WO2017195804A1 - 15β-ヒドロキシ-酢酸オサテロンの結晶多形 - Google Patents
15β-ヒドロキシ-酢酸オサテロンの結晶多形 Download PDFInfo
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- C07J73/001—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms by one hetero atom
- C07J73/003—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms by one hetero atom by oxygen as hetero atom
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P13/08—Drugs for disorders of the urinary system of the prostate
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- A61P17/00—Drugs for dermatological disorders
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
- A61P5/28—Antiandrogens
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- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J73/00—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P17/08—Antiseborrheics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/14—Drugs for dermatological disorders for baldness or alopecia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Definitions
- the present invention relates to a crystal polymorph of 17 ⁇ -acetoxy-6-chloro-15 ⁇ -hydroxy-2-oxapregna-4,6-diene-3,20-dione (15 ⁇ -hydroxy-osaterone acetate).
- Patent Document 1 discloses 17 ⁇ -acetoxy-6-chloro-15 ⁇ -hydroxy-2-oxapregna-4,6-diene-3,20-dione (15 ⁇ -hydroxy-acetate acetate). This compound has anti-androgenic activity (anti-androgenic activity), and prevents and treats androgen-dependent diseases such as benign prostatic hyperplasia, prostate cancer, alopecia, hirsutism, wound, seborrhea, etc. , It is disclosed to be effective as a drug in treatment.
- This Patent Document 1 describes the synthesis of 15 ⁇ -hydroxy-osaterone acetate, but does not describe the crystal of 15 ⁇ -hydroxy-osaterone acetate.
- Non-Patent Document 1 is a document relating to a method for producing the above compound, and this document includes 15 ⁇ , 17 ⁇ -diacetoxy-6-chloro-2.
- a mixture of oxapregna-4,6-diene-3,20-dione, potassium carbonate, methanol and water is stirred at room temperature, water is added to the reaction mixture, the product is extracted with ethyl acetate and the organic phase is washed with water. After washing and drying over anhydrous magnesium sulfate and distilling off the solvent, the obtained crude product was purified by TLC to obtain 15 ⁇ -hydroxy-acetatelone acetate (mp 285-288 ° C. (acetone-hexane)). It is described.
- B-form crystals 15 ⁇ -hydroxy-osaterone acetate crystals
- thermal stability 15 ⁇ -hydroxy-osaterone acetate crystals
- the obtained B-form crystals are not sufficiently stable.
- the purity decrease with storage and storage stability thermal stability
- the crystal form cannot be maintained even when pressure is applied due to pulverization or crushing, resulting in a decrease in purity.
- the powder fluidity is low, the handling property in the formulation operation of the preparation is low, and the drug content in the preparation fluctuates, making it difficult to obtain a preparation with a stable content.
- B-form crystals not only have a high maximum plasma concentration C max of the drug, but also have a short time T max to reach C max . Therefore, since Cmax is reached within a short time and exhibits rapid absorption, there is a concern about safety.
- an object of the present invention is to provide 15 ⁇ -hydroxy-acetatelone crystal polymorph A having improved stability compared to conventional crystal polymorph B.
- Another object of the present invention is to provide a crystalline polymorph A of 15 ⁇ -hydroxy-acetate acetate which is improved in powder flowability and suitable for preparing a stable preparation having no variation in drug content.
- Still another object of the present invention is to provide a highly safe crystalline polymorph A of 15 ⁇ -hydroxy-acetate acetate that does not reach the maximum plasma concentration C max of the drug within a short time in pharmacokinetics. It is in.
- the present inventors have found that when 15 ⁇ -hydroxy-osaterone acetate is crystallized using a predetermined solvent, it has high stability, high powder flowability, and safety. The inventors have found that a crystal exhibiting a highly pharmacokinetic profile can be obtained, thereby completing the present invention.
- the crystalline polymorph A of 15 ⁇ -hydroxy-osaterone acetate of the present invention has a diffraction peak characteristic of the following diffraction angle 2 ⁇ in the powder X-ray diffraction spectrum.
- the crystalline polymorph A may further have a characteristic peak not found in the crystalline polymorph B.
- the crystal polymorph A has a diffraction angle that is the same as that of the crystal polymorph B
- the crystal polymorph A may have a peak having a higher intensity than the crystal polymorph B.
- the melting point of crystalline polymorph A of 15 ⁇ -hydroxy-osaterone acetate may be about 280 to 283 ° C. (eg, 281 to 282 ° C.).
- the crystal form of the crystal polymorph A of 15 ⁇ -hydroxy-osaterone acetate may be, for example, a prism crystal.
- the crystalline polymorph A of 15 ⁇ -hydroxy-osaterone acetate of the present invention is dissolved by heating 15 ⁇ -hydroxy-osaterone acetate in a mixed solvent of ethanol and water, and the solution (for example, a saturated solution) is cooled (in particular, (Slow cooling).
- the present invention also includes a pharmaceutical composition
- a pharmaceutical composition comprising the 15 ⁇ -hydroxy-osaterone acetate polymorph A and a carrier.
- the pharmaceutical composition may be in tablet form.
- the crystalline polymorph A of 15 ⁇ -hydroxy-osaterone acetate can improve the stability (storage stability, stability against pressure or crushing force such as crushing and compression) as compared with the conventional crystalline polymorph B. . Therefore, it is suitable for preparation of formulations such as tablets.
- the crystalline polymorph A of 15 ⁇ -hydroxy-osaterone acetate has high powder flowability and can improve workability, and can prepare a stable preparation without variation in drug content.
- the maximum plasma concentration C max is not reached within a short time, rapid absorption can be suppressed, and safety can be improved.
- FIG. 1 is a graph showing a powder X-ray diffraction spectrum of polymorph A of 15 ⁇ -hydroxy-osaterone acetate obtained in Example 1.
- FIG. 2 is a photomicrograph of crystalline polymorph A of 15 ⁇ -hydroxy-osaterone acetate obtained in Example 1.
- FIG. 3 is a graph showing a powder X-ray diffraction spectrum of crystal polymorph B of 15 ⁇ -hydroxy-osaterone acetate obtained in Comparative Example.
- FIG. 4 is a photomicrograph of crystalline polymorph B of 15 ⁇ -hydroxy-osaterone acetate obtained in the comparative example.
- FIG. 5 is a graph showing the results of the thermal stability test in Experimental Example 1.
- the crystalline polymorph A of 15 ⁇ -hydroxy-osaterone acetate of the present invention can be characterized by a diffraction peak in a powder X-ray diffraction spectrum.
- a powder X-ray-diffraction spectrum can be measured on the conditions of the usual method, for example, the below-mentioned Example.
- the diffraction angle 2 ⁇ indicating the diffraction peak may vary by about ⁇ 0.2 ° (for example, ⁇ 0.1 °) depending on the measurement conditions, sample preparation, and the like.
- the crystal polymorph A of 15 ⁇ -hydroxy-osaterone acetate of the present invention has a characteristic diffraction peak not found in crystal polymorph B at the following diffraction angle 2 ⁇ .
- the crystalline polymorph A has a relatively weak intensity and has a characteristic peak not found in the crystalline polymorph B.
- the crystal polymorph B has a diffraction peak having a higher intensity than that of the crystal polymorph B.
- the crystal polymorph B has a common diffraction angle, it may have a peak having a smaller intensity than the crystal polymorph B.
- a diffraction peak is also shown at °, 24.9 ° ⁇ 0.2 °.
- the order of the intensity of the diffraction peaks in the powder X-ray diffraction spectrum in the crystal polymorph A of 15 ⁇ -hydroxy-osaterone acetate is as follows.
- the crystal polymorph A of 15 ⁇ -hydroxy-acetate acetate has a melting point of 280 to 283 ° C. (for example, 281 to 282 ° C.) as measured by the capillary method (heating rate 2 ° C./min) Below the melting point of Form B (285-286 ° C.).
- DSC differential scanning calorimeter
- the crystal form of the crystal form A of 15 ⁇ -hydroxy-osaterone acetate is not particularly limited, but is usually a prismatic crystal (prism crystal) when observed with a microscope.
- the particle size of the crystalline polymorph A is not particularly limited.
- the average particle diameter measured based on the laser diffraction method is often about 30 to 50 ⁇ m.
- the crystal polymorph A of 15 ⁇ -hydroxy-osaterone acetate has the characteristics that the powder flowability is high and the angle of repose is small.
- the powdered polymorphic form 15 ⁇ -hydroxy-osaterone acetate is measured three times in accordance with the Japanese Pharmacopoeia (Pharmacopeia) angle of repose measurement method, and the average angle of repose is, for example, 30 to It is 38 °, preferably 32-37 ° (eg, 33-37 °), more preferably about 34-36 °.
- the polycrystal B of 15 ⁇ -hydroxy-osaterone acetate has an average angle of repose of, for example, about 42 to 52 ° (eg, 44 to 50 °, particularly 45 to 47 °) in the same measurement as above.
- the angle of repose is fixed at 4.5 cm from the lower end of the funnel to the deposition surface (upper surface of a cylinder having a diameter of 1.5 cm), and the funnel (the diameter of the funnel portion is 50 mm, the inner diameter of the hollow shaft portion is 7 mm, hollow An excess powder is dropped on the center portion of the cylindrical surface through a glass funnel having a shaft length of 40 mm, and the tilt angle of the deposited powder can be measured and evaluated.
- the 15 ⁇ -hydroxy-acetate acetate crystal polymorph A can be used in other polymorphs (for example, 10% by weight or less, preferably 5% by weight or less, and more preferably 2.5% by weight or less). , Crystal polymorph B, amorphous, etc.).
- the crystalline polymorph A of 15 ⁇ -hydroxy-acetate acetate can be obtained by various crystallization methods. For example, 15 ⁇ -hydroxy-acetate acetate is dissolved in an organic solvent (a good solvent such as chloroform), You may obtain by mixing with a solvent (poor solvents, such as octane), and crystallizing. In such a precipitation method, crystal polymorph A including other crystal polymorphs may be obtained.
- an organic solvent a good solvent such as chloroform
- a solvent poor solvents, such as octane
- a method for crystallization from a supersaturated solution for example, a crystallization solvent containing an organic solvent (for example, a mixed solvent of a good solvent and a poor solvent) is used to prepare a saturated solution.
- the crystal polymorph A can be precipitated by cooling (especially slow cooling) this solution.
- Good solvents include alcohols (linear or branched C 1-4 alcohols such as ethanol and isopropanol), halogenated hydrocarbons (halo C 1-3 such as dichloromethane, trichloromethane, carbon tetrachloride, trichloroethane, etc. Examples include alkanes, esters (methyl acetate, ethyl acetate, butyl acetate, etc.), ketones (acetone, methyl ethyl ketone, methyl isobutyl ketone, etc.), cyclic ethers (dioxane, tetrahydrofuran, etc.), and the like. These solvents can be used alone or in combination of two or more.
- Preferred good solvents are water-soluble solvents such as alcohols (linear or branched C 1-3 alcohols such as ethanol and isopropanol), ketones (acetone), and cyclic ethers.
- alcohols linear or branched C 1-3 alcohols such as ethanol and isopropanol
- ketones acetone
- cyclic ethers e.g., benzyl alcohols, benzyl alcoholsulfate, acetone, and cyclic ethers.
- alcohols ethanol, isopropanol
- acetone cyclic ethers
- the poor solvent examples include water, aliphatic hydrocarbons (alkanes such as hexane and octane, cycloalkanes such as cyclohexane), chain ethers (diethyl ether, diisopropyl ether, etc.), and the like.
- a preferred antisolvent is water or hexane.
- the weight ratio between the good solvent and the poor solvent is, for example, 1 to 200 parts by weight (for example, 1.5 to 100 parts by weight) of the poor solvent, preferably 2 to 50 parts by weight (for example, 100 parts by weight of the good solvent). 2 to 40 parts by weight), more preferably about 2.5 to 20 parts by weight (for example, 3 to 10 parts by weight).
- a saturated solution can be easily prepared by heating (eg, heating to 40 ° C. to reflux temperature) to dissolve 15 ⁇ -hydroxy-osaterone acetate.
- concentration of 15 ⁇ -hydroxy-osaterone acetate in the solution may be, for example, about 0.1 to 20% by weight, preferably 1 to 15% by weight, and more preferably about 3 to 10% by weight.
- 15 ⁇ -hydroxy-acetate acetate is used as a linear or branched chain.
- C 1-3 alcohol was heated and dissolved in a mixed solvent (crystallization solvent) of alcohol (ethanol, isopropanol, etc., particularly ethanol) and water, and the resulting solution (saturated solution) was cooled to 15 ⁇ -hydroxy-
- the cooling may be rapid cooling, but it is preferable to precipitate crystal polymorph A of 15 ⁇ -hydroxy-osaterone acetate by slow cooling.
- the slow cooling can usually be performed by leaving the heated solution at room temperature, and if necessary, it may be cooled to a temperature below room temperature.
- the precipitated crystals are usually filtered, washed and collected if necessary, and dried to obtain crystal polymorph A of 15 ⁇ -hydroxy-osaterone acetate.
- the crystalline polymorph A of 15 ⁇ -hydroxy-osaterone acetate of the present invention may be used alone as a pharmaceutical, or in combination with a carrier (such as a pharmacologically or physiologically acceptable carrier), a pharmaceutical composition (or formulation) It may be used as a carrier (such as a pharmacologically or physiologically acceptable carrier), a pharmaceutical composition (or formulation) It may be used as
- the carrier can be selected according to the form (ie, dosage form), dosage form, use, etc. of the pharmaceutical composition (or formulation).
- the dosage form is not particularly limited, and is a solid preparation [powder, powder, granule (granule, fine granule, etc.), pill, pill, tablet, capsule (soft capsule, hard capsule, etc.), dry syrup, Suppositories, film or sheet preparations, etc.], semi-solid preparations (creams, ointments, gels, gummies, etc.), liquids (injections, syrups, etc.), etc.
- the powder includes sprays, aerosols and the like.
- the capsule may be either a soft capsule or a hard capsule, a liquid-filled capsule, or a capsule filled with a solid agent such as a granule.
- the preparation may be a lyophilized preparation.
- the preparation of the present invention may be a preparation with controlled drug release rate (sustained release preparation, immediate release preparation).
- the preparation may be an oral administration preparation (granule, powder, tablet (sublingual tablet, orally disintegrating tablet, etc.), capsule, film preparation, etc.), or parenteral administration preparation (inhalation, transdermal administration). Preparation, nasal administration preparation, etc.).
- the preparation may be a topical preparation (ointment, patch, cataplasm, etc.).
- the preparation of the present invention is often a solid preparation (for example, an orally administered solid preparation). Therefore, in the following description, it demonstrates focusing on the component of a solid formulation.
- the carrier examples include Japanese Pharmacopoeia (Pharmacopoeia), (1) Pharmaceutical Additives Handbook, Maruzen Co., Ltd., (1989), (2) “Pharmaceutical Additives Encyclopedia 2016” (Pharmaceutical Daily Inc., 2016) (Issued in February), (3) Pharmacy, revised 5th edition, Nanedo Co., Ltd. (1997), and (4) Pharmaceutical additive standards 2003 (Pharmaceutical Daily Inc., August 2003) (For example, an excipient, a binder, a disintegrant, a lubricant, a coating agent, etc.) can be selected according to the administration route and the formulation application.
- a carrier for a solid preparation at least one carrier selected from excipients, binders and disintegrants is often used.
- the pharmaceutical composition may contain a lipid.
- excipient examples include sugars such as lactose, glucose, sucrose, mannitol, sorbitol, xylitol or sugar alcohols; starch such as corn starch; polysaccharides such as crystalline cellulose (including microcrystalline cellulose); Examples thereof include silicon oxide such as acid or silicate.
- soluble starch such as pregelatinized starch and partially pregelatinized starch; polysaccharides such as gum arabic, dextrin and sodium alginate; polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), carboxyvinyl polymer, polyacrylic acid type Synthetic polymers such as polymers, polylactic acid and polyethylene glycol; methylcellulose (MC), ethylcellulose (EC), carboxymethylcellulose (CMC), sodium carboxymethylcellulose, hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose ( Examples thereof include cellulose ethers such as HPMC).
- PVP polyvinylpyrrolidone
- PVA polyvinyl alcohol
- carboxyvinyl polymer polyacrylic acid type Synthetic polymers such as polymers, polylactic acid and polyethylene glycol
- MC methylcellulose
- EC ethylcellulose
- CMC carboxymethylcellulose
- HEC hydroxyethyl
- disintegrant examples include carboxymethyl starch sodium, carmellose, carmellose sodium, carmellose calcium, croscarmellose sodium, crospovidone, and low-substituted hydroxypropylcellulose. These carriers can be used alone or in combination of two or more.
- the coating agent examples include saccharides, cellulose derivatives such as ethyl cellulose and hydroxymethyl cellulose, polyoxyethylene glycol, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, methyl methacrylate- (meth) acrylic acid copolymer, and Eudragit (methacrylic acid). Acid / acrylic acid copolymer).
- the coating agent may be an enteric component such as cellulose phthalate, hydroxypropylmethylcellulose phthalate, methyl methacrylate- (meth) acrylic acid copolymer, or a polymer containing a basic component such as dialkylaminoalkyl (meth) acrylate ( Gastric soluble components composed of Eudragit etc.).
- the preparation may also be a capsule containing these enteric components and gastric components in the skin.
- additives can be appropriately used depending on the administration route, dosage form and the like.
- additives include lubricants, disintegration aids, antioxidants or antioxidants, stabilizers, preservatives or preservatives, bactericides or antibacterial agents, antistatic agents, flavoring agents, or masking agents. , Coloring agents, flavoring agents or fragrances, cooling agents, antifoaming agents and the like. These additives can be used alone or in combination of two or more.
- composition (or pharmaceutical preparation) of the present invention may contain other physiologically active components or pharmacologically active components as necessary.
- the pharmaceutical composition of the present invention is prepared by a conventional formulation method, for example, a production method described in the 16th revised Japanese Pharmacopeia or this production method, using an active ingredient, a carrier component, and if necessary an additive. Can be prepared by different methods.
- the crystalline polymorph A of 15 ⁇ -hydroxy-osaterone acetate of the present invention has high stability against compression or friction such as crushing and crushing as well as storage stability. Therefore, it is suitable for preparing a pharmaceutical preparation (for example, tablet) by a method in which friction acts, for example, grinding and tableting. Further, it is excellent in powder flowability, and is suitable for preparing a preparation containing a uniform content (for example, a preparation in the form of a tablet).
- the crystalline polymorph A of 15 ⁇ -hydroxy-osaterone acetate of the present invention has low toxicity, is not rapidly absorbed within a short time in pharmacokinetics, and is excellent in safety. That the crystalline polymorph A is the highest plasma concentration (C max) is small, the time to reach maximum plasma concentration (C max) of the drug (T max) is long, showing a high safety pharmacokinetics. Therefore, it can be safely administered to humans and non-human animals, usually mammals (eg, humans, mice, rats, rabbits, dogs, cats, cows, horses, pigs, monkeys, etc.).
- mammals eg, humans, mice, rats, rabbits, dogs, cats, cows, horses, pigs, monkeys, etc.
- the dosage can be selected depending on the species, age, weight, and condition (general condition, medical condition, presence of complications, etc.), administration time, dosage form, administration method, and the like of the administration target.
- the dose (daily dose) for humans is, for example, about 0.01 to 50 mg / day, preferably about 0.05 to 10 mg / day (for example, 0.5 to 5 mg / day).
- the dose for dogs is, for example, about 0.03 to 3 mg / kg, particularly about 0.1 to 1 mg / kg per day.
- the administration method may be oral administration, local administration or parenteral administration (for example, subcutaneous administration, intramuscular administration, rectal administration, vaginal administration, etc.).
- the number of administrations is not particularly limited, and may be once a day, for example, or may be multiple times a day (for example, 2 to 3 times) as necessary.
- Example 1 In the same manner as in Example 3 (f) of Patent Document 1, 15 ⁇ -hydroxy-acetatelone acetate (17 ⁇ -acetoxy-6-chloro-15 ⁇ -hydroxy-2-oxapregna-4,6-diene-3,20-dione) was used. Prepared. 20 g of a mixed solvent of ethanol / water (25: 1) was added to 1 g of the obtained 15 ⁇ -hydroxy-acetate acetate, and the mixture was refluxed to dissolve 15 ⁇ -hydroxy-acetate acetate and then slowly cooled at room temperature overnight. The precipitated crystals were filtered and washed with a small amount of the mixed solvent. By air-drying at room temperature, 0.65 g of polymorph A was obtained.
- the obtained crystal When the obtained crystal was observed with a microscope, it was a prism crystal. A micrograph of the obtained crystal is shown in FIG. Further, the melting point measured by the capillary method at a heating rate of 2 ° C./min was 281 to 282 ° C.
- the melting point measured by the capillary method was 285 to 286 ° C.
- the crystalline polymorph A has a slight decrease in the drug content, and the thermal stability (and stability over time) is extremely high as compared with the crystalline polymorph B.
- crystal polymorphs A and B were changed to light brown on the 7th day after storage, but crystal polymorph A maintained a light brown color, but crystal polymorph B became brown over time. .
- the degree of fluidity is an evaluation based on pharmacopoeia reference information (G2 physical property related powder fluidity) describing the relationship between the angle of repose and the fluidity.
- the crystalline polymorph A obtained in Example 1 has a smaller angle of repose and higher powder flowability than the crystalline polymorph B obtained in Comparative Example 1. Furthermore, the polymorph B has a large angle of repose angle, and the fluidity exhibits unstable fluidity from “39” with the standard “slightly good” to “51” with the standard “slightly poor”, whereas Crystalline polymorph A exhibits stable fluidity from the standard “good” “33” to the standard “slightly good” “38”.
- crystals are usually aged by stirring. Therefore, in such crystallization, it is very important that the crystal form is stable. That is, changing the crystal form during the crystal production process causes a difference in solubility and absorption in the living body between production lots, which causes problems such as inability to exhibit the expected medicinal effects. Under such circumstances, crystalline polymorph A is very stable while crystalline polymorph B is unstable with respect to the solvents normally used in the preparation of formulations. Therefore, crystalline polymorph A is stable in the process from crystallization to preparation of the preparation, and a stable preparation can be prepared.
- the crystalline polymorph A obtained in Example 1 has a lower maximum plasma concentration (C max ) than the crystalline polymorph B obtained in Comparative Example 1, and the highest plasma. Since the time to reach medium concentration (T max ) is long, it does not show rapid drug absorption and is a highly safe crystal.
- the crystalline polymorph A of 15 ⁇ -hydroxy-osaterone acetate of the present invention is used for the prevention or treatment of various diseases caused by antiandrogenic activity, such as benign prostatic hyperplasia, prostate cancer, alopecia, hirsutism, wound, seborrhea Available to: It is also effective in preventing or treating osteoporosis, uterine fibroids, endometriosis and the like.
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Abstract
Description
回折角度2θ=12.1°での回折強度A2=52~72(例えば、55~70)、好ましくは57~67(例えば、60~65)
回折角度2θ=14.6°での回折強度A3=8~28(例えば、10~25)、好ましくは13~23(例えば、15~20)
回折角度2θ=15.0°での回折強度A4=39~59(例えば、42~56)、好ましくは44~54(例えば、46~51)
回折角度2θ=16.2°での回折強度A5=9~29(例えば、12~26)、好ましくは14~24(例えば、16~21)
回折角度2θ=20.2°での回折強度A6=40~60(例えば、43~57)、好ましくは45~55(例えば、47~52)
回折角度2θ=20.9°での回折強度A7=13~33(例えば、15~30)、好ましくは18~28(例えば、20~25)
回折角度2θ=24.9°での回折強度A8=6~26(例えば、8~23)、好ましくは11~21(例えば、13~18)
回折角度2θ=25.6°での回折強度A9=6~26(例えば、8~23)、好ましくは11~21(例えば、13~18)
15β-ヒドロキシ-酢酸オサテロンの結晶多形Aは、種々の結晶化方法で得ることができ、例えば、15β-ヒドロキシ-酢酸オサテロンを有機溶媒(クロロホルムなどの良溶媒)に溶解し、この溶液を貧溶媒(オクタンなどの貧溶媒)と混合して晶析することにより得てもよい。このような析出法では、他の結晶多形を含む結晶多形Aが得られる場合がある。そのため、代表的には、過飽和状態の溶液から晶析する方法、例えば、有機溶媒を含む晶析溶媒(例えば、良溶媒と貧溶媒との混合溶媒)に溶解して飽和状態の溶液を調製し、この溶液を冷却(特に、徐冷)することにより、結晶多形Aを析出させることができる。
本発明の15β-ヒドロキシ-酢酸オサテロンの結晶多形Aは、単独で医薬として用いてもよく、担体(薬理学的又は生理学的に許容可能な担体など)と組み合わせて医薬組成物(又は製剤)として用いてもよい。
特許文献1の実施例3(f)と同様にして15β-ヒドロキシ-酢酸オサテロン(17α-アセトキシ-6-クロロ-15β-ヒドロキシ-2-オキサプレグナ-4,6-ジエン-3,20-ジオン)を調製した。得られた15β-ヒドロキシ-酢酸オサテロン1gにエタノール/水(25:1)混合溶媒20mLを加え、混合液を還流して15β-ヒドロキシ-酢酸オサテロンを溶解した後、室温で1晩徐冷した。析出した結晶をろ過し、少量の前記混合溶媒で洗浄した。室温で通風乾燥して結晶多形A0.65gを得た。
非特許文献1に記載の方法に基づき、15β-ヒドロキシ-酢酸オサテロン(結晶多形B)を得た。
実施例1で得られた結晶多形Aと比較例1で得られた結晶多形Bとを、それぞれ、温度100℃で28日間保存(保存条件、恒温槽 空気中)し、所定時間毎にサンプリングしてHPLCで15β-ヒドロキシ-酢酸オサテロンの純度を測定した。結果を図5に示す。
自動乳鉢粉砕器(乳棒重量124g、50回転/分)に試料(結晶多形A又は結晶多形B)50mgを入れ、1時間に亘り粉砕し、サンプリングした。PXRD分析を行い、結晶化度の変化を確認したところ、1時間後の結晶化度は、結晶多形A46.8%、結晶多形B22.2%であり、結晶多形Aが粉砕に対して安定であった。なお、PXRDスペクトルでの特徴的な回析ピーク(結晶多形Aでは2θ=17.1°での回析ピーク、結晶多形Bでは2θ=16.2°での回析ピーク)の強度比(ピーク高さ)に基づいて結晶化度を測定し、結晶化度の変化率を算出した。
ロート下端から堆積面(直径1.5cmの円柱の上面)までの高さを4.5cmに固定し、ロートを通して円柱面の中心部に過剰の粉末を落下させた。堆積した粉体の傾斜角(安息角)を測定した。この操作を3回繰り返し、安息角の平均値を算出した。
(1)アセトン/ヘプタン混合溶媒(1:1)、(2)アセトン/水混合溶媒(1:1)、(3)エタノール/水混合溶媒(1:1)に結晶多形Aを加えて撹拌したところ、結晶多形Aは、1日後、混合溶媒(1)では98%、混合溶媒(2)では99%、混合溶媒(3)では100%の割合で結晶多形Aの結晶構造を保持し、3日後、混合溶媒(1)では95%、混合溶媒(2)では98%、混合溶媒(3)では99%の割合で結晶多形Aの結晶構造を保持し、7日後でも混合溶媒(1)では95%、混合溶媒(2)では98%、混合溶媒(3)では99%の割合で結晶多形Aの結晶構造を保持していた。
実施例1で得られた結晶多形Aおよび比較例1で得られた結晶多形Bを、0.3mg/kgの用量で乳糖水和物(DFE Pharma社製)100mgと混合し、ゼラチンカプセル((株)松屋製MM、サイズ:2号)に充填してカプセル剤を調製した。第1群(5頭)の雌性イヌに結晶多形Aを含むカプセル剤を経口投与し、第2群(5頭)の雌性イヌに結晶多形Bを含むカプセル剤を経口投与し、それぞれ、経口投与後0.5、1、2、3、4、5、7、10、24、48及び72時間に血液を採取し、遠心分離により血漿を得た。LC-MS/MS(液体クロマトグラフィー-タンデム質量分析)法により、血漿中の15β-ヒドロキシ-酢酸オサテロン濃度を測定し、最高血漿中濃度到達時間(Tmax)および最高血漿濃度(Cmax)を算出した。
Claims (9)
- 15β-ヒドロキシ-酢酸オサテロンの結晶多形であって、粉末X線回折スペクトルにおいて、以下の回折角度2θに回折ピークを有する15β-ヒドロキシ-酢酸オサテロンの結晶多形A。
9.6°±0.2°,17.1°±0.2°,20.2°±0.2° - さらに、25.6°±0.2°の回折角度2θに回折ピークを有する請求項1記載の15β-ヒドロキシ-酢酸オサテロンの結晶多形A。
- 12.1°±0.2°の回折角度2θに回折ピークを有する請求項1又は2記載の15β-ヒドロキシ-酢酸オサテロンの結晶多形A。
- 14.6°±0.2°,16.2°±0.2°,20.9°±0.2°,24.9°±0.2°の回折角度2θに回折ピークを有する請求項1~3のいずれかに記載の15β-ヒドロキシ-酢酸オサテロンの結晶多形A。
- 融点280~283℃を有する請求項1~4のいずれかに記載の15β-ヒドロキシ-酢酸オサテロンの結晶多形A。
- プリズム晶である請求項1~5のいずれかに記載の15β-ヒドロキシ-酢酸オサテロンの結晶多形A。
- 15β-ヒドロキシ-酢酸オサテロンをエタノールと水との混合溶媒に加熱して溶解し、溶液を冷却し、請求項1~6のいずれかに記載の15β-ヒドロキシ-酢酸オサテロンの結晶多形Aを製造する方法。
- 請求項1~6のいずれかに記載の15β-ヒドロキシ-酢酸オサテロンの結晶多形Aと担体とを含む医薬組成物。
- 錠剤の形態である請求項8記載の医薬組成物。
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CA3021179A CA3021179A1 (en) | 2016-05-11 | 2017-05-10 | Crystalline polymorph of 15.beta.-hydroxy-osaterone acetate |
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