JP2016006090A - α-CRYSTAL POLYMORPHISM OF LEVONORGESTREL AND PRODUCTION METHOD THEREOF - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a novel crystal polymorphism of levonorgestrel which is useful as an emergency contraceptive or the like, and to provide a production method thereof, as well as to provide a pharmaceutical composition.SOLUTION: The invention provides an α-crystal polymorphism of levonorgestrel in which a diffraction angle 2θ has a diffraction peak at 2θ=17.2° ±0.2°, 18.6° ±0.2°, 22.7° ±0.2°, 31.1° ±0.2°, and 35.5° ±0.2° in powder X-ray diffraction spectrum. When the strength of the diffraction peak at 2θ=18.6° ±0.2° is X, and the strength of the diffraction peak at 2θ=31.1° ±0.2° is X, the intensity ratio X/Xof Xand Xis 25/100-400/100. The invention also provides a method for producing the α-crystal polymorphism by mixing a dioxane solution of levonorgestrel with a mixed solvent that contains water and dioxane in a weight ratio of water/dioxane=50/0-95/5.

Description

  The present invention relates to a novel crystalline polymorph α 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 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.

  In addition, “Norrevo (registered trademark) 0.75 mg” is on the market as a pharmaceutical 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)

Pharmaceutical interview form “Norrevo (registered trademark) 0.75 mg” (III. Items related to active ingredients)

  Accordingly, 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 crystalline 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 crystalline polymorph of levonorgestrel excellent in dispersibility and 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. The ability to prepare a new levonorgestrel crystal having a crystal structure different from that of the crystal. This new crystal polymorph has excellent solubility and stability, can improve bioavailability, and has excellent powder flowability and water dispersibility. As a result, the present invention was completed.

  That is, the crystal polymorph α of levonorgestrel of the present invention has a diffraction angle 2θ of 2θ = 17.2 ° ± 0.2 °, 18.6 ° ± 0.2 °, 22. It has diffraction peaks at angles of 7 ° ± 0.2 °, 31.1 ° ± 0.2 ° and 35.5 ° ± 0.2 °. The crystal polymorph α may be a prismatic crystal.

  The present invention also includes a method for producing a crystal polymorph α of levonorgestrel by precipitating the crystal polymorph α of levonorgestrel by mixing a levonorgestrel solution and a 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 may be water or a mixed solvent of water and a saturated 5- or 6-membered ring compound containing two oxygen atoms as a hetero atom. In this production method, a dioxane solution of levonorgestrel and a mixed solvent as a precipitation solvent containing water and dioxane in a weight ratio of water / dioxane = 50/50 to 95/5 are mixed, and crystal polymorphs of levonorgestrel α may be precipitated.

  The present invention also includes a pharmaceutical composition comprising the crystalline polymorph α of levonorgestrel.

  The crystalline polymorph α of levonorgestrel of the present invention has higher solubility, superior stability, and improved bioavailability compared to the conventional crystalline form. In addition, the crystalline polymorph α has higher powder flowability than the conventional crystalline form, and can suppress variation in drug content in the preparation. Furthermore, since it is excellent in water dispersibility, it can be stably formulated by using a wet granulation method using an aqueous solvent.

1 is a graph showing a powder X-ray diffraction spectrum of crystal polymorph α of levonorgestrel of Example 1. FIG. FIG. 2 is a graph showing a differential scanning calorimetry spectrum of the crystalline polymorph α of levonorgestrel of Example 1. 3 is a photomicrograph of crystalline polymorph α 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.

[Crystal polymorph α]
The crystal polymorph α of the levonorgestrel of the present invention has a diffraction angle 2θ of 2θ = 17.2 ° ± 0.2 °, 18.6 ° ± 0.2 °, 22.7 ° ± 0.2 °, 31 Has diffraction peaks at angles of 1 ° ± 0.2 ° and 35.5 ° ± 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 = 17.2 ° ± 0.2 °
X ₂ : 2θ = 18.6 ° ± 0.2 °
X ₃ : 2θ = 22.7 ° ± 0.2 °
X ₄ : 2θ = 31.1 ° ± 0.2 °
X ₅ : 2θ = 35.5 ° ± 0.2 °
The order of the diffraction peak intensities (diffraction peak heights) of the crystal polymorph α may have the following relationship. In the crystalline polymorph α, X ₁ usually appears the strongest (the highest diffraction peak) compared to X _{2 to} X ₅ . X ₂ and X ₄ may have approximately the same strength (height), and X ₃ and X ₅ may have approximately the same strength (height). X ₂ and X ₄ may be stronger (higher) than X ₃ and X ₅ . That _is, the order of X 1 to X _{5 are, X 1> X 2 ≒ X} 4> X 3 may indicate a relationship ≒ _{X 5.}

Note that the order of X _{1 to} X ₅ is not necessarily limited to this order. For example, X ₃ may be stronger (higher) than X ₂ .

The respective intensity ratios (height ratios) of X _{1 to} X ₅ may be as follows on the basis of X ₂ . For _{example, X 1 / X 2 = 200} / 100~2000 / 100, preferably 250 / 100-1000 / 100 (e.g., 300 / 100-600 / 100) may be about. Further, X ₃ / X ₂ or X ₅ / X ₂ = 10/100 to 200/100, preferably about 20/100 to 150/100 (for example, 25/100 to 100/100) may be used. Further, X ₄ / X ₂ = 25/100 to 400/100, preferably about 30/100 to 300/100 (for example, 50/100 to 200/100) may be used.

  In addition to the above-mentioned diffraction peak, the crystalline polymorph α is 2θ = 21.3 ° ± 0.2 °, 21.9 ° ± 0.2 °, 23.0 ° ± 0.2 °, 23 Have diffraction peaks at angles of 4 ° ± 0.2 °, 29.1 ° ± 0.2 °, 29.5 ° ± 0.2 ° and / or 41.8 ° ± 0.2 °. May be.

  The polymorphic α has an endothermic peak at 238 to 245 ° C., preferably 240 to 243 ° C., more preferably about 241 to 242 ° C. in the differential scanning calorimetry (DSC) spectrum, and the extrapolated onset temperature (DSC) of the DSC The melting point represented by the circumscribed intersection in the chart) is about 238.7 ° C. ± 1 ° C. (especially 238.7 ° C. ± 0.5 ° C.). The differential scanning calorimetry spectrum can be measured by a conventional method, for example, the conditions of Examples described later.

  The crystal polymorph α may be any of single crystal, twin crystal, and polycrystal, but usually it is often a single crystal. The crystal form (outer shape) may be a prismatic crystal.

  The particle size of the crystal polymorph α is not particularly limited. For example, based on the laser diffraction method, the average particle diameter is 0.01 to 500 μm, preferably 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), and usually about 0.1 to 50 μm (for example, 0.5 to 10 μm).

  Crystal polymorph α 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 α 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 α can be selected from about 10 to 40 under the conditions of a temperature of 21 ° C. and a humidity of 37%, for example, 15 to 30 (for example, 17 to 35), preferably 20 to 30. (For example, 22 to 28), more preferably about 20 to 25. The angle of repose can be measured by the method of the example.

  Further, the crystalline polymorph α is excellent in dispersibility in water. For example, the crystalline polymorph α disperses quickly and uniformly in water, but conventional levonorgestrel does not exhibit dispersibility while floating on the water surface. Therefore, the crystalline polymorph α is highly dispersible in the endocrine fluid in the living body, and can effectively absorb the active ingredient in the living body. Moreover, since the dispersibility is high, a preparation in which the crystalline polymorph α is uniformly dispersed can be efficiently prepared by a method such as a wet granulation method using an aqueous solvent in the granulation step of drug production.

  Furthermore, the crystalline polymorph α is easily absorbed because of its high dissolution rate, and has excellent bioavailability. Therefore, the crystalline polymorph α can effectively exhibit the activity of levonorgestrel even if the amount used is smaller than that of conventional levonorgestrel. For example, the dissolution rate is high not only in the acidic range [pH 1 to 4 (for example, pH 1 to 3)] but also in the neutral range [pH 5 to 8 (for example, 6 to 8)]. For example, the dissolution rate in a neutral solution (pH 6.9) is 59.5 ng / mL / hr for conventional levonorgestrel at a temperature of 37 ° C., and 86.9 ng / mL / hr for polymorph α. . The dissolution rate can be measured by the method of the example.

The crystalline polymorph α 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.
[Production method]
The crystalline polymorph α of levonorgestrel of the present invention is, for example, a levonorgestrel solution prepared by dissolving levonorgestrel in a good solvent consisting of a saturated 5- or 6-membered ring compound containing two oxygen atoms as heteroatoms, It can be produced by mixing with a precipitation solvent to precipitate the crystalline polymorph α 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 such as the method described in Synthetic Communications, 26, 1461 (2010).

  The concentration of levonorgestrel in the levonorgestrel solution is, for example, 0.1 to 20% by weight (for example, 0.5 to 10% by weight), preferably 0.5 to 7% by weight, more preferably 1 to 5% by weight. % (For example, 2 to 4% by weight). The levonorgestrel solution preferably has a high concentration in order to efficiently precipitate the crystalline polymorph α, 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 by heating at, for example, 30 to 70 ° C, preferably 35 to 60 ° C, more preferably about 35 to 50 ° C.

  The precipitation solvent may be water alone or a mixed solvent of water and a good solvent. 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 said good solvent of levonorgestrel, it is preferable that it is the same.

  The precipitation solvent is preferably a mixed solvent of water and a good solvent (for example, dioxane). The weight ratio of water in the mixed solvent to the good solvent (for example, dioxane) is, for example, water / good solvent = 50/50 to 95/5, preferably 60/40 to 90/10, more preferably 65. It may be about / 35 to 85/15 (for example, 70/30 to 80/20).

  The weight ratio of water to the good solvent in the precipitation system (in the state where the levonorgestrel solution and the precipitation solvent are mixed) is, for example, water / good solvent = 50/50 to 99/1 (for example, 55/45 to 55/45). 98/2), preferably 60/40 to 97/3 (for example, 60/40 to 90/10), more preferably about 65/35 to 85/15 (for example, 67/33 to 80/20). May be. If the amount of water is too small, the crystal polymorph α of levonorgestrel cannot be effectively precipitated. If the amount is too large, a large amount of water is required, resulting in poor economic efficiency.

  The levonorgestrel solution and the precipitation solvent are preferably mixed within a short 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. The precipitation solvent and the levonorgestrel solution may be mixed one or more times (for example, 2 to 5 times), or may be mixed at one time. It is preferable to add to the precipitation solvent one or more times (for example, 2 to 5 times), and more preferably within a short time. Moreover, you may mix the said levonorgestrel solution which may be the high concentration heated with the said precipitation solvent.

  Furthermore, the precipitation system may be agitated to precipitate the crystalline polymorph α 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 performed under cooling, for example, -10 to 25 ° C, preferably -10 to 15 ° C, particularly -5 to 10 ° C (for example, under ice cooling). You may go. If the temperature is too high, the crystalline polymorph α of levonorgestrel may not be effectively precipitated.

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

  The separation method may be, for example, natural filtration, vacuum filtration, or the like, but is a method in which no pressure acts on the crystal polymorph α, for example, natural filtration (a solution is naturally dropped from the filter cloth, It is preferable to carry out by the method of separating the solid). The separated crystalline polymorph α may be washed with a poor solvent such as water and then dried by, for example, natural drying, vacuum drying, heat drying, etc., but by natural drying so as not to exert pressure on the crystalline polymorph α. It is preferable to dry.

[Use and pharmaceutical composition]
The crystalline polymorph α 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 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, 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, 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 α 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 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
700 mg of levonorgestrel (Industriale Chimica) 700 mg was dissolved in dioxane to obtain a 25 mL levonorgestrel solution. This solution was added at once to a mixed solvent of 500 mL of water and 200 mL of dioxane under ice-cooling, and after stirring for 20 minutes, wet crystals obtained by natural filtration were washed with water. The wet crystals were dried by ventilation at 30 ° C. for 18 hours to obtain levonorgestrel crystal polymorph α653 mg.

  The measurement result of the powder X-ray diffraction spectrum of the obtained polymorphic α 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 238.7 ° C.

Comparative Example 1
After 200 mg of levonorgestrel (Industriale Chimica) was added to 12 mL of acetone 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 151 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 α of the present invention was not obtained.

Comparative Example 2
200 mg of levonorgestrel (Industriale Chimica) was dissolved in 4 mL of dimethyl sulfoxide, and 4 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 266 mg of wet crystals of levonorgestrel.

  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 α of the present invention was not obtained.

Comparative Example 3
200 mg of levonorgestrel (Industriale Chimica) was dissolved in 5.5 mL of tetrahydrofuran to obtain a levonorgestrel solution. This solution was allowed to stand at room temperature for 3 days to spontaneously evaporate the solvent to obtain 193 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 α of the present invention was not obtained.

[Crystal shape]
FIG. 3 shows a photograph of the crystal polymorph α obtained in Example 1 (manufactured by Shimadzu Corporation, “BA200”, objective lens magnification 10 ×). FIG. 3 shows levonorgestrel (Industriale Chimica, Inc .: FIG. 4 shows a photomicrograph of the body). As shown in FIG. 4, the comparative drug substance did not show a clear crystal shape, but as shown in FIG. 3, it was found that the crystal polymorph α was a prismatic crystal.

[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 α 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. In addition, the degree of fluidity is described based on Japanese Pharmacopoeia reference information (G2 Physical property-related powder fluidity; Carr, RL: Evaluating flow properties of solids. Chem. Eng. 1965; 72: 163-168.) .

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

[Dispersibility (wetting) test]
2 mg of the crystalline polymorph α powder obtained in Example 1 was added to 1.5 mL of purified water, and the mixture was stirred and allowed to stand. As a result, α form was uniformly dispersed in purified water. On the other hand, even if the comparative base was added to water in the same manner and stirred, it did not disperse while floating on the surface.

  Moreover, the transmittance (wavelength: 400 nm; Co., Ltd.) of the dispersion of the crystalline polymorph α or the comparative base (a dispersion obtained by adding 4 mg of the crystalline polymorph α or the powder of the comparative base to 3.0 ml of purified water). When the spectrophotometer (manufactured by Shimadzu Corporation) was measured, the crystalline polymorph α showed a transmittance of 23%, and the comparative original showed a transmittance of 100%. From this result, it was found that the comparative drug substance was not dispersed in water at all, but the crystalline polymorph α was uniformly dispersed in water.

  That is, the crystalline polymorph α of the present invention has improved dispersibility in the endocrine fluid (eg, gastric fluid) in the living body and improved absorption into the living body. Moreover, since the dispersibility in water is improved, it is possible to obtain a preparation in which polymorph α is uniformly distributed by a wet granulation method using an aqueous solvent, and the preparation becomes simple.

[Dissolution rate]
The crystal polymorph α obtained in Example 1 or the comparative original material was compressed with 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%. This test sample was stirred for 15 minutes under the conditions of 37 ° C. and 50 rpm, and then a part thereof was removed, and the solid content was filtered off. High performance liquid chromatography (apparatus: “LC-2010AHT” manufactured by Shimadzu Corporation) Column: Waters, “XBridge C18 5 μm”, column temperature: 35 ° C., eluent: acetonitrile / 0.1% trifluoroacetic acid aqueous solution (volume ratio 3: 2), flow rate: 1.0 mL / min, detection : UV 240 nm), and 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 Dissolution test second solution (pH 6.9)
A solution in which 1 volume of water is added to 1 volume of phosphate buffer at pH 6.8. The phosphate buffer (pH 6.8) used was a solution prepared by dissolving 3.40 g of potassium dihydrogen phosphate and 3.55 g of anhydrous disodium hydrogen phosphate in water to 1000 mL.

3. Diluted McIlvaine buffer (pH 4.0)
3. A solution prepared by adjusting pH using 0.05 mol / L disodium hydrogen phosphate and 0.025 mol / L citric acid. purified water

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

[Pharmacokinetic study 1]
Ten female rats (11 weeks of age) were randomly divided into two groups of five, and the polymorphic α obtained in Example 1 was applied to the first group of rats. Applied to rats. That is, each group of rats was given a capsule at a dose of 6.7 mg / kg and orally administered once, and the plasma unchanged substance concentration after 0.5, 1, 2, 3, 4, 6 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 3.

The individual values in FIG. 5 and Table 3 represent the mean ± SD (standard deviation) of 5 rats. In the table, C _max is the maximum plasma concentration, T _max is the time from administration to C _max , AUC _0-6 is the area under the concentration-time curve, and MRT _0-6 is the average residence time (hereinafter the same) ).

In addition, when a significant difference test (t-test) was performed, the crystal polymorph α obtained in Example 1 was significantly different in C _max and AUC _0-6 compared to the comparative drug substance (p <0. 05) was obtained.

[Pharmacokinetic study 2]
Ten female rats (11 weeks of age) were randomly divided into two groups of five, and the polymorphic α obtained in Example 1 was applied to the first group of rats. Applied to rats. That is, each group of rats was orally administered as a jelly at a dose of 6.7 mg / kg, and the unchanged plasma concentration (in blood) after 0.5, 1, 2, 3, 4, 6 hours. Levonorgestrel concentration) was measured. The jelly agent was prepared by mixing 6.7 mg of the crystalline polymorph α obtained in Example 1 or the comparative drug 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 4.

  As shown in Table 3, FIG. 5 and Table 4, and FIG. 6, the crystalline polymorph α obtained in Example 1 exhibits superior bioavailability as compared with the comparative drug substance.

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

Claims (4)

In the powder X-ray diffraction spectrum, the diffraction angle 2θ is 2θ = 17.2 ° ± 0.2 °, 18.6 ° ± 0.2 °, 22.7 ° ± 0.2 °, 31.1 ° ± 0. .2 ° and 35.5 ° ± 0.2 ° with diffraction peaks at 2θ = 18.6 ° ± 0.2 °, the intensity of the diffraction peak at X ₂ , 2θ = 31.1 ° ± when the intensity of the diffraction peaks at 0.2 ° and the _{X 4,} polymorphs levonorgestrel intensity ratio _X 4 / _{X 2} of _{X 2} and _{X 4} is 25 / 100~400 / 100 α.   The crystal polymorph α according to claim 1, which is a prismatic crystal. A method of precipitating crystal polymorph α of levonorgestrel by mixing a levonorgestrel solution and a precipitation solvent, and producing crystal polymorph α according to claim 1,
The levonorgestrel solution is a dioxane solution of levonorgestrel,
The production method, wherein the precipitation solvent is a mixed solvent containing water and dioxane at a weight ratio of water / dioxane = 50/50 to 95/5.   A solid preparation comprising the crystalline polymorph α according to claim 1 or 2.