KR0131375B1 - Manufacturing method of enteric soft capsule preparation of omeprazole - Google Patents

Abstract

In the present invention, in preparing a soft capsule containing omeprazole, 0.5 to 1 mole of a compound selected from the group consisting of cimetidine, triethanolamine and choline as stabilizers for 1 mole of omeprazole in vegetable oil containing glyceryl monostearate Suspension was carried out at a molar ratio of 3.0 mol and homogenized to prepare a suspension, which was then enclosed in a soft gelatin capsule, and the enteric coating material consisting of an enteric coating agent, a diethylphthalate plasticizer and a solvent was coated on the surface of the obtained soft capsule to form an omeprazole. It is a method for producing an enteric soft capsule. According to the present invention can be prepared by a simpler method than the conventional manufacturing method of tablets or hard capsules, there is an advantage that can be obtained a formulation ensured stability.

Description

Manufacturing method of enteric soft capsule preparation of omeprazole

1 is a comparative graph of stability according to the ph of omeprazole,

2 is a comparative graph of the stability of the suspension according to the concentration of glyceryl monostearate (GMS),

3 is a comparative graph of stability of omeprazole suspension by cimetidine,

4 is a graph of swelling ratio in artificial gastric juice according to the plasticizer type,

5 is a graph showing the effect of the plasticizer on the stability of omeprazole soft capsule,

FIG. 6 shows the stability comparison of omeprazole soft capsules according to the concentration of cimetidine, and shows the residual amount and the residual ratio of omeprazole.

7 is a comparative graph of the stability of omeprazole soft capsules containing triethanolamine as a stabilizer, and shows the residual amount and residual ratio of omeprazole,

8 and 9 are graphs measuring the difference in retention time according to excipients and stabilizers in the formulations of Example 3 (containing cimetidine) and Example 10 (containing triethanolamine).

The present invention relates to a method for preparing a soft capsule, an oral formulation of omeprazole, which inhibits gastric acid secretion and has a gastrointestinal cell protective effect. Omeprazole (5-methoxy-2 (((4-methoxy-3,5-dimethyl-2-pyridinyl) methyl) -sulfinyl) -1H-benzimidazole) has a potent gastric acid secretion inhibitory activity ( Lancet (Nov. 1223-1224), has a good effect on the treatment of gastric ulcer and duodenal ulcer. However, omeprazole was very unstable in acidity and had problems in formulation. For example, the half-life of omeprazole was about 5 hours at PH 5.0 and 12 hours at PH6.0. (See Fig. 1 and Pilforant, Cedesberg: Scand. J. Gastroenterology 1985.20 (Appendix 108) 113 to 120) In addition, omeprazole promoted decomposition in moisture or polar organic solvents, but stability could be ensured by alkalinity or moisture blocking. . Using these properties, oral formulations have been developed to allow omeprazole to reach the small intestine without being degraded in the stomach. Korean Patent Publication No. 91-4579 discloses an alkali salt of omeprazole which may be mixed with an alkali reaction compound or an omeprazole or an alkali reaction compound into a small bead or tablet core, and the core is dissolved in water or Rapidly disintegrating tablet excipients or polymeric water-soluble film-forming compounds, which are coated between the alkaline reaction core and the outer skin layer, which is an enteric coating, with one or more inert endothelial layers that may contain a PH-buffered alkaline compound, and then the endothelial coating core is added with enteric skin. It is characterized by coating. However, this method also has a problem in that it is not only secured to secure stability, but also the formulation process is complicated and a large amount of alkali compounds that are not necessary for the treatment of ulcers should be taken. In Korean Patent Laid-Open Publication No. 91-15297, a basic amino acid such as arginine, lysine, or histidine is added in place of the alkali compound of Patent Publication No. 91-4579. In this case, too, the formulation process is complicated and it is difficult to secure stability. Other methods are described in USP-2540979, US Patent Publication DE-B ₂ -2336218, DE-A ₁ -1204363, DE-A ₁ -1617615, and International Patent Application Publication No. W085 / 03436. It is protected by raising the pH with alkaline compound and then entering the skin to absorb it in the small intestine.

An object of the present invention is to make an enteric preparation that is stable in long-term storage and resistant to absorption under medium of gastric acid when taken and rapidly dissolved in neutral to alkaline media. In order to prevent attack and access of water or gastric juice, the present inventors disperse omeprazole by adding glyceryl monostearate, a suspending agent suitable for vegetable oil, especially corn oil, to prepare a suspension, and encapsulate it in a soft gelatin gexel. A method of coating with enteric skin is invented. In addition, as a result of testing various drugs as stabilizers to prevent the decomposition of omeprazole by trace oil in corn oil or gelatin, which is vegetable oil, 1 was selected from the group consisting of cimetidine, triethanolamine, and choline, which are widely used as a therapeutic agent for gastric ulcer. When the compound of the species was reinforced at a ratio of 0.5-3.0 moles with respect to 1 mole of omeprazole, it was found to have much better stability than using an existing alkalizing agent. Accordingly, the present invention stabilizes one compound selected from the group consisting of cimetidine, triethanolamine and choline, which coexist with omeprazole in the preparation of oral preparations for omeprazole, have a high stabilizing effect in terms of preparation and ensure safety for the human body. It is characterized by providing a new enteric omeprazole oral medicament that can be used zero and in particular rapidly disintegrates and elutes in the small intestine. That is, the present invention is a molar ratio of 0.5 to 3.0 moles of one compound selected from the group consisting of omeprazole, glyceryl monostearate as a suspending agent, corn oil, and cimetidine, triethanolamine and choline as stabilizers with respect to 1 mole of omeprazole. Enteric soft capsule of omeprazole containing a suspension composed of gelatin and enteric coating material, and a method for stabilizing omeprazole drugs in which omeprazole is suspended in corn oil in the presence of glyceryl monostearate as a suspending agent, Suspension of omeprazole in corn oil in the presence of a suspending agent, to prepare a suspension by the stabilization method of omeprazole drug to add one of the pharmaceutically acceptable stabilizers described above, and formulated into a soft capsule Is done.

The manufacturing method of the present invention is summarized as follows.

First, omeprazole as a main component is suspended in corn oil, which is a vegetable oil, in the presence of glyceryl monostearate as a suspending agent, and one compound selected from the group consisting of cimetidine, triethanolamine and choline as stabilizers is stabilized therein. One compound selected from the group consisting of zero cimetidine, triethanolamine and choline was added to a molar ratio of 0.5 to 3.0 moles with respect to 1 mole of omeprazole to homogenize to prepare a suspension, which was then encapsulated in soft gelatin capsules, and then enteric skin. It is a method for producing an enteric soft capsule of omeprazole by coating with an enteric coating material consisting of a replica, a plasticizer and a solvent. Hereinafter, the present invention will be described in more detail with various experiments.

1) Manufacturing process of suspension

Omeprazole should be stable in storage or on underclothes. The omeprazole was stabilized by effectively suspending it in corn oil, which is a vegetable oil without fear of hydrogen ion release. At this time, one kind of compound selected from the group consisting of cimetidine, triethanolamine and choline is added as a stabilizer to prevent discoloration and degradation over time by a small amount of water contained in gelatin and corn oil. In addition, a suspension is prepared by suspending glyceryl monostearate (GMS), a suspending agent, which has an important effect on the stability of the suspension, to the dispersion medium. First, the stabilizing effect of GMS, a suspending agent for the suspension, is shown in the following Table-1.

As can be seen in Table-1, the amount of glyceryl monostearate added when suspending omeprazole was excellent to use 5-9W / V% (see Figure 2). If less than 5% of the particles dispersed in the suspension is settled within a few hours, and when used more than 10% of the formulation does not form it should be used in the above range. Subsequently, the stability test of omeprazole according to the type of stabilizer was performed. The aqueous solution was prepared using a stabilizer of cimetidine, triethanolamine, choline, and NaHPO in a 1: 1 molar ratio with omeprazole, respectively, and left at 40 ° C. for 4 days, The content was analyzed and the results are shown in Table-2.

As a result of the above test, the residual amount of 50% or more was confirmed in the aqueous solution using cimetidine, triethanolamine or choline as the stabilizer, but the residual amount of the aqueous solution using NaHPO as the stabilizer was about 30%. Therefore, it is recommended to use cimetidine, triethanolamine or choline as a stabilizing agent in preparing oral preparations containing chimetidine, triethanolamine or choline as the main ingredient of omeprazole. Subsequently, in preparing a soft capsule containing omeprazole as a main ingredient, the effects of cimetidine, triethanolamine or choline on the stability of the omeprazole suspension were as follows. First, glyceryl monostearate (GMS) was added to corn oil, dissolved by heating, stirring, and dissolved according to the formulation of Examples 1 and 2 below. Then, cimetidine was added, omeprazole was added, and the mixture was sufficiently stirred to form a homogeneous suspension. When the amount of omeprazole was measured after 6 hours, amount remained was averaged twice, and about 83% of cimetidine (abbreviated CMT) was added and 54% of the control group without cimetidine was added. (See FIG. 3) Therefore, in designing such a suspension formulation according to the present invention, it is characterized by using one compound selected from the group consisting of cimetidine, triethanolamine and choline as a stabilizer. 5) and the experimental example (see Table 6), it can be seen that it is preferable to use the amount thereof in a molar ratio of about 0.5 to 3.0 moles with respect to 1 mole of omeprazole.

2) Preparation of soft capsule and enteric skin process

The above suspension prepared according to the method for preparing a stabilized suspension as described above is enclosed in a gelatin soft capsule. In general, gelatin contains a small amount of water, preferably gelatin, which contains as little water as possible. When the enteric coating material is coated on the outside of the gelatin soft capsule after encapsulation, the gelatin layer becomes a barrier layer to the free carboxyl groups contained in the enteric coating polymer, thereby securing the stability of the omeprazole in the suspension. As an enteric coating material, cellulose acetate phthalate or hydroxy propylmethyl cellulose phthalate, which is a coating agent, is dissolved in an organic solvent together with a plasticizer and coated on a gelatin soft capsule. Diethylphthalate or dibutyl phthalate may be used as the plasticizer (see Table 3 below). At this time, in order to know the type and amount of plasticizer used, a baratin matrix having a gastric acid permeability of the enteric coating is changed by the plasticizer, and the cellulose acetate phthalate coating solution is made of polyethylene glycol as a plasticizer and diethylphthalate The two solutions in the case of plasticizer were each coated, and the swelling ratio in each of the PH1.2 buffers was calculated (see Table 4 below). At this time, gastric acid permeability of diethyl phthalate, which is a water-insoluble plasticizer, was significantly lower than that of polyethylene glycol. It has been found preferred to use about 10-35% of the phthalate dry weight. In general, the greater the amount of plasticizer, the lower the acid resistance, so attention should be paid to the amount of diethylphthalate as a plasticizer.

As a plasticizer, 25-35 weight% of dibutyl phthalates can be used.

CAP: Cellulose Acetate Phthalate

DEP: diethyl phthalate

PEG: polyethylene glycol 8000

GEL: gelatin

Swelling ratio = (Ws-Wo / Ws) × 100

Ws: swollen weight

Wo: Weight at drying

The smaller the swelling ratio, the lower the moisture permeation rate.

The results of the swelling ratio in the gastric juice according to the types of plasticizers are shown in FIG. 4, and the effects of the omeprazole residual in the omeprazole soft capsules according to the types of plasticizers are shown in FIG. The method and dosage of the soft capsule of the present invention is preferably administered once a day, one capsule once a day. The enteric soft capsules prepared according to the present invention have an advantage that stability is more secured, easier to manufacture, and easier to take than conventional tablets or hard capsules.

Hereinafter, an embodiment of the present invention will be described in detail as follows.

Examples 1 to 22

Preparation of Stabilized Suspension. According to the following Table-5 prescription, a suspension was prepared by uniformly mixing the main components omeprazole, stabilizer, suspending agent, vegetable oil. It is the amount which can manufacture 1000 capsules per embodiment.

Suspension Stability

As described above, the suspension prepared according to Examples was measured for 7 weeks under severe conditions of 40 ° C. The suspension prepared according to Examples 2 to 5 and Examples 10 and 20 was stable for 3 weeks without any change. Maintaining the state, it was confirmed that the preferred examples of further stability is an example of Examples 4-5 and 10, 20. (See Table 6)

Example 23

Preparation of Soft Gelatin Capsules. Gelatin was mixed with water in the same volume ratio of 1: 1 as usual and to which glycerin was added as a plasticizer. At this time, the hardness of the gelatine soft capsule was changed according to the amount of glycerin added. Here, glycerin was used by mixing 40% of the weight of gelatin. Suspensions prepared according to Examples 2 to 5, 10 and 20, which were found to be preferred among Examples 1 to 22, were prepared according to the method of preparing soft capsules based on the soft capsules of the Latin capsules above. The contents were encapsulated to prepare about 950 soft capsules each.

Example 24

Coating of enteric coating material of soft capsule. The enteric coating agent prescribed in the composition of Table 3 was dissolved in a 1: 1 mixed organic solvent of solvent ethyl acetate and isopropanol in the soft capsule prepared according to Examples 2 to 5, 10 and 20, and the cellulose acetate phthalate. The (CAP) was 15% W / V and the plasticizer diethylphthalate (DEP) was coated with an enteric coating so that the amount of CAP was 30% W / V. The weight per soft capsule was about 750 mg.

Experimental Example

The formulations according to Examples 2-5, 10 and 20 above were tested for acid resistance and formulation stability studies as described below.

1. Acid resistance

Acid resistance of the formulation was studied by the following method. In order to test the acid resistance of the final product, the soft capsule has to purchase special experimental equipment. Here, in order to avoid the trouble of the test for the acid resistance test, the device manufactured by the present inventors was used. Before encapsulation, the suspension is mounted on one side of the diffusion membrane apparatus, and enzyme-free gastric fluid (USP) is added to the other side, and the enteric skin-coated gelatin membrane (the same role as the film of the soft capsule of the present invention) is placed between the apparatuses. As a result, gastric acid was permeated and tested for acid resistance of the suspension. A specially prepared diffusion membrane apparatus equipped with suspension enteric coating gelatin membrane and enzyme-free gastric juice USP was stirred at 37 ° C. and 50 rpm, and the content of omeprazole in suspension was measured over time for 6 hours, and the residual rate was calculated. First, the suspensions prepared according to Examples 2, 3, 4 and 5 containing the most suitable amount of cimetidine for the stabilization of omeprazole in molar ratios of about 1: 0.5, 1: 1, 1: 2, 1: 3 were prepared in the aqueous phase in the oil phase. Considering that the extraction process is difficult and time consuming, as shown in Table 7, there is an error in the experiment, but it can be seen that stability can be secured when the amount of cimetidine to omeprazole is used in a molar ratio of about 1:05 to 3.0. have. (See Figure 6)

In particular, the molar ratio of 1: 2 was able to maintain the content of more than 96% over 6 hours.

For reference, the enteric capsule preparation according to Example 10 using triethanolamine at a ratio of about 1 mole to 1 mole of omeprazole was also tested in the same manner as described above. As a result, a comparative graph of the residual amount and the residual ratio of omeprazole was prepared. It is shown in FIG. 7, and in FIG. 8 and FIG. 9, excipients and stabilizers in the soft capsules prepared according to Example 3 (stabilizer: cimetidine) and the soft capsules prepared according to Example 10 (stabilizer: triethanolamine). The graph shows the difference between the retention times. The experiment for Example 20, in which choline was used as a stabilizer at a ratio of about 3.0 moles to 1 mole of omeprazole, was omitted, but the stability of the suspension is considered to be similar.

As described above, the omeprazole-containing enteric soft capsule prepared according to the present invention is excellent in terms of stability of the preparation, has a simple manufacturing method, and has the advantages of easy taking, and thus it is found to be a very useful invention in industry.

Claims (2)

Omeprazole, a suspending agent of glyceryl monostearate 5-9 w / v% with respect to the suspension, corn oil and one compound selected from the group consisting of cimetidine, triethanolamine and choline as a stabilizer 0.5 to 1 mole of omeprazole A suspension consisting of a molar ratio of 3.0 moles and gelatin, and an enteric coating material consisting of an enteric coating agent, diethylphthalate or dibutyl phthalate as a plasticizer, corresponding to 10 to 35% by weight of the enteric coating solution and a solvent. Enteric soft capsule of omeprazole to be made. Omeprazole is suspended in corn oil in the presence of glyceryl monostearate, a suspending agent, in the presence of 5 to 9 w / v% of the suspension, and is selected from the group consisting of ciketidine, triethanolamine and choline as stabilizers. The compound of was added to a molar ratio of 0.5 to 3.0 moles per 1 mole of omeprazole to homogenize to prepare a suspension, which was then enclosed in a soft gelatin capsule, and then enteric coating, diethylphthalate or dibutyl phthalate as a plasticizer was used. A method for producing an enteric soft capsule preparation of omeprazole, characterized by coating with an enteric coating material composed of a solvent corresponding to 10 to 35% by weight of the solvent.