JPH09291073A - Vitamin d derivative of crystal form - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject compound excellent in storage stability, easy in handleability, and useful as a medicine for treating or preventing diseases caused by the abnormal absorption, transport or metabolism of calcium. SOLUTION: This vitamin D derivative of crystal form is represented by formula I. The derivative can be obtained by applying a crystallization treatment to a vitamin D derivative of amorphous form represented by formula II in an organic solvent containing water. For example, 10mg of the vitamin D derivative of amorphous form represented by formula II is dissolved in 0.2ml of diethyl ether, and the obtained solution is mixed with 1.35ml of toluene and subsequently stirred, until giving a homogeneous solution. The homogeneous solution is concentrated under vacuum, until being reduced to a half volume of the solution, mixed with three drops (approximately 100mg) of purified water and further stirred at room temperature for >=15hr. The treated solution is cooled to approximately 5 deg.C, and the deposited crystals are filtered off to obtain 7mg of the vitamin D derivative or crystal form.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a crystalline vitamin D derivative useful as a therapeutic or prophylactic agent for diseases caused by abnormal calcium absorption, transport or metabolism, a method for producing the same, its use and its vitamin D derivative. To a stable pharmaceutical composition containing

[0002]

[Prior art]

 Formula (2)

Embedded image Vitamin D derivative represented by [(5Z, 7E, 23S)
-26,26,26,27,27,27-hexafluoro-9,10-secocholesta-5,7,10 (19)-
Triene-1α, 3β, 23,25-tetraol]
Is known as a therapeutic or prophylactic agent for various diseases caused by abnormal calcium absorption, transport or metabolism, for example, bone diseases such as rickets, osteomalacia and osteoporosis, tumors and psoriasis. Japanese Patent Laid-Open No. 63-4524
No. 9). In Japanese Patent Laid-Open No. 63-45249,
What is specifically described in the examples as the vitamin D derivative represented by the formula (2) is in a non-crystalline state (amorphous state or non-crystalline state powder state). Activated vitamin D
There is known a technique of locally applying an external preparation as an external preparation in order to apply intractable skin diseases such as psoriasis (Japanese Patent Publication No. 3-68009, JP-A-63-1835).
34 gazette, special table Sho 62-501073 gazette, EP1
29003).

[0003]

The amorphous vitamin D derivative represented by the formula (2) has low storage stability and has problems in handling during production, formulation and the like. In addition, since active vitamin Ds are chemically unstable, particularly to light, they are placed in an unstable environment when used as an external preparation. Therefore, it has been an important subject to provide a pharmaceutical composition of active vitamin Ds which is stable to light after being applied to an affected area.

[0004]

[Means for Solving the Problems] The inventors of the present invention have made extensive studies to solve the above-mentioned problems, and expressed by the formula (1)

Embedded image It has been found that the crystalline vitamin D derivative represented by the formula (1) has very good storage stability, and found a stable pharmaceutical composition containing the vitamin D derivative.
The present invention has been completed.

That is, the present invention relates to [1] Formula (1)

Embedded image [2] The crystalline vitamin D derivative of [1], which shows the average value of the interplanar spacing d by powder X-rays and the relative intensity described in Table 1,

[Table 2] Table 1 ───────────────────────────────────── d value relative strength d value relative strength d value Relative intensity ──────────────────────────────────── 15.77 100 4.78 25 3. 31 15 10.80 10 4.54 29 3.18 8 9.58 6 4.32 13 2.96 7 8.37 15 4.23 18 2.92 6 7.89 13 4.17 13 2.76 5 7.46 8 3.92 7 2.70 5 6.65 51 3.77 10 2.66 6 6.34 31 3.73 8 2.63 7 5.96 23 3.67 5 2.54 5 5. 79 29 3.60 7 2.48 5 5.34 54 3.55 6 4.88 18 3.46 8 ─────────────────────── ──────────────

[3] Formula (2)

[Chemical 6] The method for producing a crystalline vitamin D derivative according to [1] or [2], which comprises subjecting the amorphous vitamin D derivative represented by 4] A medicine comprising the vitamin D derivative according to [1] or [2], [5] A disease caused by abnormal absorption, transport or metabolism of calcium containing the vitamin D derivative according to [1] or [2] , A therapeutic agent for tumor or psoriasis, [6] a therapeutic agent for psoriasis containing the vitamin D derivative according to [1] or [2], [7]
[1] or a pharmaceutical composition containing the vitamin D derivative according to [2] and a pharmaceutically acceptable substance, [8]
The pharmaceutical composition according to [7], which is an external preparation,

[9] The pharmaceutical composition according to [7] or [8], which contains an ultraviolet absorber, [10] the ultraviolet absorber is a benzophenone,
4-aminobenzoic acids, cinnamic acids, salicylic acids, anthranilic acids, vitamin Es, 1- (4-methoxyphenyl) -3- (4-t-butylphenyl) propane-
1,3-dione, urocanic acid, or 1-camphor

[9] The pharmaceutical composition described above, and [11]
It relates to a method for producing a pharmaceutical composition by mixing the vitamin D derivative according to [1] or [2] and a pharmaceutically acceptable substance.

The method for producing the crystalline vitamin D derivative represented by the formula (1) will be described below. This crystalline vitamin D derivative can be produced by subjecting the amorphous vitamin D derivative represented by the formula (2) to a crystallization treatment in an organic solvent containing water. Examples of the organic solvent include aliphatic hydrocarbons, aromatic hydrocarbons, ethers, ketones, esters, and the like, or a mixed solvent thereof. Specific examples of the aliphatic hydrocarbons include n-pentane, n-hexane and n-heptane. Specific examples of aromatic hydrocarbons include toluene and benzene. Specific examples of the ethers include diethyl ether, tetrahydrofuran, t-butyl methyl ether and the like.
Specific examples of the ketones include acetone, methyl ethyl ketone, and methyl isobutyl ketone. Specific examples of the esters include ethyl acetate and the like. Preferred organic solvents include aliphatic hydrocarbons, aromatic hydrocarbons, and mixed solvents of these organic solvents and ethers.

The crystallization treatment is carried out, for example, by dissolving the amorphous vitamin D derivative in an organic solvent at a temperature in the range of 10 to 35 ° C., distilling off the organic solvent if necessary, and then adding water. It can be carried out by crystallization. 0 crystallisation
You may implement at the temperature of the range of -10 degreeC. In particular, as the organic solvent, a mixed solvent of an aliphatic hydrocarbon or an aromatic hydrocarbon and an organic solvent such as ethers, ketones or esters having a boiling point lower than that of the aliphatic hydrocarbon or the aromatic hydrocarbon is used. It is preferable to dissolve the non-crystalline vitamin D derivative, distill off ethers, ketones, esters, etc., and then add water to crystallize. Further, in order to increase the yield, a part of the aliphatic hydrocarbon or aromatic hydrocarbon may be distilled off for crystallization. As the amount of the organic solvent after distilling off the organic solvent,
For example, 5 to 20 for the amorphous vitamin D derivative
The range is 0 times by weight, and preferably the range is 8 to 100 times by weight. Water may be added before the amorphous vitamin D derivative is dissolved in the organic solvent. Further, a seed crystal may be added during crystallization. As the amount of water to be added, for example, non-crystalline vitamin D
It is preferably used in an amount of 0.1 times by weight or more, preferably 1 to 20 times by weight the amount of the derivative.

The crystallization time is in the range of 30 minutes to 24 hours, although it depends on the rate of crystal precipitation. The crystallized crystalline vitamin D derivative can be isolated by filtration. At this time, you may wash with the organic solvent used as needed. This crystalline form of vitamin D derivative is dehydrated under reduced pressure and is the corresponding anhydrous crystalline form of vitamin D.
Derivatives can also be prepared.

The crystalline vitamin D derivative represented by the formula (1) can be used as a medicine. As a medicine, for example, it can be used as a therapeutic agent for diseases caused by abnormal calcium absorption, transport or metabolism, and specifically, for bone diseases such as rickets, osteomalacia, osteoporosis and psoriasis. It can be used as a therapeutic agent or a preventive agent (JP-A-63-45249).

The crystalline vitamin D derivative represented by the formula (1) can be mixed with a pharmaceutically acceptable substance to prepare a pharmaceutical composition. Such pharmaceutical compositions can take the form of local or systemic administration. Topical preparations for topical use include liquids such as lotions, extracts, suspensions and emulsions, and semisolid preparations such as oily ointments, emulsion ointments and water-soluble ointments.
Systemically, oral preparations such as tablets, granules, solutions, capsules and soft capsules, injections, suppositories, nasal preparations and the like can be mentioned. Formula (1) for topical topical formulations
The compounding amount of the crystalline vitamin D derivative represented by can be appropriately increased or decreased, but is preferably in the range of 1 ng to 1 mg per 1 g of the pharmaceutical composition, and more preferably in the range of 50 ng to 50 μg. In the case of systemic administration, the dose of the crystalline vitamin D derivative represented by the formula (1) can be appropriately increased or decreased, but it is preferably in the range of 2 ng to 100 μg per adult, and more preferably 10 ng to 20 μg. A range is more preferable. These preparations can be manufactured according to the general manufacturing method usually performed.

Examples of the pharmaceutically acceptable substance used in producing the external preparation include commonly used bases, preservatives, antioxidants and the like. Examples of the base include hydrocarbons such as mineral oil, solid paraffin, white petrolatum, liquid paraffin, gelled hydrocarbon, dimethylpolysiloxane, olive oil, sesame oil, medium-chain fatty acid triglyceride, isopropyl myristate, diisopropyl adipate, and sebacic acid. Fatty acid esters such as diethyl, stearyl alcohol, higher alcohols such as cetyl alcohol, propylene glycol, polyethylene glycol, water-soluble polyhydric alcohols such as glycerin, lower alcohols such as ethanol and isopropanol, polyoxyethylene sorbitan fatty acid ester, Examples thereof include glycerin fatty acid ester, surfactant such as polyoxyethylene hydrogenated castor oil, water and the like. As a preservative, for example, 4
-Hydroxybenzoic acid ester and the like can be mentioned. Examples of the antioxidant include 2,6-di-t-butyl-4-methylphenol and 2-t-butyl-4-methoxyphenyl.

An ultraviolet absorber is preferably added to the pharmaceutical composition. Examples of the ultraviolet absorber include benzophenones, 4-aminobenzoic acids, cinnamic acids, salicylic acids, anthranilic acids, vitamin Es, 1-
(4-Methoxyphenyl) -3- (4-t-butylphenyl) propane-1,3-dione, urocanic acids, 1-camphor and the like can be mentioned. Examples of benzophenones include 2-hydroxy-4-methoxybenzophenone, 2-hydroxy-4-methoxybenzophenone-5-sulfonic acid, sodium 2-hydroxy-4-methoxybenzophenone-5-sulfonate, and 2,2'-.
Dihydroxy-4,4'-dimethoxybenzophenone,
2,2'-dihydroxy-4,4'-dimethoxybenzophenone-5,5'-disulfonic acid disodium salt, 2,
4-dihydroxybenzophenone, 2,2 ', 4,4'
-Tetrahydroxybenzophenone etc. are mentioned. Four
Examples of -aminobenzoic acids include 4-aminobenzoic acid, ethyl 4-aminobenzoate, glyceryl 4-aminobenzoate, amyl 4-dimethylaminobenzoate, octyl 4-dimethylaminobenzoate, and the like. Examples of cinnamic acids include isopropyl 4-methoxycinnamate, ethyl 4-methoxycinnamate, 2-ethylhexyl 4-methoxycinnamate, 2-ethoxyethyl 4-methoxycinnamate, and 4-methoxycinnamic acid. Examples thereof include potassium and sodium 4-methoxycinnamate. Examples of salicylic acids include octyl salicylate, phenyl salicylate, and methyl salicylate. Examples of anthranilic acids include methyl anthranilate and homomenthyl N-acetylanthranilic acid. Examples of natural vitamin Es include natural vitamin E, tocopherol acetate and dl-α-tocopherol. Examples of urocanic acids include urocanic acid and ethyl urocanate. These ultraviolet absorbers can be used alone or in combination of two or more. Particularly preferable ultraviolet absorbers include 2-ethylhexyl 4-methoxycinnamate and tocopherol acetate. The amount of the ultraviolet absorber added may be selected in an appropriate amount depending on the type of base used and the like, but is preferably 0.01 to 2% by weight with respect to the pharmaceutical composition.

[0014]

EXAMPLES Next, the present invention will be described more specifically with reference to examples and reference examples, but the present invention is of course not limited by these. Example 1 Production of crystalline vitamin D derivative represented by formula (1) Amorphous vitamin D derivative represented by formula (2) 10 m
g was dissolved in 0.2 ml of diethyl ether, 1.34 ml of toluene was added thereto, and the mixture was stirred until it became uniform. Next, the solution was concentrated under reduced pressure to a half volume, 3 drops of purified water (about 100 mg) was added dropwise, and the mixture was stirred at room temperature for 15 hours or more. After cooling to about 5 ° C., the precipitated crystals were collected by filtration to obtain 7 mg of crystalline vitamin D derivative. The obtained vitamin D derivative showed the average value of the interplanar spacing d by powder X-rays and the relative intensity shown in Table 1.

Example 2 Production of Crystalline Vitamin D Derivative Represented by Formula (1) Amorphous Vitamin D Derivative 10m Represented by Formula (2)
g was dissolved in 0.3 ml of diethyl ether, and n-
0.5 ml of heptane was added and stirred until uniform.
Next, 3 drops of purified water was added dropwise, and the mixture was stirred at room temperature for 15 hours or more. The precipitated crystals were collected by filtration to obtain 6.5 mg of crystalline vitamin D derivative.

Example 3 Production of Crystalline Vitamin D Derivative Represented by Formula (1) Amorphous Vitamin D Derivative 10m Represented by Formula (2)
g was dissolved in 0.3 ml of diethyl ether, and n-
Hexane 0.5 ml was added and stirred until uniform.
Next, 3 drops of purified water was added dropwise, and the mixture was stirred at room temperature for 15 hours or more. The precipitated crystals were collected by filtration to obtain 7 mg of crystalline vitamin D derivative.

Example 4 Production of Crystalline Vitamin D Derivative Represented by Formula (1) Amorphous Vitamin D Derivative Represented by Formula (2) 1.5
6 g was dissolved in diethyl ether 14.4 ml, toluene 15.6 ml was added thereto, and the mixture was stirred until it became uniform. Next, the solution was concentrated under reduced pressure until the liquid volume became about half, 5.23 ml of purified water was added, and 5 mg of seed crystals were added,
The mixture was stirred at room temperature for 15 hours or longer. The precipitated crystals are collected by filtration,
1.33 g of crystalline vitamin D derivative was obtained.

Example 5 Production of Crystalline Vitamin D Derivative Represented by Formula (1) Amorphous Vitamin D Derivative 10m Represented by Formula (2)
g was dissolved in 0.5 ml of acetone, and toluene 1.
0 ml was added and stirred until uniform. Next, the solution was concentrated under reduced pressure until the liquid volume became about half, 3 drops of purified water was added dropwise, and the mixture was stirred at room temperature for 15 hours or more. The precipitated crystals were collected by filtration to obtain 7 mg of crystalline vitamin D derivative.

Example 6 Production of Crystalline Vitamin D Derivative Represented by Formula (1) Amorphous Vitamin D Derivative 10m Represented by Formula (2)
g was dissolved in 0.2 ml of ethyl acetate, 1.0 ml of toluene was added thereto, and the mixture was stirred until it became uniform. Next, the solution was concentrated under reduced pressure until the liquid volume became about half, 3 drops of purified water was added dropwise, and the mixture was stirred at room temperature for 15 hours or more. The precipitated crystals were collected by filtration to obtain 5 mg of crystalline vitamin D derivative.

Example 7 Production of Crystalline Vitamin D Derivative Represented by Formula (1) Amorphous Vitamin D Derivative 10m Represented by Formula (2)
g was dissolved in 0.2 ml of ethyl acetate, 1.0 ml of n-hexane was added thereto, and the mixture was stirred until it became uniform. next,
The solution was concentrated under reduced pressure until the liquid volume was reduced to about half, 3 drops of purified water was added dropwise, and the mixture was stirred at room temperature for 15 hours or more. The precipitated crystals were collected by filtration to obtain a crystalline vitamin D derivative.

Example 8 A crystalline vitamin D derivative represented by the formula (1) and a formula
Storage stability of the amorphous vitamin D derivative represented by (2)
The crystalline vitamin D derivative represented by the formula (1) and the amorphous vitamin D derivative represented by the formula (2) obtained in Qualitative Example 4 are each in a fixed amount (about 1 to 1. (5 mg) was accurately weighed and stored in the air at room temperature under non-shaded conditions for 1 to 5 weeks. The absolute amount of the vitamin D derivative present therein was analyzed by the absolute calibration curve method using high performance liquid chromatography. The result is shown in FIG. As can be seen from this figure, crystalline vitamin D represented by formula (1)
The derivative was hardly decomposed, whereas the amorphous vitamin D derivative represented by the formula (2) was considerably decomposed.

Example 9 Production of Ointment 8.27 mg of crystalline vitamin D derivative of the formula (1) obtained in Example 4, 2,6-di-t-butyl-4
-Methylphenol 0.498 g, 2-methoxyhexyl 4-methoxycinnamate 1 g, and ethanol 0.2 g, isopropyl myristate was added to make a total amount of 51 g, and after stirring, melt-mixed with white petrolatum 949 g at 40 ° C, By cooling to room temperature with stirring, 1000 g of a pharmaceutical composition as an ointment was obtained.

Example 10 Preparation of liquid preparation for external use 2.07 mg of crystalline vitamin D derivative represented by formula (1) obtained in Example 4, 2,6-di-t-butyl-4
-Methylphenol 0.498 g, 2-methoxyhexyl 4-methoxycinnamate 1 g, and ethanol 0.2 g were added with isopropyl myristate to make the total amount 51 g, and after stirring, ethanol was added to make the total amount 1000 ml for external use. A pharmaceutical composition which is a liquid preparation was obtained.

Example 11 Stability of Pharmaceutical Composition The ointment obtained in Example 9 was filled in an aluminum tube and stored at room temperature for 1 year, which was represented by the formula (1) present in the pharmaceutical composition. The residual amount of the crystalline vitamin D derivative was measured by the internal standard method using high performance liquid chromatography, and it was 100%.

[0025]

The crystalline vitamin D derivative represented by the formula (1) of the present invention is superior in storage stability to the amorphous vitamin D derivative represented by the formula (2). Manufacturing,
It is easy to handle when preparing formulations. Furthermore, a high-purity vitamin D derivative of the present invention can be obtained by performing a crystallization operation. In addition, the pharmaceutical composition of the present invention is extremely stable, and particularly in the external preparation containing an ultraviolet absorber, the vitamin D derivative is stable for a therapeutically sufficient time even under the condition of being exposed to light of about 1000 lux. Kept in.

[0026]

[Brief description of drawings]

FIG. 1 shows the stability of a crystalline vitamin D derivative represented by the formula (1) and an amorphous vitamin D derivative represented by the formula (2) in air at room temperature under non-shading conditions. FIG.

Claims (11)

[Claims] (1) Formula (1) A crystalline vitamin D derivative represented by: 2. The crystalline vitamin D derivative according to claim 1, which shows the average value of the interplanar spacing d by powder X-rays and the relative intensity shown in Table 1. [Table 1] Table 1 ───────────────────────────────────── d value Relative strength d value Relative strength d value Relative intensity ──────────────────────────────────── 15.77 100 4.78 25 3. 31 15 10.80 10 4.54 29 3.18 8 9.58 6 4.32 13 2.96 7 8.37 15 4.23 18 2.92 6 7.89 13 4.17 13 2.76 5 7.46 8 3.92 7 2.70 5 6.65 51 3.77 10 2.66 6 6.34 31 3.73 8 2.63 7 5.96 23 3.67 5 2.54 5 5. 79 29 3.60 7 2.48 5 5.34 54 3.55 6 4.88 18 3.46 8 ─────────────────────── ────────────── 3. Formula (2) The method for producing a crystalline vitamin D derivative according to claim 1 or 2, wherein the amorphous vitamin D derivative represented by is subjected to a crystallization treatment in an organic solvent containing water. 4. A medicine comprising the vitamin D derivative according to claim 1 or 2. 5. A therapeutic agent for diseases, tumors or psoriasis caused by abnormal absorption, transport or metabolism of calcium, which comprises the vitamin D derivative according to claim 1 or 2. 6. A therapeutic agent for psoriasis containing the vitamin D derivative according to claim 1 or 2. 7. A pharmaceutical composition containing the vitamin D derivative according to claim 1 or 2, and a pharmaceutically acceptable substance. 8. The pharmaceutical composition according to claim 7, which is an external preparation. 9. The pharmaceutical composition according to claim 7, which contains an ultraviolet absorber. 10. The ultraviolet absorbers are benzophenones, 4
-Aminobenzoic acids, cinnamic acids, salicylic acids, anthranilic acids, vitamin Es, 1- (4-methoxyphenyl) -3- (4-t-butylphenyl) propane-
The pharmaceutical composition according to claim 9, which is 1,3-dione, urocanic acid, or 1-camphor. 11. Vitamin D according to claim 1 or 2.
A method for producing a pharmaceutical composition by mixing a derivative and a pharmaceutically acceptable substance.