JP6125547B2 - Amorphous levonorgestrel, solid dispersion and process for producing them - Google Patents

Description

  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 (17β-hydroxy-18a-homo-19-nor-17α-pregna-4-en-20-in-3-one) is known as a steroid compound that exhibits a contraceptive effect mainly by an ovulation inhibitory action. It is sold as an emergency contraceptive in countries around the world, including Japan, the United States and Europe.

  WO2009 / 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. Moreover, manufacturing the crystal | crystallization of levonorgestrel by the method of adding n-heptane to the ethyl acetate solution of levonorgestrel and cooling and the method of cooling the methanol solution of levonorgestrel is also disclosed.

  However, these crystals have a problem of low solubility.

WO2009 / 035527 (Claims, Examples, FIG. 4)

  Accordingly, an object of the present invention is to provide a novel form of levonorgestrel having excellent 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.

  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.

  That is, 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 also 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 polymer / levonorgestrel weight ratio may be about polymer / levonogestrel = 90 / 10-50 / 50.

  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.

  Furthermore, the present invention also includes a pharmaceutical composition comprising amorphous levonorgestrel or the solid dispersion.

  In the present invention, since levonorgestrel is in an amorphous form, it is superior in 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.

1 is a graph showing a powder X-ray diffraction spectrum of amorphous levonorgestrel of Example 1. FIG. 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]
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 due to 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.).

  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.

  The amorphous levonorgestrel may be in the form of a powder, for example, having an average particle diameter of 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, about 0.1-50 micrometers (for example, 0.5-10 micrometers) may be sufficient.

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.

  The imino form can be produced by reacting levonorgestrel with ammonia or a primary amine in the presence or absence of a solvent to iminate the 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. _-10 cycloalkylamine; C _6-10 arylamine such as aniline; C _6-10 arylC _1-4 alkylamine such as benzylamine. Preferred primary amines may be C _1-6 alkyl amines (eg, C _1-4 alkyl amines such as ethylamine, propylamine, butylamine). The primary amines may be used alone or in combination of two or more.

  The ratio (molar ratio) between levonorgestrel and 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. Equivalent or more (for example, 1.5 to 90 equivalents), more preferably 2 or more equivalents (for example, 2 to 80 equivalents).

  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.

  If necessary, the above imination reaction may be performed in the presence of a catalyst. 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.

  The above imination reaction may be performed under heating. The heating temperature is appropriately determined depending on the boiling point 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 ° C 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 hydrolysis of the imino form can be performed in the presence of water. The amount (molar ratio) of water is 1 equivalent or more (for example, 1 to 20 equivalents), preferably 1.5 equivalents or more (for example, 1.5 to 10 equivalents), more preferably 2 to 1 equivalent of imino form. What is necessary is just more than an equivalent (for example, 2-5 equivalent). The amount of water may preferably be a large excess with respect to the imino form.

  The 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.

  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, -10 ° C to 100 ° C, preferably -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. 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.

[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 _-4 alkylcellulose), cellulose ethers such as hydroxyalkylalkylcellulose (such as hydroxy _C2-4 alkyl _C1-4 alkylcellulose such as hydroxypropylmethylcellulose); soluble starch such as pregelatinized starch, partially pregelatinized starch; 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.

  Examples of the insoluble polymer include ethyl cellulose and polyvinyl acetate.

  Examples of the gastric polymer include polyvinyl acetal diethylaminoacetate (such as AEA Sankyo), aminoalkyl methacrylate copolymer (such as Eudragit E, Eudragit RS) and the like.

  Examples of enteric polymers include cellulose esters such as cellulose acetate phthalate, hydroxypropylmethylcellulose acetate phthalate, and hydroxypropylmethylcellulose phthalate succinate; methacrylic acid-methyl methacrylate copolymers (Eudragit L, Eudragit S, etc.), methacrylic acid -Enteric acrylic polymers such as ethyl acrylate copolymer (such as Eudragit L30D-55) and ethyl acrylate-methyl methacrylate copolymer (such as Eudragit NE30D).

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, water-soluble polymers, 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 hydroxypropyl methyl cellulose, etc.) are used. .

  Moreover, the stability of levonorgestrel in the solid dispersion can be increased 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.

  The 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 (for example, 1.5 to 30 mPa · s), particularly 20 mPa · s or less (for example, 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.

  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 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 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.

  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.

  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. It can be improved. For example, when a solid dispersion is dissolved in a 1% Tween 80 aqueous solution at 37 ° C., the solubility of levonorgestrel is 15 to 40 μg / mL, preferably 18 to 35 μg / mL, more preferably about 20 to 30 μg / mL. Also good.

  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.

(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.

  The dissolution may be performed under heating as 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 such as evaporation or distillation under normal pressure or reduced pressure, or spray drying. Further, the obtained solid dispersion may be washed and dried.

  In addition, you may grind | pulverize the obtained solid dispersion as needed, and you may adjust to a desired particle size.

[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).

  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.

  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.

  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.

  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, or methyl methacrylate- (meth) acrylic acid copolymer, and 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.

  In the preparation, known additives can be appropriately used depending on the administration route and dosage form. 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.

  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).

  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. 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).

  The administration method may be oral administration, local administration or parenteral administration (for example, subcutaneous administration, intramuscular administration, rectal administration, vaginal administration, etc.).

  The frequency of administration is not particularly limited, and may be, for example, once a day, or may be multiple times a day (for example, 2 to 3 times) as necessary.

  Hereinafter, the present invention will be described in more detail based on examples, but the present invention is not limited to these examples.

[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 °.

[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.

  The residue was dissolved in 4 mL of N, N-dimethylformamide, and the resulting solution was poured into 40 mL of ice water and then stirred at room temperature for 15 minutes. Thereafter, a tan solid precipitated in ice water was collected by filtration.

  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.

  Moreover, the differential scanning calorimetry spectrum of the obtained tan solid was measured with a differential scanning calorimeter. The measurement results are shown in FIG.

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.

  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.

  When the powder X-ray diffraction spectrum of the obtained tan solid was measured, the same results as in FIG. 1 were obtained, and it can be seen that levonorgestrel contained in this solid was amorphous.

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.

  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.

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.

  When the 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.

[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 concentration of levonorgestrel in the filtrate. The results are shown in Table 1 and FIG.

  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.

  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. I think that.

  The amorphous levonorgestrel and the solid dispersion of the present invention are suitably used as an emergency contraceptive.

Claims (7)

  A solid dispersion in which levonorgestrel is dispersed in an amorphous form in a water-soluble cellulose ether, wherein the water-soluble cellulose ether contains at least one selected from hydroxypropylmethylcellulose and hydroxypropylcellulose. body. The solid dispersion according to claim 1, wherein the water-soluble cellulose ethers have a solution viscosity of 500 mPa · s or less at a concentration of 2% by weight and a temperature of 20 ° C.   The solid dispersion according to claim 1 or 2, wherein the weight ratio of the water-soluble cellulose ethers to levonorgestrel is water-soluble cellulose ethers / levonorgestrel = 90/10 to 50/50.   A method for producing an amorphous levonogestrel having an exothermic peak at 51 to 61 ° C. in a differential scanning calorimetry spectrum by hydrolyzing an imino form of levonorgestrel iminized with ammonia or a primary amine.   A method for producing a solid dispersion according to any one of claims 1 to 3, wherein the solvent is removed from a solution containing levonorgestrel, a water-soluble cellulose ether, and a solvent, wherein the water-soluble cellulose The production method, wherein the ether comprises at least one selected from hydroxypropylmethylcellulose and hydroxypropylcellulose. A pharmaceutical composition comprising a solid dispersion according to any of claims 1 to 3.   The pharmaceutical composition according to claim 6, which is an emergency contraceptive.

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