JP6200493B2 - Amorphous uripristal acetate - Google Patents

Description

  The present invention relates to a novel ulipristal acetate ester (especially amorphous ulipristal acetate ester) useful as a contraceptive or as a prophylactic and / or therapeutic agent for uterine fibroids, and a method for producing the same.

  Uripristal acetate [17α-acetoxy-11β- (4-N, N-dimethylaminophenyl) -19-norpregna-4,9-diene-3,20-dione; hereinafter may be referred to as UPA] It is a steroid compound having antiprogesterone activity and antiglucocorticoid activity, and is marketed as an emergency contraceptive in the United States and Europe.

  As a crystal of ulipristal acetate ester, for example, Japanese Patent No. 2957725 (Patent Document 1) describes a UPA crystal having a melting point of 118 to 121 ° C. recrystallized from a mixed solvent of methanol and water. WO96 / 30390 (patent document 2) describes UPA crystals having a melting point of 183 to 185 ° C. crystallized from diethyl ether. JP-T-2006-519255 (Patent Document 3) describes UPA crystals having a melting point of 183 to 185 ° C. recrystallized from an aqueous ethanol solution (90%). JP-T-2006-515869 (Patent Document 4) describes UPA crystals having a melting point of 189 ° C. recrystallized from a mixed solvent of ethanol / water = 80/20. JP-T-2009-539964 (Patent Document 5) describes UPA crystals having a melting point of 184 to 186 ° C. recrystallized from a mixed solvent of ethanol (230 mL) and water (260 mL).

  There is still a need for new forms of ulipristal acetate with improved solubility and / or bioavailability.

Japanese Patent No. 2957725 (Claims, Examples) WO96 / 30390 (Claims, Examples) JP-T-2006-519255 (Claims, Examples) JP 2006-515869 A (Claims, Examples) JP-T 2009-539964 (Claims, Examples)

  Accordingly, an object of the present invention is to provide a novel amorphous ulipristal acetate ester useful as a prophylactic and / or therapeutic agent for uterine fibroids and a method for producing the same. The novel ulipristal acetate ester may be useful as a contraceptive (contraceptive) (for example, an emergency contraceptive (emergency contraceptive)). The novel amorphous ulipristal acetate is also associated with, for example, gynecological diseases (or disorders) (uterine or leiomyoma, endometriosis, uterine bleeding, endometrial dislocation or dislocation) It may also be useful as a therapeutic and / or prophylactic agent for pain and the like.

  Another object of the present invention is to provide a novel ulipristal acetate ester which is excellent in solubility, absorbability and the like and can improve bioavailability and a method for producing the same.

  As a result of intensive studies to achieve the above-mentioned problems, the present inventors have dissolved ulipristal acetate ester in a specific solvent, and concentrated (solidified or dried) this solution to obtain a conventional crystal form. Different amorphous uripristal acetates can be obtained without intermingling with other forms, and this uripristal acetate substance containing amorphous uripristal acetate has properties such as solubility and absorbability And found that bioavailability can be improved. The amorphous ulipristal acetate ester of the present invention can reduce the dosage of ulipristal acetate ester administered to a patient, and can obtain a necessary therapeutic or contraceptive effect. The present invention has been completed based on the above findings.

  The first aspect of the present invention is amorphous (amorphous form or amorphous) uripristal acetate.

  In some embodiments, the amorphous ulipristal acetate has the X-ray diffraction pattern shown in FIG. Preferably, this X-ray diffraction pattern is obtained using a diffractometer equipped with a Cu K α1 source.

  In some further or other embodiments, the amorphous ulipristal acetate of the present invention has an exothermic peak on the order of 135-145 ° C. in the differential scanning calorimetry spectrum. The amorphous uripristal acetate ester of the present invention may further have a differential scanning calorimetric spectrum shown in FIG.

  Another aspect of the present invention is a uripristal acetate material (also referred to herein as a “ulipristal acetate mixture”) comprising amorphous ulipristal acetate.

The ulipristal acetate material (or composition or mixture) may further comprise ulipristal acetate crystals (polymorphic crystals of ulipristal acetate). The ulipristal acetate crystals are, for example,
(1) The following diffraction angles 2θ: 9.2 ± 0.2 °, 11.4 ± 0.2 °, 11.7 ± 0.2 °, 12.0 ± 0.2 °, 15.2 ± 0 Polycrystalline ulipristal acetate having powder X-ray diffraction patterns including diffraction peaks at .2 °, 17.0 ± 0.2 °, 17.2 ± 0.2 ° and 24.4 ± 0.2 ° Form A (A-form crystal),
(2) The following diffraction angle 2θ: 6.4 ± 0.2 °, 8.4 ± 0.2 °, 9.4 ± 0.2 °, 9.6 ± 0.2 °, 11.8 ± 0 .2 °, 12.8 ± 0.2 °, 15.3 ± 0.2 °, 16.7 ± 0.2 °, 17.5 ± 0.2 °, 18.6 ± 0.2 °, 19 Powder X-ray diffraction patterns having diffraction peaks at 3 ± 0.2 °, 21.0 ± 0.2 ° and 25.5 ± 0.2 ° were obtained using crystalline polymorph B of ulipristal acetate (form B crystal),
(3) The following diffraction angles 2θ: 9.0 ± 0.2 °, 9.3 ± 0.2 °, 10.8 ± 0.2 °, 11.5 ± 0.2 °, 12.2 ± 0 .2 °, 13.1 ± 0.2 °, 14.3 ± 0.2 °, 15.6 ± 0.2 °, 15.7 ± 0.2 °, 15.9 ± 0.2 °, 16 .6 ± 0.2 °, 17.6 ± 0.2 °, 17.9 ± 0.2 °, 18.9 ± 0.2 °, 19.3 ± 0.2 ° and 23.8 ± 0. It can be selected from the crystalline polymorph C (form C crystal) of ulipristal acetate having a powder X-ray diffraction pattern including a diffraction peak at 2 °.

  The diffraction angle having a peak (or peak angle) includes a range of variation of ± 0.2 ° (variable range). In the same crystal form, even if a plurality of peak angles (diffraction angles) including a range of variation overlap, the measured peak angles are independent from each other. For example, the C-type crystal has diffraction peaks at 9.0 ± 0.2 ° and 9.3 ± 0.2 °, and the two diffraction angle ranges overlap from 9.1 to 9.2 °. But there are two independent peaks at different diffraction angle positions (one at 9.0 ± 0.2 ° and one at 9.3 ± 0.2 °) Means.

  The ratio of amorphous uripristal acetate ester and ulipristal acetate crystal is the former / the latter (weight ratio) = 0.5 / 99.5 to 99.5 / 0.5 (for example, 10/90 to 99). / 1) degree may be sufficient. The above weight ratio is the differential scanning calorimetry spectrum, and the calorific value of the exothermic peak of the reference ulipristal acetate ester containing amorphous ulipristal acetate ester and uripristal acetate crystal in a predetermined weight ratio is measured. Thus, analysis can be performed based on the relationship between the weight ratio and the calorific value.

  The present invention further relates to a pharmaceutical composition comprising an amorphous uripristal acetate or ulipristal acetate substance according to the present invention and a pharmaceutically acceptable excipient. This pharmaceutical composition may be used as a contraceptive, for example an emergency contraceptive. Furthermore, the pharmaceutical composition of the present invention may be used to treat and / or prevent gynecological diseases such as uterine fibroids, endometriosis, uterine bleeding, pain associated with endometrial dislocation or dislocation. Good.

  A further aspect of the present invention is the process for producing the amorphous uripristal acetate or ulipristal acetate material of the present invention.

  In the present invention, raw material ulipristal acetate (such as ulipristal acetate crystals such as polymorph A) is dissolved in a halogenated hydrocarbon, and the solution is concentrated to obtain amorphous ulipristal acetate. Also included is a method of making an ester or ulipristal acetate material. In addition, the present invention provides amorphous uripristal acetate and uliprister by pulverizing raw material ulipristal acetate (such as crystal polymorphs A, B and C). Also included is a method of making a ulipristal acetate material (or a ulipristal acetate mixture) comprising a bisacetate crystal.

  In the present invention, the uripristal acetate substance containing amorphous uripristal acetate and amorphous ulipristal acetate has higher solubility than conventional crystal forms, excellent absorbability, and the like. Availability can be improved. Further, the solubility of the crystalline uripristal acetate can be improved by mixing the amorphous ulipristal acetate with the crystalline ulipristal acetate. The amorphous uripristal acetate ester and ulipristal acetate substance (or composition or mixture) of the present invention are useful as a prophylactic and / or therapeutic agent for uterine fibroids, and are safe as pharmaceuticals (or pharmaceuticals). Also excellent. The amorphous uripristal acetate and ulipristal acetate materials of the present invention are useful as contraceptives.

1 is a graph showing a powder X-ray diffraction spectrum of amorphous uripristal acetate of Example 1. FIG. FIG. 2 is a graph showing a differential scanning calorimetric spectrum of amorphous uripristal acetate of Example 1. FIG. 3 is a graph showing a powder X-ray diffraction spectrum of the A-type crystal of the comparative example. FIG. 4 is a graph showing a differential scanning calorimetric spectrum of a comparative example A-type crystal. FIG. 5 is a graph showing a powder X-ray diffraction spectrum of the B-form crystal of Example 3. FIG. 6 is a graph showing a differential scanning calorimetry spectrum of the B-type crystal of Example 3. FIG. 7 is a graph showing a powder X-ray diffraction spectrum of the C-form crystal of Example 4. FIG. 8 is a graph showing the differential scanning calorimetry spectrum of the C-type crystal of Example 4. FIG. 9 is a graph showing the relationship between the grinding time of the amorphous ulipristal acetate ester of Example 1 and the powder X-ray diffraction spectrum. FIG. 10 is a graph showing the relationship between the grinding time of the A-type crystal of the comparative example and the powder X-ray diffraction spectrum.

[Uripristar acetate material]
As used herein, ulipristal acetate material refers to ulipristal acetate in the form of a polymorphic mixture or composition. The uripristal acetate material according to the present invention comprises at least the amorphous ulipristal acetate of the present invention. In some embodiments, the ulipristal acetate material according to the present invention comprises at least 5% by weight of an amorphous of the present invention. The weight percentage is the percentage of the total weight of the uripristal acetate material.

  As used herein, at least 5% by weight amorphous is at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80% by weight, including at least 90% by weight amorphous. In a preferred embodiment, amorphous is the major polymorph of ulipristal acetate present within the ulipristal acetate material of the present invention. This means that the uripristal acetate material of the present invention is amorphous, preferably at least 90%, more preferably at least 95%, even more preferably at least 99.5%, in an amount not less than 50% by weight. It is meant to include amorphous by weight. The remaining polymorph present in the ulipristal acetate material of the present invention may be any crystalline form of ulipristal acetate. In some embodiments, the ulipristal acetate material of the present invention consists essentially of the amorphous form described herein.

  A feature of the present invention resides in amorphous (amorphous or amorphous) uripristal acetate. Therefore, the ulipristal acetate substance (or composition or mixture) of the present invention contains at least amorphous (amorphous or amorphous) uripristal acetate.

  Amorphous uripristal acetate or ulipristal acetate material is characterized by a powder X-ray diffraction pattern. That is, the uripristal acetate substance exhibits a diffraction pattern derived from at least amorphous uripristal acetate in the powder X-ray diffraction spectrum.

  Amorphous ulipristal acetate has substantially no diffraction peak derived from the crystal structure in the powder X-ray diffraction spectrum, and has a halo figure derived from scattering of incident X-rays.

  In some embodiments, the amorphous uripristal acetate of the present invention exhibits the X-ray diffraction pattern represented in FIG.

  Also, the amorphous ulipristal acetate or ulipristal acetate material of the present invention is characterized by a differential scanning calorimetric pattern. That is, the amorphous ulipristal acetate or ulipristal acetate substance shows a pattern derived from at least the amorphous ulipristal acetate in the differential scanning calorimetry spectrum.

  The amorphous ulipristal acetate ester is shifted downward from the baseline to about 95 to 130 ° C. (for example, 100 to 125 ° C., preferably 105 to 120 ° C.) in the differential scanning calorimetry spectrum (glass transition temperature (Tg)). ) May be indicated.

  In addition, the amorphous uripristal acetate ester may have an exothermic peak at about 135 to 145 ° C. (for example, 137 to 143 ° C., preferably 139 to 141 ° C.) in the differential scanning calorimetry spectrum. The exothermic peak is presumed to be a peak resulting from the transition from the amorphous form to the crystalline form (A form). The calorific value corresponding to the exothermic peak may be about 5 to 30 J, preferably 8 to 28 J, more preferably about 10 to 25 J (for example, 11 to 20 J) per 1 g of amorphous uripristal acetate. The calorific value can be calculated based on the weight and the exothermic peak area of the amorphous uripristal acetate used in a differential scanning calorimeter (DSC).

  Furthermore, the amorphous uripristal acetate ester may have an endothermic peak at about 180 to 192 ° C., preferably about 183 to 190 ° C. in the differential scanning calorimetry spectrum. The endothermic peak is presumed to be a peak due to melting of the transferred crystal (A-type crystal).

  In some embodiments, the amorphous ulipristal acetate of the present invention has a differential scanning calorimetry spectrum as shown in FIG.

The ulipristal acetate substance of the present invention may contain amorphous uripristal acetate ester, and may further contain uripristal acetate crystal (polymorph crystal). As ulipristal acetate crystals,
(1) The following diffraction angles 2θ: 9.2 ± 0.2 °, 11.4 ± 0.2 °, 11.7 ± 0.2 °, 12.0 ± 0.2 °, 15.2 ± 0 Polycrystalline ulipristal acetate having powder X-ray diffraction spectra including diffraction peaks at .2 °, 17.0 ± 0.2 °, 17.2 ± 0.2 ° and 24.4 ± 0.2 ° Form A (A-form crystal),
(2) The following diffraction angle 2θ: 6.4 ± 0.2 °, 8.4 ± 0.2 °, 9.4 ± 0.2 °, 9.6 ± 0.2 °, 11.8 ± 0 .2 °, 12.8 ± 0.2 °, 15.3 ± 0.2 °, 16.7 ± 0.2 °, 17.5 ± 0.2 °, 18.6 ± 0.2 °, 19 Crystalline polymorph B of uripristal acetate having powder X-ray diffraction spectra containing diffraction peaks at 3 ± 0.2 °, 21.0 ± 0.2 ° and 25.5 ± 0.2 ° (form B) crystal),
(3) The following diffraction angles 2θ: 9.0 ± 0.2 °, 9.3 ± 0.2 °, 10.8 ± 0.2 °, 11.5 ± 0.2 °, 12.2 ± 0 .2 °, 13.1 ± 0.2 °, 14.3 ± 0.2 °, 15.6 ± 0.2 °, 15.7 ± 0.2 °, 15.9 ± 0.2 °, 16 .6 ± 0.2 °, 17.6 ± 0.2 °, 17.9 ± 0.2 °, 18.9 ± 0.2 °, 19.3 ± 0.2 ° and 23.8 ± 0. Examples thereof include crystal polymorph C (C-form crystal) of ulipristal acetate having a powder X-ray diffraction spectrum including a diffraction peak at 2 °.

  The powder X-ray diffraction spectrum can be measured using a conventional method, preferably a diffractometer having a Cu K α-1 ray source, for example, under the conditions of the examples described later. The diffraction angle 2θ indicating the diffraction peak may vary by about ± 0.2 ° (for example, ± 0.1 °) depending on the measurement conditions and the sample state. However, if the crystal structure is the same, the number of characteristic diffraction peaks does not change greatly, and almost the same powder X-ray diffraction pattern is exhibited.

  As the ulipristal acetate crystal, in the differential scanning calorimetry spectrum, for example, polymorph A having an endothermic peak (melting point) at about 180 to 192 ° C. (preferably 183 to 190 ° C.), 160 to 170 ° C. (for example, Crystal polymorph B having an endothermic peak (melting point) of about 165 to 169 ° C, preferably 166 to 168 ° C, and an endothermic peak of about 135 to 145 ° C (eg, 137 to 143 ° C, preferably 139 to 141 ° C) Examples thereof include crystal polymorph C having a melting point).

  In addition, the crystalline polymorph C (or uripristal acetate substance containing the crystalline polymorph C) is further about 145 to 170 ° C. (for example, 160 to 167 ° C., preferably 163 to 165 ° C.) in the differential scanning calorimetry spectrum. May have an exothermic peak, and may have an endothermic peak at about 180 to 192 ° C. (preferably 183 to 190 ° C.). The exothermic peak is presumed to be due to the transition from crystalline polymorph C (C crystal) to crystalline polymorph A (A crystal), and the endothermic peak is due to melting of crystalline polymorph A (A crystal). It is estimated that the peak is due.

  For example, crystalline polymorph A may have the powder X-ray diffraction pattern shown in FIG. 3 or described in Table 1 and / or the differential scanning calorimetry spectrum shown in FIG. Crystalline polymorph B may have the powder X-ray diffraction pattern shown in FIG. 5 or described in Table 2 and / or the differential scanning calorimetry spectrum shown in FIG. Crystalline polymorph C may have the powder X-ray diffraction pattern shown in FIG. 7 or described in Table 3 and / or the differential scanning calorimetry spectrum shown in FIG.

  The uripristal acetate crystals may be used alone or in combination of two or more. Among these ulipristal acetate crystals, preferred ulipristal acetate crystals are B-form crystals and C-form crystals (particularly C-form crystals) from the viewpoint of solubility.

  The ulipristal acetate crystal (or each crystal polymorph) may be a single crystal, twin or polycrystal. The form (external shape) of ulipristal acetate crystal (or each polymorph) is not particularly limited, and for example, triclinic, monoclinic, orthorhombic (tetragonal), tetragonal, cubic, and trigonal It may be a crystal (rhombohedral crystal), a hexagonal crystal, or the like, or may be a spherulite, a body crystal, a bark crystal, a needle crystal (for example, a beard crystal), or the like.

  The ratio (weight ratio) between amorphous uripristal acetate ester and uripristal acetate crystal in the uripristal acetate substance (Uripristal acetate mixture, composition or mixed crystal) is the former / the latter = It can be selected from a range of about 0.5 / 99.5 to 99.5 / 0.5 (for example, 1/99 to 99/1), for example, 10/90 to 99/1 (for example, 20/80 to 99). / 1), preferably 30/70 to 98/2 (eg 40/60 to 97/3), more preferably 50/50 to 96/4 (eg 60/40 to 95/5, preferably 70 / 30 to 95/5). The ratio (weight ratio) is the former / the latter = 15/85 to 85/15 (for example, 25/75 to 75/25), preferably 30/70 to 70/30 (for example, 40/60 to 60). / 40) degree may be sufficient.

  Uripristal acetate material (Uripristal acetate mixture, composition or mixed crystal) containing amorphous ulipristal acetate and crystalline ulipristal acetate has structural characteristics derived from each form (powder X A diffraction peak in a line diffraction spectrum, an endothermic peak in a differential scanning calorimetry spectrum, etc.). In many cases, the intensity ratio of diffraction peaks (or endothermic peaks) of each form corresponds to the blending ratio of each form.

In addition, ulipristal acetate ester (Uripristal acetate substance, mixture, composition or mixed crystal, or amorphous uripristal acetate ester, or crystalline polymorphs of ulipristal acetate ester) is a low molecular compound. (Or solvent) may be contained (or adhered). The low molecular compound (or solvent) is not particularly limited as long as it is pharmaceutically acceptable. For example, water, an organic solvent [for example, halogenated hydrocarbon (such as chloroform), alcohols (for example, 1-propanol, C _1-4 alkanols such as 2-propanol), ethers (such as cyclic ethers such as tetrahydrofuran), ketones (such as acetone), esters (such as ethyl formate), sulfoxides (such as dimethyl sulfoxide), amides (such as N, N-dimethylformamide and the like), cyclic amines (pyridine and the like)] and the like. These low molecular compounds (or solvents) may be used alone or in combination of two or more. The content (or adhesion amount) of the low molecular compound is, for example, 30 parts by weight or less, preferably 20 parts by weight or less, more preferably 10 parts by weight or less (for example, 0 parts by weight) with respect to 100 parts by weight of ulipristal acetate. 0.001 to 1 part by weight).

  The particle size of the amorphous ulipristal acetate ester or ulipristal acetate substance is not particularly limited, and, for example, based on laser diffraction method, the average particle size (average particle diameter) is 0.1 μm to 1 mm (for example, 0.5 μm to 1 mm), preferably about 1 to 500 μm (for example, 2 to 100 μm), and usually about 5 to 50 μm (for example, 5 to 30 μm). The average particle diameter of ulipristal acetate may be about 0.1 to 5 μm (for example, 0.5 to 3 μm). The amorphous uripristal acetate or ulipristal acetate material of the present invention may be micronized.

  Amorphous uripristal acetate or ulipristal acetate material has high solvent solubility and excellent bioavailability. For example, the solubility of amorphous uripristal acetate or uripristal acetate substance in a mixed solvent of ethanol and water [ethanol / water (volume ratio) = 10/90] is 10 to 30 μg / mL at 37 ° C. , Preferably 12 to 27 μg / mL, more preferably about 15 to 25 μg / mL.

[Method of producing uripristal acetate substance or amorphous uripristal acetate]
The method for producing the uripristal acetate substance or amorphous uripristal acetate of the present invention is not particularly limited as long as the powder X-ray diffraction spectrum or the differential scanning calorimetry spectrum is obtained. The method for producing the uripristal acetate substance or amorphous uripristal acetate of the present invention is, for example, by dissolving a raw material ulipristal acetate (for example, ulipristal acetate crystal etc.) in a halogenated hydrocarbon, Step (i) of concentrating the solution. By this step (i), an amorphous form can be efficiently obtained without substantially mixing crystal forms.

(Process (i))
The raw material ulipristal acetate can be produced by a conventional method. From the viewpoint of purity and yield, for example, 3,3- (1,2-ethanedioxy) -5α-hydroxy-11β- (4-N, N— Dimethylaminophenyl) -17α-acetoxy-19-norpregna-9-en-20-one and acid (for example, organic acids such as acetic acid and trifluoroacetic acid; inorganic acids such as hydrochloric acid, sulfuric acid, monopotassium sulfate, and phosphoric acid) Can be prepared by the reaction. Details of this reaction can be referred to, for example, JP-T-2006-519255, JP-T-2006-515869, and the like.

  As the raw material ulipristal acetate, the above reaction mixture may be used as it is, and a crude product obtained by purifying the above reaction mixture by conventional purification means (filtration, centrifugation, chromatography, etc.) is used. May be. Moreover, as raw material ulipristal acetate, ulipristal acetate crystals crystallized (or recrystallized) from a solution (crystallization system) containing the above reaction mixture (or crude purified product) and a crystallization solvent are used. May be used. Furthermore, as the raw material ulipristal acetate, ulipristal acetate crystals obtained by repeating the crystallization step a plurality of times (for example, 2 to 4 times) may be used.

Examples of the halogen atom of the halogenated hydrocarbon include chlorine and bromine. A preferred halogen atom is chlorine. Examples of the halogenated hydrocarbon include halo C _1-2 alkanes such as dichloromethane, 1,2-dichloroethane, chloroform, trichloroethylene, carbon tetrachloride, and combinations thereof. Of these halogenated hydrocarbons, dichloro C _1-2 alkanes such as dichloromethane are preferred.

  The proportion of the halogenated hydrocarbon is, for example, about 0.1 to 50 mL, preferably 0.5 to 40 mL, more preferably about 1 to 30 mL (for example, 5 to 20 mL) with respect to 1 g of raw material ulipristal acetate. There may be.

  Concentration may be performed at room temperature to under heating (for example, a temperature of 20 to 100 ° C, preferably 25 to 95 ° C, more preferably about 30 to 90 ° C). Concentration may be performed under reduced pressure to normal pressure (for example, pressure 50 to 1013 hPa, preferably 70 to 1000 hPa, more preferably about 100 to 900 hPa, usually 500 hPa or less). Further, the concentration rate may be, for example, 0.01 to 10 mL / min, preferably 0.1 to 8 mL / min, and more preferably about 1 to 5 mL / min.

  After the concentration, if necessary, drying (natural drying, ventilation drying, reduced pressure drying, etc.) may be performed. Usually, drying under reduced pressure [for example, drying at 50 hPa or less, preferably 20 hPa or less (for example, about 1 to 15 hPa)] There are many cases to do. The drying may be performed at room temperature to under heating, preferably about 25 to 80 ° C., more preferably about 30 to 70 ° C. (for example, 40 to 70 ° C.). The drying time may be, for example, about 1 to 20 hours (for example, 5 to 20 hours), preferably about 1.5 to 18 hours (for example, 10 to 18 hours). Amorphous uripristal acetate can be efficiently produced by such concentration and drying, in particular, by concentrating and drying the halogenated hydrocarbon solution of the raw material ulipristal acetate under heating and reduced pressure.

  In addition, you may perform process (i) repeatedly in multiple times (for example, 2-4 times).

  In addition to the step (i), the method for producing the ulipristal acetate substance is based on crystallization or transition associated with a solvent (crystallization from a solution, concentration of a solution, transition in a solvent (dispersion medium)). The step (ii) of forming uripristal acetate crystals, the step of mixing the amorphous uripristal acetate obtained in step (i) and the uripristal acetate crystals obtained in step (ii) ( and iii).

(Process (ii))
The method for forming ulipristal acetate crystals is not particularly limited. For example, a cooling method (a method in which raw ulipristal acetate is dissolved in a solvent and cooling this solution), a poor solvent addition method (raw uliprister) A method in which a ruthenium acetate is dissolved in a solvent and a poor solvent is added to the solution), an evaporation method (a method in which the raw material uripristal acetate is dissolved in a solvent and the solution is concentrated), a stirring suspension method (a raw material uri Examples thereof include a method of dispersing pristol acetate in a solvent and stirring this dispersion.

  As a raw material ulipristal acetate used for the formation process of a uripristal acetate crystal | crystallization, the raw material ulipristal acetate described in the term of process (i) etc. are mentioned, for example.

Examples of the solvent (or crystallization solvent) include water, organic solvents [for example, aliphatic hydrocarbons (such as hexane), aromatic hydrocarbons (such as toluene), alcohols (ethanol, 1-propanol, 2-propanol, C _1-4 alkanols such as 1-butanol), esters (ethyl formate, ethyl acetate, isopropyl acetate, isobutyl acetate, etc.), ketones (acetone, methyl ethyl ketone, etc.), ethers (chain ethers such as diethyl ether; Cyclic ethers such as dioxane and tetrahydrofuran), sulfoxides (such as dimethyl sulfoxide), amides (such as N, N-dimethylformamide, N, N-dimethylacetamide), nitriles (such as acetonitrile), cyclic amines (such as pyridine) )] And the like. These solvents can be used alone or as a mixed solvent.

  The ratio of the solvent is, for example, about 0.1 to 500 mL, preferably 0.5 to 400 mL, and more preferably about 1 to 300 mL (for example, 2 to 200 mL) with respect to 1 g of raw material ulipristal acetate. Good.

  As a typical method for producing ulipristal acetate crystals, methods for producing A-type crystals, B-type crystals and C-type crystals will be described below.

  The A-form crystal is crystallized, for example, by dissolving an isopropanol solvate crystal of ulipristal acetate in a mixed solvent of ethanol and water, and adding a seed crystal (crystal polymorph A or B) to this solution. May be prepared.

  The B-type crystal may be prepared by, for example, dissolving raw material ulipristal acetate in ethanol and cooling (quenching etc.) this solution. It may be prepared by dissolving in at least one solvent selected from ethyl acetate and concentrating the solution.

  The C-form crystal may be prepared, for example, by dissolving an isopropyl solvate crystal of ulipristal acetate in a mixed solvent of ethanol and water and crystallizing the solution without adding a seed crystal. .

  In the mixed solvent of ethanol and water used for the production of A-form crystals and C-form crystals, the ratio of ethanol to water (volume ratio) is, for example, the former / the latter = about 85/15 to 75/25. May be.

(Step (iii))
The mixing method of amorphous uripristal acetate and ulipristal acetate crystals is not particularly limited, and is usually a conventional mixer [for example, a container rotating type mixer (for example, a rotating cylindrical shape, a double cone shape, a V shape). Etc.) and container-fixed mixers (ribbon type, screw type, etc.)] are often used. The mixing ratio of the amorphous ulipristal acetate ester and the uripristal acetate crystal can be appropriately selected according to the content of each form.

  The uripristal acetate substance containing amorphous uripristal acetate and ulipristal acetate crystals may be prepared through steps (i) to (iii), but from the viewpoint of productivity, Step of pulverizing (or finely pulverizing) raw material uripristal acetate ester (for example, ulipristal acetate ester crystal such as A-form crystal, B-form crystal, and C-form crystal) without going through i) to (iii) It may be prepared via (iv).

(Process (iv))
The method for pulverizing the raw material ulipristal acetate (for example, ulipristal acetate crystal) can be appropriately selected according to the desired particle size and the proportion of amorphous material, and may be a method for pulverization using a mortar. Compressive or impact pulverizers such as crushers, atomizers and hammer mills; shear pulverizers such as cutter mills; impact pulverizers such as ball mills; There may be. Since the uripristal acetate substance containing amorphous uripristal acetate can be prepared by such pulverization, the present invention is suitable for preparing a preparation through a pulverization process and a compression process (or tableting process). Yes.

[Use and pharmaceutical composition]
The amorphous ulipristal acetate or ulipristal acetate substance of the present invention has an anti-glucocorticoid activity in addition to the anti-progesterone activity, and is therefore preferably used as a selective progesterone receptor modulator. Specifically, the amorphous ulipristal acetate ester or ulipristal acetate substance of the present invention is used for gynecological diseases [for example, uterine fibroids or diseases caused by uterine fibroids (metastatic leiomyoma, dysmenorrhea, excessive Such as menstruation, anemia, infertility, constipation, frequent urination, low back pain, etc.)]. The amorphous uripristal acetate or ulipristal acetate substance of the present invention is also useful as an emergency contraceptive (eg, emergency contraceptive).

  The amorphous uripristal acetate or ulipristal acetate substance of the present invention may also be useful as a medicament for treating and / or preventing gynecological diseases, for example. As used herein, gynecological diseases include, but are not limited to, hysteromyoma or leiomyoma, endometriosis, uterine bleeding, pain associated with dislocation of the endometrium.

  The present invention also treats female patients comprising administering to a female patient (preferably a gynecological patient) a therapeutically effective amount of the amorphous uripristal acetate or ulipristal acetate substance of the present invention. It also relates to how to do it.

  A further aspect of the present invention is a method of contracepting a woman in need of contraception, wherein the method comprises providing an effective amount of the amorphous uripristal acetate or ulipristal acetate substance of the present invention to the woman for contraception. Administration.

  The contraceptive method of the present invention may be an emergency contraceptive method in which the administration of the amorphous uripristal acetate ester or ulipristal acetate substance of the present invention is performed within 120 hours after unprotected sexual intercourse. Alternatively, the contraceptive method may be a normal contraceptive method in which the administration of ulipristal acetate is repeated for several consecutive days in the menstrual cycle. Alternatively, the contraceptive method of the present invention may be an on-demand contraceptive method described in WO2010 / 119029, the disclosure of which is incorporated herein by reference. Preferably, the administration of ulipristal acetate in the contraceptive method of the present invention is orally.

  The invention further relates to the use of the amorphous ulipristal acetate or ulipristal acetate substance according to the invention in the manufacture of a contraceptive or in the manufacture of a medicament for treating gynecological diseases.

  The above amorphous ulipristal acetate or ulipristal acetate substance may be used alone as a medicament, or a pharmaceutical composition (or formulation) in combination with a carrier (such as a pharmacologically or physiologically acceptable carrier). ).

  In a further aspect, the present invention relates to a pharmaceutical composition comprising the amorphous uripristal acetate or ulipristal acetate material of the present invention and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition of the present invention is such that at least 5% by weight of the ulipristal acetate present in the pharmaceutical composition is the amorphous ulipristal acetate of the present invention. is there. In some further embodiments, the ulipristal acetate present in the composition is predominantly amorphous. This means that the pharmaceutical composition of the present invention comprises no less than 50% of the amorphous ulipristal acetate of the present invention relative to the total weight of ulipristal acetate present in the composition. It means that you may go out. In some embodiments, the amorphous ulipristal acetate of the present invention is at least 60 wt%, preferably at least 80 wt%, and even at least 80 wt%, based on the total weight of ulipristal acetate present in the composition. Occupies 90% by weight. The pharmaceutical composition comprises 0.01% to 80% by weight of the amorphous uripristal acetate or ulipristal acetate material of the present invention, and 20% to 99.99% excipient (s). It may contain% by weight.

  In the pharmaceutical composition of the present invention, the excipient 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 excipient include, for example, Japanese Pharmacopoeia (Pharmacopoeia), (1) Pharmaceutical Additive Handbook, Maruzen Co., Ltd., (1989), (2) “Pharmaceutical Additives Encyclopedia 2007” (Pharmaceutical Daily Inc., (Issued July 2007), (3) Pharmacy, revised 5th edition, Nanedo Co., Ltd. (1997), and (4) Pharmaceutical Additives Standard 2003 (Pharmaceutical Daily Inc., August 2003) It can be selected according to the administration route and the pharmaceutical application from among the components (for example, excipient, binder, disintegrant, lubricant, coating agent, etc.). For example, at least one excipient selected from a diluent, a binder and a disintegrant is often used as an excipient for a solid preparation. The pharmaceutical composition may contain a lipid.

  Examples of the diluent include sugars such as lactose, glucose, sucrose, mannitol, sorbitol, and xylitol or sugar alcohols; starch such as corn starch; polysaccharides such as crystalline cellulose (including microcrystalline cellulose); light anhydrous silicic acid Examples thereof include silicon oxide and 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 excipients can be used alone or in combination of two or more.

  The pharmaceutical composition may be in a coated (or coated) form. 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 (methacrylic acid). Acrylic acid copolymer) is used. 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. Alternatively, the pharmaceutical composition may be a coated tablet or a plain tablet.

  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.

  In addition, the pharmaceutical composition (or pharmaceutical preparation) of the present invention may contain other physiologically active components or pharmacologically active components (for example, follicular hormone agents) as necessary.

  The pharmaceutical composition of the present invention is prepared by a conventional formulation method using, for example, an active ingredient, an excipient component, and, if necessary, an additive, for example, a production method described in the 16th revision Japanese Pharmacopoeia or this production method. It can be prepared by a method according to.

  The pharmaceutical composition may comprise 1 mg to 50 mg, preferably 5 mg to 40 mg, eg 5, 10, 15, 20 or 30 mg per dosage unit of ulipristal acetate ester.

  The amorphous ulipristal acetate ester or ulipristal acetate substance (including gynecological disease prevention and / or treatment agent, contraceptive agent, and pharmaceutical composition) of the present invention has low toxicity and excellent safety. It is safely administered to females of humans and non-human animals, usually mammals (eg, humans, mice, rats, rabbits, dogs, cats, cows, horses, pigs, monkeys, etc.). The dosage can be selected depending on the species, age, weight, and condition (general condition, medical condition, presence of complications, etc.), administration time, dosage form, administration method, and the like of the administration target. For example, the dose (daily dose) for humans is, for example, about 1 to 50 mg / day, preferably about 5 to 40 mg / day.

  The administration method may be oral administration, local administration or parenteral administration (for example, subcutaneous administration, intravenous 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 (XRD) was measured under the conditions of radiation source: Cu K (α1), tube voltage: 40 kV, tube current: 40 mA, sampling interval: 0.1 °, 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 the condition of a heating rate of 2 ° C./min.

[solubility]
A test sample was prepared by adding 40 mg of each of the uripristal acetate esters of Comparative Examples and Examples to 40 mL of a mixed solvent of ethanol and water at 37 ° C. [ethanol / water (volume ratio) = 10/90]. After stirring the sample with a magnetic stirrer for 5 minutes, a part of the sample was taken, the solid content was filtered off, and the uripristal acetate content was determined by high performance liquid chromatography (column: ODS, column temperature: 40 ° C., eluent: The solubility was calculated by quantification using a 0.1% aqueous trifluoroacetic acid / acetonitrile mixture (volume ratio 3: 2), flow rate: 1.0 mL / min, detection: UV 302 nm).

[Absorption test in dogs]
Capsules were prepared by filling the ulipristal acetate esters of Comparative Examples and Examples into gelatin capsules (manufacturer: Qualicaps Co., Ltd., size: 00, lot: C0079A), respectively. Capsules are orally administered to 6 female dogs at a dose of 25 mg / kg (converted to uripristal acetate), and blood is collected at 0.5, 1, 2, 4, 6, 24 and 48 hours after oral administration. Plasma was obtained by centrifugation. The ulipristal acetate concentration in the plasma was measured by LC-MS / MS (liquid chromatography-tandem mass spectrometry) method, the plasma concentration elimination half-life (T _1/2 ), the maximum plasma concentration arrival time (T _max ) and maximum plasma concentration (C _max ) were calculated. In addition, to the female dog, the capsule was administered twice with a one-week administration interval (drug holiday) by the crossover method.

[Crushing stability (stability of pulverized product)]
Each sample of comparative ulipristal acetate crystal polymorph A (form A crystal) and 500 mg of the amorphous uripristal acetate ester of Example 1 was put into an automatic mortar grinder (500 g magnetic pestle, 50 rpm, one rotation). And rotated for 7 days. Sampling was performed on the 1st, 2nd, 4th and 7th days from the start of grinding, and the powder X-ray diffraction spectrum (XRD) was measured.

  Further, the residual ratio of the crystal form accompanying pulverization was calculated as the ratio of the peak intensity of XRD, with the initial value before pulverization being 100%. The A-type crystal used a peak at 2θ = 15.27 °. Moreover, since the peak intensity varies depending on the measurement date, the peak intensity was corrected by the peak intensity of the inspection silicon standard material every measurement day.

Comparative Example 3,3- (1,2-ethanedioxy) -5α-hydroxy-11β- (4-N, N-dimethylaminophenyl) -17α-acetoxy-19-norpregna-9-en-20-one [carbinol Acetate] 38.5 g was placed in a flask at a temperature of 20 to 22 ° C. in a nitrogen atmosphere, and 385 mL of deionized water and 17.91 g of potassium hydrogen sulfate were added. The resulting suspension was stirred for about 4 hours until completely dissolved. The completion of the reaction was confirmed by thin layer chromatography (TLC).

Neutral Al ₂ O ₃ 3.85 g was added to the reaction solution, stirred for 30 minutes, the suspension was filtered, and the insoluble particulate matter was washed with 38.5 mL of deionized water. 325 mL of ethyl acetate was added to the filtrate and the pH was adjusted between 7.0 and 7.2 with 7% (w / v) sodium bicarbonate solution. The mixture was left for 15 minutes, the phases were separated and the aqueous phase was discarded. After adding 192.5 mL of deionized water to the resulting organic phase and stirring for 10 minutes, the mixture was allowed to stand for 15 minutes, the phases were separated and the aqueous phase was discarded.

  The obtained organic phase was concentrated in vacuo to obtain a crude uripristal acetate residue. To this residue was added 38.5 mL of isopropanol, and the mixture was concentrated in vacuo. The same amount (38.5 mL) of isopropanol was added to the resulting residue. And concentrated in vacuo again. 77 mL of isopropanol was added to the obtained solid product and dissolved by heating. The solution was allowed to cool to 0-5 ° C and held at this temperature for 1 hour. The obtained suspension was filtered, and the filter cake was washed with cold isopropanol to obtain isopropanol hemisorbate crystals in a yield of 96 mol%.

  6. Using 10 g of isopropanol hemisorbate crystal, crystallize ulipristal acetate according to Japanese Patent Publication No. 2006-515869, and crystal polymorph A (A-form crystal) of ulipristal acetate having a melting point of 189 ° C. 5 g was obtained.

Example 1
1.5 g of uripristal acetate crystals obtained in the comparative example were dissolved in 10 mL of dichloromethane, and concentrated under reduced pressure on a water bath at 60 ° C. under a pressure of 500 hPa or less for 2 to 3 minutes. The obtained residue was dried under reduced pressure for 15 hours at a temperature of 50 ° C. and a pressure of 15 hPa or less to obtain 1.5 g of uripristal acetate ester. An amorphous powder X-ray diffraction spectrum is shown in FIG. 1, and a differential scanning calorimetry spectrum is shown in FIG.

Example 2
By mixing 0.1 g of uripristal acetate crystal obtained in Comparative Example and 0.1 g of amorphous obtained in Example 1, ulipristal acetate ester (A-form crystal) was obtained. A powder X-ray diffraction spectrum of the A-form crystal is shown in FIG. 3, and a differential scanning calorimetry spectrum is shown in FIG. Table 1 shows the diffraction peak intensity and the relative intensity at each diffraction angle (lattice spacing d value) of the A-form crystal.

Example 3
1.3 g of uripristal acetate crystals obtained in the comparative example were dissolved in 6.5 mL of ethanol by heating and left at 26 ° C. for 1 hour and then at 4 ° C. for 16 hours. The obtained precipitate was collected by filtration and dried under reduced pressure until reaching a constant weight, to obtain 1.0 g of B-form crystals. By mixing 0.1 g of this B-form crystal and 0.1 g of the amorphous obtained in Example 1, ulipristal acetate (B-form crystal) was obtained. In addition, the powder X-ray diffraction spectrum of the B-form crystal is shown in FIG. 5, and the differential scanning calorimetry spectrum is shown in FIG. Table 2 shows the diffraction peak intensity and the relative intensity at each diffraction angle (lattice spacing d value) of the B-form crystal.

Example 4
1.761 g of ulipristal acetate crystals obtained in the comparative example were dissolved by heating in 10 mL of isopropanol, and the solvent was distilled off under reduced pressure. To the obtained residue, 9 mL of isopropanol was added and dissolved by heating, and the solvent was distilled off under reduced pressure. 9 mL of isopropanol was added to the resulting residue and dissolved by heating, and this solution was left in an ice-water bath for 1 hour. The obtained precipitate was collected by filtration to obtain 1.782 g of wet crystals of ulipristal acetate ester isopropanol hemisolvate. 1.782 g of this wet crystal was dissolved by heating in 17.8 mL of a mixed solvent of ethanol and water [ethanol / water (volume ratio) = 80/20] and stirred at room temperature for 17 hours. The resulting precipitate was collected by filtration and dried under reduced pressure at 100 ° C. to obtain 1.0 g of C-type crystals. By mixing 0.1 g of the C-form crystals and 0.1 g of the amorphous obtained in Example 1, a ulipristal acetate material was obtained. In addition, the powder X-ray diffraction spectrum of C-type crystal is shown in FIG. 7, and the differential scanning calorific value spectrum is shown in FIG. Table 3 shows the diffraction peak intensity and the relative intensity at each diffraction angle (lattice spacing d value) of the C-shaped crystal.

  The results of Comparative Examples and Examples are shown in Tables 4 and 5.

  As is clear from Table 4, Examples 1 to 4 have significantly higher solubility and excellent bioavailability than the comparative examples.

As is apparent from Table 5, Example 1 is superior in both T _max and C _max in comparison with the comparative example, and exhibits good pharmacokinetics as a drug that is quickly absorbed into the living body. I understand.

[Crushing stability (stability of pulverized product)]
The pulverization stability of the A-type crystals of ulipristal acetate obtained in Comparative Example and the amorphous uripristal acetate obtained in Example 1 was improved by the residual ratio (%) of the crystal form accompanying pulverization. When examined, the results shown in Table 6, FIG. 9 and FIG. 10 were obtained.

  As is clear from Table 6 and FIG. 9, the amorphous form did not change at all even after 7 days of pulverization. On the other hand, as apparent from Table 6 and FIG. 10, the initial crystal form of the A-form crystal changed rapidly after pulverization for 1 day, and the A-form crystal completely disappeared after pulverization for 4 days.

Formulation Example 1
Capsules were obtained by filling the amorphous obtained in Example 1 into No. 0 capsules.

Formulation Example 2
According to the following prescription, the amorphous material obtained in Example 1 and the carrier component were mixed, the mixture was granulated by a dry granulation method, and the granulated product was granulated to obtain granules.

[Prescription]
Amorphous 300 mg obtained in Example 1
Crystalline cellulose 590mg
Sodium carboxymethyl starch 50mg
Glycerin fatty acid ester 50mg
Talc 10mg
Total amount 1000mg

Formulation Example 3
According to the following prescription, the granule obtained in Preparation Example 2 and the carrier component were mixed and tableted to obtain a tablet.

[Prescription]
100 mg of granules obtained in Formulation Example 2
Crystalline cellulose 174mg
Glycerin fatty acid ester 20mg
Talc 4mg
Light anhydrous silicic acid 2mg
Total amount 300mg

Formulation Example 4
Film-coated tablets were obtained by coating the tablets obtained in Formulation Example 3 using the coating agent of the following formulation.

[Prescription of coating agent]
Hypromellose 70.5% by weight
Titanium oxide 20.5% by weight
Propylene glycol 6.9% by weight
Iron sesquioxide 2.1% by weight

  The amorphous uripristal acetate or ulipristal acetate substance of the present invention has extremely high solubility and excellent absorbability as compared with the conventional crystal form, and can improve bioavailability. Therefore, the amorphous ulipristal acetate or ulipristal acetate substance of the present invention is suitably used as a selective progesterone receptor modulator. In addition, the amorphous ulipristal acetate ester or ulipristal acetate substance of the present invention is used for gynecological diseases [for example, uterine fibroids or diseases caused by uterine fibroids (metastatic smooth muscle species, dysmenorrhea, excessive menstruation, Anemia, infertility, constipation, frequent urination, low back pain, etc.)] and the like. In addition, the amorphous uripristal acetate or ulipristal acetate material of the present invention is also useful as an emergency contraceptive.

Claims (11)

Uri pre Stahl acid ester mixture containing a non-amorphous Uri pre Stahl acid ester, and Uri pre Stahl acetate crystals. The ulipristal acetate ester mixture according to claim 1, wherein the amorphous ulipristal acetate ester has an exothermic peak at 135 to 145 ° C in a differential scanning calorimetry spectrum. The ulipristal acetate ester mixture according to claim 1 or 2 , wherein the ulipristal acetate crystal is a crystalline polymorph C having a powder X-ray diffraction pattern including a diffraction peak at the following diffraction angle 2θ.
Diffraction angle 2θ: 9.0 ± 0.2 °, 9.3 ± 0.2 °, 10.8 ± 0.2 °, 11.5 ± 0.2 °, 12.2 ± 0.2 °, 13 0.1 ± 0.2 °, 14.3 ± 0.2 °, 15.6 ± 0.2 °, 15.7 ± 0.2 °, 15.9 ± 0.2 °, 16.6 ± 0. 2 °, 17.6 ± 0.2 °, 17.9 ± 0.2 °, 18.9 ± 0.2 °, 19.3 ± 0.2 °, 23.8 ± 0.2 ° The ulipristal acetate ester mixture according to claim 1 or 2 , wherein the ulipristal acetate ester crystal is polymorph B having a powder X-ray diffraction pattern including a diffraction peak at the following diffraction angle 2θ.
Diffraction angle 2θ: 6.4 ± 0.2 °, 8.4 ± 0.2 °, 9.4 ± 0.2 °, 9.6 ± 0.2 °, 11.8 ± 0.2 °, 12 0.8 ± 0.2 °, 15.3 ± 0.2 °, 16.7 ± 0.2 °, 17.5 ± 0.2 °, 18.6 ± 0.2 °, 19.3 ± 0. 2 °, 21.0 ± 0.2 °, 25.5 ± 0.2 ° Ratio of the amorphous Uri pre Stahl acetate and selling pre Stahl acetate crystals (weight ratio), according to claim 1 to 4, the former / the latter = 0.5 / 99.5 to 99.5 / 0.5 Uri pre Stahl acid ester mixture according to any one. And Uri pre Stahl acid ester mixture according to any one of 請 Motomeko 1-5, pharmaceutical compositions comprising a pharmaceutically acceptable excipient. Look including the Uri pre Stahl acid ester mixture according to any one of 請 Motomeko 1-5,
Endometriosis ; endometriosis; uterine bleeding; pain associated with dislocation or metastasis of endometrium; disease caused by uterine fibroids, metastatic leiomyoma, dysmenorrhea, hypermenorrhea, anemia , infertility, prevention of constipation, frequent urination, diseases selected from low back pain and / or jigs 療剤. A contraceptive containing the ulipristal acetate ester mixture according to any one of claims 1 to 5. By milling U replicator Stahl acid esters, process for preparing Uri pre Stahl acid ester mixture according to any one of claims 1 to 5. A method for producing an uripristal acetate mixture according to any one of claims 1 to 5, wherein amorphous uripristal acetate and ulipristal acetate crystals are mixed. The c replicator Stahl acid ester is dissolved in a halogenated hydrocarbon, the solution was concentrated and manufacturing amorphous Uri pre Stahl acid esters, prepared how according to claim 10, wherein mixing with Uri pre Stahl acetate crystalline .

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