AU1354100A

AU1354100A - The stable oral pharmaceutical preparation containing omeprazole or its analogues and process for the production

Info

Publication number: AU1354100A
Application number: AU13541/00A
Authority: AU
Inventors: Pei-Wen Hsieh; Tsung-Min Hsu; Yu-Pei Wang
Original assignee: NANG KUANG PHARMACEUTICAL CO Ltd
Current assignee: NANG KUANG PHARMACEUTICAL CO Ltd
Priority date: 1999-01-27
Filing date: 2000-01-24
Publication date: 2000-09-07
Also published as: JP2000212085A; TW404832B

Description

THE STABLE ORAL PHARMACEUTICAL PREPARATION CONTAINING OMEPRAZOLE OR ITS ANALOGUES AND PROCESS FOR THE PRODUCTION BACKGROUND OF THE INVENTION 1. Field of The Invention: The present invention relates to an oral pharmaceutical preparation containing omeprazole or the analogues and a manufacture to process the oral pharmaceutical preparation.

10 2. Description of Related Art: Omeprazole, 5-methoxy-2{[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl] sulfinyl}- 1 H-benzimidazole, is a compound not soluble in the water but soluble in the alkaline solution. The omeprazole is also known as a powerful inhibitor against gastric juice secretion and it provides an irreversible inhibition about H/K ATPase in the human 15 body such that it is possible to cure the duodenal ulcer. The omeprazole is apt to co dissolve in an environment of low pH value. For instance, a period of half life of the omeprazole is less than 10 minutes at a pH value less than 4, and 16 hours at a pH value of 6. Nevertheless, the omeprazole with a pH value of 11 will last 10 months of stability. Furthermore, organic solvents such as methyl dichloride and moisture substantially influence the stability of omeprazole either. Based on preceding features, an oral pharmaceutical dosage containing the omeprazole is required to avoid contacting the gastric juice.

In order to prevent from contacting the gastric juice so as to influence the activity thereof, the medicine has to be covered with enteric coating. But, enteric coating are made of acid compound such that it results in decomposes of the omeprazole while it touches the enteric coating. In this way, a colour change of the medicine will occur seriously. In addition, the omeprazole is insoluble in an acid or a neutral solution such that it is necessary to mix with alkaline substance, solubilizing agent, or surfactants in order to improve the solubility thereof.

An oral medicine containing omeprazole disclosed in Taiwanese Patent Publication No. 147352 (Application No. 76102439) is featured that in US. Pat. No.

2 4,786,505 describes an omeprazole oral dosage form, where omeprazole together with an alkaline reacting compound or an alkaline salt of omeprazole optionally together with an alkaline compound as the core material, one subcoating layers including inert reacting compounds which are soluble or rapidly disintegrating in water, or polymeric water soluble filmforming compounds, optionally containing pHbuffering alkaline compounds and an enteric coating.

It has been pointed out in above said prior art reference that 85% of active substance can be kept for two hours in a medium liquid having a pH value equivalent to that of the gastric juice (pH And, at least 75% of omeprazole should be 10 dissolution in a medium liquid having a pH value equivalent to that of the intestinal juice (pH 6.8).

the process mentioned above requires certain expensive equipment such that it causes to waste a lot of production cost and labour hours. Moreover, it requires many transitional operations in order to proceed the whole making process.

15 Taiwanese Patent Publication No. 289733 (Patent Application No. 84104486) disclosed a making process regarding omeprazole. The process comprises the omeprazole mixed with part of excipient is dissolved or suspended in an binder .solution composed of alcohol, water, and liquid ammonia. Then, the solution is sprayed onto a sugar seed made of sucrose or microcrystalline cellulose. Next, a particle made from above said step is sprayed by a solution composed of alcohol, water, and liquid ammonia containing binder and excipient to constitute a subcoating layer. Finally, an enteric coating is treated to cover the subcoating layer.

It can be understood that above process has reduced the steps related to transitional operations, but the soluble medium contains liquid ammonia such that an air pollution becomes unavoidable in large-scale and makes the workers uncomfortable and inconvenient so as to influence their health.

The present invention has developed an oral medicine of microgranules containing omeprazole and the analogues to overcome the disadvantages mentioned above.

3 SUMMARY OF THE INVENTION The present invention is to provide a medicine with enteric coating, which can be swiftly dissolved in a neutral or a alkaline medium liquid and contains a well stabilised omeprazole or the analogues. The medicine has the following features: a mixture of omeprazole or the analogues and solubilizing agents of pH value 7 is sprayed onto a sugar seed constituted by sucrose or microcrystalline cellulose to form microgranules containing active drug; the microgranules are coated by one or multiple layers of nodules material to form a subcoating layer; and the outermost layer is coated by an enteric coating to obtain a desired pharmaceutical 10 microgranules preparation.

BRIEF DESCRIPTION OF THE DRAWINGS The present invention can be more fully understood by referring to the following description and accompanying drawing, in which: 15 Fig. 1 is a diagram showing a comparison between dissociation curves of the product in accordance with the present invention and the product sold in the market.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT Sugar seed S 20 The sugar seed in the medicine in accordance with the present invention is eatable and offered by the material vendor. The sugar seed is made of sucrose, lactose, starch, other carbohydrates, or microcrystalline cellulose.

Active drug layer The active drug layer is composed of omeprazole or the analogues and solubilizing agents of pH 7. The manufacture of process the active drug layer is that the solubilizing agent is dissolved in pure water, or a solution composed of the water/alcohol, or water/ other alcohol mixing with dissolving medium. Then, the omeprazole is put in above said solution and the solution is agitated such that the omeprazole is suspended in the solution. Next, the solution is sprayed onto the sugar seed to form microgranules with active drug. The proportion of omeprazole to the solubilizing agent of pH value 7 should be between 80:1 and 2:1, and the molecular weight of polyvinyl alcohol should be between 20,000 and 100,000. The solubilizing agent can be polyvinyl alcohol, dioctyl sodium sulfosuccinate, glyceryl monooleate, polyoxyethylene sorbitan fatty acid, polyoxyethylene alkyl ethers, glyceryl monostearate, and etc.

Subcoating layer The subcoating layer is made of nodulised material such as lactose, sucrose, starch, mannitol, dextrose, maltodextrin, microcrystalline cellulose, kaolin, and silicon 10 dioxide. These materials can be used alone or in a form of mixing each other.

Above said materials are dissolved or suspended in a solution of binder with alcohol or pure water or water/alcohol mixed dissolving medium. The binder used is selected from pharmaceutically acceptable soluble substances such as polyethylene glycol, polyvinylpyrrolidone, hydroxypropyl cellulose, or hydroxypropyl methyl cellulose.

0** Enteric coating The enteric coating used in the medicine is an ordinary polymer of enteric coating such as cellulose acetate phthalate, cellulose acetate succinate, shellac, polyvinyl acetate phthalate, polyvinyl butyrate phthalate, methyl methacrylate/ 20 methacrylic acid copolymer L or S, hydroxypropyl methyl cellulose acetate succinate, or hydroxypropyl methyl cellulose phthalate. The polymer of enteric coating is dissolved in a water solution or a proper organic solvent such as acetone, alcohol, isopropyl acetone, and methane dichloride, or a mixed solution thereof. Besides, the enteric coating may or may not contain a pharmaceutically acceptable plastic agent such as diethyl phthalate, dibutyl phthalate, triacetin, triehtyl citrate, tributyl citrate, polyethylene glycol, or the like. The quantity of the plasticiser is normally adjustable in accordance with each enteric coating, and a normal range thereof can be between 1 to 20% of the weight of each polymer of enteric coating. Additionally, expecient such as talc and pH alkaline buffering salt such as dibasic sodium phosphate can be added too.

The solution formed by omeprazole and solubilizing agent of pH value 7 in the manufacture process of the present invention can be dried and made as powder.

The sugar seed can be covered by the powder with binder, and then covered by subcoating layer and enteric coating successively to constitute a desired microgranules.

The powder is then compressed to form tablets, and the tablets is then covered by a subcoating layer and an enteric coating successively to constitute a tablet product.

10 The microgranules made by the process of the present invention can be filled in a capsule or mixed with excipient so as to be compressed as tablets for use.

The microgranules made by the process of the present invention can be circular, elliptical or any other shape of particle.

The omeprazole in the process of the present invention can be substituted by lansoprazole, perprazole, rabeprazole or pentoprazole optionally.

Experiment 1

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COMPOSITION

S. Sugar seed Active drug layer Omeprazole 200g Polyvinyl alcohol Subcoating layer Lactose 240g Water/alcohol solution with 4% polyvinyl alcohol 250ml Enteric coating Hydroxypropyl methyl cellulose phthalate Polyethylene glycol (PEG-4000) 18g Gross weight 708q Grs wih The manufacture process of above composition is performed according to the present invention. Firstly, 80g of polyvinyl alcohol are dissolved in a mixed dissolving medium of water/alcohol (6/4 200g of omeprazole are then suspended in above said solution, and the mingled solution is sprayed onto 80g of sugar seed to obtain a microgranules containing active drug. Next, the lactose is suspended in a solution of water/alcohol containing 4% polyvinyl alcohol. Said microgranules with active drug is covered by said solution in a form of fluidised bed and dried to obtain microgranules with subcoating layer. Finally, 90g of hydroxypropyl methyl cellulose phthalate are dissolved in water/alcohol solution to form film coating, and then add 18g of 10 polyethylene in the solution as a plasticiser and agitate the solution evenly. Finally, the agitated solution is sprayed onto the microgranules with subcoating layer to obtain a desired microgranules.

Experiment 2

COMPOSITION

Sugar seed Active drug layer Omeprazole 200g Polyvinyl alcohol Subcoatinq layer Lactose 240g Water/alcohol solution with 4% polyvinyl alcohol 250ml Enteric coating Hydroxypropyl methyl cellulose phthalate Talc Polyethylene glycol (PEG-4000) 18g Gross weight 768g The manufacture process of above composition is proceeded according to the present invention. Firstly, 80g of polyvinyl alcohol are dissolved in a mixed dissolving medium of water/alcohol (6/4 200g of omeprazole are then suspended in above said solution, and the mingled solution is sprayed onto 80g of sugar seed to obtain a microgranules containing active drug. Next, the lactose is suspended in a solution of water/alcohol containing 4% polyvinyl alcohol. Said microgranules with active drug is covered by said solution in a form of fluidised bed and dried to obtain microgranules with subcoating layer. Finally, 90g of hydroxypropyl methyl cellulose phthalate are dissolved in water/alcohol solution to form film coating, and then add 18g of polyethylene in the solution as a plasticiser and 60g of talc and agitate the solution evenly. Finally, the agitated solution is sprayed onto the microgranules with subcoating layer to obtain a desired microgranules.

Experiment 3

COMPOSITION

Sugar seed Active drug layer Omeprazole 200g Polyvinyl alcohol Subcoating layer Lactose 240g 8% Polyvinylpyrrolidone solution 250ml Enteric coating Hydroxypropyl methyl cellulose phthalate Talc Dibasic sodium phosphate Polyethylene glycol (PEG-4000) 18g Gross weight 778g The manufacture process of above composition is proceeded according to the present invention. Firstly, 80g of polyvinyl alcohol are dissolved in a mixed dissolving medium of water/alcohol (6/4 200g of omeprazole are then suspended in above said solution, and the mingled solution is sprayed onto 80g of sugar seed to obtain a microgranules containing active drug. Next, the lactose is suspended in a solution of water/alcohol with 8% polyvinylpyrrolidone. Said microgranules with active drug is covered by said solution in a form of fluidised bed and dried to obtain microgranules with subcoating layer. Finally, 90g of hydroxypropyl methyl cellulose phthalate are dissolved in water/alcohol solution to form film coating, and then add 18g of polyethylene in the solution as a plasticiser, 1 Og of dibasic sodium phosphate and of talc, and agitate the solution evenly. The agitated solution is sprayed onto the microgranules with subcoating layer to obtain a desired microgranules.

Experiment 4 10 According to U. S. pharmacopoeia X X III, an experiment procedure for stability test in acceleration is conducted. The microgranules containing omeprazole made in experiments 2 and 3 each is exposed under a temperature of 40°C and 75% of relative humidity and the change of the appearance and the mass are observed in respect to the time. It is noted that a 6 months period of storage for the microgranules under this circumstance is equivalent to a 3 years period of storage under a normal temperature. In other words, it means if the medicine can be kept unchanged under this circumstance for about a week, a highly safety can be •guaranteed for actual application. A result of the test is listed in table 1. From table 1, it can be seen that the microgranules made by the present invention method can 20 be obtained a well stability.

Table 1: Experiment and observed results in a test of stability Item Storage Period Appearance Weight Embodiment 2 0 day white 40.02 mg day white 39.89 mg 180 day slight brown white 39.74 mg Embodiment 3 0 day white 39.50 mg day white 38.69 mg 180 day slight brown white 38.15 mg 9 Experiment The dissolution of the microgranules containing omeprazole made in experiment 1 is measured and compared to that of the product sold in the market.

Referring to Fig. 1, it can be found the dissolution of the product of the present invention pretty matches that of the product sold in the market.

While the invention has been described with reference to preferred experiments thereof, it is to be understood that modifications or variations may be easily made without departing from the spirit of this invention, which is defined by the appended claims.

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Claims

1. A composition of oral pharmaceutical preparation containing omeprazole, including a sugar seed: 6% to 12% a medicine layer; an omeprazole: 7.5% to 14.5% a polyvinyl alcohol: 0.1% to 7% a subcoating layer: 32% to 60% and an enteric coating layer: 26% to

2. A manufacture process of oral pharmaceutical preparation containing an active ingredient of omeprazole, including following steps: 1) suspending the omeprazole on a polyvinyl alcohol solution or a solution constituted by a mixed solvent median of water/alcohol; 2) spraying the solution obtained in step 1 onto a sugar seed composed of sucrose, lactose, starch, or other carbohydrates, or microcrystalline cellulose to form microgranules; 3) coating the microgranules one or more than layers of subcoating by way of binder with nodulised material; and 4) finally, coating an enteric coating on the subcoating layer to acquire microgranules product.

3. A manufacture process as defined in claim 2, wherein the binder can be polyethylene glycol, polyvinylpyrrolidone, hydroxypropyl cellulose, polyvinyl alcohol or hydroxypropyl methyl cellulose.

4. A manufacture process as defined in claim 2 or claim 3, wherein the nodulised material can be sucrose, lactose, starch, mannitol, dextrose, maltodextrin, microcrystalline cellulose, kaolin, or silicon dioxide. 11 A manufacture process as defined in any one of claim 2 to claim 4, wherein the enteric coating can be cellulose acetate phthalate, cellulose acetate succinate, shellac, polyvinyl acetate phthalate, polyvinyl butyrate phthalate, methyl methacrylate/methacrylic acid copolymer L or S, hydroxypropyl methyl cellulose acetate succinate, or hydroxypropyl methyl cellulose phthalate.

6. A composition of oral pharmaceutical preparation containing omeprazole, including a sugar seed: 6% to 12% a medicine layer; an omeprazole: 7.5% to 14.5% a solubilizing agent of pH value 7: 0.1% to 7% a subcoating layer: 32% to 60% and an enteric coating layer: 26% to

7. A manufacture process of oral pharmaceutical preparation containing an active ingredient of omeprazole, including following steps: 1) suspending the omeprazole on a solvent solubilizing agent of pH value 7 or a solution constituted by a mixed solvent median of water/alcohol; 2) spraying the solution obtained in step 1 onto a sugar seed composed of sucrose, lactose, starch, or other carbohydrates, or microcrystalline cellulose to form microgranules; 3) coating the microgranules one or more than layers of subcoating by way of binder with nodulised material; and 4) finally, coating an enteric coating on the subcoating layer to acquire microgranules product.

8. A manufacture process defined in claim 7, wherein the solvent solubilizing agent of pH value 7 can be polyvinyl alcohol, dioctyl sodium sulfosuccinate, glyceryl monooleate, polyoxyethylene sorbitan fatty acid, polyoxyethylene alkyl ethers or glyceryl monostearate.

9. A manufacture process as defined in claim 7 or claim 8, wherein the binder can be polyethylene glycol, polyvinylpyrrolidone, hydroxypropyl cellulose, polyvinyl alcohol or hydroxypropyl methyl cellulose. A manufacture process as defined in any one of claim 7 to claim 9, wherein the nodulised material can be sucrose, lactose, starch, mannitol, dextrose, maltodextrin, microcrystalline cellulose, kaolin, or silicon dioxide.

11. A manufacture process as defined in any one of claim 7 to claim 10, wherein the enteric coating can be cellulose acetate phthalate, cellulose acetate succinate, shellac, polyvinyl acetate phthalate, polyvinyl butyrate phthalate, methyl methacrylate/methacrylic acid copolymer L or S, hydroxypropyl methyl cellulose acetate succinate, or hydroxypropyl methyl cellulose phthalate.

12. A manufacture process of oral pharmaceutical microgranules preparation containing omeprazole, including following steps: 1) suspending the omeprazole on a solvent solubilizing agent of pH value 7 or a solution constituted by a mixed solvent median of water/alcohol; 2) drying the solution obtained in step 1 and making into powder, and covering said powder onto a sugar seed composed of sucrose, lactose, starch, or other carbohydrates, or microcrystalline cellulose to form microgranules; 3) coating the microgranules one or more than layers of subcoating by way of binder with nodulised material; and 4) finally, coating an enteric coating on the subcoating layer to acquire a microgranules product.

13. A manufacture process of oral pharmaceutical preparation containing of omeprazole, including following steps: 1) suspending the omeprazole on a solvent solubilizing agent of pH value 7 or a solution constituted by a mixed solvent median of water/alcohol; 2) drying the solution obtained in step 1 and making into powder, and then compressing said powder to form tablets; 3) coating the bare tablet one or more layers of subcoating by way of a binder with nodulised material; and 4) finally, coating enteric coating on the subcoating to acquire a required tablet product.

14. A composition of oral pharmaceutical preparation including: a sugar seed: 6% to 12% a medicine layer; an active principal selected from omeprazole, lansoprazole, perprazole, rebeprazole, or pentoprazole: 7.5% to 14.5% a polyvinyl alcohol: 0.1% to 7% a subcoating layer: 32% to 60% and an enteric coating layer: 26% to

15. A composition of oral pharmaceutical preparation including: a sugar seed: 6% to 12% a medicine layer; an active principal selected from omeprazole, lansoprazole, perprazole, rebeprazole, or pentoprazole: 7.5% to 14.5% a solubilizing agent of pH value 7: 0.1% to 7% a subcoating layer: 32% to 60% and an enteric coating layer: 26% to

16. An oral pharmaceutical preparation containing an active ingredient of omeprazole described in claims 2, 3, 4, 5, 7, 8, 9, 10, 11, or 12, wherein the microgranules could be filled into capsules. 14

17. An oral pharmaceutical preparation containing an active ingredient of omeprazole described in claims 2, 3, 4, 5, 7, 8, 9, 10, 11, or 12, wherein the microgranules are mixed with excipient to be compressed into a tablet.

18. A composition of oral pharmaceutical preparation substantially as hereinbefore defined with reference to the examples.

19. A manufacture process of oral pharmaceutical preparation substantially as hereinbefore defined with reference to the examples. 9 DATED THIS TWENTY-FOURTH DAY OF JANUARY 2000 9 NANG KUANG PHARMACEUTICAL CO., LTD. BY PAE PIZZEYS PATENT AND TRADE MARK ATTORNEYS *o