JPH08325145A - Stable isopropylantipyrine-containing preparation - Google Patents

Abstract

PURPOSE: To obtain the stable, small and single preparation containing two or more kinds of medicinal active ingredients which are liable to change, when compounded with each other. CONSTITUTION: A core containing isopropylantipyrine and a medicinal active ingredient causing a change, when compounded with the isopropylantipyrine, is produced. The core is preferably a tablet, and on the production of the core, if necessary, medicinally usable additives are suitably compounded. The core is successively covered with plural coating layers by known coating methods and by the use of known devices. The first coating layer comprises a barrier layer containing hydroxypropylmethyl cellulose, etc., as a skin agent. The amount of the coating film is 1-10wt.% based on the core. The second layer is produced by coating a solution containing the isopropylantipyrine. The third layer comprises a moisture-proof layer containing a water-insoluble polymer and a water-soluble polymer. The composition comprising polyvinylacetal dimethylaminoacetate (3-25wt.%) and hydroxypropylmethyl cellulose (75-97wt.%) is especially preferably coated for the third layer.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to the formation of a stable single preparation of two or more pharmaceutically active ingredients which are liable to change in their formulation.

[0002]

2. Description of the Related Art In designing a drug product, a method of forming a laminated tablet and a dry-coated tablet in a tablet, as a means for forming a stable single drug product of two or more kinds of pharmaceutically active ingredients that are likely to cause a change in the composition, or It is well known to use granules and capsules as separate granules. In particular, it is known that isopropylantipyrine and acetaminophen are contraindicated for compounding, and it is known that continuous tableting with a mixture is not possible because they wet due to complex formation and sticking occurs during tableting. In order to improve this, Japanese Unexamined Patent Publication (Kokai) No. 5-163138 discloses a technique of forming a two-layer tablet of isopropylantipyrine and acetaminophen. However, a double-layer tablet requires a special device, and when it is mixed with multiple components as a cold medicine, it has a drawback that it is difficult to reduce the size.

[0003]

Under the above circumstances, the present invention provides a stable and miniaturized single preparation of two or more kinds of pharmaceutically active ingredients which are liable to cause a mixture change by a simple method. The purpose is to

[0004]

Means for Solving the Problems As a result of intensive studies for solving the above problems, the present inventor has found that a core containing a pharmaceutically active ingredient is coated with a film agent to form a first layer and then a solution containing isopropylantipyrine. The present invention has been completed by discovering that a stable isopropylanthripyrin-containing preparation can be obtained by coating the above with the above as a second layer and further coating the third layer with a water-insoluble polymer and a water-soluble polymer. That is, the present invention provides a core containing at least one pharmaceutically active ingredient that causes a compounding change with isopropylantipyrine, a barrier layer containing at least one pharmaceutically usable film forming agent in the first layer, and isopropyl antipyrine in the second layer. And a stable isopropylantipyrine-containing preparation comprising a moisture-proof layer containing a water-insoluble polymer and a water-soluble polymer in the third layer.

The present invention will be described in detail below. First, a core containing isopropylantipyrine and a pharmaceutically active ingredient that causes a formulation change is produced. Examples of the pharmaceutically active ingredient that causes a change in the composition with isopropylantipyrine include acetaminophen, isopropamide iodide, chlorpheniramine maleate, dextromethorphan hydrobromide, anhydrous caffeine, or sodium ascorbate. The core is not particularly limited as long as it is in the form of an ordinary solid preparation such as tablets, granules, fine granules or crystals of a pharmaceutically active ingredient, but tablets are particularly preferable. The manufacturing method itself may be performed by a known method. At this time, optionally pharmaceutically usable additives, for example, lactose, corn starch, crystalline cellulose, anhydrous calcium hydrogen phosphate, excipients such as magnesium aluminometasilicate, carboxymethyl cellulose calcium,
A low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, disintegrating agent such as croscarmellose sodium, and a lubricant such as magnesium stearate and talc may be appropriately added.

The core thus obtained is sequentially coated with each layer. The coating method may be carried out by a coating method and apparatus known per se, and examples thereof include a pan coating method, a fluidized bed coating method and a centrifugal fluidized coating method.

First, the first layer is coated. The film-forming agent is not particularly limited, but water-soluble polymers such as hydroxypropylmethyl cellulose, methyl cellulose, and hydroxypropyl cellulose are preferable. The coating amount is preferably 1 to 10% by weight with respect to the core.

Next, a solution containing isopropylantipyrine is coated. At this time, a water-soluble polymer such as hydroxypropylmethylcellulose, methylcellulose, or hydroxypropylcellulose is selected as the film forming agent, and the amount used is 5% of isopropylantipyrine.
-30% by weight is desirable.

The third layer of the preparation of the present invention comprises a water-insoluble polymer and a water-soluble polymer, and particularly preferably polyvinyl acetal dieraminoacetate (3 to 25% by weight): hydroxypropyl methylcellulose (75 to
A coating having a composition of 97% by weight is desirable.

At this time, if necessary, a surfactant or the like can be added to the coating liquid for the purpose of an anti-tacking agent, a coloring agent, a flavoring agent, a plasticizer, a disintegrating agent, or a defoaming agent. . The third layer is applied for the purpose of preventing whiskers derived from isopropylantipyrine and improving stability, masking the bitterness of isopropylantipyrine, and increasing the commercial value by its beautiful appearance.

[0011]

EXAMPLES Next, the present invention will be specifically described with reference to Examples and Comparative Examples, but the present invention is not limited thereto. Example 1 20.2 parts by weight of acetaminophen, 2.2 parts by weight of dextromethorphan hydrobromide, 2.7 parts by weight of methylephedrine hydrochloride, 0.3 part by weight of dl-chlorpheniramine maleate, anhydrous caffeine Polyvinylpyrrolidone 2.0 was added to a mixed powder consisting of 3.4 parts by weight, sodium L-ascorbate 22.5 parts by weight, lactose 16.9 parts by weight, corn starch 7.2 parts by weight and carboxymethylcellulose calcium 2.6 parts by weight. An ethanol solution in which 1 part by weight and 0.3 part by weight of isopropamide iodide are dissolved is uniformly dispersed, wet granulated and dried, and then 0.7 part by weight of magnesium stearate is added and mixed to obtain granules. A plain tablet obtained by tableting this was coated with 1.2 parts by weight of hydroxypropylmethylcellulose as the first layer (hereinafter referred to as FC (I) film), and then with isopropylantipyrine 13.5 as the second layer. Parts by weight, 2.3 parts by weight of hydroxypropylmethylcellulose are coated. (This is hereinafter referred to as FC (II) film.) Finally, as a third layer, 1.9 parts by weight of hydroxypropylmethyl cellulose and 0.1 part by weight of polyvinyl acetal diethylaminoacetate (AEA) are coated. (This is hereinafter referred to as FC (III) film.)

Comparative Example 1 A target formulation was prepared in the same manner as in Example 1 except that the coating amount of hydroxypropylmethylcellulose in the FC (I) film was 0.4 part by weight.

Comparative Example 2 The desired preparation was obtained in the same manner as in Example 1, except that polyvinyl acetal diethylaminoacetate was not added to the FC (III) film.

Comparative Example 3 A preparation having the same composition as in Example 1 but containing isopropylantipyrine in a plain tablet was prepared.

Test Example 1. Appearance Change and Stability The tablets obtained from Example 1 and Comparative Example 1 were stored for 2 weeks under the condition of 50 ° C. tightly sealed, and the appearance change and stability were compared. The results are shown in Table 3. (Results) In Comparative Example 1 in which the FCI film was a small amount of 0.4% by weight based on the uncoated tablets, a considerable discoloration was observed after 2 weeks of storage, and a decrease in the content was also observed. On the other hand, the first embodiment of the present invention
No discoloration was observed, and there was no component with reduced content, indicating good stability.

2. Change in Appearance Each of the tablets obtained in Example 1 and Comparative Example 2 was stored for 2 weeks under the condition of 50 ° C. stoppering, and the change in appearance was compared. The results are shown in Table 4. (Results) Whisker was intensely generated in Comparative Example 2, whereas no whisker was observed in Example 1. This is because AEA filled the holes in which FCIII became a dense film so that whiskers could grow.

3. Physical Properties and Change in Appearance The physical properties of the tablets obtained in Example 1 and Comparative Example 3 were evaluated, and the tablets were stored for 2 weeks under the condition of 50 ° C. tight stopper, and the appearance changes were compared. The results are shown in Table 5. (Result) 1. Physical properties When isopropylantipyrine and acetaminophen coexist, the blending changes and the melting point is lowered, so that the phenomenon that the granules are melted by frictional heat during tableting is observed. Therefore, no tableting failure was observed in Example 1 in which isopropylantipyrine was added to the film to isolate it from acetaminophen and the like, but a severe tableting failure was observed in Comparative Example 3 in which both were present. 2. Change in Appearance In Comparative Example 3, violent discoloration is observed due to wetting due to interaction between isopropylantipyrine and acetaminophen. On the other hand, in Example 1, no discoloration was observed, indicating that the quality was extremely stable.

[0018]

[Results of the Invention] The preparations obtained by the present invention were mixed with each other such as isopropylantipyrine and acetaminophen, isopropamide iodide, chlorpheniramine maleate, dextromethorphan hydrobromide, anhydrous caffeine and sodium ascorbate. The stability is maintained even if a pharmaceutically active ingredient that easily causes further,
It is a formulation that is stable and does not easily change its appearance.
In addition, whiskers derived from isopropylantipyrine were also prevented, resulting in an extremely stable formulation.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display area A61K 31/375 A61K 31/375 31/44 31/44 31/485 31/485 31/52 31 / 52 47/32 47/32 D J Z 47/38 47/38 D J Z // (A61K 31/415 31: 165) (A61K 31/415 31:16) (A61K 31/415 31:44) (A61K 31/415 31: 485) (A61K 31/415 31:52) (A61K 31/415 31: 375) (72) Inventor Keiichi Kato 1-3-45 Kuragakiuchi, Ibaraki City, Osaka Prefecture Sumitomo Pharmaceuticals Co., Ltd.

Claims (6)

[Claims] 1. A core containing isopropylantipyrine and one or more kinds of pharmaceutically active ingredients that cause a change in the composition, No. 1
From a barrier layer containing at least one pharmaceutically usable film forming agent to the layer, a layer containing isopropylantipyrine in the second layer, and a moisture-proof layer containing a water-insoluble polymer and a water-soluble polymer in the third layer A stable formulation containing isopropylantipyrine. 2. The preparation according to claim 1, wherein the core containing at least one pharmaceutically active ingredient that causes a change in the composition with isopropylantipyrine is a tablet. 3. The amount of coating agent in the first layer is 1 to 10 relative to the core.
The formulation according to claim 1 or 2, which is a weight%. 4. The preparation according to claim 1, 2 or 3, wherein the water-insoluble polymer of the third layer is polyvinyl acetal diethylaminoacetate and the water-soluble polymer is hydroxypropylmethyl cellulose. 5. The composition of the third layer has a polyvinyl acetal diethylaminoacetate content of 3 to 25% by weight and a hydroxypropylmethylcellulose content of 75 to 97% by weight.
The preparation according to claim 1, 2, 3 or 4. 6. A pharmaceutical active ingredient which causes a change in the composition with isopropylantipyrine is acetaminophen, isopropamide iodide, chlorpheniramine maleate, dextromethorphan hydrobromide, anhydrous caffeine, or sodium ascorbate. The formulation of 1, 2, 3, 4, or 5.