JP5122380B2 - Quick-disintegrating tablet with controlled drug release and process for producing the same - Google Patents

Description

  The present invention relates to a tablet that rapidly disintegrates in the oral cavity and that can control the release of a drug, and a method for producing such a tablet.

  In recent years, the proportion of elderly people in the population has rapidly increased, and accordingly, development of drugs for elderly patients has been promoted. Elderly people have various physiological functions, and in particular, from the viewpoint of ease of taking drugs orally, a decrease in swallowing power has become a focus of attention in pharmacotherapy for elderly patients. For this reason, the dosage form has been devised. Specifically, liquid or paste in which a drug is dispersed and dissolved is filled in a pocket of a blister sheet previously molded into a tablet shape and freeze-dried (Japanese Patent Publication No. Sho 62-50445) or wet containing a drug A dosage form that is rapidly dissolved in the oral cavity by using a tablet (Japanese Patent Laid-Open No. Hei 8-19589), which is prepared by filling powder in a mold, compression molding at a low pressure, and then drying it has been studied.

  However, since the above-mentioned fast-disintegrating tablets disintegrate very rapidly, it is known that the drug release rate does not depend on the disintegration of the tablet but only on the solubility of the drug. On the other hand, there are a large number of tablets devised so as to control the release of the drug using various sustained-release mechanisms, but these release-controlled tablets are not devised to rapidly disintegrate in the oral cavity. In other words, there is no known fast-disintegrating tablet that controls disintegration of a drug that is rapidly disintegrated in the oral cavity so that it can be easily swallowed, but is designed to control the release of the drug.

  Therefore, we tried to develop a fast-disintegrating tablet that was rapidly disintegrated in the oral cavity so that it could be swallowed, but was designed to control the release of the drug. Conventional methods for forming a film of a water-insoluble and pH-independent polymer film on the tablet surface, which is employed in the drug release mechanism of sustained-release tablets, and tablets with a matrix of polymer, wax, etc. are used in the oral cavity. Then it does not collapse easily. As a result of intensive studies to achieve the above object, the present inventor has found that the object can be achieved by the following configuration, and has completed the present invention.

In the present invention, (1) (a) granules in which a drug is contained in a water-soluble polymer matrix or wax matrix, and / or (b) drug-containing granules are coated with a water-soluble polymer or a water-insoluble polymer film. It is a tablet produced by mixing granules and (2) an excipient, (3) adding a solvent and kneading, and (4) molding into a mold, or a method for producing the tablet.

  The water-soluble polymer in the present invention is one or more water-soluble polymers selected from hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, and polyvinyl alcohol. These water-soluble polymers may be used alone or in combination of two or more.

  The wax in the present invention is fat obtained by adding hydrogen to hydrogenated oil, that is, fish oil or vegetable or animal fatty oil, and examples thereof include hydrogenated cottonseed oil, hydrogenated soybean oil, and hydrogenated castor oil.

  In order to produce granules, formulation aids such as lactose, mannitol, crystalline cellulose, starch and the like can be used together. That is, the granules in the present invention can be obtained by adding a water-soluble polymer or wax to a drug, further adding an excipient such as lactose or mannitol as necessary, adding a solvent, kneading and granulating and drying. In the granule thus obtained, since the drug is dispersed in a polymer or wax matrix, the drug is gradually released in water or in the gastrointestinal tract.

The granule in the present invention is also obtained by adding an excipient such as lactose or mannitol to the drug, adding a small amount of a binder and a solvent, granulating the granule, and dispersing ordinary granules not dispersed in a polymer matrix different from the above. It can also be obtained by manufacturing and coating the granules with a water-soluble polymer and / or a water-insoluble polymer. Again, the drug is gradually released in water or in the gastrointestinal tract. These granulation and coating can be performed by a commonly used apparatus.

  The water-insoluble polymer in the present invention is one or more water-insoluble polymers selected from ethyl cellulose, methyl methacrylate / methacrylic acid copolymer, methyl acrylate / methacrylic acid copolymer, and cellulose acetate phthalate. Two or more of these water-insoluble polymers may be used in combination, or may be combined with a water-soluble polymer. The particle size of the granules thus obtained is preferably 400 μm or less. In the case of 400 μm or less, the tablet has almost no rough feeling after disintegration in the mouth, and the dosage is good.

  Excipients in the present invention are saccharides such as mannitol, lactose, sucrose, erythritol, xylitol, D-sorbitol, glucose, maltose, maltitol, crystalline cellulose, carboxymethylcellulose, carboxymethylcellulose calcium, crosslinked sodium carboxymethylcellulose, low substitution degree It means a cellulose derivative such as hydroxypropylcellulose, starches such as corn starch, wheat starch and potato starch, and starch derivatives such as partially pregelatinized starch. These excipients can be used in combination of two or more. In particular, mannitol, lactose, erythritol, xylitol and starches are preferable. The amount ratio of the granule and the excipient is not particularly limited, but it is usually 2 parts by weight or more, preferably 3 parts by weight or more with respect to 1 part by weight of the granule. You may mix a medicine with an excipient | filler.

  In the present invention, a binder can be mixed together with granules and excipients. By using a binder, the hardness of the tablet can be increased, and pharmaceutical properties such as a reduction in friability can be improved. The binder means polyvinylpyrrolidone, hydroxypropylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, pullulan, gum arabic, gelatin, polyvinyl alcohol, dextran, dextrin, xanthan gum and the like. These binders may be used alone or in combination of two or more. Particularly preferred are polyvinylpyrrolidone, hydroxypropylcellulose, methylcellulose, and hydroxypropylmethylcellulose. The drug used in the present invention is not particularly limited, but it is particularly useful when a drug having good solubility in water or a drug having an unpleasant taste is used.

The tablet according to the present invention can be obtained by mixing the above-mentioned granules with an excipient and, if necessary, a binder, adding a solvent, kneading, filling the wet powder into a mold, molding and drying. it can. In the present invention, a binder can be used as necessary. However, the binder may be mixed together with granules / excipients, and only the solvent may be added, or the granules / shaped excipients may be dissolved or dispersed in the solvent. It may be added to the agent mixture. When the amount of the binder is too large, the tablet disintegration is slow, so that the amount is usually 5% or less, preferably 3% or less, based on the weight of the granule and excipient. The composition of the solvent is not particularly limited, but usually a highly safe solvent for humans is used, and examples thereof include water, ethanol, propanol and the like, and these may be used in combination. The amount of the solvent varies depending on the type of drug, excipient, etc., but is usually 1 to 20% by weight, preferably 3 to 18% by weight, based on the weight of the mixture of granules and excipient. If the amount of the solvent is small, sufficient strength as a tablet cannot be obtained, and if it is too large, the mixture becomes pasty and filling molding becomes impossible.

  For the molding of tablets, a so-called mold (mold) tablet manufacturing device can be used, but if a device that can be compression-molded through a film after filling the mold is used, there is no harshness during manufacturing, the appearance is good, and the weight Tablets with small deviation and friability can be obtained. The obtained tablet has a disintegration time in the oral cavity of 30 seconds or less.

  Drugs are gradually released in water or in the gastrointestinal tract from granules in which the drug is contained in a water-soluble polymer matrix or wax matrix or a drug-containing granule coated with a water-soluble polymer and / or a water-insoluble polymer film Is done. In other words, in these granules, the release of the drug in water or in the gastrointestinal tract is controlled. That is, the tablet according to the present invention can control the release of the drug despite the rapid disintegration in the oral cavity so that it can be easily swallowed, and thereby the blood concentration of the drug can be controlled. Moreover, the unpleasant taste and smell of the drug can be suppressed. Further, since it is compressed at a very low pressure, there is little destruction of the drug-containing particles, there is little influence on the intended drug release, and it can be rapidly disintegrated within 30 seconds in the oral cavity. Moreover, in the case of a drug having an unpleasant taste, it has a concealing effect. Conventionally, in the case of tablets using wet powder, it has been considered impossible to control the release of the drug, so these are extremely remarkable effects.

  Hereinafter, specific embodiments of the present invention will be described by way of examples, but the present invention is not limited thereto. In the examples, parts and% represent parts by weight and% by weight, respectively.

Example 1
<Preparation of drug-containing granules> 60 parts of loxoprofen sodium (manufactured by Daito Co., Ltd.) and 18 parts of sodium carboxymethylcellulose (manufactured by Gotoku Pharmaceutical Co., Ltd.) are mixed using a stirring mixer, and purified water is added to the mixture. The mixture was granulated and dried. Thereafter, the particle size of the dried powder was adjusted using a particle sizer (Power Mill (product name), manufactured by Showa Giken Co., Ltd.).
<Preparation of tablets> To 78 parts of the above granules, 320 parts of mannitol (manufactured by Towa Kasei Co., Ltd.) were mixed using a stirring mixer, and 2 parts of polyvinyl pyrrolidone (PVP K-30 (product name), made by ISP) were mixed. Was dissolved in a 50% (w / w) ethanol aqueous solution and kneaded. The kneaded product was filled into a mold using a wet powder molding machine (EMT15 (model number), manufactured by Sankyo Seisakusho Co., Ltd.), and then dried.

Comparative Example 1
60 parts of loxoprofen sodium (manufactured by Daito Co., Ltd.) and 338 parts of mannitol (manufactured by Towa Kasei Co., Ltd.) were mixed using a stirrer type mixer, and polyvinylpyrrolidone (PVPK-30 (product name), manufactured by ISP) 2 A solution obtained by dissolving the part in 50% (w / w) ethanol was added and kneaded. The kneaded product was filled into a mold using a wet powder molding machine (EMT15 (model number), manufactured by Sankyo Seisakusho Co., Ltd.), and then dried.

Example 2
<Preparation of drug-containing granules> 10 parts of maprotiline hydrochloride (manufactured by cyphabitol) and 10 parts of hardened oil (manufactured by Loveliwax (product name), Freund Sangyo Co., Ltd.) were mixed using an agitating mixer, and an extruder ((stock) ) And made from Kurimoto Steel). Thereafter, the granulated material was aligned in particle size using a particle sizer (Power Mill (product name), manufactured by Showa Giken Co., Ltd.).
<Preparation of tablet> 257 parts of mannitol (manufactured by Towa Kasei Co., Ltd.) was mixed with 20 parts of the granule using a stirring mixer, and 3 parts of polyvinylpyrrolidone (PVPK-30, made by ISP) was mixed with 25% (w / w). w) A solution dissolved in ethanol was added and kneaded. The kneaded product was filled into a mold using a wet powder molding machine (EMT15 (model number), manufactured by Sankyo Seisakusho Co., Ltd.), and then dried.

Comparative Example 2
10 parts of maprotiline hydrochloride (manufactured by cifabitol) and 267 parts of mannitol (manufactured by Towa Kasei Co., Ltd.) were mixed using a stirrer-type mixer, and 3 parts of polyvinylpyrrolidone (PVPK-30, manufactured by ISP) was mixed with 25% (w / w). ) A solution dissolved in ethanol was added and kneaded. The kneaded product was filled into a mold using a wet powder molding machine (EMT15 (model number), manufactured by Sankyo Seisakusho Co., Ltd.), and then dried.

The following tests were conducted using the tablets obtained in the above examples.
1. Disintegration test Table 1 shows the disintegration test results measured according to the Japanese Pharmacopoeia Disintegration Test Method. The collapse end point determination was performed with a collapse end automatic detection device (destopper (product name): manufactured by Toyama Sangyo Co., Ltd.).

  From Table 1, it can be seen that there is no difference in the disintegration time between the tablet obtained in the example and the tablet obtained in the comparative example, and both disintegrate very quickly.

Dissolution test FIGS. 1 and 2 show the dissolution test results measured according to the Japanese Pharmacopoeia dissolution test method (second method: paddle method). The test solution was water and the paddle rotation speed was 50. From the above, it is clear that the tablet according to the present invention exhibits rapid disintegration and can control the release of the drug.

It is a figure which shows the elution of loxoprofen. It is a figure which shows elution of the maprotiline hydrochloride.

Claims (12)

(1) (a) granules in which a drug is contained in a wax matrix, and / or (b) granules in which a drug-containing granule is coated with a water-soluble polymer or a water-insoluble polymer film, and (2) an excipient. (3) A sustained-release intraoral rapidly disintegrating tablet formed by adding a solvent and kneading and (4) placing the wet powder in a mold.   The tablet according to claim 1, wherein the water-soluble polymer is at least one water-soluble polymer selected from hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, and polyvinyl alcohol, and the wax is hydrogenated oil. .   The tablet according to claim 1 or 2, wherein the water-insoluble polymer is at least one water-insoluble polymer selected from ethyl cellulose, methyl methacrylate / methacrylic acid copolymer, methyl acrylate / methacrylic acid copolymer, and cellulose acetate phthalate.   Excipients are mannitol, lactose, sucrose, erythritol, xylitol, D-sorbitol, glucose, maltose, maltitol sugar, crystalline cellulose, carboxymethylcellulose, carboxymethylcellulose calcium, crosslinked sodium carboxymethylcellulose, low substituted hydroxypropylcellulose cellulose The tablet according to any one of claims 1 to 3, which is at least one water-soluble polymer selected from derivatives, corn starch, wheat starch, potato starch, and starch derivatives of partially pregelatinized starch.   The tablet which added the binder in the tablet of Claims 1-4, and was shape | molded.   6. The binder is at least one binder selected from polyvinylpyrrolidone, hydroxypropylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, pullulan, gum arabic, gelatin, polyvinyl alcohol, dextran, dextrin, and xanthan gum. The tablet described.   The tablet according to claim 5 or 6, wherein the addition amount of the binder is 3% by weight or less based on the mixture of the granule and the excipient.   The tablet according to any one of claims 1 to 7, wherein the addition amount of the solvent is 3 to 18% by weight based on the mixture of the granule and the excipient.   The tablet according to claim 1, wherein the solvent is water, a water-alcohol mixed solvent, or alcohol.   The tablet according to claim 1, wherein the tablet disintegrates within 30 seconds in the oral cavity. (1) (a) granules in which a drug is contained in a wax matrix, and / or (b) granules in which a drug-containing granule is coated with a water-soluble polymer or a water-insoluble polymer film, and (2) an excipient. (3) A method for producing a sustained-release intraoral rapidly disintegrating tablet, wherein a solvent is added and kneaded (4) a wet powder is placed in a mold and molded.   12. The method for producing a tablet according to claim 11, wherein the wet powder is put into a mold and molded through a film.

Images