JP2678556B2 - Antiarrhythmic drug and method for producing the same - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an antiarrhythmic drug and a method for producing the same, and particularly to α- [2- [bis (1-methylethyl) amino] ethyl] -α-phenyl-2-pyridineacetamide or its pharmaceutical preparation. The present invention relates to an antiarrhythmic drug containing an acid addition salt that is acceptable as an active ingredient, and a manufacturing method capable of manufacturing the antiarrhythmic drug with a simple device and in simple steps.

[0002]

2. Description of the Related Art In the treatment of antiarrhythmia, the disease to be treated requires a long-term and continuous treatment, and therefore the pharmacological action of the antiarrhythmia is required to be as constant and continuous as possible. ing. In this case, in order to maintain the activity for a certain period, various changes in the shape of the drug,
Means such as selecting other components in the matrix and components of the coating layer that coats the matrix together with the active component are adopted.

As such an antiarrhythmic drug, for example, Japanese Patent Publication No. 1-41606 discloses α- [2- [bis (1-methylethyl) amino] ethyl] -α-phenyl-2-pyridineacetamide as an active ingredient. Antiarrhythmic drugs are indicated.

The manufacturing process of this antiarrhythmic drug is shown in FIG.
As shown in (A), α- [2- [bis (1-methylethyl) amino] ethyl] -α-phenyl-2-pyridineacetamide phosphate (referred to as disopyramide phosphate in the figure) and monostearin. Glyceryl acidate and sugar are mixed, heated, melted and granulated, then PVP (polyvinylpyrrolidone) is added, and the granule and granulation process is followed to form Mg.
-St (magnesium stearate) is added, and the mixture is tableted to obtain tablets, and then the sustained-release tablets are obtained through the steps shown.

[0005]

However, the manufacturing process of this antiarrhythmic drug requires a process of mixing, heating, and melting the components occupying most of the tablet, so that the apparatus required for this process becomes large, And it requires special equipment. Furthermore, since the granulation step is required twice, the manufacturing process of the sustained release tablet becomes complicated. An ester of glycerin such as glyceryl monostearate and a fatty acid having 10 to 22 carbon atoms is eluted in an aqueous solution of a surfactant due to its physical properties.

[0006] Regarding monoglyceryl monostearate, a sustained release agent containing a large amount of monostearate was investigated for the effect of wetting in a dissolution test of an aqueous solution of a surfactant, and as a result, the dissolution was accelerated and bioavailability was affected by dietary factors. It has been pointed out. (J. Jhn. So
c. Hoep. Pham 7 (3) pp. 307-30
(P. 9)

An object of the present invention is to solve the above-mentioned problems of the prior art and to provide an antiarrhythmic drug which can be manufactured by a simple process with existing devices used for usual formulation, and a simple process. It is to provide the manufacturing method.

[0008]

In order to achieve the above object, the antiarrhythmic drug of the present invention comprises: (a) α- [2- [bis (1-methylethyl) amino] ethyl] -α-phenyl -2-Pyridineacetamide or a pharmaceutically acceptable acid addition salt thereof : 60 to 80% by weight
%, (B) ethyl cellulose : 5 to 30% by weight (c) ester of glycerin and fatty acid having 10 to 22 carbon atoms: 1 to 10% by weight .

The method for producing the antiarrhythmic drug of the present invention
Is (a) α- [2- [bis (1-methylethyl) amino]]
Ethyl] -α-phenyl-2-pyridineacetamide
Is its pharmaceutically acceptable acid addition salt: 60-80% by weight
And (b) ethyl cellulose: 5 to 30% by weightAnd (c) d of glycerin and fatty acid having 10 to 22 carbon atoms
Steal1 to 10% by weightAnd, by mixing, granulating and tableting
First step of producing a drug and tablets obtained in the first step
A second step of obtaining a sustained release agent after heating at least the
It is characterized by doing.

In the antiarrhythmic drug of the present invention, (a) as an active ingredient is α- [2- [bis (1-methylethyl) amino] ethyl] -α-phenyl-2-pyridineacetamide or its pharmaceutically acceptable Acid addition salt.
Examples of the acid addition salt include α- [2- [bis (1-methylethyl) amino] ethyl] -α-phenyl-2-pyridineacetamide salts such as phosphate, chloride, bromide, acetate and ethylene. Suitable examples thereof include disulfonate and sodium hydrogensulfate. Among these acid addition salts, the phosphate of α- [2- [bis (1-methylethyl) amino] ethyl] -α-phenyl-2-pyridineacetamide is particularly desirable. Further, (b) as an essential component is ethyl cellulose.

Further, (c) as an essential component is an ester of glycerin and a fatty acid having 10 to 22 carbon atoms. The ester may be a mono, di or triester of glycerin. Examples of these esters include glycerin monostearate, distearate and tristearate, glycerin monopalmitate, dipalmitate and tripalmitate,
Mention may be made of the dilauric and trilauric acid esters of glycerin, the monocapric acid esters, dicapric acid esters and tricapric acid esters of glycerin, and the monomyristic acid esters, dimyristic acid esters and trimyristic acid esters of glycerin. Of these esters, glyceryl monostearate is particularly preferable. These esters can be used alone or in combination.

The proportions of the above-mentioned essential components (a), (b) and (c) are (a) α- [2- [bis (1-methylethyl) amino] ethyl] -α-phenyl-2- Pyridine acetamide or a pharmaceutically acceptable acid addition salt thereof: 60 to 80% by weight, (b) ethyl cellulose: 5 to
30% by weight, (c) ester of glycerin and fatty acid having 10 to 22 carbon atoms: 1 to 10% by weight.

The distribution ratio of the component (a) of α- [2- [bis (1-methylethyl) amino] ethyl] -α-phenyl-2-pyridineacetamide or a pharmaceutically acceptable acid addition salt thereof is 60. If it is less than 80% by weight, elution tends to be slow, while if it is more than 80% by weight, elution tends to be fast.

When the blending ratio of the ethyl cellulose (b) is less than 5% by weight, the active ingredient (a) elutes too fast, while when it exceeds 30% by weight, the active ingredient (a) is dissolved. The dissolution is too slow and the active ingredient does not function effectively. Furthermore, when the blending ratio of the ester (c) of glycerin and a fatty acid having 10 to 22 carbon atoms is less than 1% by weight,
The sustained release function does not work effectively, while if it is more than 5% by weight, elution will be delayed.

The matrix in the antiarrhythmic drug of the present invention may contain various optional components in addition to the above-mentioned essential components as required. Examples of such an optional component include a lubricant and PVP (polyvinylpyrrolidone). Examples of the lubricant include stearic acid, salts of stearic acid such as zinc, calcium, aluminum and magnesium, and talc. Of these, magnesium stearate is particularly preferable.

In the present invention, when a tablet is produced, as shown in FIG. 3 (B), the acid of α- [2- [bis (1-methylethyl) amino] ethyl] -α-phenyl-2-pyridineacetamide is used. Α- [2- [bis (1
-Methylethyl) amino] ethyl] -α-phenyl-2
-Pyridine acetamide phosphate (indicated as disopyramide phosphate in the figure), ethyl cellulose as a binder, and glyceryl monostearate as an ester of glycerin and a fatty acid having 10 to 22 carbon atoms are mixed and produced by a high-speed mixer. Granulate, dry and size. Next, magnesium stearate as a lubricant is added to this granulated product to give a tableting powder, which is then tableted.

The tablets obtained are then heated. The heating condition at this time is preferably a temperature slightly higher than the melting point of the ester of glycerin and a fatty acid having 10 to 22 carbon atoms, and particularly in the case of glyceryl monostearate, the melting point is 50 to 7
Since it is 0 ° C, about 80 ° C is preferable.

Next, HPM was added to the tablets to mask the bitterness.
A water-soluble coating agent such as C is coated. In addition to HPMC (hydroxypropylmethylcellulose), a pH-independent, water-insoluble, pharmaceutically acceptable film-forming polymer such as ethyl cellulose and aminoalkyl methacrylate copolymer can be used as the sustained-release agent.

[0019]

The present invention relates to (a) α- [2- [bis (1-methylethyl) amino] ethyl] -α-phenyl-2-pyridineacetamide or a pharmaceutically acceptable acid addition salt thereof, and (b) ) Ethyl cellulose and (c) glycerin and ester of fatty acid having 10 to 22 carbon atoms are mixed / granulated /
A tablet is manufactured by tableting, and the conventional method for manufacturing an antiarrhythmic drug requires a step of granulating after mixing, heating and melting of disopyramide phosphate, glyceryl monostearate and sugar.

That is, since the present invention does not require a step of heating and melting the active ingredient, an existing apparatus used for usual formulation is sufficient. Further, in the process until obtaining a tablet, the granulation process is sufficient for one process and does not require two granulation processes as in the conventional method for producing an antiarrhythmic drug.

In the present invention, the content of the ester of (c) glycerin and the fatty acid having 10 to 22 carbon atoms, which has a high elution rate in an aqueous solution of the surfactant, is minimized, and (b) the amount of ethyl cellulose is the above ( It can be increased corresponding to the decrease amount of the component a), whereby the dissolution rate can be adjusted to a desired value as a sustained release agent.

[0022]

【Example】

 Example 1 A sustained release tablet having the following composition was produced. Disopyramide phosphate 193.5 mg Glyceryl monostearate 7.5 mg Ethylcellulose 52.0 mg Magnesium stearate 3.0 mg ──────────────────────── ──── Total 256.0 mg

After mixing disopyramide phosphate, glyceryl monostearate [Reodol MS-50, (manufactured by Kao Corporation)] and ethyl cellulose [ethyl cellulose N-7-F, (manufactured by Shin-Etsu Chemical Co.)] by a commonly used method. Wet granulated. The granulated product was dried at 50 ° C. and then tableted.
Next, the tablets were heated at 80 ° C. in a shelf dryer to give sustained-release tablets.

The tablet prepared in Example 1 was sprayed with the coating solution having the following formulation by a commonly used method to give a weight of 26.
The tablets were coated with 2 mg. Hydroxypropyl methylcellulose 5.0% Titanium oxide 1.0% PEG6000 (polyethylene glycol) 0.5% Water 93.5% ──────────────────────── ──── Total 100.0% For this tablet, 12th revision Japanese Pharmacopoeia Dissolution Test Method 2
FIG. 1 shows the result of an elution test conducted by using 900 ml of water as an eluent according to the method (paddle method, 100 rpm).

Example 2 A coated tablet was produced in the same manner as in Example 1 except that the amount of glyceryl monostearate in Example 1 was changed to 5 mg, and the same dissolution test as in Example 1 was carried out. Figure 1
Shown in

Example 3 The amount of glyceryl monostearate of Example 1 was 10 mg.
The coated tablet was produced in the same manner as in Example 1 except that the above was carried out, and the same dissolution test as in Example 1 was carried out. The results are shown in FIG.

Next, the coated tablets obtained by the method of Example 1 above were each treated with a nonionic surfactant according to the 12th revised Japanese Pharmacopoeia dissolution test method 2nd method (paddle method, 100 rpm). The results of the dissolution test with an aqueous solution are shown in FIG. The% shown in FIG. 2 is the concentration of the nonionic surfactant in the aqueous solution. From FIG. 2, it is understood that the sustained-release agent of this example has a desired elution rate with a nonionic surfactant aqueous solution as a sustained-release agent. In addition, the first embodiment
The coated tablet in (1) could have a small diameter of 9 mm, and was effective for the elderly to take.

[0028]

Industrial Applicability As described above, according to the present invention, since it can be produced by using a relatively small apparatus used for usual formulation, no special occupation equipment is required, and
Tablets can be manufactured by a simple process. Also,
(C) The content of the ester of glycerin and a fatty acid having 10 to 22 carbon atoms can be minimized, and the amount of (b) ethyl cellulose can be increased corresponding to the decrease amount of the component (a). The dissolution rate can be adjusted to a desired value as a sustained release agent.

[Brief description of the drawings]

FIG. 1 is a graph showing the results of a dissolution test of the antiarrhythmic drug of the present invention with water.

FIG. 2 is a graph showing the results of a dissolution test of the antiarrhythmic drug of the present invention with a surfactant aqueous solution.

FIG. 3A is a process diagram showing a conventional process for producing an antiarrhythmic drug, and FIG. 3B is a process diagram showing a process for producing the antiarrhythmic drug of the present invention.

Continuation of the front page (56) References Japanese Patent Publication 1-41606 (JP, B2) Sadao Iguchi, "Comprehensive Technology for New Drug Development Systems-Bases and Additives" (Sho 60- 7-12) R & D Planning P.P. 427, 433-434 Pharmaceutical Additives Study Group, “Practical Drug Additives” (1974) Chemical Industry Co. 3, 106-107 Yoshinobu Nakai, Manabu Hanano, "New Pharmaceutical Science" (1987) P. 40-41

Claims (6)

(57) [Claims] 1. (a) α- [2- [bis (1-methylethyl) amino] ethyl] -α-phenyl-2-pyridineacetamide or a pharmaceutically acceptable acid addition salt thereof : 60
80% by weight, (b) ethyl cellulose : 5 to 30% by weight (c) ester of glycerin and fatty acid having 10 to 22 carbon atoms: 1 to 10% by weight , an antiarrhythmic drug. 2. α- [2- [bis (1-methylethyl)]
The acid addition salt of amino] ethyl] -α-phenyl-2-pyridineacetamide is α- [2- [bis (1-methylethyl) amino] ethyl] -α-phenyl-2-pyridineacetamide phosphate. The antiarrhythmic drug according to claim 1. 3. The antiarrhythmic drug according to claim 1, wherein the ester of glycerin and a fatty acid having 10 to 22 carbon atoms is glyceryl monostearate. 4. The antiarrhythmic drug according to claim 1, further comprising a lubricant in the components (a), (b) and (c). 5. The lubricant is stearate.
4. The antiarrhythmic drug according to 4 . 6. (a) α- [2- [bis (1-methylethyl) amino] ethyl] -α-phenyl-2-pyridineacetamide or a pharmaceutically acceptable acid addition salt thereof : 60
-80% by weight , (b) ethyl cellulose : 5 to 30% by weight , (c) ester of glycerin and fatty acid having 10 to 22 carbon atoms : 1 to 10% by weight , mixed, granulated and tableted. An antiarrhythmic drug, comprising: a first step of producing a tablet by using the above method; and a second step of obtaining a sustained release agent after at least heating the tablet obtained in the first step.