JP2923139B2 - Agent - Google Patents

Description

Detailed Description of the Invention

[0001]

The present invention relates to 3-phenyl-5-{2-(1-pyrrolidinylmethyl)butyryl}isoxazole or a pharmacologically acceptable salt thereof, which is useful as a central muscle relaxant. The present invention relates to a stable preparation containing the optical isomer or a pharmacologically acceptable salt thereof as an active ingredient.

[0002]

2. Description of the Related Art (±)-3-phenyl-5-{2-(1
-Pyrrolidinylmethyl)butyryl}isoxazole or a pharmacologically acceptable salt thereof has an excellent muscle relaxant action, and treatment of muscle tone due to diseases such as low back pain, disc herniation, and cervical shoulder arm syndrome. It is useful as an active ingredient of an agent (JP-A-3-157375). This compound has optical isomerism, and the (+)-form is a compound more effective than the (-)-form or the racemic form (Japanese Patent Application No. 04-022703).
The (+) form can be produced by optically resolving the racemic form using an optically active sulfonic acid. However, 3-
Phenyl-5-{2-(1-pyrrolidinylmethyl)butyryl}isoxazole or its salt is suitable for oral, transdermal, transmucosal or intratissue administration although it is relatively stable in itself. Additives that are commonly used to make dosage forms, such as lactose and other additives, become extremely unstable with respect to temperature and humidity, and become significantly colored over time,
Cause decomposition. In addition, the optically active substance has a disadvantage that it changes into a racemic body over time when the above dosage form is used. Therefore, it has been extremely difficult to produce a stable preparation containing the above compound or a salt thereof as an active ingredient.

[0003]

DISCLOSURE OF THE INVENTION The object of the present invention is 3-phenyl-5-{2-(1-pyrrolidinylmethyl)butyryl}isoxazole which is useful as a muscle relaxant or its pharmacologically acceptable. Salt, (+)-3-phenyl-
5-{2-(1-pyrrolidinylmethyl)butyryl}isoxazole or a pharmaceutically acceptable salt thereof or (-)-3-phenyl-5-{2-(1-pyrrolidinylmethyl)butyryl } It is to provide a stable preparation containing isoxazole or a pharmaceutically acceptable salt thereof as an active ingredient.

[0004]

In order to solve the above problems, the present inventors have made various additions to 3-phenyl-5-{2-(1-pyrrolidinylmethyl)butyryl}isoxazole or a salt thereof. As a result of diligent examination of the effects of temperature and humidity on aqueous solutions, powders, and solid molded products to which substances have been added, the inventors have found that the purpose can be achieved by using certain additives, and have completed the present invention. .. That is, the present invention provides 3-phenyl-5-{2-(1-pyrrolidinylmethyl)butyryl}isoxazole or a pharmacologically acceptable salt thereof, (+)-3-phenyl-5-.
{2-(1-Pyrrolidinylmethyl)butyryl}isoxazole or a pharmacologically acceptable salt thereof or (-)-3-phenyl-5-{2-(1-pyrrolidinylmethyl)butyryl}iso A preparation comprising oxazole or a pharmacologically acceptable salt thereof and an acidic substance.

In general, the preparation is manufactured by formulating the active ingredient with one or more additives. However, according to the study by the present inventors, 3-phenyl-5-{2-(1-pyrrolidinylmethyl)butyryl}isoxazole or a salt thereof is a sugar such as lactose, sucrose, D-mannitol, or crystalline cellulose. , Cellulose such as hydroxypropyl cellulose, methyl cellulose, etc., corn starch, hydroxypropyl starch, starch such as partially pregelatinized starch, silicic acid such as light anhydrous silicic acid, talc, magnesium stearate, polyethylene glycol Addition of commonly used additives such as 6000, polysorbate 80, polyvinylpyrrolidone K25, polyvinyl alcohol, etc. causes coloring and decomposition, and (+) form causes racemization to prepare a stable preparation. Was found to be extremely difficult.
In such a situation, it is inevitable to manufacture a formulation by a combination formulation in which additives that do not relatively affect the stability of the active ingredient are combined. However, for example, magnesium stearate, which is extremely useful as a lubricant but its formulation is not preferable, is used as a lubricant by using hardened oil or the like, which is expected to have the same function as this and has relatively little influence on the stability of the active ingredient. In that case, tableting problems such as capping and sticking were observed during tableting, and a good preparation could not be manufactured. Further, generally, in the production of the preparation, a solvent such as water or ethanol is used for dissolving the active ingredient and the binder, and 3-phenyl-5-{2-( 1-pyrrolidinylmethyl)
When a preparation containing butyryl}isoxazole or a salt thereof is produced, coloring and decomposition occur over time. Therefore, the production was attempted by a method without using a solvent, but a stable formulation worthy of being provided as a pharmaceutical was not obtained.

[0006] However, as a result of various studies, by adding an acidic substance as in the present invention, the problem of stability of the active ingredient was almost completely suppressed, including the shift to isomerization by blending with a commonly used additive. Therefore, it becomes possible to mix these additives, and whether or not a solvent is used,
Stable and allowed the production of good formulations. 3-phenyl-5-{2-(1-pyrrolidinylmethyl)butyryl}isoxazole or a salt thereof, which is the active ingredient of the preparation of the present invention, can be produced, for example, by the method described in JP-A-3-157375. it can. The (+) form can be produced by optically resolving the racemic form using an optically active sulfonic acid. The acidic substances used in the present invention include mineral acids such as hydrochloric acid, sulfuric acid and phosphoric acid; acetic acid, lactic acid, fumaric acid, tartaric acid, succinic acid, citric acid, oxalic acid, malonic acid, maleic acid, malic acid, stearic acid, Carboxylic acids such as adipic acid; Sulfonic acids such as aminoethanesulfonic acid; Acidic polysaccharides such as alginic acid; Acidic amino acids such as glutamic acid and aspartic acid; Salts of amino acids such as glycine hydrochloride, aspartic acid hydrochloride and glutamic acid hydrochloride with mineral acids Can be illustrated, and these can use 1 type(s) or 2 or more types. Especially, a salt of an amino acid and a mineral acid is preferable. The amount used is not particularly limited, but preferably 1 to 30% by weight relative to the active ingredient. Examples of the dosage form include granules and capsules.
Solids such as tablets and tablets coated as necessary
Formulations, liquid formulations such as injections, ointments, poultices, suppositories, etc.
The semi-solid formulation of
3-phenyl-5-{2-(1
-Pyrrolidinylmethyl)butyryl}isoxazole or
Or its pharmacologically acceptable salts and acidic substances
Thus, the preparation of the present invention can be obtained.

In the present invention, solid preparations such as granules, capsules and tablets are produced by directly adding an acidic substance to the active ingredient or dissolving the acidic substance in water or a suitable solvent. In addition, if necessary, acidic substances
It can be produced by a method commonly used by those skilled in the art by appropriately using an excipient, a binder, a disintegrating agent, a lubricant, a coating agent and the like added with . For example, at least 3 as an active ingredient
-Phenyl-5-{2-(1-pyrrolidinylmethyl)bu
Tyryl}isoxazole or its pharmacologically acceptable
To form a plain tablet containing the salt and acidic substance
And coat it with a coating containing stearic acid.
Then, the preparation of the present invention can be prepared. As excipients, lactose, anhydrous lactose, mannitol, corn starch, crystalline cellulose, etc., as binders, hydroxypropyl cellulose, polyvinylpyrrolidone, methyl cellulose, etc., as disintegrants, carboxymethyl cellulose, carboxymethyl cellulose calcium, low-substituted hydroxypropyl. Examples include cellulose, partially pregelatinized starch and the like, lubricants such as magnesium stearate, calcium stearate and stearic acid, and coating agents such as hydroxypropylmethyl cellulose, methacrylic acid acrylic acid copolymer and hydroxypropyl methylcellulose phthalate. You can The solvent used may be water, ethanol, acetone, methylene chloride or a mixed solvent thereof.

In order to produce a liquid preparation, for example, an injection, after dissolving the active ingredient in an aqueous solution prepared by adding an acidic substance to water for injection,
It can be produced by a method commonly used by those skilled in the art, using an isotonic agent, a preservative, a soothing agent, etc., if necessary. Examples of the isotonicity agent include D-mannitol, examples of the preservative include methyl paraoxybenzoate, and examples of the soothing agent include benzyl alcohol. The pH of the liquid agent is preferably 2.0 to 4.0. Furthermore, the liquid preparation thus produced may be freeze-dried, and can also be applied to the production of semisolid preparations such as ointments, poultices and suppositories. In carrying out the production method of the present invention, production equipment generally used may be used if necessary and production may be carried out by a conventional method.
The clinical dose of the preparation of the present invention depends on the symptom to be treated, the degree thereof, the administration method and the like, but it is usually 3-phenyl-5-{2-(1-pyrrolidinyl) which is an active ingredient for adults. The amount of (methyl)butyryl}isoxazole or a salt thereof is usually 5 to 1000 mg/day, and preferably 10 to 300 mg/day.

Further, the dosage form may be an oral administration drug such as powder, granules, tablets, capsules and syrups,
Alternatively, it may be a parenteral administration agent such as an injection, a suppository, a transdermal agent and the like.

[0010]

[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-prepared by the method described in JP-A-3-157375
(1-Pyrrolidinylmethyl)butyryl}isoxazo-
10 g (0.03 mol) of sodium chloride was dissolved in a mixed solution of 60 ml of water and 70 ml of ethyl acetate. 6 in this solution
72 ml of an aqueous sodium hydrogen carbonate solution was added dropwise. The reaction solution was stirred for 10 minutes and then separated to obtain an organic layer. The aqueous layer was extracted again with 60 ml of ethyl acetate, and the obtained organic layer was combined with the previously obtained organic layer and dried over anhydrous sodium sulfate. To the filtrate obtained by filtering off sodium sulfate, L-10-camphorsulfonic acid ([α] ²⁰ _D =21° (c=2,
Water)) 14.2 g (0.06 mol) was added and dissolved by stirring for 30 minutes. 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}isoxazo-
L-L- 10- camphor sulfonate was obtained. Yield 9.5 g Yield 42% Melting point 115.8-116.3° 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 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 washed 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 the 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 A prescribed amount of the active ingredient ((+)-3-phenyl-5-{2-
(1-Pyrrolidinylmethyl)butyryl}isoxazo-
(Hydrochloric acid salt), D-mannitol and an acidic substance were mixed and formed into tablets with a tableting machine to obtain samples a to e of the present invention. In addition, a comparative control sample f
Got

[0011] Example 2 Prescription amount of active ingredient ((+)-3-phenyl-5-{2-
(1-Pyrrolidinylmethyl)butyryl}isoxazo-
(Hydrochloric acid salt), lactose, carboxymethylcellulose, fumaric acid or glutamic acid hydrochloride, and granulated by a dry granulation method.

Next, magnesium stearate is added and mixed, and then tablets are formed using a tableting machine. Further, the tablets thus obtained were coated with a water-based coating solution containing hydroxypropylmethylcellulose and titanium oxide in a prescribed amount according to a conventional method to obtain Samples g and h of the present invention. Also,
A comparative control sample i was obtained in the same manner except that the acidic substance was not added. Example 3 Prescription amount of active ingredient ((+)-3-phenyl-5-{2-
(1-Pyrrolidinylmethyl)butyryl}isoxazo-
(Hydrochloric acid salt), anhydrous lactose, carboxymethyl cellulose and glutamic acid hydrochloride are granulated by a wet granulation method using an alcohol solution or an aqueous solution of hydroxypropyl cellulose and dried to give granules. Then, magnesium stearate is added, and tablets are formed using a tableting machine. Thereafter, the obtained tablets were operated in the same manner as in Example 2 to obtain the present invention sample j (j-1 to 3; solvent alcohol, j-4; solvent).
Water) was obtained.

A prescribed amount of the above-mentioned active ingredient, anhydrous lactose,
Carboxymethyl cellulose is granulated by a wet granulation method using an alcohol solution of hydroxypropyl cellulose and dried to obtain granules. Next, magnesium stearate is added, and tablets are formed using a tablet machine. Thereafter, the obtained tablet was treated in the same manner as in Example 2 to obtain a comparative control sample k. Example 4 Prescription amount of active ingredient ((+)-3-phenyl-5-{2-
(1-Pyrrolidinylmethyl)butyryl}isoxazo-
(Hydrochloride), D-mannitol, and an acidic substance were dissolved in water for injection, filtered through a 0.22 μm membrane filter, dispensed into ampoules by aseptic operation, and sealed to obtain samples 1 to p of the present invention. .. Moreover, the thing except the acidic substance was operated similarly, and the comparative control sample q was obtained. Test Example 1 Each sample of Examples 1 to 3 was stored under conditions of 25° C., 40° C., 50° C. and 60° C., or 40° C. relative humidity 75%, and its appearance was observed with time and discoloration by a color difference meter. The degree (color difference) was measured, and the degradation products and isomers ((-) isomers) were measured by high performance liquid chromatography.

Each sample of Example 4 was stored at 40° C., and the content of the active ingredient was measured with time by high performance liquid chromatography. Table 1 shows the appearance, color difference, decomposition products, and isomer ratios of the samples obtained in Examples 1 to 3 when stored at 50° C. for 1 month. Table 2 shows the residual ratio of the active ingredient when the sample obtained in Example 4 was stored at 40° C. for 6 hours. Also, 25°C, 4
The tablets of Examples 1 to 3 were more stable than the comparative controls even when stored at 0° C. and 60° C. or 40° C. and 75% relative humidity.

[Table 1]

[Table 2]

[0015]

INDUSTRIAL APPLICABILITY The preparation of the present invention is a stable preparation with very little coloring or generation of decomposition products.

─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Isamu Takakura 453 Ninkai, Toyama City, Toyama Prefecture (58) Fields investigated (Int.Cl. ⁶ , DB name) A61K 31/42 A61K 47/04 A61K 47/12 A61K 47/16 A61K 47/36 CA (STN)

Claims (5)

(57) [Claims] 1. (±)-3-Phenyl-5-{2-(1
-Pyrrolidinylmethyl)butyryl}isoxazole or a preparation containing a pharmacologically acceptable salt thereof and an acidic substance. 2. (+)-3-Phenyl-5-{2-(1
-Pyrrolidinylmethyl)butyryl}isoxazole or a preparation containing a pharmacologically acceptable salt thereof and an acidic substance. 3. (-)-3-Phenyl-5-{2-(1
-Pyrrolidinylmethyl)butyryl}isoxazole or a preparation containing a pharmacologically acceptable salt thereof and an acidic substance. 4. The preparation according to claim 1, wherein the acidic substance is selected from the group consisting of mineral acids, carboxylic acids, sulfonic acids, acidic polysaccharides, acidic amino acids and salts of amino acids with mineral acids. .. 5. The acidic substance is one or more selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, succinic acid, fumaric acid, tartaric acid, glutamic acid, aspartic acid and glutamic acid hydrochloride. The formulation according to any one of claims.