KR0128855B1 - Process for preparing controlled release pellet type of diltiazem - Google Patents

Abstract

The membrane coated sustained-release pellet fomulation containing a once-a-day diliazem dosage, was prepared by an aqueous membrane coating. Thus, 1.8 kg of diltiagem, 0.8 kg of lactose and 0.4 kg of sodium alginate were crushed and mixed, followed by pelletizing with 5 % of aqueous hydroxypropyl cellulose binding solution in 0.7 kg of sugar seed. A mixed solution of 670 g of Eudragit RS50D, 20 g of stearic acid, 4 g of arabia rubber, 60 g of talc and 10 g of sodium lauryl sulfate containing 20 solid content was coated on the pellet.

Description

[Name of invention]

Method for preparing slow-release pellet formulation of diltiazem

Detailed description of the invention

The present invention provides a membrane-coated pellet-type pharmaceutical formulation containing diltiazem and / or diltiazem hydrochloride (hereinafter referred to as diltiazem), which can be taken once daily. It relates to a manufacturing method. That is, the present invention relates to a useful method for preparing a diltiazem sustained release pellet having a release control ability similar to that of a general organic solvent coating with an aqueous membrane coating having a specific composition.

[Technical Background and Conventional Problems]

Diltiazem, a benzothiazepine derivative, is a calcium antagonist that inhibits the influx of calcium from smooth muscle and heart muscle, and is more effective in the same class of verapamil, nifedipine, and nicardipine or in the coronary artery dilatation. It is known as an effective drug mainly for chronic heart disease, angina pectoris, hypertension. In fact, the daily dose of the drug is reported to increase from 90mg in mild to 360mg in severe. However, the blood half-life is short, about 3 to 5 hours, and is administered 3-4 times daily. Recently, sustained release formulations have been developed for administration twice a day and once a day. However, in the conventional membrane coating, an organic solvent is used to dissolve the water-insoluble polymer, which is a problem that the problems such as removal of residual solvent, causing environmental pollution, increase of solvent recovery cost are increasing day by day. Accordingly, Eudragit, a form in which a water-soluble polymer of acrylic acid is dispersed in water at Rhoem Pharma in Germany, has recently been widely used as a coating material. However, in order to prepare a once-a-day preparation for which release should be controlled for 24 hours, Eudragit alone is difficult, and insoluble polymers such as ethylcellulose, cellulose acetate, polyvinyl chloride, etc. are mixed and used in an organic solvent. There is a situation.

U.S. Patent Nos. 4,894,240, 5,002,776, 5,229,135, and European Patent Publication No. 514814, etc., describe the composition and preparation of diltiazem in a daily dosage form for 24 hours. Here, membrane coating is the main technology, which dissolves or disperses water-insoluble polymers in organic solvents to form controlled release formulations. Therefore, the present invention provides a composition and a method for preparing the diltiazem sustained-release pellet formulation that can be controlled for 24 hours by water-based coating without using any organic solvent in the release-controlled membrane coating. In other words, the performance of the membrane coating is determined by the dissolution test, in the present invention, 20% or less in 1 hour, 30% or less in 2 hours, 45% or less in 4 hours, 60% or less in 6 hours, 80-95 in 12 hours. %, A formulation with elution characteristics of at least 95% at 24 hours.

In addition, in the preparation of a 24-hour long-acting formulation, the membrane is coated so that the drug is continuously released in small amounts by diffusion. In this case, the initial release (within 2 hours) of drug release is low. This is because, after absorbing more than a certain amount of water, the dissolution curve of the first- or zero-order reaction equation is drawn. Therefore, a method of filling the capsules by adding 10-25% by weight of rapid-release pellets in consideration of the initial blood concentration has been widely used. In most of the pellet formulations, the shape of the capsules filled in the capsules is the final product. In the case of the western pellets, the capsules are filled in No. 0 capsules so as to balance the content of all additives added so that the diltiazem content per capsule is 180 mg or 300 mg. .

Therefore, in the present invention, 10-20% of the total amount of the immediate release pellet may be added to increase the initial dissolution amount. On the other hand, if you look at the content of diltiazem, depending on the severity of the symptom, up to 360 mg of the daily dosage form is manufactured. Currently, 180 mg of sustained-release pellets are sold in the highest content in Korea. Published in the Journal of Cardivoascular Pharmacology, 16 (1), 38-45 (1990). Therefore, in the present invention, the diltiazem content is made into 180mg and 300mg to determine the duration of 24 hours through the dissolution test.

An object of the present invention is to prepare a new sustained-release pellet that can maintain sufficient drug even once a day for patients requiring long-term treatment such as angina and hypertension by using diltiazem as a sustained-release pellet formulation. The present invention relates to a composition and a method for performing membrane coating having the same effect by a water-based coating method rather than a conventional organic solvent coating method.

The present invention relates to a method for preparing sustained-release pellets that can be controlled for 24 hours by making a diltiazem-containing pellet containing a predetermined amount of diltiazem and coating the membrane around the water-based coating method.

In order to manufacture the diltiazem-containing pellet of the present invention, a fluidized bed granulator and a conventional coating pan are used. In the present invention, a fluidized bed granulator is mainly used. In the manufacturing method, first, the sugar seed was diltiazem and excipients, and the water-soluble polymer having a high wetting effect and gel formation degree was pulverized and uniformly mixed in a ball mill. The solution is used to prepare diltiazem containing pellets. Excipients that can be used herein include water-soluble excipients such as pharmaceutically useful lactose, dextrose, mannitol, sorbitol, and water-insoluble excipients such as microcrystalline cellulose, calcium carbonate, calcium phosphate, and one or two or more thereof. It may be. Sodium and Alginate, Carbopol, and Karaya Gum are polymers that have a high wet and gel effect. They form a gel when the drug comes out through the membrane in contact with water. It is added to prevent pellets from leaving at once and to keep the pellets in a stable shape for 24 hours. As the water-soluble polymer used as the binder, polyvinyl alcohol, polyvinylpyrrolidone, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hygioxyethyl cellulose or a mixture thereof is suitable, so that the concentration of the binder is 4- 15% by weight is useful. And here the most suitable is hydroxypropylcellulose.

According to the content ratio of the diltiazem-containing pellet, the main drug, diltiazem, is 40-80% by weight, and the sugar seed is 15-30% by weight, and the excipient is within 30% by weight depending on the target drug amount. 4-15% by weight is useful as a water-soluble polymer for the wetting and gel effects, and the binder is dissolved in water and sprayed at 5 to 15% by weight. The amount of the polymer is 5-10% by weight. to be.

The content ratio is a numerical value set experimentally for spraying the binder solution to the sugar seed in the fluidized bed granulator to efficiently prepare a mixed powder of drug, excipient, wetting and gel effect polymer into diltiazem-containing ferret. However, in the case of the wet and gel effect polymers, the content ratio was 5-20% by weight with respect to the drug content, and the effect described above was the greatest, and in the case of the excipient, the amount of drug in the final pellet was set to 180 mg and 300 mg. It can be added or subtracted. When diltiazem-containing pellets are prepared, the water content is dried to 2% or less, and the aqueous membrane coating, which is a main feature of the present invention, is performed.

The polymers used here are water-dispersed polymers such as Eudragit RS30D, Eudragit NE30D, Eudragit RL30D, which are acrylic acid copolymers of Germany-Palm Corporation, and hydroxypropylmethyl from Shin-Etsu, Japan. It is a polymer capable of water-based coating, such as cellulose-solubilized Metolose SR. However, as mentioned above, Eudragit or Metolos, even when used alone or in combination of two or more, has a 100% elution within 8 hours when coated at a typical thickness (50-80 μm diameter). In addition, it is difficult to maintain 6 hours for water-soluble drugs such as diltiazem. And it is difficult to control the 24 hour release because the holding time between the start time and the end time of elution is only 3 to 5 hours. For this reason, in most cases, membrane coating is carried out by mixing a predetermined amount of insoluble polymer in an organic solvent.

However, in the present invention, a homogeneous dispersion of fatty acids in water using an emulsifier is added to Eudragit or Mettolose to develop a new formulation having a 24-hour longevity by membrane coating. As the fatty acid used herein, fatty acids such as stearic acid, palmitic acid, lauric acid and eleostearic acid are suitable and preferably stearic acid. In addition, natural emulsifiers are used as emulsifiers, because general synthetic emulsifiers may cause chemical reactions during preparation or preservation, and especially when mixed with coating liquids. Natural emulsifiers such as gum arabic, gelatin, lacithin, cholesterol are used and most suitably gum arabic.

In order to prepare the coating solution, first, stearic acid and gum arabic are mixed at a ratio of 10: 1 to 10: 4 and softened in a suitable container for 30 minutes, and then poured with a small amount of water to soften again for 10 minutes. This is lyophilized to increase the physical binding strength of stearic acid and gum arabic. After lyophilization, water is poured into 10 to 20% solids and then uniformly dispersed in the mixer. It is mixed with a certain amount of Eudragit or Metolose to coat. Here, the ratio of stearic acid to solid content of Eudragit or metholose is preferably used within 30%, more preferably 10 to 20% by weight. This is because when the stearic acid is more than 30% of Eudragit or metholose, the surface of the coating film is uneven and brittle, making it difficult to effectively coat. Therefore, when we observed the surface state by making the film of about 80㎛, the stearic acid is within 30% of Eudragit or metholose, and there is no significant effect on the general properties of the film and the surface is almost uniform. Suitable for coating of containing pellets.

In addition, the degree of membrane coating for the diltiazem-containing pellets is suitably coated with 20 to 30% by weight of solids per content of the pellets, wherein the coating thickness was 60 to 100 µm. In the coating of more than 30%, elution by diffusion appeared only after 3 hours of dissolution, and the above range was determined because there was no further increase in retention time. In addition, 10-20% by weight of diltiazem-containing pellets before membrane coating are added as immediate release pellets to increase the amount of additional release.

The following examples and comparative examples are set forth to illustrate the subject matter of the present invention.

Example 1

1.8 kg of diltiazem, 0.8 kg of lactose and 0.4 kg of sodium alginate were uniformly pulverized and mixed to pass through a 50 mesh standard network, and the powder was added to 0.7 kg of sugar seed (0.5-0.71 mm) on a fluidized bed granulator. A diltiazem-containing pellet is prepared by using an aqueous solution of hydroxypropyl cellulose as a binding solution. Next, the membrane coating is prepared in such a way that the solid content is 20% at a ratio of 670 g of Eudragit RS30D, 20 g of stearic acid, 4 g of gum arabic, 60 g of talc, and 10 g of sodium lauryl sulfate. Herein, the stearic acid and the gum arabic are emulsified, lyophilized and mixed, and then mixed with Eudragit and other additives and diluted with water so that the solid content is 20%. This is coated on 1.0 kg of diltiazem-containing pellets to produce a final pellet. The sustained-release pellet of the present invention can know the amount of drug eluted with time through the dissolution test in vitro.

Conditions of Dissolution Test: USP XXI Paddle Method, 100rpm, 37O ℃

0.05M-KCL solution (pH 7.0)

Elution time

1 hour 4.1%

2 hours 9.8%

3 hours 18.5%

4 hours 27.3%

6 hours 49.6%

12 hours 82.3%

16 hours 93.2%

24 hours 100.1%

EXAMPLE

3.9 kg of diltiazem and 0.3 kg of sodium alginate were uniformly pulverized and mixed to pass through a 50 mesh standard network, and then the powder was added to 0.4 kg of sugar seed (0.35-0.5 mm) in a 5% hydroxypropyl cellulose on a fluidized bed granulator. A diltiazem-containing pellet is prepared using the aqueous solution as a binding solution. Next, the membrane coating is prepared in such a way that the solid content is 20% at a ratio of Eudragit RS30D 670g, stearic acid 30g, gum arabic 4g, talc 50g, sodium lauryl sulfate 10g. Herein, the stearic acid and the gum arabic are emulsified, lyophilized and mixed, and then mixed with Eudragit and other additives and diluted with water so that the solid content is 20%. The final pellet is prepared by coating this on 1.0 kg of diltiazem-containing pellets.

Dissolution test is carried out in the same manner as in Example 1.

Elution time

1 hour 3.8%

2 hours 8.2%

3 hours 16.5%

4 hours 30.3%

6 hours 51.2%

12 hours 84.9%

16 hours 94.2%

24 hours 99.7%

Comparative Example 1

1.8 kg of diltiazem and 0.4 kg of sodium alginate were uniformly pulverized and mixed, passed through a 50 mesh standard network, and then the powder was added to a sugar seed (0.5-0.7 mm) 0.7 kg in a 5% hydroxypropyl cellulose on a fluidized bed granulator. A diltiazem-containing pellet is prepared using the aqueous solution as a binding solution. Next, the membrane coating is prepared with a liquid content of 20% at a ratio of Eudragit RS30D 670g, talc 80g, sodium lauryl sulfate 14g. Here, without using stearic acid and gum arabic, Eudragit and other additives are mixed and diluted with water to a solid content of 20% to produce 1470 g of coating solution. This is coated on 1.0 kg of diltiazem-containing pellets to produce a final pellet. The pellets were eluted at least 95% after 6 hours as follows.

Elution time

1 hour 8.3%

2 hours 48.6%

3 hours 75.9%

4 hours 86.2%

6 hours 96.4%

8 hours 100.1%

Example 3

1.8 kg of diltiazem, 0.8 kg of lactose and 0.4 kg of sodium alginate were uniformly pulverized and mixed to pass through a 50 mesh standard network, and the powder was added to 0.7 kg of sugar seed (0.5-0.71 mm) on a fluidized bed granulator. A diltiazem-containing pellet is prepared by using an aqueous solution of hydroxypropyl cellulose as a binding solution. Next, the membrane coating is prepared so that the solid content is 20% at a ratio of 200 g of metlosose SM, 20 g of stearic acid, 4 g of gum arabic, 60 g of talc, and 10 g of sodium lauryl sulfate. Here, the stearic acid and the gum arabic are emulsified, lyophilized, and mixed in the above-described manner. Then, the mixture of metlosose and other additives is diluted with water so that the solid content is 20%, and a coating solution of 1470 g is prepared. This is coated on 1.0 kg of diltiazem-containing pellets to produce a final pellet.

Do the dissolution test in the same way.

Elution time

1 hour 7.2%

2 hours 11.7%

3 hours 20.0%

4 hours 30.2%

6 hours 51.1%

12 hours 86.7%

16 hours 95.5%

24 hours 100.4%

Example 4

In the final membrane-coated pellets of Example 1, 10% of immediate-release granules are added and the total drug amount is the same, followed by dissolution test.

Elution time

1 hour 15.1%

2 hours 21.7%

3 hours 28.8%

4 hours 35.7%

6 hours 50.2%

12 hours 83.4%

16 hours 93.3%

24 hours 99.6%

Example 5

In the final membrane-coated pellets of Example 2, 10% of immediate-release granules are added and the total drug amount is the same, followed by dissolution test.

Elution time

1 hour 17.2%

2 hours 25.1%

3 hours 32.3%

4 hours 40.8%

6 hours 51.3%

12 hours 85.1%

16 hours 94.8%

24 hours 100.7%

Comparative Example

The two products currently on the market and the pellets prepared in Examples 1 and 4 were subjected to dissolution test under the same conditions and compared with each other.

* Diltelan: Importing myotropic drugs (contain 180mg diltiazem, once-daily)

* HER-SR: Tanabesa (240mg diltiazem, once daily preparation)

Time Elution Example 5 diltelan HER-SR

1 hour 4.1% 15.1% 8.1% 18.0%

2 hours 9.8% 21.7% 11.3% 23.5%

3 hours 18.5% 28.8% 18.1% 30.1%

4 hours 27.3% 35.7% 27.5% 37.0%

5 hours 39.6% 42.6% 38.4% 44.5%

6 hours 49.6% 50.2% 48.2% 51.5%

8 hours 63.8% 64.3% 65.0% 65.0%

12 hours 82.3% 83.4% 85.7% 83.0%

16 hours 93.2% 93.3% 95.4% 93.4%

20 hours 96.4% 97.4% 99.1% 97.5%

24 hours 100.1% 99.6% 101.0% 100.0%

Claims (2)

In preparing a once-a-day membrane-coated sustained-release pellet formulation containing diltiazem, a pellet containing 5-20% by weight of sodium alginate relative to diltiazem was added 10: 1- 10: 4 is a method for producing a membrane-coated sustained-release pellet formulation, characterized in that the membrane coating the composition added to the polymer for water-based coating. The membrane-coated sustained-release pellet according to claim 1, wherein the polymer for waterborne coating is hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, methylacrylate-methylmethacrylate copolymer, methylcellulose. Method of Preparation of the Formulation.