WO2014175304A1

WO2014175304A1 - β CRYSTALLINE POLYMORPH OF LEVONORGESTREL, AND MANUFACTURING METHOD FOR SAME

Info

Publication number: WO2014175304A1
Application number: PCT/JP2014/061365
Authority: WO
Inventors: 茂樹岩下; 林　博之; 隆義中川; 宏一宮崎
Original assignee: あすか製薬株式会社
Priority date: 2013-04-24
Filing date: 2014-04-23
Publication date: 2014-10-30
Also published as: JPWO2014175304A1; JP2016006091A; JP5809368B2

Abstract

　Provided are a new crystalline form of levonorgestrel, which is useful as an emergency contraception, etc., a manufacturing method for the same, and a drug composition.　The powder X-ray diffraction spectrum of this β crystalline polymorph of levonorgestrel has diffraction peaks where the diffraction angle (2θ) is an angle of 2θ=13.9°±0.2°, 14.5°±0.2°, 21.3°±0.2°, 24.9°±0.2°, and 28.2°±0.2°, and has essentially no diffraction peak at the angle 2θ=18.6°±0.2°.

Description

Crystalline polymorph β of levonorgestrel and method for producing the same

The present invention relates to a novel crystalline polymorph β of levonorgestrel useful as an emergency contraceptive and the like, 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 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.

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.

In addition, “Norrevo (registered trademark) 0.75 mg” is sold as a medicine containing the same levonorgestrel crystal as the above crystal. This pharmaceutical interview form (Non-patent Document 1) discloses that the crystal has a melting point of 232 to 239 ° C., and no crystal polymorphism is observed in the crystal.

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

Therefore, an object of the present invention is to provide a novel crystalline polymorph of levonorgestrel useful as an emergency contraceptive and the like, a method for producing the same, and a pharmaceutical composition.

Another object of the present invention is to provide a novel crystal polymorph of levonorgestrel which is excellent in solubility and stability and can improve bioavailability, a method for producing the same, and a pharmaceutical composition.

Still another object of the present invention is to provide a novel crystal polymorph of levonorgestrel having excellent fluidity, a method for producing the same, and a pharmaceutical composition.

In order to achieve the above-mentioned problems, the present inventors have intensively studied the crystallization conditions of levonorgestrel. It has been found that a new levonorgestrel crystal having a crystal structure different from that of a crystal can be prepared, and that this new crystal polymorph has excellent solubility and stability, can improve bioavailability, and has excellent powder flowability. The present invention has been completed.

That is, the crystalline polymorph β of levonorgestrel of the present invention is 2θ = 13.9 ° ± 0.2 °, 14.5 ° ± 0.2 °, 21.3 ° ± 0. Diffraction peaks at angles of 2 °, 24.9 ° ± 0.2 °, and 28.2 ° ± 0.2 °, substantially having diffraction peaks at an angle of 2θ = 18.6 ° ± 0.2 ° Not shown. The crystal polymorph β may be a plate (plate) or a needle crystal.

The present invention also includes a method for producing the crystal polymorph β of levonorgestrel by precipitating the crystal polymorph β of levonorgestrel by mixing the levonorgestrel solution and the precipitation solvent. The levonorgestrel solution contains a saturated 5- or 6-membered ring compound containing two oxygen atoms as a hetero atom as a solvent. The precipitation solvent is at least one poor solvent selected from C _4-10 alkanes and C _4-10 cycloalkanes, or this poor solvent and a saturated 5- or 6-membered ring compound containing two oxygen atoms as heteroatoms. A mixed solvent may be used. In this production method, a dioxane solution of levonorgestrel and hexane as a precipitation solvent may be mixed to precipitate the crystal polymorph β of levonorgestrel.

The present invention also encompasses a pharmaceutical composition comprising the crystalline polymorph β of levonorgestrel.

The crystalline polymorph β of levonorgestrel of the present invention has higher solubility, superior stability and improved bioavailability as compared with the conventional crystalline form. In addition, the crystalline polymorph β has high powder fluidity and can suppress variation in drug content in the preparation.

1 is a graph showing a powder X-ray diffraction spectrum of crystalline polymorph β of levonorgestrel of Example 1. FIG. FIG. 2 is a graph showing a differential scanning calorimetric spectrum of crystalline polymorph β of levonorgestrel of Example 1. 3 is a photomicrograph of crystalline polymorph β of levonorgestrel obtained in Example 1. FIG. FIG. 4 is a photomicrograph of levonorgestrel (comparative drug substance). FIG. 5 is a graph showing the results of Pharmacokinetic Test 1. FIG. 6 is a graph showing the results of pharmacokinetic test 2.

[Crystalline polymorph β]
The crystal polymorph β of levonorgestrel of the present invention has a diffraction angle 2θ of 2θ = 13.9 ° ± 0.2 °, 14.5 ° ± 0.2 °, 21.3 ° ± 0.2 °, 24 It has diffraction peaks at angles of .9 ° ± 0.2 ° and 28.2 ° ± 0.2 °. The crystalline polymorph β does not substantially show a diffraction peak at an angle of 2θ = 18.6 ° ± 0.2 °.

When the intensity (height) of the diffraction peak at each diffraction angle 2θ is X ₁ to X ₅ as follows,
X ₁ : 2θ = 13.9 ° ± 0.2 °
X ₂ : 2θ = 14.5 ° ± 0.2 °
X ₃ : 2θ = 21.3 ° ± 0.2 °
X ₄ : 2θ = 24.9 ° ± 0.2 °
X ₅ : 2θ = 28.2 ° ± 0.2 °
The order of the diffraction peak intensity (diffraction peak height) of the crystalline polymorph β may have the following relationship. In the crystal polymorph β, X ₁ and X ₂ usually appear stronger (diffractive peaks are highest) than X ₃ to X ₅ . X ₁ may be stronger (higher), weaker (lower), or equivalent strength (height) than X ₂ . X ₃ is stronger than _{X 4} and _{X 5} (high) at best, may be substantially equivalent in strength (height) and _{X 4} and _{X 5.} That is, the order of X ₁ to X ₅ may indicate a relationship of X ₁ , X ₂ > X ₃ > X ₄ ≈X ₅ .

Note that the order of X ₁ to X ₅ is not necessarily limited to this order. For example, X ₄ may be stronger (higher) than X ₃ .

The respective intensity ratios (height ratios) of X ₁ to X ₅ may be as follows on the basis of X ₄ . For example, X ₁ / X ₄ or X ₂ / X ₄ = 200/100 to 40000/100, preferably about 250/100 to 30000/100 (for example, 300/100 to 15000/100) may be used. Further, X ₃ / X ₄ = 100/100 to 2000/100, preferably about 200/100 to 1500/100 (for example, 400/100 to 1000/100) may be used. Further, X ₅ / X ₄ may be about 10/100 to 1000/100, preferably about 20/100 to 500/100 (for example, 40/100 to 250/100). The intensity ratio between X ₁ and X ₂ is, for example, about X ₁ / X ₂ = 5/100 to 2000/100, preferably about 20/100 to 1500/100 (for example, 80/100 to 1000/100). It may be.

In addition to the above-mentioned diffraction peak, the crystalline polymorph β has 2θ = 19.9 ° ± 0.2 °, 22.6 ° ± 0.2 °, 31.4 ° ± 0.2 °, 35 It may have a diffraction peak at an angle of 3 ° ± 0.2 ° and / or 43.3 ° ± 0.2 °.

Crystalline polymorph β has an endothermic peak at 238 to 245 ° C., preferably 240 to 243 ° C., more preferably 241 to 242 ° C. in the differential scanning calorimetry (DSC) spectrum. The melting point represented by the circumscribed intersection in the chart) is about 239.4 ° C. ± 1 ° C. (especially 239.4 ° C. ± 0.5 ° C.).

The crystal polymorph β may be any of single crystal, twin crystal, and polycrystal, but is usually a single crystal in many cases. The form (outer shape) of the crystal may be a plate (plate) or a needle crystal.

The particle size of the crystalline polymorph β is not particularly limited, and for example, based on the laser diffraction method, the average particle diameter is 0.01 to 500 μm, preferably about 0.1 to 300 μm (for example, 1 to 250 μm). More preferably, it may be about 2 to 200 μm (for example, 5 to 100 μm), usually about 0.1 to 50 μm (for example, 0.5 to 10 μm).

Crystalline polymorph β has high powder flowability. Therefore, even in the preparation of a preparation having a low content of active ingredients, it can be prepared by automatic calculation in a small lot. In addition, since the conventional levonorgestrel has low powder fluidity, in the preparation of a preparation containing a trace amount of an active ingredient, variation in the content of the active ingredient becomes large. In addition, the crystalline polymorph β can be obtained as a preparation with little variation in the content of the active ingredient even when a production method such as a direct tableting method that does not require a granulation step is used. The angle of repose (°) of the crystalline polymorph β is, for example, about 20 to 45 (for example, 25 to 42), preferably about 30 to 40, more preferably about 35 to 39 under the conditions of a temperature of 21 ° C. and a humidity of 37%. It may be. The angle of repose can be measured by the method of the example.

In addition, crystalline polymorph β is easily absorbed due to its high dissolution rate, and is excellent in bioavailability. Therefore, crystalline polymorph β can effectively exhibit the activity of levonorgestrel even if the amount used is smaller than that of conventional levonorgestrel. For example, the dissolution rate in an acidic solution (pH 1.2) is 72.5 ng / mL / hr for conventional levonorgestrel and 83.1 ng / mL / hr for crystalline polymorph β at a temperature of 37 ° C. The dissolution rate can be measured by the method of the example.

Moreover, the crystalline polymorph β of levonorgestrel of the present invention is excellent in stability and stable to heat, light and humidity. For example, it can exist stably as a crystal for 1 month or more, preferably 2 months or more, more preferably 6 months or more in a room temperature environment.

Furthermore, since the crystalline polymorph β of levonorgestrel of the present invention is highly stable against friction, it can exist stably while maintaining the crystalline form even when a frictional force is applied by grinding or the like.
[Production method]
The crystalline polymorph β of levonorgestrel of the present invention is, for example, a levonorgestrel solution prepared by dissolving levonorgestrel in a good solvent composed of a saturated 5- or 6-membered ring compound containing two oxygen atoms as heteroatoms, It can be produced by mixing the precipitation solvent to precipitate the crystalline polymorph β of levonorgestrel. As the good solvent (the 5- or 6-membered ring compound), for example, dioxane, dioxolane and the like are used, and one kind or two or more kinds may be used. Of the good solvents, dioxane is preferred.

The levonorgestrel can be produced by a conventional method, for example, the method described in Synthetic Communications, 26, 1461 (2010).

The concentration of levonorgestrel in the levonorgestrel solution is, for example, 0.1 to 20 wt% (eg 0.5 to 10 wt%), preferably 0.5 to 7 wt%, more preferably 1 to 5 wt%. % (For example, 2 to 4% by weight). The levonorgestrel solution preferably has a high concentration in order to precipitate the crystalline polymorph β efficiently, and the levonorgestrel may be supersaturated at the temperature of the precipitation system (for example, under cooling). The high-concentration levonorgestrel solution may be prepared, for example, by heating at about 30 to 70 ° C., preferably about 35 to 60 ° C., more preferably about 35 to 50 ° C.

The precipitation solvent may be a poor solvent alone or a mixed solvent of a poor solvent and a good solvent. As the poor solvent, for example, C _4-10 alkane (pentane, hexane, heptane, octane, etc.), C _4-10 cycloalkane (cyclopentane, cyclohexane, etc.) and the like are used, either alone or in combination of two or more. May be. A preferred antisolvent is hexane. As the good solvent in the mixed solvent, a saturated 5- or 6-membered ring compound (for example, dioxane or dioxolane) containing two oxygen atoms as a hetero atom is used, as described above, either alone or in combination of two or more. May be. Moreover, although the kind of good solvent in a mixed solvent may differ from the good solvent of levonorgestrel, it is preferable that it is the same.

In the above mixed solvent, the weight ratio of the poor solvent (for example, hexane) and the good solvent (for example, dioxane) is, for example, poor solvent / good solvent = 50/50 to 97/3, preferably 60/40 to It may be about 95/5, more preferably about 70/30 to 93/7 (for example, 75/25 to 90/10).

The weight ratio of the poor solvent to the good solvent in the precipitation system is, for example, poor solvent / good solvent = 50/50 to 99/1, preferably 55/45 to 98/2, more preferably 60/40 to It may be about 97/3. If the amount of the poor solvent is too small, the crystalline polymorph β of levonorgestrel cannot be effectively precipitated. If the amount is too large, a large amount of the poor solvent is required, resulting in poor economic efficiency.

It is preferable that the levonorgestrel solution and the precipitation solvent are gradually mixed over time. As a mixing method, for example, the precipitation solvent may be added to the levonorgestrel solution. However, since the operation is easy, it is more preferable to add the levonorgestrel solution to the precipitation solvent. As the addition method, for example, the above-mentioned poor solvent or mixed solvent may be added dropwise to the levonorgestrel solution. The levonogestrel solution may be a heated high-concentration solution, and the levonogestrel solution may be mixed with the precipitation solvent.

The mixing speed is selected depending on the concentration of the levonorgestrel solution. For example, when the total weight of the levonorgestrel solution is 100 parts by weight, the levonorgestrel solution is 0.01 to 50 parts by weight / minute, preferably 0. It may be 1 to 10 parts by weight / minute, in particular 0.5 to 5 parts by weight / minute.

Furthermore, the precipitation system may be stirred to precipitate the crystalline polymorph β from the precipitation system. The stirring time is not particularly limited, and may be, for example, about 1 minute to 1 day, and preferably about 10 minutes to 3 hours (for example, 10 minutes to 1 hour).

The above precipitation can usually be carried out under cooling, for example, under a temperature condition of about −10 to 25 ° C., preferably −10 to 15 ° C., particularly −5 to 10 ° C. (eg under ice cooling). You may go. If the temperature is too high, the crystalline polymorph β of levonorgestrel may not be effectively precipitated.

The crystalline polymorph β precipitated in the mixture can be isolated from the mixture by a method such as filtration. Further, the crystalline polymorph β may be washed and dried.

The separation method may be, for example, natural filtration, vacuum filtration, or the like, but a method in which no pressure acts on the crystalline polymorph β, for example, natural filtration (the solution is allowed to fall naturally from the filter cloth, It is preferable to carry out by the method of separating the solid). The separated crystalline polymorph β is washed with a poor solvent such as hydrocarbons (aliphatic, alicyclic or aromatic hydrocarbons such as hexane) and then dried by, for example, natural drying, vacuum drying, heat drying, etc. However, it is preferable to dry by natural drying.

[Use and pharmaceutical composition]
The crystalline polymorph β of levonorgestrel of the present invention is 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 thing (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.).

Also included are sprays such as the above powders, 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). In addition, the preparation may be an oral administration preparation (granule, powder, tablet (sublingual tablet, orally disintegrating tablet, etc.), capsule, film preparation, etc.), or parenteral administration preparation (inhalation, transdermal administration). Preparation, nasal administration preparation, etc.). Further, the preparation may be a topical preparation (ointment, patch, cataplasm, etc.).

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, and Eudragit (methacrylic acid). Acid / acrylic acid copolymer). The coating agent may be an enteric component such as cellulose phthalate, hydroxypropylmethylcellulose phthalate, methyl methacrylate- (meth) acrylic acid copolymer, or a polymer (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.

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, stabilizers, preservatives or preservatives, bactericides or antibacterial agents, antistatic agents, flavoring agents, or masking agents. , Coloring agents, flavoring agents or fragrances, cooling agents, antifoaming agents and the like. These additives can be used alone or in combination of two or more.

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 crystalline polymorph β of levonorgestrel of the present invention has low toxicity and excellent safety, and is a human and non-human animal, usually a mammal (eg, human, mouse, rat, rabbit, dog, cat, bovine , 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 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.

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
700 mg of levonorgestrel (Industriale Chimica) 700 mg was dissolved in dioxane to obtain a 25 mL levonorgestrel solution. This solution was added dropwise to 1 L of hexane over 74 minutes under ice cooling, and after stirring for 20 minutes, wet crystals obtained by natural filtration were washed with hexane. The wet crystals were dried by ventilation at 30 ° C. for 18 hours to obtain levonorgestrel crystal polymorph β629 mg.

The measurement result of the powder X-ray diffraction spectrum of the obtained polymorph β of levonorgestrel is shown in FIG. 1, and the measurement result of the differential scanning calorimetry spectrum is shown in FIG. From FIG. 2, the extrapolated onset temperature (melting point) of DSC was 239.4 ° C.

Comparative Example 1
After 200 mg of levonorgestrel (Industriale Chimica) was added to 12 mL of acetonitrile and heated to reflux temperature to dissolve levonorgestrel, the resulting levonorgestrel solution was allowed to stand overnight at room temperature. Crystals precipitated in this solution were collected by filtration to obtain 183 mg of levonorgestrel crystals.

When the powder X-ray diffraction spectrum of the obtained levonorgestrel crystal was measured, it was a known crystal in WO2009 / 035527, and the crystal polymorph β of the present invention was not obtained.

Comparative Example 2
200 mg of levonorgestrel (Industriale Chimica) was dissolved in 3 mL of N, N-dimethylacetamide, and 3 mL of water was added to the resulting levonorgestrel solution while stirring at room temperature. Crystals precipitated in this solution were collected by filtration to obtain 249 mg of wet crystals of levonorgestrel.

Comparative Example 3
200 mg of levonorgestrel (Industriale Chimica) was dissolved in 5 mL of chloroform to obtain a levonorgestrel solution. This solution was allowed to stand at room temperature for 3 days to spontaneously evaporate the solvent to obtain 188 mg of levonorgestrel crystals.

[Crystal shape]
FIG. 3 shows a photograph of the crystal polymorph β obtained in Example 1 (manufactured by Shimadzu Corporation, “BA200”, objective lens magnification 10 ×). FIG. 3 shows a levonorgestrel (Industriale Chimica Co., Ltd .: FIG. 4 shows a photomicrograph of the body). As shown in FIG. 4, the comparative drug substance did not show a clear crystal shape. However, as shown in FIG. 3, the crystal polymorph β has a plate shape (plate side) with a long side / short side = about 3 to 10. ) Or needle-like crystals.

[Fluidity test]
The height from the lower end of the funnel to the deposition surface is fixed at 4.5 cm, and the crystalline polymorph β obtained in Example 1 or the powdery sample of the comparative base is dropped from the lower end of the funnel to the deposition surface, and the deposition surface Was measured under the conditions of a temperature of 21 ° C. and a humidity of 37%. The results are shown in Table 1. The degree of fluidity based on Japanese Pharmacopoeia reference information (G2 physical properties-related powder fluidity; Carr, RL: Evaluating flow properties of solids. Chem. Eng. 1965; 72: 163-168.). Was described.

As shown in Table 1, the crystalline polymorph β obtained in Example 1 is superior in powder flowability as compared with the comparative raw material.

[Dissolution rate]
The crystalline polymorph β obtained in Example 1 or the comparative original material was compressed using a 5 mm diameter punch at a pressure of 10 kN for 3 seconds to solidify into a fixed shape, thereby obtaining pellets. A test sample was obtained by adding 50 mg of this pellet preparation to 900 mL of the following elution solvent containing Tween 80 at a concentration of 1%. The test sample was stirred for 15 minutes at 37 ° C. and 50 rpm, a part of the sample was removed, the solid content was filtered off, and high performance liquid chromatography (equipment: “LC-2010AHT” manufactured by Shimadzu Corporation) was obtained. Column: “X Bridge C18 5 μm” manufactured by Waters Co., column temperature: 35 ° C., eluent: acetonitrile / 0.1% trifluoroacetic acid aqueous solution (volume ratio 3: 2), flow rate: 1.0 mL / min, detection: The dissolution rate (ng / mL / hr) was calculated. The results are shown in Table 2.

(Elution solvent)
1. Dissolution test first solution (pH 1.2)
1. A solution prepared by adding water to 2.0 g of sodium chloride and 7.0 mL of hydrochloric acid to make 1000 mL purified water

As shown in Table 2, the crystalline polymorph β obtained in Example 1 is easily absorbed because it has a higher dissolution rate than the comparative base.

[Pharmacokinetic study 1]
Two female rats (11 weeks of age) were prepared, and the crystalline polymorph β obtained in Example 1 was applied to one, and the comparative drug substance was applied to the other. That is, each rat was orally administered at a dose of 6.7 mg / kg as a jelly agent, and the plasma unchanged substance concentration (in blood) after 0.5, 1, 2, 3, 4, 6, 8 hours Levonorgestrel concentration) was measured. The jelly agent was prepared by mixing 6.7 mg of the crystalline polymorph β obtained in Example 1 or the comparative original substance in 10 mL of MediGel Sucrose (manufactured by Clear H ₂ O). The transition of the unchanged body concentration in plasma is shown in FIG. The pharmacokinetic parameters are shown in Table 3.

In the table, C _max is the maximum plasma concentration, T _max is the time from administration to C _max , AUC _0-8 is the area under the concentration-time curve, and MRT _0-8 is the average residence time.
[Pharmacokinetic study 2]
Two female dogs (4 years old) were prepared, and the crystalline polymorph β obtained in Example 1 was applied to one, and the comparative drug substance was applied to the other. That is, each dog was filled with capsules at a dose of 0.67 mg / kg and administered orally once, and the unchanged plasma concentration after 0.5, 1, 2, 3, 4, 6, 8 hours ( Blood levonorgestrel concentration) was measured. The transition of the unchanged body concentration in plasma is shown in FIG. The pharmacokinetic parameters are shown in Table 4.

In the table, C _max is the maximum plasma concentration, T _max is the time from administration to C _max , AUC _0-8 is the area under the concentration-time curve, MRT _0-8 is the average residence time, and t _1/2 is halved Indicates the period.

As shown in Tables 3 and 4 and FIGS. 5 and 6, the crystalline polymorph β obtained in Example 1 shows superior bioavailability as compared with the comparative drug substance.

The crystalline polymorph β of levonorgestrel according to the present invention is suitably used as an emergency contraceptive and the like because it has extremely high solubility compared to the conventional crystal form, is excellent in stability, and can improve bioavailability. .

Claims

In the powder X-ray diffraction spectrum, the diffraction angle 2θ is 2θ = 13.9 ° ± 0.2 °, 14.5 ° ± 0.2 °, 21.3 ° ± 0.2 °, 24.9 ° ± 0. Crystalline polymorphs of levonorgestrel with diffraction peaks at angles of .2 ° and 28.2 ° ± 0.2 ° and substantially no diffraction peaks at an angle of 2θ = 18.6 ° ± 0.2 ° β.
The crystal polymorph β according to claim 1, which is a plate-like (plate-like) or needle-like crystal.
A method for precipitating crystal polymorph β of levonorgestrel by mixing a levonorgestrel solution and a precipitation solvent, and producing crystal polymorph β according to claim 1,
The levonorgestrel solution contains a saturated 5- or 6-membered ring compound containing two oxygen atoms as a hetero atom as a solvent,
The precipitation solvent is at least one poor solvent selected from C 4-10 alkanes and C 4-10 cycloalkanes, or a saturated 5- or 6-membered ring compound containing two oxygen atoms as heteroatoms and the poor solvent. A production method which is a mixed solvent.
The method for producing crystalline polymorph β according to claim 3, wherein a dioxane solution of levonorgestrel and hexane as a precipitation solvent are mixed.
A pharmaceutical composition comprising the crystalline polymorph β according to claim 1 or 2.