JPH08133975A - Long-acting preparation containing disopyramide phosphate and its production - Google Patents

Abstract

PURPOSE: To obtain long-acting preparation by adding disopyramide phosphate to a matrix comprising a water-insoluble polymer matrix base and a binder. CONSTITUTION: Disopyramide phosphate is granulated together with a water- insoluble polymer matrix base such as ethylcellulose and one or two kinds of binders such as hydroxypropyl methylcellulose phthalate in a usual manner, then subjected to compression molding to give the objective long-acting preparation. The weight ratio of disopyramide phosphate to the water-insoluble polymer matrix base is 1/0.05 to 1/0.5. In no need of special operations, this preparation can be practically produced without special equipment and device. Since sufficiently stabilized long-activity can be attained by about twice doses, the compliance of patients is improved.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention contains disopyramide phosphate in a matrix composed of one or more water-insoluble polymer matrix bases and binders. The present invention relates to a sustained-release preparation and a method for producing the same by granulation and compression molding.

[0002]

2. Description of the Related Art Disopyramide; [Chemical name α- (2-diisopropylaminoethyl) -α-phenyl-2-pyridineacetamide] is an antiarrhythmic drug developed by Roussel-Yucraf in France. It was released in France. Since then, its excellent therapeutic effect has been evaluated in various countries around the world, and in 1976, water-soluble disopyramide phosphate was developed as an injection. Furthermore, for the purpose of increasing patient compliance, a sustained release tablet, which enhances the sustained effect and is effective by administration twice a day, has been developed, and has been widely clinically used under the trade name of Lismodern R tablet in each country since 1980. There is.

As a method for suppressing the water-solubility of disopyramide phosphate to form a sustained-release preparation, granules obtained by melting crystals of disopyramide phosphate together with glycerin fatty acid ester and sucrose at 65 ° C. Method of compression molding after coating with pyrrolidone (Japanese Patent Publication No. 1-4160)
No. 6), a method for forming microcapsules of disopyramide phosphate by using biodegradable polymer substances such as polylactic acid and polyglycolic acid, and sugar-derived natural polymer substances such as chitin and hyaluronic acid. (JP-A-1-
156912) is known. However, these methods require special manufacturing equipment, and some of them are still unsatisfactory in terms of complexity of manufacturing operation and production cost.

[0004]

The object of the present invention is to formulate a product by a method that is easy to put into practical use, without using any special equipment or device, requiring no special manufacturing operation, and
It is an object of the present invention to provide a compact and easy-to-administer preparation containing disopyramide phosphate, which can be expected to have a sufficiently stable sustained effect by administration about twice a day, and therefore can improve patient compliance, and a method for producing the same.

[0005]

According to the present invention, disopyramide phosphate is granulated by a conventional method using one or more of a water-insoluble polymer matrix base and a binder, and then compressed. By molding, it is possible to obtain the disopyramide phosphate-containing sustained-release preparation for the above purpose.

Examples of the water-insoluble polymer matrix base used in the present invention include ethyl cellulose, ethyl acrylate / methyl methacrylate copolymer emulsion, aminoalkyl methacrylate copolymer RS (ethyl acrylate / methacrylic acid). Aminoalkyl methacrylic acid copolymers such as methyl methacrylic acid trimethylammonium ethyl copolymer) are preferably used. Further, as the binder, hydroxymethylcellulose phthalate, hydroxypropylmethylacetate succinate, carboxymethylethylcellulose, methacrylic acid copolymers LD, L, and S (methacrylic acid and methyl methacrylate, ethyl acrylate, meta acrylate, respectively) Copolymer with methyl acrylate), aminoalkyl methacrylate copolymer E (methyl methacrylate / butyl methacrylate / dimethylaminoethyl methacrylate copolymer), hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl acetal diethylaminoacetate Etc. are preferably used.

The granulation method may be either a spray method or a kneading method. For example, in the case of spray granulation, a fluidized bed granulator is used, and a mixture of disopyramide phosphate and an excipient is first added to a water-insoluble polymer matrix. Spray granulate by spraying water emulsion or ethanol solution of base, then spray granulate using water or ethanol solution of binder, double coating water-insoluble polymer matrix base and binder . In the case of kneading granulation, for example, using a universal kneading machine, an ethanol solution of a water-insoluble polymer matrix base is added dropwise to a mixture of disopyramide phosphate and an excipient, kneading and granulating, and after drying. Further, a water or ethanol solution of a binder is added dropwise to knead and granulate, and two-step coating is performed as in the spray granulation method.

The granulation method does not necessarily require two-step coating, but for example, disopyramide phosphate, a water-insoluble polymer matrix base and a binder are mixed together using a suitable solvent such as ethanol, and the same as above. Alternatively, spray granulation or kneading granulation may be performed. When performing two-step coating, either the water-insoluble polymer matrix base or the binder may be used first for granulation, but the release of the main drug may be slightly dependent on the type of the base and the combination with the binder. Because of different sex, disopyramide phosphate gastric juice (pH 1.
It is preferable to adjust so that the dissolution properties of both solutions are as equal as possible while observing the relationship between 2) and the dissolution properties of intestinal fluid (pH 6.8).

The granules thus obtained can be administered as a continuous granules as they are, but if the granules are appropriately sized, a lubricant is added, and the mixture is tableted by a conventional method, the disopyramide phosphate is maintained. A sex tablet is obtained. Hereinafter, the present invention will be described in more detail with reference to Examples and Test Examples.
These do not limit the invention in any way.

[0010]

EXAMPLE 1 580.5 g of disopyramide phosphate and 74.4 g of lactose are put into a flow coater FLO-1 type (trade name: manufactured by Freund Sangyo) and mixed. Ethyl cellulose (ETOCEL N-7-G, trade name: manufactured by Shin-Etsu Chemical) 105
g and 6.0 g of triethyl citrate are dissolved in 90% ethanol and a 12% solution is spray granulated by Chosei City. Furthermore, methacrylic acid copolymer LD (Eudragit L
-30D-55, trade name: Higuchi Shokai Co., Ltd.) 120 g (solid component 36 g) diluted with water so that the solid component becomes 10%,
Spray granulate. After drying, size-regulated with a No. 20 sieve, 8.1 g of magnesium stearate was added to and mixed with the resulting granules, and the mixture was tableted using a rotary tableting machine to give 270 mg of phosphoric acid per tablet. A sustained-release tablet containing disopyramide (content 193.5 mg) is obtained.

[0011]

Example 2 387 g of disopyramide phosphate and lactose 1
0.8 g is added to a flow coater FLO-1 type and mixed. Ethyl cellulose (Aquacoat, trade name: Asahi Kasei) 366.6 g (solid component 110 g) was diluted with water so that the solid component was 10%, and triethyl citrate 4.
The liquid added with 4 g is spray granulated. Furthermore, methacrylic acid copolymer LD (Eudragit L-30D-55)
80 g (solid component 24 g) is diluted with water so that the solid component is 10%, and spray granulated. After drying, it was sieved with a No. 20 sieve, 3.8 g of magnesium stearate was added to and mixed with the obtained granules, and the mixture was tableted using a rotary tableting machine to give 270 mg of phosphoric acid per tablet. A sustained-release tablet containing disopyramide (content 193.5 mg) is obtained.

[0012]

Example 3 A universal kneading machine 3X-DMV-Qr (manufactured by Dalton) was used, and ethyl cellulose (Ethocel N-7-G) 11 was added.
In a solution of 0 g dissolved in 110 ml of ethanol, 387 g of disopyramide phosphate, 14.9 g of lactose and methacrylic acid copolymer L (Eudragit L100, trade name:
20 g of Higuchi Shokai Co., Ltd. is added and kneaded and granulated. After drying
Sifted through a No. 20 sieve, and the obtained granular material was silicic acid anhydride (Carplex # 80, trade name: Shionogi Pharmaceutical Co., Ltd.)
2.7 g and 5.4 g of magnesium stearate are added and mixed, and the mixture is tableted using a rotary tableting machine to give disopyramide phosphate-containing sustained-release tablets (content 193.5 mg) with a weight of 270 mg per tablet.

[0013]

Example 4 In a universal kneading machine 3X-DMV-Qr, 110 g of ethyl cellulose (Ethocel N-7-G) was dissolved in 110 ml of ethanol, and disopyramide phosphate 3 was added.
87 g, lactose 14.9 g and methacrylic acid copolymer S (Eudragit S100, trade name: Higuchi Shokai) 2
Add 0 g and knead and granulate. After drying, it was sieve-sized with a No. 20 sieve, and 2.7 g of silicic acid anhydride (Carplex # 80) and magnesium stearate 5.4 were added to the obtained granules.
g and mixed, tableted using a rotary tableting machine,
A sustained-release tablet containing disopyramide phosphate (content 193.5 mg) weighing 270 mg per tablet is obtained.

[0014]

Example 5 In a universal kneading machine 3X-DMV-Qr, 110 g of ethyl cellulose (Ethocel N-7-G) was dissolved in 110 ml of ethanol, and disopyramide phosphate 3 was added.
87 g and lactose 14.9 g are added, kneaded, granulated, and dried. Further, 80 g of methacrylic acid copolymer LD (24 g of solid component) is diluted with water to a solid component content of 10%, and spray granulated. After drying, size-adjust with a No. 20 sieve,
Silicic anhydride (Carplex # 80) was added to the obtained granules.
2.7 g and 5.4 g of magnesium stearate are added and mixed, and the mixture is tableted using a rotary tableting machine to give disopyramide phosphate-containing sustained-release tablets (content 193.5 mg) with a weight of 270 mg per tablet.

The sustained release preparation of the present invention obtained in Examples, and
The results of measuring the release properties of disopyramide phosphate and the blood concentration thereof when orally administered to humans with respect to commercially available Lismodern capsules (immediate release preparations) and Lismodern R tablets (sustained release preparations) are described below.

[0016]

[Experimental Example 1] (Dissolution test in water) Using a Japanese Pharmacopoeia dissolution tester, the dissolution rates of disopyramide phosphate were compared by the paddle method. The test solution is the pharmacopoeia 1st liquid (pH 1.2) and 2nd liquid (pH 6.8)
The amount of liquid used was 900 ml for a sample corresponding to 193.5 mg of disopyramide phosphate. Set temperature is 3
7 ° C., the paddle rotation speed was 100 rpm, and the amount of disopyramide phosphate eluted in the test solution was determined by measuring the absorbance (measurement wavelength: 26
(0 nm), the sample solution collected at each time was filtered through a membrane filter (0.45μ) and then measured. The test results are shown in Table 1, and the numerical value is the average of 6 measurements.

[Table 1]

[0017]

[Experimental Example 2] (Human administration test) The sustained-release preparation of the present invention (Example 1, containing 193.5 mg of disopyramide phosphate) was orally administered to 6 healthy adult males, and blood was collected over time after administration to obtain blood. The disopyramide phosphate concentration was measured by gas chromatography. The test results are as shown in FIG. 1, and the numerical value is the average of 6 measurements.

[0018]

As described above, the disopyramide phosphate sustained-release preparation of the present invention (1) does not impair the efficacy of disopyramide phosphate, and its dissolution rate is almost the same in both gastric juice and intestinal juice. And (2) a stable effective blood concentration suitable for twice-daily administration can be obtained, and (3) a sustained release effect of disopyramide phosphate can be produced with consistently stable quality, (4) It has various advantages that it does not require a special material, equipment, or technique as a formulation means, and can be industrially advantageously carried out using commonly used formulation raw materials and formulation equipment.

As is clear from the test results in Table 1, the sustained effect is delayed in control as compared with the quick-release Lismodern capsule, and is evaluated to be almost equivalent to the sustained-release preparation Lismodern R tablet. It As shown in FIG. 1, the change in blood concentration when administered to humans reached the maximum concentration in 5 hours, and the effective blood concentration continued for about 12 hours from 2 hours after administration, It shows a highly safe dissolution pattern as a sustained-release preparation for twice-daily administration.

[Brief description of drawings]

FIG. 1 is an explanatory diagram showing the time course of blood disopyramide phosphate concentration when the disopyramide phosphate sustained-release preparation of the present invention (Example 1) is orally administered to a human.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification number Reference number within the agency FI Technical indication location A61K 47/38 C (72) Inventor Tetsuya Takahashi 5-12-8 Yamanoue, Hirakata-shi, Osaka

Claims (11)

[Claims] 1. A sustained-release preparation comprising disopyramide phosphate in a matrix comprising one or more water-insoluble polymer matrix bases and one or more binders. 2. The sustained-release preparation according to claim 1, wherein the water-insoluble polymer matrix base is ethyl cellulose, ethyl acrylate / methyl methacrylate copolymer or aminoalkyl methacrylate copolymer RS. 3. The binder is hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, methacrylic acid copolymer LD, L, S, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl acetal diethylaminoacetate, The sustained-release preparation according to claim 1, which is or / and an aminoalkyl methacrylate copolymer E. 4. The sustained-release preparation according to claim 1, wherein the weight ratio of the disopyramide phosphate to the water-insoluble polymer matrix base is 1: 0.05 to 1: 0.5. 5. The sustained-release preparation according to claim 1, wherein the weight ratio of the disopyramide phosphate to the binder is 1: 0.02 to 1: 0.2. 6. A disopyramide phosphate-containing compound, characterized by using one or more kinds of disopyramide phosphate, a water-insoluble polymer matrix base and a binder, and granulating and compression-molding by a conventional method. How to make a sustained release formulation. 7. The granulation step is divided into two steps, and first, granulation is carried out by a conventional method using disopyramide phosphate and one or more kinds of water-insoluble polymer matrix bases, and the obtained granules are obtained. Further, it is characterized in that it is granulated by a conventional method using one kind or two or more kinds of binders, and then compression molded.
A method for producing a sustained-release preparation containing disopyramide phosphate. 8. The method for producing a sustained-release preparation according to claim 6, wherein the water-insoluble matrix polymer base is ethyl cellulose, ethyl acrylate / methyl methacrylate copolymer, or aminoalkyl methacrylate copolymer RS. . 9. The binder is hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, methacrylic acid copolymer LD, L, S, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl acetal diethylaminoacetate, The method for producing a sustained-release preparation according to claims 6 and 7, which is or / and aminoalkyl methacrylate copolymer E. 10. The weight ratio of disopyramide phosphate to water-insoluble polymer matrix base is from 1: 0.05 to 1: 0.5.
The method for producing a sustained-release preparation according to claim 6 or 7, wherein 11. The method for producing a sustained-release preparation according to claim 6, wherein the weight ratio of the disopyramide phosphate to the binder is 1: 0.02 to 1: 0.2.