WO1991006291A1 - Preparation a liberation entretenue - Google Patents

Preparation a liberation entretenue Download PDF

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Publication number
WO1991006291A1
WO1991006291A1 PCT/JP1990/001364 JP9001364W WO9106291A1 WO 1991006291 A1 WO1991006291 A1 WO 1991006291A1 JP 9001364 W JP9001364 W JP 9001364W WO 9106291 A1 WO9106291 A1 WO 9106291A1
Authority
WO
WIPO (PCT)
Prior art keywords
substance
drug
solubility
release
hydrochloride
Prior art date
Application number
PCT/JP1990/001364
Other languages
English (en)
Japanese (ja)
Inventor
Makoto Sugiyama
Kouichi Ushimaru
Tomini Ando
Kouichi Nakamichi
Hiroyuki Yasuura
Original Assignee
Nippon Shinyaku Co., Ltd.
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 Nippon Shinyaku Co., Ltd. filed Critical Nippon Shinyaku Co., Ltd.
Priority to JP51462290A priority Critical patent/JP3158435B2/ja
Publication of WO1991006291A1 publication Critical patent/WO1991006291A1/fr

Links

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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2886—Dragees; Coated pills or tablets, e.g. with film or compression coating having two or more different drug-free coatings; Tablets of the type inert core-drug layer-inactive layer
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings

Definitions

  • the present invention is directed to a drug for maintaining a constant release rate in the body of a drug having the property of having a high solubility in an acidic region and a low solubility in a neutral or alkaline region as a physicochemical property of the drug. It relates to a release preparation.
  • preparations in which a poorly soluble substance is coated on the surface of tablets or granules preparations mixed in tablets or granules, preparations in which a polymer compound is mixed to control drug release, and the like are known.
  • the drug has a physicochemical property that the solubility is high in the acidic region and the solubility decreases in the neutral or alkaline region
  • the drug is manufactured by the general manufacturing method as described above.
  • Sustained-release preparations exhibit a release property dependent on the solubility of the drug in liquid form.
  • the release rate of the drug is high in the acidic region, and neutral to low Slow phenomena occur in the alkaline region.
  • the return pH in the gastrointestinal tract shows an acidic region of about 1 to 3 in the stomach and about 5 to 8 neutral to alkaline region in the small intestine.
  • the pH in the gastrointestinal tract is inevitably affected, and there is a concern that drug release with individual differences and sometimes irregular drug release may occur even in the same person, resulting in variations in blood concentration, Or, there is a risk of lowering the bay endurance.
  • an organic acid and an ice-soluble polymer are mixed in the formulation, and the eluate penetrating into the formulation is reduced to the low PH region.
  • a method of making the release rate less affected by the pH of the test solution Japanese Patent Application Laid-Open No. 62-283926.
  • the purpose of the present invention is to create a completely new sustained-release formulation that eliminates the above-mentioned disadvantages for drugs that have the property of decreasing solubility in the neutral to alkaline region, with high solubility in the acidic region. It was an issue to be solved.
  • the gist of the present invention is to form a double film on the surface of a drug.
  • the double coating means a coating of a substance that is permanently insoluble and whose permanent solubility does not change due to wave properties, and a coating of a substance that dissolves at a pH of 5 or more. Also, it means a film of a substance that does not dissolve at a pH of 7 or less, and a film of a substance that dissolves at a pH of 5 or more.
  • the drug which is the object of the present invention possesses such a property that its solubility is high in the acidic region and the solubility decreases in the neutral to alkaline region as its physicochemical properties.
  • the release rate is controlled by applying only a PH-independent film agent to such drugs, and the release test is performed using JP Pharmaceutical First Solution (H1.2) and JP Pharmaceutical Second Solution (PH6.8 ),
  • the solubility of the drug in the liquid is different, so that the amount of drug that passes through the coated film thickness differs depending on the liquid. Being slow with two liquids Becomes This means fast release in the stomach and slow release in the small intestine, making it impossible to obtain a stable sustained release formulation.
  • the present invention seeks to solve such a problem.
  • the film of the substance soluble on PH51 which is on the surface, has the properties of an intestinal coating agent, and therefore does not dissolve in the acidic region, and does not dissolve in water. It shows the same mechanism as a film of a substance that is insoluble and does not change its solubility in water due to liquidity, or a film of a substance that does not dissolve at pH of 7 or less.
  • a film of a substance that dissolves at a pH of 5 or more, a film of a substance that is insoluble in water and whose solubility in water does not change due to liquidity, or a film of a substance that does not dissolve at a pH of 7 or less Since release is performed through the added film thickness, it exhibits an excellent release suppressing effect in an acidic region where drug solubility is high.
  • a coating of a substance which is insoluble in ice and whose solubility in ice does not change due to liquidity a coating of a substance which does not dissolve below PHT, or a coating of a substance which dissolves at pH 5 or more.
  • the film of the substance that dissolves on the PH 521 in the surface layer dissolves immediately, and the ice-insoluble and Film or pH of a substance whose solubility in water does not change due to sputum properties
  • the present invention relates to a substance which dissolves at a pH of 5 or more on a film of a substance which is insoluble in water and whose solubility in water does not change due to liquidity, or on a film of a substance which does not dissolve at a pH of 7 or less.
  • the drug film permeates in the acidic region where the substance film that dissolves at pH 5 or higher does not dissolve, and in the neutral to alkaline region where the substance film that dissolves at pH 5 or higher dissolves.
  • the film thickness to be used is different, and by using this difference in film thickness, it is possible to obtain a release rate that is not affected by the liquid property.
  • the film thickness or the thickness of the coating of a substance that is permanently insoluble and does not change its solubility in liquid due to liquidity is determined by the film thickness obtained by adding the film thickness of the material that does not dissolve at pH 7 or less and the film thickness of the material that dissolves at pH 5 or more.
  • the usage ratio of the coating of a substance that dissolves at pH 5 £ 1 is the coating of a substance that is water-insoluble and does not change its solubility in ice due to liquidity, or a coating that does not dissolve under PH 7 i3 ⁇ 4. 1 to 10 times, preferably 2 to 5 times, the effect of the preparation of the present invention even if a double membrane is applied at a ratio exceeding this range. You can't get it.
  • This usage ratio is defined as a film of a substance that dissolves in ⁇ 5 or more, a film of a substance that is ice-insoluble and does not change its solubility in water due to liquidity, or a film of a substance that does not dissolve in ⁇ 7 or less.
  • the thickness ratio is specified, but the drug release rate can be adjusted by changing the thickness of the two films while keeping this ratio constant.
  • the object can be achieved by a simple method simply by adjusting the amount of a substance to be coated in the production of a pharmaceutical preparation. This is also one of the important effects of the present invention that enhance the convenience of the present invention.
  • Examples of the material constituting the film according to the present invention which is insoluble and whose dissolution is not affected by the liquid property include, but are not limited to, the following.
  • Ethylcellulose, amino alkyl methacrylate copolymer (Eudragit RS, RN100 SPL, RN100, RSPM), higher fatty acids, higher fatty acid ester derivatives, high-grade alcohol, high-grade alcohol Fats and oils such as ester derivatives and waxes.
  • Examples of the material constituting the film of the substance that does not dissolve at pH of 7 or less according to the present invention include the following.
  • Examples of the material of the film of the substance that dissolves at a pH of 5 or more according to the present invention include the following.
  • Hydroxypropyl propyl methyl cellulose phthalate HP-55, HP-55S, HP-50), cellulose acetate phthalate, lip mouth ), Carboxysilyl methylcellulose, methacrylic acid copolymer (Budragit L30D55, 100) 0. These materials are permanent and insoluble in the drug or 1 part of the composition containing them.
  • the coating of a substance whose solubility in water does not change due to the liquid property or the coating of a substance that does not dissolve at a pH of 7 or less may be applied in an amount of 0.01 to 0.5 part, preferably 0.05 to 0.3 part.
  • a plasticizer that is usually used in pharmaceuticals can be added to these for the purpose of forming a uniform and good film.
  • a plasticizer that is usually used in pharmaceuticals
  • propylene glycol, polyethylene glycol, glycerin, triethyl citrate and the like can be used.
  • water-soluble mosquitoes or powders can be added to these materials for the purpose of promoting release.
  • One or two kinds of commonly used pharmaceutically substances can be used.
  • hydroxypropyl cellulose, hydroxy pi-xypropylmethyl cellulose, methyl reserulose, polyvinylpyrrolidone, polyvinyl alcohol, talc, cone starch, mannit, Lactose or the like can be used.
  • the drug used in the present invention generally has different solubility in the acidic region and the neutral to alkaline region, and the release rate in the neutral to alkaline region compared to the acidic region. Any kind of drug can be applied as long as the drug decreases. The following various drugs can be given as typical examples of these.
  • Coronary vasodilators Dilazep hydrochloride, trimetadine hydrochloride, etafunon hydrochloride
  • Example 1 Example 1
  • Non-barrel (Front) 24 to 32 Mesh 900 g is put into a centrifugal transfer type granulator (Front CF-360), and a 5% solution of hydroxypropyl cellulose is added. (50% ethanol in water) while spraying the mixture, gradually adding a mixture of 100 g of oxybutynin hydrochloride, 680 g of corn starch, and 70 g of low-substituted hydroxypropylcellulose, granulating, and drying to obtain a ball of about 1800 g. Next, 500 g of the spherical granules were introduced into a centrifugal flow type coating granulator, and 25 g of ethyl cellulose and propylene glycol were added.
  • Example 1 500 g of the spheroidal granules obtained in Example 1 were charged into a centrifugal flow type coating granulator, and ethanol / methylene chloride containing 50 g of ethyl cellulose, 5 g of propylene glycol, and 15 g of talc was used. (1 /.1) Spray the mixed solution About 560 g of coated granules were obtained [Pre-granule 1].
  • a centrifugal flow type coating granulator which contains 100 g of hydroxypropyl methylcellulose acetate succinate (AQOAT L), 20 g of triethyl citrate, and 30 g of talc. Ethanol Z water (6Z4) mixed solution
  • 900 g of the non-barrel 24 to 32 mesh is put into a centrifugal flow type coating granulator, and sprayed with a 5% solution of hydroxypropylcellulose (50% ethanol, Seinaga) while 4—Jetylami No. 1, 1-dimethyl-2 — Butynyl (Sat) 1 or — Cyclohexyl-Pull-Ni-D-Collate noisy T-c ⁇ Ride Mono-Hydrate 100g, Corn Starch 680g, Low Substitution A mixture of 70 g of hydroxypropyl cellulose cellulose was gradually added and granulated, followed by drying to obtain about 1800 g of spherical granules.
  • Pre-granules 13 of the coated granules thus obtained and Product 13 of the present invention were each weighed in an amount equivalent to 300 tng of flavoxate hydrochloride, and a dissolution test was carried out according to Test Example 1.
  • the absorbance was measured at 316 nm using a spectrophotometer (manufactured by Hitachi).
  • Pre-granules 14 of the resulting coated granules and the product 14 of the present invention were used in combination with 4—Jetyl-mino-1,1-dimethyl-2—butynyl (sat) 1-cyclohexylyl-phenylidarylate
  • Nono Lee de port Kurorai de Monohai Dre preparative 10 m g equivalent amount weighed and a dissolution test was performed according to test example 1. Measurements were taken at each time interval and sampled at high speed by liquid chromatography.
  • FIG. 1 shows a 3 ⁇ particle one 1 obtained in each of Example 1, elution tests ⁇ grains one 2 hydrochloride Okishipuchinin obtained in Example 2 results in the first solution Japanese Pharmacopoeia
  • the elution curve represents the elution curve
  • the triangle represents the elution curve for JP 2nd solution.
  • the horizontal axis represents time (minutes) and the vertical axis represents dissolution rate (%).
  • FIG. 2 and 4 show the dissolution test results of oxyptinin hydrochloride of the product of the present invention 1 obtained in Example 1 and the product of the present invention 1 obtained in Example 2, respectively.
  • .DELTA Represents the elution curve of .B 1st liquid
  • .DELTA Represents the elution curve of JP 2nd liquid.
  • the horizontal axis represents time (min) and the vertical axis represents the dissolution rate (%).
  • FIG. 5 shows the results of the dissolution test of the pregranules 13 obtained in Example 3 using flavoxacin hydrochloride.
  • ⁇ represents the elution curve of the second solution of JP.
  • the horizontal axis represents time (minutes), and the vertical axis represents dissolution rate (%).
  • FIG. 6 shows the results of a dissolution test of flavoxate hydrochloride of Product 13 of the present invention obtained in Example 3.
  • ⁇ indicates the JP The elution curve is shown, and ⁇ shows the elution curve of JP2 solution.
  • the horizontal axis represents time (minutes), and the vertical axis represents dissolution rate ().
  • Figure 4 shows the pre-granules obtained in Example 4-14- 4-ethyl-mino 1,1-dimethyl-2-butynyl (sat) hexyl mono-phenylglycolate-noid ⁇ 3
  • the results of the dissolution test of D-monohydrate are shown.
  • ⁇ represents the elution curve of the second JP liquid.
  • the horizontal axis represents time (minutes), and the vertical axis represents dissolution rate (%).
  • Fig. 8 shows the product of the present invention obtained in Example 4, 4- (4-ethyl) amino-1,1-dimethyl-2-butynyl (Ethyl), one cyclohexyl, and one monounylglycolate monodrotita D-ray.
  • the results of the dissolution test of demonohydrate are shown.
  • the symbol represents the elution curve of the first solution of JP, and the symbol ⁇ represents the elution curve of the second solution of JP.
  • the horizontal axis represents time (minutes), and the vertical axis represents dissolution rate (%). '
  • the sustained-release preparation according to the present invention becomes a useful device when sealed in a drug having a property of high solubility in an acidic region and low solubility in a neutral to alkaline region. obtain.

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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Préparation à libération entretenue à double revêtement, pouvant libérer un médicament in vivo à un rythme constant, comprenant une part d'un médicament présentant une solubilité élevée dans une région acide, ainsi qu'une faible solubilité dans une région neutre ou alcaline, ou une composition ayant le même contenu, 0,01 à 0,5 part, de préférence 0,05 à 0,3 part d'une matière de revêtement, appliquée à la surface du médicament ou de la composition, comprenant essentiellement soit une substance insoluble dans l'eau et ne modifiant pas la solubilité dans l'eau selon la nature du liquide, soit une substance insoluble à un pH de 7 ou moins, et 0,05 à 5 parts de préférence 0,1 à 1,5 parts d'une matière de revêtement appliquée à son tour à ladite substance, comprenant une substance soluble à un pH de 5 ou plus.
PCT/JP1990/001364 1989-10-26 1990-10-24 Preparation a liberation entretenue WO1991006291A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP51462290A JP3158435B2 (ja) 1989-10-26 1990-10-24 徐放性製剤

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP1/279292 1989-10-26
JP27929289 1989-10-26

Publications (1)

Publication Number Publication Date
WO1991006291A1 true WO1991006291A1 (fr) 1991-05-16

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1990/001364 WO1991006291A1 (fr) 1989-10-26 1990-10-24 Preparation a liberation entretenue

Country Status (2)

Country Link
JP (1) JP3158435B2 (fr)
WO (1) WO1991006291A1 (fr)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001076557A1 (fr) * 2000-04-10 2001-10-18 Sumitomo Pharmaceuticals Co., Ltd. Preparations a liberation prolongee
JP2004300148A (ja) * 2003-03-17 2004-10-28 Takeda Chem Ind Ltd 放出制御組成物
US7619007B2 (en) 2004-11-23 2009-11-17 Adamas Pharmaceuticals, Inc. Method and composition for administering an NMDA receptor antagonist to a subject
US8058291B2 (en) 2005-04-06 2011-11-15 Adamas Pharmaceuticals, Inc. Methods and compositions for the treatment of CNS-related conditions
JP2013199488A (ja) * 2006-08-31 2013-10-03 Aptalis Pharmatech Inc 弱塩基性薬剤の固溶体を含む薬剤送達システム
US8741343B2 (en) 2009-12-02 2014-06-03 Adamas Pharmaceuticals, Inc. Method of administering amantadine prior to a sleep period
US8778979B2 (en) 2005-04-05 2014-07-15 Yale University Glutamate agents in the treatment of mental disorders
US10154971B2 (en) 2013-06-17 2018-12-18 Adamas Pharma, Llc Methods of administering amantadine

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS63115812A (ja) * 1986-06-17 1988-05-20 レコルダチ　インダストリア　シミカ　エ　フア−マシユ−テイカ　エス．ピ−．エ− 持続性定量薬剤徐放システム
JPH01230513A (ja) * 1987-11-06 1989-09-14 Tanabe Seiyaku Co Ltd 持効性製剤

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS63115812A (ja) * 1986-06-17 1988-05-20 レコルダチ　インダストリア　シミカ　エ　フア−マシユ−テイカ　エス．ピ−．エ− 持続性定量薬剤徐放システム
JPH01230513A (ja) * 1987-11-06 1989-09-14 Tanabe Seiyaku Co Ltd 持効性製剤

Cited By (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001076557A1 (fr) * 2000-04-10 2001-10-18 Sumitomo Pharmaceuticals Co., Ltd. Preparations a liberation prolongee
JP2004300148A (ja) * 2003-03-17 2004-10-28 Takeda Chem Ind Ltd 放出制御組成物
US8338485B2 (en) 2004-11-23 2012-12-25 Adamas Pharmaceuticals, Inc. Compositions for the treatment of CNS-related conditions
US8168209B2 (en) 2004-11-23 2012-05-01 Adamas Pharmaceuticals, Inc. Method and composition for administering an NMDA receptor antagonist to a subject
US8173708B2 (en) 2004-11-23 2012-05-08 Adamas Pharmaceuticals, Inc. Method and composition for administering an NMDA receptor antagonist to a subject
US7619007B2 (en) 2004-11-23 2009-11-17 Adamas Pharmaceuticals, Inc. Method and composition for administering an NMDA receptor antagonist to a subject
US8329752B2 (en) 2004-11-23 2012-12-11 Adamas Pharmaceuticals, Inc. Composition for administering an NMDA receptor antagonist to a subject
US8580858B2 (en) 2004-11-23 2013-11-12 Adamas Pharmaceuticals, Inc. Compositions for the treatment of CNS-related conditions
US8338486B2 (en) 2004-11-23 2012-12-25 Adamas Pharmaceuticals, Inc. Methods for the treatment of CNS-related conditions
US8362085B2 (en) 2004-11-23 2013-01-29 Adamas Pharmaceuticals, Inc. Method for administering an NMDA receptor antagonist to a subject
US8426472B2 (en) 2004-11-23 2013-04-23 Adamas Pharmaceuticals, Inc. Method and composition for administering an NMDA receptor antagonist to a subject
US8598233B2 (en) 2004-11-23 2013-12-03 Adamas Pharmacueticals, Inc. Method for administering an NMDA receptor antagonist to a subject
US10052318B2 (en) 2005-04-05 2018-08-21 Yale University Glutamate agents in the treatment of mental disorders
US8778979B2 (en) 2005-04-05 2014-07-15 Yale University Glutamate agents in the treatment of mental disorders
US8283379B2 (en) 2005-04-06 2012-10-09 Adamas Pharmaceuticals, Inc. Methods and compositions for the treatment of CNS-related conditions
US8293794B2 (en) 2005-04-06 2012-10-23 Adamas Pharmaceuticals, Inc. Methods and compositions for the treatment of CNS-related conditions
US8058291B2 (en) 2005-04-06 2011-11-15 Adamas Pharmaceuticals, Inc. Methods and compositions for the treatment of CNS-related conditions
JP2013199488A (ja) * 2006-08-31 2013-10-03 Aptalis Pharmatech Inc 弱塩基性薬剤の固溶体を含む薬剤送達システム
US8741343B2 (en) 2009-12-02 2014-06-03 Adamas Pharmaceuticals, Inc. Method of administering amantadine prior to a sleep period
US9867791B2 (en) 2009-12-02 2018-01-16 Adamas Pharma, Llc Method of administering amantadine prior to a sleep period
US9867792B2 (en) 2009-12-02 2018-01-16 Adamas Pharma, Llc Method of administering amantadine prior to a sleep period
US9867793B2 (en) 2009-12-02 2018-01-16 Adamas Pharma, Llc Method of administering amantadine prior to a sleep period
US9877933B2 (en) 2009-12-02 2018-01-30 Adamas Pharma, Llc Method of administering amantadine prior to a sleep period
US11197835B2 (en) 2009-12-02 2021-12-14 Adamas Pharma, Llc Method of administering amantadine prior to a sleep period
US10154971B2 (en) 2013-06-17 2018-12-18 Adamas Pharma, Llc Methods of administering amantadine
US10646456B2 (en) 2013-06-17 2020-05-12 Adamas Pharma, Llc Methods of administering amantadine
US11903908B2 (en) 2013-06-17 2024-02-20 Adamas Pharma, Llc Methods of administering amantadine

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