WO1997034601A1 - Compositions medicamenteuses a solubilite amelioree - Google Patents

Compositions medicamenteuses a solubilite amelioree Download PDF

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Publication number
WO1997034601A1
WO1997034601A1 PCT/JP1997/000853 JP9700853W WO9734601A1 WO 1997034601 A1 WO1997034601 A1 WO 1997034601A1 JP 9700853 W JP9700853 W JP 9700853W WO 9734601 A1 WO9734601 A1 WO 9734601A1
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WO
WIPO (PCT)
Prior art keywords
present
drug
pyridylmethyl
hydroxy
dimethyl
Prior art date
Application number
PCT/JP1997/000853
Other languages
English (en)
Japanese (ja)
Inventor
Hisao Furitsu
Yukiko Inoue
Akira Kato
Hidenobu Ando
Original Assignee
Eisai 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 Eisai Co., Ltd. filed Critical Eisai Co., Ltd.
Publication of WO1997034601A1 publication Critical patent/WO1997034601A1/fr

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Classifications

    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4436—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom
    • 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

Definitions

  • the present invention relates to a pharmaceutical composition containing 6-hydroxy-5,7-dimethyl-2-methylamino-4- (3-pyridylmethyl) benzothiazole, which has improved solubility and which can be controlled in release.
  • 6-Hydroxy-1,5,7-dimethyl-12-methylamino 4- (3-pyridylmethyl) benzothiazole (hereinafter sometimes referred to as the compound of the present invention) is a drug for treating ulcerative colitis and Crohn's disease It is a compound under development.
  • the compounds according to the invention have a very low solubility, especially in the alkaline region.
  • fine powdering of the drug fine powdering of the drug, formation of solvates, increase of surface area by solid surface adsorption, polymorphism, mixing and grinding with excipients, solid dispersion, etc.
  • water-repellent salts such as metal salts of fatty acids and acrylic acid-based polymers And those utilizing the interaction between Eudragit RS (trade name) and organic acids.
  • 6-hydroxy-5,7-dimethyl-2-methylamino-4- (3-pyridyl T-methyl) benzothiazol does not substantially dissolve in neutral to alkaline water depending on the usual formulation, so its absorption rate when administered to a living body may be low and its fluctuation may be large.
  • the method based on pulverization has a limited effect, and the use of surfactants has problems in terms of safety.
  • the present invention comprises dissolving or dispersing 6-hydroxy-1,5,7-dimethyl-12-methylamino-4- (3-1-pyridylmethyl) benzothiazole and a polymer substance in a solvent, and then distilling off the solvent. It is a pharmaceutical composition. Further, it is a pharmaceutical composition obtained by molding 6-hydroxy-5,7-dimethyl-12-methylamino-14- (3-pyridylmethyl) benzothiazole and a polymer substance by a stirring compression type extrusion granulator. .
  • the present invention is a drug composition obtained by further adding a water-soluble polymer substance to the above-mentioned drug composition.
  • 6-Hydroxy-1,5,7-dimethyl-1-methylamino-4- (3-pyridylmethyl) benzothiazole has the following structural formula:
  • the high molecular substance in the present invention means a high molecular substance dissolved or dispersed in water, and specifically, hydroxypropyl methylcellulose phthalate, hydroxypropynolemethinolecinolate, and canoleboxymethinoletinolate.
  • ethyl acrylate means a copolymer, and preferred examples thereof include hydroxypropylmethylcellulose phthalate and canoleboxymethylethylcellulose.
  • Preferred as the water-soluble polymer substance to be further added to the drug composition are hydroxypropyl senorelose, hydroxyl butylmethylcellulose, carboxymethinolethynolacese / rerose, methizoresenorelose, and polyvinyl acetate.
  • the solvent in the present invention means a solvent capable of dissolving or dispersing 6-hydroxy-1,5,7-dimethyl-12-methylamino41- (3-pyridylmethyl) benzothiazole and a polymer substance, for example, water
  • a solvent capable of dissolving or dispersing 6-hydroxy-1,5,7-dimethyl-12-methylamino41- (3-pyridylmethyl) benzothiazole and a polymer substance, for example, water
  • examples include ethanol, methanol, dichloromethane, and chloroform.
  • these solvents can be used in combination.
  • the mixing ratio of the water-Z ethanol mixed solvent is usually 1 to 90% of water, and the ethanol is 99 to: L0 ⁇ 1 ⁇ 2. More preferably, it is 1 to 30% of water and 99 to 70% of ethanol.
  • the mixing ratio in which the compound according to the present invention and the high molecular substance are both dissolved can be appropriately selected.
  • the compound of the present invention and the water-soluble polymer substance
  • the agitation compression type extrusion granulator in the present invention refers to a screen or a nozzle while stirring and mixing the compound of the present invention and a water-soluble polymer substance with a screw or the like installed in the granulator.
  • a machine that extrudes under pressure and performs granulation molding Some preferred examples include a twin-screw extruder. During granulation and molding, the temperature is usually raised to 30 to 180 ° C.
  • the compound of the present invention may be a solid dispersion.
  • the solid dispersion refers to a state in which the compound according to the present invention is dispersed in a polymer material that is a medium, and means that the compound is in a molecular state or an amorphous state. When it is not a body, that is, for example, even if it is dispersed in a crystalline state, the effects of the present invention can be obtained.
  • a drug composition formed by adding a powder of a water-soluble polymer to the above-mentioned drug composition, or a water-soluble polymer dissolved in a solvent is used.
  • the above-mentioned drug composition can be made into a drug composition which is formed into granules.
  • the release of 6-hydroxy-1,5,7-dimethyl-2-methylamino-4- (3-pyridylmethyl) benzothiazole is freely controlled by the type and amount of water-soluble polymer added, and the absorption improvement effect does not decrease. As a result, the drug can be delivered to the target site in a required amount for a required time, and an excellent drug effect can be obtained.
  • the mixing ratio of (3-pyridylmethyl) benzothiazole and the polymer substance is 6-hydroxy-5,7-dimethyl-2-methylamino-1- (3-pyridylmethyl) benzothiazole per 1 part by weight of polymer
  • the substance is at least 1 part by weight, preferably at least 4 parts by weight.
  • the upper limit of the mixing ratio of the polymer substance is usually 20 parts by weight or less.
  • the production method of the composition according to the present invention is obtained, for example, by dissolving the compound according to the present invention and hydroxypropylmethylcellulose phthalate in a mixed solvent of 85% ethanol / water and evaporating the solvent to dryness. Can be.
  • the obtained composition can be pulverized and sieved, and if necessary, mixed with other substances to prepare granules, tablets and the like.
  • a compound according to the present invention and a hydroxypropylcellulose acetate lid The composition according to the present invention can be obtained by mixing the rates and granulating with a biaxial extruder. In this case, the mixture is 40-120.
  • composition C can be heated and plasticizers such as Jardin wax, sugar ester, and stearic acid can be added.
  • plasticizers such as Green wax, sugar ester, and stearic acid
  • the obtained composition can be pulverized and sieved, and if necessary, mixed with other substances to prepare a preparation such as a granule or a tablet.
  • the ratio of the case where the water-soluble polymer substance is further added to the 6-hydroxy-1,5,7-dimethyl-2-methylamino-4- (3-pyridylmethyl) benzothiazol-containing drug composition in the present invention is as follows.
  • the water-soluble polymer is used in an amount of 0.01 to 10 parts by weight, preferably 0.02 to 5 parts by weight, more preferably 0.05 to 0.5 part by weight, based on 1 part by weight of the drug composition. 5 parts by weight. It is appropriately selected depending on the purpose of the release control.
  • a water-soluble polymer substance is added to the above-mentioned drug composition and then mixed and tableted, or the composition is formed into granules by using a water-soluble polymer substance dissolved in a solvent. It can be manufactured by doing. In the case of tablets and granules, formulation aids such as commonly used disintegrants and lubricants can be used. Action:
  • 6-hydroxy-1,5,7-dimethyl-12-methylamino-14- (3-pyridylmethyl) benzothiazole is not decomposed, its crystal structure is changed, and the original crystal form is exhibited.
  • the solubility is transiently higher than the solubility.
  • the compound according to the present invention is absorbed from the digestive tract, and the effect can be more reliably exhibited.
  • v type of water soluble polymer and the amount by 6-arsenide Dorokishi one 5, 7-dimethyl one 2 - Mechiruamino one 4 one (3-pyridylmethyl) release of benzothiazole Ichiru is freely controlled, and improved absorption The effect does not decrease. This makes it possible to deliver a required amount of a drug to a target site for a required time, thereby achieving an excellent drug effect.
  • FIG. 1 is a diagram showing the elution of the compound according to the present invention when various polymer substances are blended.
  • FIG. 2 is a diagram showing elution when a substance according to the present invention is mixed with carboxymethylethylcellulose at various ratios and produced by a biaxial extruder.
  • FIG. 3 is a graph showing changes in the blood glucose level of the substance of the present invention when the substance of the present invention and carboxymethylethyl cellulose mixture are produced by a biaxial extruder and administered to a beagle dog. is there.
  • FIG. 4 is a diagram showing the elution of the compound according to the present invention from tablets obtained by tableting after adding various types of polymer substances to powder.
  • FIG. 5 is a diagram showing the dissolution of the compound according to the present invention from tablets obtained by tableting after adding powder of hydroxymethyl pill methyl cellulose.
  • FIG. 6 is a diagram showing the dissolution of the compound according to the present invention from a tablet obtained by tableting after adding powder of carboxymethylethylcellulose.
  • FIG. 7 is a diagram showing the elution of the compound according to the present invention from granules produced by dissolving methacrylic acid / methyl acrylate / copolymer in ethanol.
  • a mixture of 100 g of hydroxypropynolemethinolecellulose phthalate and 200 g of 6-hydroxy-5,7-dimethyl-2-methylamino-141- (3-pyridylmethyl) benzothiazole is mixed with 200 g to form a biaxial type.
  • Ekusutoru one da one sieved and crushed 3 the composition prepared a composition according to the present invention warmed to 8 0 C in Jietsu Bok mill, A powder was produced.
  • Example 2 To 10 g of the composition obtained in Example 1, 2.5 g of powder of carboxymethylethylcellulose, hydroxypropylmethylcellulose, polybutylpyrrolidone, methylcellulose or hydroxy-5-hydroxypropylcellulose was added. A post-lubricating agent was added, and the mixture was compressed at a pressure of 600 kg to produce a tablet having a diameter of 9 mm and a tablet of 300 mg.
  • Hydroxypropyl methylcellulose was added to 10 g of the composition obtained in Example 2 after adding 5%, 12.5% or 25% powder, and the mixture was compressed at a pressure of 800 kg to give a tablet having a diameter of 9 mm and 1 tablet. 30 Omg tablets were produced.
  • compositions according to the present invention exhibited higher solubility and a higher dissolution rate than the control.
  • - 1 to 1 part by weight of the compound of the present invention was mixed with 3 to 10 parts by weight of carboxymethylethylcellulose to obtain a biaxial type.
  • the composition according to the present invention manufactured by an extruder the results of measuring the elution (37 ° C, 900 mi, paddle method, 100 rpm) of the compound of the present invention in two solutions of S station, and Figure 2 shows.
  • FIG. 4 shows the results obtained by measuring the elution of the compound with the paddle method at 100 rpm.
  • the solid dispersion according to the present invention was used. It is clear that the solid composition according to the present invention can control the release in one Japanese Pharmacopoeia by the added water-soluble polymer substance while maintaining the solubility in the two Japanese Pharmacopoeia.
  • FIG. 5 shows the results of the measurement using the paddle method at 100 rpm.
  • the solid composition according to the present invention was released in 1st JP by the added hydroxypropylmethyl cellulose while maintaining the solubility in 2nd PS. It is clear that the control of is possible.
  • FIG. 7 shows the results of measuring the elution of the compound by the paddle method at 100 rpm.
  • the solid dispersion according to the present invention was used. It is clear that the solid composition according to the present invention can control the release in one Japanese Pharmacopoeia by the addition amount of methacrylic acid / methyl acrylate / copolymer while maintaining the solubility in two Japanese Pharmacopoeia. is there.

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

Abstract

Compositions médicamenteuses à solubilité améliorée, et compositions médicamenteuses à solubilité améliorée et à dissolution contrôlée. L'invention concerne une composition médicamenteuse préparée par dissolution ou dispersion de 6-hydroxy-5,7-diméthyl-2-méthylamino-4-(3-pyridylméthyl)benzothiazole et d'une substance polymère dans un solvant, puis par distillation de la solution ou de la dispersion obtenue, de façon à éliminer le solvant; une autre composition médicamenteuse préparée par formage simultané du 6-hydroxy-5,7-diméthyl-2-méthylamino-4-(3-pyridylméthyl)benzothiazole et d'une substance polymère au moyen d'un granulateur d'extrusion de type à agitation et compression; ainsi que d'autres compositions médicamenteuses préparées par adjonction de substances polymères hydrosolubles à ces compositions.
PCT/JP1997/000853 1996-03-18 1997-03-18 Compositions medicamenteuses a solubilite amelioree WO1997034601A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP8/60986 1996-03-18
JP6098696 1996-03-18

Publications (1)

Publication Number Publication Date
WO1997034601A1 true WO1997034601A1 (fr) 1997-09-25

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008114859A1 (fr) * 2007-03-22 2008-09-25 Astellas Pharma Inc. Composition pharmaceutique contenant un dérivé de pyrazole

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5446837A (en) * 1977-09-19 1979-04-13 Kanebo Ltd Easily absorbable nifedipin composition, its preparation, and anti-stenocardia containing the same
JPS58183615A (ja) * 1982-04-19 1983-10-26 エラン・コ−ポレ−シヨン・リミテツド 高度溶解性医薬及びその製造法
JPS6038322A (ja) * 1983-08-11 1985-02-27 Fujisawa Pharmaceut Co Ltd ジヒドロピリジンａ物質含有易溶性固形製剤
JPH0249720A (ja) * 1988-05-18 1990-02-20 Mitsubishi Kasei Corp 難溶性薬剤組成物
JPH05139973A (ja) * 1991-11-20 1993-06-08 Shin Etsu Chem Co Ltd ニフエジピン含有固形製剤の製造方法
JPH05178855A (ja) * 1991-04-04 1993-07-20 Eisai Co Ltd ベンゾチアゾール誘導体

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5446837A (en) * 1977-09-19 1979-04-13 Kanebo Ltd Easily absorbable nifedipin composition, its preparation, and anti-stenocardia containing the same
JPS58183615A (ja) * 1982-04-19 1983-10-26 エラン・コ−ポレ−シヨン・リミテツド 高度溶解性医薬及びその製造法
JPS6038322A (ja) * 1983-08-11 1985-02-27 Fujisawa Pharmaceut Co Ltd ジヒドロピリジンａ物質含有易溶性固形製剤
JPH0249720A (ja) * 1988-05-18 1990-02-20 Mitsubishi Kasei Corp 難溶性薬剤組成物
JPH05178855A (ja) * 1991-04-04 1993-07-20 Eisai Co Ltd ベンゾチアゾール誘導体
JPH05139973A (ja) * 1991-11-20 1993-06-08 Shin Etsu Chem Co Ltd ニフエジピン含有固形製剤の製造方法

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
BASIC COURSE ON MEDICINE DEVELOPMENT X, (18), "Pharmaceutical Engineering (in Japanese)", (CHIJIN SHOKAN), March 1971, p. 119-127. *
RECENT PREPARATIVE TECHNIQUE OF DRUGS AND ITS APPLICATION I TECHNIQUE OF DRUGS AND ITS APPLICATION I (IYAKU JOURNAL-SHA), September 1983, HIROSHI FUJIWARA, "Continuation of Wet Granulation (in Japanese)", p. 47-50. *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008114859A1 (fr) * 2007-03-22 2008-09-25 Astellas Pharma Inc. Composition pharmaceutique contenant un dérivé de pyrazole

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