JP2010155854A - Sustained release pharmaceutical formulation - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a formulation of a new type in which a rise in the maximum blood cilostazole concentration is suppressed and a suitable blood cilostazole concentration can be kept by sustainedly releasing cilostazole in a dosage necessary for exhibiting its effect over a long time. <P>SOLUTION: The pharmaceutical formulation contains cilostazole, a pH-independent polymeric substance, and a hydrophilic hydrogel-forming substance. The pH-independent polymeric substance is a fully saponified polyvinyl alcohol. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention relates to a pharmaceutical preparation excellent in sustainability.

  The pharmacologically active ingredient is usually used in the form of a tablet obtained by adding an excipient or other ingredients to this and then administered orally. However, since tablets disintegrate rapidly in the body, a large amount of pharmacologically active ingredients are released into the body in a short time, and the blood concentration of the pharmacologically active ingredients increases, resulting in various side effects. there were.

  This invention makes it a subject to provide the pharmaceutical formulation excellent in sustainability.

  The present inventors have solved the above-mentioned problems in conventional preparations, and by continuously releasing only the amount necessary for exerting the effect of the pharmacologically active ingredient over a long period of time, Various studies have been conducted to develop a new type of preparation that can suppress an increase in concentration and maintain an appropriate blood concentration. As a result, it has been found that the subject of the present invention can be solved by making the pharmacologically active ingredient a specific pharmaceutical preparation. The present invention has been completed based on such findings.

  That is, the present invention comprises a pharmacologically active ingredient, a hydrophilic hydrogel-forming substance, and at least one pH-independent polymer substance selected from the group consisting of fully saponified polyvinyl alcohol, aminoalkyl methacrylate copolymer RS and ethyl cellulose. It relates to the pharmaceutical preparation contained.

Embodiments of the pharmaceutical preparation of the present invention are shown below.
1. A pharmaceutical preparation comprising a pharmacologically active ingredient, a hydrophilic hydrogel-forming substance and a pH-independent polymer substance.
2. A pharmaceutical preparation comprising a pharmacologically active ingredient, a hydrophilic hydrogel-forming substance, and at least one pH-independent polymeric substance selected from the group consisting of fully saponified polyvinyl alcohol, aminoalkyl methacrylate copolymer RS and ethylcellulose.
3. 2. The pharmaceutical preparation according to 1 above, wherein the pH-independent polymer substance is completely saponified polyvinyl alcohol.
4). 4. The pharmaceutical preparation according to any one of 1 to 3, wherein the hydrophilic hydrogel-forming substance is at least one selected from the group consisting of hydroxypropylcellulose and hydroxypropylmethylcellulose.
5). A pharmaceutical preparation comprising an inner core part containing (A) a pharmacologically active ingredient and an outer layer part containing (B) a pharmacologically active ingredient, a pH-independent polymer substance and a hydrophilic hydrogel-forming substance.
6). A dry-coated tablet comprising an inner core part containing (A) a pharmacologically active ingredient and an outer layer part containing (B) a pharmacologically active ingredient, a pH-independent polymer substance and a hydrophilic hydrogel-forming substance.
7). 7. The nucleated particle according to 6 above, wherein the pH-independent polymer substance is at least one pH-independent polymer substance selected from the group consisting of fully saponified polyvinyl alcohol, aminoalkyl methacrylate copolymer RS and ethyl cellulose. tablet.
8). 7. The dry-coated tablet according to 6 above, wherein the pH-independent polymer substance is completely saponified polyvinyl alcohol.
9. The pharmacologically active ingredient dry-coated tablet according to the above 6, wherein the hydrophilic hydrogel-forming substance is hydroxypropylmethylcellulose.
10. The nucleated particle according to 9 above, wherein the pH-independent polymer substance is at least one pH-independent polymer substance selected from the group consisting of fully saponified polyvinyl alcohol, aminoalkyl methacrylate copolymer RS and ethyl cellulose. tablet.
11. 7. The dry-coated tablet according to 6 above, wherein the pH-independent polymer substance is completely saponified polyvinyl alcohol.
12 The dry-coated tablet according to 6 to 8 above, wherein the outer layer part further contains a readily water-soluble substance.
13. The dry-coated tablet according to 6 to 12 above, wherein the pharmacologically active ingredient is cilostazol.
14 The above 7, 10 or 10 containing about 2 to 50% by weight of at least one pH-independent polymer selected from the group consisting of fully saponified polyvinyl alcohol, aminoalkyl methacrylate copolymer RS and ethyl cellulose in the outer layer part 12. The dry-coated tablet according to 12.
15. 13. The dry-coated tablet according to 9, 10, or 12, wherein the outer layer part contains about 5 to 35% by weight of hydroxypropylmethylcellulose.
16. In the outer layer portion, at least one pH-independent polymer substance selected from the group consisting of completely saponified polyvinyl alcohol, aminoalkyl methacrylate copolymer RS and ethylcellulose is about 2 to 50% by weight, and hydroxypropylmethylcellulose is 5 to 5%. 13. The dry-coated tablet according to 10 or 12 above, containing about 35% by weight.
17. 17. The dry-coated tablet according to 16 above, wherein the readily water-soluble substance is D-mannitol, and the outer layer portion contains about 3 to 20% by weight of D-mannitol.
18. The dry-coated tablet according to 9, 10, 12, 14, 15, 16, or 17 above, wherein the viscosity of hydroxypropyl methylcellulose in a 2% aqueous solution at 20 ° C. is about 200 to 6000 cps.
19. The dry-coated tablet according to 18 above, wherein the viscosity of hydroxypropylmethylcellulose in a 2% aqueous solution at 20 ° C. is about 200 to 1000 cps.
20. In the outer layer portion, at least one pH-independent polymer substance selected from the group consisting of completely saponified polyvinyl alcohol, aminoalkyl methacrylate copolymer RS and ethyl cellulose is about 5 to 50% by weight, and hydroxypropyl methylcellulose is 5 to 5%. 20. The dry-coated tablet according to 19 above, containing about 35% by weight.
21. In the outer layer part, at least one pH-independent polymer substance selected from the group consisting of completely saponified polyvinyl alcohol, aminoalkyl methacrylate copolymer RS and ethyl cellulose is about 8 to 45% by weight, and hydroxypropylmethyl cellulose is 10 to 10%. 20. The dry-coated tablet according to 19 above, containing about 30% by weight and about 3-20% by weight of D-mannitol.
22. The dry-coated tablet according to 18 above, wherein the viscosity of hydroxypropylmethylcellulose in a 2% aqueous solution at 20 ° C. is about 3000 to 6000 cps.
23. In the outer layer portion, at least one pH-independent polymer substance selected from the group consisting of completely saponified polyvinyl alcohol, aminoalkyl methacrylate copolymer RS and ethyl cellulose is about 2 to 30% by weight, and hydroxypropylmethyl cellulose is 5 to 5%. 23. The dry-coated tablet according to the above 22, containing about 35% by weight.
24. In the outer layer portion, at least one pH-independent polymer substance selected from the group consisting of completely saponified polyvinyl alcohol, aminoalkyl methacrylate copolymer RS and ethyl cellulose is about 5 to 25% by weight, and hydroxypropyl methylcellulose is 10 to 10%. 23. The dry-coated tablet according to 22 above, containing about 30% by weight and about 3-20% by weight of D-mannitol.
25. The ratio of at least one pH-independent polymer selected from the group consisting of fully saponified polyvinyl alcohol, aminoalkyl methacrylate copolymer RS, and ethylcellulose, which is sieved with a sieve having an aperture of about 150 μm, is a total pH-independent type. 25. The dry-coated tablet according to 7, 10, 14, 16, 17, 20, 21, 23, or 24, which is about 70% by weight or less of the polymer substance.
26. The ratio of at least one pH-independent polymer selected from the group consisting of fully saponified polyvinyl alcohol, aminoalkyl methacrylate copolymer RS, and ethylcellulose, which is sieved with a sieve having an opening of about 75 μm, is independent of the total pH. 26. The dry-coated tablet according to 25 above, which is about 60% by weight or less of the polymer substance.
27. The dry-coated tablet according to any one of the above 4-26, wherein the inner core tablet contains a pharmacologically active ingredient, a hydrophilic hydrogel-forming substance, a surfactant and a disintegrant.
28. The dissolution rate of a pharmacologically active ingredient from a nucleated tablet is (a) about 5 to 25% after 2 hours and 10 after 4 hours in a dissolution test using a sinker according to dissolution test method 2 (paddle method) of the Japanese Pharmacopoeia. About 50% or more after about 10 hours, and (b) about 10 to 60% after 2 hours in the dissolution test using beads according to the second method (paddle method) of the Japanese Pharmacopoeia The dry-coated tablet according to any one of 4 to 27, which is about 25% or more after 4 hours.
29. The dissolution rate of the pharmacologically active ingredient from the nucleated tablet is (a) a dissolution test using a sinker according to the Japanese Pharmacopoeia dissolution test method 2 (paddle method), about 5-15% after 2 hours and 10 after 4 hours. About 40% or more after about 10 hours, and (b) in a dissolution test using beads according to the second method (paddle method) of the Japanese Pharmacopoeia, about 10 to 40% after 2 hours, The dry-coated tablet according to any one of the above 19 to 21, which is about 25% or more after 4 hours.
30. The dissolution rate of a pharmacologically active ingredient from a nucleated tablet is (a) about 5 to 25% after 2 hours and 20 after 4 hours in a dissolution test using a sinker according to the second dissolution method (paddle method) of the Japanese Pharmacopoeia. About 50% or more after about 10 hours, and (b) about 20 to 60% after 2 hours in the dissolution test using beads according to the second method (paddle method) of the Japanese Pharmacopoeia The dry-coated tablet according to any one of the above 22 to 24, which is about 60% or more after 4 hours.

  The pharmaceutical preparation of the present invention is a pharmaceutical tablet containing a pharmacologically active ingredient, a hydrophilic hydrogel-forming substance and a pH-independent polymer substance, and is preferably used for the purpose of maintaining blood concentration for a longer time. Is a nucleated tablet composed of an inner core part and an outer layer part covering the inner core part.

  The pharmaceutical preparation of the present invention has a great feature in that the outer layer portion further contains a pH-independent polymer substance in addition to the pharmacologically active ingredient and the hydrophilic hydrogel-forming substance.

  As pharmacologically active ingredients to be blended in the outer layer part, known substances can be widely used. Examples of such pharmacologically active substances include respiratory preparations, digestive organ preparations, circulatory organ preparations, central nervous system preparations, peripheral nerve preparations, antibiotic preparations, chemotherapeutic agents, antitumor agents, and platelet aggregation. Listed are normal pharmacologically active substances that are blended in various preparations such as inhibitors, antiallergic agents, and vitamins. Specific examples thereof include theophylline, cilostazol, grepafloxacin, carteolol, procaterol, rebamipide, aripiprazole and the like.

  The hydrophilic hydrogel-forming substance blended in the outer layer part is a high molecular weight substance that swells and forms a gel when contacted with water. For example, methylcellulose, hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC) And cellulose derivatives such as sodium carboxymethylcellulose, partially saponified polyvinyl alcohol, and the like. Among these, HPMC is particularly preferable. These may be used alone or in combination.

  As HPMC, various HPMCs having different viscosities, for example, a low-viscosity HPMC in which the viscosity of a 2% aqueous solution at 20 ° C. is about 200 to 1000 cps, a high viscosity HPMC in which the viscosity of a 2% aqueous solution at 20 ° C. is about 3000 to 6000 cps, etc. Can be used. In general, when HPMC having a high viscosity is used, the release rate of the active ingredient (pharmacologically active ingredient) from the formulation decreases, and when HPMC having a low viscosity is used, the release rate tends to increase. The release of the pharmacologically active ingredient from the outer layer part can be adjusted by selecting and combining appropriately.

  The pH-independent polymer substance blended in the outer layer part is a pharmaceutically acceptable and pharmacologically inactive substance, and a pH-independent matrix together with the pharmacologically active ingredient and the hydrophilic hydrogel-forming substance. And imparting strength to the outer layer portion, so that the outer layer portion can be gradually and stably disintegrated in an environment with a strong mechanical stimulus such as the digestive tract.

  Examples of such pH-independent polymeric substances include pH-independent specific water-insoluble polymers that are commonly used as bases and films for sustained-release preparations, preferably water-insoluble polymers. Methacrylate copolymer, aminoalkyl methacrylate copolymer RS (Eudragit RSPO), water-insoluble cellulose such as ethyl cellulose and cellulose acetate, fully saponified polyvinyl alcohol and the like can be used. The degree of saponification of fully saponified polyvinyl alcohol is usually about 90% or more, preferably about 95% or more, more preferably 97% or more. The viscosity of the water-insoluble polymer in a 4% aqueous solution is usually 3 cps or more, preferably 5 cps or more, more preferably 10 cps or more, and further preferably 15 cps or more.

  Among these pH-independent polymer substances, fully saponified polyvinyl alcohol, aminoalkyl methacrylate copolymer RS and ethyl cellulose are preferable, and fully saponified polyvinyl alcohol is particularly preferable.

  These pH-independent polymer substances are used alone or in combination.

  In the present invention, among the pH-independent polymer substances, the ratio of the pH-independent polymer substance that is sieved with a sieve having an opening of about 150 μm is about 70% by weight or less. A pH-independent polymer substance in which the proportion of the pH-independent polymer substance sieved with a sieve having an opening of about 75 μm is about 60% by weight or less is particularly preferred. By using such a pH-independent polymer substance, a pharmaceutical preparation with extremely excellent sustainability can be obtained.

  The pharmaceutical preparation of the present invention is less susceptible to fluctuations in dissolution due to meals and can release pharmacologically active ingredients continuously. The pharmaceutical preparation of the present invention is less susceptible to mechanical stimuli such as meals taken after meals and intense gastrointestinal motility, as well as on an empty stomach, and can significantly reduce the release of pharmacologically active ingredients, and the blood of pharmacologically active ingredients An increase in medium concentration can be suppressed.

  In the present invention, an easily water-soluble substance can be further blended in the outer layer portion. Examples of the readily water-soluble substance to be blended in the outer layer part include saccharides such as D-mannitol, D-sorbitol, D-xylitol, lactose, sucrose, glucose, anhydrous maltose, D-fructose, dextran; polyethylene glycol, polyvinylpyrrolidone, etc. Water-soluble polymer substances; surfactants such as polyoxyethylene polyoxypropylene glycol and polyoxyethylene sorbitan higher fatty acid esters; salts such as sodium chloride and magnesium chloride; organic acids such as tartaric acid and citric acid; glycine, β- Examples include amino acids such as alanine and lysine hydrochloride; aminosaccharides such as meglumine. These may be used alone or in combination.

  In the present invention, a hydrophilic hydrogel-forming substance is generally added to the outer layer part in an amount of about 5 to 35% by weight, preferably about 7 to 33% by weight, more preferably 10 to 30% by weight, based on the weight of the outer layer part. It can be contained within a range of the degree.

  In the present invention, in the outer layer portion, the pH-independent polymer substance is generally about 2 to 50% by weight, preferably about 5 to 45% by weight, more preferably 5 to 5% by weight based on the weight of the outer layer portion. It can be contained within a range of about 40% by weight.

  The optimum usage amount of the pH-independent polymer substance may vary depending on the type of hydrophilic hydrogel-forming substance used.

  For example, when a low-viscosity HPMC whose viscosity of a 2% aqueous solution at 20 ° C. is about 200 to 1000 cps is used as a hydrophilic hydrogel-forming substance, a pH-independent polymer substance (particularly, completely saponified polyvinyl alcohol, aminoalkyl meta At least one pH-independent polymer substance selected from the group consisting of acrylate copolymer RS and ethyl cellulose) is usually about 5 to 50% by weight, preferably 10 to 45% by weight, based on the weight of the outer layer. About 15 to 40% by weight, more preferably about 15 to 40% by weight. In some cases, a pH-independent polymer material (especially at least one pH-independent polymer material selected from the group consisting of fully saponified polyvinyl alcohol, aminoalkyl methacrylate copolymer RS and ethyl cellulose) is used in the outer layer portion. In general, it may be used in an amount of about 5 to 50% by weight, preferably about 8 to 40% by weight, more preferably about 10 to 35% by weight. In some cases, a pH-independent polymer material (especially at least one pH-independent polymer material selected from the group consisting of fully saponified polyvinyl alcohol, aminoalkyl methacrylate copolymer RS and ethyl cellulose) is used in the outer layer portion. In general, it may be used in an amount of about 5 to 50% by weight, preferably about 8 to 45% by weight, more preferably about 10 to 40% by weight.

  When a high-viscosity HPMC whose viscosity of a 2% aqueous solution at 20 ° C. is about 3000 to 6000 cps is used as a hydrophilic hydrogel-forming substance, a pH-independent polymer substance (especially completely saponified polyvinyl alcohol, aminoalkyl) is used. The at least one pH-independent polymer substance selected from the group consisting of the methacrylate copolymer RS and ethyl cellulose) is usually about 2 to 30% by weight, preferably 5 to 25% by weight, based on the weight of the outer layer part. %, More preferably about 5 to 20% by weight.

  In the present invention, in the outer layer part, the water-soluble substance is generally about 3 to 20% by weight, preferably about 5 to 18% by weight, more preferably about 5 to 15% by weight, based on the weight of the outer layer part. It can be contained within the range.

  Furthermore, in addition to the pharmacologically active ingredient, the hydrophilic hydrogel-forming substance, the pH-independent polymer substance and the water-soluble substance, the outer layer part may be, for example, corn starch, potato starch, alpha starch, Dextrin, starch such as carboxymethyl starch, light anhydrous silicic acid, synthetic aluminum silicate, magnesium aluminate metasilicate, calcium phosphate, calcium carbonate and other inorganic salts, paraffin, wax, oils such as higher fatty acids, celluloses, etc. Excipients; disintegrating agents such as starches, croscarmellose sodium, carboxymethyl starch sodium, carboxymethylcellulose, carboxymethylcellulose calcium, low-substituted hydroxypropylcellulose, crystalline cellulose, crosslinked polyvinylpyrrolidone; Magnesium stearate, talc, lubricants such as synthetic aluminum silicate; can include a variety of food dyes solubilizing agents such as coloring agents such as such.

  The final composition of the outer layer part of the present invention is such that the dissolution rate of the pharmacologically active ingredient from the tablet having the same composition as the outer layer part is (a) a sinker according to the Japanese Pharmacopoeia dissolution test method 2 (paddle method) In a dissolution test (hereinafter referred to as “the sinker method”), about 5 to 25% after 2 hours, about 10 to 50% after 4 hours, and about 40% or more after 10 hours, and (b) dissolution of Japanese Pharmacopoeia In a dissolution test using beads by the second test method (paddle method) (hereinafter referred to as “bead method”), it is desirable to adjust so that it becomes about 10% to 60% after 2 hours and about 25% or more after 4 hours. .

  In some cases, the nucleated tablet of the present invention has a dissolution rate of a pharmacologically active ingredient according to (a) a dissolution test using a sinker according to the Japanese Pharmacopoeia dissolution test method 2 (paddle method) (hereinafter referred to as “sinker method”). In about 5 to 15% after 2 hours, about 10 to 30% after 4 hours and about 40% or more after 10 hours, and (b) beads by the second method of Japanese Pharmacopoeia dissolution (paddle method) In the dissolution test used (hereinafter referred to as “bead method”), it is about 10 to 25% after 2 hours, about 25 to 45% after 4 hours, and about 50% or more after 10 hours.

  In some cases, the nucleated tablet of the present invention has a dissolution rate of a pharmacologically active ingredient according to (a) a dissolution test using a sinker according to the Japanese Pharmacopoeia dissolution test method 2 (paddle method) (hereinafter referred to as “sinker method”). In about 5 to 15% after 2 hours, about 10 to 40% after 4 hours and about 50% or more after 10 hours, and (b) beads by the second method of Japanese Pharmacopoeia dissolution test (paddle method) In the dissolution test used (hereinafter referred to as “bead method”), it is about 10 to 40% after 2 hours and about 30% or more after 4 hours.

  In some cases, the nucleated tablet of the present invention has a dissolution rate of a pharmacologically active ingredient according to (a) a dissolution test using a sinker according to the Japanese Pharmacopoeia dissolution test method 2 (paddle method) (hereinafter referred to as “sinker method”). In about 5 to 25% after 2 hours, about 20 to 50% after 4 hours, and about 50% or more after 10 hours, and (b) beads by the Japanese Pharmacopoeia dissolution test method 2 (paddle method) In the dissolution test used (hereinafter referred to as “bead method”), it is about 20 to 60% after 2 hours and about 60% or more after 4 hours.

  In some cases, the nucleated tablet of the present invention has a dissolution rate of a pharmacologically active ingredient according to (a) a dissolution test using a sinker according to the Japanese Pharmacopoeia dissolution test method 2 (paddle method) (hereinafter referred to as “sinker method”). In about 5 to 15% after 2 hours, about 10 to 40% after 4 hours, and about 40 to 95% after 10 hours, and (b) beads by the second method of Japanese Pharmacopoeia dissolution (paddle method) In a dissolution test using the above (hereinafter referred to as “bead method”), it is about 10 to 40% after 2 hours and about 25% or more after 4 hours.

  In the present specification, the sinker method and the bead method are carried out under the following conditions.

  Sinker method: 700 ml of a 0.45% sodium lauryl sulfate aqueous solution containing 5 g of sodium chloride was used as a test solution, one tablet was placed in the sinker, and the paddle rotation speed was 50 rpm according to the JP 13 dissolution test method (second method paddle method). The elution rate was determined by testing and measuring the absorbance.

  Bead method: 700 ml of 0.45% sodium lauryl sulfate aqueous solution containing 5 g of sodium chloride was used as a test solution, and about 1500 polystyrene beads having a diameter of 6 mm were placed therein. One tablet was fixed to the front of the paddle in the rotational direction with double-sided tape, and tested at a paddle rotation speed of 50 rpm by the JP 13 dissolution test method (second method paddle method). The absorbance was measured to determine the elution rate.

  The inner core part constituting the dry-coated tablet of the present invention preferably contains a pharmacologically active ingredient and a hydrophilic hydrogel-forming substance, but is not particularly limited.

  The pharmacologically active ingredient blended in the inner core part is the same as the pharmacologically active ingredient blended in the outer layer part, but the pharmacologically active ingredient blended in the inner core part and the pharmacologically active ingredient blended in the outer layer part are different. It may be. As the pharmacologically active ingredient blended in the inner core part, the same pharmacologically active ingredient blended in the outer layer part described above can be used.

  Examples of the hydrophilic hydrogel-forming substance blended in the inner core include hydrophilic polymer substances such as hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, methylcellulose, and polyethylene oxide; polymer polymers such as carrageenan, guar gum, and gum arabic. Examples include saccharides. These may be used alone or in combination. Preferred hydrophilic hydrogel forming materials are hydroxypropylcellulose, hydroxypropylmethylcellulose and polyethylene oxide, and particularly preferred hydrophilic hydrogel forming materials are hydroxypropylmethylcellulose.

  In the inner core part, the hydrophilic hydrogel-forming substance is generally in the range of about 5 to 90% by weight, preferably about 10 to 80% by weight, more preferably about 10 to 70% by weight, based on the weight of the inner core part. It can be contained within.

  In addition to the hydrophilic hydrogel-forming substance, the inner core portion can contain a surfactant and a disintegrant.

  As the surfactant, those conventionally known in this field can be widely used. For example, alkyl sulfates such as sodium lauryl sulfate and magnesium lauryl sulfate; polyglycerin fatty acid esters such as decaglyceryl monolaurate and decaglyceryl monomyristate; Polyoxyethylene sorbitan fatty acid esters such as polyoxyethylene sorbitan monooleate; Polyethylene glycol fatty acid esters such as polyoxyethylene monostearate; Polyoxyethylene alkyl ethers such as polyoxyethylene lauryl ether; Poly such as polyoxyethylene hydrogenated castor oil Examples thereof include oxyethylene castor oil and hydrogenated castor oil; sucrose fatty acid esters such as sucrose stearate and sucrose balmitate. These may be used alone or in combination.

  As the disintegrant, those conventionally known in this field can be widely used, and examples thereof include low-substituted hydroxypropylcellulose, croscarmellose sodium, crospovidone, sodium carboxymethyl starch and the like. These may be used alone or in combination. Preferred disintegrants are low substituted hydroxypropylcellulose and croscarmellose sodium, and particularly preferred disintegrants are low substituted hydroxypropylcellulose.

  Furthermore, in the inner core, for example, starches such as corn starch, potato starch, alpha starch, dextrin, carboxymethyl starch, sugars such as lactose, sucrose, glucose, mannitol, sorbitol, light anhydrous silicic acid , Synthetic aluminum silicate, magnesium metasilicate aluminate, calcium phosphate, calcium carbonate and other inorganic salts, paraffin, wax, higher fatty acid and other fats and oils such as cellulose; magnesium stearate, talc, synthetic aluminum silicate Lubricants such as: various coloring agents such as food dyes can be included.

  The cored tablet of the present invention is prepared by, for example, preparing an inner core tablet that becomes an inner core part by a method known per se, and then using an nucleated tableting machine (press coater) to convert the inner core tablet into the outer layer part having the composition described above. It can manufacture by coating with.

  The inner core tablet (inner core part) may be coated with a thin film prior to coating with the outer layer part. Examples of the film coating base include cellulose-based water-soluble coating bases such as HPC, HPMC, hydroxyethylcellulose, and methylhydroxyethylcellulose, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, and phthalic acetate. Examples thereof include cellulose-based enteric coating bases such as cellulose, and other enteric film coating bases such as methacrylic acid copolymers and shellac.

  Furthermore, the nucleated tablet of the present invention may be provided with at least one film coating. Examples of such film coating include cellulose water-soluble coatings. As the cellulose-based water-soluble coating, HPMC is preferably used from the viewpoint of film forming property, and HPMC having a viscosity of a 2% aqueous solution at 20 ° C. of about 100 cps or less, particularly about 15 cps or less is particularly suitable. A plasticizer such as polyethylene glycol can be added to these film coating bases as necessary.

  The dry-coated tablet of the present invention can generally contain about 50 to 300 mg, preferably about 70 to 250 mg of a pharmacologically active ingredient per tablet. The relative ratio of the content of the pharmacologically active ingredient in the inner core part and the outer layer part is not particularly limited, but the weight ratio of the pharmacologically active ingredient content in the inner core part / the pharmacologically active ingredient content in the outer layer part is generally 10 / It can be in the range of 90 to 95/5, preferably 20/80 to 90/10, more preferably 30/70 to 80/20.

  From the viewpoint of preventing erosion of the inner core tablet, the outer layer of the dry coated tablet of the present invention has a thickness of 1 mm or more on one side, preferably 1.5 mm or more, more preferably about 1.5 to 3 mm.

  Since the pharmaceutical preparation of the present invention has the structure described above, after oral administration, the digestive juice and water are absorbed in the upper digestive tract and the outer layer forms an erosion matrix. It is not easily disintegrated even by the movement of the gel, and it gradually becomes a gel from the outside, and the pharmacologically active ingredient is stably released from the surface over time, and then the drug release from the matrix layer of the outer layer is completed. Around this time, the preparation reaches the lower gastrointestinal tract with low water content, and drug release from the inner core begins.

  Therefore, the pharmaceutical preparation of the present invention improves the stability of the gastrointestinal tract against strong peristalsis / mechanical movement, and has an excellent effect of maintaining the effective blood concentration of the pharmacologically active ingredient once a day.

  The pharmaceutical preparation of the present invention suppresses an increase in the maximum blood concentration of the pharmacologically active ingredient and releases an appropriate amount of blood by continuously releasing only the amount necessary for exerting the effect of the pharmacologically active ingredient over a long period of time. A new type of formulation that can maintain medium concentrations.

  Since the pharmaceutical preparation of the present invention does not rapidly disintegrate in the living body, a large amount of the pharmacologically active ingredient is not released in the living body in a short time, and the blood concentration of the pharmacologically active ingredient is not increased. As a result, it is unlikely to cause side effects such as headache, headache, and pain.

FIG. 1 is a graph showing the relationship between the time for dissolution tests using the sinker method and the bead method and the dissolution rate of cilostazol. FIG. 2 is a graph showing the relationship between the time in the dissolution test by the sinker method and the dissolution rate of cilostazol. FIG. 3 is a graph showing the relationship between the time in the dissolution test by the bead method and the dissolution rate of cilostazol.

  The present invention will be further clarified by the following examples.

Example 1
1600 g of cilostazol, 300 g of sodium lauryl sulfate (surfactant, manufactured by Nikko Chemicals), 400 g of hydroxypropylcellulose (LH-31, manufactured by Shin-Etsu Chemical Co., Ltd.), 120 g of hydroxypropylmethylcellulose (Metroze 90SH400, manufactured by Shin-Etsu Chemical Co., Ltd.), crystals 80 g of cellulose (Avicel PH301, manufactured by Asahi Kasei Co., Ltd.), 78 g of hydroxypropyl cellulose (HPC-L, manufactured by Nippon Soda Co., Ltd.) and 10 g of magnesium oxide (manufactured by Kyowa Chemical Co., Ltd.) are mixed, granulated using purified water, and compressed into tablets. Granules for use were obtained. Mg stearate (manufactured by Taihei Chemical Co., Ltd.) was added thereto, and an inner core tablet weighing 130 mg was tableted with a 7 mm diameter punch.

  Separately, 960 g of cilostazol, 800 g of hydroxypropylmethylcellulose (Metroze 90SH400, manufactured by Shin-Etsu Chemical Co., Ltd.), 400 g of D-mannitol (manufactured by Kyowa Hakko), 1200 g of ethylcellulose (Ethocel 7 cps Standard Premium, manufactured by Dow Chemical Company) and 616 g of lactose Were mixed and granulated with purified water to obtain granules for tableting. Mg stearate was added to obtain a nucleated tablet having a diameter of 11 mm and 630 mg including the inner core tablet.

Example 2
Granules for tableting were obtained in the same manner as in Example 1 except that 800 g of ethyl cellulose (Ethocel 7 cps Standard Premium, manufactured by Dow Chemical Company) and 1016 g of lactose were used. Further, in the same manner as in Example 1, a nucleated tablet having a diameter of 11 mm and 630 mg was obtained.

Example 3
Granules for tableting were obtained in the same manner as in Example 1 except that 400 g of ethyl cellulose (Ethocel 7 cps Standard Premium, manufactured by Dow Chemical Company) and 1416 g of lactose were used. Further, in the same manner as in Example 1, a nucleated tablet having a diameter of 11 mm and 630 mg was obtained.

  The formulations of Examples 1 to 3 are shown in Table 1.

Examples 4-6
Granules for tableting were obtained in the same manner as in Example 1 except that hydroxypropylmethylcellulose (Metroze 90SH4000, manufactured by Shin-Etsu Chemical Co., Ltd.) was used instead of hydroxypropylmethylcellulose (Metroze 90SH400, manufactured by Shin-Etsu Chemical Co., Ltd.). Further, in the same manner as in Example 1, a nucleated tablet having a diameter of 11 mm and 630 mg was obtained.

  The formulations of Examples 4 to 6 are shown in Table 2.

Test example 1
A predetermined amount of cilostazol, hydroxypropylmethylcellulose (Metroze 90SH400, manufactured by Shin-Etsu Chemical Co., Ltd.) and ethylcellulose (filtered with a sieve having an opening of 500 μm, Etocel 7 cps Standard Premium, manufactured by Dow Chemical Co., Ltd.) are mixed in a predetermined amount, and purified water is used. After granulation and drying, the mixture was sized with a sieve having an opening of 850 μm and added with magnesium stearate, and then tableted with a mortar having a diameter of 11 mm to obtain a tablet having a weight of 500 mg. Each tablet contained 120 mg of cilostazol, 100 mg of hydroxypropylmethylcellulose, 277 mg of ethylcellulose, and 3 mg of Mg stearate.

  Using this tablet, a test for determining the dissolution rate of cilostazol was conducted.

  For the dissolution test, the sinker method and the bead method were used. These test methods are as described above. In both the sinker method and the bead method, the elution rate of cilostazol was determined every other hour until 18 hours passed from the start of the test. The results are shown in FIG.

Example 7
1600 g of cilostazol, 300 g of sodium lauryl sulfate (surfactant, manufactured by Nikko Chemicals), 400 g of hydroxypropylcellulose (LH-31, manufactured by Shin-Etsu Chemical Co., Ltd.), 120 g of hydroxypropylmethylcellulose (Metroze 90SH400, manufactured by Shin-Etsu Chemical Co., Ltd.), crystals 80 g of cellulose (Avicel PH301, manufactured by Asahi Kasei Co., Ltd.), 78 g of hydroxypropyl cellulose (HPC-L, manufactured by Nippon Soda Co., Ltd.) and 10 g of magnesium oxide (manufactured by Kyowa Chemical Co., Ltd.) are mixed, granulated using purified water, and compressed into tablets. Granules for use were obtained. Mg stearate (manufactured by Taihei Chemical Co., Ltd.) was added thereto, and an inner core tablet weighing 130 mg was tableted with a 7 mm diameter punch.

  Separately, 960 g of cilostazol, 800 g of hydroxypropyl methylcellulose (Metroze 90SH400, manufactured by Shin-Etsu Chemical Co., Ltd.), 400 g of D-mannitol (manufactured by Kyowa Hakko), fully saponified polyvinyl alcohol (PVA NH-20, saponification rate 98.5) ˜99.4% (manufactured by Nippon Synthetic Chemical Industry Co., Ltd.) 1200 g and lactose 616 g were mixed and granulated using purified water to obtain granules for tableting. Mg stearate was added to obtain a nucleated tablet having a diameter of 11 mm and 630 mg including the inner core tablet.

Example 8
1600 g of cilostazol, 300 g of sodium lauryl sulfate (surfactant, manufactured by Nikko Chemicals), 400 g of hydroxypropylcellulose (LH-31, manufactured by Shin-Etsu Chemical Co., Ltd.), 120 g of hydroxypropylmethylcellulose (Metroze 90SH400, manufactured by Shin-Etsu Chemical Co., Ltd.), crystals 80 g of cellulose (Avicel PH301, manufactured by Asahi Kasei Co., Ltd.), 78 g of hydroxypropyl cellulose (HPC-L, manufactured by Nippon Soda Co., Ltd.) and 10 g of magnesium oxide (manufactured by Kyowa Chemical Co., Ltd.) are mixed, granulated using purified water, and compressed into tablets. Granules for use were obtained. Mg stearate (manufactured by Taihei Chemical Co., Ltd.) was added thereto, and an inner core tablet weighing 130 mg was tableted with a 7 mm diameter punch.

  Separately, 960 g of cilostazol, 800 g of hydroxypropyl methylcellulose (Metroise 90SH400, manufactured by Shin-Etsu Chemical Co., Ltd.), 400 g of D-mannitol (manufactured by Kyowa Hakko), 1200 g of aminoalkyl methacrylate copolymer RS (Eudragit RSPO, manufactured by Reem) and lactose 616 g was mixed and granulated with purified water to obtain granules for tableting. Mg stearate was added to obtain a nucleated tablet having a diameter of 11 mm and 630 mg including the inner core tablet.

Examples 9-11
50 g of cilostazol, 30 g of hydroxypropylmethylcellulose (Metroze 90SH400, manufactured by Shin-Etsu Chemical Co., Ltd.), 80 g of hydroxypropylmethylcellulose (Metroze 90SH100, manufactured by Shin-Etsu Chemical Co., Ltd.) and 22.5 g of Macrogol 6000 (manufactured by Sanyo Chemical Co., Ltd.) The mixture was stirred while heating to 70 ° C., cooled, and then sized with a sieve having an opening of 850 μm.

  After adding and mixing 40 g of the pH-independent polymer substance to this granulated product, 1.5 g of Mg stearate (manufactured by Taihei Chemical Co., Ltd.) is added, and the mixture is compressed with a mortar having a diameter of 8.5 mm 224 mg tablets were obtained.

The following were used as the pH-independent polymer substance.
pH-independent polymer A: completely saponified polyvinyl alcohol (PVA, NH-20, saponification rate 98.5-99.4%, 4% aqueous solution viscosity 35-43 cps , Manufactured by Nippon Synthetic Industry Co., Ltd.)
pH-independent polymeric substance B: ethyl cellulose (sized with a sieve having an opening of 710 μm, 7 cps standard premium, manufactured by Dow)
pH-independent polymeric substance C: aminoalkyl methacrylate copolymer RS (Eudragit RSPO, manufactured by Laem)
Comparative Example 1
Instead of pH-independent polymer, partially saponified polyvinyl alcohol (PVA, GH-20, saponification rate 86.5-89.0%, saponification rate 86.5%, 4% viscosity 40% aqueous solution) A tablet having a weight of 224 mg was obtained in the same manner as in Example 9 except that 40 g (˜46 cps, manufactured by Nippon Synthetic Industry Co., Ltd.) was added.

Comparative Example 2
To the sized product obtained in Example 9, 1 g of Mg stearate (manufactured by Taihei Chemical Co., Ltd.) was added and tableted with a mortar having a diameter of 8.5 mm to obtain a tablet having a weight of 183.5 mg.

Test example 2
The dissolution test was performed about each tablet obtained in Examples 9-11 and Comparative Examples 1-2. The sinker method and bead method in Test Example 2 are as follows.

  Sinker method: Using 600 ml of 0.3% sodium lauryl sulfate aqueous solution as a test solution, put one tablet into the sinker, and test it at a paddle rotation speed of 50 rpm according to JP 13 dissolution test method (second method paddle method). The dissolution rate was determined by measurement.

  Bead method: Using 600 ml of 0.3% sodium lauryl sulfate aqueous solution as a test solution, about 2000 polystyrene beads having a diameter of 6 mm were placed. One tablet was fixed to the front of the paddle in the rotational direction with double-sided tape, and tested at a paddle rotation speed of 50 rpm by the JP 13 dissolution test method (second method paddle method). The absorbance was measured to determine the elution rate.

  The dissolution test result by the sinker method is shown in FIG. 2, and the dissolution test result by the bead method is shown in FIG.

  From FIG. 3, in the bead method, suppression of cilostazol elution when a pH-independent polymer substance is added and complete saponified polyvinyl alcohol gives particularly good results among pH-independent polymer substances. I understand.

Claims (7)

A pharmaceutical preparation comprising cilostazol, a hydrophilic hydrogel-forming substance and fully saponified polyvinyl alcohol. The pharmaceutical preparation according to claim 1, wherein the hydrophilic hydrogel-forming substance is hydroxypropylmethylcellulose. The pharmaceutical preparation according to claim 2, wherein the pharmaceutical preparation is a nucleated tablet. The pharmaceutical preparation according to claim 3, wherein the nucleated tablet comprises (A) an inner core part containing cilostazol and (B) an outer layer part containing cilostazol, fully saponified polyvinyl alcohol and hydroxypropylmethylcellulose. The pharmaceutical preparation according to claim 4, wherein the outer layer portion further contains a readily water-soluble substance. The pharmaceutical preparation according to claim 5, wherein the readily water-soluble substance is D-mannitol. The pharmaceutical preparation according to claim 6, comprising about 2 to 50% by weight of fully saponified polyvinyl alcohol, about 5 to 35% by weight of hydroxypropylmethylcellulose and about 3 to 20% by weight of D-mannitol.

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