JP2000212085A - Highly stable oral medicinal preparation containing omeprazole or othrer analog, and production thereof - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a highly stable oral medicinal preparation formed out of a fine granular nucleus part, a medicinal layer consisting of omeprazole and a polyvinyl alcohol, an intermediate covering layer and an coating membrane layer. SOLUTION: This highly stable oral medicinal preparation consists of (A) 6-12 w/w % spherical fine granular shaped fine granular nucleus part, (B) a medicinal layer consisting of (i) 7.5-14.5 w/w % Omeprazole and (ii) 0.1-7 w/w % polyvinyl alcohol, (C) 32-60 w/w % intermediate coating layer and (D) 26-50 w/w % enteric coating membrane layer. The preparation is obtained preferably by spraying a solution obtained by suspending the component (i) in an aqueous solution or a mixed liquid of water with ethanol of the component (ii) over the component A formed with a sucrose, lactose starch or the other sugars, or a microcrystalline cellulose to form a medicinal layer, then coating the medicinal layer with a binder or a spherical shape-material to form one layer or multiple layers of the component C and then coating an enteric coating membrane to form pellets.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a highly stable oral pharmaceutical preparation containing omeprazole or another analog and a method for producing the same.

[0002]

Omeprazole, 5-methoxy-2-{[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl} -1H-benzimitazole, is insoluble but alkaline. Dissolves in aqueous solution. It is also known as a potent inhibitor of gastric juice secretion. In humans, H / K adenosine triphosphatase (ATPase) has an irreversible inhibitory effect and is therefore used for the treatment of duodenal ulcer. However, omeprazole degrades rapidly in low pH environments, for example at pH 4
At the following times, the half-life is less than sufficient: at pH 6 the half-life is about 16 hours and at pH 11 its stability is about 10 months. In addition, organic solvents such as dichloromethane and moisture can affect the stability of omeprazole.
Due to the above properties, it is necessary to prevent the oral preparation of omeprazole from coming into contact with gastric juice.

In order to avoid contact between omeprazole and gastric juice to affect its activity, the portion containing the nuclear drug must be coated with an enteric coating. Conventional enteric coatings are made of acidic compounds, and if omeprazole is directly covered, omeprazole will be decomposed and destroyed, resulting in severe discoloration of the preparation. In addition, since omeprazole is insoluble in an acidic or neutral aqueous solution, it is necessary to promote the dissolution of omeprazole by mixing with an alkaline substance or adding a solubilizer or a surfactant.

[0004] Taiwan Patent No. 76102439 (publication No. 147352)
Relates to an oral formulation of omeprazole, characterized by omeprazole and an alkaline reaction compound, or a nuclear drug-containing portion with or without an alkaline salt of omeprazole and an alkaline compound, and a pH within it.
It is a preparation containing an intermediate coating layer formed of a single or multilayer slow-reacting compound or polymer water-soluble coating containing or not containing an alkaline compound, and an enteric coating. The above patent discloses that 85% of the active substance is released after 2 hours in a solvent solution having a pH value (pH 1.2) corresponding to gastric juice,
In a solvent solution of pf 6.8 corresponding to intestinal fluid, 75% of omeprazole is released. Such a manufacturing method requires special and expensive equipment, and increases production cost and time. In the manufacturing process, the operation must be switched many times.

[0005] Also, Taiwan Patent No. 84104486 (publication 289733)
No.) relates to a method for producing an omeprazole preparation, which comprises dissolving or suspending omeprazole and some excipients in a binder solution composed of ethanol, water and aqueous ammonia, and further comprising sucrose or microcrystalline cellulose. Spraying on the core portion to be formed, followed by spraying the drug layer with a solution composed of ethanol, water and aqueous ammonia containing a binder and an excipient to form an intermediate coating layer,
Finally, the enteric coating is treated. Although the above-mentioned manufacturing method reduces the switching of the operation, since the solvent solution used contains ammonia water, it causes air pollution and impairs the health of workers.

[0006]

SUMMARY OF THE INVENTION In order to solve such problems, an object of the present invention is to provide a highly stable oral pharmaceutical preparation containing omeprazole or other analogs and a method for producing the same.

[0007]

SUMMARY OF THE INVENTION The present invention relates to an enteric solvent containing omeprazole or other analogs which rapidly dissolves in a neutral to alkaline solution and has high stability, and a method for producing the same. This drug product forms a drug layer by spraying a mixture of omeprazole and a solubilizer having a pH of 7 or less on a spherical fine-granular core composed of sucrose or microcrystalline cellulose, and further forms a one-layer or multi-layer spherical material. The above drug layer is coated with an intermediate coating layer formed of a film consisting of: and the outermost layer is an enteric coating layer to prepare a preparation.

[0008]

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS First, a mixture of omeprazole or other analogs and a solubilizing agent having a pH of 7 or less is coded on a spherical fine-granular nucleus composed of sucrose or microcrystalline cellulose and contains a drug. Form a sphere. Subsequently, an intermediate coating layer is formed by coating with a film formed of one or more spheroidizing materials. Finally, the outermost layer is coated with an enteric coating to form a drug layer.

[0009] The spherical fine-granular core used in the present invention is formed of a neutral edible material, and is mainly composed of sucrose, lactose, starch or other saccharides, or microcrystalline cellulose.

[0010] The drug layer used in the present invention is composed of omeprazole or other similar substances and a solubilizer having a pH of 7 or less. The solution comprises a solubilizer having a pH of 7 or less in pure water, or a mixed solvent of water and ethanol, or water and other alcohols. A drug layer is formed by directly spraying a spherical fine-granular core portion with a solution obtained by dissolving or suspending omeprazole in the above solution and stirring. Among them, the proportion of omeprazole and the solubilizing agent of pH ≦ 7 is 80: 〜2: 1.
And the molecular weight of polyvinyl alcohol is 20,000
It should be between 0 and 100,000. The solubilizer is selected from polyvinyl alcohol, dioctyl sodium sulfone sulfonate, glyceryl monooleate, oxyethylene polysorbitan fatty acid, polyoxyethylene alkyl ester, and glyceryl monostearate.

The intermediate coating layer used in the present invention comprises a spheroidizing material such as lactose, sucrose, starch, mannitol, dextrose, maltodextrin, microcrystalline cellulose, kaolin, and silicon dioxide. These materials can be used alone or in combination. The above materials, binder and ethanol, or pure water,
Alternatively, it is dissolved or suspended in a solution composed of a mixed solvent of water and ethanol. The binder is a water-soluble substance selected from the range acceptable for pharmacy, for example, polyethylene glycol, polyvinylpyrrolidone, hydroxypropylcellulose, hydroxypropylmethylcellulose and the like.

The enteric coating used in the present invention is cellulose acetate phthalate, cellulose acetate succinate, shellac,
Poly (vinyl phthalate), Poly (vinyl phthalate), L
-Or a general enteric polymer such as S-methyl methacrylate / methacrylic acid copolymer, hydroxypropylmethylcellulose acetate succinate, or hydroxypropylmethylcellulose phthalate. This is dissolved in a solution in water or a suitable organic solvent such as acetone, ethanol, isopropyl alcohol and dichloromethane, or a mixed solution thereof. The enteric coating may or may not include a pharmaceutically acceptable plasticizer, such as diethyl phthalate, dibutyl phthalate, triacetin, triethyl citrate, tributyl citrate, polyethylene glycol or a similar plasticizer. The dose of the plasticizer is adjusted depending on the type of enteric coating, but is generally within the range of 1 to 20% by weight of the enteric coating polymer. Other excipients, for example, talc powder or pH alkaline buffer salts such as disodium phosphate may be added.

The solution comprising omeprazole and a solubilizer having a pH of 7 or less according to the present invention is dried to form a powder, and the above-mentioned solubilizer is used to coat the spherical fine-granular core with the powder. The intermediate coating layer and the enteric coating layer are sprayed to form a drug layer. Further, a solution composed of omeprazole and a solubilizing agent having a pH of 7 or less in the present invention is dried and then turned into a powder, which is compressed into an uncoated tablet, and further coated with an intermediate coating layer and an enteric coating layer. Tablets can also be formed. Further, tablets may be formed after filling the pellets directly into capsules or mixing with other excipients. The drug layer may be a granular material having a circular shape, an elliptical shape, or any other shape. The present invention provides omeprazole, lansoprazole, perprazole, and rabeprazole.
azole) or pentoprazole (Pentoprazole).

[0014]

Embodiment 1 According to the above formula, first, polyethylene alcohol 80
g in a mixed solvent of water and ethanol (6/4 v / v), and 200 g of omeprazole are suspended in the above solution. Subsequently, this mixed solution is sprayed onto 80 g of the spherical fine-grained core to form a drug layer. Further, lactose is dissolved in a 4% aqueous solution of polyvinyl alcohol and ethanol, and this is sprayed onto the drug layer using a fluid bed and dried to form an intermediate coating layer. Finally, 90 g of propyl methylcellulose phthalate is dissolved in a mixture of water and ethanol, and 18 g of polyethylene glycol as a plasticizer is further added.
The solution is uniformly stirred to form an enteric coating layer solution, and the above solution is sprayed on the intermediate coating layer to obtain pellets.

[0015]

Embodiment 2 According to the above formula, first, polyethylene alcohol 80
g is dissolved in a mixed solvent of water and ethanol (6/4 v / v), and 200 g of omeprazole is suspended in the above solution. Subsequently, this mixed solution is sprayed onto 80 g of the spherical fine-grained core to form a drug layer. Further, lactose is dissolved in a 4% aqueous solution of polyvinyl alcohol and ethanol, and this is sprayed onto the drug layer using a fluid bed and dried to form an intermediate coating layer. Finally, 90 g of propyl methylcellulose phthalate is dissolved in a mixture of water and ethanol, and 18 g of polyethylene glycol as a plasticizer is further added.
And talc powder are added and stirred uniformly to form an enteric coating layer solution, and the above solution is sprayed on the intermediate coating layer to obtain pellets.

[0016]

Embodiment 3 According to the above formula, first, polyethylene alcohol 80
g is dissolved in a mixed solvent of water and ethanol (6/4 v / v), and 200 g of omeprazole is suspended in the above solution. Subsequently, this mixed solution is sprayed onto 80 g of the spherical fine-grained core to form a drug layer. Further, lactose is dissolved in a 4% aqueous solution of polyvinyl alcohol and ethanol, and this is sprayed onto the drug layer using a fluid bed and dried to form an intermediate coating layer. Finally, 90 g of propyl methylcellulose phthalate is dissolved in a mixture of water and ethanol, 18 g of polyethylene glycol as a plasticizer and 10 g of disodium phosphate are added to adsorb the free acid released by the enteric coating, and 60 g of talc powder is further added. In addition, the mixture is uniformly stirred to form an enteric coating layer solution, and the above solution is sprayed on the intermediate coating layer to obtain pellets.

[0017]

Example 4 According to the experimental method of the accelerated stability test described in the United States Pharmacopoeia (USP XX (3)), the drug layer preparation containing omeprazole of the above Examples 2 and 3 was prepared at 40 ° C., 75% At the relative temperature of, changes over time in appearance and content were observed. Six months of storage under such conditions is equivalent to three years of storage at room temperature. This means that a sufficiently high stability for practical use can be ensured if the medicament remains intact for about a week under the above conditions. The results are summarized in Table 1. As can be seen from Table 1, a highly stable drug layer can be obtained by using the preparation and the production method of the present invention.

[0018]

[0019]

Example 5 The dissolution rate of omeprazole from the omeprazole-containing pellet of Example 1 was measured and, at the same time, compared with the commercial product, and the results are summarized in FIG. As can be seen from FIG. 1, the dissolution rates of the formulation of the present invention and the commercial product are as follows:
There is considerable agreement.

[0020]

EFFECTS OF THE INVENTION The oral pharmaceutical preparation containing omeprazole or other analogs of the present invention and the method for producing the same ensure long-term storage stability of the preparation of omeprazole or other analogs.

[Brief description of the drawings]

FIG. 1 is a graph showing elution contrast curves of the preparation of the present invention and a commercial product.

Claims (17)

[Claims] 1. 6% to 12% (W / W) spherical fine-grained spherical fine-grained nucleus part; 7.5% to 14.5% (W / W) omeprazole;
1% to 7% (W / W) polyvinyl alcohol drug layer, 32% to 60% (W / W) intermediate coating layer, 26% to 50% (W / W) enteric coating layer An oral pharmaceutical preparation containing omeprazole, characterized by being formed from 2. A solution obtained by suspending omeprazole in an aqueous solution of polyvinyl alcohol or a mixture of water and ethanol, and applying a solution obtained by suspending sucrose, lactose, starch, or other saccharides, or microcrystalline cellulose to a spherical fine-grained sphere. A drug layer is formed by spraying the granular core portion, and then the drug layer is coated with a binder and a spheroidizing material to form a single or multi-layer intermediate coating layer. Finally, an enteric coating is coated to form a pellet. A method for producing an oral pharmaceutical preparation containing omeprazole, characterized in that: 3. The omeprazole according to claim 2, wherein the binder is at least one selected from polyethylene glycol, polyvinylpyrrolidone, hydroxypropylcellulose, polyvinyl alcohol and hydroxypropylmethylcellulose. To make oral pharmaceutical preparations. 4. The method according to claim 2, wherein the spheroidizing material is at least one selected from lactose, sucrose, starch, mannitol, dextrose, maltodextrin, microcrystalline cellulose, kaolin and silicon dioxide. A method for producing an oral pharmaceutical preparation containing omeprazole according to the above. 5. The enteric film polymer is cellulose acetate phthalate, cellulose acetate succinate, shellac, poly (vinyl phthalate), poly (vinyl butyrate), L- or S-methyl methacrylate / methacrylic acid copolymer, The method for producing an oral pharmaceutical preparation containing omeprazole according to claim 2, wherein the method is at least one selected from hydroxypropylmethylcellulose acetate succinate and hydroxypropylmethylcellulose phthalate. 6. 6% to 12% (W / W) of spherical fine-grained nuclei; 7.5% to 14.5% (W / W) of omeprazole;
1% to 7% (W / W) of a drug layer consisting of a solubilizer having a pH ≦ 7; 32% to 60% (W / W) of an intermediate coating layer; 26% to 50% (W / W) An oral pharmaceutical preparation containing omeprazole, which is formed from an enteric coating layer of the present invention. 7. A solution constituted by dissolving or suspending omeprazole in an aqueous solution of a solubilizer having a pH of ≦ 7 or a mixture of water and ethanol, using sucrose, lactose, starch or other saccharides, or microcrystalline cellulose. Spray on the spherical fine granular nucleus formed to form a drug layer,
Subsequently, the drug layer is coated with a binder and a spheroidizing material to form a one or more intermediate coating layer, and finally, an enteric coating is coated to form a pellet, containing omeprazole as an active molecule. To make oral pharmaceutical preparations. 8. The solubilizer having a pH ≦ 7 is selected from polyvinyl alcohol, sodium dioctyl sulfone succinate, glyceryl monooleate, oxyethylene polysorbitan fatty acid, polyoxyethylene alkyl ester, glyceryl monostearate and the like. A method for producing an oral pharmaceutical preparation containing omeprazole according to claim 7, characterized in that: 9. The binder comprises polyethylene glycol, polyvinylpyrrolidone, hydroxypropylcellulose,
8. It is selected from polyvinyl alcohol, hydroxypropyl methylcellulose and the like.
5. A method for producing an oral pharmaceutical preparation comprising omeprazole or omeprazole according to item 1. 10. The omeprazole according to claim 7, wherein the spheroidizing material is selected from lactose, sucrose, starch, mannitol, dextrose, maltodextrin, microcrystalline cellulose, kaolin and silicon dioxide. To make oral pharmaceutical preparations. 11. The enteric film polymer is cellulose acetate phthalate, cellulose acetate succinate, shellac, poly (vinyl phthalate), poly (vinyl butyrate), L- or S-methyl methacrylate / methacrylic acid copolymer, amber. The method for producing an oral pharmaceutical preparation containing omeprazole according to claim 7, which is selected from hydroxypropylmethylcellulose acetate and hydroxypropylmethylcellulose phthalate. 12. First, a solution formed by dissolving or suspending omeprazole in an aqueous solution of a solubilizing agent having a pH of 7 or a mixed solution of water and ethanol is dried, and then powdered, and further using the binder. , Coating the powder on sucrose, lactose, starch or other saccharides, or a spherical fine-grained nucleus formed of microcrystalline cellulose, forming a drug layer, and then binding the drug layer with a binder and a spheroidizing material. A method for producing an oral pharmaceutical drug layer containing omeprazole, characterized in that the medicament is coated with omeprazole to form a single or multi-layered intermediate coating layer and finally coated with an enteric coating to form a pellet. 13. First, a solution formed by dissolving or suspending omeprazole in an aqueous solution of a solubilizing agent having a pH of 7 or a mixture of water and ethanol is dried, and then powdered. A tablet, with the binder and the spheroidizing material, coating the uncoated tablet to form a single or multiple intermediate coating layer, and finally coating the enteric coating to form a tablet, A method for preparing an oral pharmaceutical tablet containing omeprazole. 14. Omeprazole may be lansoprazole, perprazole, rabeprazole or pentoprazole.
2. The oral pharmaceutical preparation according to claim 1, wherein the oral pharmaceutical preparation can be replaced with (toprazole) or the like. 15. Omeprazole is lansoprazole, perprazole, rabeprazole or pentoprazole.
The oral pharmaceutical preparation according to claim 6, wherein the oral pharmaceutical preparation can be replaced with (toprazole) or the like. 16. The method of claim 2, 3, 4, 5, 7, 8, 9,
An oral pharmaceutical capsule containing omeprazole as an active molecule, characterized in that the drug layer obtained in 10, 11, or 12 is filled in a capsule and used. 17. The method of claim 2, 3, 4, 5, 7, 8, 9,
Mixing the drug layer obtained in 10, 11 or 12 with other excipients and compressing to form tablets.
Oral pharmaceutical tablets containing omeprazole as active molecule.