JPH09169639A - Stable teprenone-containing solid preparation and its production - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject preparation preservable for a long period of time under a room temperature storage condition without causing change with the lapse of time such as reduction in content and coloring phenomena, by previously adsorbing teprenone on silicon dioxide fine powder and then mixing teprenone with sodium ascorbate. SOLUTION: (A) Teprenone is blended with (B) silicon dioxide fine powder, adsorbed on the component B and powdered. Then the power is mixed with (C) powder of a metal salt of ascorbic acid (preferably sodium ascorbate). The weight ratio of the component A, the component B and the component C is 1: about 0.5-1.5: about 0.05-0.5 to give the objective preparation. The preparation is preferably blended with a binder solution having dissolved an excipient such as D-mannitol and an anhydrous organic solvent and granulated.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to improving the quality of teprenone preparations, and more particularly to a method for producing a stabilized teprenone-containing solid preparation which prevents decomposition of the main drug component over a long period of time and ensures a stable effect. Regarding

[0002]

2. Description of the Related Art Teprenone: [Chemical name, 6, 10, 14,
18-Tetramethyl-5,9,13,17-nonadecatetraen-2-one] is a prenylketone-based compound that has been known for a long time, and its gastric mucosal repair function is recognized again with various isoprene-based drugs. In recent years, it has come into the limelight as a therapeutic agent for peptic ulcer. It is said that most of the prenylketone compounds are oily substances and are extremely easily oxidatively decomposed by oxygen in the air. Teprenone is also a colorless to pale yellow transparent oily substance, which itself
Similarly, it is easily oxidatively decomposed, and in particular, when it is made into a solid preparation for internal use and a preparation having a large surface area is prepared by using an excipient or the like, the degree of decomposition is further increased, and it is said that quality assurance is difficult.

Generally, various antioxidants can be used as a method for preventing air oxidation of oily substances. Tocopherol, butylated hydroxytoluene (BHT) and butylated hydroxyanisole are used for prenyl ketone compounds. (BHA), gallic acid propyl ester (P
Phenolic antioxidants such as G) are effective.
-9096), a teprenone formulation stabilized by inclusion of tocopherol has already been developed. On the other hand, addition of a so-called fatty acid ester of ascorbic acid, which is a fat-soluble form of water-soluble ascorbic acid, is effective in preventing the oxidation of teprenone (JP-A-6-56658).
It is said that.

[0004]

[Problems to be Solved by the Invention] The fat-soluble antioxidant is
It is considered that a sufficient antioxidant effect cannot be expected unless it is dissolved in the target oily substance. For this reason, it is usually necessary to dissolve the antioxidant in order to formulate it into a formulation, but when handling viscous oily substances, this dissolution process becomes complicated and it is still satisfactory in terms of productivity. There is something I can't get. Furthermore, in the case of teprenone, the effect of adding an antioxidant was also questioned.

The object of the present invention is that it is easy to put into practical use and can be economically implemented, and there is no change in quality such as a decrease in the content of the active ingredient and discoloration of the product due to changes over time, and a long-term stabilizing effect is obtained. It is to provide a solid preparation containing teprenone stably, which can be guaranteed. Further, in order to achieve this purpose, it is difficult to oxidatively decompose or color itself, and the effect is exhibited only by contacting oily teprenone,
It was necessary to find a non-lipophilic antioxidant.

[0006]

According to the present invention, oily teprenone is kneaded with fine powder of silicon dioxide, adsorbed to the fine powder to be powdered, and mixed with powder of a metal salt of ascorbic acid to stabilize teprenone. The method for producing a solid preparation contained in, and the preparation thus obtained. The present invention
Among ascorbic acids, the metal salt thereof is based on the new finding that the above-mentioned problems can be surprisingly solved depending on the usage.

As the silicon dioxide fine powder, light anhydrous silicic acid fine powder of the Japanese Pharmacopoeia is suitable, and it is preferable to use it in a weight ratio of about 0.5 to 1.5 with respect to teprenone. 1: 0 from the viewpoint of degree of oxidation and antioxidant effect.
It is preferable to use 8 to 1.0. As the metal salt of ascorbic acid, sodium ascorbate is preferable, and its admixture amount with respect to teprenone is usually 1: about 0.05 to 0.5 by weight, but particularly 1 from the viewpoint of the antioxidant effect and the coloration preventing effect. : It is preferably about 0.1 to 0.2.

In the present invention, the order of the steps is important, in which the oily teprenone is first adsorbed on the silicon dioxide fine powder and then admixed with sodium ascorbate. The solid preparation obtained by mixing the above three components can be used as it is, but, if necessary, further granulated by adding a binder solution dissolved in an anhydrous organic solvent together with a suitable excipient, If so, it is also possible to prepare an arbitrary solid preparation by using a generally used auxiliary drug raw material such as a suitable disintegrant and lubricant.

[0009] Generally, ascorbic acids are used alone or in combination as synergists of other antioxidants and are frequently used for the antioxidant of drugs and foods. It has been found that metal salts such as sodium and potassium ascorbate are effective, but free acids and esters are not. Further, as the carrier for adsorbing teprenone, in addition to silicon dioxide fine powder, it is also possible to use powders having a large surface area such as aluminum hydroxide, aluminum silicate, magnesium stearate, magnesium aluminometasilicate, and Avicel. However, silicon dioxide fine powder was most suitable in terms of oil absorption and stabilizing effect.

When an excipient is used, commonly used carriers such as Avicel, starch, lactose, dextrin, calcium phosphate can be used, but the coloring phenomenon of the preparation due to the oxidative decomposition of teprenone and the antioxidant itself. The most suitable is the compounding of D-mannitol, which is also expected to have the effect of masking, and it is preferable that its proportion in the preparation is as high as possible. In the present invention, as described above,
In particular, how to use the metal salt of ascorbic acid, particularly the order of addition is an important point.For example, even if sodium ascorbate is added to oily teprenone first and mixed, and the mixture is adsorbed on the silicon dioxide fine powder, the antioxidant effect is obtained. Is hardly recognized. This is probably because sodium ascorbate particles are wrapped in oily teprenone,
It is presumed that the antioxidant function cannot be exhibited because there is no contact with oxygen in the air.

That is, according to the present invention, the antioxidative function of the metal salt of ascorbic acid could be sufficiently exhibited by the fact that teprenone was first adsorbed to silicon dioxide fine powder to be powdered,
By mixing with sodium ascorbate, especially sodium ascorbate whose particle number has been increased to increase the number of particles, and homogenizing it, a coating layer of sodium ascorbate powder is formed on the surface of teprenone powdery particles and directly contacted with air. It is thought that this is because the opportunity was reduced. Further, in the process of producing the solid preparation of teprenone according to the present invention, it is important to eliminate coexistence of water as much as possible. The presence of water accelerates the oxidative decomposition of the metal salt of ascorbic acid itself which is a stabilizer, and also causes the coloring of the preparation, or the release phenomenon of teprenone due to moisture absorption supersaturation from the silicon dioxide fine powder adsorbing teprenone. Is also visible.

[0012]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, Examples of the present invention, reference examples in the case where a metal salt of ascorbic acid is not mixed, and when a free acid or ester is used in place of the metal salt of ascorbic acid, and those The present invention will be described in more detail with reference to the following test examples, but these do not limit the present invention in any way. Teprenone is usually composed of about 2: 3 of monocis and all-trans isomers, and the purity is generally 97% or more. In each of the following examples, such teprenone was used as a standard product. Unless otherwise specified,% means% by weight.

[Examples] (Example 1) 50 g of silicon dioxide fine powder (Shionogi: Light anhydrous silicic acid Carplex CS-50) was charged into a universal mixing stirrer (Dalton: 3XDMV-01-Qr, hereinafter the same). To this, 50 g of oily teprenone is added, kneaded, adsorbed and powdered. In addition to this, sodium ascorbate (Tanabe Seiyaku Co., Ltd .: fine powder ASK-P-10KR, 150 mesh, hereinafter the same) 1
After adding 0 g and mixing, 220 g of D-mannitol (Rhone Poulin Japan) is mixed and homogenized.
Furthermore, after adding 145 g of lactose (DMV: 200 mesh, the same below) and mixing, 25 g of hydroxypropyl cellulose (Shin-Etsu Chemical: HPC-SSL, the same below) was mixed with 10 parts of ethanol.
Add 0 ml of the dissolved solution and knead. Mixing slurry 5
00g was put into Flow Coater FLO-1 type (Freund Sangyo, the same below), dried by blasting at 40 ° C, and then sized to give a particle size of 0.0
075-0.5 mm fine granules are obtained. It is packaged in a film sheet to give a fine-grained preparation containing 500 mg each of teprenone.

(Example 2) 50 g of silicon dioxide fine powder (Freund Industry: Light anhydrous silicic acid adsolider) was put into a universal mixing stirrer, and 50 g of oily teprenone was added thereto, kneaded, adsorbed and powdered. . To this, 10 g of fine powder of sodium ascorbate was added and mixed,
Further add 5 g of lactose and homogenize. A solution obtained by dissolving 5 g of hydroxypropyl cellulose in 20 ml of ethanol is added and kneaded. 120g of the mixed slurry was put into a flow coater, dried by blowing air at 40 ° C, and then sized to obtain a particle size of 0.075.
~ 0.5 mm fine granules are obtained. No. 4 capsules are divided and filled to give capsules containing 50 mg each of teprenone.

(Example 3) 50 g of silicon dioxide fine powder (Freund Industrial Co., Ltd.) was placed in a universal mixing stirrer, and 50 g of oily teprenone was added thereto, and kneaded and adsorbed to obtain powder. To this, 10 g of sodium ascorbate is added and mixed. To this, 15 g of hydroxypropyl methylcellulose 2910 (Shin-Etsu Chemical: TC-5R) was added to absolute ethanol 1
Add a solution dissolved in 00 ml and knead to granulate. Then, the mixture is transferred to a flow coater, and 220 g of D-mannitol (rhone-poulein) and 140 g of lactose are added and mixed, and then a solution of 15 g of hydroxypropylcellulose in 400 ml of ethanol is sprayed for granulation. Mixing slurry 500
After being blow-dried at 40 ° C, the particles are sized and the particle size is 0.075-0.0.
Obtain 5 mm granules. It is packaged in a film sheet to give a fine-grained preparation containing 500 mg each of teprenone.

Reference Example 1 80 g of silicon dioxide fine powder (Shionogi) is put into a universal mixing stirrer, and 50 g of oily teprenone is added thereto, and kneaded and adsorbed to obtain powder.
To this, 345 g of sucrose was further added and mixed, and then 25 g of hydroxypropyl cellulose was added to 100 m of ethanol.
Add the melted solution to l and knead. Mixed slurry 50
0 g was put in a flow coater, dried by blowing air at 40 ° C., and then sized to obtain granules having a particle size of 0.075 to 0.5 mm.

(Reference Example 2) 50 g of silicon dioxide fine powder (Shionogi) was put into a universal mixing stirrer, and 50 g of oily teprenone was added thereto, and the mixture was kneaded and adsorbed to obtain powder.
In addition, 5 g of fine powder of ascorbic acid and lactose (D
MV: 200 mesh) 10 g, and mix to homogenize.
Hydroxypropyl cellulose 5g ethanol 20ml
Add the melted solution and knead. Mixing slurry 120
Then, g was put in a flow coater, dried by blowing air at 40 ° C., and then sized to obtain granules having a particle size of 0.075 to 0.5 mm.

Reference Example 3 50 g of silicon dioxide fine powder (Shionogi) was put into a universal mixing stirrer, and a mixture of 50 g of oily teprenone and 5 g of ascorbic acid stearate ester (Daiichi Pharmaceutical Co., Ltd.) was added. , Knead and adsorb. Add lOg lactose and mix to homogenize. A solution obtained by dissolving 5 g of hydroxypropyl cellulose in 20 ml of ethanol is added and kneaded. 120g of mixed slurry
Was placed in a flow coater, dried by blowing air at 40 ° C., and then sized to obtain granules having a particle size of 0.075 to 0.5 mm.

The stability test of teprenone of the teprenone-stabilized preparation of the present invention obtained in the example and the control preparation obtained in the reference example is shown below.

(Test Example 1) Stability Test Each formulation of Example and each granular material of Reference Example were placed in an opened glass bottle and stored in the same environment at 55 ° C. for 4 weeks. Taking 0.1 g of teprenone equivalent from each stored sample, n-
Hexane was added, and the mixture was shaken and then centrifuged, and the supernatant was used to measure the remaining amount of teprenone by gas chromatography. In addition, the change of the appearance of each sample was observed. The results are as shown in Table 1.

[Table 1]

[0021]

As shown in Table 1, the teprenone preparation obtained by the method of the present invention shows no degradation of teprenone for 4 weeks even under the severe condition of storage at 55 ° C. under open conditions. . Therefore, it is a stable solid preparation of teprenone that can be stored under ordinary room temperature storage conditions for a long period of time without causing a change in content or a coloring phenomenon and the like. Moreover, the production of the present preparation does not require any special operation or device, and the present invention is suitable for practical use. It has been separately confirmed that the antioxidative effect of sodium ascorbate on the teprenone preparation is comparable to that of phenolic antioxidants such as tocopherol and butylated hydroxytoluene (BHT).

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Masaya Higashi 701, Minami Tsuchiyama, Tsuchiyama-cho, Koga-gun, Shiga (72) Inventor Yukio Hirooka 9, 6th, Kojogaoka, Mizuguchi-cho, Koga-gun, Shiga (72) Tetsuya Takahashi 5-12-8 Yamanoue, Hirakata-shi, Osaka

Claims (8)

[Claims] 1. A method for producing a stable solid preparation containing teprenone, which comprises kneading teprenone with fine powder of silicon dioxide, adsorbing to the fine powder to pulverize, and then mixing with powder of metal salt of ascorbic acid. . 2. The method for producing a teprenone-containing solid preparation according to claim 1, wherein the metal salt of ascorbic acid is sodium ascorbate. 3. The weight ratio of teprenone, silicon dioxide fine powder, and ascorbic acid metal salt powder is 1: about 0.5 to 1.
5: The method for producing a solid preparation containing teprenone according to claim 1 or 2, wherein the production amount is about 0.05 to 0.5. 4. The obtained solid preparation, together with an excipient,
The method for producing a solid preparation containing teprenone according to claim 1 or 2, further comprising adding a binding solution dissolved in an anhydrous organic solvent, kneading and granulating. 5. The method for producing a solid preparation containing teprenone according to claim 4, wherein the excipient is D-mannitol. 6. A stable solid preparation containing teprenone, which comprises granules obtained by adsorbing oily teprenone to silicon dioxide fine powder and then admixing it with metal ascorbate powder. 7. The teprenone-containing solid preparation according to claim 6, wherein the metal salt of ascorbic acid is sodium ascorbate. 8. The weight ratio of teprenone, silicon dioxide fine powder, and ascorbic acid metal salt powder is 1: about 0.5 to 1.
5: The solid preparation containing teprenone according to claim 6 or 7, which is about 0.05 to 0.5.