JPH0329046B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a method for producing a stable pipesanate hydrochloride formulation. More specifically, the present invention relates to a method for producing a stable pipesanate hydrochloride preparation, which is characterized by adding aluminum silicate and starch hydrolyzate to an aqueous solution of pipesanate hydrochloride, and granulating and drying the mixture. Pipesanate hydrochloride, which is the main component of the object of the present invention, is a hydrochloride of a tertiary amine, and is a water-soluble pharmaceutical commonly used as a useful cholinergic blocker, mainly in combination with antacids. Because it is structurally an ester of benzylic acid and piperidine ethanol, it is known that this crystal is easily decomposed by moisture, heat, and basic substances, and therefore it is difficult to treat the drug as a basic drug. A major drawback is that preparations formulated with acid agents are particularly susceptible to decomposition and have a short shelf life. Coating methods with synthetic or natural polymer membranes or waxy substances, which have traditionally 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. not fully obtained,
In addition, 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 case of the method of forming an clathrate compound using cyclodextrin, the production cost is high, and production is not suitable for industrial use, so that stable production is not currently possible. The present inventors have conducted extensive research to improve the above-mentioned drawbacks, stabilize the water-soluble pharmaceutical preparation of pipesanate hydrochloride of the present invention, and more preferably enable mass production at low cost.As a result, aluminum silicate and starch hydrolyzate,
They discovered the surprising fact that pipesanate hydrochloride cannot be stabilized by using each alone, but pipesanate hydrochloride becomes extremely stable when both coexist, leading to the completion of the present invention. In carrying out the present invention, aluminum silicate and starch hydrolyzate are first added to an aqueous solution of pipesanate hydrochloride, but both can be added at the same time.
Any order may be used without affecting the effects of the present invention. After mixing and uniformly stirring the obtained liquid 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 simultaneous granulation and drying. 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 has a large fine structure for increasing the adsorption capacity.
In addition, starch hydrolyzate has a basic skeleton of glucose residues obtained by hydrolyzing starch with enzymes. Expressed as solids x 100. Hereinafter, it will be abbreviated as DE value. ] has a value of 2 to 36, preferably has a DE value of 2 to 20 with low hygroscopic properties, has almost no DE value and has a cyclic structure of glucose residues This does not apply to cyclodextrin, which is characterized by The concentration of the aqueous solution of pipesanate hydrochloride used in the present invention is 1 to 5 w/v%, and the concentration is selected depending on the method of granulation and drying to be performed later. That is, when drying after granulation, the amount is 1 to 3%, and when selecting a process in which granulation and drying are performed at the same time, the amount is 2 to 5%. Furthermore, 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; In contrast, it is preferable to use 5 to 50 parts of aluminum silicate powder and 1 to 5 parts of starch hydrolyzate. Further, the drying temperature for wet granulation drying varies depending on the drying method, but it is preferable that the product temperature of the preparation is 50 to 60°. 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 are shown in the table. Stability test [Test] 1.0g of test preparation was placed in polycello packaging material 40x
The product was sealed to 60 mm and accelerated testing was conducted 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 amount of pipesanate hydrochloride remaining in the product. The results are shown in the table.

[Table] [Test] After mixing 0.1 g of the test preparation and 0.9 g of the basic substance Japanese Pharmacopoeia precipitated calcium carbonate or Japanese Pharmacopoeia magnesium carbonate, the mixture was sealed in a polycello packaging material 40 x 60 mm. We investigated the effects of moisture and heat on formulations in the presence of basic substances. The results are shown in the table.

[Table] The stabilization mechanism in the present invention is discussed below, but the present invention is not limited to this idea. 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. Due to its influence, only 1/2 to 1/3 of the amount of pipesanate hydrochloride is present immediately after production, and if a basic substance is present, the results will be even worse. This result shows that pipesanate 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, reference example 2
Similar to the above stability test results, in the test formulation in which the starch hydrolyzate and an aqueous solution of pipesanate hydrochloride were simply mixed and the slurry was dried, only 1/2 to 1/3 of the amount of pipesanate hydrochloride remained immediately after production. do not have. This result shows that starch hydrolyzate has inclusion power,
This seems to indicate that the starch hydrolyzate does not cover and protect pipesanate hydrochloride because it does not have 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 pipesanate hydrochloride in the formulations was almost the same immediately after production and after 6 months, and therefore It is completely unaffected by water, heat and basic substances. This means that water-soluble pipesanate hydrochloride, aluminum silicate powder with a microstructure, and water-soluble starch hydrolyzate are the three components. ×20
It is thought that the starch hydrolyzate is adsorbed on the surface and covered with a protective colloid-like coating film during the drying process, which protects and stabilizes pipesanate hydrochloride from the effects of moisture, heat, and basic substances. Examples are shown below. Example 1 Add 1.67 g of 60° warm water to 50 g of pipesanate hydrochloride to make a 3W/V% solution, add 650 g of Japanese Pharmacopoeia synthetic aluminum silicate to the solution, mix uniformly, and then hydrolyze starch with a DE value of 2. 125g
After adding and kneading and granulating using a 42 mesh sieve,
Fine grains were obtained by shelf drying at 50°. Yield: 785g. Example 2 500 g of pipesanate hydrochloride was added with 16.7 g of warm water at 60° to make a 3 w/v% solution, and 5.5 kg of Japanese Pharmacopoeia synthetic aluminum silicate and 2.25 kg of starch hydrolyzate with a DE value of 20 were simultaneously added to the solution to make it homogeneous. The slurry was spray-dried at a heat input temperature of 210° to obtain fine particles. Yield: 7.76Kg. Example 3 The same pipesanate hydrochloride used in Example 2
6.5 kg of Japanese Pharmacopoeia natural aluminum silicate and 1.25 kg of starch hydrolyzate with a DE value of 8 were simultaneously added to a 3 w/v% aqueous solution of 16.7 kg, mixed uniformly, and the slurry was spray-dried at a heat input temperature of 220°. Fine grains were obtained.
Yield: 7.82g. Example 4 The same pipesanate hydrochloride used in Example 1
Add 250g of starch hydrolyzate with a DE value of 19 to a 3w/v% aqueous solution of 1.67, mix uniformly, then add 525g of Japanese Pharmacopoeia natural aluminum silicate, knead, and granulate and dry using a 20-mesh sieve. After that, it was dried on a shelf at 50° to obtain fine grains. Yield: 768g. Reference example 1 Same pipesanate hydrochloride as used in Example 2
7.75 kg of Japanese Pharmacopoeia synthetic aluminum silicate was added to 16.7% of a 3w/v% aqueous solution and mixed uniformly, and the slurry was spray-dried at a heat input temperature of 210° to obtain fine particles. Yield: 7.8Kg. Reference Example 2 The same pipesanate hydrochloride used in Example 1
250 g of a starch hydrolyzate having a DE value of 19 was added to a 3 w/v aqueous solution of 16.7 and kneaded. After granulation using a 42 mesh sieve, the mixture was dried on a shelf at 50° to obtain fine granules. Yield: 282g.

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 the mixture. 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. 3 The DE 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.
36. A method for producing a stable pipesanate hydrochloride formulation according to claim 1.