KR101048487B1 - Trimebutin Maleic Acid - Google Patents

Abstract

The present invention relates to a sustained release formulation containing maleic acid trimethbutin, wherein the maleic acid trimethbutin sustained-release tablet according to the present invention is any one selected from the group consisting of polyvinylacetate, polymethacrylate, polyacrylate, and ethylcellulose. It is characterized by a tablet containing maleic acid trimebuterin coated with a polymer. In addition to being easy to manufacture, the maleic acid trimebuterin sustained release tablet according to the present invention has a uniform elution pattern and a desirable sustained release pattern.

Trimebutin Maleic Acid, Sustained Release Tablet

Description

Sustained release tablet containing trimebutine maleate}

The present invention relates to a sustained release formulation containing maleic acid trimerbutin.

Trimebutin maleic acid is an anticholinergic drug that inhibits excessive colon and digestive system movements. Trimebutin maleic acid acts on the Enkephalin receptor, a motion regulator that is present in the inner nerve layer of the gastrointestinal wall, normalizing hyperactivity or reduced gastrointestinal motility, effectively improving functional dyspepsia and irritable bowel syndrome. It has little effect and has been used safely for long-term patients, children and the elderly. In particular, it has been very useful in the treatment of pain associated with dysfunction of the digestive system and in the treatment of pain and discomfort associated with functional intestinal disorders.

Trimebutin maleate is commercially available for three immediate release tablets and two daily tablets of sustained release tablets, of which sustained release tablets have been more widely used because they are easier to take.

In this regard, French Patent No. 2,640,876 discloses a pharmaceutical composition comprising trimebuterine maleate as an active ingredient, which provides a technique for matrix tableting using hydroxypropylmethylcellulose having a viscosity between 3,000 and 5,000 cps. have. However, the above patent uses an excess of polymer and other various excipients corresponding to 15 to 20% by weight of the total composition for the purpose of sustained release purposes, which is not easy to manufacture and the uniformity of the matrix is not ensured. There is a disadvantage that it is difficult to implement a uniform dissolution aspect.

In addition, Korean Patent No. 10-2004-0000928 discloses a technique for achieving a sustained release target by matrix refinement of maleic acid trimethbutin with polymethacrylate polymers. However, in forming a tablet matrix, polymethacrylate is very difficult to form a uniform composition, and its elution pattern is very irregular, which is not suitable for forming a matrix sustained-release tablet.

Therefore, the technical problem to be achieved by the present invention is to provide a sustained-release tablet containing maleic acid trimeth butene, which is easier to manufacture and ensure the uniformity of the dissolution pattern by supplementing the disadvantages of the conventional trimethyl butyene sustained release formulation.

In order to achieve the above technical problem, the present invention is a maleic acid trimebutin-containing tablets coated with any one polymer selected from the group consisting of polyvinylacetate, polymethacrylate, polyacrylate and ethyl cellulose Trimebutin sustained release tablet.

The sustained-release tablet containing maleic acid trimethbutin according to the present invention is a process for preparing a tablet containing maleic acid trimethbutin and coated with polyvinylacetate, polymethacrylate, polyacrylate or ethylcellulose to prepare sustained-release tablets. Manufactured through the process.

Tablets containing maleic acid trimebuterin prior to coating with a specific polymer according to the present invention may be added excipients, binders, lubricants, disintegrants, etc., which can be used pharmaceutically, and those skilled in the art to which the present invention pertains. It may be prepared into a tablet according to methods well known to the art.

For example, excipients have low pharmacological activity and low cost such as starch, sorbitol, citric acid, mannitol, sucrose, colloidal silica, spray dried lactose, anhydrous lactose, calcium dihydrogen phosphate, anhydrous dibasic phosphate, microcrystalline cellulose, etc. The components may be used alone or in combination, and as a disintegrant, lactose, starch, sodium starch glycolate, crospovidone, croscarmellose sodium, maltodextrin, and the like may be used alone or in combination. Glidants are used to ensure smooth flow during tableting of granulators, transfer of tablets, etc., or to prevent sticking and capping during tableting. Suitable glidants include colloidal silica , Talc, magnesium stearate and the like can be used. As the binder, polyvinylpyrrolidone, hydroxypropylmethylcellulose, or the like may be used.

Tablets containing maleic acid trimebuterin according to the present invention may be prepared as tablets according to methods known to those skilled in the art. For example, a direct method of tableting immediately after mixing the powder, a dry method of preparing dry granules after tableting dry granules, and preparing a wet granule using a binder and a solvent such as water and ethanol. The wet granules are then compressed into tablets to produce tablets.

In the sustained-release tablet of trimebutin maleic acid of the present invention, in order to achieve sustained release by delaying the release of the drug, and to maintain a uniform pattern of drug release, a specific polymer such as polyvinylacetate, polymethacrylate, polyacrylate or ethylcellulose is used. It is preferable to place the polymer coating layer at a certain thickness on the outside of the tablet containing maleic acid trimethbutin, instead of preparing a sustained-release tablet having a large dissolution deviation, and having a uniform dissolution pattern. Containing sustained-release tablets can be provided.

In order to achieve the above object, the amount of the specific polymer is preferably 1.5 to 6% by weight based on the total weight of the tablet before coating. This is because if the amount of the specific polymer is less than 1.5% by weight, the dissolution rate of trimebuterine maleate is too fast to achieve desirable sustained release, and if it exceeds 6% by weight, the dissolution rate of the main component is too slow.

Kollicoat SR 30D ™ may be used as the polyvinyl acetate, Eudragit RS 30D ™ or RL 30D ™ may be used as a polymethacrylate, and Kollicoat EMM 30D ™ may be used as a polyacrylate, and ethylcellulose Furnace Aqualon N50 ™ can be used.

In addition to being easy to manufacture, the maleic acid trimebuterin sustained release tablet according to the present invention has a uniform elution pattern and a desirable sustained release pattern.

Hereinafter, examples and the like will be described in detail to help understand the present invention. However, embodiments according to the present invention can be modified in many different forms, the scope of the invention should not be construed as limited to the following examples. Embodiments of the present invention are provided to more fully describe the present invention to those skilled in the art.

≪ Example 1 >

[One] Definition of maleic acid trimmebutin  Produce

300 g of maleic acid trimebuterin, 120 g of lactose and 40 g of hypromellose were uniformly mixed. 25 g of povidone, previously dissolved in anhydrous ethanol, was granulated, 10 g of hard silicic anhydride, 3 g of stearic acid, 8 g of magnesium stearate, and 4 g of talc were added, mixed uniformly, and tableted to prepare a tablet containing maleic acid trimerbutin. It was.

[2] release coating processes

A mixture of 90 g of Kollicoat SR 30D (27 g as a solid), 3 g of propylene glycol, and 60 g of purified water was uniformly prepared to prepare a coating solution, followed by coating trimethbutin maleic acid tablets prepared in [1] to prepare a sustained-release tablet of maleic acid.

<Example 2>

[One] Definition of maleic acid trimmebutin  Produce

300 g of maleic acid trimebuterin, 120 g of lactose and 40 g of hypromellose were uniformly mixed. 25 g of povidone, previously dissolved in anhydrous ethanol, was granulated, 10 g of hard silicic anhydride, 3 g of stearic acid, 8 g of magnesium stearate, and 4 g of talc were added, mixed uniformly, and tableted to prepare a tablet containing maleic acid trimerbutin. It was.

[2] release coating processes

90 g of Eudragit RS 30D (27 g as a solid), 3 g of triacetin, and 60 g of purified water were uniformly mixed to prepare a coating solution, and then trimethbutin maleic acid tablets were prepared by coating maleic acid trimerbutin sustained-release tablet.

<Example 3>

[One] Definition of maleic acid trimmebutin  Produce

300 g of maleic acid trimebuterin, 120 g of lactose and 40 g of hypromellose were uniformly mixed. 25 g of povidone, previously dissolved in anhydrous ethanol, was granulated, 10 g of hard silicic anhydride, 3 g of stearic acid, 8 g of magnesium stearate, and 4 g of talc were added, mixed uniformly, and tableted to prepare a tablet containing maleic acid trimerbutin. It was.

[2] release coating processes

A mixture of 90 g of Kollicoat EMM 30D (27 g as a solid), 3 g of propylene glycol, and 60 g of purified water was uniformly prepared to prepare a coating solution, followed by coating the maleic acid trimerbutin tablet prepared in [1] to prepare a sustained-release maleic acid tablet.

<Example 4>

[One] Definition of maleic acid trimmebutin  Produce

300 g of maleic acid trimebuterin, 120 g of lactose and 40 g of hypromellose were uniformly mixed. 25 g of povidone, previously dissolved in anhydrous ethanol, was granulated, 10 g of hard silicic anhydride, 3 g of stearic acid, 8 g of magnesium stearate, and 4 g of talc were added, mixed uniformly, and tableted to prepare a tablet containing maleic acid trimerbutin. It was.

[2] release coating processes

13 g of ethyl cellulose and 2 g of polyethylene glycol were uniformly dissolved in 520 g of 1: 1 co-solvent of ethanol and methylene chloride anhydrous to prepare a coating solution, and then coated with trimebutin maleic acid tablets prepared in [1]. Was prepared.

Comparative Example 1

300 g of maleic acid trimebuterin, 150 g of lactose and 40 g of hypromellose were uniformly mixed. 25 g of povidone, previously dissolved in anhydrous ethanol, was granulated, 10 g of hard silicic anhydride, 3 g of stearic acid, 8 g of magnesium stearate, and 4 g of talc were added, mixed uniformly, and tableted to prepare a tablet containing maleic acid trimerbutin. It was.

<Experiment 1> Dissolution rate ratio evaluation

Comparative evaluation of the dissolution rate was tested using Example 1-4 and Comparative Example 1, the test results are shown in Table 1. As the elution medium, purified water was used, and it was tested according to the paddle method of the Korean Pharmacopoeia elution test, the stirring speed was 50 rpm, and the eluate was collected at 1, 4, 8 and 12 hours after the start of the elution test. Using a 0.45 um membrane filter as the sample solution, the absorbance was measured at 267 nm using an ultraviolet visible absorbance spectrometer. The results are shown in Table 1 and FIG. 1.

Eluate
Sampling time (hr) Dissolution rate (%) Example 1 Example 2 Example 3 Example 4 Comparative Example 1 One 10.62 9.25 11.24 9.21 74.35 4 32.15 29.57 32.15 28.87 98.65 8 68.63 68.33 69.21 61.35 98.77 12 85.77 88.62 91.36 89.22 99.98

As can be seen in Table 1, the sustained-release tablet of maleic acid trimebuterine prepared by the method of the present invention is eluted [1 hour (5 to 15%), 4 hours (20 to 40%), 8 hours (45 to 70). %), 12 hours (85% or more)].

1 is a dissolution rate test results of the sustained-release tablet maleic acid trimebuterin according to the embodiment of the present invention.

Claims (2)

Polyvinylacetate, Kollicoat SR 30D (trade name); Polymethacrylate Eudragit RS 30D (Eudragit RS 30D, trade name) or Eudragit RL 30D (trade name); And it is a coating tablet containing maleic acid trimebuterin coated 1.5 to 6% by weight relative to the total weight of the tablet before coating with any one polymer selected from the group consisting of polyacrylate Colicoat EMM 30D (Kollicoat EMM 30D, trade name), Tablets include trimebuterine maleate; Any one or more excipients selected from the group consisting of starch, lactose, calcium dihydrogen phosphate, anhydrous dibasic calcium phosphate and microcrystalline cellulose; Polyvinylpyrrolidone, hydroxypropylmethylcellulose, or mixtures thereof; And a lubricant which is colloidal silica, talc, magnesium stearate, stearic acid or a mixture thereof, The tablets had an elution rate of 45-70% and 85-100% for 8 and 12 hours, respectively, in the dissolution test using purified water as the dissolution medium. Such sustained release rates of the coated tablets were not observed in the tablets before coating and were achieved after the coating. Trimethylbutane maleic sustained-release tablet characterized in that it is. delete

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