロ株式会社 Particules de composition pharmaceutique et préparation se délitant par voie orale comprenant celles-ci
JP2018065776A (ja) * 2016-10-21 2018-04-26 ニプロ株式会社 医薬組成物粒子とそれを含む口腔内崩壊製剤、医薬組成物粒子の製造方法
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CN108066297A (zh) * 2016-11-16 2018-05-25 深圳万和制药有限公司 治疗老年痴呆症的定位释放美金刚口腔崩解片组合物
JP2018172363A (ja) * 2017-03-31 2018-11-08 大原薬品工業株式会社 腸溶性組成物中に含まれる薬物塩の溶出性を改善する方法

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