WO2014175302A1 - Amorphous levonorgestrel, solid dispersion, and manufacturing method for same - Google Patents

Amorphous levonorgestrel, solid dispersion, and manufacturing method for same Download PDF

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WO2014175302A1
WO2014175302A1 PCT/JP2014/061363 JP2014061363W WO2014175302A1 WO 2014175302 A1 WO2014175302 A1 WO 2014175302A1 JP 2014061363 W JP2014061363 W JP 2014061363W WO 2014175302 A1 WO2014175302 A1 WO 2014175302A1
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levonorgestrel
polymer
amorphous
solid dispersion
cellulose
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PCT/JP2014/061363
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French (fr)
Japanese (ja)
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茂樹 岩下
林　博之
隆義 中川
宏一 宮崎
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あすか製薬株式会社
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Priority to JP2014561677A priority Critical patent/JP6125547B2/en
Publication of WO2014175302A1 publication Critical patent/WO2014175302A1/en

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    • 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
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/567—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in position 17 alpha, e.g. mestranol, norethandrolone
    • 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
    • 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
    • A61P15/18—Feminine contraceptives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
    • C07J1/0051—Estrane derivatives
    • C07J1/0081—Substituted in position 17 alfa and 17 beta
    • C07J1/0088—Substituted in position 17 alfa and 17 beta the substituent in position 17 alfa being an unsaturated hydrocarbon group
    • C07J1/0096—Alkynyl derivatives

Definitions

  • the present invention relates to amorphous levonogestrel useful as an emergency contraceptive, a solid dispersion containing levonogestrel, a method for producing the same, and a pharmaceutical composition.
  • Levonorgestrel (17 ⁇ -hydroxy-18a-homo-19-nor-17 ⁇ -pregna-4-en-20-in-3-one) is known as a steroidal compound that exhibits a contraceptive effect mainly due to ovulation inhibition. It is sold as an emergency contraceptive in countries around the world, including Japan, the United States and Europe.
  • Patent Document 1 discloses a levonorgestrel crystal specified by a powder X-ray diffraction chart. This document discloses a method for producing levonorgestrel crystals by slowly adding water to a solution of levonorgestrel dissolved in methanol at reflux temperature and then cooling. Further, it is also disclosed that n-heptane is added to an ethyl acetate solution of levonorgestrel and cooled, or that a levonorgestrel crystal is produced by a method of cooling a methanol solution of levonorgestrel.
  • an object of the present invention is to provide a novel form of levonorgestrel excellent in solubility, a method for producing the same, and a pharmaceutical composition.
  • Another object of the present invention is to provide a solid dispersion of levonorgestrel having excellent solubility and stability, a method for producing the same, and a pharmaceutical composition.
  • levonorgestrel in order to produce amorphous levonorgestrel, the present inventors tried a spray drying method known as a general method for producing an amorphous drug.
  • a spray drying method known as a general method for producing an amorphous drug.
  • levonorgestrel since levonorgestrel is extremely easy to crystallize, even if a solution of levonorgestrel was spray-dried, amorphous levonorgestrel could not be obtained.
  • the present inventors have found that levonorgestrel can be obtained by hydrolyzing the imino form of levonorgestrel, despite the fact that levonorgestrel is a compound that is extremely easily crystallized.
  • the amorphous levonorgestrel of the present invention has an exothermic peak at 51 to 61 ° C. in the differential scanning calorimetry spectrum.
  • the present invention includes a solid dispersion in which levonorgestrel is dispersed in an amorphous form in a polymer.
  • the polymer may be a pharmacologically acceptable water-soluble polymer.
  • the present invention includes a method for producing an amorphous levonogestrel by hydrolyzing an imino form of levonogestrel iminized with ammonia or a primary amine, a solution containing levonogestrel, a polymer, and a solvent. And a method for producing the solid dispersion is also included.
  • the present invention also includes a pharmaceutical composition comprising amorphous levonorgestrel or the solid dispersion.
  • levonorgestrel is in an amorphous form, and thus has superior solubility compared to conventional crystals.
  • levonorgestrel is dispersed in an amorphous form, and is excellent in solubility and stability.
  • FIG. 1 is a graph showing a powder X-ray diffraction spectrum of amorphous levonorgestrel of Example 1.
  • FIG. 2 is a graph showing a differential scanning calorimetric spectrum of the amorphous levonorgestrel of Example 1.
  • FIG. 3 is a graph showing a powder X-ray diffraction spectrum of the amorphous levonorgestrel of Example 3.
  • FIG. 4 is a graph showing the solubility of the amorphous levonogestrel of Example 3 and the levonogestrel crystal of Comparative Example 1.
  • Amorphous levonorgestrel does not substantially have a diffraction peak derived from a crystal structure in a powder X-ray diffraction spectrum, and exhibits a halo diffraction pattern derived from scattering of incident X-rays.
  • amorphous levonorgestrel has an exothermic peak derived from crystal transition in the differential scanning calorimetry spectrum.
  • the exothermic peak may be, for example, about 51 to 61 ° C., preferably about 53 to 59 ° C. (for example, 55 to 57 ° C.).
  • powder X-ray diffraction spectrum and the differential scanning calorimetry spectrum can be measured by a conventional method, for example, the conditions of Examples described later.
  • the amorphous levonorgestrel may be in the form of a powder.
  • the average particle diameter is 0.01 to 500 ⁇ m, preferably about 0.1 to 300 ⁇ m (for example, 1 to 250 ⁇ m) based on a laser diffraction method. Usually, it may be about 0.1 to 50 ⁇ m (for example, 0.5 to 10 ⁇ m).
  • Amorphous levonorgestrel has high solubility and can improve bioavailability.
  • Amorphous levonorgestrel can be produced, for example, by iminating the 3-position oxo group ( ⁇ O) of levonorgestrel with ammonia or a primary amine and hydrolyzing the produced imino form.
  • the above-mentioned imino form can be produced by reacting levonorgestrel with ammonia or a primary amine in the presence or absence of a solvent and iminating levonorgestrel.
  • the levonorgestrel can be produced by a conventional method, for example, the method described in Synthetic Communications, 26, 1461-1465 (1996).
  • Examples of the primary amine include linear or branched C 1-6 alkylamines such as ethylamine, propylamine, isopropylamine, butylamine, isobutylamine, s-butylamine, and hexylamine; and C 4 such as cyclohexylamine.
  • C 1-6 alkylamines such as ethylamine, propylamine, isopropylamine, butylamine, isobutylamine, s-butylamine, and hexylamine; and C 4 such as cyclohexylamine.
  • a preferred primary amine may be a C 1-6 alkyl amine (eg, a C 1-4 alkyl amine such as ethylamine, propylamine, butylamine
  • the ratio (molar ratio) of levonorgestrel to ammonia or the primary amine is 1 equivalent or more (for example, 1 to 100 equivalents) of ammonia or primary amine, preferably 1.5 to 1 equivalent of levonorgestrel. It may be an equivalent or more (for example, 1.5 to 90 equivalent), more preferably 2 equivalent or more (for example, 2 to 80 equivalent).
  • the solvent examples include alcohols (alkanols such as ethanol, propanol and isopropanol; alkylene glycols such as ethylene glycol and propylene glycol) and hydrocarbons (aliphatic hydrocarbons such as hexane and alicyclic hydrocarbons such as cyclohexane).
  • alcohols alkanols such as ethanol, propanol and isopropanol
  • alkylene glycols such as ethylene glycol and propylene glycol
  • hydrocarbons aliphatic hydrocarbons such as hexane and alicyclic hydrocarbons such as cyclohexane
  • Aromatic hydrocarbons such as toluene and xylene), halogenated hydrocarbons (such as methylene chloride and chloroform), ethers (chain ethers such as dimethyl ether and diethyl ether, cyclic ethers such as dioxane and tetrahydrofuran), amides (N, N-dimethylformamide, N, N-dimethylacetamide etc.), sulfoxides (dimethylsulfoxide etc.), nitriles (acetonitrile, benzonitrile etc.) and the like. You may use a solvent individually or as a mixed solvent. If necessary, the primary amine may be used as a solvent.
  • the above imination reaction may be carried out in the presence of a catalyst, if necessary.
  • catalysts include Lewis acid catalysts such as acidic metal oxides (aluminum oxide, silicon dioxide, titanium dioxide, etc.), acidic metal halides (aluminum chloride, titanium tetrachloride, etc.), trimethylsilyl triflate, boron trifluoride diethyl ether, etc. Is mentioned.
  • the above imination reaction may be performed under heating.
  • the heating temperature is appropriately determined depending on the boiling points of the solvent and the iminating agent (such as the amines), and is not higher than the reflux temperature, for example, 30 to 100 ° C., preferably 35 to 75 ° C., more preferably about 40 to 60 ° C. It may be.
  • the reaction is usually carried out at a temperature below the boiling point of the iminating agent.
  • the produced imino form may be isolated by a conventional method such as extraction, distillation, concentration, drying, filtration, crystallization, or chromatography. Further, the above solution may be subjected to hydrolysis without isolating the imino form.
  • the above-mentioned imino form can be hydrolyzed in the presence of water.
  • the amount (molar ratio) of water is 1 equivalent or more (eg, 1 to 20 equivalents), preferably 1.5 equivalents or more (eg, 1.5 to 10 equivalents), more preferably 2 to 1 equivalent of the imino form. It may be equal to or more (for example, 2 to 5 equivalents).
  • the amount of water may preferably be a large excess with respect to the imino form.
  • Hydrolysis may be further performed in the presence of a catalyst.
  • the catalyst include inorganic acids such as hydrochloric acid, sulfuric acid, and phosphoric acid; organic acids such as carboxylic acids (such as acetic acid, trifluoroacetic acid, and fumaric acid), sulfonic acids (such as methanesulfonic acid and benzenesulfonic acid), and metal salts. It may be a solid acid such as (alumina, silica alumina, etc.), zeolite (mordenite, beta zeolite, etc.), and hydrochloric acid, sulfuric acid, etc. are preferred.
  • the catalyst may be used alone or in combination of two or more.
  • the hydrolysis temperature is not particularly limited as long as it is not higher than the reflux temperature, and the hydrolysis may be performed under ice cooling.
  • the hydrolysis temperature may be, for example, about ⁇ 10 ° C. to 100 ° C., preferably about ⁇ 5 ° C. to 80 ° C., more preferably about 0 ° C. to 60 ° C.
  • Amorphous levonorgestrel produced by hydrolysis may be isolated by conventional methods such as concentration, drying and filtration.
  • amorphous levonorgestrel may precipitate in the system.
  • the deposited amorphous levonorgestrel can be filtered, washed and dried as necessary, and isolated.
  • Solid dispersion In the solid dispersion of the present invention, levonorgestrel is dispersed in an amorphous form in the polymer.
  • the polymer may be a water-soluble polymer or a water-insoluble polymer.
  • the water-insoluble polymer may be an insoluble polymer, a gastric polymer, or an enteric polymer.
  • the water-soluble polymers for example, (such as methylcellulose) a water-soluble alkyl cellulose, carboxyalkyl cellulose (such as carboxymethyl cellulose) or a salt thereof (sodium carboxymethyl cellulose), hydroxyalkyl cellulose (hydroxyethyl cellulose, hydroxy C 2, such as hydroxypropylcellulose soluble starch, such as pregelatinized starch, partially pregelatinized starch; -4 alkyl cellulose), cellulose ethers such as hydroxyalkyl alkylcelluloses (such as hydroxypropyl C 2-4 alkyl C 1-4 alkyl celluloses such as hydroxypropyl methylcellulose); Natural such as gum arabic, pullulan, agar, tragacanth, sodium alginate, sodium hyaluronate Sugars; polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol, and the like synthetic polymers such as carboxyvinyl polymers.
  • hydroxyalkyl cellulose hydroxyeth
  • insoluble polymers examples include ethyl cellulose and polyvinyl acetate.
  • gastric soluble polymer examples include polyvinyl acetal diethylaminoacetate (AEA Sankyo, etc.), aminoalkyl methacrylate copolymers (Eudragit E, Eudragit RS, etc.) and the like.
  • enteric polymers examples include cellulose esters such as cellulose acetate phthalate, hydroxypropylmethylcellulose acetate phthalate, hydroxypropylmethylcellulose phthalate succinate; methacrylic acid-methyl methacrylate copolymers (Eudragit L, Eudragit S, etc.), methacrylic acid, and the like.
  • -Enteric acrylic polymers such as ethyl acrylate copolymer (such as Eudragit L30D-55) and ethyl acrylate-methyl methacrylate copolymer (such as Eudragit NE30D).
  • the preferred polymer can be selected from pharmacologically acceptable water-soluble polymers, gastric polymers and enteric polymers. More preferably, a water-soluble polymer, particularly cellulose ethers (for example, hydroxy C 2-3 alkyl cellulose such as hydroxypropyl cellulose, hydroxy C 2-3 alkyl C 1-2 alkyl cellulose such as hydroxypropylmethyl cellulose, etc.) is used. .
  • cellulose ethers for example, hydroxy C 2-3 alkyl cellulose such as hydroxypropyl cellulose, hydroxy C 2-3 alkyl C 1-2 alkyl cellulose such as hydroxypropylmethyl cellulose, etc.
  • the stability of levonorgestrel in the solid dispersion can be enhanced by using a polymer having a high glass transition temperature (Tg) as the polymer.
  • Tg glass transition temperature
  • the glass transition temperature of the polymer may be room temperature or higher, for example, 30 to 140 ° C., preferably 40 to 120 ° C., more preferably 50 to 100 ° C.
  • the above polymer is preferably a polymer having a low solution viscosity in order to improve the dissolution property of levonorgestrel.
  • the solution viscosity of the polymer is, for example, 500 mPa ⁇ s or less (eg, 400 mPa ⁇ s or less, 300 mPa ⁇ s or less, or 200 mPa ⁇ s or less) at a concentration of 2% by weight and a temperature of 20 ° C., preferably 100 mPa ⁇ s or less (for example, 1 to 70 mPa ⁇ s), more preferably 50 mPa ⁇ s or less (eg, 1.5 to 30 mPa ⁇ s), particularly 20 mPa ⁇ s or less (eg, 1.5 to 15 mPa ⁇ s), Usually, it is 10 mPa ⁇ s or less (for example, 2 to 10 mPa ⁇ s), particularly about 2 to 8 mPa
  • the solution viscosity can be measured with a capillary viscometer at a concentration of 2% by weight and a temperature of 20 ° C., and usually varies within a range of 70 to 150% (particularly 80 to 130%) around the viscosity value. It is said.
  • the value of the displayed viscosity includes such fluctuations.
  • the polymer is preferably a polymer having a low average molecular weight.
  • the weight average molecular weight of the polymer is, for example, 100,000 or less (for example, 1000 to 70000), preferably 50,000 or less (for example, 3000 to 30000) in terms of polystyrene as measured by GPC (gel permeation chromatography). Preferably, it may be about 20,000 or less (for example, 5000 to 15000).
  • the solid dispersion may be in the form of powder, and the average particle size may be the same as that of the above-mentioned amorphous levonorgestrel.
  • the solid dispersion because levonorgestrel is dispersed in molecular size, the solid dispersion improves the solubility of levonorgestrel and shows about twice the solubility compared to conventionally known crystals. Can be improved.
  • the solubility of levonorgestrel is about 15 to 40 ⁇ g / mL, preferably about 18 to 35 ⁇ g / mL, more preferably about 20 to 30 ⁇ g / mL. Also good.
  • the amorphous form can be stably maintained because the amorphous levonorgestrel is constrained by the polymer.
  • levonorgestrel is stably present in an amorphous form, for example, in a room temperature environment for 1 month or more, preferably 2 months or more, more preferably 3 months or more (for example, 6 months or more). Can be prevented.
  • the solid dispersion of the present invention can be produced by dissolving levonorgestrel and the polymer in a solvent at the same ratio as described above, and removing the solvent while preventing crystallization.
  • a solvent that can be used in the above-described method for producing amorphous levonorgestrel can be used.
  • alcohols ethanol, propanol, isopropanol, etc.
  • halogenated hydrocarbons methylene chloride, chloroform, etc.
  • ethers Dioxane, tetrahydrofuran, etc.
  • amides N, N-dimethylformamide, N, N-dimethylacetamide, etc.
  • sulfoxides dimethylsulfoxide, etc.
  • nitriles acetonitrile, benzonitrile, etc.
  • a mixed solvent thereof It may be.
  • the above dissolution may be performed under heating if necessary.
  • the heating temperature can be appropriately selected depending on the boiling point of the solvent, and may be not higher than the reflux temperature, for example, 30 to 100 ° C., preferably 35 to 75 ° C., more preferably about 40 to 60 ° C.
  • the solvent can be removed by a conventional method, for example, evaporation or distillation under normal pressure or reduced pressure, or spray drying. Further, the obtained solid dispersion may be washed and dried.
  • the obtained solid dispersion may be pulverized as necessary and sized to a desired particle size.
  • the amorphous levonorgestrel and solid dispersion of the present invention are suitably used as an emergency contraceptive, and may be used alone as a medicine, or in combination with a carrier (such as a pharmacologically or physiologically acceptable carrier). You may use as a composition (or formulation).
  • the carrier is appropriately 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, etc.), semi-solid preparations (creams, ointments, gels, gummies, film preparations, sheet preparations, etc.), liquids (solutions, suspensions, emulsions, syrups, elixirs, lotions) , Injections, drops, etc.).
  • the capsule may be 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 preparations are oral preparations (eg granules, powders, tablets (sublingual tablets, orally disintegrating tablets, etc.), capsules, syrups, emulsions, suspensions, jellies, gummies, film preparations, etc.). It may be a parenteral preparation (inhalant, transdermal preparation, nasal preparation, etc.).
  • the preparation may be a topical preparation (injection (subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, etc.), suspension, ointment, patch, patch, etc.) Good.
  • the carrier examples include Japanese Pharmacopoeia (Pharmacopoeia), (1) Pharmaceutical Additive Handbook, Maruzen Co., Ltd., (1989), (2) “Pharmaceutical Additives Encyclopedia 2007” (Pharmaceutical Daily Inc., 2007) Issued in July), (3) Pharmacy, revised 5th edition, Nanedo Co., Ltd. (1997), and (4) Pharmaceutical Additives Standard 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, Eudragit (meta Acrylic 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 (including a basic component such as dialkylaminoalkyl (meth) acrylate) ( Gastric soluble components composed of Eudragit etc.).
  • the preparation may 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, emulsifiers, dispersants, suspending agents, solubilizers, solubilizers, thickeners, pH adjusters.
  • buffering agents, 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, tonicity agents examples include soothing agents.
  • These additives can be used alone or in combination of two or more.
  • the pharmaceutical composition (or pharmaceutical preparation) of the present invention may contain other physiologically active ingredients or pharmacologically active ingredients (for example, estradiol, ethinyl estradiol, estradiol benzoate, estriol, estriol acetate benzoate, if necessary).
  • pharmacologically active ingredients for example, estradiol, ethinyl estradiol, estradiol benzoate, estriol, estriol acetate benzoate, if necessary.
  • follicular hormone agents such as acid esters).
  • 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 amorphous levonorgestrel and solid dispersion of the present invention have low toxicity and excellent safety, and human and non-human animals, usually mammals (eg, humans, mice, rats, rabbits, dogs, cats, It is safely administered to females such as cattle, 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 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.
  • differential scanning calorimetry spectrum The differential scanning calorific spectrum was measured using a differential scanning calorimeter (model: DSC8230L) under conditions of a heating rate of 10 ° C./min.
  • Example 1 2 mL of propylamine was added to 200 mg of levonorgestrel (Industriale Chimica), heated to 40 ° C. to dissolve levonorgestrel, and then allowed to stand at room temperature for 4 days to spontaneously evaporate propylamine.
  • levonorgestrel Industriale Chimica
  • FIG. 1 shows that the levonorgestrel contained in this solid is amorphous.
  • Example 2 15 mL of propylamine was added to 1 g of levonorgestrel (Industriale Chimica) and heated to reflux for 2 hours to obtain a solution. This solution was allowed to stand at room temperature for 2 days, and then propylamine in the solution was distilled off under reduced pressure to obtain a propylimino form of levonorgestrel.
  • levonorgestrel Industriale Chimica
  • Example 3 30 mg of levonorgestrel (Industriale Chimica) dissolved in 3 mL of chloroform, hydroxypropyl methylcellulose (“TC-5R” manufactured by Shin-Etsu Chemical Co., Ltd., concentration 2 wt%, aqueous solution viscosity 6 mPa ⁇ s at 20 ° C.) 90 mg was added and dissolved. Thereafter, chloroform was distilled off under reduced pressure, the residue was dried under reduced pressure, and then pulverized in a mortar to obtain a white powder.
  • TC-5R hydroxypropyl methylcellulose
  • FIG. 3 shows that this white powder is a solid dispersion containing levonorgestrel in an amorphous form.
  • Comparative Example 1 A commercially available crystal of levonorgestrel (Industriale Chimica) was used as Comparative Example 1.
  • Comparative Example 2 1 g of levonorgestrel (Industriale Chimica) was dissolved in 500 mL of ethanol. Then, using a spray drying device (“Pluvis Mini-Spray Model GS-31” manufactured by Yamato Scientific Co., Ltd.), the solution is spray dried under the conditions of drying medium: nitrogen gas, drying temperature: 90 ° C. to obtain a white powder. It was.
  • the amorphous levonorgestrel and solid dispersion of the present invention are suitably used as an emergency contraceptive.

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Abstract

　Provided are a new form of levonorgestrel, which is useful as an emergency contraception, etc., a solid dispersion of levonorgestrel, a manufacturing method for the same, and a drug composition.　The differential scanning calorimetry spectrum of this amorphous levonorgestrel has an exothermic peak at 51-61℃. This solid dispersion contains levonorgestrel dispersed in an amorphous state in a polymer. Said polymer may be a pharmaceutically acceptable water-soluble polymer. The weight ratio of the polymer to the levonorgestrel may be, in terms of polymer/levonorgestrel, 90/10-50/50.

Description

無定形レボノルゲストレル、固体分散体及びそれらの製造方法Amorphous levonorgestrel, solid dispersion and process for producing them
　本発明は、緊急避妊薬などとして有用な無定形レボノルゲストレル、レボノルゲストレルを含む固体分散体及びそれらの製造方法、並びに医薬組成物に関する。 The present invention relates to amorphous levonogestrel useful as an emergency contraceptive, a solid dispersion containing levonogestrel, a method for producing the same, and a pharmaceutical composition.
　レボノルゲストレル（１７β－ヒドロキシ－１８ａ－ホモ－１９－ノル－１７α－プレグナ－４－エン－２０－イン－３－オン）は、主に排卵抑制作用により避妊効果を示すステロイド化合物として知られており、日本や米国、欧州を含む世界各国において緊急避妊薬として販売されている。 Levonorgestrel (17β-hydroxy-18a-homo-19-nor-17α-pregna-4-en-20-in-3-one) is known as a steroidal compound that exhibits a contraceptive effect mainly due to ovulation inhibition. It is sold as an emergency contraceptive in countries around the world, including Japan, the United States and Europe.
　ＷＯ２００９／０３５５２７号公報（特許文献１）には、粉末Ｘ線回折チャートで特定されたレボノルゲストレル結晶が開示されている。この文献には、還流温度のメタノールにレボノルゲストレルを溶解した溶液に、水をゆっくりと加え、その後冷却することにより、レボノルゲストレルの結晶を製造する方法が開示されている。また、レボノルゲストレルの酢酸エチル溶液にｎ－ヘプタンを加えて冷却する方法や、レボノルゲストレルのメタノール溶液を冷却する方法によりレボノルゲストレルの結晶を製造することについても開示されている。 WO 2009/035527 (Patent Document 1) discloses a levonorgestrel crystal specified by a powder X-ray diffraction chart. This document discloses a method for producing levonorgestrel crystals by slowly adding water to a solution of levonorgestrel dissolved in methanol at reflux temperature and then cooling. Further, it is also disclosed that n-heptane is added to an ethyl acetate solution of levonorgestrel and cooled, or that a levonorgestrel crystal is produced by a method of cooling a methanol solution of levonorgestrel.
　しかし、これらの結晶は、溶解性が低いという問題がある。 However, these crystals have a problem of low solubility.
ＷＯ２００９／０３５５２７号公報（特許請求の範囲、実施例、図４）WO2009 / 035527 (Claims, Examples, FIG. 4)
　従って、本発明の目的は、溶解性に優れたレボノルゲストレルの新規形態及びその製造方法、並びに医薬組成物を提供することにある。 Therefore, an object of the present invention is to provide a novel form of levonorgestrel excellent in solubility, a method for producing the same, and a pharmaceutical composition.
　本発明の他の目的は、溶解性及び安定性に優れたレボノルゲストレルの固体分散体及びその製造方法、並びに医薬組成物を提供することにある。 Another object of the present invention is to provide a solid dispersion of levonorgestrel having excellent solubility and stability, a method for producing the same, and a pharmaceutical composition.
　まず、本発明者らは、無定形のレボノルゲストレルを製造するため、無定形薬剤を製造する一般的方法として知られているスプレードライ法を試みた。しかし、レボノルゲストレルは極めて結晶化しやすいため、レボノルゲストレルの溶液をスプレードライしても、無定形のレボノルゲストレルを得ることはできなかった。本発明者らは、前記課題を達成するため鋭意検討した結果、レボノルゲストレルが極めて結晶化しやすい化合物であるにもかかわらず、（１）レボノルゲストレルのイミノ体を加水分解することにより、レボノルゲストレルが無定形の形態で得られること、（２）レボノルゲストレルとポリマーとを含む溶液から溶媒を除去することにより、レボノルゲストレルが無定形の形態で分散した固体分散体が得られること、これらの無定形レボノルゲストレル及び固体分散体は溶解性に優れていることを見いだし、本発明を完成した。 First, in order to produce amorphous levonorgestrel, the present inventors tried a spray drying method known as a general method for producing an amorphous drug. However, since levonorgestrel is extremely easy to crystallize, even if a solution of levonorgestrel was spray-dried, amorphous levonorgestrel could not be obtained. As a result of intensive studies to achieve the above-mentioned problems, the present inventors have found that levonorgestrel can be obtained by hydrolyzing the imino form of levonorgestrel, despite the fact that levonorgestrel is a compound that is extremely easily crystallized. Obtained in an amorphous form, (2) a solid dispersion in which levonorgestrel is dispersed in an amorphous form is obtained by removing the solvent from the solution containing levonorgestrel and the polymer, and these amorphous forms It was found that levonorgestrel and solid dispersion were excellent in solubility, and the present invention was completed.
　すなわち、本発明の無定形レボノルゲストレルは、示差走査熱量スペクトルにおいて、５１～６１℃に発熱ピークを有する。 That is, the amorphous levonorgestrel of the present invention has an exothermic peak at 51 to 61 ° C. in the differential scanning calorimetry spectrum.
　本発明には、ポリマーにレボノルゲストレルが無定形の形態で分散している固体分散体も含まれる。前記ポリマーは、薬理学的に許容可能な水溶性ポリマーであってもよい。前記ポリマーとレボノルゲストレルとの重量比は、ポリマー／レボノルゲストレル＝９０／１０～５０／５０程度であってもよい。 The present invention includes a solid dispersion in which levonorgestrel is dispersed in an amorphous form in a polymer. The polymer may be a pharmacologically acceptable water-soluble polymer. The weight ratio of the polymer to levonorgestrel may be about polymer / levonogestrel = 90/10 to 50/50.
　本発明には、アンモニア又は第１級アミンによりイミノ化したレボノルゲストレルのイミノ体を加水分解し、無定形レボノルゲストレルを製造する方法と、レボノルゲストレルと、ポリマーと、溶媒とを含む溶液から前記溶媒を除去し、前記固体分散体を製造する方法も含まれる。 The present invention includes a method for producing an amorphous levonogestrel by hydrolyzing an imino form of levonogestrel iminized with ammonia or a primary amine, a solution containing levonogestrel, a polymer, and a solvent. And a method for producing the solid dispersion is also included.
　さらに、本発明は、無定形レボノルゲストレル又は前記固体分散体を含む医薬組成物も包含する。 Furthermore, the present invention also includes a pharmaceutical composition comprising amorphous levonorgestrel or the solid dispersion.
　本発明では、レボノルゲストレルが無定形の形態であるため、従来の結晶と比較して溶解性に優れている。また、本発明の固体分散体は、レボノルゲストレルが無定形の形態で分散しており、溶解性及び安定性にも優れている。 In the present invention, levonorgestrel is in an amorphous form, and thus has superior solubility compared to conventional crystals. In the solid dispersion of the present invention, levonorgestrel is dispersed in an amorphous form, and is excellent in solubility and stability.
図１は、実施例１の無定形レボノルゲストレルの粉末Ｘ線回折スペクトルを示すグラフである。1 is a graph showing a powder X-ray diffraction spectrum of amorphous levonorgestrel of Example 1. FIG. 図２は、実施例１の無定形レボノルゲストレルの示差走査熱量スペクトルを示すグラフである。FIG. 2 is a graph showing a differential scanning calorimetric spectrum of the amorphous levonorgestrel of Example 1. 図３は、実施例３の無定形レボノルゲストレルの粉末Ｘ線回折スペクトルを示すグラフである。FIG. 3 is a graph showing a powder X-ray diffraction spectrum of the amorphous levonorgestrel of Example 3. 図４は、実施例３の無定形レボノルゲストレル及び比較例１のレボノルゲストレル結晶の溶解度を示すグラフである。FIG. 4 is a graph showing the solubility of the amorphous levonogestrel of Example 3 and the levonogestrel crystal of Comparative Example 1.
［無定形レボノルゲストレル］
　無定形レボノルゲストレルは、粉末Ｘ線回折スペクトルにおいて、結晶構造に由来する回折ピークを実質的に有しておらず、入射Ｘ線の散乱に由来するハロー回折パターンを示す。 [Amorphous Levonorgestrel]
Amorphous levonorgestrel does not substantially have a diffraction peak derived from a crystal structure in a powder X-ray diffraction spectrum, and exhibits a halo diffraction pattern derived from scattering of incident X-rays.
　また、無定形レボノルゲストレルは、示差走査熱量スペクトルにおいて、結晶転移に由来する発熱ピークを有している。前記発熱ピークは、例えば、５１～６１℃、好ましくは５３～５９℃（例えば、５５～５７℃）程度であってもよい。 In addition, amorphous levonorgestrel has an exothermic peak derived from crystal transition in the differential scanning calorimetry spectrum. The exothermic peak may be, for example, about 51 to 61 ° C., preferably about 53 to 59 ° C. (for example, 55 to 57 ° C.).
　なお、粉末Ｘ線回折スペクトル及び示差走査熱量スペクトルは、慣用の方法、例えば、後述の実施例の条件で測定できる。 Note that the powder X-ray diffraction spectrum and the differential scanning calorimetry spectrum can be measured by a conventional method, for example, the conditions of Examples described later.
　無定形レボノルゲストレルは、粉末状であってもよく、例えば、レーザー回折法に基づいて、平均粒子径が０．０１～５００μｍ、好ましくは０．１～３００μｍ（例えば、１～２５０μｍ）程度であってもよく、通常、０．１～５０μｍ（例えば、０．５～１０μｍ）程度であってもよい。 The amorphous levonorgestrel may be in the form of a powder. For example, the average particle diameter is 0.01 to 500 μm, preferably about 0.1 to 300 μm (for example, 1 to 250 μm) based on a laser diffraction method. Usually, it may be about 0.1 to 50 μm (for example, 0.5 to 10 μm).
　無定形レボノルゲストレルは、溶解性が高く、バイオアベイラビリティを向上できる。
（製造方法）
　無定形レボノルゲストレルは、例えば、レボノルゲストレルの３位のオキソ基（＝Ｏ）をアンモニア又は第１級アミンによりイミノ化し、生成したイミノ体を加水分解することにより製造できる。 Amorphous levonorgestrel has high solubility and can improve bioavailability.
(Production method)
Amorphous levonorgestrel can be produced, for example, by iminating the 3-position oxo group (═O) of levonorgestrel with ammonia or a primary amine and hydrolyzing the produced imino form.
　上記イミノ体は、溶媒の存在下または非存在下、レボノルゲストレルと、アンモニア又は第１級アミンとを反応させ、レボノルゲストレルをイミノ化することにより製造できる。前記レボノルゲストレルは、慣用の方法、例えば、Synthetic Communications, 26, 1461-1465(1996)に記載の方法などにより製造できる。 The above-mentioned imino form can be produced by reacting levonorgestrel with ammonia or a primary amine in the presence or absence of a solvent and iminating levonorgestrel. The levonorgestrel can be produced by a conventional method, for example, the method described in Synthetic Communications, 26, 1461-1465 (1996).
　上記第１級アミンは、例えば、エチルアミン、プロピルアミン、イソプロピルアミン、ブチルアミン、イソブチルアミン、ｓ－ブチルアミン、ヘキシルアミン等の直鎖状又は分岐鎖状Ｃ１－６アルキルアミン；シクロヘキシルアミン等のＣ４－１０シクロアルキルアミン；アニリンなどのＣ６－１０アリールアミン；ベンジルアミンなどのＣ６－１０アリールＣ１－４アルキルアミンなどが挙げられる。好ましい第１級アミンは、Ｃ１－６アルキルアミン（例えば、エチルアミン、プロピルアミン、ブチルアミンなどのＣ１－４アルキルアミン）であってもよい。上記第１級アミンは、単独で又は２種以上を使用してもよい。 Examples of the primary amine include linear or branched C 1-6 alkylamines such as ethylamine, propylamine, isopropylamine, butylamine, isobutylamine, s-butylamine, and hexylamine; and C 4 such as cyclohexylamine. -10 cycloalkylamine; C 6-10 arylamine such as aniline; C 6-10 arylC 1-4 alkylamine such as benzylamine and the like. A preferred primary amine may be a C 1-6 alkyl amine (eg, a C 1-4 alkyl amine such as ethylamine, propylamine, butylamine). The primary amines may be used alone or in combination of two or more.
　レボノルゲストレルとアンモニア又は上記第１級アミンとの比（モル比）は、レボノルゲストレル１当量に対し、アンモニア又は第１級アミンが１当量以上（例えば、１～１００当量）、好ましくは１．５当量以上（例えば、１．５～９０当量）、より好ましくは２当量以上（例えば、２～８０当量）であってもよい。 The ratio (molar ratio) of levonorgestrel to ammonia or the primary amine is 1 equivalent or more (for example, 1 to 100 equivalents) of ammonia or primary amine, preferably 1.5 to 1 equivalent of levonorgestrel. It may be an equivalent or more (for example, 1.5 to 90 equivalent), more preferably 2 equivalent or more (for example, 2 to 80 equivalent).
　上記溶媒は、例えば、アルコール類（エタノール、プロパノール、イソプロパノールなどのアルカノール；エチレングリコール、プロピレングリコールなどのアルキレングリコールなど）、炭化水素類（ヘキサンなどの脂肪族炭化水素、シクロヘキサンなどの脂環族炭化水素、トルエン、キシレンなどの芳香族炭化水素など）、ハロゲン化炭化水素類（塩化メチレン、クロロホルムなど）、エーテル類（ジメチルエーテル、ジエチルエーテルなどの鎖状エーテル、ジオキサン、テトラヒドロフランなどの環状エーテルなど）、アミド類（Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミドなど）、スルホキシド類（ジメチルスルホキシドなど）、ニトリル類（アセトニトリル、ベンゾニトリルなど）などが挙げられる。溶媒は単独で又は混合溶媒として使用してもよい。また、必要であれば、上記第１級アミンを溶媒として用いてもよい。 Examples of the solvent include alcohols (alkanols such as ethanol, propanol and isopropanol; alkylene glycols such as ethylene glycol and propylene glycol) and hydrocarbons (aliphatic hydrocarbons such as hexane and alicyclic hydrocarbons such as cyclohexane). , Aromatic hydrocarbons such as toluene and xylene), halogenated hydrocarbons (such as methylene chloride and chloroform), ethers (chain ethers such as dimethyl ether and diethyl ether, cyclic ethers such as dioxane and tetrahydrofuran), amides (N, N-dimethylformamide, N, N-dimethylacetamide etc.), sulfoxides (dimethylsulfoxide etc.), nitriles (acetonitrile, benzonitrile etc.) and the like. You may use a solvent individually or as a mixed solvent. If necessary, the primary amine may be used as a solvent.
　上記イミノ化反応は、必要であれば、触媒の存在下で行ってもよい。触媒としては、ルイス酸触媒、例えば、酸性金属酸化物（酸化アルミニウム、二酸化ケイ素、二酸化チタンなど）、酸性金属ハロゲン化物（塩化アルミニウム、四塩化チタンなど）、トリメチルシリルトリフラート、三フッ化ホウ素ジエチルエーテルなどが挙げられる。 The above imination reaction may be carried out in the presence of a catalyst, if necessary. Examples of catalysts include Lewis acid catalysts such as acidic metal oxides (aluminum oxide, silicon dioxide, titanium dioxide, etc.), acidic metal halides (aluminum chloride, titanium tetrachloride, etc.), trimethylsilyl triflate, boron trifluoride diethyl ether, etc. Is mentioned.
　上記イミノ化反応は、加熱下で行ってもよい。加熱温度は、上記溶媒及びイミノ化剤（前記アミン類など）の沸点によって適宜定められ、還流温度以下、例えば、３０～１００℃、好ましくは３５℃～７５℃、より好ましくは４０～６０℃程度であってもよい。反応は、通常、イミノ化剤の沸点以下の温度で行う場合が多い。 The above imination reaction may be performed under heating. The heating temperature is appropriately determined depending on the boiling points of the solvent and the iminating agent (such as the amines), and is not higher than the reflux temperature, for example, 30 to 100 ° C., preferably 35 to 75 ° C., more preferably about 40 to 60 ° C. It may be. The reaction is usually carried out at a temperature below the boiling point of the iminating agent.
　なお、生成したイミノ体は、抽出、蒸留、濃縮、乾固、ろ過、晶析、クロマトグラフィーなど慣用の方法で単離してもよい。また、イミノ体を単離することなく、上記溶液を加水分解に供してもよい。 The produced imino form may be isolated by a conventional method such as extraction, distillation, concentration, drying, filtration, crystallization, or chromatography. Further, the above solution may be subjected to hydrolysis without isolating the imino form.
　上記イミノ体の加水分解は、水の存在下で行うことができる。水の量（モル比）は、イミノ体１当量に対し、１当量以上（例えば、１～２０当量）、好ましくは１．５当量以上（例えば、１．５～１０当量）、より好ましくは２当量以上（例えば、２～５当量）であればよい。水の量は上記イミノ体に対し、好ましくは、大過剰量であってもよい。 The above-mentioned imino form can be hydrolyzed in the presence of water. The amount (molar ratio) of water is 1 equivalent or more (eg, 1 to 20 equivalents), preferably 1.5 equivalents or more (eg, 1.5 to 10 equivalents), more preferably 2 to 1 equivalent of the imino form. It may be equal to or more (for example, 2 to 5 equivalents). The amount of water may preferably be a large excess with respect to the imino form.
　加水分解は、さらに触媒の存在下で行ってもよい。触媒としては、例えば、塩酸、硫酸、リン酸などの無機酸；カルボン酸（酢酸、トリフルオロ酢酸、フマル酸など）、スルホン酸（メタンスルホン酸、ベンゼンスルホン酸など）などの有機酸、金属塩（アルミナ、シリカアルミナなど）、ゼオライト（モルデナイト、ベータゼオライトなど）などの固体酸などであってもよく、塩酸、硫酸などが好ましい。触媒は単独で又は２種以上を使用してもよい。 Hydrolysis may be further performed in the presence of a catalyst. Examples of the catalyst include inorganic acids such as hydrochloric acid, sulfuric acid, and phosphoric acid; organic acids such as carboxylic acids (such as acetic acid, trifluoroacetic acid, and fumaric acid), sulfonic acids (such as methanesulfonic acid and benzenesulfonic acid), and metal salts. It may be a solid acid such as (alumina, silica alumina, etc.), zeolite (mordenite, beta zeolite, etc.), and hydrochloric acid, sulfuric acid, etc. are preferred. The catalyst may be used alone or in combination of two or more.
　加水分解温度は、還流温度以下であれば特に限定されず、加水分解は氷冷下で行ってもよい。加水分解温度は、例えば、－１０℃～１００℃、好ましくは－５℃～８０℃、より好ましくは０℃～６０℃程度であってもよい。 The hydrolysis temperature is not particularly limited as long as it is not higher than the reflux temperature, and the hydrolysis may be performed under ice cooling. The hydrolysis temperature may be, for example, about −10 ° C. to 100 ° C., preferably about −5 ° C. to 80 ° C., more preferably about 0 ° C. to 60 ° C.
　加水分解により生成した無定形レボノルゲストレルは、濃縮、乾固、ろ過などの慣用の方法で単離してもよい。また、系中に無定形レボノルゲストレルが析出することがある。このような場合には、析出した無定形レボノルゲストレルをろ過し、必要により洗浄及び乾燥させて、単離することができる。 Amorphous levonorgestrel produced by hydrolysis may be isolated by conventional methods such as concentration, drying and filtration. In addition, amorphous levonorgestrel may precipitate in the system. In such a case, the deposited amorphous levonorgestrel can be filtered, washed and dried as necessary, and isolated.
　［固体分散体］
　本発明の固体分散体は、レボノルゲストレルがポリマーに無定形（アモルファス）の形態で分散している。前記ポリマーは、水溶性ポリマーであってもよく、水不溶性ポリマーであってもよい。また、水不溶性ポリマーは、不溶性ポリマー、胃溶性ポリマーあるいは腸溶性ポリマーであってもよい。 [Solid dispersion]
In the solid dispersion of the present invention, levonorgestrel is dispersed in an amorphous form in the polymer. The polymer may be a water-soluble polymer or a water-insoluble polymer. The water-insoluble polymer may be an insoluble polymer, a gastric polymer, or an enteric polymer.
　水溶性ポリマーとしては、例えば、水溶性アルキルセルロース（メチルセルロースなど）、カルボキシアルキルセルロース（カルボキシメチルセルロースなど）又はその塩（カルボキシメチルセルロースナトリウムなど）、ヒドロキシアルキルセルロース（ヒドロキシエチルセルロース、ヒドロキシプロピルセルロースなどのヒドロキシＣ２－４アルキルセルロースなど）、ヒドロキシアルキルアルキルセルロース（ヒドロキシプロピルメチルセルロースなどのヒドロキシＣ２－４アルキルＣ１－４アルキルセルロースなど）などのセルロースエーテル類；アルファ化デンプン、部分アルファ化デンプンなどの可溶性デンプン；アラビアゴム、プルラン、カンテン、トラガント、アルギン酸ナトリウム、ヒアルロン酸ナトリウムなどの天然多糖類；ポリビニルピロリドン、ポリビニルアルコール、ポリエチレングリコール、カルボキシビニルポリマーなどの合成高分子などが挙げられる。 The water-soluble polymers, for example, (such as methylcellulose) a water-soluble alkyl cellulose, carboxyalkyl cellulose (such as carboxymethyl cellulose) or a salt thereof (sodium carboxymethyl cellulose), hydroxyalkyl cellulose (hydroxyethyl cellulose, hydroxy C 2, such as hydroxypropylcellulose soluble starch, such as pregelatinized starch, partially pregelatinized starch; -4 alkyl cellulose), cellulose ethers such as hydroxyalkyl alkylcelluloses (such as hydroxypropyl C 2-4 alkyl C 1-4 alkyl celluloses such as hydroxypropyl methylcellulose); Natural such as gum arabic, pullulan, agar, tragacanth, sodium alginate, sodium hyaluronate Sugars; polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol, and the like synthetic polymers such as carboxyvinyl polymers.
　不溶性ポリマーとしては、例えば、エチルセルロース、ポリ酢酸ビニルなどが挙げられる。 Examples of insoluble polymers include ethyl cellulose and polyvinyl acetate.
　胃溶性ポリマーとしては、例えば、ポリビニルアセタールジエチルアミノアセテート（ＡＥＡ三共など）、アミノアルキルメタクリレート共重合体（オイドラギットＥ、オイドラギットＲＳなど）などが挙げられる。 Examples of the gastric soluble polymer include polyvinyl acetal diethylaminoacetate (AEA Sankyo, etc.), aminoalkyl methacrylate copolymers (Eudragit E, Eudragit RS, etc.) and the like.
　腸溶性ポリマーとしては、例えば、セルロースアセテートフタレート、ヒドロキシプロピルメチルセルロースアセテートフタレート、ヒドロキシプロピルメチルセルロースフタレートサクシネートなどのセルロースエステル類；メタクリル酸－メタクリル酸メチル共重合体（オイドラギットＬ、オイドラギットＳなど）、メタクリル酸－アクリル酸エチル共重合体（オイドラギットＬ３０Ｄ－５５など）、アクリル酸エチル－メタクリル酸メチル共重合体（オイドラギットＮＥ３０Ｄなど）などの腸溶性アクリル酸系ポリマー類などが挙げられる。 Examples of enteric polymers include cellulose esters such as cellulose acetate phthalate, hydroxypropylmethylcellulose acetate phthalate, hydroxypropylmethylcellulose phthalate succinate; methacrylic acid-methyl methacrylate copolymers (Eudragit L, Eudragit S, etc.), methacrylic acid, and the like. -Enteric acrylic polymers such as ethyl acrylate copolymer (such as Eudragit L30D-55) and ethyl acrylate-methyl methacrylate copolymer (such as Eudragit NE30D).
　上記ポリマーは、単独で又は二種以上組み合わせて使用してもよい。好ましい上記ポリマーは、薬理学的に許容可能な水溶性ポリマー、胃溶性ポリマー及び腸溶性ポリマーから選択できる。より好ましくは水溶性ポリマー、特にセルロースエーテル類（例えば、ヒドロキシプロピルセルロースなどのヒドロキシＣ２－３アルキルセルロース、ヒドロキシプロピルメチルセルロースなどのヒドロキシＣ２－３アルキルＣ１－２アルキルセルロースなど）が使用される。 You may use the said polymer individually or in combination of 2 or more types. The preferred polymer can be selected from pharmacologically acceptable water-soluble polymers, gastric polymers and enteric polymers. More preferably, a water-soluble polymer, particularly cellulose ethers (for example, hydroxy C 2-3 alkyl cellulose such as hydroxypropyl cellulose, hydroxy C 2-3 alkyl C 1-2 alkyl cellulose such as hydroxypropylmethyl cellulose, etc.) is used. .
　また、上記ポリマーとして、ガラス転移温度（Ｔｇ）の高いポリマーを用いることにより、固体分散体中のレボノルゲストレルの安定性を高めることができる。そのため、上記ポリマーのガラス転移温度は、室温以上、例えば、３０～１４０℃、好ましくは４０～１２０℃、より好ましくは５０～１００℃であってもよい。 Moreover, the stability of levonorgestrel in the solid dispersion can be enhanced by using a polymer having a high glass transition temperature (Tg) as the polymer. Therefore, the glass transition temperature of the polymer may be room temperature or higher, for example, 30 to 140 ° C., preferably 40 to 120 ° C., more preferably 50 to 100 ° C.
　上記ポリマーは、レボノルゲストレルの溶出性を向上させるため、溶液粘度が低いポリマーが好ましい。上記ポリマーの溶液粘度は、例えば、濃度２重量％及び温度２０℃において５００ｍＰａ・ｓ以下（例えば、４００ｍＰａ・ｓ以下、３００ｍＰａ・ｓ以下、又は２００ｍＰａ・ｓ以下）、好ましくは１００ｍＰａ・ｓ以下（例えば、１～７０ｍＰａ・ｓ）、さらに好ましくは５０ｍＰａ・ｓ以下（例えば、１．５～３０ｍＰａ・ｓ）、特に２０ｍＰａ・ｓ以下（例えば、１．５～１５ｍＰａ・ｓ）程度であってもよく、通常、１０ｍＰａ・ｓ以下（例えば、２～１０ｍＰａ・ｓ）、特に２～８ｍＰａ・ｓ程度である。なお、前記溶液粘度は、濃度２重量％及び温度２０℃において、毛細管粘度計により測定でき、通常、前記粘度の値を中心として７０～１５０％（特に、８０～１３０％）の範囲で変動すると言われている。本発明でも表示粘度の値はこのような変動を含むものとする。 The above polymer is preferably a polymer having a low solution viscosity in order to improve the dissolution property of levonorgestrel. The solution viscosity of the polymer is, for example, 500 mPa · s or less (eg, 400 mPa · s or less, 300 mPa · s or less, or 200 mPa · s or less) at a concentration of 2% by weight and a temperature of 20 ° C., preferably 100 mPa · s or less (for example, 1 to 70 mPa · s), more preferably 50 mPa · s or less (eg, 1.5 to 30 mPa · s), particularly 20 mPa · s or less (eg, 1.5 to 15 mPa · s), Usually, it is 10 mPa · s or less (for example, 2 to 10 mPa · s), particularly about 2 to 8 mPa · s. The solution viscosity can be measured with a capillary viscometer at a concentration of 2% by weight and a temperature of 20 ° C., and usually varies within a range of 70 to 150% (particularly 80 to 130%) around the viscosity value. It is said. In the present invention, the value of the displayed viscosity includes such fluctuations.
　また、上記ポリマーは、平均分子量が低いポリマーが好ましい。上記ポリマーの重量平均分子量は、ＧＰＣ（ゲルパーミエーションクロマトグラフィー）による測定においてポリスチレン換算で、例えば、１０万以下（例えば、１０００～７００００）、好ましくは５万以下（例えば、３０００～３００００）、より好ましくは２万以下（例えば、５０００～１５０００）程度であってもよい。 The polymer is preferably a polymer having a low average molecular weight. The weight average molecular weight of the polymer is, for example, 100,000 or less (for example, 1000 to 70000), preferably 50,000 or less (for example, 3000 to 30000) in terms of polystyrene as measured by GPC (gel permeation chromatography). Preferably, it may be about 20,000 or less (for example, 5000 to 15000).
　固体分散体に含まれるレボノルゲストレルとポリマーとの重量比は、例えば、レボノルゲストレル／ポリマー＝２／９８～６０／４０（例えば、５／９５～５０／５０）、より好ましくは１０／９０～５０／５０、さらに好ましくは１５／８５～４０／６０（例えば、２０／８０～３５／６５）程度であってもよい。ポリマーが少なすぎると、レボノルゲストレルが結晶化し易くなり、多すぎると、製剤処方及び投与スケジュール等に支障をきたす可能性がある。 The weight ratio of levonorgestrel and polymer contained in the solid dispersion is, for example, levonorgestrel / polymer = 2/98 to 60/40 (for example, 5/95 to 50/50), more preferably 10/90 to 50 / 50, more preferably about 15/85 to 40/60 (for example, 20/80 to 35/65). If the amount of the polymer is too small, the levonogestrel tends to crystallize, and if it is too large, the preparation formulation and administration schedule may be hindered.
　固体分散体は、粉末状であってもよく、平均粒子径は、前述の無定形レボノルゲストレルと同程度であってもよい。 The solid dispersion may be in the form of powder, and the average particle size may be the same as that of the above-mentioned amorphous levonorgestrel.
　固体分散体において、レボノルゲストレルが分子サイズで分散しているためか、固体分散体はレボノルゲストレルの溶解性を向上させ、従来公知の結晶に比べて２倍程度の溶解度を示すため、バイオアベイラビリティを向上できる。例えば、３７℃の１％Ｔｗｅｅｎ８０水溶液に固体分散体を溶解したとき、レボノルゲストレルの溶解度は、１５～４０μｇ／ｍＬ、好ましくは１８～３５μｇ／ｍＬ、さらに好ましくは２０～３０μｇ／ｍＬ程度であってもよい。 In the solid dispersion, because levonorgestrel is dispersed in molecular size, the solid dispersion improves the solubility of levonorgestrel and shows about twice the solubility compared to conventionally known crystals. Can be improved. For example, when the solid dispersion is dissolved in 1% Tween 80 aqueous solution at 37 ° C., the solubility of levonorgestrel is about 15 to 40 μg / mL, preferably about 18 to 35 μg / mL, more preferably about 20 to 30 μg / mL. Also good.
　また、固体分散体中では、無定形レボノルゲストレルがポリマーに拘束されているためか、無定形の形態を安定して維持できる。固体分散体中において、レボノルゲストレルは、例えば、室温環境下で１箇月以上、好ましくは２箇月以上、より好ましくは３箇月以上（例えば、６箇月以上）無定形の形態で安定に存在し、結晶化を防止できる。 In the solid dispersion, the amorphous form can be stably maintained because the amorphous levonorgestrel is constrained by the polymer. In the solid dispersion, levonorgestrel is stably present in an amorphous form, for example, in a room temperature environment for 1 month or more, preferably 2 months or more, more preferably 3 months or more (for example, 6 months or more). Can be prevented.
　（製造方法）
　本発明の固体分散体は、レボノルゲストレルと前記ポリマーとを、前記と同様の割合で溶媒に溶解し、結晶化を防ぎつつ溶媒を除去することにより製造することができる。溶媒は、前述の無定形レボノルゲストレルの製造方法で使用可能な溶媒を用いることができ、例えば、アルコール類（エタノール、プロパノール、イソプロパノールなど）、ハロゲン化炭化水素類（塩化メチレン、クロロホルムなど）、エーテル類（ジオキサン、テトラヒドロフランなど）、アミド類（Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミドなど）、スルホキシド類（ジメチルスルホキシドなど）、ニトリル類（アセトニトリル、ベンゾニトリルなど）、又はこれらの混合溶媒であってもよい。 (Production method)
The solid dispersion of the present invention can be produced by dissolving levonorgestrel and the polymer in a solvent at the same ratio as described above, and removing the solvent while preventing crystallization. As the solvent, a solvent that can be used in the above-described method for producing amorphous levonorgestrel can be used. For example, alcohols (ethanol, propanol, isopropanol, etc.), halogenated hydrocarbons (methylene chloride, chloroform, etc.), ethers (Dioxane, tetrahydrofuran, etc.), amides (N, N-dimethylformamide, N, N-dimethylacetamide, etc.), sulfoxides (dimethylsulfoxide, etc.), nitriles (acetonitrile, benzonitrile, etc.), or a mixed solvent thereof It may be.
　上記溶解は、必要により加熱下で行ってもよい。加熱温度は、上記溶媒の沸点によって適宜選択でき、還流温度以下、例えば、３０～１００℃、好ましくは３５℃～７５℃、より好ましくは４０～６０℃程度であってもよい。 The above dissolution may be performed under heating if necessary. The heating temperature can be appropriately selected depending on the boiling point of the solvent, and may be not higher than the reflux temperature, for example, 30 to 100 ° C., preferably 35 to 75 ° C., more preferably about 40 to 60 ° C.
　溶媒は、慣用の方法、例えば、常圧下又は減圧下の蒸発又は留去や、スプレードライなどの方法で除去できる。さらに、得られた固体分散体を洗浄し、乾燥させてもよい。 The solvent can be removed by a conventional method, for example, evaporation or distillation under normal pressure or reduced pressure, or spray drying. Further, the obtained solid dispersion may be washed and dried.
　なお、得られた固体分散体は、必要に応じて粉砕し、所望の粒子サイズに整粒してもよい。 In addition, the obtained solid dispersion may be pulverized as necessary and sized to a desired particle size.
　［用途および医薬組成物］
　本発明の無定形レボノルゲストレル及び固体分散体は、緊急避妊薬として好適に用いられ、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。 [Use and pharmaceutical composition]
The amorphous levonorgestrel and solid dispersion of the present invention are suitably used as an emergency contraceptive, and may be used alone as a medicine, or in combination with a carrier (such as a pharmacologically or physiologically acceptable carrier). You may use as a composition (or formulation).
　本発明の医薬組成物において、担体は、医薬組成物（又は製剤）の形態（すなわち、剤形）、投与形態、用途などに応じて、適宜選択される。剤形は特に制限されず、固形製剤（粉剤、散剤、粒剤（顆粒剤、細粒剤など）、丸剤、ピル、錠剤、カプセル剤（軟カプセル剤、硬カプセル剤など）、ドライシロップ剤、坐剤など）、半固形製剤（クリーム剤、軟膏剤、ゲル剤、グミ剤、フィルム状製剤、シート状製剤など）、液剤（溶液剤、懸濁剤、乳剤、シロップ剤、エリキシル剤、ローション剤、注射剤、点滴剤など）などであってもよい。また、前記粉剤及び／又は液剤などのスプレー剤、エアゾール剤なども含まれる。なお、カプセル剤は、液体充填カプセルであってもよく、顆粒剤などの固形剤を充填したカプセルであってもよい。また、製剤は凍結乾燥製剤であってもよい。さらに、本発明の製剤は、薬剤の放出速度が制御された製剤（徐放性製剤、速放性製剤）であってもよい。また、製剤は経口投与製剤（顆粒剤、散剤、錠剤（舌下錠、口腔内崩壊錠など）、カプセル剤、シロップ剤、乳剤、懸濁剤、ゼリー剤、グミ剤、フィルム製剤など）であってもよく、非経口投与製剤（吸入剤、経皮投与製剤、経鼻投与製剤など）であってもよい。さらに、製剤は局所投与製剤（注射剤（皮下注射剤、静脈内注射剤、筋肉内注射剤、腹腔内注射剤など）、懸濁剤、軟膏剤、貼付剤、パップ剤など）であってもよい。 In the pharmaceutical composition of the present invention, the carrier is appropriately 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, etc.), semi-solid preparations (creams, ointments, gels, gummies, film preparations, sheet preparations, etc.), liquids (solutions, suspensions, emulsions, syrups, elixirs, lotions) , Injections, drops, etc.). Also included are sprays such as the powders and / or liquids, aerosols and the like. The capsule may be a liquid-filled capsule or a capsule filled with a solid agent such as a granule. The preparation may be a lyophilized preparation. Furthermore, the preparation of the present invention may be a preparation with controlled drug release rate (sustained release preparation, immediate release preparation). The preparations are oral preparations (eg granules, powders, tablets (sublingual tablets, orally disintegrating tablets, etc.), capsules, syrups, emulsions, suspensions, jellies, gummies, film preparations, etc.). It may be a parenteral preparation (inhalant, transdermal preparation, nasal preparation, etc.). Furthermore, the preparation may be a topical preparation (injection (subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, etc.), suspension, ointment, patch, patch, etc.) Good.
　前記担体は、例えば、日本薬局方（局方）の他、（１）医薬品添加物ハンドブック、丸善（株）、（１９８９）、（２）「医薬品添加物事典２００７」（薬事日報社、２００７年７月発行）、（３）薬剤学、改訂第５版、（株）南江堂（１９９７）、及び（４）医薬品添加物規格２００３（薬事日報社、２００３年８月）などに収載されている成分（例えば、賦形剤、結合剤、崩壊剤、滑沢剤、コーティング剤など）の中から、投与経路及び製剤用途に応じて選択できる。例えば、固形製剤の担体としては、賦形剤、結合剤および崩壊剤から選択された少なくとも一種の担体を使用する場合が多い。また、医薬組成物は脂質を含んでいてもよい。 Examples of the carrier include Japanese Pharmacopoeia (Pharmacopoeia), (1) Pharmaceutical Additive Handbook, Maruzen Co., Ltd., (1989), (2) “Pharmaceutical Additives Encyclopedia 2007” (Pharmaceutical Daily Inc., 2007) Issued in July), (3) Pharmacy, revised 5th edition, Nanedo Co., Ltd. (1997), and (4) Pharmaceutical Additives Standard 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. For example, as 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.
　前記賦形剤としては、乳糖、ブドウ糖、ショ糖、マンニトール、ソルビトール、キシリトールなどの糖類又は糖アルコール類；トウモロコシデンプンなどのデンプン；結晶セルロース（微結晶セルロースも含む）などの多糖類；軽質無水ケイ酸などの酸化ケイ素又はケイ酸塩などが例示できる。結合剤としては、アルファ化デンプン、部分アルファ化デンプンなどの可溶性デンプン；アラビアゴム、デキストリン、アルギン酸ナトリウムなどの多糖類；ポリビニルピロリドン（ＰＶＰ）、ポリビニルアルコール（ＰＶＡ）、カルボキシビニルポリマー、ポリアクリル酸系ポリマー、ポリ乳酸、ポリエチレングリコールなどの合成高分子；メチルセルロース（ＭＣ）、エチルセルロース（ＥＣ）、カルボキシメチルセルロース（ＣＭＣ）、カルボキシメチルセルロースナトリウム、ヒドロキシエチルセルロース（ＨＥＣ）、ヒドロキシプロピルセルロース（ＨＰＣ）、ヒドロキシプロピルメチルセルロース（ＨＰＭＣ）などのセルロースエーテル類などが例示できる。崩壊剤としては、カルボキシメチルスターチナトリウム、カルメロース、カルメロースナトリウム、カルメロースカルシウム、クロスカルメロースナトリウム、クロスポビドン、低置換度ヒドロキシプロピルセルロースなどが例示できる。これらの担体は、単独で又は二種以上組み合わせて使用できる。 Examples of the excipient 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. As a binder, 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). Examples of the disintegrant 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.
　なお、前記コーティング剤としては、例えば、糖類、エチルセルロース、ヒドロキシメチルセルロースなどのセルロース誘導体、ポリオキシエチレングリコール、セルロースアセテートフタレート、ヒドロキシプロピルメチルセルロースフタレート、メチルメタクリレート－（メタ）アクリル酸共重合体、オイドラギット（メタアクリル酸・アクリル酸共重合物）などが用いられる。コーティング剤は、セルロースフタレート、ヒドロキシプロピルメチルセルロースフタレート、メチルメタクリレート－（メタ）アクリル酸共重合体などの腸溶性成分であってもよく、ジアルキルアミノアルキル（メタ）アクリレートなどの塩基性成分を含むポリマー（オイドラギットなど）で構成された胃溶性成分であってもよい。また、製剤は、これらの腸溶性成分や胃溶性成分を剤皮に含むカプセル剤であってもよい。 Examples of the coating agent 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, Eudragit (meta Acrylic 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 (including a basic component such as dialkylaminoalkyl (meth) acrylate) ( Gastric soluble components composed of Eudragit etc.). In addition, the preparation may be a capsule containing these enteric components and gastric components in the skin.
　製剤においては、投与経路や剤形などに応じて、公知の添加剤を適宜使用することができる。このような添加剤としては、例えば、滑沢剤、崩壊補助剤、抗酸化剤又は酸化防止剤、乳化剤、分散剤、懸濁化剤、溶解剤、溶解補助剤、増粘剤、ｐＨ調整剤又は緩衝剤、安定剤、防腐剤又は保存剤、殺菌剤又は抗菌剤、帯電防止剤、矯味剤又はマスキング剤、着色剤、矯臭剤又は香料、清涼化剤、消泡剤、等張化剤、無痛化剤などが挙げられる。これらの添加剤は単独で又は二種以上組み合わせて使用できる。 In the preparation, known additives can be appropriately used depending on the administration route, dosage form and the like. Examples of such additives include lubricants, disintegration aids, antioxidants or antioxidants, emulsifiers, dispersants, suspending agents, solubilizers, solubilizers, thickeners, pH adjusters. Or buffering agents, 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, tonicity agents, Examples include soothing agents. These additives can be used alone or in combination of two or more.
　なお、本発明の医薬組成物（又は医薬製剤）は、必要に応じて、他の生理活性成分又は薬理活性成分（例えば、エストラジオール、エチニルエストラジオール、エストラジオール安息香酸エステル、エストリオール、エストリオール酢酸エステル安息香酸エステルなどの卵胞ホルモン剤など）を含んでいてもよい。 The pharmaceutical composition (or pharmaceutical preparation) of the present invention may contain other physiologically active ingredients or pharmacologically active ingredients (for example, estradiol, ethinyl estradiol, estradiol benzoate, estriol, estriol acetate benzoate, if necessary). And follicular hormone agents such as acid esters).
　本発明の医薬組成物は、有効成分の他、担体成分、必要により添加剤などを用いて、慣用の製剤化方法、例えば、第十六改正日本薬局方記載の製造法又はこの製造方法に準じた方法により調製できる。 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.
　本発明の無定形レボノルゲストレル及び固体分散体は、毒性も低く、その安全性も優れており、ヒト及び非ヒト動物、通常、哺乳動物（例えば、ヒト、マウス、ラット、ウサギ、イヌ、ネコ、ウシ、ウマ、ブタ、サルなど）の雌に対して、安全に投与される。投与量は、投与対象の種、年齢、体重、及び状態（一般的状態、病状、合併症の有無など）、投与時間、剤形、投与方法などに応じて、選択できる。例えば、ヒトに対する投与量（１日用量）は、例えば、０．０１～５０ｍｇ／日、好ましくは０．０５～１０ｍｇ／日（例えば、０．５～５ｍｇ／日）程度である。 The amorphous levonorgestrel and solid dispersion of the present invention have low toxicity and excellent safety, and human and non-human animals, usually mammals (eg, humans, mice, rats, rabbits, dogs, cats, It is safely administered to females such as cattle, 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. For example, 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).
　投与方法は、経口投与であってもよく、局所投与又は非経口投与（例えば、皮下投与、筋肉内投与、直腸投与、膣投与など）であってもよい。 The administration method may be oral administration, local administration or parenteral administration (for example, subcutaneous administration, intramuscular administration, rectal administration, vaginal administration, etc.).
　投与回数は、特に制限されず、例えば、１日１回であってもよく、必要に応じて１日複数回（例えば、２～３回）であってもよい。 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.
　以下に、実施例に基づいて本発明をより詳細に説明するが、本発明はこれらの実施例によって限定されるものではない。 Hereinafter, the present invention will be described in more detail based on examples, but the present invention is not limited to these examples.
　［粉末Ｘ線回折スペクトル］
　粉末Ｘ線回折スペクトルは、線源：Ｃｕ Ｋ（α１）、管電圧：４０ｋＶ、管電流：４０ｍＡ、サンプリング間隔：０．０１°、スキャン速度１０°／分の条件で測定した。なお、粉末Ｘ線回折チャートにおいて、回折ピークは、ピーク幅の閾値を０．１°として、二次微分法によりサーチした。 [Powder X-ray diffraction spectrum]
The powder X-ray diffraction spectrum was measured under the conditions of radiation source: Cu K (α1), tube voltage: 40 kV, tube current: 40 mA, sampling interval: 0.01 °, and scan rate of 10 ° / min. In the powder X-ray diffraction chart, the diffraction peak was searched by the second derivative method with the peak width threshold being 0.1 °.
　［示差走査熱量スペクトル］
　示差走査熱量スペクトルは、示差走査熱量計（型式：ＤＳＣ８２３０Ｌ）を用いて、昇温速度１０℃／分の条件で測定した。 [Differential scanning calorimetry spectrum]
The differential scanning calorific spectrum was measured using a differential scanning calorimeter (model: DSC8230L) under conditions of a heating rate of 10 ° C./min.
　実施例１
　レボノルゲストレル（Industriale Chimica社製）２００ｍｇにプロピルアミン２ｍＬを加え、４０℃に加熱してレボノルゲストレルを溶解させた後、室温で４日間放置して、プロピルアミンを自然蒸発させた。 Example 1
2 mL of propylamine was added to 200 mg of levonorgestrel (Industriale Chimica), heated to 40 ° C. to dissolve levonorgestrel, and then allowed to stand at room temperature for 4 days to spontaneously evaporate propylamine.
　残渣をＮ，Ｎ－ジメチルホルムアミド４ｍＬに溶解し、得られた溶液を氷水４０ｍＬに投入した後、室温で１５分間攪拌した。その後、氷水中に析出した黄褐色の固体をろ取した。 The residue was dissolved in 4 mL of N, N-dimethylformamide, and the resulting solution was poured into 40 mL of ice water and stirred at room temperature for 15 minutes. Thereafter, a tan solid precipitated in ice water was collected by filtration.
　得られた黄褐色固体の粉末Ｘ線回折スペクトルの測定結果を図１に示す。図１より、この固体に含まれるレボノルゲストレルは無定形であることがわかる。 The measurement result of the powder X-ray diffraction spectrum of the obtained tan solid is shown in FIG. FIG. 1 shows that the levonorgestrel contained in this solid is amorphous.
　また、得られた黄褐色固体の示差走査熱量スペクトルを、示差走査熱量計にて測定した。測定結果を図２に示す。 Moreover, the differential scanning calorific spectrum of the obtained tan solid was measured with a differential scanning calorimeter. The measurement results are shown in FIG.
　実施例２
　レボノルゲストレル（Industriale Chimica社製）１ｇにプロピルアミン１５ｍＬを加え、２時間加熱還流して溶液を得た。この溶液を室温で２日間放置した後、溶液中のプロピルアミンを減圧留去して、レボノルゲストレルのプロピルイミノ体を得た。 Example 2
15 mL of propylamine was added to 1 g of levonorgestrel (Industriale Chimica) and heated to reflux for 2 hours to obtain a solution. This solution was allowed to stand at room temperature for 2 days, and then propylamine in the solution was distilled off under reduced pressure to obtain a propylimino form of levonorgestrel.
　上記プロピルイミノ体のうち５０ｍｇをプロピルアミン０．５ｍＬに溶解し、得られた溶液を氷水１０ｍＬに添加した後、室温で２時間攪拌した。その後、氷水中に析出した黄褐色の固体をろ取した。 50 mg of the propylimino compound was dissolved in 0.5 mL of propylamine, and the resulting solution was added to 10 mL of ice water, followed by stirring at room temperature for 2 hours. Thereafter, a tan solid precipitated in ice water was collected by filtration.
　得られた黄褐色固体の粉末Ｘ線回折スペクトルを測定したところ、図１と同様の結果が得られたことから、この固体に含まれるレボノルゲストレルは無定形であることがわかる。 When the powder X-ray diffraction spectrum of the obtained tan solid was measured, the same results as in FIG. 1 were obtained, and thus it was found that levonorgestrel contained in this solid was amorphous.
　実施例３
　レボノルゲストレル（Industriale Chimica社製）３０ｍｇをクロロホルム３ｍＬに溶解し、ヒドロキシプロピルメチルセルロース（信越化学工業（株）社製「ＴＣ－５Ｒ」、濃度２重量％及び温度２０℃における水溶液粘度６ｍＰａ・ｓ）９０ｍｇを添加して溶解した。その後、クロロホルムを減圧留去し、残渣を減圧乾燥した後、乳鉢で粉砕することにより、白色粉末を得た。 Example 3
30 mg of levonorgestrel (Industriale Chimica) dissolved in 3 mL of chloroform, hydroxypropyl methylcellulose (“TC-5R” manufactured by Shin-Etsu Chemical Co., Ltd., concentration 2 wt%, aqueous solution viscosity 6 mPa · s at 20 ° C.) 90 mg Was added and dissolved. Thereafter, chloroform was distilled off under reduced pressure, the residue was dried under reduced pressure, and then pulverized in a mortar to obtain a white powder.
　得られた白色粉末の粉末Ｘ線回折スペクトルの測定結果を図３に示す。図３より、この白色粉末はレボノルゲストレルを無定形の形態で含む固体分散体であることがわかる。 The measurement result of the powder X-ray diffraction spectrum of the obtained white powder is shown in FIG. FIG. 3 shows that this white powder is a solid dispersion containing levonorgestrel in an amorphous form.
　比較例１
　市販のレボノルゲストレル（Industriale Chimica社製）の結晶を比較例１とした。 Comparative Example 1
A commercially available crystal of levonorgestrel (Industriale Chimica) was used as Comparative Example 1.
　比較例２
　レボノルゲストレル（Industriale Chimica社製）１ｇをエタノール５００ｍＬに溶解した。その後、噴霧乾燥装置（ヤマト科学株式会社製「Pluvis Mini-Spray Model GS-31」）を用いて、乾燥媒体：窒素ガス、乾燥温度：９０℃の条件で溶液を噴霧乾燥し、白色粉末を得た。 Comparative Example 2
1 g of levonorgestrel (Industriale Chimica) was dissolved in 500 mL of ethanol. Then, using a spray drying device (“Pluvis Mini-Spray Model GS-31” manufactured by Yamato Scientific Co., Ltd.), the solution is spray dried under the conditions of drying medium: nitrogen gas, drying temperature: 90 ° C. to obtain a white powder. It was.
　得られた白色粉末の粉末Ｘ線回折スペクトルを測定したところ、ＷＯ２００９／０３５５２７号公報で公知の結晶であり、無定形レボノルゲストレルは得られなかった。 When a powder X-ray diffraction spectrum of the obtained white powder was measured, it was a known crystal in WO2009 / 035527, and amorphous levonorgestrel was not obtained.
　［溶解度及び溶解速度測定］
　実施例３の固体分散体の粉末１０ｍｇ（レボノルゲストレルを２．５ｍｇ含む）又は比較例１の結晶粉末２．５ｍｇとヒドロキシプロピルメチルセルロース７．５ｍｇとを均一にした混合物１０ｍｇを、３７℃の１％Ｔｗｅｅｎ８０水溶液４０ｍＬに添加し、試験液を攪拌しつつ、添加から一定時間毎に２ｍＬをサンプリングし、クロマトディスク（孔径０．２μｍ）でろ過し、高性能液体クロマトグラフ（装置：島津製作所製「ＬＣ－２０１０ＡＨＴ」、検出器：ＵＶ２４０ｎｍ、カラム：ウォーターズ社製「ＸＢｒｉｄｇｅ　Ｃ１８　５μｍ」、カラム温度：３５℃付近の一定温度、移動相：アセトニトリル／０．１％トリフルオロ酢酸水溶液の混液（３：２））によりろ液のレボノルゲストレル濃度を測定した。結果を表１及び図４に示す。 [Measurement of solubility and dissolution rate]
10 mg of a powder of the solid dispersion of Example 3 (including 2.5 mg of levonorgestrel) or 10 mg of a mixture of 2.5 mg of the crystal powder of Comparative Example 1 and 7.5 mg of hydroxypropylmethylcellulose were mixed with 1% at 37 ° C. Add to 40 mL of Tween 80 aqueous solution and sample 2 mL at regular intervals from the addition while stirring the test solution, filter through a chromatographic disk (pore size 0.2 μm), and use a high performance liquid chromatograph (equipment: “LC” manufactured by Shimadzu Corporation) −2010AHT ”, detector: UV 240 nm, column:“ X Bridge C18 5 μm ”manufactured by Waters, column temperature: constant temperature around 35 ° C., mobile phase: acetonitrile / 0.1% trifluoroacetic acid aqueous solution (3: 2) ) To measure the levonorgestrel concentration in the filtrate. The results are shown in Table 1 and FIG.
Figure JPOXMLDOC01-appb-T000001
Figure JPOXMLDOC01-appb-T000001
　表１及び図４から明らかなように、１分後のレボノルゲストレル濃度を比較することにより、実施例３の固体分散体は、比較例１の結晶に比べて、１６倍の速さで溶解していることがわかる。また、比較例１の結晶及び実施例３の固体分散体の最大濃度を比較すると、実施例３の固体分散体は、比較例１の結晶の２倍の溶解度を示すことがわかる。さらに、比較例１の結晶では、添加から２４０分後に最大濃度となるのに対し、実施例３の固体分散体では、添加から３０分後に最大濃度となることから、実施例３の固体分散体は、比較例１の結晶の８倍の速さで最大濃度に到達することがわかる。 As is clear from Table 1 and FIG. 4, by comparing the levonogestrel concentration after 1 minute, the solid dispersion of Example 3 was dissolved 16 times faster than the crystals of Comparative Example 1. You can see that Further, comparing the maximum concentration of the crystals of Comparative Example 1 and the solid dispersion of Example 3, it can be seen that the solid dispersion of Example 3 exhibits twice the solubility of the crystals of Comparative Example 1. Further, in the crystal of Comparative Example 1, the maximum concentration is obtained 240 minutes after the addition, whereas in the solid dispersion of Example 3, the maximum concentration is obtained 30 minutes after the addition. Therefore, the solid dispersion of Example 3 is obtained. It can be seen that the maximum concentration is reached 8 times faster than the crystal of Comparative Example 1.
　なお、実施例３の固体分散体の測定において、添加から３０分を過ぎるとレボノルゲストレル濃度が緩やかに低下しているのは、測定系において粒子状の固体分散体の凝集が生じたことに起因すると考えられる。 In addition, in the measurement of the solid dispersion of Example 3, the levonorgestrel concentration gradually decreased after 30 minutes from the addition because the aggregation of the particulate solid dispersion occurred in the measurement system. It is thought that.
　本発明の無定形レボノルゲストレル及び固体分散体は、緊急避妊剤などとして好適に用いられる。 The amorphous levonorgestrel and solid dispersion of the present invention are suitably used as an emergency contraceptive.

Claims (7)

  1. 　示差走査熱量スペクトルにおいて、５１～６１℃に発熱ピークを有する無定形レボノルゲストレル。 Amorphous levonorgestrel having an exothermic peak at 51 to 61 ° C. in the differential scanning calorimetry spectrum.
  2. 　ポリマーにレボノルゲストレルが無定形の形態で分散している固体分散体。 A solid dispersion in which levonorgestrel is dispersed in an amorphous form in a polymer.
  3. 　ポリマーが薬理学的に許容可能な水溶性ポリマーである請求項２記載の固体分散体。 3. The solid dispersion according to claim 2, wherein the polymer is a pharmacologically acceptable water-soluble polymer.
  4. 　ポリマーとレボノルゲストレルとの重量比が、ポリマー／レボノルゲストレル＝９０／１０～５０／５０である請求項２又は３記載の固体分散体。 The solid dispersion according to claim 2 or 3, wherein the weight ratio of the polymer to levonorgestrel is polymer / levonogestrel = 90/10 to 50/50.
  5. 　アンモニア又は第１級アミンによりイミノ化したレボノルゲストレルのイミノ体を加水分解して、請求項１記載の無定形レボノルゲストレルを製造する方法。 A process for producing an amorphous levonogestrel according to claim 1 by hydrolyzing an imino form of levonorgestrel iminized with ammonia or a primary amine.
  6. 　レボノルゲストレルと、ポリマーと、溶媒とを含む溶液から前記溶媒を除去して、請求項２～４のいずれかに記載の固体分散体を製造する方法。 The method for producing a solid dispersion according to any one of claims 2 to 4, wherein the solvent is removed from a solution containing levonorgestrel, a polymer, and a solvent.
  7. 　請求項１記載の無定形レボノルゲストレル又は請求項２～４のいずれかに記載の固体分散体を含む医薬組成物。 A pharmaceutical composition comprising the amorphous levonorgestrel according to claim 1 or the solid dispersion according to any one of claims 2 to 4.
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