WO1996025158A1 - Composition a base de derives de l'azulene et son procede d'obtention - Google Patents

Composition a base de derives de l'azulene et son procede d'obtention Download PDF

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Publication number
WO1996025158A1
WO1996025158A1 PCT/JP1996/000327 JP9600327W WO9625158A1 WO 1996025158 A1 WO1996025158 A1 WO 1996025158A1 JP 9600327 W JP9600327 W JP 9600327W WO 9625158 A1 WO9625158 A1 WO 9625158A1
Authority
WO
WIPO (PCT)
Prior art keywords
gasn
pharmaceutical composition
aldioxa
receptor antagonist
histamine
Prior art date
Application number
PCT/JP1996/000327
Other languages
English (en)
Japanese (ja)
Inventor
Yoshimi Hashimoto
Yasushi Egawa
Hideyuki Kishimoto
Original Assignee
Yamanouchi Pharmaceutical 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 Yamanouchi Pharmaceutical Co., Ltd. filed Critical Yamanouchi Pharmaceutical Co., Ltd.
Priority to AU46756/96A priority Critical patent/AU4675696A/en
Publication of WO1996025158A1 publication Critical patent/WO1996025158A1/fr

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Classifications

    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • the present invention relates to a stable pharmaceutical composition of sodium 1,4-dimethyl-7-isopropylazulene-13-sulfonate and a method for producing the same.
  • the present invention also relates to a histamine H2 receptor antagonist-containing pharmaceutical composition having excellent efficacy and stability for treating and preventing gastrointestinal diseases and a method for producing the same.
  • GASN 1,4-Dimethyl-17-isopropylazulene-3-sodium sulfonate
  • Guaiazulene (Matricaria Chamomill L.) is a derivative of guaiazulene (chemical name: 1,4-dimethinoleh 7-isopropinoleazulene). Guaiazulene has anti-inflammatory and anti-ulcer properties, and is insoluble in liquid at room temperature.Water-soluble GAS N is widely used and has high safety, so it is used as a solid preparation such as tablets and granules. It is widely used for medical, medical and pharmaceutical products.
  • GASN was not sufficiently stable as a drug, and could not be stored for a long period of time even if the drug was manufactured in the usual way. This is due to the GASN force, 'sublimation', and the gradual decomposition by light and oxygen in ⁇ .
  • JP-A-58-154548 stabilization with edetic acid and its salts
  • Japanese Patent Laid-Open Publication No. Hei 1-112126 stabilization with calcium gayate
  • JP-A-4-1243382 stabilization with sucralfate
  • sucralfate JP-A-6-227972
  • aldioxa (chemical name: dihydroxy [(2-hydroxy-5-oxo-2-imidazoline-141-yl) ureido] aluminum) directly acts on the gastric mucosa to promote granulation formation, antacid and anti-pepsin. It is widely used as a medical or over-the-counter drug alone or in combination as a preventive and therapeutic agent for gastric 'duodenal ulcer, acute and chronic gastritis. In addition to the disclosure that it contributes to the stability of other pharmaceutical compounds, there have been reports suggesting that it also contributes to the stability of other drugs.
  • Histamine H 2 receptor antagonists inhibit gastric acid secretion by antagonizing hissamine in the histomin H2 receptors in gastric parietal cells, and mainly treat gastric and duodenal ulcers and acute and chronic gastritis It is widely used as a therapeutic agent for gastrointestinal diseases.
  • a combination of a hissamine H2 receptor antagonist and another drug is also being studied.
  • Japanese Patent Application Laid-Open No. Sho 58-208220 discloses a hissamine H2 receptor antagonist and aldioxa.
  • An agent for treating peptic ulcer and preventing relapse and recurrence as an active ingredient is disclosed.
  • the present inventor has found that a stable GASN-containing preparation can be produced by blending GDASN with aldioxa and performing wet granulation.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a histamine H2 receptor antagonist, GASN and argioxa, wherein at least GASN and argioxa are contained in a wet-granulated granule.
  • GASN is stable as a commercial drug due to stabilization of GASN, and has gastrointestinal tract diseases such as gastric ulcer and acute / chronic gastritis.
  • the present inventors have found that it is possible to provide a pharmaceutical composition having remarkably excellent therapeutic and preventive effects on the present invention, and have completed the present invention. That is, the present invention is a GASN-containing pharmaceutical composition obtained by blending GASN and argioxa and granulating the mixture by wet granulation.
  • the present invention is a method for producing a GASN-containing pharmaceutical composition, which comprises mixing GASN and ardioxa and granulating the mixture by wet granulation.
  • the present invention relates to a pharmaceutical composition containing a histamine H2 receptor antagonist, GASN and argioxa, wherein at least GASN and argioxa are contained in a granulated product * standing by a wet granulation method.
  • a pharmaceutical composition comprising a hismin H2 receptor antagonist.
  • the present invention further provides a granulation force by mixing GASN, argioxa and a histamine H2 receptor antagonist and granulating by wet granulation, or a mixture of GASN and argioxa and granulating by wet granulation.
  • a manufacturing method of the His evening Min H 2 receptor antagonist containing pharmaceutical composition which is to be blended with His evening Min H 2 receptor antagonists.
  • the reference of the GASN-containing pharmaceutical composition of the present invention includes a pharmaceutical composition comprising GASN and argioxa, a granulated product obtained by a wet granulation method, and wherein the granulated product comprises GASN and argioxa.
  • the GASN-containing pharmaceutical composition of the present invention contains one or more wet-granulated particles, each particle containing GASN, and an aldioxa for stabilizing GASN, and It can be said that a pharmaceutical composition is characterized in that GASN and aldoxane power are uniformly dispersed within the polymer. It has been pointed out that simply mixing GASN and argioxa does not achieve the goal of GASN stability.
  • Toko filtration to as hiss evening Min H 2 receptor antagonist containing pharmaceutical compositions of the present invention shall apply in pharmaceutical compositions containing a histamine H2 receptor antagonist and GASN and Arujiokisa, the pharmaceutical composition Is characterized by containing at least a granulated product of GASN and argioxa granulated by a wet granulation method.
  • GASN and argioxa are uniformly dispersed in the particles of the granulated product, and the mixture with this and a hissamine H2 receptor antagonist stabilizes GASN for a long period of time.
  • the histamine H2 receptor antagonist-containing pharmaceutical composition contains one or more wet-granulated particles, each of which contains at least GASN and an algioxa for stabilizing GASN. It is assumed that GASN and ardioxa are uniformly dispersed in each particle, and that the histamine H2 receptor antagonist is contained as a component of the composition inside or outside the particle. It can be said to be a pharmaceutical composition.
  • the term “granulation” simply refers to granules (ie, particles) having a substantially uniform shape using a drug substance having various shapes such as a powder, an agglomerate, a solution, or a melt. It means the whole process of making, and "granulating" in a particular way means to make grains of almost uniform shape and size in that particular way.
  • the “wet granulation method” applied to the GASN-containing pharmaceutical composition and the histamine H 2 receptor antagonist-containing pharmaceutical composition of the present invention refers to granulation by adding a liquid binder to a drug substance raw material powder ( In other words, a method of making grains of almost uniform shape and size).
  • the “wet granulation method” includes everything included in the above definition. Specifically, for example, (1) a binder solution is added to the raw material powder, the mixture is kneaded, and the combined material is squeezed onto a screen and extruded. Extrusion granulation method using extrusion granulation equipment (eg, cylindrical granulator FG type, manufactured by Fukae Kogyo Co., Ltd. Twin Dome Gran, manufactured by Fuji Padal Co., Ltd.), 2 Speed mill (Showa engineering) ⁇ ), power mill (Danoretone 3 ⁇ 4 ⁇ ), etc. to crush the wet mixture to a certain size by crushing the wet mixture.
  • extrusion granulation equipment eg, cylindrical granulator FG type, manufactured by Fukae Kogyo Co., Ltd. Twin Dome Gran, manufactured by Fuji Padal Co., Ltd.
  • 2 Speed mill Showa engineering
  • power mill Disoretone 3 ⁇ 4 ⁇
  • ⁇ Agitation granulation method in which granulation is performed while mixing and agitating using a Henshenole mixer (Rheinstahl Henshel AG tt), a vertical mixer, etc., a 3 ⁇ 4 core fluidized granulation device (eg, manufactured by Freund Corporation), Mouth Processor (Eromatic Judges Sangyo), make spherical particles by either or coating spraying the binder raw material is rolled using Marumerizer one (Fuji Paudarune ⁇ ⁇ ) or the like Tumbling granulation, spray drier for spraying liquid or suspension and drying sprayed droplets
  • a layer of raw material powder is formed by air flow, and a binder solution is sprayed into the layer while drying, and particles adhere and aggregate by liquid crosslinking.
  • This method uses a fluidized-bed granulator (eg, Spiral Flow, manufactured by Freund Sangyo Co., Ltd .; Nummarmerizer I, Fuji Baudal).
  • the “GASN-containing pharmaceutical composition” of the present invention is a pharmaceutical composition containing GASN and argioxa, which is produced through a granulation step by a wet granulation method.
  • Granules and granules include all forms including wet granulation processes such as ⁇ ! Life, tablets, pills, cheabnole tablets and capseno ⁇ .
  • the “pharmaceutical composition containing a histamine H 2 receptor antagonist” of the present invention contains a histamine H 2 receptor antagonist, GASN and argioxa, and is manufactured through a granulation step by a wet granulation method.
  • a pharmaceutical composition comprising a granulated product containing at least GASN and argioxa, which is obtained by granulating a histamine H2 receptor antagonist, GASN and argioxa by wet granulation.
  • various formulations may be prepared by blending GASN and aldioxa and granulating them by a wet granulation method, and blending a histamine H 2 receptor antagonist.
  • Examples of the pharmaceutical composition of the pharmaceutical composition include fine granules and granules, as well as tablets, pills, chew nore tablets and capsules. At least GASN and argioxa are blended and the granulation step by wet granulation is carried out. All formulation forms which are included in the present invention are included.
  • the compounding amount of the components of the GASN-containing pharmaceutical composition or the histamine H2 receptor antagonist-containing pharmaceutical composition of the present invention is from 0.01 parts by weight to 250 parts by weight of Ardioxa per 1 part by weight of GASN. Force ⁇ preferred. If the amount is less than 0.01 parts by weight, GASN may not be sufficiently stabilized, and there may be a case.
  • the content of Aldioxa is 0.5 to 100 parts by weight based on 1 part by weight of GASN.
  • the desired effect can be achieved even if the amount of argioxa compounded for stabilizing GAS N is less than or equal to the amount of drug effect.
  • the GASN-containing pharmaceutical composition or the histamine H2 receptor antagonist-containing pharmaceutical composition of the present invention preferably contains, at a daily dose, 1.2 mg to 6 mg of GASN and 0.6 mg to 60 Omg of aldioxa. contains.
  • the hiss evening Min H 2 receptor antagonist is a component of the histamine H 2 receptor antagonist containing pharmaceutical compositions of the present invention, for example famotidine, Ranichijinku cimetidine, Rokisajin, including but nizatidine, particularly limited to It does not do.
  • pharmaceutically acceptable salts thereof for example, hydrochloride, hydrobromide, iodine bT citrate, sulfate, fumarate, maleate, succinate, liquor, picrine Salts formed with inorganic or organic acids, such as acid salts.
  • famotidine which has a low dose and has a potent and long-term effect on suppressing gastric acid secretion.
  • the amount of the histamine H2 receptor antagonist can usually be used in a clinically acceptable amount.
  • various drugs for hissamine H2 receptor antagonists each of which has an appropriate dose. For example, taking famotidine as an example, it is strongly preferable to use 0.5 mg to 500 mg per dose, more preferably 1 mg to 10 Omg.
  • the most preferred embodiment of the histamine H2 receptor antagonist-containing pharmaceutical composition of the present invention is a daily dosage of 1 mg to 100 mg of famotidine, 1.2 mg to 6 mg of GASN, and 0.6 mg to 600 mg of argioxa. Contains mg.
  • binder used in the wet granulation of the present invention examples include hydroxypropyl cellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, macrogol and the like, and the like. It does not matter if the binder is used for wet granulation.
  • the GASN-containing pharmaceutical composition or the histamine H2 receptor antagonist-containing pharmaceutical composition of the present invention may contain, in addition to the above, additives suitable for formulation.
  • Additives include lactose, sucrose, corn starch, light maleic anhydride, microcrystalline cellulose, sorbitol, xylitol, mannite, and other excipients, carboxymethylcellulose, croscarmellose sodium, low degree of substitution.
  • Hydroxypro Ability to add disintegrants such as pill cellulose, lubricants such as magnesium stearate, calcium stearate, and talc, as well as humectants, suspending agents, sweeteners, flavoring agents, flavoring agents, preservatives, etc. ,'it can.
  • the GASN-containing pharmaceutical composition or the histamine H2 receptor antagonist-containing pharmaceutical composition of the present invention is capable of using a suitable solvent in granulation, and the solvent is a GASN force;
  • the solvent include water, lower fatty alcohols, and aqueous solutions of these alcohols.
  • the mixing ratio in the case of the aqueous solution of alcohol is not particularly limited.
  • lower fats and alcohols linear or branched alcohols having 1 to 4 carbon atoms are preferable, and methanol and ethanol are particularly preferable.
  • the GASN-containing pharmaceutical composition or the histamine H2 receptor antagonist-containing pharmaceutical composition of the present invention is produced by granulating GASN and aldioxa by a wet granulation method. It is iJ ⁇ that GASN is mixed with an aldioxa and, if necessary, other additives and a binder and a solvent are used, whereby the adioxa and GASN are uniformly dispersed in each particle. As a result, the microstructure in each particle is easily brought into contact with GAZO and GASN, and a remarkable stabilizing effect of GASN is achieved.
  • the histamine H 2 receptor antagonist may be wet-granulated together with GASN and aldioxa, or GASN and aldioxa were previously wet-granulated.
  • the granules and the hismin H2 receptor antagonist may be further formulated by an appropriate method.
  • histamine H 2 receptor antagonist, G ASN, adioxa and an excipient may be mixed in a bed granulation dryer, sprayed with a suitable binder such as an aqueous hydroxypropyl cellulose solution, granulated and dried.
  • histamine H2 receptor antagonist, GASN and aldioxa, and other additives as necessary Granulation using a suitable amount of a solvent and drying are preferred.
  • the histamine H2 receptor antagonist or its granule is blended after mixing GAS N and other additives according to ⁇ and other additives, granulating and drying using an appropriate amount of a binder and a solvent, It may be further formulated as required.
  • the GASN-containing pharmaceutical composition or the histamine H2 receptor antagonist-containing pharmaceutical composition of the present invention can be obtained by the above-mentioned granulation method or through a further usual preparation process to obtain granules, powders, fine granules, tablets, It can be made into a dosage form suitable for oral administration such as pills, chew nore tablets and capsules.
  • Difficult case 6 Take 2 g of GASN, 50 g of aldioxa, 2.5 g of famotidine, 402.5 g of lactose and 125 g of corn starch, and granulate using a 7.5% hydroxypropylcellulose aqueous solution as a binder in a fluidized bed granulating dryer. After drying, the granules were obtained.
  • the dried product was pulverized with a sample mill, and 370 g of sorbitol was taken.
  • the mixture was granulated and dried in a 5-t layer dryer using a 10% aqueous solution of hydroxypropylcellulose as a binder to obtain granules. This was filled into the first capsule in 300 mg increments using a capsule filling machine to obtain a capsule.
  • Example 1 a composition corresponding to Example 1 is obtained. However, it is strongly different that Argioxa was not combined. GASN2g, lactose 350 g and corn siden 133 g of starch was taken, and granulated and dried using a fluidized bed granulating dryer using a 10% aqueous solution of hydroxypropylcellulose as a binder to obtain a composition.
  • Comparative Example 2 corresponds to the stabilization method described in JP-A-58-154548, in which GASN is spray-dried and the solvent is distilled off.
  • a stable GASN-containing pharmaceutical composition can be provided by blending GASN and ardioxa and performing wet granulation.
  • a pharmaceutical composition comprising a histamine H2 receptor antagonist, GASN and aldioxa, wherein at least histamine H2 receptor is contained in the granulated granules obtained by wet granulation of GASN and aldioxa.
  • a histamine H2 receptor-containing pharmaceutical composition that has excellent therapeutic and preventive effects on gastrointestinal diseases such as gastric ulcer and acute / chronic gastritis, and is a commercially available drug. It is stable enough to withstand long-term storage. The stabilizing effect of the present invention will be described with reference to test examples.
  • compositions of Examples 1 and 2 which are the pharmaceutical compositions containing GAS N of the present invention, and Comparative Examples
  • Each of the compositions 1 to 3 was taken, sealed in a glass bottle, and stored in a thermostat at 40 and a relative humidity of 75%.
  • the residual ratio of GASN after 2 months was measured by the HPLC method.
  • the results, that is, the remaining ratio (%) of GASN at 40% and 75% relative humidity are shown in the table.
  • compositions of Examples 1 and 2 in which Argioxa was blended showed that the residual ratio of GASN was dripped compared to the composition of Comparative Example 1 in which Algioxa was not blended. Therefore, the effect of the stabilization effect of Ardoxa, according to II, is according to Kafen.
  • the compositions of Examples 1 and 2 have more stabilized GASN.
  • the pharmaceutical composition containing a histamine H 2 receptor antagonist of the present invention was stable enough to withstand the distribution process as a commercial drug.
  • the therapeutic and preventive effects of gastrointestinal diseases such as gastric ulcer, acute and chronic gastritis, etc. of the pharmaceutical composition containing a His-amine H2 receptor antagonist of the present invention can be obtained by using a commonly used animal experimental model and Can be confirmed by clinical trials.

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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)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention porte;(a) sur un médicament contenant de l'aldioxia et du 1, 4-diméthyl-7-isopropylazulène-3-sulfonate de sodium (GASN) et se présentant sous forme de granulés préparés par granulation par voie humide; et sur un médicament contenant un antagoniste du récepteur de l'histamine H2, du GASN et de l'aldoxia, dans lequel au moins le GASN et l'aldoxia sont présents dans les granulés préparés par granulation par voie humide.
PCT/JP1996/000327 1995-02-16 1996-02-15 Composition a base de derives de l'azulene et son procede d'obtention WO1996025158A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU46756/96A AU4675696A (en) 1995-02-16 1996-02-15 Medicinal composition containing azulene derivative and process for producing the same

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP7/28021 1995-02-16
JP2802195 1995-02-16

Publications (1)

Publication Number Publication Date
WO1996025158A1 true WO1996025158A1 (fr) 1996-08-22

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Application Number Title Priority Date Filing Date
PCT/JP1996/000327 WO1996025158A1 (fr) 1995-02-16 1996-02-15 Composition a base de derives de l'azulene et son procede d'obtention

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AU (1) AU4675696A (fr)
WO (1) WO1996025158A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS58208220A (ja) * 1982-05-31 1983-12-03 Grelan Pharmaceut Co Ltd 消化性潰瘍治療剤
JPS58208233A (ja) * 1982-05-31 1983-12-03 Grelan Pharmaceut Co Ltd 消化性潰瘍治療配合剤
JPH05331031A (ja) * 1992-05-27 1993-12-14 Kao Corp 口腔用組成物
JPH06227972A (ja) * 1993-02-03 1994-08-16 Chugai Pharmaceut Co Ltd アズレン誘導体の安定な製剤およびその製造方法

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS58208220A (ja) * 1982-05-31 1983-12-03 Grelan Pharmaceut Co Ltd 消化性潰瘍治療剤
JPS58208233A (ja) * 1982-05-31 1983-12-03 Grelan Pharmaceut Co Ltd 消化性潰瘍治療配合剤
JPH05331031A (ja) * 1992-05-27 1993-12-14 Kao Corp 口腔用組成物
JPH06227972A (ja) * 1993-02-03 1994-08-16 Chugai Pharmaceut Co Ltd アズレン誘導体の安定な製剤およびその製造方法

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AU4675696A (en) 1996-09-04

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