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WO1999022739A1 - Composition medicinale a base d'un compose steroidien - Google Patents

Composition medicinale a base d'un compose steroidien Download PDF

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Publication number
WO1999022739A1
WO1999022739A1 PCT/JP1998/004936 JP9804936W WO9922739A1 WO 1999022739 A1 WO1999022739 A1 WO 1999022739A1 JP 9804936 W JP9804936 W JP 9804936W WO 9922739 A1 WO9922739 A1 WO 9922739A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
group
alkyl group
steroid compound
degree
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/JP1998/004936
Other languages
English (en)
Japanese (ja)
Inventor
Akio Miwa
Tomohiro Yamahira
Atsuo Ishibe
Shigeru Itai
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.)
Taisho Pharmaceutical Co Ltd
Original Assignee
Taisho 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 Taisho Pharmaceutical Co Ltd filed Critical Taisho Pharmaceutical Co Ltd
Priority to AU96512/98A priority Critical patent/AU9651298A/en
Publication of WO1999022739A1 publication Critical patent/WO1999022739A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L5/00—Compositions of polysaccharides or of their derivatives not provided for in groups C08L1/00 or C08L3/00
    • C08L5/08—Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers

Definitions

  • the present invention relates to a technique for solubilizing a hydrophobic steroid compound using a chitosan derivative into which a hydrophilic group and a hydrophobic group have been introduced.
  • Japanese Patent Publication No. Sho 63-28414 discloses a preparation in which the dissolution property of a hydrophobic drug is improved by using chitin and / or chitosan.
  • No. 34 discloses a formulation in which the solubility and dissolution properties of a hydrophobic drug in water using chitosan of low molecular weight have been improved.
  • a formulation has been disclosed in which the solubility and dissolution properties of a hydrophobic drug in water are improved using chitosan and an insoluble high molecular weight chitosan.
  • An object of the present invention is to provide a pharmaceutical composition containing a steroid compound which can form a micelle-like aqueous composition, whereby a drug which is insoluble in water and cannot be injected with an injection can be prepared.
  • Oral drugs have poor solubility and can promote absorption of poorly absorbed drugs. Disclosure of the invention
  • the present inventors have conducted intensive studies on the above objects, and as a result, introduced a hydrophilic group and a hydrophobic group.
  • the present inventors have found that a novel chitosan derivative forms a micelle-like aqueous composition with a hydrophobic steroid compound and completed the present invention.
  • the present invention provides the following (1) and (2)
  • R 1 represents a hydrogen atom, an acetyl group, an alkyl group having 9 to 21 carbon atoms or an alkanol group having 9 to 21 carbon atoms
  • R 2 represents a hydrogen atom or a carboxy-C 5 alkyl group.
  • the degree of deacetylation of the N-acetyl group represented by R 1 is 70 to 100% (100 when one monosaccharide is deacetylated per monosaccharide).
  • the degree of substitution of the alkyl group represented by R 1 is 10 to 100% (100% when one is substituted per monosaccharide), and carboxy-C ⁇ 5
  • a pharmaceutical composition comprising a salt thereof and another aspect of the present invention provides a method for solubilizing a steroid compound of the formula [I].
  • the chitosan derivative or a Lee de compound This is a method for solubilizing a steroid compound, which comprises mixing with a salt to form a micelle-like aqueous composition.
  • the alkyl group having 11 carbon atoms represented by R means a linear or branched alkyl group, such as methyl, ethyl, isobutyl, isopentyl, and isopentyl. It is a xyl group, an isoheptyl group, an isooctyl group, a nonyl group, a decyl group, etc., and can exert more effects on a nonyl group or a decyl group from the viewpoint of hydrophobicity and efficacy.
  • the carboxymethyl chitin-converted molecular weight was converted to the molecular weight of the raw material carboxymethyl chitin before introducing an alkyl group having 921 carbon atoms or an alkanol group having 921 carbon atoms in the above formula [II]. Refers to molecular weight.
  • the alkyl group having 9 21 carbon atoms represented by R 1 may be either a straight-chain or a branched chain, and is preferably a straight-chain C 3 —2 , alkyl group That is, it is an alkyl group represented by the formula (CH 2 ) dilemmaCH 3 (wherein, n is an integer of 8 20)
  • An alkanoyl group having 9 21 carbon atoms represented by R 1 may be linear or branched, preferably linear saturated C 9 -!
  • the steroid compound in the present invention is a novel compound having an antitumor activity, and particularly exhibits an antitumor activity when R is a nonyl group or a decyl group.
  • the steroid compound is a steide derivative 3/3, 12; 3; 3; described in the literature (Chem. Ber., Vol. 100, p. 464, 1967).
  • -dihydroxy-5 ⁇ -pregnane-20-one (1) as a starting material, it can be synthesized according to the production methods shown in the following schemes 1 and 2.
  • the following is an outline of a method for synthesizing a steroid compound in which R is a nonyl group or a decyl group. Manufacturing scheme 1
  • MOM Metoki acac: Asechi
  • the compound (1) is reacted with methyl methyl ether in the presence of a base such as N, N-diisopropylethylamine to obtain a derivative (2) in which the hydroxyl groups at the 3- and 12-positions are protected.
  • the compound (2) is reacted with a Grignard reagent prepared from 1-promodedecane or 1-bromoundecane to give the 20-position alcohol (3): a low-polar isomer and (4): a high-polar isomer.
  • Tert-butyl hydroperoxide or cumene hydroperoxide is allowed to act on compound (5) in the presence of a catalytic amount of vanadium acetyl acetonate and in the presence or absence of a base such as sodium bicarbonate; 20,22_ / 3-epoxy compound (6): Highly polar isomer and 20,22-hi-epoxy compound (7): Low polar isomer about 10: 1 to 5: 1 Obtain by ratio.
  • the mixture of compound (6) and compound (7) is reacted with acetic anhydride in a solvent such as pyridine in the presence of a salt such as 4-dimethylaminopyridine to give the 3 ⁇ , 12 ⁇ -diethoxycetoxy derivative (8 ) And (9).
  • the compound (12) is reacted with tert-butyl hydroperoxide or cumene hydroperoxide in the presence of a catalytic amount of vanadium acetyl acetonate to give a 20,21-epoxy compound (12).
  • the compound (12) is reacted with a base such as potassium carbonate in a lower alcohol such as methanol to obtain the steroid compound (13) of the present invention.
  • the present invention provides a micelle-like aqueous composition comprising a steroid compound and a chitin derivative, or a dry composition thereof.
  • the micelle-like aqueous composition referred to in the present invention means a solution-like composition in which a steroid compound is uniformly dispersed in an aqueous solvent, becomes visually clear or milky white, and the drug is solubilized.
  • the aqueous solvent used here include distilled water.
  • salts, sugars, acids and the like may be appropriately added thereto, and examples thereof include distilled water for injection, physiological saline, sugar solution, infusion solution, and buffer solution.
  • the above-mentioned water-soluble solvent may contain a water-soluble organic solvent, for example, a small amount of ethanol or the like, as long as it does not show toxicity.
  • a composition obtained by appropriately drying the aqueous composition by a conventional drying means is referred to as a dry composition.
  • a weight ratio of 1:. 0 5 to 1: is preferably 5.
  • the means for solubilization is not particularly limited, but it is preferable to apply a temperature when the chitosan derivative is swelled, and the temperature is 20 to 100, more preferably 40 to 60 ° C.
  • sonication is preferred.
  • the dissolution amount is affected by the sonication time, and the treatment time is from 10 to 120 minutes, more preferably from 20 to 40 minutes.
  • 2 parts by weight of a chitosan derivative is stirred at an elevated temperature to swell and dissolve the polymer. Thereafter, 1 part by weight of a steroid compound is added and subjected to ultrasonic treatment to obtain a micelle-like aqueous composition in which the drug is uniformly dispersed.
  • a sterilized solution for example, sterilized distilled water is used in preparing a solution of the aqueous composition or the like, and sterilized by filtration through a membrane filter or the like.
  • the pharmaceutical composition of the present invention may be either a micelle-like aqueous composition or a dry composition thereof, but a dry composition is more preferable because the steroid compound is stably stored.
  • a method of once converting an aqueous composition into a dry product by various drying means may be used.
  • the drying means include a freeze drying method, a spray drying method, and a reduced pressure drying method, and the freeze drying method is particularly preferable.
  • the micelle-like aqueous composition or dry composition of the present invention thus obtained can be used as preparations for injections, oral preparations, suppositories, transmucosal administration preparations, and external preparations.
  • the compound numbers described in Production Examples correspond to the compound numbers shown in Scheme 1 and Scheme 2.
  • a attached to the compound numbers described in Production Examples indicates a case where R of the compound shown in Scheme 1 and Scheme 2 is a nonyl group (n—C 9 Hi 9 ), and b is a scheme 1 and Scheme 2 shows a case where R of the compound shown in FIG. 2 is a decyl group (n—C 10 H 2 i).
  • the molecular weight of carboxymethyl chitin was measured by the method of Inoue et al. (Inoue Y., Kaneko M. and Tokura S., Rep. Progr. Polym. Phys. Jap., 25, 759 (1982)). Deacetylation degree, carboxymethylation degree and laurylation degree are analyzed by elemental analysis of chitin and its derivatives. The degree of substitution was calculated from the obtained elemental composition by measuring with a total analyzer (24000 CHN elemental analyzer manufactured by Perkin Elmer Co., Ltd.).
  • the micelles containing the compound (13a) were dialyzed against purified water at room temperature for 1 ⁇ at room temperature, centrifuged at 3000 rpm for 30 minutes, and the supernatant was filtered through a membrane filter with a pore size of 5 zm. A composition was obtained.
  • the micelle-like composition is dispensed into vials in a daily dose (approximately 5.2 ml) (drug concentration: 1.2 mg Zm1), freeze-dried (Kyowa Vacuum Technology's Triomaster-A-04), and stored. did.
  • the particle diameter of the sample of the example was measured by the dynamic light scattering method.
  • Distribution display weight distribution
  • (13a) is a poorly soluble drug that hardly dissolves in water (solubility in water is 0.001 mg / m1 or less), but in the examples, (13a) is used as a micelle-like aqueous composition. The amount of dissolution was significantly increased by the inclusion. Further, the micelle particle size distribution of the example showed a substantially single peak in the weight distribution display, and the average particle size was 73 nm. The composition Became a clear or pale milky solution. Industrial applicability
  • the steroid compound was solubilized by using a chitosan derivative into which a hydrophilic group and a hydrophobic group were introduced. Therefore, it is possible to formulate a steroid compound which has been difficult to inject because of its water insolubility, and it can be expected to have an absorption-promoting effect even for a drug which has poor solubility due to poor solubility in an oral preparation or the like.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Polymers & Plastics (AREA)
  • Dispersion Chemistry (AREA)
  • Molecular Biology (AREA)
  • Biophysics (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Steroid Compounds (AREA)

Abstract

L'invention concerne une composition micellaire aqueuse renfermant un dérivé de chitosane pourvus de groupes hydrophiles et hydrophobes et un composé stéroïdien. L'invention concerne également un procédé de solubilisation d'un composé stéroïdien consistant à ajouter un dérivé de chitosane pourvus de groupes hydrophiles et hydrophobes dans un milieu aqueux, en même temps que le composé stéroïdien de manière à former une composition micellaire aqueuse. Le composé stéroïdien ainsi solubilisé permet d'utiliser en tant que solution parentérale un médicament insoluble dans l'eau inapte à être injecté en raison de son caractère insoluble dans l'eau. Ledit composé sert également à accélérer l'absorption d'un médicament qui, lorsqu'il était utilisé sous forme de préparations perorales, présentait une faible absorbabilité du fait de sa faible solubilité.
PCT/JP1998/004936 1997-10-31 1998-10-30 Composition medicinale a base d'un compose steroidien Ceased WO1999022739A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU96512/98A AU9651298A (en) 1997-10-31 1998-10-30 Medicinal steroid compound composition

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP30037597 1997-10-31
JP9/300375 1997-10-31

Publications (1)

Publication Number Publication Date
WO1999022739A1 true WO1999022739A1 (fr) 1999-05-14

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PCT/JP1998/004936 Ceased WO1999022739A1 (fr) 1997-10-31 1998-10-30 Composition medicinale a base d'un compose steroidien

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AU (1) AU9651298A (fr)
WO (1) WO1999022739A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001052896A3 (fr) * 2000-01-18 2002-03-07 Eurand Int Compositions a biodisponibilite orale amelioree
WO2003015827A1 (fr) * 2001-08-18 2003-02-27 Korea Institute Of Science And Technology Complexe de chitosane-substance anticancereuse formant automatiquement des corps par agregation et son procede de preparation
CN111714468A (zh) * 2020-06-30 2020-09-29 郑州大学 一种siNRA递送系统复合物及其制备方法和用途

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH02131434A (ja) * 1988-11-11 1990-05-21 Masaki Odagiri 薬剤組成物
JPH0517371A (ja) * 1991-07-09 1993-01-26 Kurita Water Ind Ltd 薬剤組成物
JPH07224087A (ja) * 1993-12-15 1995-08-22 Taisho Pharmaceut Co Ltd ステロイド誘導体

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH02131434A (ja) * 1988-11-11 1990-05-21 Masaki Odagiri 薬剤組成物
JPH0517371A (ja) * 1991-07-09 1993-01-26 Kurita Water Ind Ltd 薬剤組成物
JPH07224087A (ja) * 1993-12-15 1995-08-22 Taisho Pharmaceut Co Ltd ステロイド誘導体

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001052896A3 (fr) * 2000-01-18 2002-03-07 Eurand Int Compositions a biodisponibilite orale amelioree
WO2003015827A1 (fr) * 2001-08-18 2003-02-27 Korea Institute Of Science And Technology Complexe de chitosane-substance anticancereuse formant automatiquement des corps par agregation et son procede de preparation
US7511023B2 (en) 2001-08-18 2009-03-31 Korea Institute Of Science And Technology Anticancer drug-chitosan complex forming self-aggregates and preparation method thereof
CN100493614C (zh) * 2001-08-18 2009-06-03 韩国科学技术研究院 形成自聚集体的抗癌药-脱乙酰壳多糖复合体以及其制备方法
CN111714468A (zh) * 2020-06-30 2020-09-29 郑州大学 一种siNRA递送系统复合物及其制备方法和用途

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Publication number Publication date
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