JPH06199666A - Preparation for internal use - Google Patents

Abstract

PURPOSE:To obtain a preparation for internal use comprising 3-phenyl-5-{2-(1- pyrrolidinylmethyl)butyryl}isoxazole or its pharmacologically permissible salt. CONSTITUTION:3-Phenyl-5-{2-(1-pyrrolidinylmethyl)butyryl}isoxazole or its pharmacologically permissible salt is mixed with vegetable fats and oils to give a stable preparation having extremely low coloring and formation of decomposition product.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to (±) -3-phenyl-5- {2- (1-pyrrolidinylmethyl) butyryl} isoxazole or its optical isomers, which are useful as central muscle relaxants. The present invention provides a stable internal preparation containing a pharmacologically acceptable salt of as an active ingredient.

[0002]

2. Description of the Related Art (±) -3-phenyl-5- {2- (1
-Pyrrolidinylmethyl) butyryl} isoxazole or its optical isomer or a pharmacologically acceptable salt thereof is a compound useful as a central muscle relaxant against diseases such as cervical-shoulder-arm syndrome and low back pain. There is (JP-A-3-1573)
75). In general, additives such as a carrier, an excipient, a disintegrating agent, a lubricant, a binder and the like for formulation are used in the solid formulation of the above compound. In addition, purified water, alcohol, a simple syrup, a preservative and the like are used when preparing a liquid formulation for internal use.

[0003]

DISCLOSURE OF THE INVENTION The inventors of the present invention described the above 3
-Phenyl-5- {2- (1-pyrrolidinylmethyl) butyryl} isoxazole or a pharmacologically acceptable salt thereof was investigated as a solid formulation, and as a result, obtained by using a commonly used additive. When the obtained tablets were stored under warm and humid conditions, problems such as coloration of tablets and remarkable decomposition of active ingredient with time were observed. It was also found that the decomposition of the active ingredient is promoted every time the person skilled in the art carries out the formulation steps such as granulation, tableting, coating and the like which are usually carried out. Furthermore, since there was concern about the stability of the active ingredient in a solvent, the stability in purified water was examined, and it was found to be extremely unstable.

The present invention is based on the above circumstances and is (±) -3.
-Phenyl-5- {2- (1-pyrrolidinylmethyl) butyryl} isoxazole or an optical isomer thereof or a pharmacologically acceptable salt thereof as an active ingredient to provide a stable internal preparation Is.

[0005]

As a result of various studies to solve these problems, the present inventors have found that vegetable oils and fats, especially unsaturated fatty acid double bonds present in these oils and fats, are partially or entirely. It was found that the hydrogenated oil obtained by hydrogenating hydrogen peroxide is effective for stabilizing the preparation, and completed the present invention.

That is, the present invention provides (±) -3-phenyl-5- {2- (1-pyrrolidinylmethyl) butyryl} isoxazole or a pharmaceutically acceptable salt thereof, (+)-3. -Phenyl-5- {2- (1-pyrrolidinylmethyl) butyryl} isoxazole or a pharmaceutically acceptable salt thereof, (-)-3-phenyl-5
-{2- (1-pyrrolidinylmethyl) butyryl} isoxazole or a pharmacologically acceptable salt thereof,
The present invention provides a stable internal preparation which comprises at least one selected from the group consisting of vegetable oils and fats as a main compounding ingredient.

3-phenyl-5- {2- (1-pyrrolidinylmethyl) butyryl} which is the active ingredient of the preparation of the present invention
Isoxazole or a pharmaceutically acceptable salt thereof can be produced, for example, by the method described in JP-A-3-157375. The optical isomer can be obtained by optical resolution from a racemate using an optically active sulfonic acid.

The vegetable fats and oils used in the present invention are vegetable fatty oils for edible use, and include, for example, drying oil such as soybean oil, semi-drying oil such as sesame oil and rapeseed oil, non-drying oil such as peanut oil,
Examples include vegetable oils such as coconut oil and palm kernel oil, preferably soybean oil, peanut oil, sesame oil, rapeseed oil, coconut oil, palm kernel oil or hardened oils thereof, and more preferably vegetable fats thereof. A hydrogenated oil obtained by hydrogenating a part or all of the double bonds of unsaturated fatty acids existing in the oil is preferable.

When making a solid formulation or a liquid formulation, it is necessary to appropriately select depending on the properties of the vegetable oil and fat to be used,
For example, vegetable oils and fats that are solid at room temperature are used for solid preparations, and those that are liquid at room temperature are used for liquid preparations. The amount of these vegetable oils and fats to be used is not particularly limited, but is preferably 1 to 10 times the amount of the active ingredient.

Next, specific formulation examples of the present invention will be described. The dosage form to be formulated in the present invention is a granule,
Examples include solid preparations such as fine granules, tablets and capsules, suspensions and the like. Among them, as a method for producing a solid preparation, for example, a method in which a vegetable oil which is solid at room temperature as an active ingredient is dissolved in an appropriate amount in an organic solvent such as alcohol or methylene chloride, a spray coating method, a kneading method, etc. A method of coating and mixing and granulating is mentioned. Alternatively, the active ingredient and vegetable oil may be uniformly dissolved in an organic solvent and granulated by a spray drying method, a spray cooling method or the like. The obtained granulated product is dried and the solvent is removed. However, due to environmental problems caused by the use of organic solvents, residual solvents in preparations, stability of active ingredients in solvents, and the like, granulation methods that do not use these solvents are desired. Therefore, in the present invention, the active ingredient is uniformly mixed in the heated and melted vegetable oil and fat, and a solid containing the active ingredient is obtained by slow cooling, and a melt granulation method of pulverizing as necessary. Is preferably adopted.

Further, the obtained granulated product is sized to a desired particle size to obtain granules, fine granules or tableting granules.
A tablet can be prepared by tableting the granules obtained as described above with a tableting machine. Further, if necessary, a lubricant such as stearic acid, an excipient such as lactose, a disintegrating agent such as carboxymethyl cellulose, a surfactant such as lecithin, and the like may be appropriately added. The suspending agent is obtained by suspending the active ingredient by a suitable method in vegetable oils and fats which are liquid at room temperature to make the whole quality uniform. Furthermore, in order to make the dosage form easy to administer orally, it is possible to fill it into a hard capsule or the like.

[0012]

[Production of (+)-3-phenyl-5- {2- (1-pyrrolidinylmethyl) butyryl} isoxazole hydrochloride]

1) (+)-3-phenyl-5- {2- (1-pyrrolidinylmethyl) butyryl} isoxazole L-10-
Camphor-sulfonate 3-phenyl-5- {2- (1-pyrrolidinylmethyl) butyryl} isoxazole hydrochloride 10 g (0.0) produced by the method described in JP-A-3-157375.
3 mol) was dissolved in a mixed solution of 60 ml of water and 70 ml of ethyl acetate. 72 ml of a 6% sodium hydrogen carbonate aqueous solution was added dropwise to this solution. The reaction solution was stirred for 10 minutes and then separated to obtain an organic layer. The aqueous layer is again ethyl acetate 60
The organic layer obtained by extraction with ml was combined with the previously obtained organic layer and dried over anhydrous sodium sulfate. 14.2 g of L-10-camphorsulfonic acid ([α] ²⁰ _D = 21 ° (c = 2, water)) was added to the filtrate obtained by filtering off sodium sulfate.
(0.06 mol) was added and stirred for 30 minutes to dissolve. The reaction solution was stirred under ice cooling for 6 hours, and the precipitated crystals were collected by filtration, washed with ethyl acetate, and dried under reduced pressure to obtain the desired (+)-3-phenyl-5- {2- (1- Pyrrolidinylmethyl) butyryl} isoxazole L-camphor
A sulfonate salt was obtained. Yield 9.5 g Yield 42% Melting point 115.8 to 116.3 ° C. [α] ²⁰ _D = -14.4 ° (c = 0.5, ethanol) Optical purity 98.7% ee 2) (+ ) -3-Phenyl-5- {2- (1-pyrrolidinylmethyl) butyryl} isoxazol hydrochloride (+)-3-phenyl-5- {2- (1-pyrrolidinylmethyl) butyryl} isoxazo -L L-10-camphor sulfonate 9.4 g (12.3 mmol) was dissolved in a mixed solution of water 54 ml and ethyl acetate 54 ml,
30 ml of a 10% sodium carbonate aqueous solution was added dropwise. The reaction solution was stirred for 10 minutes and then separated to obtain an organic layer. The obtained organic layer was washed with 15 ml of a 10% sodium carbonate aqueous solution and further with 15 ml of water. 2 in this organic layer
28 ml of N hydrochloric acid was added and liquid separation extraction was carried out to obtain an aqueous layer. The organic layer was extracted again with 15 ml of 2N hydrochloric acid, and the obtained aqueous layer was combined with the previously obtained aqueous layer. Chloroform layer was obtained by adding 17.6 ml of chloroform to the obtained aqueous solution and extracting. The chloroform layer obtained by extracting the aqueous layer again with 17.6 ml of chloroform was combined with the previously obtained chloroform layer.
The obtained chloroform solution was dried over anhydrous sodium sulfate. 106 ml of ethyl acetate was added dropwise to a chloroform solution obtained by filtering out sodium sulfate. This solution was stirred under ice cooling for 3 hours. The precipitated crystals are collected by filtration and washed with ethyl acetate to give the desired (+)-3-phenyl-5-
{2- (1-Pyrrolidinylmethyl) butyryl} isoxazole hydrochloride was obtained. Yield 3.4 g Yield 82% Melting point 158 to 159.5 ° C. [α] ²⁰ _D = + 29 ° (c = 0.5, water) Optical purity 99.9% ee or higher NMR (CDCl ₃ , δ _PPM ); 0 .99 (3H, t,
J = 7.3 Hz), 1.77 to 1.83 (1H, m),
1.88-1.97 (1H, m), 1.98-2.11.
(2H, m), 2.11 to 2.23 (2H, m), 2.
70-2.78 (1H, m), 2.79-2.95 (1
H, m), 3.33 (1H, m), 3.47 to 3.64.
(1H, m), 3.68 to 3.71 (1H, m), 3.
83-3.87 (1H, m), 4.33-4.38 (1
H, m), 7.48 to 7.50 (3H, m), 7.76
(1H, s), 7.87~7.90 ( 2H, m) Elemental analysis _{(C 18 H 22 N 2 O} 2 · HCl) Calculated C: 64.57, H: 6.92, N: 8. Three
7, Cl: 10.59 measured value C: 64.51, H: 6.96, N: 8.2
0, Cl: 10.42

Example 1 Hardened soybean oil was heated and melted at 65 ° C., and a prescribed amount of active ingredient ((+)-3-phenyl-5- {2- (1-pyrrolidinylmethyl) butyryl} iso was prepared. (Oxazole hydrochloride) was uniformly mixed using a high speed stirrer and cooled to room temperature to obtain a solid. Granules (1
2 to 48 mesh). Further, the above granules were made into tablets with a tableting machine to obtain sample A of the present invention. Also, comparative sample B
Each of -D was prepared by mixing the raw materials of the formulation examples to prepare granules for tableting by a dry granulation method, and tablets were produced by a tableting machine.

[0014]

[Table 1]

Example 2 Each raw material of the formulation example was uniformly suspended or dissolved by a high-speed stirrer, and further filled in an airtight container to prepare Samples E to G of the present invention.
Comparative control samples H were obtained respectively. The coconut oil / palm kernel oil used here was hydrogenated and contained saturated fatty acids as main components.

[0016]

[Table 2]

Test Example Each of the samples of Examples 1 and 2 was stored under the conditions of 40 ° C. or 40 ° C. and 80% relative humidity, and the amount of decomposition products was determined with time by high performance liquid chromatography using a normal phase optical resolution column. It was measured by. Table 3 shows the sample obtained in Example 1 at 40 ° C.
2 shows the test results by high performance liquid chromatography when stored for 2 months. Table 4 shows the test results by the high performance liquid chromatography method when the sample obtained in Example 2 was stored at 40 ° C. for 1 week. Table 5 shows the test results of the sample E stored at 50 ° C. or 60 ° C. for 1 week by high performance liquid chromatography. Also,
Even when stored at 40 ° C. and 80% relative humidity, the samples of Examples 1 and 2 were more stable than their respective comparative controls.

[0018]

[Table 3]

[0019]

[Table 4]

[0020]

[Table 5]

[0021]

INDUSTRIAL APPLICABILITY According to the present invention, stable securing of the active ingredient during formulation, which has not been achieved by the conventional techniques, is sufficiently achieved.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Internal reference number FI technical display area A61K 47/44 B 7433-4C

Claims (4)

[Claims] 1. (±) -3-Phenyl-5- {2- (1
-Pyrrolidinylmethyl) butyryl} isoxazole or a pharmacologically acceptable salt thereof, wherein at least one selected from the group consisting of vegetable oils and fats is used as a main ingredient. Formulation. 2. (+)-3-Phenyl-5- {2- (1
-Pyrrolidinylmethyl) butyryl} isoxazole or a pharmacologically acceptable salt thereof, wherein at least one selected from the group consisting of vegetable oils and fats is used as a main ingredient. Formulation. 3. (−)-3-Phenyl-5- {2- (1
-Pyrrolidinylmethyl) butyryl} isoxazole or a pharmacologically acceptable salt thereof, wherein at least one selected from the group consisting of vegetable oils and fats is used as a main ingredient. Formulation. 4. A vegetable fat or oil is a vegetable fatty oil for edible use, such as soybean oil, peanut oil, sesame oil, rapeseed oil, coconut oil,
The internal preparation according to any one of claims 1 to 3, which is selected from the group consisting of palm kernel oil or hydrogenated oils thereof.