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WO2003032998A1 - Particules fines a liberation prolongee et procede de fabrication - Google Patents

Particules fines a liberation prolongee et procede de fabrication Download PDF

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Publication number
WO2003032998A1
WO2003032998A1 PCT/JP2002/010643 JP0210643W WO03032998A1 WO 2003032998 A1 WO2003032998 A1 WO 2003032998A1 JP 0210643 W JP0210643 W JP 0210643W WO 03032998 A1 WO03032998 A1 WO 03032998A1
Authority
WO
WIPO (PCT)
Prior art keywords
theophylline
water
fine particles
insoluble polymer
sustained
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/JP2002/010643
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English (en)
Japanese (ja)
Inventor
Nobuhiro Higo
Tatsuo Nomura
Yasunari Shinkai
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Mitsubishi Tanabe Pharma Corp
Original Assignee
Mitsubishi Pharma Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Mitsubishi Pharma Corp filed Critical Mitsubishi Pharma Corp
Priority to JP2003535801A priority Critical patent/JPWO2003032998A1/ja
Publication of WO2003032998A1 publication Critical patent/WO2003032998A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics

Definitions

  • the present invention relates to sustained-release microparticles containing theophylline suitable for once-daily administration preparations (hereinafter sometimes abbreviated as the microparticles of the present invention).
  • Theophylline which is widely used as a symptomatic treatment for acute and chronic bronchial asthma, is known to have a short biological half-life.
  • theophylline since theophylline is used in a wide range of patients, from infants to the elderly, sufficient drug efficacy can be maintained by administering twice a day or less from the viewpoint of improving compliance, and syrups and dry syrups can be maintained.
  • sustained-release microparticle preparations in dosage forms such as preservatives.
  • theophylline-containing sustained-release microparticle preparations have been prepared using a cellulose acetate polymer (Japanese Patent Application Laid-Open No. 61-09711) and a cellulose derivative. And a preparation using an (meth) acrylic polymer (JP-A-2001-166627) are known. +
  • the controlled-release type microparticles having a film-controlling (coating) type require a large amount of a coating film, and have a drawback that they are difficult to dissolve in the initial stage of leaching after ingestion.
  • functional fine particle preparations which have been attracting attention in recent years, the volume of each unit of the active ingredient is reduced due to the properties of the fine particles themselves, and conversely, the surface area becomes large.
  • problems such as the curvature of the coating surface caused by these arise.
  • the physical properties of the active ingredient are further emphasized in the microparticle preparation, it is very difficult to impart the functionality of the microparticles.
  • the functional microparticle preparation itself has been practically used compared to tablets, granules and capsules. Also less.
  • the sustained-release theophylline-containing microparticle preparations have been used as twice-daily preparations.
  • theophylline-containing sustained-release microparticles which can be administered once a day, that is, maintain sufficient drug efficacy for 24 hours, and their formulations have not been obtained.
  • the present inventors have conducted intensive studies to solve the above-mentioned problems, and as a result, obtained a fine granulation of the theophylline, the wax and the water-insoluble polymer to form a microparticle for the theophylline-containing sustained-release fine particles.
  • coating with a water-insoluble polymer makes it possible to freely control the sustained-release pattern, and to provide a long-lasting pattern.
  • the inventors have found that sustained-release microparticles containing theophylline that can be dissolved over time can be produced, and have completed the present invention. Further, the theophylline-containing sustained-release microparticles of the present invention can be produced in actual production, and can be made into a formulation suitable for once-a-day administration.
  • the present invention is as follows.
  • It contains theophylline, wax and water-insoluble polymer, and the ratio of theophylline, wax and water-insoluble polymer is 10% by weight of theophylline with respect to 10% by weight of theophylline. Fine particles containing 30 to 130 parts by weight of water and 7 to 35 parts by weight of water-insoluble polymer.
  • Theophylline-containing sustained release characterized by coating 25 to 45 parts by weight of a water-insoluble polymer with respect to 100 parts by weight of the elemental fine particles of the above (1) to (4). Particles.
  • the ratio of theophylline to the wax and the water-insoluble polymer is 100 parts by weight, including theophylline, wax and water-insoluble polymer.
  • elemental fine particles which are ternary small matrices, with 30 to 130 parts by weight of resins and 7 to 35 parts by weight of water-insoluble polymer, were prepared.
  • the coated fine particles containing theophylline are prepared by coating with 25 to 45 parts by weight of a water-insoluble polymer per 100 parts by weight of the elementary fine particles. .
  • the fine particles are granulated with an aqueous dispersion of the water-insoluble polymer, wax and water-insoluble polymer in accordance with the above ratio, and dried, crushed, and sized to produce fine particles. I do. Further, 25 to 45 parts by weight of a water-insoluble polymer is coated with respect to 100 parts by weight of the elemental fine particles to obtain sustained-release theophylline-containing fine particles.
  • FIG. 1 is a graph showing the dissolution rate of theophylline-containing sustained-release fine particles obtained in Comparative Example and Examples 1, 2, 3, and 4.
  • the elemental fine particles of the present invention contain theophylline, wax and water-insoluble polymer, and the ratio of theophylline to the wax and water-insoluble polymer is theophylline 1.
  • the wax is 30 to 130 parts by weight and the water-insoluble polymer is 7 to 35 parts by weight, preferably 100% by weight, preferably 100% by weight. Parts by weight
  • the amount of waxes is 40 to 100 parts by weight, and the amount of water-insoluble polymer is 10 to 25 parts by weight. More preferably, the ratio is 100 to 70 parts by weight of theophylline, 40 to 70 parts by weight of wax, and 1 to 20 parts by weight of the water-insoluble polymer.
  • fine particles are granulated using an aqueous dispersion of theophylline, wax and a water-insoluble polymer to produce dried, crushed, sized, and sieved fine particles. Furthermore, 25 to 45 parts by weight (preferably 25 to 35 parts by weight) of the water-insoluble polymer is coated with respect to 100 parts by weight of the elemental fine particles, and the theophylline-containing sustained release is obtained. Obtain fine particles. Preferably, the particles are granulated by rolling the water and the wax, spraying an aqueous dispersion of a water-insoluble polymer, and drying and sieving. Produce fine particles. Further, 25 to 45 parts by weight of a water-insoluble polymer is coated with respect to 100 parts by weight of the elemental fine particles to obtain theophylline-containing sustained-release fine particles.
  • Sustained-release microparticles containing theophylline include theophylline, 'wax and water-insoluble polymer, and the ratio of theophylline to wax and water-insoluble polymer Is 100 to 100 parts by weight of theophylline, the wax force is 30 to 130 parts by weight, and water-insoluble.
  • the polymer is preferably 40 to 100 parts by weight.
  • the ratio of the theophylline to the wax and the water-insoluble polymer is 100 to 100 parts by weight of theophylline, and the wax force S is 40 to 70 parts by weight, and the water-insoluble polymer is 100 parts by weight. More preferred is 40 to 75 parts by weight of reamer.
  • Theophylline used in the present invention can be produced by a known production method. In order to achieve the object of the present invention, it is preferable that the average particle size be adjusted to 50 ⁇ m or less. Further, it is more preferable that the average particle size is adjusted to 10 ⁇ m or less.
  • the elementary fine particles in the present invention are preferably those whose average particle diameter is adjusted to 30 to 80 ⁇ to achieve the object of the present invention. No. Further, the average particle size is more preferably 40 to 6 ° ⁇ m. Further, the specific surface area is preferably from 0.1 to 0.25 m 2 Z g.
  • the average particle diameter and specific surface area of theophylline, elementary microparticles, and the sustained release microparticles containing theophylline can be measured by dry laser particle size distribution measurement or the like.
  • wax used in the present invention examples include fatty acids such as stearic acid, capric acid, raurilic acid, myristylic acid, palmitic acid and pendenic acid, and the like.
  • Higher alcohols such as fatty acid salts, raw alcohol, myristyl alcohol, cetyl phenol, stearyl phenol, stearyl phenol, stearin, myristine, and palmitin
  • Polyesters such as glycerin fatty acid esters such as glycerol, raurin, etc.
  • the wax has a melting point of 60 ° C. or more.
  • the final preparation should preferably have low odor due to its large surface area. Examples of hardened oils having these properties include Lovereux 101 and 103, manufactured by Freund Sangyo Co., Ltd.
  • water-insoluble polymer examples include cellulose derivatives (cellulose ethers (eg, ethyl cenorylose, ethyl methinoresorenolose, ethynolepropynolenoseloose, isopropynolenoseolose).
  • Senorose such as mouth and butinoresenolose, etc.Senore, such as tenorene, benzonoresenole, etc.Senorose, etc.
  • Cyano Anorekinore Cellulose esters for example, cellulose acetate petitate, cenorylose acetate, cenorylose porion pionate, cenorylose butyrate
  • Cellulose fatty acid esters such as senorose acetate propionate, hydroxymethyl cinolenate acetate succinate, cellulose acetate phthalate, hydroxy Phenolic aromatic cellulose esters such as cyclopropyl methylcellulose phthalate), etc.
  • acrylic polymers for example, ) Homo- or copolymers of acryl-based monomers ((meth) acrylic acid, (meth) acrylic acid ester monomers, etc.), (meta) acrylic Monomer and copolymerizable monomer (Bullester monomer, N, N-dialkylaminoethyl (meth) acrylate, heterocyclic vinyl monomer, polymerizable unsaturated dicarboxylic acid or derivative thereof)
  • a vinyl-based monomers for
  • the ethyl cellulose orifices, cellulose acetate butyrate and (meth) acrylic polymers especially ethyl cellulose It is desirable to use bases and (meth) acrylic polymers.
  • etylsenolaces include, for example, etinoreserose, aqueous dispersion of etinoresorose, etinolemethinoresorenose, and ethinolepropyrose, and among these, particularly e.
  • Tilcellulose and ethylcellulose aqueous dispersions can be preferably used.
  • Acrylic polymers include those manufactured by Rohm Pharma (Higuchi Shokai) Co., Ltd., trade name Eudragit; RSPO, tradename Eudragit RLPO, tradename Eudragit. NE30D, trade name Eudragit RS30D, tradename Eudragit RL30D, and the like. Of these, Eudragit RSPO and Eudragit RS3 0 D, Eudragit NE 30 D can be used preferably. In the present invention, A mixture of two or more of these can be used as a water-insoluble polymer.
  • a mixed aqueous dispersion of a cellulose derivative and a (meth) acrylic polymer is particularly preferable.
  • Ethyl cellulose aqueous dispersion and Eudragit NE3 • D are even more preferred.
  • the average particle size of the theophylline-containing sustained-release fine particles obtained by the present invention is 40 to 270 ⁇ , preferably 80 to 210 ⁇ m, more preferably 90 to 90 ⁇ m. It is desirable to set it to 130 ⁇ . Further, the specific surface area is preferably from 0.01 to 0.1 lm 2 / g.
  • the theophylline-containing sustained-release fine particles of the present invention are obtained by granulating a powder containing theophylline, citrus, and water-insoluble polymer into fine particles to obtain fine particles, and further forming a water-insoluble polymer. You can get it by coating.
  • the coating may be performed by coating in order to impart functionality to the fine particles, and coating by the waste method is preferable.
  • the dissolution rate of the theophylline-containing sustained-release microparticles of the present invention is, for example, after 3 hours: 25% to 55%; After 7 hours: 45% to 75%, After 12 hours: 60% to 90%, After 24 hours: 85% or more.
  • after 3 hours: 25% to 55% after 7 hours: 50% to 70%
  • after 12 hours: 60% to 85% after 24 hours: 85% That is all.
  • Preferred dissolution rates of the sustained-release microparticles are, for example, after 3 hours: 55% to 85%, after 7 hours, 75 to 100%, and after 12 hours, 85% or more.
  • the preparation form using the theophylline-containing sustained-release fine particles of the present invention is not particularly limited, and examples thereof include dry syrups, tablets, capsules, suspensions, and suppositories. These preparations contain other ingredients, such as excipients (e.g., crystalline cellulose, starches such as corn starch, lactose, powdered sugar, granulated sugar, glucose, mannitol, light caffeic anhydride, talc).
  • excipients e.g., crystalline cellulose, starches such as corn starch, lactose, powdered sugar, granulated sugar, glucose, mannitol, light caffeic anhydride, talc.
  • binders for example, sucrose, gelatin, arabia gum powder, methinoreserulose, hydroxy-mouth pinoreseno-relose, canoleoxyme-tino-reseno-relose, crystalline seno-relose
  • binders for example, sucrose, gelatin, arabia gum powder, methinoreserulose, hydroxy-mouth pinoreseno-relose, canoleoxyme-tino-reseno-relose, crystalline seno-relose
  • disintegrants for example, Boxime Chinoreseno-Role Scanoresium, Cross Carmel Melon Sodium, Cross-linked Poly Burpyrrolidone, low-substituted hydroxypropyl cellulose, starches, etc.
  • lubricants magnesium ste
  • the theophylline-containing sustained release fine particles of the present invention are preferably used in the form of a dry syrup.
  • the dry mouth preparation may be composed of at least the fine particles of the present invention, and may be a granular preparation obtained by granulating the fine particles of the present invention. Granulation can be performed by a conventional method, for example, using the fine particles of the present invention, an excipient, Z or a binder, and the like.
  • the dissolution rate in the examples was measured under the following conditions.
  • Test method Japanese Pharmacopoeia Dissolution Test Method 2 (Paddle Method)
  • Test solution Japanese Pharmacopoeia Disintegration Test Solution 2 with 0.02% polysorbate 80 added
  • the obtained theophylline-containing sustained-release microparticles (88% yield) had an average particle size of about 114 ⁇ m, and were 3 hours, 7 hours, 12 hours, and 24 hours.
  • the subsequent elution rates were 41%, 61%, 81%, and 100%, respectively (FIG. 1).
  • Example 2 In the same manner as in Example 1, the ethylcellulose aqueous dispersion of Example 1 was replaced with a metaacrylic polymer dispersion (trade name: Oydragit RS30D, manufactured by Rohm Pharma Co., Ltd.). (Solid content: 30 parts by weight). Thereafter, the particles were ground and dried in the same manner as in Example 1 to obtain fine particles having an average particle diameter of 76 ⁇ m. Coating and sieving operations similar to those in Example 1 were performed using these elementary fine particles to obtain sustained-release fine particles containing theophylline (88% yield).
  • a metaacrylic polymer dispersion trade name: Oydragit RS30D, manufactured by Rohm Pharma Co., Ltd.
  • the average particle size of the obtained theophylline-containing sustained-release microparticles is about 250 ⁇ m, and the elution rates after 3, 7, 12, and 24 hours are respectively as follows: They were 40%, 61%, 81% and 98% (Fig. 1).
  • Example 1 the trade name of the hardened oil of Example 1 The kneading was carried out by replacing Tas 101 with the hardened oil trade name Lapri-Wax 103 (manufactured by Freund Corporation). Thereafter, the same pulverization and drying as in Example 1 were performed to obtain fine particles having an average particle diameter of 44 ⁇ m. Coating and sieving operations similar to those in Example 1 were performed using the fine particles to obtain sustained-release theophylline-containing fine particles (yield: about 70%).
  • the average particle size of the obtained theophylline-containing sustained-release microparticles is about 210 ⁇ m, and the elution rates after 3 hours, 7 hours, 12 hours, and 24 hours are respectively 5 They were 1% 63%, 72% and 89% (Fig. 1).
  • the mixture was sieved to obtain sustained-release theophylline-containing fine particles (yield: 75%).
  • the average particle size of the obtained theophylline-containing sustained-release microparticles is about 115 ⁇ m, and the dissolution rates after 3 hours, 7 hours, 12 hours, and 24 hours are 3 They were 5%, 56%, 78% and 95% (Fig. 1).
  • the dissolution rate was examined in the same manner as in the example using Teodor Dry Syrup (trade name) (Niken Kagaku Co., Ltd.) as a twice-daily formulation.
  • the elution rates were 1 hour value: 42%, 2 hour value: 61%, 5 hour value: 83% (Fig. 1).
  • the theophylline-containing sustained release that can elute a certain amount of theophylline for a long time by using a combination of wax and water-insoluble polymer. Fine particles could be obtained, and the dissolution rate of the fine particles of the present invention showed an elution pattern that could be administered once a day as shown in FIG. Therefore, it is understood that the use of the fine particles of the present invention can provide a theophylline-containing sustained-release preparation for once-a-day administration.

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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Pulmonology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des particules fines à libération prolongée contenant de la théophylline, pouvant servir de préparation pharmaceutique destinée à être administrée une fois par jour. Lesdites particules fines à libération prolongée peuvent être obtenues par pulvérisation d'une poudre contenant de la théophylline, d'une cire et d'un polymère insoluble dans l'eau, et revêtement desdites particules fines avec un polymère insoluble dans l'eau. Du fait de l'utilisation combinée d'une cire et d'un polymère insoluble dans l'eau, les particules fines peuvent libérer de la théophylline à une vitesse donnée à long terme. Les particules selon l'invention présentent un motif de libération prolongée, et peuvent ainsi être administrées une fois par jour.
PCT/JP2002/010643 2001-10-15 2002-10-15 Particules fines a liberation prolongee et procede de fabrication Ceased WO2003032998A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP2003535801A JPWO2003032998A1 (ja) 2001-10-15 2002-10-15 徐放性微粒子及びその製造方法

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JP2001-317319 2001-10-15
JP2001317319 2001-10-15

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN119157848A (zh) * 2024-10-17 2024-12-20 华润双鹤利民药业（济南）有限公司 一种枸橼酸托法替布缓释片制剂及其制备方法

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0257310A1 (fr) * 1986-07-28 1988-03-02 Bio -Dar Ltd. Comprimés fabriqués à partir de microcapsules à libération prolongée
US5162110A (en) * 1990-12-19 1992-11-10 Rhone-Poulenc Rorer Pharmaceuticals Inc. Binding theophylline to ion exchange resins
JPH0920686A (ja) * 1995-07-07 1997-01-21 Teikoku Seiyaku Co Ltd 持続性製剤およびその製法
EP1025848A1 (fr) * 1997-09-30 2000-08-09 Nikken Chemicals Company, Limited Comprime de theophylline a liberation prolongee
JP2001106627A (ja) * 1999-08-04 2001-04-17 Sawai Pharmaceutical Co Ltd 徐放性微粒子製剤及びその製造方法
JP2002179571A (ja) * 2000-12-11 2002-06-26 Nikken Chem Co Ltd 小型徐放性錠剤

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0257310A1 (fr) * 1986-07-28 1988-03-02 Bio -Dar Ltd. Comprimés fabriqués à partir de microcapsules à libération prolongée
US5162110A (en) * 1990-12-19 1992-11-10 Rhone-Poulenc Rorer Pharmaceuticals Inc. Binding theophylline to ion exchange resins
US5413782A (en) * 1990-12-19 1995-05-09 Rhone-Poulenc Rorer Pharmaceuticals Inc. Binding pharmaceuticals to ion exchange resins
JPH0920686A (ja) * 1995-07-07 1997-01-21 Teikoku Seiyaku Co Ltd 持続性製剤およびその製法
EP1025848A1 (fr) * 1997-09-30 2000-08-09 Nikken Chemicals Company, Limited Comprime de theophylline a liberation prolongee
JP2001106627A (ja) * 1999-08-04 2001-04-17 Sawai Pharmaceutical Co Ltd 徐放性微粒子製剤及びその製造方法
JP2002179571A (ja) * 2000-12-11 2002-06-26 Nikken Chem Co Ltd 小型徐放性錠剤

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN119157848A (zh) * 2024-10-17 2024-12-20 华润双鹤利民药业（济南）有限公司 一种枸橼酸托法替布缓释片制剂及其制备方法

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