KR101220829B1

KR101220829B1 - Sustained-release tablet containing trimebutine

Info

Publication number: KR101220829B1
Application number: KR1020100069014A
Authority: KR
Inventors: 어진; 김창환; 한창균; 정현근; 김양중; 김종걸; 박정기
Original assignee: 안국약품 주식회사
Priority date: 2010-07-16
Filing date: 2010-07-16
Publication date: 2013-01-10
Also published as: KR20120008262A; EA023139B1; WO2012008675A1; EA201390014A1

Abstract

The present invention relates to a trimebutin-containing sustained-release tablet, and more specifically, it consists of a two-layer structure of the upper layer and the lower layer adjacent to each other, wherein the upper layer and the lower layer include an active ingredient and a hydrophilic sustained-release polyethylene oxide, respectively, There is no problem such as hardness decrease or tableting disorder in the process, and further relates to a trimebutin-containing sustained-release tablet having an excellent dissolution pattern.

Description

Sustained-release tablet containing trimebutine

Trimebutine, i.e. 3, 4, 5-trimethoxy benzoic acid 2- (dimethylamino) -2-phenylbutyl ester (3, 4, 5-trimethoxy benzoic acid-2-dimethyl amino-2-phenybutyl ester ) And its malate salts are known drugs that act on peripheral Encephalinergic receptors involved in digestion.

This trimebuterine is itself or in the form of a salt with maleic acid, and is used for the treatment of digestive problems such as abdominal pain, indigestion, nausea and vomiting, or irritable bowel syndrome and non-infectious gastrointestinal disorders such as constipation or diarrhea. , In the form of injections, suppositories, and suspensions for oral administration.

Looking at conventionally known techniques for sustained-release tablets of trimebuterin, for example, in Korean Patent No. 0939642 (registration date; Dec. 22, 2005), 30-60% by weight of trimebuterin maleate, and to prepare a core Trimebutin maleate tablets for oral administration are introduced that include a core containing a carrier that enhances the release of an appropriate carrier and active ingredient, and a water-soluble temporary coating that is sufficiently effective to prevent disintegration of the core and premature release of the active ingredient. .

In addition, Korean Patent No. 0483716 (registration date; 2005.04.08) has 30-60% by weight of trimebuterin or maleic acid trimerbutin, 20-40% by weight lactose, 0.1-10% by weight of calcium dihydrogen phosphate, povidone K A sustained-release tablet composition of trimebuterine or trimebuterine maleate containing 0.1-30% by weight of -30 and 5-25% of Eudragit RL-PO by lubricant, excipient and sustained-release agent is introduced.

However, such conventional trimebutin-containing sustained-release tablets have an inconvenience of being too large for patients to take since the weight of one tablet in excess of an excess sustained release mechanism is over 700 mg.

In addition, tableting disorders such as sticking occurs during tablet tableting or when the hardness of the tablet is too low. Often, when the sustained-release tablet has a low hardness, the release pattern of the active ingredient is excessive. This can cause problems such as causing an outflow.

Accordingly, an object of the present invention is to solve the problems such as hardness decrease and tableting disorder, which are problems of the prior art in sustained-release tablets containing trimebuterin or salts thereof, the overall manufacturing process is simple and easy, and further, the bioavailability is It is to provide a trimebutin-containing sustained-release tablet which is the same as a conventional tablet but exhibits a more stable release pattern.

The problems to be solved by the present invention are summarized as follows.

First, the weight of one tablet is designed not to exceed 500mg to improve the convenience of patients taking.

Second, it is intended to obtain a new and safe release delay effect by using a hydrophilic sustained release polyethylene oxide.

Third, as a two-layer structure consisting of the upper layer and the lower layer, it is intended to implement a slow release tablet that can more safely and completely control the release rate.

Fourth, to solve the problems such as sticking (sticking) or hardness decrease in the tableting process.

Fifth, the release rate of the active ingredient is to maintain a constant zero-order reaction rate, while at the same time the bioavailability is to implement a sustained-release tablet at least the same as the conventional commercial product or superior to the conventional commercial product.

In order to achieve the above object, the trimebutin-containing sustained-release tablet according to the present invention is composed of an upper layer and a lower layer adjacent to each other and a film coating layer surrounding them, and includes 300 mg of maleic acid trimerbutin as an active ingredient in one tablet and has a weight of one tablet. 480-500 mg, the upper layer contains 100 to 110 parts by weight of trimeric acid maleate, 12 to 30 parts by weight of polyethylene oxide, and 6 to 20 parts by weight of hypromellose, and the lower layer contains 190 to 200 maleic acid trimerbutin. It is characterized in that the weight part, 25 to 55 parts by weight of polyethylene oxide, 10 to 35 parts by weight of hypromellose is included.

In addition, the trimetabutin-containing sustained-release tablet according to the present invention is 105 mg of maleic acid trimebuterin, 6.25-18.25 mg of hypromellose, 15-27 mg of polyethylene oxide, 22.75 mg of fumaric acid, 1.75 mg of hydroxypropyl cellulose, magnesium stearate An upper layer composed of 7 mg and 1 mg of a coloring agent; Lower layer consisting of 195 mg of maleic acid trimebutin, 11.75 to 33.75 mg of hypromellose, 28 to 50 mg of polyethylene oxide, 42.25 mg of fumaric acid, 3.25 mg of hydroxypropyl cellulose, and 13 mg of magnesium stearate; A film coating layer surrounding the upper and lower layers together; Characterized in that consisting of.

The trimebutin-containing sustained-release tablet according to the present invention exhibits the same pharmacological effect as conventional commercial tablets to be administered three or more times a day, even if administered twice a day, and at the same time, the weight of one tablet is reduced to 500 mg or less. Patients have high drug compliance.

In addition, the overall manufacturing process is easy by solving problems such as low hardness and tableting disorders that appear in the process of manufacturing a trimebuterin-containing tablet in the prior art, in particular, there is an effect suitable for mass production.

1 is a real picture of the sustained-release tablet according to the invention,
Figure 2 is a graph showing the elution profile in distilled water for slow release tablets according to the present invention.

Hereinafter, the present invention will be described in detail.

The trimebutin-containing sustained-release tablet according to the present invention contains 300 mg of maleic acid trimerbutin as an active ingredient in one tablet, and has a total weight of 480 to 500 mg, and includes an upper layer and a lower layer adjacent to each other and a film coating layer surrounding them.

And in the upper part, the upper part contains 100 to 110 parts by weight of trimerbutane maleic acid, 12 to 30 parts by weight of polyethylene oxide, 6 to 20 parts by weight of hypromellose, and the lower layer is 190 to 200 parts by weight of maleic acid trimerbutin and 25 to 55 parts by weight of polyethylene oxide and 10 to 35 parts by weight of hypromellose are included.

In the present invention, "hypromellose" is an abbreviation of "hydroxypropyl methyl cellulose."

The film coating layer is the same as a conventional coating layer, it is made of hypromellose and polyethylene glycol. The weight of the film coating layer is preferably applied so as to about 2 to 3% with respect to the weight of the upper and lower layers.

Polyethylene oxide (polyethylene oxide) used as a sustained release base in the present invention is a hydrophilic material, and can play a significant role in miniaturizing the tablet size because it can significantly improve the viscosity even in a small amount compared to conventionally known sustained release bases. . It also has a very characteristic function of reducing tableting disorders such as sticking and improving the hardness of tablets.

The polyethylene oxide may be used POLYOX (trade name) sold by Colorcon (Colorcon), each having a different viscosity depending on the molecular weight, in the present invention, it is preferable to use a molecular weight of 300,000 to 7,000,000.

If a molecular weight of more than 7,000,000 polystyrene oxide is used, the elution pattern to be obtained in the present invention cannot be realized. On the contrary, if a molecular weight of less than 300,000 polypropylene oxide is used, a higher amount of polyethylene oxide may be used to obtain a desired viscosity. As a result, the tablet itself becomes larger in size, which may cause inconvenience to the patient as with conventional trimebuterine sustained release tablets.

In the present invention, in order to form a double layer structure of the upper layer portion and the lower layer portion is compressed using a multilayer tablet press. In this case, it is preferable to configure the upper layer and the lower layer to be easily distinguished by the naked eye by adding a colorant to at least one of the upper and lower layers as shown in FIG. 1.

As described above, the sustained-release tablet according to the present invention is formed in a double layer structure of the upper layer and the lower layer, and thus can more safely and effectively control drug release as compared to the conventional single layer structure.

In addition, by differently configuring the color of the upper and lower layers, it is possible to provide a better aesthetic feeling to the doctor, pharmacist or patients.

Hereinafter, examples of the present invention will be described.

Example 1

division Ingredient Weight (mg) ratio(%) Upper part Maleic Acid Trimmebutin 105.0 21.60 Hypromellose 18.25 3.76 Polyethylene Oxide 15.0 3.09 Fumaric acid 22.75 4.68 Hydroxypropylcellulose 1.75 0.36 Magnesium stearate 7.0 1.44 coloring agent 1.0 0.21 Lower tier Maleic Acid Trimmebutin 195.0 40.12 Hypromellose 33.75 6.94 Polyethylene Oxide 28.0 5.76 Fumaric acid 42.25 8.69 Hydroxypropylcellulose 3.25 0.67 Magnesium stearate 13.0 2.67 Sum 486 mg 100%

1) Preparation of the upper layer composition: After mixing the maleic acid trimerbutin, hypromellose, and fumaric acid according to the composition ratio of the upper layer in Table 1, by adding a binder made by dissolving the hydroxypropyl cellulose and the colorant to the granulation process After drying. Next, after the sizing process, the polyethylene oxide is mixed, and magnesium stearate is further added and mixed to prepare an upper layer composition.

2) Preparation of the lower layer composition: After mixing the maleic acid trimerbutin, hypromellose, and fumaric acid according to the composition ratio of the lower layer in Table 1, and added to the binder made by dissolving hydroxypropyl cellulose to dry after granulation process do. Next, after the sizing process, the polyethylene oxide is mixed, and magnesium stearate is further added and mixed to prepare an upper layer composition.

3) Tableting and coating: Tableting the upper layer composition and the lower layer composition with a multi-layer tablet press to form an upper layer and a lower layer, and by applying a hypromellose and polyethylene glycol in a conventional manner to form a film coating layer by weight of one tablet This 500 mg sustained release tablet was prepared.

[Example 2]

In the same manner as in Example 1, the upper layer and the lower layer is composed of a composition ratio as shown in Table 2 below to prepare a trimebutin-containing sustained-release tablet.

division Ingredient Weight (mg) ratio(%) Upper part Maleic Acid Trimmebutin 105.0 21.60 Hypromellose 12.25 2.52 Polyethylene Oxide 21.0 4.32 Fumaric acid 22.75 4.68 Hydroxypropylcellulose 1.75 0.36 Magnesium stearate 7.0 1.44 coloring agent 1.0 0.21 Lower tier Maleic Acid Trimmebutin 195.0 40.12 Hypromellose 22.75 4.68 Polyethylene Oxide 39.0 8.02 Fumaric acid 42.25 8.69 Hydroxypropylcellulose 3.25 0.67 Magnesium stearate 13.0 2.67 Sum 486 mg 100%

[Example 3]

division Ingredient Weight (mg) ratio(%) Upper part Maleic Acid Trimmebutin 105.0 21.60 Hypromellose 6.25 1.29 Polyethylene Oxide 27.0 5.56 Fumaric acid 22.75 4.68 Hydroxypropylcellulose 1.75 0.36 Magnesium stearate 7.0 1.44 coloring agent 1.0 0.21 Lower tier Maleic Acid Trimmebutin 195.0 40.12 Hypromellose 11.75 2.42 Polyethylene Oxide 50.0 10.29 Fumaric acid 42.25 8.69 Hydroxypropylcellulose 3.25 0.67 Magnesium stearate 13.0 2.67 Sum 486 mg 100%

Dissolution Test

For the sustained release tablets prepared according to Examples 1 to 3 above, a dissolution test was carried out in 50 rpm paddle test in distilled water, and the results are shown graphically in FIG. 2.

As shown in FIG. 2, it can be seen that the maleic acid-containing sustained-release tablet according to the present invention exhibits a very ideal release pattern while maintaining a zero-order reaction rate for 8 hours after the dissolution test.

Claims

Consisting of the upper and lower layers adjacent to each other and the film coating layer surrounding them, which contains 300 mg of maleic acid trimethbutin as an active ingredient in one tablet, and the weight of one tablet is 480-500 mg,
The upper layer includes 100 to 110 parts by weight of trimerbutane maleate, 12 to 30 parts by weight of polystyrene oxide having a molecular weight of 300,000 to 7,000,000, 6 to 20 parts by weight of hypromellose,
The lower layer contains trimebutin-containing sustained-release, characterized in that 190 to 200 parts by weight of maleic acid trimerbutin, 25 to 55 parts by weight of polystyrene oxide having a molecular weight of 300,000 to 7,000,000, and 10 to 35 parts by weight of hypromellose. refine.

delete

2. The sustained-release tablet containing trimebbutin according to claim 1, wherein at least one of the upper layer and the lower layer contains a colorant.

Upper layer consisting of 105 mg of maleic acid trimebuterin, 6.25-18.25 mg of hypromellose, 15-27 mg of polyethylene oxide having a molecular weight of 300,000 to 7,000,000, 22.75 mg of fumaric acid, 1.75 mg of hydroxypropyl cellulose, 7 mg of magnesium stearate, and 1 mg of a coloring agent;
A lower layer consisting of 195 mg of maleic acid trimebutin, 11.75 to 33.75 mg of hypromellose, 28 to 50 mg of polyethylene oxide having a molecular weight of 300,000 to 7,000,000, 42.25 mg of fumaric acid, 3.25 mg of hydroxypropyl cellulose, and 13 mg of magnesium stearate;
A film coating layer surrounding the upper and lower layers together; Trimebutin-containing sustained-release tablet, characterized in that consisting of