JPS6089479A - Production of stable pipethanate hydrochloride pharmaceutical - Google Patents

Abstract

PURPOSE:To obtain the titled pharmaceutical useful as cholinergic blockers by a method for mass production without decomposition by moisture, heat, etc., by granulating and drying an aqueous solution of pipethanate hydrochloride containing both aluminum silicate and starch hydrolyzate. CONSTITUTION:An aqueous solution of pipethanate hydrochloride is incorporated with aluminum silicate in an amount of preferably 5-50pts. based on one pt. pipethanate hydrochloride, aluminum silicate powder and starch hydrolyzate in an amount of preferably 1-5pts., based on 1pt. pipethanate hydrochloride, and the resultant mixture is granulated and dried. The concentration of the aqueous solution of the pipethanate hydrochloride is 1-5W/V%, but is preferably 1-3% for granulating and then drying, and 2-5% for the simultaneous granulating and drying. The drying temperature in wet granulating and drying is preferably 50- 60 deg.C for the mixture to be formulated into the pharmaceutical. The starch hydrolyzate is preferably obtained by hydrolyzing starch with an enzyme and has glucose residues in the basic skeleton and further 2-20DE (dextrose equivalent) value.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing stable bipesanate hydrochloride formulations. More specifically, the present invention relates to a method for producing a stable bipesanate hydrochloride preparation, which is characterized by adding aluminum silicate and starch hydrolyzate to an aqueous solution of bipesanate hydrochloride, followed by granulation and drying.

Pipesanate hydrochloride, which is the main component of the object of the present invention, is the 6th
It is a water-soluble drug that is a useful cholinergic blocker and is commonly used in combination with antacids. Because it is an ester of benzylic acid and piperidine ethanol, it is known that this crystal is easily decomposed by moisture, heat, and basic substances, and is therefore used as an antacid, which is a basic drug. A major drawback is that preparations formulated with these drugs are particularly susceptible to decomposition and have a short shelf life.

Coating methods with synthetic or natural polymer membranes or waxy substances, which have been known as methods for stabilizing unstable water-soluble pharmaceuticals, are complicated to operate and the coating is uneven, making it difficult to obtain stable products. Furthermore, the encapsulation method using silicic acid or silicate hydrogel has drawbacks such as the need to prepare and use a special hydrogel and poor drying efficiency. Furthermore, in the method of forming an clathrate compound using cyclodextrin, the manufacturing cost is high, and production is not suitable for industrial use, so that stable production is not currently possible.

The present inventors have conducted intensive research to improve the above-mentioned drawbacks, stabilize the water-soluble pharmaceutical bipesanate hydrochloride formulation of the present invention, and more preferably enable mass production at low cost.As a result, aluminum silicate The inventors discovered the surprising fact that bipesanate hydrochloride cannot be stabilized when used alone and starch hydrolyzate, but bipesanate hydrochloride becomes extremely stable when both are used together, and the present invention was completed based on this discovery. I ended up letting it happen.

In carrying out the present invention, aluminum silicate and starch hydrolyzate are first added to an aqueous solution of pipesanate hydrochloride, but both may be added simultaneously or sequentially without affecting the effects of the present invention. After mixing and uniformly stirring the obtained mixture, the obtained slurry mixture is then granulated and dried by extrusion molding, granulation with a marmerizer, and shelf drying, fluidized bed granulation drying, Although any granulation and drying method such as spray granulation drying may be used, spray drying is preferred because it allows stable production in large quantities and allows granulation and drying to be performed simultaneously.

The aluminum silicate used in the present invention is natural or synthetic aluminum silicate according to the Japanese Pharmacopoeia, and is suitable because it has many acidic points on the surface and a large fine structure for increasing the adsorption ability. In addition, starch hydrolyzate is DexstroseE!, which has a basic skeleton of glucose residues obtained by hydrolyzing starch with enzymes. qu
ivalent value is an indication of the quality of starch and is expressed as direct reducing sugar (as glucose)/total solids x 100. Hereinafter, it will be abbreviated as DE value.

] has a value of 2' to 66, preferably 2 to 20, which has a property of low hygroscopicity, and has a [C value, has almost no DE value and has a cyclic structure of glucose residues. This does not apply to cyclodextrin, which is characterized by its structure.

The concentration of the aqueous solution of bipesanate hydrochloride used in the present invention is 1 to
5 w/v%, and the concentration is selected in relation to the method of granulation and drying that will be carried out later. That is, it should be 1 to 6% when drying after granulation, and 2 to 5% when selecting a process in which granulation and drying are performed at the same time.

In addition, the blending ratio of aluminum silicate and starch hydrolyzate used in the present invention to pipesanate hydrochloride is determined by the surface properties of the aluminum silicate powder, such as pore diameter, pore volume, and specific surface area. , 5 to 50 parts of aluminum silicate powder, 1 part of starch hydrolyzate
It is recommended to use ~5 parts. In addition, the drying temperature for wet granulation drying varies depending on the drying method.
0 is preferred.

The stable pipesanate hydrochloride preparation obtained in the present invention can be used as it is as a single preparation, but it can also maintain stability for a long period of time even when combined with an antacid.

The following stability tests were conducted using the formulations obtained in Examples 1 to 4 and Reference Examples 1 to 2 of the present invention as test formulations, and the results were presented in Omoteko and Natsu.

Stability test [Testing process] Test formulation 1.09 was wrapped in polycello packaging material 40X6C.
1+mk: The product was sealed and subjected to an accelerated test for 6 months under the conditions of 40', 75% RH and 50°, and the effects of moisture and heat on the product were investigated based on the residual amount of pipesanate hydrochloride in the product.

The results were shown to the surface engineer.

[Test 1] After mixing 0.19 g of the test preparation and 0.9 g of Japanese Pharmacopoeia precipitated calcium carbonate or Japanese Pharmacopoeia magnesium carbonate, which is a basic substance, polycello packaging material 40 x 6
The test tube was sealed to a diameter of 0 mm, and the effects of moisture and heat on the preparation in the presence of a basic substance were investigated in the same manner as in the "Experimental Engineering" section below.

The results are shown in Table A.

＼ Although the consideration regarding the stabilization mechanism in the present invention is as follows, the present invention is not limited to this consideration.

From the stability test results using the test formulation, it was found that the test formulation of Reference Example 1, which was prepared by simply mixing aluminum silicate powder and pipesanate hydrochloride aqueous solution and drying the slurry, was free from moisture and heat 6 months after the stability test. 1/2 immediately after manufacturing due to influence
Only ~1/6 of the amount of pipesanate hydrochloride is present, and the results are even worse if basic substances are present. This result is
This shows that pivesanate hydrochloride crystallizes on the surface of the aluminum silicate powder during the drying process, so complete adsorption and encapsulation is not achieved.

On the other hand, in the test formulation of Reference Example 2 in which the starch hydrolyzate and the bipesanate hydrochloride aqueous solution were simply mixed and the slurry was dried, the pipesanate hydrochloride was 1/2 to 1/2 the same as the above stability test results. Only 6 quantities remain. This result seems to indicate that the starch hydrolyzate does not cover and protect bipesanate hydrochloride because the starch hydrolyzate does not have inclusion or adsorption power.

On the other hand, even when the test formulations obtained in Examples 1 to 4 were subjected to stability tests under accelerated abuse conditions, the residual amount of bipesanate hydrochloride in the formulations was almost the same immediately after production and after 6 months.
Therefore, it is completely unaffected by water, heat, and basic substances. This means that water-soluble bipesanate hydrochloride, aluminum silicate powder with a fine structure, and easily water-soluble starch hydrolyzate are the kings, and aluminum silicate with 10-100A pores is mixed with pipesanate hydrochloride (molecular diameter 7 XX2
oλ) is adsorbed on the surface, and during the drying process, the starch hydrolyzate is covered with a protective colloid-like coating film, and moisture,
It is thought to protect and stabilize bipesanate hydrochloride from the effects of heat and basic substances.

Examples are shown below.

Example 1 Pipesanate hydrochloride,) 50 g of 60° warm water 1.67 g
1 was added to make a 6W/v% solution, 650 ml of Japanese Pharmacopoeia synthetic aluminum silicate was added to the solution, and mixed uniformly. Next, starch hydrolyzate 1259 with a DI value of 2 was added and kneaded, and 42 mesh After granulation using a sieve, the mixture was dried on a shelf at 50° to obtain fine granules. Benefit! 785g.

Example 2 16.71 g of 60° warm water was added to 500 g of pipesanate hydrochloride to make a 3 w/v% solution, and 5.5 kg of Japanese Pharmacopoeia synthetic aluminum silicate and 2.25 ~ of DII2O3 starch hydrolyzate were simultaneously added to the solution. The slurry was spray-dried at a heat input temperature of 210° to obtain fine particles. Yield 7.76PC9゜Example 6 Pibesanate hydrochloride same as used in Example 2 3w/v%
To the aqueous solution 16.77, 6.5 kg of Japanese Pharmacopoeia natural aluminum silicate and 1.25 starch hydrolyzate with a DE value of 8 and 9 were simultaneously added and mixed uniformly, and the slurry was spray-dried at a heat input temperature of 220°. Fine grains were obtained. Earned amount 7.82k
g.

Example 4 Same pipesanate hydrochloride as used in Example 1 3w/v%
Starch hydrolyzate with DI value of 19 2 in aqueous solution 1.671
50 g of the mixture was added and mixed uniformly, and then Japanese Pharmacopoeia Natural Aluminum Silicate 5259 was added and kneaded. After granulation drying using a 20 mesh sieve, the mixture was dried on a shelf at 50° to obtain fine granules. Amount obtained: 7689° Reference Example 1 Pipesanate hydrochloride, the same as used in Example 2, 3 w/v%
7.75 kg of Japanese Pharmacopoeia synthetic aluminum silicate was added to 16.7 kg of the aqueous solution and mixed uniformly, and the slurry was spray-dried at a heat input temperature of 210° to obtain fine particles. Amount of tatami 7.
8kg0 Reference Example 2 Same vibesanate hydrochloride as used in Example 1 5*/v%
250 g of a starch hydrolyzate having a DID value of 19 was added to 1.671 g of an aqueous solution and kneaded, granulated using a 42 mesh sieve and dried on a shelf at 50° to obtain fine granules. Obtained amount 2829゜ Patent applicant Fuji Chemical Industry Co., Ltd. 7-i-3- Procedural amendment (method) % formula % 1. Indication of case Patent application No. 197886 of 1988 2.
) Name of Amei Process for producing stable bipesanate hydrochloride preparation 3, person making the amendment Patent applicant Ken Toyama Nakanikafugunkamiichimachocohouonji Address 55 Yokohoonji, Nakashinyo Gujo City, Toyama Prefecture

Claims (1)

[Scope of Claims] (1) A method for producing a stable pipesanate hydrochloride preparation, which comprises adding aluminum silicate and starch hydrolyzate to an aqueous solution of pipesanate hydrochloride and granulating and drying. (2) The method for producing stable pipesanate hydrochloride according to claim 1, wherein 5 to 50 parts of aluminum silicate and 1 to 5 parts of starch hydrolyzate are used for 1 part of pipesanate hydrochloride. (8) The DFi value of the starch hydrolyzate (however, the DE value is an indication of the quality of starch sugar and is expressed as direct reducing sugar (as glucose)/total solids x 100) is 2 to 66. A method for producing a stable bipesanate hydrochloride formulation according to claim 1.