TWI281868B - Composition comprises sustained-release fine particles for quick-disintegrating tablets in the buccal cavity and manufacturing method thereof - Google Patents

Abstract

The present invention relates to a composition comprising sustained-release fine particles, characterized in that it contains sustained-release fine particles that can be used in quick-disintegrating tablets in the buccal cavity, one or more fillers selected from the group consisting of sugars or sugar alcohols, and one or more binders for quick-disintegrating tablets in the buccal cavity selected from the group consisting of sugars of high moldability and water-soluble polymer substances, and in that the sustained-release fine particles are granulated with filler and binder for quick-disintegrating tablets in the buccal cavity, and a manufacturing method thereof.

Description

1281868 (1) Description of the Invention [Technical Field of the Invention] The present invention relates to a composition comprising sustained release fine particles for oral cavity. In more detail, the present invention is a sustained release fine granule for a rapidly disintegrating ingot, characterized in that the granule and one or more chelating agents selected from the group consisting of saccharides or sugar alcohols, and the adhesive for the rapid disintegration ingot are made The granulated product is granulated, and the ratio of the sustained release fine granules in the entire composition is from 0 to 15%. [Prior Art] The present invention "sustained release fine granules" means that a sustained release treatment of a fine particle containing a drug and having a sustained release treatment of from about 0.1 μm to about 3 50 μm means to produce a pharmaceutically well-known π mitigation The example of H can be an understanding process that produces a gradual release of the drug, an enteric treatment, a treatment, and a release treatment of such combinations. Re-dissolved is called "enteric-soluble slow-release fine granules." Various intraoral disintegration tablets have been developed in the past so that they can be easily taken by people, children, etc., which have weak coerciveness even without water. In addition, the use in recent years has led to the provision of sustained release work in the oral cavity of rapidly disintegrating ingots. The first generation of intraorally rapidly disintegrating ingots, such as "ZydisTM" by R·p, etc., are known to be via freeze-drying. These first-generation intra-oral rapid disintegrating ingots are basically in-situ rapidly disintegrating ingots, including the oral cavity, including slow-release fines, which are used in the oral cavity as soon as they are not granulated, and which pass through various average particle sizes. The treatment can produce gastric dissolution according to the time release, can produce the intestines can be in, including the elderly need for a variety of drugs.. Scherer household sales of pharmaceutical preparations by the use of drugs (2) 1281868 Liquid or suspension is manufactured by freeze-drying or special drying. Therefore, the manufacturing procedure in liquid state is necessary and there is no discussion about providing sustained release function. Various second generation oral rapid disintegration All of them are known, including those who use disintegrants (Japanese Laid-Open No. Hei 1 0- 18243 6, International Early Publications Booklet WO 98/02185, etc.), which are characterized by being used as a binder. High-molecule sugar spray and/or granulation on low-molecule sugars and when further ingot strength is required, it can be moistened and dried (International Early Publications Booklet WO 95/20380 (corresponding to US Patent 5,576,014, Japanese License) No. 312141), etc., and these are manufactured by tabletting. It has been considered to rapidly disintegrate ingots containing fine particles, and the fine particles and the like are subjected to sustained release treatment, for example, by polymer coating. Coverage, in order to solve the obvious contradiction problem of providing the sustained release function of such second-generation oral rapid disintegrating tablets. However, even if there have been attempts to simply use the sustained-release treated fine particles and the oral rapid disintegration ingots The mixing of the sputum and the ingot formation of the mixture will also result in segregation in the precipitation process due to the difference in apparent specific gravity and fluidity between the sputum and the sustained release granules. The word '' The release fine particles are unevenly dispersed in the sputum and are in a state of segregation when they are unevenly dispersed. The uniformity of the drug content constituting the tablet can be determined after the tablet is prepared to determine the segregation phenomenon. The coefficient of variation (CV%) of the drug content (as shown below) is 3.5%, that is, no segregation occurs, and if the coefficient of variation exceeds 3.5%, segregation occurs. There are a variety of problems. For example, there are the following problems: (1) due to the contact between the face of the puncher in the ingot and the sustained release fine particles - 8- (3) 1281868 ' or the slow release particles themselves The direct contact between the ingots is directly transmitted to the slow-release fine particles, which leads to the destruction of the sustained-release fine particles and promotes dissolution after they are made into ingots. (2) The degree of damage of the sustained-release fine particles will follow It is variated by the degree of segregation. Therefore, it is not possible to achieve controlled dissolution as a design target of a sustained-release fine granule preparation with good reproducibility after tableting, and (3) the number of sustained-release fine granules contained in one ingot will be Undulating and not ensuring uniformity of drug content, etc. .

An invention relating to a method for producing spherical fine particles is disclosed in International Early Publications Publication No. WO 00/24379, which is capable of easily producing a controlled release pharmaceutical preparation by a special tumbling granulation method. The manufacturing method of this booklet includes special tumbling granulation of such spherical fine particles and shows that the dissolution can be controlled by coating the spherical fine particles and the spherical fine particles can be used in the rapidly disintegrating ingot in the oral cavity. However, our investigations have determined that the above problems occur and that the target cannot be completed if the rapidly disintegrating ingot in the oral cavity contains only the spherical particles which have been subjected to the sustained release treatment. Furthermore, no particular means of successful resolution of such problems are disclosed or indicated in this specification. Therefore, although it is still unknown, there is still a need for an in-oral rapid disintegration ingot including sustained-release fine granules, which is used to make the sustained-release fine granules after being made into ingots, because the ingots are ingots. As a result of the inhibition of the sustained-release fine particles under pressure, the dissolution of the drug is promoted, and even after the ingot is formed, the control for the purpose of the sustained-release fine particle preparation can be dissolved to achieve good reproducibility, and the drug content is ensured. Uniformity. SUMMARY OF THE INVENTION -9- (4) 1281868 In these cases, the inventors of the present invention focused on the study of the rapid disintegration of the ingot in the oral cavity and the prevention of rapid disintegration of the ingot in the oral cavity by the fine particles and the sputum filling agent. Separation (this is the origin of various problems). As a result of repeated experiments, they are prepared according to the granulation of all or part of the individual slow-release fine-grained surfaces coated by the filler, including slow-release fines ( Some of the granulated products which are aggregated in this granulation process can successfully complete the present invention by preventing the segregation of the sustained release fine granules and the chelating agent. By "granulation" is meant herein the manufacture of particles or powders that are substantially uniform in size. As a result of further detailed investigation, when 0 to 15% of the un-granulated sustained-release fine particles are obtained in the final obtained overall composition, the segregation of the sustained-release fine particles and the sputum-filling agent can be considered as a prevention. When several kinds of particles are aggregated in this manner, segregation is often easily caused as a result of an increase in the apparent specific gravity between the fine fillers and the fine flowability. However, it is completely achievable that by avoiding the direct contact between the punching machine surface and the slow-release fine particles or the slow-release fine particles, it is possible not only to ensure uniform content during the ingot making but also to simultaneously neutralize in the ingot. Stress and achieve good reproducibility of the solution in which the target is located. That is, the present invention relates to a slow-release fine-grained material for use in an intra-oral rapid disintegrating tablet, which is characterized in that it comprises a drug-containing sustained-release fine particle and one or a self-contained group Agent: saccharide and sugar alcohol, the granulated product made by the adhesive for rapidly disintegrating the ingot in the cavity, and the proportion of the sustained release fine granule in the whole composition is 〇 to 丨 5%. Release of fine particles using a slow release method. Use the 塡 program to find together and shape the result, the ratio is . The granules and sputum deteriorate, the nature of the singer is self-sufficient, and the composition of the controlled solution is selected from the use of sputum in the unscented -10-(5) 1281868 2. The above-mentioned item 1 contains the sustained release of the rapidly disintegrating ingot in the mouth. a composition of fine particles, wherein the adhesive for the rapidly disintegrating ingot in the oral cavity is one or more selected from the group consisting of high molding sugars, water-soluble polymer materials, and low melting sugars. . 3. The composition for sustained release fine granules for use in an orally rapidly disintegrating ingot of the above item 2, wherein the saccharide and the sugar alcohol are one or more selected from the group consisting of: low molding sugar Classes, high melting point sugars and low melting point sugars. 4. The composition containing the sustained-release fine particles for the rapid disintegration in the oral cavity in the above three items, wherein the mixing ratio of the sustained-release fine-grain '塡 filling agent' and the adhesive for the rapid disintegrating ingot in the oral cavity 1 to 50%, 20 to 98%, and 1 to 30%, respectively. 5. The composition for sustained release fine granules for use in an orally rapidly disintegrating ingot of the above item 4, wherein the rapidly disintegrating fine particles have an average particle diameter of from about 1 μm to about 3 50 μm. 6. The composition comprising sustained release fine particles for use in an orally rapidly disintegrating ingot of the above 5, wherein the sustained release fine particles comprise at least crystalline cellulose particles, a drug, and a polymeric substance. 7. The composition containing sustained release fine granules for rapid disintegration in the oral cavity in the above item 6, wherein the drug is tamsulosin hy drochloride 0 8. The oral cavity rapidly collapses in the above 7 items A composition containing sustained-release fine particles for use in an ingot, wherein the sustained-release fine particles are enteric sustained-release fine particles. 9. The composition comprising sustained release fine granules for rapid disintegration in the oral cavity in the above item 8, wherein the polymer substance is hydroxypropylmethylcellulose, B-11-(6)1281868-based cellulose, Eudragit L30D55' and Eudragit NE30D. 10. The composition for sustained release fine granules for use in a rapid disintegration tablet for oral cavity in the above item 9, wherein the adhesive for the rapid disintegration tablet in the oral cavity is one or more selected from the group consisting of: Maltose, trehalose, sorbitol, and maltitol. 11. An intraorally rapidly disintegrating ingot comprising the composition of the sustained release fine particles described in the above item 10. 12. In the oral rapid disintegration in item 1 above, the coefficient of variation (CV%) of the drug content as an indicator of the uniformity of the contents is 3.5% or less. A method for producing a composition containing sustained-release fine particles for use in a rapidly disintegrating ingot in an oral cavity, which comprises a sustained release fine particle containing a drug and one or more selected from the group consisting of the following Agents: saccharides and sugar alcohols, granulated products made by using a binder for rapidly disintegrating ingots in the oral cavity, and in the proportion of ungranulated slow-release fine particles in the overall composition of 0 to 15%. 14. The method for producing a sustained release fine granule composition for use in an orally rapidly disintegrating ingot in the above item 13, wherein the adhesive for the intra-oral rapid disintegration tablet is one or more selected from the group consisting of Middle: high molding sugars, water soluble polymer materials, and low melting sugars. 15. The method for producing a sustained-release fine particle-containing composition for use in an orally rapidly disintegrating ingot in the above item 14, wherein the saccharide and the sugar alcohol are one or more selected from the group consisting of: low Molded sugars, high melting point sugars and low melting point sugars. 16. The method for producing a composition comprising a slow-12(7)1281868 release fine particle for use in a rapid disintegrating ingot for oral cavity, wherein the sustained release fine particle, the sputum filling agent, and the oral cavity are fast The mixing ratio of the binder for disintegrating ingots is 1 to 50%, 20 to 98%, and 1 to 30%, respectively. 17. The method of claim 7, wherein the rapidly disintegrating fine particles have an average particle diameter of from about 0.1 micron to about 3 50 micrometers. 18. The method of claim 7, wherein the sustained release fine particles comprise at least crystalline cellulose particles, a drug, and a polymeric substance. 19. The method of claim 18, wherein the drug is tamsulosin hydrochloride for use in the manufacture of a sustained release fine granule for use in an orally rapidly disintegrating ingot. 20. The method for producing a composition comprising a slow release fine granule for use in a rapidly disintegrating ingot in an oral cavity according to the above item 19, wherein the sustained release fine granule is enteric sustained release fine. 2 1. The method for producing a composition containing sustained-release fine particles for rapid disintegration in an oral cavity, wherein the polymer substance is hydroxypropylmethylcellulose, ethylcellulose, Eudragit L30D55' And Eudragit NE30D 〇 22. The method for producing a composition containing sustained-release fine particles for rapid disintegration in the oral cavity in the above item 21, wherein the adhesive for the rapid disintegration ingot in the oral cavity is one or more selected from the group consisting of Among the following groups are: maltose 'trehalose, sorbitol, and maltitol. 23. A method of producing a rapidly disintegrating ingot in an oral cavity, the in-oral rapidly disintegrating ingot comprising a group of sustained release fine particles prepared by the method described in the above item 22, 13 - (8) !281868 consist of. 24. The above 23 items in the rapid disintegration in the oral cavity are used as the content uniformity index of the drug content coefficient of variation of 3 · 5 % or lower. The binder of the "adhesive for rapid disintegration of ingots of the present invention" is particularly useful for the preparation of rapidly disintegrating ingots in the oral cavity. It can be selected in various ways for the "squeezing agent" of the present invention. The description is included, including its specific examples. In the present invention, "ungranulated slow-release fine granules" means slow-release fine granules in which a binder for a fast disintegrating tablet is used to form a granulated product together with a chelating agent. In addition, "ungranulated and sustained-release, 1 system was calculated by the following method using the following formula, and the particle size distribution and the particle size including the sustained-release fine particle composition were calculated by the following method: Ungranulated slow-release fine Ratio of grains (%) +

Here, the estimate of Σ is calculated from i=i (Gw-(P〃G is obtained from the previous point. Ρ:: the ratio of the sustained-release fine particles on the minimum pore size sieve in the distribution) Except in the case of 0%) ° p2 : the ratio of the slow release of fine particles in the second smallest pore in the slow release fine particle size distribution (except for the case where 0% is). Hole, fourth, etc. P3, p4, etc., and the method of the same, (CV%) refers to the commonly used binder, the details will be in the lower oral cavity when granulation is not granulated in the proportion of sustained-release fine particles The ratio is equal to 値i - G i)) i)) 値 负 之 之 细 细 细 细 细 细 细 细 细 细 细 细 细 细 细 细 细 细 细 细 细 细 Pi Pi Pi Pi Pi Pi Pi

Gi : The ratio of the particle size distribution of the composition on the same pore size sieve as P! G2: the ratio of the particle size distribution of the composition on the same pore size sieve as P2; the third, fourth, etc., and so on, are G3, g4, etc., and all of them are represented by G. " adjusting the proportion of ungranulated slow-release fine particles in the total composition to 15% or less, in other words, in the present invention, that is, the proportion of unreleased fine-release fine particles is low, that is, Most of the sustained release fines are included in each granulated product. In addition, it also means that the controlled release of the sustained release fine particles and the chelating agent is controlled. The "granulated product" in the present invention means that the sustained release fine granules, the chelating agent and the adhesive for the rapid disintegration in the oral cavity are composed of the adhesive. The granulated product, and the granulated product which does not include the sustained-release fine granule is specifically defined as "a granulated product which does not include the sustained-release fine granules. That is, the specific composition form of the present invention includes the "granulated product", "Ungranulated slow-release fine granules", and "excluding granulated products of sustained-release fine granules".

Furthermore, the intra-oral rapid disintegration tablet of the present invention refers to an ingot having a disintegration time of 0 to 2 minutes in the oral cavity, preferably 0 to 1 minute, and may be disclosed in the early international album WO 98/02 1 85, International Early Disclosure Booklet W〇9 5 /203 80, Japanese Patent Publication Hei 1 0- 1 82436, U.S. Patent Application No. 1 0/1 42,08 1 (corresponding to International Patent Application PCT/JP 02/0448 1), etc. disclosed. Furthermore, "the dissolution promotion of the sustained-release fine particles is inhibited" and "the realization of the controlled dissolution as the target of the sustained-release fine particles" means that in the present invention, the dissolution rate of the sustained-release fine particles is in the oral cavity. There is no difference between the dissolution rates of fast disintegrating ingots -15-(10) 1281868. Specifically, in the dissolution test of the sustained release fine granules and the dissolution test of the rapidly disintegrating ingot in the oral cavity including the sustained release fine granules, and in comparison with the dissolution of the drug of the sustained release fine granules, the dissolution rate of the sustained release fine granules is The difference between the dissolution rates of the rapidly disintegrating ingots in the oral cavity is 0 to 1 at each dissolution point of the drug dissolution rate of the sustained release fine particles of about 30%, about 50%, and about 80%. 5 %. If the sustained release fine particles are enteric sustained release fine particles, the above evaluation cannot be carried out under the condition that p Η is 1.2, and the dissolution rate of the enteric sustained release fine particles and the oral cavity are two hours after the start of the dissolution test. The difference between the dissolution rates of the rapidly disintegrating ingots is from 0 to 10%. Further, "good reproducibility" means that even if the rapid disintegration of the ingot in the oral cavity is at a different time, the dissolution of the rapidly disintegrating ingot in the oral cavity and the dissolution of the sustained-release fine particles constituting the ingot are compared as described above. In the case of the difference, the same result is obtained. In addition, the "drug content coefficient of variation (CV%)" is an index of content uniformity in the present invention. The content uniformity test described below is carried out and calculated by the following formula [CV] %]: CV% = (standard deviation of each content) / (average content) χ 100 " C to 3.5% of CV%" can be regarded as no segregation, the obtained tablets have little fluctuations in the drug content Uncertain, and can be called "the drug content uniformity is ensured". Furthermore, "more than 3.5% of CV%" can be regarded as a sharp fluctuation in the drug content, and can be said to be "poor uniformity". By the way, π 0 to 3. 5 % CV % " is the appropriate range of the coefficient of variation of the invention -16 (1) 1281868, which is clearly required for quality assurance and indicates a composition with a fixed drug content. The present invention contains a composition containing sustained-release fine particles and a method for producing the same. The drug to be used in the present invention is not particularly limited as long as it can be used as an active ingredient requiring sustained release, that is, it is therapeutically effective or its prevention. Examples of such drugs are hypnotic sedatives, sleep inducers, anxiolytics, anti-epileptics, antidepressants, anti-Parkinson's drugs, psychotropic drugs, central nervous system drugs, local Anesthetics, skeletal muscle relaxants, autonomic drugs, antipyretic and analgesics, anti-inflammatory drugs, anticonvulsants, anti-stun drugs, cardiotonic drugs, arrhythmic drugs, diuretics, hypotensive drugs, vasoconstrictors, vasodilators Circulatory system medication, hyperlipidemia medication, promotion of respiratory medicine, cough medicine, expectorant, cough expectorant, tracheal dilator, anti-dysentery medicine, control of intestinal function medication, gastric ulcer medicine, appetizer, antacid medicine, light Laxatives, choleretic drugs, gastrointestinal drugs, adrenocortical hormones, hormones 'urogenital drugs, vitamins' hemostatic drugs, liver disease drugs, gout drugs, diabetes drugs, antihistamines, antibiotics, antibacterial agents, anti-neoplastic tumor agents , chemotherapeutic drugs, multi-dose cold drugs, nutritional fortification drugs, osteoporosis drugs, etc. Examples of such drugs are anti-inflammatory drugs, antipyretics, anti-caries agents or analgesics, such as indomethacin 3 female diacetate (diclofenac) 'dichloroaniline phenylacetate, codeine, ibuprofen (lbuprofen), phenylbutazone, oxyfenbutazone, painkiller (mepirizole), aspirin, -17- (12) 1281868 idensamide, acetaminophen, aminopyrine, phenacetin, brominated Butyl scopolamine bromide, oral horse, etomidoline, pentazocine, fenoprofen calcium, naproxen, celecoxib, Vardecoxib, tramadole, etc; anti-rheumatic drugs, such as etodolac; anti-tuberculosis drugs, such as isoniazid (isoniazide), ethambutol chloride, etc.; circulatory system drugs, for example, isosorbid nitrate, Nitroglycerin, nitrate ratio! Nifedipine, bardnipidine hydrochloride, nicardipine hydrochloride, dipyridamile, amrinone, indenolol hydrochloride, hydralazine hydrochloride, methyldopa, furosemide Furosemide), spironolactone, guanetidine nitrate, resperine, amosulalol hydrochloride, lisinoopril, metoprolol, pilocarbpine, tasosartan, etc.; physiological neuropharmaceuticals such as chlorpromazine hydrochloride Chlorpromazine hydrochloride ), amitriptyline hydrochloride, nemonapride, haloperidole, moperone hy droc hlori de, perphenazine, diazepam, lorazepam , chlordiazepoxide, adinazolam, alprazolam, methylphenidate-18- (13) 1281868 (methylphenidate), milnasivram, peroxetin, risperidone, sodium valproate ( Sodium valproate), etc. Spitting drugs such as methopolproamide, ramose tron hydrochloride, granisetron hydrochloride, ondansetron hydrochloride, azasetron hydrochloride, etc.; antihistamines, such as chlorpheniramine maleate, diphenhydramine hydrochloride , etc.; vitamins, such as thiamine nitrate, tocopherol hydrochloride, sicotiamine, pyridoxine phosphate, cobamamide, ascorbic acid, scutellarin, etc.; anti-gout drugs, for example, dokhordol, autumn Narcissus, pr 〇benamide, etc.; anti-Parkinson's disease drugs such as levodopa, selegiline, etc.; hypnotic sedatives such as amobabital, bromwarelyl urea, middawan (midazolam), chloral hydrate, etc.; anti-neoplastic drugs, such as fluorourethane, B. carmofur, aclarubicin hydrochloride, cyclophosphamide, thiotepa, Anti-allergic drugs, such as pseudoephedrine, terfenadine, etc.; antidepressants, Such as phenylpropanolamine, ephedrine, etc.; drugs for the treatment of diabetes, such as acethexamide, insulin, torbutamide, desmopressine, glibizide, etc.; diuretics, such as hydrochlorothiazide, polythiazide, triaterene, Etc.; tracheal dilators, such as aminophylline, formoterol fumarate, tea, etc.; cough medicines, such as codeine phosphate, noscapine, no.甲特喃-19- (14) 1281868 (dimemorphan phosphate ) 'dextromethorphan, etc.; antiarrhythmic drugs, such as quinidine nitrate, digitosiη, propafenone hydrochloride (propafenone hydrochloride), procainamide, etc.; surface anesthetics such as aminoethyl benzoate, lidocaine, dibucaine hy drochloride, etc.; antiepileptic drugs , for example, phenytoin, etoduccimide, primidone, etc.; synthesis of corticosteroids, such as hydrogen Hydrocortisone 'prednisolone, triamcinolone, betamethasone, etc.; digestive tract medications, such as famotidine, ranitidine hydrochloride ( Ranitidine hydrochloride ) , dimethisone , sucralfate , sulpiride , tepronone , praunotol , 5-aminosalic acid , sulfasalazine , LOS ( omeprazole ) , lannoprazole , etc.; central nervous system medications, such as indeloxazine, idebenone, thiapride hydrochloride, bifermerane hy drochloride, calcium pantothenate, etc.; treatment of hyperlipidemia, such as pravastatin sodium (pravastatin sodium), new Sinvastatin, lovastatin, prevastatin, josamycin, etc.; antibiotics such as ampicillin phthalizy 1 hydrochloride, cefotetan, josamycin, etc. BPH therapeutics, such as tamsulosin -20-(15) 1281868 hydrochloride , dox Azocin mesilate, terazosine hydrochloride, etc; anti-swollen drugs, such as pranrucast, accorde (zafirlukast), albuterol (albuterol), ambrozole, budesonide, leverbuterol, etc.; Prostaglandin I-derived agents, such as ve丨aprost s 〇dium, etc.; antithrombotic drugs, hypotensive drugs, drugs for treating heart failure, drugs for treating various diabetes mellitus, drugs for treating gastric ulcers, drugs for treating skin ulcers, Medicine for treating hyperlipidemia (previously), anti-swollen medicine (previously), etc. These drugs may be used in their free form or in the form of any pharmaceutically acceptable salt. Further, the present invention may include a drug that does not require sustained release. In addition, a combination of two or more drugs can be used. There is no particular limitation on the amount of the drug, as long as it is usually effective for the treatment, but it is preferably 50 w/w% or more, preferably 20 w/w%, based on the weight of the ingot. The lower one. For example, when it exceeds 50 w / w % in terms of the weight of the ingot, the ratio of the fine particles to the sputum is high and the granulation by the sputum may be insufficient. These drugs are all sustained-released and contained in a fine-grained form in the sustained-release fine particles. Under this form, the release of the drug can be controlled according to the following conventional methods. The particle size of the sustained-release fine particles is not particularly limited as long as it is within a range in which no rough feeling is felt in the oral cavity. Preferably, the average particle size is from about 0. 1 micron to about 3,500 microns, more preferably from about 5 microns to about 250 microns, and even more preferably from about 50 microns to about 250 microns. If it is less than 0.1 μm, it is difficult to provide sustained release using the current pharmaceutical technology, and if it is larger than 3 50 μm, it will cause a very violent feeling in the mouth - 21 - (16) 1281868, for example, a rough feeling. Further, the sustained-release fine particles of the present invention can be produced by a conventional method. For example, it can be used in medicines and microcrystalline fibers as disclosed in US Patent Application No. 4,772,475 (corresponding to U.S. Patent Application No. 4,772,475) and International Publication No. 4/772,379. After adding the polymer, the slow release fine particles are prepared by agitating granulation method or a bubbling bed granulation method, or may be applied by a conventional coating method such as fluidized bed coating or drum fluidized coating. Commercially available microcrystalline cellulose particles (avicel particles, Asahi kasei, product name Celphere 1 Ο 2 ', etc.) are coated with a drug and then coated with a polymer material to form a controlled release film to form a sustained release fine particle (Α ν ice 1 Π h ο, Ν 〇. 4 Ο, ρ. 1 6 - 3 3, Asahi Kasei Corp.). In addition, it is also possible to use a crystalline ceramide of about 1 micrometer to about 15 micrometers, in particular crystalline lactose, sugar granules, salt, corn starch, cerium oxide (silicone), etc., wherein the size of the sustained-release fine granules is considered. (about 0·1 to about 3 50 microns). Under the precoating with a water-soluble polymer material, a water-insoluble polymer material may also be used, and in this case, the edge of the ruthenium which becomes a core is rounded. Further, a solution or suspension of the drug and the polymer substance may be spray-dried using a suitable apparatus such as a spray dryer to prepare a sustained release fine particle. Examples of the solvent used for preparing these sustained-release fine particles are water, an organic solvent, and the like. Examples of organic solvents are alcohols, especially methanol, ethanol, propanol, isopropanol, etc., halogenated alkanes, especially dichloromethane, chloroform, ethyl chloride, trichloroethane, carbon tetrachloride, etc. , ketones, especially acetone, methyl ethyl ketone, etc., nitriles, especially acetonitrile, etc., and hydrocarbons, especially n-hexane, cyclohexane, and the like. Mixtures of these organic solvents may be used singly or in two or more appropriate ratios, and the same -22-(17) 1281868 may be used in combination with water in an appropriate ratio. The polymer material used for preparing the sustained release fine particles can be selected according to the purpose of use. Examples thereof are water-insoluble polymers, gastric-soluble polymers, enteric polymers, enamel substances, and the like. Examples of water-insoluble polymers are water-insoluble cellulose ethers such as ethyl cellulose, Aqua coat (trade name, Asahi Kasei), etc., water-insoluble acrylic copolymers such as ethyl acrylate-methyl methacrylate-methyl Acrylic acid methylammonium ethyl ester copolymer (for example, trade name Eudragit RS, ROhm), methyl methacrylate-ethyl acrylate copolymer dispersion (for example, trade name: Eudragit NE3 0D, R0hmg, etc., And similar examples of gastric-soluble polymers are gastric-soluble polyvinyl derivatives such as polyvinyl acetal diethylaminoacetate, etc., gastric-soluble c-acid storage copolymers such as methyl methacrylate - Butyl methacrylate-dimethylaminoethyl methacrylate (e.g., trade name Eudragit E, ROhm), and the like. Examples of enteric polymers are enteric cellulose polymers such as hydroxypropyl. Methyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, hydroxymethyl ethyl cellulose phthalate, carboxymethyl ethyl cellulose, etc., enteric acrylic copolymer , such as methacryl An acid methyl methacrylate copolymer (for example, trade name: Eudragit L100, Eudragit S', both from ROhm), methacrylic acid-ethyl acrylate copolymer (for example, trade name: Eudragit L 1 00-5 5 , Eudragit L30D55, R0hm), et al., and the like. Examples of waxy substances are solid oils and fats, such as hydrogenated sesame oil, hydrogenated coconut oil, tallow, etc., high carbon fatty acids such as stearic acid, lauric acid, Myristic acid, palmitic acid, etc., and high carbonic acid alcohols, such as cetyl alcohol, stearyl alcohol, -23 (18) 1281868, etc. Among them, methacrylic acid-ethyl acrylate copolymer is suitable for providing enteric solubility. pH-independent water-insoluble polymers, particularly ethyl cellulose, are more suitable for providing sustained release, whereby the drug is gradually released. One or two or more of these may be used for the purpose of controlling dissolution. A suitable combination of polymer materials. Further, a plasticizer may be added as needed. Examples of such plasticizers are triacetin, triethyl citrate, dibutyl sebacate, and ethyl sulfonate. Glycerate-acrylate, acrylic acid B An ester-methyl methacrylate copolymer dispersion (for example, trade name: Eudragit NE30D, R0hm), etc., and preferably a dispersion of ethyl acrylate or methyl methacrylate copolymer. Further, water can be dissolved. A polymer, a saccharide, or the like is mixed with the above polymer substance such as a water-insoluble polymer, a stomach-soluble polymer, an enteric polymer, or the like, or a scorpion-like substance, etc. Examples of such substances are hydroxypropylcellulose, Examples of the hydroxypropylmethylcellulose, polyvinylpyrrolidone, and polyvinyl alcohol are water-soluble polymer materials. Examples of the saccharide are maltose, maltitol, and the like, and examples of the salt are sodium chloride, and the like. The amount of polymer and saccharide used herein can be adjusted as needed to control the rate of dissolution of the drug. Further, a single or a combination of two or more of these polymers and a saccharide may be used. Incidentally, the water-soluble polymer substances, saccharides, and salts used herein are added to easily control the dissolution of the drug from the sustained-release fine particles, and they should be distinguished from those used for the preparation of the composition of the present invention. . The "塡剂" used in the present invention is not particularly limited as long as it is a pharmaceutically acceptable sugar or sugar alcohol. An example of a sugar or sugar alcohol is the low-molecule saccharide disclosed in the International Early Publications booklet WO 95/203 80. Specific examples of -24-(19) 1281868 are xylitol, erythritol, glucose, mannitol, sucrose, and lactose. Preferred among them are mannitol, lactose and erythritol. Further, a single one of these sugars or a combination of two or more thereof may be used. Here, "low-molecule sugar" means, for example, that when 150 mg of sugar is ingots at an ingot pressure of 10 to 50 kg/cm 2 using an 8 mm diameter punch, it shows less than 2 kp Ingot hardness (see WO 95 /2 0 3 S0 (corresponding to U.S. Patent No. 5,576,0 1 4, Japanese Patent No. 3 1 22 1 4 1). Further, it may also be selected from high melting point sugars and low Melting point saccharide (U.S. Patent Application Serial No. 1/0/142,081 (corresponding to International Patent Application No. PCT/JP02/0448 1). The low melting point saccharide used in the present invention is not particularly limited as long as it is in U.S. Patent Application No. 10 / 1 42,08 1 (corresponding to the pharmaceutically acceptable and low melting point sugars listed in International Patent Application PCT/JP0 2/0448 1 ), and having a higher ratio than the drug and the high melting point sugar used in the present invention a low melting point, but preferably a sugar having a melting point of from about 80 to about 180 ° C and more preferably a sugar having a melting point of from about 90 to 150 t. An example of such a sugar is glucose (single hydrate) , melting point 83 ° C), xylitol (melting point 93 ° C), trehalose (dihydrate, melting point 9 7 ° C), Yamanashi Alcohol (melting point 1 10 ° C), erythritol (melting point 122 ° C), glucose (166 V), sucrose (melting point about 170 ° C), etc. One of the groups selected from the group can be used. Or two or more sugars. Among these sugars, one or two or more polysaccharides selected from the group consisting of glucose, xylitol, trehalose, sorbitol, maltose, erythrose Alcohol, maltitol, and their hydrates. Ideally trehalose, maltose, erythritol, or mannose-25 (20) 1281868 sugar alcohols, especially trehalose and/or erythritol, because of this If the sugar itself is only slightly hygroscopic and thus easy to handle, a single one of these sugars or a combination of two or more of them may be used. These sugars may also be used in the form of their hydrates as a hydrate of sugar. And the anhydrates each having a different melting point, the heating temperature must be selected as needed. The "high melting point sugar" used in the present invention is in U.S. Patent Application No. 10/142,081 (corresponding to the patent application) High melting point sugars listed in PCT/JP02/0448 1) which have the melting point and the low melting point used in the present invention The difference in melting point is 10 t: or higher, preferably, the difference in melting point is 20 ° C or more. Consider the difference between the temperature set by the heating device and the temperature of the ingot as the heating object. In the preferred case, it is preferred to select a sugar having a large difference between their melting points. In particular, xylitol (melting point 9 3 ° C), trehalose (dihydrate, Melting point 9 7 ° C), sorbitol (hydrate, melting point slightly below 100 ° C), maltose (melting point 10 2 ° C), sorbitol (melting point 1 10 ° C), erythritol (melting point 12 2 ° C), glucose (melting point 14 6 ° C), maltitol (melting point 150 ° C), mannitol (melting point 166 ° C), sucrose (melting point about 170 ° C), lactose (melting point 202 ° C ),Wait. One or two or more kinds of sugars selected from the group consisting of such or the like can be used. The explanation of the high melting point sugar actually overlaps with the low melting point sugar, but because of the "high melting point sugar, the 1 line is selected in relation to its low melting point sugar, so the same sugar is not selected. The present invention" is high. Melting point sugars '' and 'low melting point sugars' are selected as needed to take into account the chemical nature of the drug used, ie the stability of the drug relative to temperature. The specific terms are used to describe "high melting point sugar" and "low melting point" When the sugar is between -26-(21) 1281868, when glucose (monohydrate, melting point 8 3 ° C) is used in the present invention as "low melting point sugar", xylitol, seaweed Sugar, sorbitol, erythritol, glucose, maltitol, mannitol, sucrose, lactose, and the like can be used as "high melting point sugars". Further, in the present invention, xylitol (melting point 93 ° C) or trehalose (dihydrate, 97 ° C) is used as the M low melting point sugar "under the sorbitol, erythritol, glucose, maltitol" The hydrates of mannitol, sucrose, lactose, and the like can be used as "high melting point glycosides. In the present invention, erythritol (melting point 1 22 ° C) is used as "low melting point sugar" Glucose, maltitol, mannitol, sucrose or lactose can be used as the "local melting point sugar M. In addition, in the present invention, mannitol (melting point 150 ° C) is used as the "low melting point sugar" You can use mannitol, sucrose or lactose as "high melting point sugar". Further, in the present invention, when sugar (melting point: about 170 ° C) is used as the "low melting point sugar", lactose can be used as the "high melting point sugar". As described, "high melting point sugar" is selected as needed according to the type of sugar used in the present invention. In selecting sugars such that there is a large difference between their melting points, "high melting point sugar" preferably has one or two or more sugars selected from the group consisting of glucose, maltitol, mannitol. , sucrose and lactose, and more preferably mannitol, sucrose and lactose. These are used as needed in a single amount or in a mixture of two or more. The high-molecule sugars listed in the International Early Publications Booklet WO 95/203 80 are selected in the U.S. Patent Application Serial No. 10/1 4 2,0 8 1 (corresponding to International Patent Application PCT/JP 02/0448 1). The column of low-melting sugar, or a water-soluble polymer substance, is used in the present invention for "adhesive fast disintegrating ingots for bonding -27-(22) 1281868". For example, maltose (preferably maltose syrup (maltose content 83% or higher)), trehalose, sorbitol, or maltitol "high-molecule sugar" and preferably maltose and trehalose . Here, "high-molecule sugar" means that when using an 8 mm diameter puncher, 150 mg of sugar is ingots at a pressure of 10 to 50 kg/cm 2 of ingot, showing 2 kp or more. The hardness of the ingot (see WO 95 /2 〇 3 SO (corresponding to U.S. Patent No. 5,576,014, Japanese Patent No. 3122141). The above low melting point sugar is the low melting point sugar here. Further, hydroxypropyl cellulose, Hydroxypropyl methylcellulose, polyvinylpyrrolidone, copoly vidone, polyvinyl alcohol, etc., are water-soluble polymer materials. A single type or a combination of two or more types may be used. Adhesive for rapid disintegration of ingots in the mouth. Under the environment of storage in the form of starting materials and pharmaceutical preparations, preferably hydroxypropyl cellulose with low hygroscopicity, hydroxypropyl group a cellulose, or a copolymerized vinylpyrrolidone, and is preferably a copolymerized vinylpyrrolidone. Further, the "adhesive for rapid disintegration ingot in the oral cavity" of the present invention may be one or two or more selected from the group consisting of the following Among them: "High molding sugar "," water-soluble polymer substance", and "low-melting sugar" I: "塡": high-melting sugar, "adhesive for rapid disintegration of ingots in the mouth": high-molecule saccharides, Or water-soluble polymer substance, II: "squeezing agent": high-melting sugar, "adhesive for rapid disintegration in the mouth": low-melting sugar, III: "filling agent": high-melting sugar, "oral "Binder for rapid disintegration ingots": low-melting sugar and water-soluble polymer substances, with - 28- (23) 1281868 IV: "塡": high-melting sugar and low-melting sugar," rapid collapse in the mouth "Binder for disintegration" ····························································································· Example. For a demonstration of IV, it is preferred to select erythrose as a "low-melting sugar", lactose and/or mannitol as "still melting sugar" and mannitol as a rapid disintegration in the cavity. Adhesive for ingots ("highly molded sugars,"), or red As a "low-melting sugar", lactose and/or mannitol are selected as "high-melting sugar", and copolymerized vinylpyrrolidone is also used as a binder for intracavitary rapid disintegration ingots ("water-soluble polymer"). In the present invention, the amount of the M-filler is adjusted as needed according to the dose of the drug and/or the size of the ingot. When the dose of the drug is small, by increasing the amount of the present invention, and when the dose is large, The dosage of the present invention is reduced, and the amount is adjusted as needed to obtain a tablet having a desired size. Usually, it is preferably used in an amount of 20 to 1, 〇〇〇 mg per ingot, preferably. 50 to 500 mg, even better, 1 to 400 mg. If the amount of the stimulating agent is less than 20 mg, the possibility of complete granulation may not be completed. Further, when the amount of the sputum filling is more than 1,000 mg, the content of the sputum is too large relative to the amount of saliva in the oral cavity, and this causes a strange feeling in the mouth.

In the present invention, the amount of the "adhesive for rapid disintegration in the mouth" is usually preferably from 0.5 to 50 w/w%, more preferably from 1 to 30 w, based on the weight of the "charge" of the present invention. /w%, even better, 1 to 20 w/w%. If it is less than 〇· 5 w / w % relative to M -29 - (24) 1281868, it will be used as a binder. The function cannot be fully realized. In addition, if it is the size, 50 w/w% of the weight of the 〃 , , , , , , , , , , , , , , 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 且 且 且 且 且 且Good properties cannot be obtained when disintegrating. Although the mixing ratio of 'slow release fine granules', '塡 剂 & 、, and,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 'But when giving examples, their blend ratio is preferably 50% '20 to 98%, and 1 to 30%, more preferably 1 to 20%, 60 to 98%, and 1 To 20%. In addition to the "admixtures, and, and adhesives for rapid disintegration of ingots in the oral cavity" used in the present invention, various additives which are pharmaceutically acceptable and used as additives may be added. These additives may be mixed with the chelating agent at the time of granulating the sustained-release fine granules, or they may be used in the form of a mixture and the composition of the present invention at the time of tableting. Examples of such additives are disintegrants, sour flavoring agents, foaming agents, artificial sweeteners, perfumes, lubricants, colorants, stabilizers, and the like. One of these additives or a combination of two or more thereof may be used. Further, the amount of addition is not particularly limited as long as it is a pharmaceutically acceptable amount for those skilled in the art and it is within the range not detracting from the results of the present invention. Examples of disintegrants are starches such as corn starch, etc., calcium carboxymethylcellulose, partially alpha-converted starch, crosslinked polyvinylpyrrolidone (cr〇SpQV1don), low-substituted hydroxypropylcellulose. ,Wait. Examples of sour flavoring agents are citric acid, tartaric acid, malic acid, and the like. Examples of the blowing agent are calcium hydrogencarbonate, and the like. Examples of artificial sweeteners are sodium saccharin, dipotassium glycyrrhizinate, aspartame, stevia, • 3 (7-(25) 1281868 sormatin, etc. Examples of spices are lemon, lemon - Lyme, orange, menthol, etc. Examples of the lubricant are magnesium stearate, calcium stearate, sucrose fatty acid ester, polyethylene glycol, talc, stearic acid, etc. Examples of coloring agents are foods. Coloring materials, such as yellow food dye No. 5, red food dye No. 2, blue food dye No. 2, etc.; food precipitation coloring material; iron oxide red, etc. The stabilizer is selected according to the drug after various tests are carried out. Such additives of one kind or a combination of two or more thereof may be added in an appropriate amount as needed. Heretofore, the procedure for producing the composition containing the sustained-release fine particles of the present invention, particularly the production conditions, and the like, will be described in detail. Heretofore, the preparation method of the sustained-release fine particle-containing composition for the rapid disintegration tablet in the oral cavity of the present invention will be described as follows: (a) The amount of the drug which can be effectively treated or prevented can be controlled and the sustained release rate of the drug can be controlled. Fine particle manufacturing process' (b) Procedures for granulating "bonding agents for rapid disintegration in the mouth""sustained-release fine-grain '' and π-filling agents. Procedure (a): Slow-release fine-grain manufacturing procedure as before Here, the sustained-release fine granules are produced by a conventional method. There is no particular limitation on this method and it may be optionally used as long as it is a target usable for controlling dissolution. For example, a binder such as hydroxypropyl group is used. Cellulose or the like coats the drug layer on commercially available crystalline cellulose particles, crystallized lactose, sugar granules, salt, cerium oxide, etc., and then coated with a polymer substance such as a water-insoluble polymer substance, gastric solubility a polymer substance, an enteric polymer substance, a scorpion substance, or the like to prepare a sustained release fine granule. It is also possible to use -31 - (26) 1281868 a polymer substance such as a water-insoluble polymer substance, a stomach-soluble polymer substance, The enteric polymer material, the waxy substance, and the like are laminated on the commercially available crystalline cellulose particles, crystalline lactose, sugar granules, salt, silica sand, etc., together with the drug to produce a sustained release fine granule. Object After the solution is added to the drug and the microcrystalline cellulose, the sustained release fine granules are produced by agitation granulation method or a drum fluidized granulation method. The above-mentioned coating can be further carried out on the sustained release fine granules and can be applied via coating as needed. The enteric polymer materials give them an enteric function. For example, a fluidized bed granulator can be used for coating. Temperature, and other, spray volume, spray air volume, etc. are set so that water can be used. In the case of coating, the product temperature is about 40. (: to about 60 ° C and about 30 ° C to about 60 ° C when using an organic solvent. The concentration of the drug used in coating, the polymer The percentage and amount of the substance, etc. can be adjusted as needed according to the desired dissolution rate. Procedure (b): Granulation procedure The granulation method of the present invention is not particularly limited as long as it can be used by using "塡剂" and The fast disintegrating ingot can be made into a sustained release fine particle by using a binder. For example, fluidized bed granulation, agitation granulation, tumbling granulation, or the like can be selected as the granulation method. Among them, the fluidized bed granulation method is preferable in terms of productivity. The solution of the "in-oral rapid disintegration ingot adhesive" used in the present invention dissolved and/or suspended in a pharmaceutically acceptable solvent can be sprayed onto the mixture of the sustained release fine particles and the "squeezing agent". The method of forming the particles and the composition of the composition can be selected as the fluidized bed granulation method. At this time, the sustained release fine particles should be covered with a "塡剂". The manufacturing condition is preferably, for example, , about 25 -32- (27) 1281868 ° C to about 40 ° C product temperature and about 0.2 to about 5% water content. In addition, preferably by intermittent spraying granulation. "Distributing cloth" means a method of spraying and interrupting, and is a spraying method for granulation, which includes repeating, for example, a cycle of spraying for 10 seconds and then drying for 30 seconds. Further, the cycle can be set as needed for manufacturing. In addition, the spraying time-drying time can be appropriately selected. It can also be granulated after adding the above additives as needed. π塡filling agent " can be used as a commercial product. In "塡剂" When the average particle diameter is larger than the average particle diameter of the sustained-release fine particles, it is preferable to use the "塡剂&qu Ot; pulverized with a suitable pulverizing device, such as a hammer mill, a sample mill, a nail grinder, etc. to help granulate with the sustained-release fine granules. Preferably, the acne is rapidly disintegrated in the oral cavity. When the agent π is a high mold-forming sugar, it is dissolved in water to form a solution. The liquid concentration should be, for example, 10 to 40 w/w%, more preferably 20 to 3 Ow/w% for rapid disintegration in the oral cavity. The adhesive strength of the ingot is maximized. If the liquid concentration is less than 1 〇 w / w %, the liquid volume will be too large and the program will take more time, and if the liquid concentration is higher than 40 w/w%, The procedure will be completed in a relatively short period of time and thus it is difficult to maintain the spray time and drying time cycle. Further, the composition containing the sustained release fine particles of the present invention can be used in the rapid disintegration of the ingot in the oral cavity' and the method includes (c : a procedure for granulating the composition obtained in the procedure (b) to produce a lake and (d): a procedure for humidifying and drying the ingot obtained in the procedure (c) as needed. Also, when the above high melting point sugar is selected When using a low-melting sugar to make a composition, the program (d') can be used: Program (c) Ingot heating, and program (e): Method of cooling after program (d). Program (d) can also be implemented after programs (d,) and -33- (28) 1281868 (e). Procedure (c) : The granulation process •• ingot making is carried out by conventional methods. There is no particular limitation on this, as long as it is a method for obtaining the shape of the ingot under the minimum pressure required to maintain the shape of the ingot. Such a "making ingot" can be used, for example, a general ingot making machine, such as a single ingot making machine or a rotary ingot making machine, etc., adding a desired additive to the above "composition" from a lubricant such as stearic acid. Magnesium is started and then implemented. Furthermore, the above-mentioned "compositions can be made into ingots" using an externally lubricated ingot forming machine. Usually, the ingot pressure of about 25 to about 800 kg/punching is preferred, preferably. From about 50 to about 500 kg / L, the best is about 50 to about 300 kg / L. Procedure (d): Wetting and drying procedures in the granulation process as "intraoral rapid disintegration ingots When the sugar used in the binder is amorphous and the strength of the ingot obtained by the ingot forming process is reduced due to moisture absorption, that is, the "binder for rapidly disintegrating ingot in the oral cavity" used in the present invention is high in moldability. When sugar is used and maltose, sorbitol, or trehalose is used, the following humidification and drying procedures are preferably used. "Humidification" is carried out in accordance with a drying procedure, and "drying" is followed by humidification. Programs after the program. There are no special restrictions on their methods, as long as they are The present invention, "rapidly disintegrating binder ingots used orally ,, never sugar crystallization method may be of amorphous substance. The condition of this "wetting" is determined by the inclusion of a drug-containing sustained-release fine particle, the "adhesive for rapid disintegration in the oral cavity" used in the present invention, -34 (29) 1281868 and a mixture of "anthraquinone". Apparent critical relative humidity. Wetting is typically carried out to at least the critical relative humidity of the mixture. For example, the humidity is preferably from about 30 to about 1 〇〇rh% and more preferably from about 50 to about 90 RH%. The temperature at which the temperature is preferably from about 15 to about 50 ° C and more preferably from about 20 to about 4 ° C ° with respect to the wetting time, preferably from 1 to 48 hours and more preferably 12 to 2 4 hours. There is no particular limitation on "drying" as long as it can eliminate the moisture absorbed by the humidification. Related, drying, and conditions, preferably from about 1 〇 to about 10 0 °C, more preferably from about 20 to about 60 ° C, and the most preferred is from about 25 to about 4 art. For drying time, preferably from 30 minutes to 10 hours and more preferably from 1 to 4 hours. Procedure (d '): Heating procedure The "heating" in the present invention is carried out by a conventional method, and is not particularly limited as long as it is a process (C) The obtained molded particles may be brought to a temperature at least the temperature of the melting point of the above "low melting point sugar". The "heating" procedure can be carried out by using, for example, air drying. The type of "low melting point sugar" is optionally used, and is not particularly limited as long as it is the melting point or higher of the "low melting point sugar" used in the present invention and the "high melting point sugar" has a melting point or The best is fine. When using the "low melting point sugar" used in the present invention, it is from about 80 to about 18 〇 ° C, preferably from about 90 to about 150 ° C. The time conditions are selected according to the type of sugar used, the desired strength of the ingot, the disintegration performance in the oral cavity, etc., but it is usually 0.5 to 120 minutes. 'I father's good 1 to 60 minutes' is better 2 30 minutes. -35- (30) 1281868 Procedure (e): Cooling procedure The "cooling" of the present invention is carried out by a conventional method, and is not particularly limited as long as it can solidify the melted low melting point sugar used in the present invention. The method can be. This "cooling" can be carried out, for example, by standing at room temperature or storing in a low temperature gas cylinder, such as a refrigerator.

Next, an example of a method for producing a composition containing sustained-release fine particles for use in an orally disintegrating tablet of the present invention will be given below: First, a fluidized bed is formed using a suitable binder (for example, hydroxypropylmethylcellulose). A granulator, etc., coats the drug on commercially available crystalline cellulose particles (e.g., Celphere 102). Then, if necessary, a mixture of a water-insoluble polymer material (for example, ethyl cellulose) and a water-soluble polymer (for example, hydroxypropylmethylcellulose) is coated with a fluidized bed granulator, or the like to obtain a desired one. Dissolved. These fine granules and sugars (for example, mannitol) are then intermittently granulated by using a fluidized bed granulator or the like as an adhesive for rapid disintegration in the oral cavity (for example, maltose) (for example, spraying for 10 seconds). Then, the cycle of drying for 30 seconds is carried out to obtain a composition containing sustained-release fine particles for rapid disintegration of the oral cavity of the present invention. An intra-oral rapid disintegrating tablet containing sustained-release fine particles may be added with a desired additive such as a suitable lubricant such as magnesium stearate through a composition containing a sustained-release fine particle for a rapidly disintegrating ingot in the oral cavity of the present invention. And prepared using an ingot making mechanism. [Embodiment] DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will be further illustrated by the following examples, but the description of the present invention is not limited by the examples. Method for evaluating a composition containing sustained-release fine particles [Determination of particle size distribution of a composition for slow-release fine particles and sustained-release fine particles] Particle size distribution using a sieve type particle size distribution guide (Seishin Enterprise Co., Led Robot Sifter) is measured on screens of 30, 42, 60, 80, 100, 150, 200 and 250 mesh. [Measurement of the ratio of the particle size of the composition containing the sustained-release fine particles] The amount of the composition remaining on each of the openings having the above-mentioned opening size and the amount of each partial particle were measured. The total amount was set to 100%, and the proportion of the residual amount per sieve was calculated and used as the proportion of the particle diameter. Further, by arranging the content ratio of the particle diameters in the order of the opening diameter of each sieve, a quantitative distribution of the particle diameters is obtained. Incidentally, any method can be used to determine the amount of the quantitation as long as the contained drug can be completely recovered from the composition, and the measurement is carried out in an assay suitable for each drug. [Ratio of ungranulated slow-release fine particles] The particle size distribution of the sustained-release fine particles and the particle size distribution of the composition containing the sustained-release fine particles were measured and calculated by the following formula: Ungranulated sustained-release Proportion of fine particles (%) + (P iG i)) Here, the estimate of Σ is calculated from ι = 1 to (Gi...(Pi-G ,)) 値 before the negative one. -37- (32) 1281868 P1 : The ratio of the sustained release fines on the minimum pore size sieve to the slow release fine particle size distribution (except for the case where the enthalpy is 0%). That is, 15.0% on the 150 mesh in the following examples. P2: the proportion of the sustained-release fine particles on the second minimum aperture ornament in the sustained-release fine particle size distribution (except in the case where 値% is )%). That is, '70.6% on the 100 mesh in the example below. Its third smallest hole 'fourth' and the like are also referred to as P3, P4, etc., and all of them are denoted by P. G!: The ratio of the particle size distribution of the composition on the same pore size sieve as Pi is 値. That is, in the following embodiment, 2 · 5 % on the 150 mesh. G2: the ratio of the particle size distribution of the composition on the same pore size sieve as p2, i.e., 14.3% on the 100 mesh in the following examples. The third and fourth, and so on, are G3, G4, etc., and all of them are represented by G. For example, if the measurement result is as follows: Slow release fine particle size distribution Example 1 The distribution of the particle size of the composition 3 0 On the mesh (%) 0 19.0 42 On the mesh (%) 0 22.4 60 mesh Upper (%) 0 23.5 80 mesh (%) 14.4 18.2 100 mesh (%) 70.6 14.3 150 mesh (%) 15.0 2.5 2 00 mesh (%) 0 0 200 mesh pass (%) 0 0 -38- (33) 1281868 Proportion of ungranulated slow-release fine particles (%) = Gi + I(G1 + i-(Pi-G〇) = Gi + (G2-(Pi-Gi)) + (G2-(P2- G2)) +......... =2.5+(14.3-(15-2.5))+(18.2-(70.6-14.3))+(23.5-(14.4-18.2)) =2.5+(+ 1.8) + (-38.1) If the 値 in the parentheses is negative, 'meaning that the sustained-release fine granules are solidified and the particle size is greater than at least one level. Therefore, 'no further evaluation is performed = 2.5 + ( + 1.8) = 4.3 Evaluation method of rapid disintegration ingot in the mouth [Hardness test] The measurement was carried out using a Schleunigei* ingot hardness tester (Schleuniger Co., Ltd.). The test was carried out with 5 ingots and showed an average barium. The hardness is expressed by the force required to pulverize the ingot (unit kp). The larger the number, the harder the ingot. [Crispability] The measurement was carried out using a friability tester (model PTFR-A, Pharma Test Co.). The friability was measured using a 6 gram ingot, which is the weight of the ingot after being inverted 1 rpm at a turnover speed of 25 rpm. The percentage of the reduction is shown in the table. The smaller the surface of the ingot is, the stronger the surface of the ingot. [Intraoral disintegration test] The healthy adult man places the invention in the mouth of the mouth without water and measures until the tablet is completely disintegrated only by saliva. And the time until dissolution. [Content homogeneity test] The component analysis measures the drug content of each of the 10 ingots containing -39-(34) 1281868 and uses the above formula to show the coefficient of variation (CV %) of the drug content. Dissolution test] Tested according to Japanese Pharmacopoeia, Revised Version 12, with Dissolution Test Method Νο. 2. Example 1 80 g of tamsulosin hydrochloride and 80 g of hydroxypropylcellulose (TC5E, Shin-Etsu Chemical Co .,Ltd·) was dissolved in a mixture of 304 g of pure water and 2,73 6 g of methanol. Introduced 4,000 g of Celphere 102 (brand name, Asahi Kasei, in a fluidized bed granulator (Freund Industries, FL0-5) Average grain The diameter is about 127 μm, the particle size is about 50 to about 150 μm) and the solution is applied by side spraying method (spray volume 100 g/min, spray air pressure 4 kg/cm 2 , product temperature) 40 ° C, inlet temperature 80 ° C) to obtain tamsulosin hydrochloride particles. In addition, 533 g of ethyl cellulose (Nissin Chemistry Co.) and 187 g of propylmethylcellulose (TC5E, brand name, Shin-Etsu C hemica 1 C 〇·, L td ·) were dissolved in 6 9 8 A mixture of pure water and 2 2,5 8 2 g of methanol. 4000 g of tamsulosin hydrochloride particles were introduced into a fluidized bed granulator (Freund Industries, FLO-5) and coated with a side spray method using this solution (spray volume 40 g/min, spray air) The pressure is 4 kg/cm 2 , the product temperature is 50 ° C, and the inlet temperature is 60 ° C to obtain a sustained release fine particle. Introduce 4000 g of this slow-release fine granule in a fluidized bed granulator (F reund I ndustries, FL〇-5) and use 2,000 g of Aquacoat (brand name, Asahi Kasei), 4,000 g Eudragit -40- (35) 1281868 L30D55 (brand name, R0hm), 667 grams of Eudragit NE30D (brand name 'R5hm) ' and 6,667 grams of pure water for coating (spray volume 40 g / min, spray air pressure 4 kg / cm ^ 2, product The temperature was 50 ° C and the inlet temperature was 60 ° C to obtain enteric sustained-release fine particles. 3 6 8 g of these enteric sustained-release fine granules, 2,5 60 g of mannitol (Towa Kasei Co., Ltd.), and 640 g of lactose (Domomilk) were used to contain 400 g of maltose (Hayashibara Co., Ltd.) ., brand name: S unma 11 S ) 40 % w / w aqueous solution was granulated in a fluidized bed granulator (F reund Industries, FLO-5) (spray volume 200 g / min, spray cloth The composition of the present invention was obtained at an air pressure of 1.5 kg/cm 2 , a product temperature of 29 ° C, an inlet temperature of 80 ° C, a spray cycle: 10 seconds of spraying and 30 seconds of drying. After further mixing 32 g of calcium stearate with the obtained composition, a rotary granulator was used to produce 0.2 mg of tamsulosin hydrochloride at an ingot pressure of 100 kg/punch and an initial hardness of 1.0 kp. 200 mg ingots of bismuth ingots. Next, the ingots were placed at 25 ° C / 75 % RH, and humidified by heating at a fixed humidity for 18 hours using a thermostat (Tabaiespec Co., Ltd., PR-35C). They were then dried at 30 ° C and 40% RH for 3 hours. The resulting ingots showed a hardness of 5.9 kp (η = 5), a friability of 0.8% (100 rpm) and an intraoral disintegration time of .20 seconds (η = 3). Furthermore, the content uniformity evaluation result, CV% = 2.1%, proved to have good content uniformity. Comparative Example 1 -41 - (36) 1281868 First, 319.3 g of mannitol (Towa Kasei Co., Ltd.), and 77.7 g of lactose (Domomilk) were used containing 50 g of maltose (Hayashibara Co., Ltd., The brand name: Sunmalt S) 20% w / w aqueous solution was granulated in a Freund Industries, unit-glatt (spray volume 10 g / min, spray air pressure 1.5 kg / Square centimeters, product temperature 30 °C, inlet temperature 60 t, spray cycle: continuous spray). After 45.2 g of the enteric sustained-release fine granules prepared in Example 1 and 5 g of calcium stearate were mixed with the obtained product, a rotary granulator was used at an ingot pressure of 93 kg/punching and 1.0 kp. A 200 mg ingot containing 0.2 mg of tamsulosin hydrochloride was produced at an initial hardness. Next, the ingots were placed at 25 ° C / 75% RH, and humidified by heating at a fixed humidity for 18 hours using an incubator (Tabaiespec Co., Ltd., PR-35C). They were then dried at 30 t and 40% RH for 3 hours. The resulting ingots showed a hardness of 4.1 kp (η = 5) and an intra-oral disintegration time of 15 seconds (η = 3). Furthermore, the content uniformity evaluation result, CV% = 5.6%, proved to have poor content uniformity. Comparative Example 2 First, 45.2 g of the enteric sustained-release fine granules prepared in Example 1, 319.3 g of mannitol (Towa Kasei Co., Ltd.), and 79.7 g of lactose (Domomilk) were used containing 50 g of maltose (Hayashibara). C 〇·, L t d., brand name · S unma 11 S ) 20% w / w aqueous solution was granulated in a fluidized bed granulator (Freund Industries, unit-glatt) (spray volume) 10 g / min, spray air pressure 1.5 kg / cm -42 - (37) 1281868 minutes, product temperature 30 ° C, inlet temperature 60 ° C, spray cloth cloth). A transfer granulator mixing 5 g of calcium stearate with the obtained product at a tableting pressure of 96 kg/punch and 1.0 kp to produce 200 tablets containing 坦·2 mg of tamsulosin hydrochloride ingots. These ingots were placed at 25 ° C / 75% RH (Tabaiespec Co., Ltd., PR-35C) at a fixed humidity for 18 hours. The ingots were then dried at 30 ° C and 40% RH to give a hardness of 3.7 kp (η = 5 ) and an intracavitary disintegration time (η = 3). Furthermore, the content uniformity CV% = 4.0% proved to have poor content uniformity. Experiment 1 (Quantitative analysis amount of particle size distribution) The particle size distribution of the sustained-release fine particles obtained in Example 1 and the particle size distribution and particle diameter of the two compositions (Table 1) and Comparative Examples 1 and 2) The quantitative analysis distribution together shows the ί ring: after continuous spraying, the initial hardness of the spin is used in milligrams. Heat and dry for 3 hours under the incubator. 1 5 second mouth evaluation results, Example 1 and product (Table-43-(38) 1281868 Table 1. Particle size distribution of sustained-release fine particles and particle size distribution of Examples 1 and 2 composition] Quantitative analysis of distributed slow-release fine particles Example 1 Example 1 Group Example 2 Composition Example 2 Group size distribution composition Particle size distribution Particle size distribution Quantitative analysis distribution of the particle diameter distribution of the product Quantitative analysis of the distribution average particle size (micron) 165 393 204 30 mesh (%) 〇 26.9 19.0 1.5 1.1 42 mesh (%) 〇 29.7 22.4 5.1 6.2 60 mesh (%) 0 23.8 23.5 23.1 27.2 80 mesh (% 14.4 9.8 18.2 31.5 43.4 100 mesh (%) 70.6 2.8 14.3 15.2 17.6 150 mesh (%) 15.0 3.1 2.5 16.1 4.3 200 mesh (%) 0 1.5 0 5.1 0 200 mesh pass (%) 0 2.5 0 2.5 0 Ratio of ungranulated product (%) 4.3 11.2 -44 - (39) 1281868 Table 2. Particle size distribution of sustained-release fine particles and composition of Comparative Examples 1 and 2 ί Kiss particle size distribution and:] Quantitative analysis of particle size distribution Released fine particles Comparative Example 1 Production Comparative Example 1 Production Comparative Example 2 Yield of the product of Comparative Example 2 Particle size distribution particle size distribution particle size distribution quantitative distribution distribution analysis distribution distribution average particle size (micron) 165 179 196 30 mesh (%) 〇 4.7 0 3.1 2.1 42 mesh ( %) 0 8.0 0 11.3 10.3 60 mesh (%) 0 13.8 0 17.8 19.3 80 mesh (%) 14.4 23.6 14.2 23.4 42.2 100 mesh (%) 70.6 18.9 70.9 12.8 4.9 150 mesh (%) 15.0 17.8 14.4 13.8 4.9 200 mesh (%) 0 8.4 0 8.8 0 200 mesh passage (%) 0 4.9 〇9.0 0 ratio of ungranulated product (%) 99.2 16.0 -45- (40) 1281868

Most of the sustained-release fine granules were within the 80-100 mesh and the quantitative analysis of the particle size distributions of Examples 1 and 2 determined that most of the sustained-release fine granules were coated by granulation and contained slow-release fine granules. The distribution of the composition is shifted toward the direction of large particle size. On the other hand, with respect to the product distribution of Comparative Example 2, it was confirmed that the apparent particle diameter was large, but the quantitative analysis of the particle size distribution did not necessarily coincide with the product distribution. In particular, the ratio of quantitative analysis of 80 to 100 mesh which is lower than the lower ungranulated slow-release fine particles is 20% or more, and many unreleased fine-release fine particles are observed.

Further, as a result of microscopic observation of the composition and the product, many ungranulated sustained-release fine particles were observed in the 80 to 150 mesh portion of the product of Comparative Example 2. On the other hand, almost no unreleased fine-grained fine particles were observed for the composition of Example 1. For example, the discovery of the above data is obtained even if observed through a microscope. Thus, it was found that these results confirmed that the sustained release fine particles were completely granulated by the chelating agent in the compositions of Comparative Examples 1 and 2. Further, when the ratio of the ungranulated product was 4.3% (Example 1) and 11.2% (Example 2), the coefficient of variation was 2.2 (CV%) and 2.1 (CV%), respectively, and when not granulated. When the ratio of the products was 9 9 · 2 % (Comparative Example 1) and 1 6.0 % (Comparative Example 2), the coefficients of variation were 5 · 6 ( CV % ) and 4.0 ( CV % ), respectively. Therefore, if the ratio of the ungranulated product is 16% or more, the results show that the coefficient of variation (CV%) which is an index of content uniformity is large and exceeds 3.5% of allowable enthalpy. Experiment 2 (Dissolution test) The ingots of Examples 1 and 2 and Comparative Examples 1 and 2 were subjected to a dissolution test -46-(41) 1281868 and the results were compared with the dissolution rate only when the sustained-release fine particles were used. The experimental conditions were a paddle method of 100 rpm, and 500 ml of Japanese Pharmacopoeia Disintegration Test Method 1st fluid (pH 1.2) and 2nd fluid (pH 6.8) were used as experimental fluids. The experimental results show that after the dissolution test was started using the test fluid of pH 1.2 for up to 2 hours, in the examples, there was almost no difference in the dissolution rate between the sustained release fine particles and the ingot (the difference after 2 hours was 0.7%), and even with the test fluid of pH 6.8, the difference in dissolution rate between the sustained release fine particles and the ingot is always less than 15 when the sustained release fine particle dissolution rate is 30%, 50%, and 80%. % were 2.9%, 5.8 %, and 5.1%, respectively, and it was confirmed that dissolution at the time of ingot formation was not promoted (Figs. 1 and 2). On the other hand, in the comparative example, the dissolution rate was accelerated when the ingot was formed under the release-release fine particles (Fig. 3, the difference in number after 2 hours was 15.9% and 12.8%). It can be judged that this is because, unlike the fact that the sustained-release fine particles in Example 1 did not appear on the surface of the ingot, it was observed in Comparative Examples 1 and 2 that the sustained-release fine particles appeared on the surface of the ingot, and therefore, The sustained release fine particles are destroyed as a result of the contact between the surface of the puncher and the sustained release fine particles. Therefore, it can be confirmed that with the present invention, the sustained release fine particles can be thoroughly granulated by the hydrazine agent and the dissolution promoting phenomenon at the time of ingot formation can be avoided. Example 2 First, 2,609 g of mannitol (T〇wa Kasei Co., Ltd.), and 653 g of lactose (Domomilk) were pulverized in a needle mill pulverizing apparatus -47 - (42) 1281868 (Hosokawa Micron). . The pulverized product and 307 g of the enteric sustained-release fine granules prepared in Example 1 were subjected to the use of a 20% w/w aqueous solution containing 400 g of maltose (Hayashibara Co., Ltd., brand name: Sunmalt S). Granulation in a bed granulator (F reund I ndustries, FL〇-5) (spray volume 100 g / min, spray air pressure 1.5 kg / cm ^ 2, product temperature 28 ° C, inlet temperature 80 ° C, Spray cycle: 20 seconds spray -30 seconds dry). After mixing 32 g of calcium stearate with the resultant composition, a spin granulator was used to produce 0.1 mg of tamsulosin hydrochloride at an ingot pressure of 100 kg/punch and an initial hardness of 1.0 kp. 120 mg ingots. Next, the ingots were placed at 25 ° C / 70% RH, and stored by humidification at a fixed humidity for 18 hours using an incubator (Tabaiespec Co., Ltd., PR-35C). They were then dried at 30 ° C and 40% RH for 3 hours. The resulting ingots had a hardness of 5.2 kp (η = 5), a friability of 0.6% (100 rpm) and an intraoral disintegration time of 20 seconds (η = 3). Furthermore, the content uniformity evaluation result, CV% = 2.2%, determined that the ingot had good content uniformity. In addition, as a result of performing a dissolution test on the obtained sustained-release fine particles and ingots, the dissolution rate difference between the sustained-release fine particles and the ingot was 4.7 after the dissolution test was started for 2 hours using the test fluid of ρ Η 1 · 2 . %, and even with the test fluid of pH 6.8, the difference in dissolution rate between the sustained release fine particles and the ingot is always smaller than when the sustained release fine particle dissolution rate is 30%, 50%, and 80%. 15% were 2.3%, 2.4%, and 1.4%, respectively, and it was confirmed that the dissolution at the time of tableting was not promoted. Further, the same composition as above and the same production method M^ tablet were used. The obtained tablet had a hardness of 5 · 6 kp (η = 5 ), 〇 · 6 % of brittle -48- (43) 1281868 (100 rpm) and 25 seconds of intraoral disintegration time (η = 3) . Furthermore, the content of the sentence was evaluated by the sentence, CV% = 2.5 %. As the above-mentioned founder, the results of the dissolution test and the tablet were not revealed. Therefore, with the present invention, a composition containing sustained-release fine particles can be prepared, and content uniformity can be ensured by preventing segregation between the sustained-release fine particles and the chelating agent. In addition, it can be determined that reproducibility is obtained. Example 3 200 g of Yoshitomi Fine Chemicals Co., Ltd. and 60 g of hydroxypropylmethylcellulose (TC5E, Shin-Etsu Chemical Co., Ltd.) were dissolved in 720 g of methanol. And a mixture of 720 g of dichloromethane. Introduce 300 grams of Celphere 102 (brand name, Asahi Kasei, average particle size about 127 microns, particle size from about 50 to about 150 microns) in a fluid bed granulator (Freund Industries, unit-glatt) and use this solution to borrow It was coated by a side spray method (spray volume 14 g/min, spray air pressure 3 kg/cm 2 , product temperature 32 t:, inlet temperature 45 ° C) to obtain acetaminophen particles. Separately, 48 g of ethyl cellulose (Nissin Chemistry Co.) and 12 g of propylmethylcellulose (TC5E, brand name, Shin-Etsu Chemical Co., Ltd.) were dissolved in 57 g of pure water and 1, 083 grams of methanol in a mixture. 300 g of acetaminophen particles were introduced into a fluidized bed granulator (Freund Industries, uni-glatt) and coated with a side spray method using this solution (spray volume 8 g/min, spray air pressure) 3 kg / cm ^ 2, product temperature 38 ° C, inlet temperature 67 ° C) to obtain sustained release fine particles. 66-49-(44) 1281868 g of this sustained-release fine granule and 3 1 4 · 25 g of mannitol pulverized by a needle mill pulverizing apparatus (η 〇s 〇kawa Micron) (Towa Kasei Co., Ltd. .) Granulation was carried out in a first-class bed granulator (Freund Industries, uni-glatt) using a 30% w/w aqueous solution containing 67.5 g of maltose (Hayashibara Co., Ltd., brand name: Sunmalt S). Liquid volume 15 g / min, spray air pressure 1 · 1 kg / cm ^ 2, product temperature 30 ° C, inlet temperature 3 8 ° C, spray cycle: 30 seconds spray - 3 0 seconds dry Invention composition. The ratio of the ungranulated slow-release fine particles was 0.0%. After mixing 2.25 g of magnesium stearate with the resulting composition, a rotary granulator was used to produce a 450 mg of acetaminophen at a bark pressure of 25 kg/punch and an initial hardness of 2.0 kp. Mg ingots. Next, these ingots were placed at 25 ° C / 75% RH, and stored by humidification at a fixed humidity for 24 hours using an incubator (Tabaiespec Co., Ltd., PR-SSC). They were then dried at 3 (TC and 40% RH for 3 hours. The resulting ingots showed a hardness of 3.5 kp (n = 5) and an intraoral disintegration time of 12 seconds (η = 1). The content uniformity evaluation result, CV% = 1.2%, was determined to have good content uniformity. In addition, after 2.8 hours from the initial dissolution test (when the sustained release fine particles had about 30% dissolution), after 5 hours (when the sustained release fine particles are dissolved by about 50%), and after 9 hours (when the sustained release fine particles are dissolved by about 80%), the dissolution rate of the slow release fine particles and the ingot is compared and the difference is calculated. , 4.9% after 2.8 hours, 4.6 % after 5 hours, and 2.5% after 9 hours, it can be confirmed that the promotion of slow release fine particle dissolution can be prevented at any time. • 50- (45) 1281868 Example 4 600 g of ginseng (Yoshitomi Fine Chemicals Co., Ltd.) and 120 g of hydroxypropylmethylcellulose (TC5E, Shin-Etsu Chemical Co., Ltd.) were dissolved in 1,440 g. In a mixture of methanol and 1,440 g of dichloromethane, 300 g of salt was introduced into a fluid bed granulator (Freund Industries, unit-glatt) (Shin Nihon Salt Co. Ltd. EF-7 grade 0, average particle size of about 67 microns, particle size of about 75 microns or less) and using this solution to coat by side spray method (spray volume 10 g / min, spray air Pressure 3 kg / cm ^ 2, product temperature 33 ° C, inlet temperature 5 5 ° C) to get acetaminophen particles. In addition, 72 grams of ethyl cellulose (Nissin Chemistry Co.) and 8 grams of hydroxypropyl methyl Cellulose (TC5E, brand name, Shin-Etsu C hemica 1 C 〇., L td ·) was dissolved in a mixture of 7 6 g of pure water and 1,4 4 g of methanol. In a fluidized bed granulator ( Freund Industries, uni-glatt) was introduced with 400 g of acetaminophen particles and coated with a side spray method using this solution (spray volume 10 g/min, spray air pressure 3 kg/cm 2 , product temperature) 39t, inlet temperature 70t) to obtain sustained-release fine particles. Then, 76.5 g of this sustained-release fine granule and 393.4 g of mannitol (Towa Kasei Co., Ltd.) pulverized by a needle mill pulverizing apparatus (Hosokawa Micron) were used. Use 20% w containing 52.5 grams of maltose (Hayashibara Co., Ltd., brand name · S unmalt S ) The /w aqueous solution was granulated in a first-class bed granulator (Freund Industries, uni-glatt) (spray volume 15 g/min, spray air pressure lo kg/cm 2 , product -51 - (46) 1281868 The composition of the present invention was obtained at a temperature of 29 ° C, an inlet temperature of 35 t:, a spray cycle: 20 seconds of spray drying for 40 seconds. The proportion of ungranulated slow-release fine granules was 10.8%. After mixing 2.6 g of magnesium stearate with the obtained composition, the ingot pressure of 50 kg/punching and the start of 1.9 kp were used using a rotary granulator. A 350 mg ingot containing 25 mg of acetaminophen was made under hardness. Next, the ingots were placed at 25 ° C / 75% RH, and stored by humidification at a fixed humidity for 24 hours using an incubator (Tabaiespec C〇·, Ltd., PR-3 5C). They were then dried at 30 ° C and 40% RH for 3 hours. The resulting ingots showed a hardness of 4.8 kp (η = 5), a brittleness of 1 · 23% (100 rpm), and an intraoral disintegration time of 13 seconds (η = 1). Furthermore, the content uniformity evaluation result, CV% = 2.4%, was confirmed to have good content uniformity. In addition, after 2.8 hours from the initial dissolution test (when the sustained release fine particles have about 30% dissolution), after 5 hours (when the sustained release fine particles have about 50% dissolution), and after 9.5 hours (after slowing down) When the release of the fine particles is about 80%, the dissolution rate of the slow release fine particles and the ingot is compared and the difference is calculated, which is 5.5% after 2.8 hours, 3.5% after 5 hours, and 3.1 after 9.5 hours. %, it can be determined that the promotion of sustained release fine particle dissolution can be prevented at any time. Example 5 1,200 g of Yoshitomi Fine Chemicals Co., Ltd. and 120 g of hydroxypropylmethylcellulose (TC5E, Shin-Etsu Chemical Co., Ltd.) were dissolved in 2,640. A mixture of gram of methanol and 2,640 grams of dichloromethane. Fluidized bed granulator (Freund -52- (47) 1281868

Industries, unit-glatt) is introduced with 300 g of salt (Shin Nihon Salt Co., Ltd. EF-70 grade, average particle size of about 67 μm, particle size of about 75 μm or less) and using this solution The side spray method was applied (spray volume 16 g/min, spray air pressure 3 kg/cm 2 'product temperature 30 ° C, inlet temperature 75 ° C) to obtain acetaminophen particles. In addition, 45.9 g of ethyl cellulose (Nissin Chemistry Co.) and 5.1 g of hydroxypropyl methylcellulose (TC5E, brand name, Shin-Etsu Chemical Co., Ltd.) were dissolved in 45.8 g of pure water and 920.5 g of a mixture of methanol. 300 g of acetaminophen particles were introduced into a fluidized bed granulator (Freund Industries, uni-glatt) and coated with a side spray method using this solution (spray volume 8 g/min, spray air pressure) 2 · 5 kg / cm ^ 2, product temperature 3 9 ° C, inlet temperature 75 ° C) to obtain sustained release fine particles. Then, 116.4 g of this sustained-release fine granule and 542.7 g of mannitol (Towa Kasei Co., Ltd.) pulverized by a needle mill pulverizing apparatus (Hosokawa Micron) were used to contain 117 g of maltose (Hayashibara Co., Ltd., The brand name: Sunmalt S) 30% w/w aqueous solution was granulated in a first-class bed granulator (Freund Industries, uni-glatt) (spray volume 15 g / min, spray air pressure 1. 1 The composition of the present invention was obtained in kg/cm 2 , product temperature 2 81 :, inlet temperature 3 5 ° C, spray cycle: 20 seconds spray - 40 seconds drying. The ratio of the ungranulated slow release fine particles was 1.6%. After mixing 3.9 g of magnesium stearate with the resulting composition, it was made using a rotary granulator at a tableting pressure of 200 kg/punch and a starting-53-(48) 1281868 hardness of 1.9 kp. 5 20 mg ingots for heat pain. Next, the ingots were placed at 25 ° C / 75% RH, and stored by humidification at a fixed humidity for 24 hours using an incubator (Tabaiespec Co., Ltd., PR-35C). They were then dried at 3 (TC and 40% RH for 3 hours. The resulting sharpness showed a hardness of 6.4 kp (η = 5) and a friability of 1 · 13% (1 0 0 rpm) And 21 seconds of intraoral disintegration time (η = 1). Furthermore, the content uniformity evaluation result, CV% = 3.3%, was determined to have good content uniformity. In addition, 2.5 hours after the initial dissolution test (when the sustained-release fine particles are dissolved at about 30%), after 5 hours (when the sustained-release fine particles are dissolved by about 50%), and after 9.5 hours (when the sustained-release fine particles have about 80% dissolution) ), comparing the dissolution rate of the slow release fine particles to the ingot and calculating the difference, it is 8.8% after 2.5 hours, 6.3% after 5 hours, and 3.3% after 9.5 hours, which can be determined to be prevented at any time. Promotion of sustained release fines dissolution. Example 6 40 grams of ethyl cellulose (Nissin Chemistry Co.) was dissolved in a mixture of 3 80 grams of methanol and 3 80 grams of dichloromethane. In a fluidized bed granulator (Freund Industries, unit-glatt) is introduced with 400 g of salt (Shin Nihon Salt Co., Ltd. EF-70 grade, average particle size of about 67 microns, particle size of about 75 microns or less) And using this solution to coat by side spraying method (spray volume 6 g/min, spray air pressure 2 kg/cm 2 , product temperature 28 T:, inlet temperature 60 ° C) to obtain ingot core particles. Then, 1,200 g of acetaminophen (Yoshitomi Fine Chemicals Co., Ltd.) and 1,200 g of hydroxypropylmethylcellulose-54-(49) 1281868 (TC5E, Shi n-Etsu Chemical) were added. Co·, Ltd.) was dissolved in a mixture of 2,640 g of methanol and 2,640 g of methylene chloride. 300 g of the above ingot was introduced into a fluidized bed granulator (Freund Industries, unit-glatt) and the solution was used by the side. Spray coating method (spray volume 15 g / min, spray air pressure 3 kg / cm ^ 2, product temperature 30 ° C, inlet temperature 7 (TC) to get acetaminophen particles. In addition, 47.2 g Ethylcellulose (Nissin Chemistry Co.) and 5.3 g of hydroxypropylmethylcellulose (TC5E, brand name, Shin-Etsu Chemical Co., Ltd.) were dissolved in a mixture of 49.9 g of purified water and 947.6 g of methanol. Introducing 650 grams of supplement in a fluidized bed granulator (Freund Industries, uni-glatt) The painful particles were coated with this solution by side spraying method (spray volume 8 g/min, spray air pressure 2.5 kg/cm 2 , product temperature 37 ° C, inlet temperature 75 ° C) to obtain sustained release Fine particles. Then, 116.4 g of this sustained-release fine granule and 542.7 g of mannitol (Towa Kasei Co., Ltd.) pulverized by a needle mill pulverizing apparatus (Hosokawa Micron Co., Ltd.) were used to contain 117 g of maltose (Hayashibara Co). ·, Ltd., brand name: Sunmalt S) 30% w/w aqueous solution in a first-class bed granulator (Freund Industries, uni-glaU) for granulation (spray volume 15 g / min, spray cloth The composition of the present invention was obtained at an air pressure of 1.1 kg/cm 2 , a product temperature of 30 ° C, an inlet temperature of 40 ° C, and a spray cycle: 20 seconds of spray drying for 40 seconds. The ratio of the ungranulated slow release fine particles was 3.9%. After mixing 3.9 g of magnesium stearate with the resultant composition, it was made using a rotary granulator at a casting pressure of 140 kg/punching and a starting-55-(50) 1281868 hardness of 2.6 kp. A dose of 5 20 mg of indomethacin ingots. Then, the ingots were placed at 25 ° C / 75% RH, and stored by humidification at a fixed humidity for 24 hours using an incubator (Tabaiespec Co., Ltd., PR-35C). They were then dried at 30 ° C and 40% RH for 3 hours. The resulting ingots showed a hardness of 5.9 kp (η = 5), a brittleness of 1.64% (100 revolutions) and an intraoral disintegration time of 26 seconds (η = 1). Furthermore, the content uniformity evaluation result, CV % = 2 · 0 %, was confirmed to have good content uniformity. In addition, after 2.3 hours from the initial dissolution test (when the sustained release fine particles were dissolved at about 30%), after 5.5 hours (when the sustained release fine particles were about 50% dissolved), and after 13.5 hours (after slowing down) When the release of the fine particles is about 80%, the dissolution rate of the slow release fine particles and the ingot is compared and the difference is calculated, which is 0.6% after 2.3 hours, 1.2% after 5.5 hours, and 3.2 after 13.5 hours. %, it can be determined that the promotion of sustained release fine particle dissolution can be prevented at any time. Example 7 80 g of tamsulosin hydrochloride and 80 g of hydroxypropylcellulose (TC5E, Shin-Etsu Chemical Co., Ltd.) were dissolved in a mixture of 304 g of pure water and 2,736 g of methanol. Introduce 400 grams of Celphere 102 (brand name, Asahi Kasei, average particle size about 127 microns, particle size from about 50 to about 150 microns) in a fluid bed granulator (Freund Industries, FLO-5) and use this solution to borrow It was coated by a side spray method (spray volume 100 g/min, spray air pressure 4 kg/cm 2 , product temperature 4 〇t, inlet temperature 80 ° C) to obtain tamsulosin hydrochloride particles. -56- (51) 1281868 In addition, 43.7 g of ethyl cellulose (Nissin Chemistry Co_) and 12.3 g of hydroxypropyl methylcellulose (TC5E, brand name, Shin-Etsu Chemical Co., Ltd.) were dissolved in 43.9. A mixture of gram of pure water and 833.4 grams of methanol. 400 g of tamsulosin hydrochloride particles were introduced into a fluidized bed granulator (Freund Industries, uni-glatt) and coated with a side spray method using this solution (spray volume 6 g/min, spray air) The pressure is 4 kg/cm 2 , the product temperature is 40 ° C, and the inlet temperature is 63 ° C to obtain a sustained release fine particle. Next, 300 g of this sustained-release fine granule was introduced into a fluidized bed granulator (Freund Industries, uni-glatt) and used with 90 g of Aquacoat (brand name, Asahi Kasei), 180 g of Eudragit L30D55 (brand name, R0hm). , 30 grams of Eudragit NE30D (brand name, R0hm), and a mixture of 300 grams of pure water for coating (spray volume 6 g / min, spray air pressure 3 kg / cm ^ 2, product temperature 40 ° C, inlet temperature 75.5 t) to obtain enteric sustained-release fine particles. Then, 92.5 g of these enteric sustained-release fine particles, 568.2 g of mannitol (Towa Kasei Co., Ltd.)' and 142.1 g of a needle mill pulverizing apparatus (Hosokawa Micron Co., Ltd.) were pulverized. Peroxidized CDomomlk) and 72 grams of erythrose (Nikken Chemicals Co., Ltd.) using a 5% w/w aqueous solution containing 18 grams of copolymerized vinylpyrrolidone (BASF Co., brand name Kollidon VA64) in a fluidized bed Granulation in a granulator (Freund Industries, uni-glatt) (spray volume g / min 'spray air pressure 0.5 kg / cm ^ 2, product temperature 4 ° ° C, inlet temperature 70 ° C, spray cycle: The composition of the present invention was obtained by spraying in 15 seconds for 30 seconds to dry-57-(52) 1281868. The ratio of the ungranulated slow-release fine particles was 3.0%. After further mixing 7.2 g of calcium stearate with the obtained composition, a rotary granulator was used to produce 0.4 mg of hydrochloric acid at a starting hardness of 0.6 kp. 300 mg ingot of sorosin ingot. Next, the ingots were placed at 120 ° C, heated using a mold oven (model No. MOV-l 12P, Sanyo Corporation) for 13 minutes, and then cooled at room temperature for 30 minutes. The obtained ingots showed a hardness of 6.8 kp (η = 5), a friability of 0.28% (100 rpm), and an intraoral disintegration time of 27 seconds (η = 3). Furthermore, the content uniformity evaluation result, CV% = 1.6%, proved to have good content uniformity. In addition, after 1 hour of the initial dissolution test (when the sustained release fine particles have about 30% dissolution), after 2 hours (when the sustained release fine particles have about 50% dissolution), and after 6 hours (slow When the release of the fine particles is about 80%, the dissolution rate of the slow release fine particles and the ingot is compared and the difference is calculated, which is 1.1% after 1 hour, 2.8% after 2 hours, and 9.4 after 6 hours. %, it can be determined that the promotion of sustained release fine particle dissolution can be prevented at any time. Example 8 1,200 g of nicardipine hydrochloride and 120 g of hydroxypropylmethylcellulose (TC5E, Shin-Etsu Chemical Co., Ltd.) were dissolved in a mixture of 4,800 g of methanol and 4,800 g of dichloromethane. in. Introduce 300 g of sulphur dioxide (Silica Gel, Sigma, average particle size of about 48 μm, particle size of about 75 μm or less) in a fluidized bed granulator (Freund Industries, unit-glatt) and use this The solution was coated by side spraying -56- (53) 1281868 (spray volume 18 g/min, spray air pressure 3 kg/cm 2 , product temperature 30 ° C, inlet temperature 70 ° C) Nicardipine hydrochloride granules were obtained. In addition, 54 g of ethyl cellulose (Nissin Chemistry Co.) and 6 g of hydroxypropyl methylcellulose (TC5E, brand name, Shin-Etsu C hemica 1 C 〇., L t d .) Dissolved in a mixture of 57 g of pure water and 1, 3 g of methanol. 300 g of nicardipine hydrochloride particles were introduced into a fluidized bed granulator (Freund Industries, uni-glatt) and coated with a side spray method using this solution (spray volume 8 g/min, spray air pressure) 2.5 kg / cm ^ 2, product temperature 3 9 ° C, inlet temperature 75 ° C) to obtain sustained release fine particles. Then, 60 g of this sustained-release fine granule, 254.4 g of mannitol (Towa Kasei Co., Ltd.) and 63·6 g of the sterilized lactose (Domomilk) by a needle mill pulverizing apparatus (Hosokawa Micron), and 12 g were placed. The erythritol (Nik ken Chemicals Co., Ltd.) was granulated in a first-class bed using a 5% w/w aqueous solution containing 8 g of a copolymerized vinyl oxime ketone (BASF Co·, brand name Kollidon VA64). Granulation in a machine (Freund Industries, uni-glatt) (spray volume 15 g / min, spray air pressure 0.5 kg / cm ^ 2, product temperature 39 ° C, inlet temperature 50 ° C, spray cycle: 5 seconds The composition of the present invention was obtained by spraying the bell cloth-1 for 5 seconds. The ratio of the ungranulated slow-release fine particles was 7.9%. After mixing 2 g of magnesium stearate with the resultant composition, a 400 mg ingot containing 20 mg of nicardipine hydrochloride ingot was produced using a rotary granulator at an initial hardness of 0.6 kp. Next, the ingots were placed at -130-(54) 1281868 at 130 ° C, heated using a model oven (model No. M0V-112P, Sanyo Corporation) for 10 minutes' and then cooled at room temperature. 30 minutes. The resulting ingots showed a hardness of 3.7 kp (η = 5) 5 0.1% friability (1 〇 〇) and an intraoral disintegration time of 20 seconds (η = 3). Furthermore, the content uniformity evaluation result, C V % = 1 · 1 %, proved to have good content uniformity. In addition, after 5 hours from the initial dissolution test (when the sustained release fine particles have about 30% dissolution) 2 hours later (when the sustained release fine particles have about 50% dissolution), and 5. 5 After the hour (when the sustained release fine particles are dissolved at about 8 %), the dissolution rate of the slow release fine particles and the ingot is compared and the difference is calculated, which is 10.3% after 0.5 hours and 12.8 after 2 hours. % and 6.6% after 5.5 hours, it can be confirmed that the promotion of sustained release fine particle dissolution can be prevented at any time. Example 9 80 g of tamsulosin hydrochloride and 80 g of hydroxypropylcellulose (TC5E, Shin-Etsu Chemical Co., Ltd.) were dissolved in a mixture of 304 g of pure water and 2,73 g of methanol. . Introduce 400 grams of Celphere 102 (brand name, Asatn Kasei, average particle size about 127 microns, particle size from about 50 to about 150 microns) in a fluid bed granulator (Freund Industries, FL0-5) and use this solution to borrow It was coated by a side spray method (spray volume of 100 g/min, spray air pressure of 4 kg/cm 2 , product temperature of 4 (TC, inlet temperature of 80 ° C) to obtain tamsulosin hydrochloride particles. 561.6 g of ethyl cellulose (Nissin Chemistry Co.) and 158.4 g of hydroxypropyl methylcellulose (TC5E, brand name, 60-(55) 1281868

Shin-Etsu Chemical Co., Ltd.) was dissolved in a mixture of 564 g of pure water and 10,716 g of methanol. 4000 g of tamsulosin hydrochloride particles were introduced into a fluidized bed granulator (Freund Industnes, FL0-5) and coated with a side spray method using this solution (spray volume 40 g/min, spray air) The pressure is 4 kg/cm 2 , the product temperature is 40 ° C, and the inlet temperature is 54 t ) to obtain a sustained release fine particle. Next, 4,000 g of this sustained-release fine granule was introduced into a fluidized bed granulator (Freund Industries, FLO-5) and used to contain 800 g of Aquacoat (brand name, Asahi Kasei), 1,600 g of Eudragit L30D55 (brand name, R0hm), 266.7 grams of Eudragit NE30D (brand name, R6hm) ' and 5,3 3 3 grams of pure water mixture coating (spray volume 60 g / min, spray air pressure 4.5 kg / cm ^ 2, product temperature 5 0 ° C, inlet temperature 84 ° C) to obtain enteric sustained-release fine particles. Then, 392.7 g of these enteric sustained-release fine particles, 2,540.2 g of mannitol (Tow a Kasei Co., Ltd.), and 63 5.1 g of a needle mill pulverizing apparatus (Hosokawa Micron Co., Ltd.) were pulverized. The lactose (Domomilk) was subjected to a 20% w/w aqueous solution containing 400 g of maltose (Hayashibara Co., Ltd., brand name: Sunmalt S) in a fluidized bed granulator (Freund Industries, FLO-5). Granulation (spray volume 100 g / min, spray air pressure 1.5 kg / cm ^ 2, product temperature 33 ° C, inlet temperature 48 ° C, spray cycle: 20 seconds spray -30 seconds dry) Composition of the invention. The proportion of ungranulated slow-release fine granules was 1 · 1 %. After further mixing 2 2 g of calcium stearate with the obtained composition -61 - (56) 1281868, using a rotary granulator at 2.1 kp A 300 mg ingot containing ί mg of tamsulosin hydrochloride ingot was prepared at the initial hardness. Next, this was waited at 25 ° C / 75% RH, and humidified by heating at a constant humidity for 24 hours using an incubator (Tabaiespec Co., PR-35C). It was then dried at 30 ° C and 40% RH for 3 hours. The obtained ingots showed a hardness of t kp (η = 5), a brittleness of 1.67% (100 rpm) and an intraoral disintegration time of 20 (η = 1). Furthermore, the content uniformity evaluation, CV % = 1.6%, proved to have good content uniformity. In addition, after the initial dissolution test for 2 hours (when the sustained release fine particles have about 30% dissolution), after 4 hours (when the sustained release fine particles have about 50% dissolution), after the hour (the release of the fine particles is about When 80% is dissolved, compare the slow release to the dissolution rate of the ingot and calculate the difference, which is 7.5% after 2 hours, 6.4% after 2 hours, and 1.5% after 8 hours. It can be determined at any time. Prevents the promotion of slow release of fine particles. Industrial Applicability The present invention relates to a composition containing sustained-release fine particles, which provides a contradictory function, that is, even if the ingots rapidly disintegrate in the oral cavity, they have sustained release properties. Further, the present invention is characterized in that it is suppressed by the phenomenon that the sustained release fine particles are destroyed under the tableting pressure at the time of tableting, thereby causing the dissolution of the drug to be promoted, and even after the ingot is formed under good reproducibility. Achieved controlled dissolution as a design target for slow release fine grain processing. In this way, the design of the sustained release fine granule preparation can be simplified 'and thus more so that it can be guaranteed to be good ί 0.4 Ingot Ltd., ί 4.1 seconds estimated in the solution with 8 fine particles 4 small It can be seen that the solution can be used to make ingots in the preparation of the drug -62- (57) 1281868 content uniformity characteristics. In addition, it is possible to present a composition containing sustained-release fine particles, which is a step of rapidly disintegrating an ingot into a product containing a sustained-release fine particle in the development of a rapidly disintegrating ingot in a plurality of oral cavity, particularly in Industrial manufacturing steps, and further, the quality of the quality assurance process has obvious utility 0 [Simple diagram]

Fig. 1 shows the results of a dissolution test of the sharpening agent and the sustained-release fine particles of Example 1 using Japan Pharmacopoeia 1st Fluid for D i s i n t e g r a t i ο η T e s t s. Fig. 2 shows the results of a dissolution test of the sample of Example 1 and the sustained-release fine particles by using Japan Pharmacopoeia 2nd Fluid for D i s i n t e g r a t i ο η T e s t s. Figure 3 is a comparison of Comparative Examples 1 and 2 tablets and sustained release fines using Japan Pharmacopoeia 1st Fluid for D i s i n t e g r a t i ο η T e s t s

The results obtained by the dissolution test. -63-

Claims (1)

%月日修(more)本本本 I 6 Announcement, Patent Application Scope: Patent No. 92 1 00259 Patent Application Revision of Chinese Patent Application Revision of the Republic of China on February 16, 1996 1 · An intra-oral rapid disintegration ingot A composition containing sustained-release fine particles, characterized in that it comprises a drug-containing sustained-release fine particle having an average particle diameter of 0.1 μm to 350 μm and one or two or more selected from the group consisting of the following Tanning agents: saccharides and sugar alcohols, which are used with one or two or more binders selected from the group consisting of the following groups of rapidly disintegrating ingots: maltose, trehalose, sorbitol, maltitol, glucose , xylitol, erythritol, mannitol, sucrose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, C〇polyvidone (co-vinylpyrrolidone), and polyvinyl alcohol. The granulated product is formed, and the proportion of the ungranulated slow-release fine granules in the overall composition is 〇1 to 5%. 2. A composition comprising a sustained release fine granule for use in a rapid disintegration tablet for oral cavity according to claim 1, wherein the adhesive for the rapidly disintegrating ingot in the oral cavity is one or two or more selected from the group consisting of the following Among the groups are high mold saccharides, water soluble polymer materials, and low melting point saccharides. 3. A composition comprising sustained release fine granules for use in an orally rapidly disintegrating ingot in the second aspect of the patent application, wherein the saccharide and the sugar alcohol are one type or a plurality selected from the group consisting of : Low molding sugars 'high; melting sugars and low melting sugars. 4. The composition of the sustained release fine granules for use in the orally rapidly disintegrating ingot of the third aspect of the patent application, wherein the sustained release fine granule, the sputum filler, and the fast disintegrating ingot in the oral cavity are bonded The mixing ratio of the agents is 1 to 50% ' 2 0 to 9 8 %, and 1 to 30%, respectively. 5. The sustained-release fine particle-containing composition for use in an orally rapidly disintegrating ingot according to the first aspect of the invention, wherein the sustained release fine particle comprises at least crystalline cellulose particles, a drug, and a polymeric substance. 6) A composition comprising a sustained release fine granule for use in a rapid disintegration tablet for oral cavity according to claim 5, wherein the drug is tamsulosin hydro chloride. 7) A composition containing sustained-release fine particles for use in an orally rapidly disintegrating ingot according to the scope of claim 6 wherein the sustained-release fine particles are enteric sustained-release fine-grained granules 8 as claimed in claim 7 A composition comprising a sustained release fine granule for rapid disintegration in the oral cavity, wherein the polymeric substance is hydroxypropylmethylcellulose, ethylcellulose, Eudragit L30D55, and Eudragit NE30D. 9. The composition comprising sustained release fine granules for use in an orally rapidly disintegrating ingot in the oral cavity of claim 8, wherein the adhesive for the rapidly disintegrating ingot in the oral cavity is one or more selected from the group consisting of Chinese · maltose, trehalose, sorbitol, and maltitol. 1 0 - A rapid disintegrating ingot in the oral cavity, which is composed of a composition containing sustained-release fine particles according to claim 9 of the patent application. 1 1 · In the oral cavity rapid disintegration ingot of claim 10, wherein the drug content coefficient of variation (CV%) as the content uniformity index is -2 - 1281868 3. 5% or less. 1 2. A method for producing a composition containing sustained-release fine particles for rapidly disintegrating tablets in an oral cavity, characterized in that it comprises a sustained release fine particle containing a drug and one or two or more selected from the group consisting of the following The sputum in the group: saccharides and sugar alcohols, using one or two or more binders selected from the group consisting of the following groups of rapidly disintegrating ingots: maltose, trehalose, sorbitol, maltose Alcohol, glucose, xylitol, erythritol, mannitol, sucrose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, copolyvidone (copolyvinylpyrrolidone), and polyvinyl alcohol, The granulated product produced, and the proportion of the ungranulated slow-release fine granules in the overall composition is from 0 to 15%. A method for producing a composition containing sustained-release fine particles for use in an orally rapidly disintegrating ingot in the oral cavity of claim 1, wherein the adhesive for the rapid disintegration ingot in the oral cavity is one or two or a plurality of selected from the group consisting of: high mold saccharides, water-soluble polymer materials, and low-melting saccharides 〇 14. As disclosed in claim 13 for the manufacture of intra-oral rapid disintegration tablets A method for continuously releasing a composition of fine particles, wherein the saccharide and the sugar alcohol are one or two or more selected from the group consisting of low mold sugars, high melting point sugars, and low melting point sugars . A method for producing a sustained-release fine particle-containing composition for rapidly disintegrating an ingot in an oral cavity according to the invention of claim 14, wherein the sustained-release fine particle, the sputum, and the oral cavity rapidly disintegrate The mixing ratio of the binder for the ingot is 1 to 50%, 20 to 98%, and 1 to 30%, respectively. </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; , and polymeric substances. 1 7 A method for producing a composition comprising a sustained-release fine particle for rapid disintegration in an oral cavity according to claim 16 of the patent application, wherein the drug is tamsulosin hydrochloride. A method for producing a composition containing a sustained release fine granule for rapidly disintegrating an ingot in an oral cavity, wherein the sustained release fine granule is an enteric sustained release fine granule. A method for producing a sustained-release fine particle-containing composition for rapidly disintegrating an ingot in an oral cavity according to the invention of claim 18, wherein the polymer substance is hydroxypropylmethylcellulose, ethylcellulose , Eudragit L30D55, and Eudragit NE30D 〇20. A method for producing a composition comprising a sustained release fine granule for use in an intraorally rapidly disintegrating ingot according to claim 19, wherein the adhesive for rapid disintegration in the oral cavity is used The agent is one or two or more selected from the group consisting of maltose, trehalose, sorbitol, and maltitol. 2 1. A method for producing a rapidly disintegrating ingot in an oral cavity. The in-oral fast disintegrating ingot is composed of a composition containing a sustained-release fine particle prepared by the method described in claim 20. 22. The method of producing a rapidly disintegrating ingot in an oral cavity according to the scope of claim 2, wherein the coefficient of variation (C V % ) of the drug content as an index of content uniformity is 3 · 5 % or less. 1281868 (5 ί 第 92100259 Patent Application Chinese schema revision - Republic of China on February 16, 1996 amendment 747442 Animal I year and month repair (more) original JL6^__ one 50 40 302010 (% ϊ蹇 example 1 sustained release fine particles-m- Example 1 Oral disintegration ingot w I Ί I--1 〇.〇 0.5 1.0 1.5 2.0 Time (hours) Figure 2 1281868 • · - I £ 1· 350403020100 0 图 S ·蹇 Example 1 Slow Release Fine Particles Comparative Example 1 Ingot Comparative Example 2 Ingot 1.0 time (4, hour)