KR0185293B1 - Extended release composition containing terbutaline sulfate and guaifenesin(1) - Google Patents

Abstract

The present invention relates to a terbutaline sulfate-guipenesine sustained-release composite pellet in which a water-insoluble coating material is coated on pellets in which terbutaline sulfate and guaifenesin are dispersed in an inert carrier. ) And a terbutaline sulfate, in which a guipene-sin sustained release single pellet (B) coated with a water-insoluble coating material on a pellet in which guapenesine is dispersed in an inert carrier is mixed at a weight ratio of 1: 0.5 to 1: 3. Guapefenesine sustained release combination formulation.

Description

Terbutalin Sulfate-Guifenecin Sustained Release Combination Preparation (1)

1 shows a model of terbutaline sulfate-guipenesin sustained-release composite pellet (1-1) and guipene-cinenic sustained-release single pellet (1-2),

Figure 2 shows a model of a sustained-release composite capsule filled with terbutaline sulfate-guifenesin sustained-release complex pellets and guapefenesine sustained-release single pellets,

Figure 3 shows the dissolution test results of terbutaline sulfate-guifenecin sustained release composite capsule,

4 is the dissolution test results of terbutaline sulfate for terbutaline sulfate-guifenecin sustained-release complex capsules and terbutaline sulfate sustained-release monoclonal preparations (comparative).

FIG. 5 shows the results of the dissolution test of guaniphenesin for terbutaline sulfate-guifenecin sustained-release complex-cell preparations and guipenecin-release sustained-release monosaccharides (comparative).

The present invention relates to a terbutaline sulfate-guifenesine sustained-release complex preparation, and more particularly, to a pellet in which terbutaline sulfate US guaifenesin is dispersed in an inert carrier. Terbutalin sulfate-Guifenecin sustained release composite pellet coated with an insoluble coating material and guipenesin sustained release single pellet coated with a water-insoluble coating material in pellets in which guapenesine was dispersed in an inert carrier (B). ) Is related to a terbutaline sulfate-guiphenesin sustained release complex preparation in which the weight ratio is 1: 0.5 to 1: 3.

Terbutaline sulfate is a sympathetic nerve stimulant that selectively expands only bronchial smooth muscle. It is a drug used for bronchial asthma. Guaifenesin is an expectorant that increases bronchial secretion and decreases phlegm viscosity. It can be used as an adjuvant for bronchodilator by weakening its strength and the like. J. Resp. Dis. 54, p78-82, (1973). Therefore, terbutaline sulfate and guapenesine are used together to reduce bronchial-pulmonary diseases such as bronchial asthma, bronchitis, emphysema, and sputum. For example, Bricanyl Compound Tablets developed by Astra, Sweden Is a simple mixed formulation of terbutalin sulfate and guapenesine.

However, bronchial-pulmonary diseases develop chronically and the onset of the disease lasts for about 1 week or longer, so the conventional simple mixed formulations that need to be administered three times a day have many limitations. In order to solve this problem, Merck has disclosed sustained-release pellets for terbutalin sulfate and guapenesine, respectively (European Patent Publication No. 147,780, 1984, 12, 19). However, since terbutaline sulfate and guapenesine have a large medicinal difference (terbutaline sulfate 7.5 mg / guapenesine 300 mg), when the sustained-release pellets for each component disclosed by Merck are filled into capsules or the like, homogeneously. Not only is it extremely difficult to mix, but there is a problem that it is difficult to fill the capsule, etc. due to the increase in volume, there is a problem that each sustained-release pellet is prepared in a separate formulation (that is, not a combination formulation) to administer.

Accordingly, the present inventors have repeatedly studied to develop a sustained release complex preparation in one dosage form by overcoming the dose difference between terbutaline sulfate and guapenesine, and thus, sustained release composite pellet containing terbutaline sulfate and a certain amount of guapenesine. And when the mixture was prepared in a single dosage form by mixing or tableting the capsules of the sustained-release single pellet with guipennesine, it was found that the two active ingredients effectively exhibit a sustained-release elution pattern to complete the present invention.

That is, in the present invention, a terbutaline sulfate-gupepenesine sustained-release composite pellet coated with a water-insoluble coating material on pellets in which terbutaline sulfate and guapenesine are dispersed in an inert carrier. Terbutalin sulfate-(A) and a guipene-sin sustained release single pellet (B) coated with a water-insoluble coating material on a pellet in which guapenesine is dispersed in an inert carrier at a weight ratio of 1: 0.5 to 1: 3. An object of the present invention is to provide a sustained release combination formulation.

Hereinafter, the present invention will be described in detail.

The sustained release preparation according to the invention consists of two types of pellets. That is, the sustained-release composite preparation in which a large amount of sustained-release composite pellet (A) containing a part of a large amount of guapenesine and terbutaline sulfate and a sustained-release single pellet (B) of the remaining guapenesine are mixed.

Therefore, the terbutal sulphate can be sustained by the sustained release composite pellet (A), and the guippenesin can be controlled in two stages by the sustained release composite pellet (A) and the sustained release single pellet (B). Terbutalin sulfate and guapenesine can be effectively sustained release.

Hereinafter, the present invention will be described in more detail.

The amount of terbutalin sulfate and guapefenesine contained in the sustained-release preparation according to the present invention can be used by varying the therapeutic purpose. Herein, the ratio of guipenecin contained in the sustained release composite pellet (A) and the sustained release single pellet (B) is preferably 1: 0.5 to 1: 3 by weight.

As an inert carrier used in the sustained release composite pellet (A) and the sustained release single pellet (B) constituting the sustained-release preparation according to the present invention, nonpareil seed, sugar seed, and the like may be used. Can be.

Water-insoluble coating materials that can be used for coating the sustained-release composite pellet (A) and the sustained-release single pellet (B) constituting the sustained-release composite preparation according to the present invention include ethyl cellulose, hydrogenated castor oil, surrelease (Surelease , Colorcon), Eudrapon or mixtures thereof. As the water-insoluble coating material, an organic solvent or a water-soluble solvent capable of dissolving or suspending it effectively may be used. As the organic solvent, ethanol, acetone, or the like may be used. In addition, although the water-insoluble coating material can change the dissolution rate of the main component according to the type and coverage, the amount of the water-insoluble coating material is preferably 3 to 30% by weight based on the total weight of each pellet to achieve an effective dissolution rate.

The sustained release composite pellet (A) and the sustained release single pellet (B) constituting the sustained release composite preparation according to the present invention can be effectively produced by the dry powder layering method (Dry powder layering method) as the above components.

For example, when pellets are prepared according to a dry powder layer method using a centrifugal granulator, the binder solution is sprayed onto an inert carrier in the CF granulator while terbutaline sulfate, guapenesine and other additives are used. The pellets were prepared by first dispersing the mixed powder of the mixture, and then coated with a water-insoluble coating material using a known coating machine (Uni-glatt or Flow-Coater) to form a terbutaline sulfate-gupepenesine sustained-release composite pellet (A). Can be prepared. In addition, in the same manner, sustained-release mono pellet (B) can be produced (FIG. 1).

The sustained release composite pellet (A) and the sustained release single pellet (B) constituting the sustained release preparation according to the present invention may contain a pharmaceutically acceptable additive such as a lubricant, a plasticizer or an excipient. The lubricant may contain colloidal silicon dioxide, silicon dioxide, magnesium stearate or talc, and the plasticizer may contain polyethylene glycol, and the like, and excipients may include lactose, white sugar, microcrystalline cellulose and calcium hydrogen phosphate. And the like.

The sustained release composite pellets (A) and sustained release single pellets (B) prepared as described above can be prepared in capsules by filling into hard capsules according to a known method (FIG. 2), and tableting as a tablet (Spacetab). It can manufacture.

Sustained release composite preparation according to the present invention can effectively sustained release each active ingredient, that is, terbutal sulfate and guapenesine, as can be seen in the test examples.

Hereinafter, the present invention will be described in more detail with reference to Examples and Test Examples. However, the present invention is not limited thereto.

[Examples 1 and 2]

[Manufacture of Pellets]

Weighing according to the content of Table 1 to prepare a terbutaline sulfate- guapenesine composite pellet and guapenesine single pellet, the content shown in Table 1 represents grams (g), respectively. Polyvinylpyrrolidone was dissolved in alcohol to prepare a binding solution. Main components, excipients and other additives were taken in the amounts shown in Table 1, mixed, and then sieved through a 20 mesh sieve to prepare a mixed powder. Each pellet was prepared by dispersing the mixed powder in an inert carrier while spraying the binder solution with a non-perival seed in the CF granulator. CF-granulator conditions at this time are shown in Table 2.

EXAMPLES 3-4

[Production of Sustained Release Pellets]

Terbutalin sulfate-guiphenesin sustained-release complex using the terbutalin sulfate-guiphenesin composite pellet prepared in Example 1 and the guipenecin single pellet prepared in Example 2 in the amounts shown in Table 3. Pellets (A) and guipenesine sustained release single pellets (B) were prepared, and the contents shown in Table 3 each represent grams (g).

Spray the Shure release solution containing the water-insoluble coating material to each pellet by using Unigrat to coat the water-insoluble coating material, and then dry it to have a water content of 2% or less and terbutaline sulfate-guifenesin Sustained release composite pellets (A) and guipennesine sustained release single pellets (B) were prepared. The coating amount was 5.4% in Example 3 and 6.4% in Example 4. Unigradt conditions at this time are shown in Table 4.

Example 5

[Production of Terbutalin Sulfate-Guifenecin Sustained Release Complex Capsule]

246 g of the terbutaline sulfate-gupepenesine sustained-release composite pellet (A) prepared in Example 3 and 230 g of the guopenesine sustained-release single pellet (B) prepared in Example 4 were mixed, and then, capsules No. 0 were used. After filling, a terbutaline sulfate-guifenecin sustained release composite capsule was prepared.

Example 6

[Preparation of Terbutalin Sulfate-Guifenecine Sustained Release Composite Tablet]

Terbutalin sulfate-guiphenesin sustained-release composite pellet (A) 246g prepared in Example 3 and guipene-sustained-release single pellet (B) 230g prepared in Example 4 were mixed, and then compressed into tablets. Sulfate-Guifenecin sustained release complex tablets were prepared.

[Test Example 1]

[Elution Test of Terbutalin Sulfate-Guifenecin Sustained Release Capsule]

The dissolution test was carried out while stirring at 100 rpm using the terbutaline sulfate-guiphenesin sustained release composite capsule prepared in Example 5 using 90 ml of water as the eluent according to USP No. 1 method. Like help

As can be seen in FIG. 3, the terbutaline sulfate-guifenecin sustained release composite capsule according to the present invention effectively exhibits a sustained release pattern.

[Test Example 2]

[Comparative Dissolution Test of Terbutalin Sulfate]

Bricanyl durules, a sustained release monoter of terbutaline sulfate , 7.5 mg, Astra, Sweden) was used as a comparative example, the dissolution test was carried out in the same manner as in Test Example 1 for the terbutaline sulfate-guiphenesin sustained release composite capsule prepared in Example 5. Same as FIG.

As can be seen in Figure 4, the terbutaline sulfate-guifenesin sustained-release composite capsule according to the present invention can be confirmed that the same as the elution pattern of the conventional terbutaline sulfate-containing sustained-release monosaccharide formulations tabu of the present invention It can be seen that the thallin sulfate-guifenecin sustained release complex capsule agent sustained release of the terbutaline sulfate.

[Test Example 3]

[Comparative Dissolution Test of Guapenesine]

Humibid Sprinkle, a sustained release monoclonal drug Sprinkle 300 mg, Adams, USA) was used as a comparative example, the dissolution test was carried out in the same manner as in Test Example 1 with respect to the terbutaline sulfate-guipenesine sustained-release composite capsule prepared in Example 5. Same as FIG.

As can be seen in Figure 5, the terbutaline sulfate-guipenesine sustained-release complex capsules according to the present invention can be confirmed that the same as the elution pattern of a conventional guipenesin-containing sustained-release single-agent formulation of the present invention It can be seen that the terbutalin sulfate-guifenecin sustained release composite capsule effectively sustained release of guifenecin.

Claims (4)

Pellet with terbutaline sulfate and guaifenesin in sugar seeds coated with ethyl cellulose or hydrogenated castor oil Terbutaline sulfate-guiaphenesin A mixture of sustained-release composite pellets (A) and sugar seed coated with guipene-sin sustained-release single pellet (B) coated with ethyl cellulose or hydrogenated castor oil The formulation of the formulation, wherein the weight ratio (A: B) of guifenesin is from 1: 0.5 to 1: 3. According to claim 1, wherein the ethyl cellulose or hydrogenated castor oil is 3 to 30% by weight based on the total weight of the sustained-release composite pellet (A) or a sustained-release single pellet (B) terbutalin sulfate-Guai Fennesine sustained release combinations. 3. A terbutaline sulfate-guiphenesine sustained-release complex capsule formulation according to claim 1 or 2, wherein the terbutaline sulfate-guiphenesin sustained release complex preparation is filled in a hard capsule. The sustained-release complex tablet (Spacetab) according to claim 1 or 2, characterized in that the terbutaline sulfate-guifenecin sustained release complex preparation is compressed.