KR20120060983A - Sustained release dosage form and manufacturing procedure of Sarpogrelate HCl - Google Patents

Abstract

PURPOSE: A sustained release composition containing sarpogrelate HCl is provided to quickly delay drug release and to enhance drug compliance. CONSTITUTION: A pharmaceutical composition contains 50-500mg of sarpogrelate HCl and one or more water-soluble polymers or water-insoluble polymer. The water-soluble polymers include hydroxyl propyl methyl cellulose, carbomer, polyethylene oxide, hydroxypropylene cellulose, xanthan gum, arabio gum, povidone. A tablet contains 5-50% of hydroxyl propyl methyl cellulose.

Description

Sustained release formulation containing safoglychloride hydrochloride and method for preparing the same

The present invention relates to a method for sustaining the release of safoglylate hydrochloride, which inhibits antiplatelet action and vasoconstriction, wherein the drug is used for sustaining the release of safoglylate hydrochloride for 8 to 10 hours or more using a hydrophilic or hydrophobic medium. To pharmaceutical preparations.

The sustained-release technology of drugs is known by the method of directly compressing with a drug using a water-soluble or water-insoluble polymer or a method of preparing tablets by tableting after granules are prepared by using a wet method. In various patents and papers, the main components are coated on pellets such as cellulose derivatives, shellac, and Jane, water-soluble polymers, pellets such as Sugasphere, water-insoluble cellulose derivatives, acrylic acid polymers, plasticizers and other additives, and dried. The method of achieving sustained release is described.

Korean Laid-Open Publication No. 2001-0009439 describes the invention of a sustained release tablet obtained by mixing and tableting a polymer such as Sephacller and hydroxypropyl cellulose or carboxymethyl cellulose. The dispersion is prepared by dispersing hydroxypropylmethylcellulose and vinylpyrrolidonevinylacetate copolymer in an organic solvent or a mixture of organic solvent and water. The resulting dispersion is simply mixed with Sephacler and then crushed to make tablets, or the mixture is struck to produce granules in a conventional manner and then compressed to prepare tablets, and pharmaceutically usable conventional It is a method of preparing a sustained release formulation for oral administration by coating the tablet with a coating agent.

Korean Patent No. 10-0483716 discloses a sustained-release tablet invention containing trimebuterin maleate and using Eudragit as a sustained release agent. This technique is also a conventional method for preparing a sustained-release tablet in a matrix form. The active ingredient and the additive are granulated in a binder solution, dried, and sieved. Then, the sustained-release agent Eudragit and the previous formulation are mixed and compressed into a sustained-release preparation. It is a method of manufacturing.

US patent US6630162 describes a method for producing a pellet formulation containing L-tartrate tolterodine and using a cellulose derivative as the release control membrane. This technique is a process of spray coating a first release control film with a water-insoluble coating on a bead such as Sugas Pierce in a fluidized bed coater, spraying the drug with a coating solution melted with a binder thereon, and finally binding the water-insoluble polymer. It is divided into a process of spray coating a film which sprays on it and controls slow release. This technique is a basic technique widely used in pellet manufacturing technology.

Republic of Korea Publication No. 10-2008-0015620 describes a drug in the form of tablets containing safoglylate and containing polyvinylacetate as a binder and calcium stearate as a lubricant for the stability of the drug. However, the technology is about immediate release releases.

Existing methods designed for sustained release of safoglylate hydrochloride have required patients to suffer foreign body pain and pain by contacting or inserting in vivo. In the present invention, the patient can simply take the conventional oral administration without such pain, and the number of doses is also reduced once a day to develop a safoacrylate hydrochloride sustained release formulation having improved medication compliance.

Sustained release preparations are usually formulations designed to be taken twice or once daily. It is an object of the present invention to prepare a sustained-release hydrochloride safoacrylate hydrochloride formulation having a sustained efficacy by taking once a day. Currently available commercially available tablets of safoacrylate hydrochloride include Yuhan Corporation's Anflag tablet, which contains 100mg of safoacrylate hydrochloride. In the present invention, a sustained-release tablet was designed once a day, and the release pattern of the drug was compared and tested by using Anflag tablet as a reference drug, and the content of the drug was 300 mg of safoglychloride hydrochloride. In addition, the dissolution rate was controlled to release the release rate of about 80% in 10 hours for a commercial formulation that is released more than 80% of the drug in 30 minutes.

As a method of delaying the release of the drug, it can be divided into a matrix system and a coating system. In the present invention, a matrix-type system using a method of tableting directly by mixing a safoacrylate hydrochloride with an additive for water-soluble polymers and other pharmaceutical products or by preparing a solvent by a wet granulation process was described and the detailed description is given below.

As described above, the present invention is expected to be able to simplify the discomfort that the patient should take the medicine three times a day and increase the medication compliance by delaying the rapid release of existing drugs. Providing sustained-release preparation technology that can be manufactured with general equipment

1 is a graph showing the dissolution rate of Examples 4-6.

The present inventors have studied two methods of preparing a matrix sustained-release tablet, a direct tableting method and a wet granulation method.

Polymers used for the purpose of delaying drug release in matrix type tablets include water-soluble polymers such as hydroxypropylmethylcellulose, carbomer, polyethylene oxide, hydroxypropylcellulose, hydroxyethylcellulose, xanthan gum, gum arabic, povidone, etc. Water insoluble polymers include waxes (pewter, yellow wax, microcrystalline wax) and celluloses.

Among them, in the present invention, hydroxypropyl methyl cellulose, carbomer and polyethylene oxide were used. ) The molecular weights of 100000-7000000 were used respectively.

In addition to the water-soluble polymers described in the examples, various kinds of additives may be used as the release controlling polymer, which is a substitute for those skilled in the art.

Since the detailed preparation method and quantity of the examples are described.

Example 1 ~ 3

Examples 1-3 are prescriptions for comparing a release pattern according to the kind of water-soluble polymer. The manufacturing method was prepared by a direct tableting method.

Sapoacrylate hydrochloride and a water-soluble polymer (hydroxypropylmethylcellulose or carbomer or polyethylene oxide), lactose and hydroxypropylcellulose were placed in a mixer and mixed for 5 minutes. Magnesium stearate was added to the mixture, followed by mixing for 3 minutes to obtain a final mixture, which was tableted in a rotary tablet press (KT-1000) to form a tablet having a hardness of 5 to 8 kgf.

Composition of Examples 1-3 Raw material name Example 1 Example 2 Example 3 Hydrochloric Acid Safoacrylate 300 300 300 Hydroxypropyl Methyl Cellulose 90SH4000 100 - - Carbomer 934P - 100 - Polyethylene Oxide (M.W. 5000000) - - 100 Citric acid 15 15 15 Lactose 50 50 50 Hydroxypropylcellulose 30 30 30 Magnesium stearate 5 5 5 Sum 500 500 500

Example 4 To 6

Examples 4 to 6 use hydroxypropylmethylcellulose as a water-soluble polymer and are formulated to evaluate the effect of each on the release of the drug using polymers of different grades of viscosity and substituents. The manufacturing method was a wet granulation method.

Hydroxypropylmethylcellulose was dissolved in anhydrous ethanol to prepare a binding solution. Separately, the saponacrylate hydrochloride, hydroxypropylmethylcellulose, and lactose were added to a high speed rotary mixer, mixed for 5 minutes, and then mixed with a preliminarily prepared binder solution to form granules. The granules thus obtained were dried in a 60? Dryer for 4 hours to obtain granules having a drying loss of 2% or less. The granules were lowered into a sieve having a diameter of 1 mm to obtain granules having a constant particle size distribution. The granules were placed in a mixer, magnesium stearate was added and mixed for 3 minutes to obtain a final mixture. The obtained mixture was tableted in a rotary tableting machine and molded into tablets having a hardness of 5 to 8 kgf.

Compositions of Examples 4-6 (unit: mg / T) Raw material name Example 4 Example 5 Example 6 Hydrochloric Acid Safoacrylate 300 300 300 Hydroxypropyl Methyl Cellulose 90SH100000 - - 150 Hydroxypropyl Methyl Cellulose 90SH10000 - 150 - Hydroxypropyl Methyl Cellulose 90SH4000 150 - - Citric acid 15 15 15 Hydroxypropylcellulose 30 30 30 Magnesium stearate 5 5 5 Sum 500 500 500

Example 7 To 8

Examples 7-8 are prescriptions compared to evaluate the effect of the addition amount of hydroxypropylmethylcellulose on the release of the drug.

The manufacturing method was the same as that of Examples 4-6.

Composition of Examples 7-9 (unit: mg / T) Raw material name Example 7 Example 8 Hydrochloric Acid Safoacrylate 300 300 Hydroxypropyl Methyl Cellulose 90SH100000 100 50 Citric acid 15 15 Lactose 50 100 Hydroxypropylcellulose 30 30 Magnesium stearate 5 5 Sum 500 500

Dissolution Rate Assessment

The target dissolution rate of the sustained release formulation was determined to be 30% or less at 1 hour, 30 to 60% at 4 hours, or 80% at 10 hours based on the pharmacokinetic properties and literature data. Dissolution test under the following conditions in accordance with Method 1 of the Dissolution Test Method of the Korean Pharmacopoeia with the tablets prepared in each Example, using commercially available anhydrous tablets (Sapporohydrochloride 100mg) as a comparative example. Was compared with the target dissolution rate. In addition, the characteristics of the thinner were observed over time to predict the resistance in the gastrointestinal tract during the dissolution test.

(Dissolution test condition)

Eluent: Water + 1% Polysorbate 80

Eluent amount: 900mL

Dissolution Method: Paddle Method

Temperature: 37 ℃ ± 5 ℃

Stirring Speed: 50rpm

The dissolution test results of the Anflag tablets and the tablets prepared in each example are as follows.

As a result, the Anflag tablet showed a dissolution rate of 91.6% 10 minutes after the start of dissolution.

Elution test result of the Anflag tablet minute Comparative Example 1 0 28.1 5 69.4 10 91.6 15 100.2 30 101.1

As a result of comparing the release rate of the drug according to the type of polymer, Example 1 using hydroxypropyl methyl cellulose and Example 3 using polyethylene oxide showed similar dissolution rates as target dissolution rates, but Example 2 using carbomer was 10 hours. The dissolution rate was about 40%, indicating overdelay. In addition, in Example 1 and Example 3, the tablets were distorted after about 4 to 5 hours of the dissolution test, so that the firmness was not good. This could lead to serious side effects due to the rapid release of the drug, which was considered to be in need of improvement.

Dissolution rate of Examples 1-3 time Example 1 Example 2 Example 3 0 0 0 0 0.5 15.2 6.1 10.3 One 23.1 10.4 17.2 2 36.4 17.3 28.7 4 58.4 27.1 47.3 6 76.1 38.2 63 8 88.2 47.2 76.8 10 97.7 58.4 85.2

As a result of the dissolution test of Examples 4-6 prepared by varying the viscosity and substituents of hydroxypropyl methyl cellulose, the higher the viscosity, the lower the release pattern. Example 4 and Example 5, the viscosity of which is relatively low, did not maintain the shape of the tablet during dissolution test and was distorted. On the other hand, Example 6 was well maintained and showed a similar pattern to the set target dissolution rate.

Dissolution rate of Examples 4-6 time Example 4 Example 5 Example 6 0 0 0 0 0.5 16.7 13.4 10.3 One 28.9 22.4 15.7 2 46.3 36.4 24.9 4 67.4 58.4 41.8 6 82.6 76.1 57.2 8 95.1 88.2 69.3 10 99.6 95.4 80.2

Example 7 and Example 8 are hydroxypropyl methylcellulose of the same grade as the sample of Example 6, and the addition amount is changed. As the addition amount decreased, the dissolution rate tended to increase. In particular, in Example 8, the tablets were not maintained, and thus the firmness of the formulations was different depending on the amount of the polymer added in the same grade.

Dissolution rate of Examples 7-8 time Example 7 Example 8 0 0 0 0.5 10.6 15.4 One 17.5 27.5 2 28.9 43.8 4 50.1 65.7 6 67.7 80.8 8 81.9 94.3 10 90.6 98.4

Claims (4)

Pharmaceutical compositions containing from 50 mg to 500 mg of saponic acid hydrochloride and one or more water-soluble or water-insoluble polymers
The pharmaceutical composition according to claim 1, which contains one or more of hydroxypropylmethylcellulose, carbomer, polyethylene oxide, hydroxypropylcellulose, hydroxyethylcellulose, xanthan gum, gum arabic and povidone.
The tablet according to claim 2, which contains 5% to 50% of hydroxypropylmethylcellulose by weight.
4. A pharmaceutical composition according to claim 3 wherein up to 30% at 1 hour, 30 to 60% at 4 hours, at least 60% of safoglycol hydrochloride is released at 10 hours.

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