TW200412245A - 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

200412245 (1) 发明. Description of the invention [Technical field to which the invention belongs] The present invention relates to a composition including slow-release fine particles for rapid disintegration of tablets in the oral cavity. In more detail, the present invention relates to slow-release granules including rapid disintegrating tablets in the oral cavity, which is characterized in that it comprises slow-release granules and one or more tinctures selected from sugars or sugar alcohols, and The granulated product granulated with the binder for rapidly disintegrating the tablets in the oral cavity, and the proportion of the un-granulated slow-release fine particles in the entire composition is 0 to 15%. [Prior art] The term "sustained-release fine particles" in the present invention means fine particles containing drugs, which have undergone various sustained-release treatments and have an average particle diameter of about 0.1 micrometers to about 350 micrometers. Various sustained-release treatments mean treatments that produce the well-known "sustained-release" properties. Examples can be treatments that can produce gradual drug release properties, treatments that can produce gastric solubility, treatments that can produce enteric properties, treatments that can release time, and treatments that can release these combinations. Furthermore, those that can be enteric are called π enteric slow-release fine particles ". Various intraoral disintegrating tablets have been previously developed so that they can be easily taken by people with weak power, including the elderly, children, etc., even without water. In addition, the use of a variety of drugs in recent years has led to the need to provide sustained-release functions to rapidly disintegrating tablets in the oral cavity. The first generation of orally rapidly disintegrating tablets, such as "ZydisTM" sold by R. P. Scherer, etc., are pharmaceutical preparations known to be manufactured by freeze-drying. These first-generation orally rapidly disintegrating tablets are basically made by freeze-drying using a drug-soluble (2) (2) 200412245 liquid or suspension, or a special drying method. Therefore, the manufacturing process in the liquid state is necessary, and there is no discussion of providing a sustained release function. Various second-generation intraoral rapid disintegrating tablets are known, including those using the function of a disintegrant (Japanese Patent Publication No. Hei 1 0-1 8243 6, International Early Reveal Booklet WO98 / 02 1 85, Etc.), they are characterized by spraying and / or granulating high-molding sugar as a binder on low-molding sugar and when the strength of the tablet is further required, they can be moistened and dried (International Early Reveal Booklet WO 95 / 203 80 (corresponding to U.S. Patent 5,576,014, Japanese Patent No. 312141), etc., and these are made by tableting. The rapid disintegration of tablets in the oral cavity containing fine particles has been considered, etc. Granules, etc. have been slow-released, for example, coated with a polymer, in order to solve the apparent contradiction of providing the slow-release function of these second-generation oral fast-disintegrating tablets. However, even if attempts have been made to simply pass Sustained-release fine granules are mixed with oral disintegration tablets for rapid disintegration of tablets, and the mixture is made into tablets, due to differences in apparent specific gravity and fluidity differences between the tablets and slow-release tablets. Segregation occurs during the ingot making process . The term "〃 分 拟" as used herein refers to a state where the sustained-release fine particles are unevenly dispersed in the tincture, and segregation occurs when they are dispersed unevenly. The composition of the tablets can be measured after the tablets are made. The homogeneity of the drug content determines the segregation phenomenon. For example, if the coefficient of variation (CV%) (as shown below) of the drug content is 0 to 3.5%, it can be said that no segregation occurs and if the coefficient of variation exceeds 3.5%, Segregation occurs. There are a variety of problems caused by this segregation. For example, there are the following problems ... (1) Due to the contact between the face of the punch and the sustained-release fine particles in the ingot. -(3) (3) 200412245, or the direct contact between the sustained-release particles themselves, so that the ingot-making pressure is directly transmitted to the sustained-release fine particles, resulting in the destruction of the sustained-release fine particles and their production Promote dissolution after tableting. (2) The degree of destruction of slow-release fine particles will vary with the degree of segregation. Therefore, the controlled dissolution cannot be achieved with good reproducibility as the design goal of slow-release fine-particle preparations. (3) The number of slow-release fine particles contained in a tablet will fluctuate And the uniformity of the drug content cannot be ensured, etc. In the International Early Disclosure Booklet WO 00/24379, an invention related to a method for manufacturing spherical fine particles was disclosed, which can be easily manufactured by a special drum granulation method Controlled release pharmaceutical preparations. The manufacturing method given in this booklet includes special drum granulation of these spherical fine particles and shows that dissolution can be controlled by coating spherical fine particles and these spherical fine particles can be used in the oral cavity In fast disintegrating tablets. However, our research has determined that the above-mentioned problems will occur and this goal cannot be achieved if the fast disintegrating tablets in the oral cavity contain only slow-release treated spherical particles. Furthermore, in There is no disclosure or instruction in this description of the special means used to successfully solve these problems. Therefore, although it is still unknown, there is still a need for the rapid disintegration of tablets in the oral cavity including slow-release granules, so that these slow-release granules are made into ingots, because As a result of suppressing the destruction of the sustained-release fine particles under pressure, the dissolution of the drug can be promoted, and even after being made into tablets, controlled dissolution as the purpose of the sustained-release fine-particle preparation can be achieved with good reproducibility, and the drug content can be ensured Uniformity. [Summary of the Invention] -9- (4) (4) 200412245 In these cases, the inventors of the present case focused on investigating the rapid disintegration tablets in the oral cavity including slow-release fine particles and preventing the rapid disintegration tablets in the oral cavity from being used. A method of releasing fine particles and tinctures to cause segregation, which is the origin of various problems. As a result of repeating various experiments, they prepared slow-release granules (some of which are included in this granulation procedure) according to a granulation procedure that can be applied to the surface of all or part of the individual sustained-release granules coated with a filler. (Gathered together) can successfully prevent the discovery of slow-release fine particles and segregation of tinctures and successfully complete the present invention. "Granulated" as used herein means making particles or powders that are substantially uniform in size and shape. As a result of further detailed investigation, it was found that when the proportion of the ungranulated slow-release fine particles in the overall composition obtained at last is 0 to 15%, segregation of the slow-release fine particles and the filler can be prevented. According to the former thought, when several kinds of particles are aggregated in this way, as the difference in apparent specific gravity between fine particles and tinctures increases and the fine particle fluidity deteriorates, the result is often easy. Ground segregation occurs. However, it is completely surprising that by avoiding the direct contact between the punch surface and the slow-release fine particles, or the slow-release fine particles themselves, not only can the content be uniformly ensured during ingot making, but also The pressure is simultaneously neutralized in the ingot, and the good reproducibility of the controlled dissolution is achieved. That is, the present invention relates to 1. A composition containing slow-release fine particles for rapidly disintegrating tablets in the oral cavity, characterized in that it comprises slow-release fine particles containing a drug and one or more groups selected from the group consisting of The tincture fillings in the group: sugars and sugar alcohols, granulated products made by using a binder for rapid disintegration of tablets in the oral cavity, and the proportion of ungranulated slow-release fine particles in the overall composition is 0 To 15%. (5) (5) 200412245 2. The composition containing slow-release fine particles for rapid disintegration of tablets in oral cavity in item 1 above, wherein the binder for rapid disintegration of tablets in oral cavity is one or more selected from the group consisting of One of the following groups: high-moldable sugars' water-soluble polymer substances, and low-melting sugars. 3. The composition containing slow-release fine particles for fast disintegrating tablets in the oral cavity of the above 2 items, wherein the sugars and sugar alcohols are one or more selected from the group consisting of: low-molding sugar Class' high melting sugars and low melting sugars. 4. The composition containing slow-release fine particles for rapid disintegration of orally disintegrating tablets in the above 3 items, wherein the mixing ratio of the slow-release fine particles, tincture, and adhesive for rapid disintegration of orally disintegrating tablets 1 to 50%, 20 to 98%, and 1 to 30%. 5. The composition containing slow-release fine particles for use in the orally rapidly disintegrating tablets of the above 4 items, wherein the average particle size of the rapidly disintegrating fine particles is about 0.1 micrometers to about 350 micrometers. 6. The composition containing sustained-release fine particles for rapid disintegration of tablets in the oral cavity of the above 5, wherein the slow-release fine particles include at least crystalline cellulose particles, a drug, and a polymer substance. 7. The composition containing slow-release fine particles for rapid disintegration of tablets in the above 6 items, wherein the drug is tamsulosin hydrochloride 〇8 · Rapid disintegration of the oral items in the above 7 items A composition containing slow-release fine particles for tablets, wherein the slow-release fine particles are enteric slow-release fine particles. 9. The composition containing slow-release fine particles for rapid disintegration of tablets in the oral cavity of the above 8 items, wherein the polymer substance is hydroxypropyl methylcellulose, a group of B-11-(6) (6) 200412245 Cellulose, Eudragit L30D55, and Eudragit NE30D. 10. The composition containing slow-release fine particles for the orally rapidly disintegrating tablets in the above 9 items, wherein the binder for the orally rapidly disintegrating tablets is one or more selected from the group consisting of: Maltose, trehalose, sorbitol, and maltitol. 11. An orally rapidly disintegrating tablet consisting of a composition of the sustained-release fine particles described in item 10 above. 12. The orally rapidly disintegrating tablets in the above 11 items, wherein the coefficient of variation (CV%) of the drug content as an index of the uniformity of the content is 3.5% or less. 13. A method for manufacturing a composition containing slow-release fine particles for rapidly disintegrating tablets in the oral cavity, characterized in that it comprises the slow-release fine particles containing a drug and one or more fillers selected from the group consisting of Agents: carbohydrates and sugar alcohols, granulated products made by using a binder for rapid disintegration of tablets in the oral cavity, and the proportion of ungranulated slow-release fine particles in the overall composition is 0 to 15%. 14. The method for manufacturing a composition containing slow-release fine particles for oral fast-disintegrating tablets in item 13 above, wherein the binder for the oral fast-disintegrating tablets is one or more selected from the group consisting of Those in the group: highly moldable sugars, water-soluble polymer substances, and low melting sugars. 15. The method for producing a composition containing slow-release fine particles for rapidly disintegrating tablets in the oral cavity in the above item 14, wherein the sugars and sugar alcohols are one or more selected from the group consisting of: low-mold Raw sugars, high melting sugars and low melting sugars. 16. The method for producing a composition containing slow -12 (7) (7) 200412245 for producing a fast disintegrating tablet in the oral cavity in the above 15 items, wherein the slow-release fine particles, tincture, and the oral cavity The mixing ratios of the binders for the internal fast disintegrating tablets are 1 to 50%, 20 to 98%, and 1 to 30%, respectively. 17. The method for producing a composition containing sustained-release fine particles for oral fast-disintegrating tablets according to item 16 above, wherein the average particle size of the fast-disintegrating fine particles is from about 0.1 micrometers to about 3-50 micrometers. 18. The method for producing a composition containing sustained-release fine particles for rapidly disintegrating tablets in the oral cavity according to item 17 above, wherein the slow-release fine particles include at least crystalline cellulose particles, a drug, and a polymer substance. 19. The method for producing a composition containing sustained-release fine particles for rapid disintegration of tablets in the oral cavity according to 18 above, wherein the drug is tamsulosin hydrochloride. 20. The method for producing a composition containing slow-release fine particles for rapid disintegration of tablets in the oral cavity according to item 19 above, wherein the slow-release fine particles are enteric slow-release fine particles. 2 1. The method for producing a composition containing slow-release fine particles for rapidly disintegrating tablets in the oral cavity in the above 20 items, wherein the polymer substance is hydroxypropyl methyl cellulose, ethyl cellulose, Eudragit L30D55, And Eudragit NE30D ° 22. The method for producing a composition containing slow-release fine particles for rapid disintegration of orally disintegrating tablets in the above item 21, wherein the adhesive for rapidly disintegrating orally disintegrating tablets is one or more selected from the group consisting of One of the following groups: maltose, trehalose, sorbitol, and maltitol. 23. A method for manufacturing a rapid disintegrating tablet in the oral cavity, the rapid disintegrating tablet in the oral cavity is a group 13- (8) (8) 200412245 containing slow-release fine particles made by the method described in item 22 above consist of. 24. The method for manufacturing a rapidly disintegrating tablet in the oral cavity of the above 23 items, wherein the coefficient of variation (CV%) of the drug content as an index of content uniformity is 3.5% or less. "Adhesive for rapid disintegration tablets in the oral cavity of the present invention" means commonly used adhesives, particularly adhesives which can be used to prepare rapid disintegration tablets in the oral cavity, and there can be various kinds of adhesives which can be used in accordance with the present invention. select. Details are explained below, including specific examples. In the present invention, "ungranulated slow-release fine particles" means slow-release fine particles that do not constitute a granulated product when the slow-release fine particles are granulated together with the tincture using a binder for rapidly disintegrating tablets in the oral cavity. . In addition, the ratio of "ungranulated sustained-release fine particles" is the ratio of the particle size distribution of the sustained-release fine particles and the content ratio of the particle size of the sustained-release fine-particle composition measured by the following method using the following formula.値 Calculated: The proportion of ungranulated slow-release fine particles (%) = G1 + Σ (G i +1-(P i-G i)) Here, the estimation of Σ is calculated from 1 = 1 to (Gi + MP—Gi)) 所得 gains a little before the negative. P !: Proportion of slow-release fine particles on the minimum-pore size sieve in these slow-release fine particle size distributions (except for the case where 0%). p2: the proportion of the sustained-release fine particles on the second smallest pore size sieve within the particle size distribution of the sustained-release fine particles (except when the value is 0%). Its third smallest hole, fourth, and so on are P3, P4, etc., and they are all represented by Pi. -14- (9) (9) 200412245 G1: The proportion of the content of the particle size distribution of the composition on the sieve with the same pore size as i. G2: The proportion of the content of the particle size distribution of the composition on the sieve with the same pore size as P2; the third, fourth, etc. are G3, g4, etc., and all of them are expressed as ⑴. " Adjust the proportion of ungranulated slow-release fine particles in the total composition to 15% or less " In the present invention, in other words, the proportion of un-granulated slow-release fine particles is low, and That is, most of the sustained-release fine particles are contained in each granulated product. In addition, it also means that the segregation of slow-release fine particles and tinctures is controlled " granulated product " in the present invention means that the slow-release fine particles, tinctures and fast-disintegrating tablets in the oral cavity are used as binders. The composition of the granulated product, and the granulated product not including the sustained-release fine particles is specifically defined as "a granulated product not including the sustained-release fine particles. That is, the specific composition form of the present invention includes "granulated products", "ungranulated slow-release fine particles", and "granulated products not including slow-release fine particles".

Furthermore, the rapidly disintegrating tablet in the oral cavity of the present invention refers to a tablet having a disintegration time in the oral cavity of 0 to 2 minutes, preferably 0 to 1 minute, and may be a booklet of early international disclosure W98 / 02 1 85, International Early Disclosure Booklet WO 9 5/203 80, Japanese Patent Publication Hei 1 0-1 82436, US Patent Application No. 1 0/1 42,08 1 (corresponding to International Patent Application PCT / JP 02/0448 1), etc. revealed in. Furthermore, the dissolution promotion of the M sustained-release fine particles is suppressed "and" achieving controlled dissolution as a [sustained-release fine particle] target "means in the present invention that the dissolution rate of the slow-release fine particles and the rapid disintegration in the oral cavity There is no difference between the dissolution rate of disintegrating tablets and -15- (10) (10) 200412245. In particular, the dissolution test of slow-release fine particles and the dissolution of rapidly disintegrating tablets in the oral cavity including slow-release fine particles are performed. In the experiment, when comparing the dissolution of the slow-release fine particles, the difference between the dissolution rate of the slow-release fine particles and the dissolution rate of the rapidly disintegrating tablets in the oral cavity, the drug dissolution rate of the slow-release fine particles was about 30 %, About 50%, and about 80% are 0 to 15% at each dissolution time point. If the sustained-release fine particles are enteric slow-release fine particles, the above evaluation cannot be performed under the condition that ρ 1.2 is 1.2 Implementation, two hours after the start of the dissolution experiment, the difference between the dissolution rate of the enteric slow-release fine particles and the dissolution rate of the fast disintegrating tablets in the oral cavity is 0 to 10%. Furthermore, π good reproducibility " It means that even if the rapid disintegration tablets in the oral cavity are obtained at different time, in the comparison of oral cavity The difference between the dissolution of the rapidly disintegrating tablet and the dissolution of the sustained-release fine particles constituting the tablet both gave the same result. In addition, the "drug content variation coefficient (CV%)" in the present invention is an index of content uniformity. Perform the content uniformity test described below and calculate [CV%] with the following formula: cv% = (standard deviation for each content) / (average content) X 1〇〇 " CV% from 0 to 3.5% " It can be considered that there is no segregation, and the drug content of the prepared tablets rarely fluctuates, and it can be said that "the uniformity of the drug content is guaranteed". Furthermore, " CV% exceeding 3.5% " can be regarded as having a large fluctuation in the content of the drug, and it can be said as "poor uniformity of content". Incidentally, "CV% of 0 to 3.5%" is an appropriate range of the coefficient of variation of the present invention. (11) (11) 200412245 This number is clearly required for quality assurance and indicates that a drug with a fixed drug is obtained. Content composition. So far, the composition containing the sustained-release fine particles of the present invention and a method for producing the same will be described in detail. There is no particular limitation on the medicament used in the present invention, as long as it can be used as an active ingredient requiring sustained release, that is, it is therapeutically effective or prophylactically effective. Examples of these drugs are hypnotic tranquilizers, sleep inducers, anxiolytics, antiepileptics, antidepressants, anti-Parkinson's drugs, psychotic drugs, central nervous system drugs, local anesthetics, skeletal muscle Relaxants, autonomics, antipyretics, analgesics, anti-inflammatory drugs, anticonvulsants, anti-dizziness drugs, cardiotonics, arrhythmic drugs, diuretics, hypotension drugs, vasoconstrictors, vasodilators, circulatory system drugs Drugs for hyperlipidemia, breath-promoting drugs, cough suppressants, expectorants, cough expectorants, tracheodilators, anti-dysentery drugs, drugs for controlling intestinal function, gastric ulcers, appetizers, acidifiers, laxatives, beneficial Gall drugs, gastrointestinal drugs, adrenocortical hormones, hormones, genitourinary drugs, vitamins, hemostatic drugs, liver disease drugs, gout drugs, diabetes drugs, antihistamines, antibiotics, antibacterial agents, anti-malignant tumor drugs, chemotherapy Medicine, multi-symptom cold medicine, nutrition-enhancing health medicine, osteoporosis medicine, etc. Examples of such drugs are anti-inflammatory drugs, antipyretics, anticonvulsants or analgesics such as indomethacin, dilofenac, sodium dichloroaniline phenylacetate, codeine, isopropyl Ibuprofen, phenylbutazone, 'oxyfenbutazone', mepirizole, 'aspirin' (12) 200412245 idensamide, acetaminophen, Aminopyrine, phenacetin, butyl scopolamine bromide, morphine, etomidoline, pentazocine, fenoprofen calcium ), Naproxen, celecoxib, vardecoxib, tramadole, etc .; antirheumatic drugs,

For example, etodolac, etc .; antituberculosis drugs, such as isoniazide, ethambutol chloride; circulatory system drugs, such as isosorbid nitrate, nitroglycerin, nitrobenzene (nifedipine), bar dnipidine hydrochloride, nicardipine hydrochloride, dipyridamile, amrinone, indenolol

hydrochloride, hydralazine hydrochloride, methyldopa, furosemide, spironolactone, guannetidine nitrate, resperine, amosulalol hydrochloride, lisinoopril, metoprolol Tests (pilocarbpine), ta sos art an, etc .; physiological and neuropharmaceuticals, such as chlorpromazine hydrochloride, amitriptyline hydrochloride, nemonapride, haloperidole, moperone hydrochloride, perphenone Perphenazine, diazepam, lorazepam, chlordiazepoxide, adinazolam, alprazolam, methylphenidate-18- (13) (13 200412245 (methylphenidate), milnasivram, peroxetin, risperidone, sodium valproate, etc .; antiemetics such as medoclopramide, ramosetron hydrochloride, granisetron hydrochloride, ondansetron hydrochloride , Azasetron hydrochlorid e, etc .; antihistamines, such as chlorpheniramine maleate, diphenhydramine hydrochloride, etc .; vitamins, such as thiamine nitrate, tocopherol hydrochloride, sicotiamine, 1¾ ol, cobalt Cobamamide, ascorbic acid, nicotinamide, etc .; anti-gout drugs, for example, allopurinol, colchicine, prqbenamide, etc .; anti-parkinsonian drugs such as levodopa, selegiline ), Etc .; hypnotic tranquilizers, such as amobarbital, bromwarelyl urea, midalam 1: 1 midazolam (chlorazo hydrate), etc .; anti-evil Tumor drugs, such as fluorouric B-d I (d 'carmofur, aclarubicin hydrochloride, cyclophosphamide, thi otepa), etc .; anti-allergic drugs, such as pseudoephedrine, terfenadine ), Etc .; anti-suppressive drugs, such as phenylpropanolamine, ephedrine, etc .; diabetes drugs, such as acethexamide, insulin, torbutamide, desmopressine, glibizide, etc .; Agents, such as hydrochlorthiazide, poly thiazide, triaterene, etc .; trachea dilators, such as amino tea test, formoterol fumarate, theophylline, etc .; Cough medicines, such as codeine phosphate, noscapine, dimemorphan phosphate (14) 200412245 (dimemorphan phosphate), methadine

(dextromethorphan), etc .; antiarrhythmic drugs, such as quinidine nitrate, digitosin, propafenone hydrochloride, procainamide, etc .; Surface anesthetics, such as aminoethyl benzoate, lidocaine, dibucaine hydrochloride, etc .; antiepileptic drugs, such as phenytoin, etoduccimide, and pdmi done , Etc .; synthetic corticosteroids, such as hydrocortisone, prednisolone, triamcinolone, betamethasone, etc .; gastrointestinal medications, such as pangastric tablets ( famotidine), ranitidine hydrochloride, dimethisone, sucralfate, sulpiride, tepronone,

praunotol, 5-aminosalicylic acid, sulfasalazine, lospr (omeprazole), lannoprazole, etc .; drugs for the central nervous system, such as indeloxazine, idebenone, thiapride hydrochloride, bifermerane hydrochloride , Calcium pantothenate, etc .; medications for treating hyperlipidemia, such as pravastatin sodium, sinvastatin, lovastatin, prevas tatin, josamycin, etc. ; Antibiotics, such as ampicillin phthalizy 1 hydrochloride, cefotetan, josamycin, etc .; BPH therapeutics, such as tamsulosin hydrochloride (tamsulosin -20- 200412245 C15) hydrochloride) 'doxazocin mesilate , Terazosine hydrochloride, etc .; anti-asthmatic drugs, such as pranrucast, Accorate (zaf irlukas t), albuterol, ambrozole, budesonide, leverbuterol, etc .; used to improve the surrounding circulation Prostaglandin I derivatives, such as velaprost sodium, etc .; antithrombotic drugs, hypotension Medicine, drug treatment for heart failure, treatment of various diabetes Merger complications of drug treatment of gastric ulcer medicine, the treatment of skin ulcer medicine, the treatment of hyperlipidemia drugs (previously), anti-asthma asthma drugs (previously), and so on. These drugs can be used in their free form or in any pharmaceutically acceptable salt form. Furthermore, the present invention may include drugs that do not require sustained release. In addition, a combination of two or more drugs may be used. There is no particular limitation on the dosage of the drug, as long as it is an amount that is often effective for treatment, but preferably 50 w / w% or more based on the weight of the tablet, more preferably 20 w / w% or The lower. For example, when it exceeds 50 w / w% in terms of the weight of the ingot, the ratio of the fine particles to the tincture is high and the granulation from the tincture is insufficient. These drugs are sustained-released and contained in a sustained-release fine particle in the form of fine particles. Under this form, the release of the drug can be controlled according to the following conventional methods. There is no particular limitation on the particle size of the sustained-release fine particles, as long as it is within a range where there is no rough feeling in the oral cavity. The average particle diameter is preferably about 0.1 micrometers to about 3.50 micrometers, more preferably about 5 micrometers to about 250 micrometers, and still more preferably about 50 micrometers to about 250 micrometers. If it is less than 0.1 micron, it will be difficult to provide sustained release using current pharmaceutical technology, and if it is greater than 350 micron, it will cause a very cramped feeling in the oral cavity (16) (16) 200412245 sensation, such as the feeling of coarse gravel. Furthermore, the sustained-release fine particles of the present invention can be prepared by conventional methods. For example, as disclosed in Japanese Patent Hei 7-72 1 29 (corresponding to U.S. Patent Application No. 4,772,475) and International Early Disclosure Booklet 00/24379, after adding polymers to drugs and microcrystalline cellulose Sustained-release fine particles are prepared by agitation granulation method or tumble fluidized bed granulation method, or conventional coating methods, such as fluidized bed coating, tumble fluidized coating, can be used as cores in commercially available microcrystalline fibers. Primed particles (avicel particles, Asahi Kasei, Celphere 02, etc.) are coated with a drug and then coated with a polymer substance to form a controlled release film to form a sustained-release fine particle (Avicel Jiho, No. 40, p. 16). -33, Asahi Kasei Corp.). In addition, crystalline tinctures of about 1 micron to about 150 microns can also be used, especially crystalline lactose, sugar granules, table salt, corn starch, silicon dioxide (silicone), etc., among which the size of the slow-release fine particles ( (About 0.1 to about 3 50 microns). Under the pre-coating with a water-soluble polymer substance, a water-insoluble polymer substance may also be used, in which case the edges of the filler which becomes the core are rounded. Alternatively, a solution or suspension of a drug and a polymer substance may be spray-dried using appropriate equipment, such as a spray drier, to produce sustained-release fine particles. Examples of the solvent used for preparing these sustained-release fine particles are water, organic solvents, and the like. Examples of organic solvents are alcohols, especially methanol, ethanol, propanol, isopropanol, etc., haloalkanes, especially dichloromethane institute, chloroform, chloroethene institute, trichloroethene institute, carbon tetrachloride, Ketones, especially acetone, methyl ethyl ketone, etc., nitriles, especially acetonitrile, etc., and hydrocarbons, especially n-hexane, cyclohexane, etc. These organic solvents may be used singly or in an appropriate ratio of two or more, and they may also be used in a mixture with water in an appropriate ratio. The polymer substance 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, maggots, and the like. Examples of water-insoluble polymers are water-insoluble cellulose ethers such as ethyl cellulose, Aquaquat (trade name, Asahi Kasei), etc., water-insoluble acrylic copolymers such as ethyl acrylate-methyl methacrylate Ester-methyl methacrylate chlorinated methyl ammonium ethyl ester copolymer (for example, trade name Eudragit RS, Rohm), methyl methacrylic acid-ethyl acrylate copolymer dispersion (for example, trade name: Eudi * agit NE3OD, Romg, etc., and the like. Examples of gastric soluble polymers are gastric soluble polyvinyl derivatives, such as polyvinyl acetal diethylaminoacetate, etc., gastric soluble acrylic copolymers For example, methyl methacrylate-butyl methacrylate-dimethylaminoethyl methacrylate (eg, Eudragit E, R6hm), etc., and the like. Examples of enteric polymers are enteric fibers Cellulose polymers such as hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, hydroxymethyl ethyl cellulose phthalate, carboxymethyl ethyl cellulose, Etc., enteric acrylic copolymer, For example, methacrylic acid-methyl methacrylate copolymer (for example, trade name: Eudragit L100, Eudragit S, both of which are from Rohm), methacrylic acid-ethyl acrylate copolymer (for example, trade name: Eudragit L 1 00 -5, 5, Eudragit L30D55, R6hm), etc., and the like. Examples of maggot-like substances are solid oils and fats, such as hydrogenated ramie oil, hydrogenated coconut oil, tallow, etc., high-carbon fatty acids such as stearic acid, Lauric acid, myristic acid, palmitic acid, etc., and high carbonate alcohols, such as cetyl alcohol, stearyl alcohol, -23- (18) (18) 200412245, etc. Among them, methacrylic acid-ethyl acrylate copolymer is more suitable It is used to provide enteric and pH-independent water-insoluble polymers, especially ethyl cellulose, which is more suitable for providing sustained release, thereby gradually releasing the drug. Single or two can be used for the purpose of controlling dissolution. Or more appropriate combination of these polymeric substances. Furthermore, 'plasticizers may be added as needed. Examples of such plasticizers are glycerol triacetate, triethyl citrate, sebacate di Butyl ester, acetylated glycerol- Ester, ethyl acrylate-methyl methacrylate copolymer dispersion (for example, trade name: Eudragit NE30D, Rohm), etc., and preferred is ethyl acrylate, methyl methacrylate copolymer dispersion. Water-soluble polymers, sugars, etc. can be mixed with the above-mentioned polymer substances, such as water-insoluble polymers, gastric-soluble polymers, enteric polymers, etc., or waxy substances, etc. Examples of such substances are hydroxypropyl Cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, polyvinyl alcohol and the like are used as water-soluble polymer substances. Examples of sugars are maltose, maltitol, and the like, and examples of salts are sodium chloride, and the like. The amounts of polymers and sugars used herein can be adjusted as needed to control the dissolution rate of the drug. Furthermore, a single or a combination of two or more of these polymers and sugars can 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 to prepare the composition of the present invention . There is no particular limitation on the " filler " used in the present invention, as long as it is a pharmaceutically acceptable sugar or sugar alcohol. Examples of sugars or sugar alcohols are the low-mold saccharides disclosed in the Early International Publication Booklet WO95 / 20380. Specific examples of (19) (19) 200412245 are xylitol, erythritol, glucose, mannitol, sucrose, and lactose. Among them, mannitol, lactose and erythritol are preferred. In addition, a single of these sugars or a combination of two or more thereof may be used. Here " low-molding sugar " means, for example, that when 150 milligrams of sugar are made into tablets using an 8 mm diameter punch at a tableting pressure of 10 to 50 kg / cm2, it shows less than 2 kp (See WO09 / 2038) (corresponding to US Patent No. 5,576,014, Japanese Patent No. 3 1 2 2 1 4 1). Furthermore, it can also be selected from high melting sugars and low melting sugars (US Patent Application No. 10/1 42, 08 1 (corresponding to International Patent Application PCT / JP02 / 0448 1). There are no particular restrictions on the low melting sugars used in the present invention as long as they are in US Patent Application 10 / 142,081 ( Corresponds to the pharmaceutically acceptable and low melting point sugars listed in the international patent application PCT / JP02 / 0448 1), and it has a relatively lower melting point than the high melting point sugars used in medicines and the present invention, but the better one Is a sugar having a melting point of about 80 to about 180 t: and more preferably a sugar having a melting point of about 90 to 150 ° C. An example of such a sugar is glucose per sugar (early hydrate 'melting point 8 3 ° C), xylitol (melting point 9 3 ° C), trehalose (dihydrate, melting point 9 7 ° C), mountain Sugar alcohol (melting point Π0 ° C), erythritol (melting point 122 ° C), glucose (166 ° C) 'sucrose (melting point about 17 0 ° C), etc. can be used from the group selected from these One or two or more sugars. Among these sugars, preferred is one or two or more polysaccharides selected from the group consisting of glucose, xylitol, trehalose, sorbitol, maltose, red Mossitol, maltitol, and their hydrates. Ideally, trehalose, maltose, erythritol, or mannose-? 5-(20) (20) 200412245 sugar alcohols, especially trehalose and / or Erythritol, because these sugars are only slightly hygroscopic in nature and are easy to handle, a single or a combination of two or more of these sugars can be used. These sugars can also be used in their hydrate form Use, when the hydrate and anhydrate of the sugar have different melting points, the heating temperature must be selected accordingly according to the needs. "High melting sugar" used in the present invention is in US Patent Application No. 1/142, High melting point sugar listed in 08 No. 1 (corresponding to patent application PCT / JP02 / 0448 1). It has a melting point and the present invention Sugars with low melting point sugars with a melting point difference of 10 ° C or higher, preferably sugars with a melting point difference of 20 \: or greater. Considering the temperature set by the heating device and the temperature of the ingot as a heating object Under the difference between them, the better ones should choose the sugars that have a larger difference between their melting points. In particular, xylitol (melting point 93 ° C), trehalose (two Hydrate, melting point 97 ° C), sorbitol (hydrate, melting point slightly below 100 ° C), maltose (melting point 102 ° C), sorbitol (melting point 110 ° c), erythritol (melting point 122 ° C), glucose (melting point 146 ° C), maltitol (melting point 150 V), mannitol (melting point 16 6 ° C), sucrose (melting point about 170 ° C), lactose (melting point 202 ° C) ,Wait. One kind or two or more kinds of sugars selected from the group consisting of these may be used. The explanation of high-melting sugars actually overlaps with low-melting sugars, but because "high-melting sugars" are selected based on their relative relationship with low-melting sugars, the same sugar is not selected. The present invention "high The "melting sugar H and π low melting sugar" are selected depending on the chemical properties of the drug used, that is, the stability of the drug with respect to temperature. When using specific terms to explain the relationship between "high melting point sugar" and "low melting point sugar", -26, (21) (21) 200412245, glucose (monohydrate, melting point 8 3 ° C) is used in the present As "low melting sugar" in the invention, xylitol, trehalose, sorbitol, erythritol, glucose, maltitol, mannitol, sucrose, lactose, and their hydrates can be used as & quot "High melting point sugar". In addition, in the present invention, xylitol (melting point 93 ° C) or trehalose (dihydrate, 97 ° C) is used as "low melting point sugar" under sorbitol , Erythritol, glucose, maltitol, mannitol, sucrose, lactose, and their hydrates can be used as " high melting point sugar ". In the present invention, erythritol (melting point 1 2 2 ° C) As "low melting point sugar", glucose 'maltitol, mannitol, sucrose or lactose can be used as "high melting point sugar". In addition, mannitol (melting point 150 ° C) is used in the present invention As π low melting point sugar, you can use mannitol, sucrose or lactose as &Quot; high melting sugar 〃. In addition, in the present invention, when saccharose (melting point of about 170 ° C) is used as "low melting point sugar", lactose can be used as "high melting point sugar". As mentioned, depending on the kind of sugar used in the present invention, "high melting point sugar" is selected as necessary. There is a large difference between their melting points when choosing sugars, " high melting sugar " is preferably one or two or more sugars selected from the group consisting of glucose, maltitol, mannose Sugar alcohols, sucrose and lactose, and more preferably mannitol, sucrose and lactose. These are used singly or as a mixture of two or more kinds as appropriate, as necessary. Select the high-model sugars listed in the International Early Disclosure Booklet WO95 / 203 80, listed in U.S. Patent Application 10 / 142,08 1 (corresponding to International Patent Application PCT / JP 02/0448 1) Low-melting sugar, or water-soluble polymer substance 'is used as the "adhesive -27- (22) (22) 200412245 agent" for rapid disintegration of tablets in the oral cavity used in the present invention. For example, maltose (preferably maltose powder (maltose content 83% or higher)), trehalose, sorbitol, or maltitol-based " high-mold sugar ", and more preferably maltose and trehalose . Here " high-moldable sugar " means that when 150 milligrams of sugar are tabletted at a pressure of 10 to 50 kg / cm2 using a 8 mm diameter punch, a 2 kp or greater is shown. Tablet hardness (see WO 95/203 80 (corresponding to US Patent 5,576,0 14, Japanese Patent No. 3122141). The above-mentioned low-melting sugar is the low-melting sugar here. Furthermore, hydroxypropyl cellulose, Hydroxypropyl methylcellulose, polyvinylpyrrolidone, copolyvidone, polyvinyl alcohol, etc. are water-soluble polymer substances. A single type or a combination of two or more types can be used. &Quot; Adhesives for rapid disintegration of tablets in the oral cavity. Considering the environment in which they are stored in the form of starting materials and pharmaceutical preparations, hydroxypropyl cellulose and hydroxypropylmethyl with low hygroscopicity are preferred. Cellulose, or copolyvinylpyrrolidone, and desirably copolyvinylpyrrolidone. In addition, the present invention "adhesive for rapid disintegration of tablets in the oral cavity" may be one or two or more selected from the group consisting of Those in the group: "High mold sugar "", "Water-soluble polymer substances", "and low-melting sugars". I: "Elixir": high-melting sugars, "adhesives for rapid disintegration of tablets in the oral cavity": highly moldable sugars Or water-soluble polymer material, II: "Essence filling": High melting point sugar, "Binder for rapid disintegration of tablets in the oral cavity": Low melting point sugar, ΠΙ: "Essence filling": High melting point sugar, " Adhesives for rapid disintegration of tablets in the oral cavity ": low-melting sugar and water-soluble polymer substances, and -2®-(23) (23) 200412245 IV:" Epistatic filler ": high-melting sugar and low-melting sugar, "Binders for rapid disintegration of tablets in the oral cavity": Water-soluble polymer substances or highly moldable sugars, which are related to the above-mentioned "fillers" and "binders for rapid disintegration of tablets in the oral cavity" of the present invention Specific specific examples of selection. For the demonstration of IV, it is better to choose erythrose as the "low melting sugar", lactose and / or mannitol as the "high melting sugar", and mannitol as the cavity. Binder for rapid disintegration of tablets ("Still Molded Sugar"), or optional Moss sugar is used as the "low melting sugar", lactose and / or mannitol are used as the "high melting sugar", and copolyvinylpyrrolidone is also used as the binder for the rapid disintegration of tablets ("water soluble polymer") In the present invention, the amount of " blanch filler " is adjusted as needed according to the dose of the drug and / or the size of the tablet. When the dose of the drug is small, the amount of the " blanch filler " of the present invention is increased and when the dose of the drug is large By reducing the amount of the " filler " of the present invention, etc., the amount can be adjusted as needed to obtain tablets of a desired size. Generally, it is preferred to use 20 to 1,000 mg per tablet, more preferably 50 to 500 mg, or even more preferably 100 to 400 mg. If the amount of tincture filler is less than 20 mg, complete granulation may not be completed. Furthermore, when the amount of tincture filling is more than 1,000 mg, the tincture filling content may be too large relative to the amount of saliva in the oral cavity, and this may cause a strange feeling in the mouth. In the present invention, the amount of the "adhesive for quick disintegrating tablets in the oral cavity" is usually preferably 0.5 to 50 w / w%, and more preferably 1 to 30 w relative to the weight of the "filler" of the present invention. / w%, even better 1 to 20 w / w%. If its weight is less than 0.5 ~~% relative to 11 (24) (24) 200412245, it will be used as It is possible that the function of the adhesive cannot be fully realized. In addition, if it is 50 w / w% of the weight of "J /", "塡 charger", it is possible to find a number of problems, including delayed disintegration 'etc.' and in use When the tablets are rapidly disintegrated in the oral cavity, good properties cannot be obtained. Although the mixing ratios of "sustained release granules", "fillers", and "adhesives for rapid disintegration of tablets in the oral cavity" cannot be clearly listed in their percentages, when an example is given, The mixing ratio is preferably 1 to 50% '20 to 98%, and 1 to 30%, and more preferably 1 to 20%, 60 to 98%, and 1 to 20%. Except for the present invention "发明Fillers, and, and adhesives for rapid disintegration of tablets in the oral cavity ", various additives that are pharmaceutically acceptable and used as additives can be added. These additives can be used in conjunction with tincture when granulating slow-release granules. Mixed, or they can be used in the form of a mixture with the composition of the present invention in the manufacture of tablets. Examples of such additives are disintegrants, sour flavors, foaming agents, artificial sweeteners, flavors, lubricants, colorants, Stabilizers, etc. One of these additives or a combination of two or more thereof may be used. Furthermore, there is no particular limitation on the amount to be added, as long as it is an amount commonly used in pharmacy by those skilled in the art and it is in What is necessary is just to fall within the range of the result of this invention. An example of a disintegrant is splashing. For example, corn starch, etc., calcium methyl cellulose, partially α-converted starch, cross-linked polyvinyl pyrrolidone (crospovidon), low-substituted hydroxypropyl cellulose, etc. Examples of sour flavoring agents are Citric acid, tartaric acid, malic acid, etc. Examples of foaming agents are bicarbonate 15, etc. Examples of artificial sweeteners are saccharin sodium, dipotassium glycyrrhizinate, aspartame, stevia ), (25) (25) 200412245 sonnatin, etc. Examples of spices are lemon, lemon-lime, orange, menthol, etc. Examples of lubricants are magnesium stearate, calcium stearate, sucrose fatty acid ester , Polyethylene glycol, talc, stearic acid, etc. Examples of colorants are food colorants, such as yellow food dye No. 5, red food dye No. 0.2, blue food dye No. 0.2, etc .; food Precipitating pigments; iron oxide red, etc. Stabilizers are selected according to the drug after various tests are performed. One or two or more combinations of these additives can be added in the appropriate amount as needed. Here it is explained in detail The present invention contains slow-release fine particles The method of manufacturing the composition, especially the manufacturing conditions, etc. So far, the method for manufacturing the composition containing slow-release fine particles for rapid disintegration of tablets in the oral cavity of the present invention will be described as follows: (a) Including effective treatment or prevention The production process of slow-release fine particles that can be used to control the dissolution rate of this drug, and (b) the "sustained-release fine particles π" and the "filler" are made with π binder for rapid disintegration of tablets in the oral cavity " Procedures for granules. Procedure (a): The manufacturing procedure of the sustained-release fine particles is as described above. The sustained-release fine particles are manufactured by conventional methods. There is no particular limitation on this method and it can be selected as needed, as long as it is available for use. The goal of controlling dissolution is sufficient. For example, a drug layer is coated on a commercially available crystalline cellulose particle, crystalline lactose, sugar particle, salt, dioxide, etc. using a binder such as hydroxypropyl cellulose, and then Then, a polymer substance such as a water-insoluble polymer substance, a stomach-soluble polymer substance, an enteric polymer substance, a waxy substance, and the like are coated thereon to make sustained-release fine particles. Alternatively, -31-(26) (26) 200412245 may be applied to a towel with a drug substance such as a water-insoluble polymer substance, a stomach-soluble polymer substance, an enteric polymer substance, a waxy substance, etc. Crystalline cellulose particles, crystalline lactose, sugar granules, salt, silica, etc. are sold to produce sustained-release fine particles. In addition, slow-release granules can also be produced by adding a solution of a polymer substance to drugs and microcrystalline cellulose by agitation granulation or drum fluidization granulation. The above-mentioned coating can be further applied to these sustained-release fine particles, and if necessary, they can be provided with an enteric function by coating an enteric polymer substance. The coating can be performed using, for example, a fluidized bed granulator. Set the temperature and other, spray volume, spray air volume, etc. so that in the case of coating with water, the product temperature is about 40 ° C to about 60 ° C and when using organic solvents is about 30 ° C to about 60 ° C. The drug concentration, percentage and amount of polymer substance used during coating can be adjusted as needed according to the desired dissolution rate. Procedure (b): The granulation procedure is not particularly limited to the granulation method of the present invention, as long as it can be used to make sustained-release fine particles by using "Halogen" and "Hydrogen Disintegrating Tablets" with binder H can. For example, fluidized bed granulation, agitation granulation, and drum granulation can be selected as the granulation method. Of these, a fluidized bed granulation method is preferred in terms of productivity. By this, a solution of the “π fast disintegrating tablet for oral disintegration in the oral cavity” solution of the present invention, which is dissolved and / or suspended in a pharmaceutically acceptable solvent, can be sprayed on the mixture of the slow-release fine particles and the “filler”. The method of making granules and manufacturing the "composition" can be selected as the fluidized bed granulation method. At this time, the "sustained-release fine particles should be covered with" quot filling agent ". The manufacturing condition is better, for example , About 2 5 -32- (27) (27) 200412245 ° C to about 40 ° C product temperature and about 0.2 to about 5% water content. In addition, it is preferred to make by intermittent spray cloth "Intermittent spraying" means intermittent spraying and is a spraying method for granulation, which includes repeating the cycle, for example, spraying for 10 seconds and then drying for 30 seconds. Furthermore, this cycle can be adjusted depending on manufacturing needs. In addition, the spraying time-drying time can be appropriately selected. It is also possible to add granules after adding the above additives if necessary. " 塡 电 剂 " can be used for commercially available products. When the average particle size of the " filler " is greater than the average particle size of the slow-release fine particles, it is preferable to use the " filler " with a suitable pulverizing device, such as a hammer mill, a sample mill, Nail mills, etc. are crushed to help with the granulation of slow-release fine particles. When the "binder for rapidly disintegrating tablets in the oral cavity" is a high-molding sugar, it is preferred to dissolve it 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% to maximize the adhesive strength of the adhesive for rapid disintegration of tablets in the oral cavity. If the liquid concentration is lower than 10 w / w%, the liquid volume will be too large and the program will take more time, while if the liquid concentration is higher than 40 w / w%, the program will be completed in a short time and therefore difficult to maintain Hold spray time-drying time cycle. Furthermore, the composition containing the slow-release fine particles of the present invention can be used in the oral fast disintegrating tablet, and the method includes (c) •• granulating the composition obtained in the procedure (b) to produce a tablet and ( d): the procedure of humidifying and drying the ingots obtained in the procedure (c) if necessary. In addition, when the above-mentioned high-melting sugar and low-melting sugar are used to make the composition, the program (d ') may be selected: heating the ingot obtained in the program (c), and the program (e): cooling after the program (d) , The method. It is also possible to implement the procedure (d) after the procedure (d ') and-33- (28) (28) 200412245 (e). Procedure (c): The ingot-making procedure " ingot-making " is implemented by conventional methods. This is not particularly limited as long as it is a method that can be used to obtain the shape of the ingot at the minimum pressure required to maintain the shape of the ingot. Such "ingot making" can be used, for example, a general ingot making machine such as a single type ingot making machine or a rotary ingot making machine, etc., and adding the necessary additives to the above-mentioned "composition", from a lubricant such as hard Magnesium stearate was started and then implemented. Furthermore, the above-mentioned "composition can be made into ingots" using an external lubricating ingot making machine. Generally, the ingot forming pressure of about 25 to about 800 kg / punch is preferred, More preferred is about 50 to about 500 kg / hole, and most preferred is about 50 to about 300 kg / hole. Procedure (d): The humidification and drying procedure is used in the granulation procedure as "intraoral rapid disintegration tablets" With a binder, when the sugar used is amorphous and the strength of the ingot obtained by the ingot making procedure is reduced due to moisture absorption, that is, in the present invention, the binder for rapid disintegration of tablets in the mouth is " When high-mold sugar is used and maltose, sorbitol, or trehalose is used, it is preferable to use the following humidification and drying procedures. "Humidification" is carried out in conjunction with a drying procedure. This is a procedure following the humidification procedure. There are no special restrictions on its method As long as the method is a method for rapidly disintegrating the tablet in the oral cavity of the present invention, the sugar used can be crystallized from an amorphous substance. The conditions for this "wetting" are determined by including the drug-containing sustained-release fine particles, the "adhesive for rapid disintegration of tablets in the oral cavity" used in the present invention, -34-(29) (29) 200412245 and Apparent critical relative humidity of the mixture. Humidification is usually applied to at least the critical relative humidity of the mixture. For example, the humidity is preferably about 30 to about 100 RH% and more preferably about 50 to about 90 RH%. The temperature at this time is preferably about 15 to about 50 t and more preferably about 20 to about 40 ° C. The humidification time is preferably 1 to 48 hours and more preferably 12 to 24 hours. There is no particular limitation on "drying" as long as it is capable of eliminating moisture absorbed through humidification. Regarding the "dry" conditions, it is usually about 10 to about 10 ° C, more preferably about 20 to about 60 ° C, and most preferably about 25 to about 40 t. The drying time is preferably 30 minutes to 10 hours and more preferably 1 to 4 hours. Process (): Heating process The "pi heating" in the present invention is implemented by conventional methods and is not particularly limited as long as it can bring the molded particles obtained by the process (c) to at least the above-mentioned " low melting point sugar "The method of the temperature with the melting point can be used. The" heating "procedure can be implemented by using, for example, ventilation drying. The temperature conditions are selected according to the type of" low melting sugar "as required, and there is no particular limitation. As long as it is the " low melting point sugar " used in the present invention, the melting point or higher and " high melting point sugar " the melting point or better. When using the " low melting point sugar " used in the present invention, , Which is about 80 to about 180 ° C, preferably about 90 to about 150 ° C. The time conditions are selected according to the type of sugar used, the desired tablet strength, the disintegration performance in the oral cavity, etc. It is usually 0.5 to 120 minutes, preferably 1 to 60 minutes, and more preferably 2 to 30 minutes.-35- (30) (30) 200412245 Program (e): Cooling program " Cooling " of the present invention It is implemented by a conventional method, and is not particularly limited as long as it is The method of solidifying the low-melting sugar used in the present invention after melting can be solidified. The " cooling " can be implemented by, for example, standing at room temperature or storing in a low-temperature air enclosure, such as a refrigerator. Next, an example of a method for manufacturing a composition containing slow-release fine particles for an orally disintegrating tablet according to the present invention is given below. First, a fluidized bed is made using a suitable adhesive (for example, hydroxypropyl methylcellulose). Granulators, etc., to coat the drug on commercially available crystalline cellulose particles (eg, Celphere 102). Then, if necessary, water-insoluble polymer material (eg, ethyl cellulose) and water-soluble polymer (eg, hydroxypropyl) A mixture of cellulose-based cellulose) is coated with a fluidized bed granulator, etc. to obtain a desired dissolution. These fine particles and sugars (eg, mannitol) are then rapidly disintegrated in the oral cavity using tablets for bonding Agent (for example, maltose) is granulated intermittently using a fluidized bed granulator (for example, a cycle of spraying for 10 seconds followed by drying for 30 seconds) to obtain the sustained-release fine particles for rapid disintegration of the present invention Composition. Sustained-release granules containing sustained-release fine particles in the oral cavity can be added to the composition containing the sustained-release fine particles used in the oral fast-disintegrating tablets of the present invention by adding required additives, such as a suitable lubricant such as magnesium stearate, etc. And prepared using ingot making mechanism. [Embodiment] Description of preferred specific examples -36- (31) (31) 200412245 The present invention will be further explained with examples below, but the explanation of the present invention is not limited to these examples. Method for evaluating compositions containing slow-release fine particles [Determination of particle size distribution of slow-release fine particles and compositions containing slow-release fine particles] The particle size is a sieve-type particle size distribution gauge (Seishin Enterprise Co. .,

Led. Robot Sifter) was measured on a 30, 42, 60, 80, 100, 150, 200, and 250 mesh sieve. _ [Quantity-type ratio measurement of particle size of composition containing sustained-release fine particles] Determine the amount of the composition remaining on each sieve with the above-mentioned opening size and the amount of each part of particles. The total amount is set to 100%, and the proportion of the residual amount on each sieve is calculated and used as the proportion of the particle diameter. In addition, the size distribution of the particle diameter was obtained by arranging the content ratio of the particle diameter in the order of the opening diameter of each sieve. Incidentally, any method can be used to determine the quantitative amount as long as the contained drug can be completely recovered from the composition, and the 0 measurement is performed by a measurement method applicable to each drug. [Proportion of Ungranulated Slow-Release Fine Particles] The particle size distribution of the slow-release fine particles and the volume-type distribution of the particle size of the composition containing the slow-release fine particles are measured and calculated by the following formula: Ungranulated slow-release The proportion of fine particles (%) = Gi + Z (G ^-(P iG 〇) Here, the estimate of Σ is calculated from i = i to (Gu ^ Pi-Gi)) 値 becomes a point before the negative becomes. -37- (32) 200412245 P !: The ratio of slow-release fine particles on the minimum-pore size sieve in such slow-release fine particle size distributions (except for cases where 値 is 0%). That is, 1 5.0% on the 150 meshes in the following examples. P2: The proportion of the sustained-release fine particles on the second smallest pore size sieve within the particle size distribution of the sustained-release fine particles (except when the value is 0%). That is, 70.6% on 100 meshes in the example below. Its third smallest hole, fourth, and so on are P3, P4, and so on, and they are all represented by Pi.

Gi: The proportion of the composition particle size distribution on the sieve with the same pore size as P! That is 2.5% on the 150 mesh in the following examples. G2: The proportion of the content of the particle size distribution of the composition on the sieve with the same aperture as p2, i.e., 14.3% on the 100 mesh in the following examples. Third, fourth, and so on are G3, G4, and so on, and they are all represented by the same. For example, if the measurement result is as follows: Slow-release fine particle size distribution Example 1 The quantitative distribution of the particle size of the composition 3 0 mesh (%) 0 19.0 42 mesh (%) 0 22.4 60 mesh On (%) 0 23.5 8 0 On the mesh (%) 14.4 18.2 1 0 0 On the mesh (%) 70.6 14.3 1 5 0 On the mesh (%) 15.0 2.5 200 On the mesh (%) 0 0 2 0 0 The mesh passed (% ) 0 0 (33) (33) 200412245 Proportion of ungranulated slow-release fine particles (%) = G] + Z (G "i_ (Pi-Gi)) = Gl + (G2- (Pl_Gl)) + (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 値 in the parentheses is negative, it means that the sustained-release fine particles are solidified to make the particle size larger by at least one level. Therefore, without further evaluation = 2.5 + (+1.8) = 4.3 Evaluation method for rapid disintegration of tablets in the oral cavity [Hardness test] The measurement was performed using a Schleunigei * tablet hardness tester (Schleuniger Co., Ltd.). The test was performed using 5 tablets and displayed Average 値. The hardness of the ingot is expressed by the force required to crush the ingot (unit kp). The larger the number, the harder the ingot is. ® [Fragility] The measurement was performed using a friability tester (model PTFR-A, Pharma Test Co.). The friability was measured using a 6 g ingot. It was 100 times after turning at 25 rpm inversion speed. The percentage of tablet weight loss is shown below. The smaller the tablet, the stronger the tablet surface. [Intraoral disintegration test] Healthy adult men place the tablet of the present invention in the oral cavity without water in the oral cavity and measure until the tablet is completely composed of saliva only. The time until disintegration and dissolution. [Content average sentence test] Component analysis measures the drug content of each of the 10 tablets containing -39- (34) (34) 200412245 and uses the formula table above as the coefficient of variation of the drug content (CV%). [Dissolution test] The test was performed with Dissolution Test Method No. 2 according to Japanese Pharmacopoeia, Revised Version 12. Example 1 80 g of tamsulosin hydrochloride and 80 g of hydroxypropyl cellulose (TC5E , Shin-Etsu Chemical Co., Ltd.) was dissolved in a mixture of 304 g of pure water and 2,7 36 g of methanol. Introduce 4,000 grams of Celphere 102 (brand name, Asahi Kasei, average particle size of about 127 microns, particle size of about 50 to about 150 microns) into a fluidized bed granulator (Freund Industries, FLO-5) and use this The solution was applied by a side spray method (a spray volume of 100 g / min, a spray air pressure of 4 kg / cm2, a product temperature of 40 ° C, and an inlet temperature of 80 ° C) to obtain tamsulosin hydrochloride particles. In addition, 533 g of ethyl cellulose (Nissin Chemistry Co ·) and 187 g of hydroxypropylmethyl cellulose (TC5E, brand name, Shin-Etsu Chemical Co., Ltd.) were dissolved in 698 g of pure water and 22, 5 82 g of methanol in a mixture. Introduce 4000 g of tamsulosin hydrochloride particles into a fluidized bed granulator (Freund Industries, FLO-5) and use this solution to apply by side spraying (spray volume 40 g / min, spray air The pressure is 4 kg / cm², the product temperature is 50 ° C, and the inlet temperature is 60 ° C) to obtain slow-release fine particles. Into a fluidized bed granulator (Freund Industries, FL0-5), introduce 4,000 grams of this slow-release granule and use 2,000 grams of Aquacoat (brand name, Asahi Kasei), 4, 0,0 grams of Eudr agit (35 ) 200412245 L30D55 C brand name, R0hm), 667 grams of Eudragit NE30D (brand name 'R0hm)' and 6,667 grams of pure water coating (spray volume 40 g / min 'spray air pressure 4 kg / cm2, Product temperature is 50 ° C and inlet temperature is 60 ° C) to obtain enteric slow-release fine particles. 3 68 g of these enteric slow-release fine particles, 2,560 g of mannitol (Towa Kasei Co., Ltd.) and 640 g of lactose (Domomilk) were used containing 400 g of maltose (Hayashibara Co., Ltd. · , Brand name:

A 40% w / w aqueous solution of Sunma 11 S) was granulated in a first-class fluidized bed granulator (Freund Industries, FLO-5) (the spray volume was 200 g / min, and the spray air pressure was 1.5 kg / Square centimeter, product temperature 29 ° C, inlet temperature 80 ° C, spraying cycle: 10 seconds spraying and 30 seconds drying) to obtain the composition of the present invention.

After further mixing 32 g of calcium stearate with the obtained composition, a rotary granulator was used to produce 0.2 mg of tamsolo hydrochloride at an ingot pressure of 100 kg / punch and an initial hardness of 1.0 kp. 200 mg tablets of osmium tablets. Next, these ingots were placed at 25 ° C / 75% RH and heated and humidified in a constant temperature oven (Tabaiespec Co., Ltd., PR-35C) for 18 hours under a fixed humidity. They were then dried at 30 ° C and 40% RH for 3 hours. The obtained ingots exhibited a hardness of 5.9 kp (η = 5), a friability of 0.8% (100 revolutions), and an intraoral disintegration time of 20 seconds (η = 3). Furthermore, the result of content uniformity evaluation, CV% = 2.1%, proved that there is good content uniformity. Comparative Example 1 -41-(36)-(36) -200412245 First, 319.3 g of mannitol (Towa Kasei Co.,

Ltd.) and 79.7 grams of lactose (Domomilk) using a 20% w / w aqueous solution containing 50 grams of maltose (Hayashibara Co., Ltd., brand name: Sunmalt S) in a first-class bed granulator (Freund Industries, unit -glatt) granulation (spray volume 10 g / min, spray air pressure 1.5 kg / cm2, product temperature 3CTC, inlet temperature 60 ° C, spray cycle: continuous spray). After 45.2 g of the enteric slow-release fine particles prepared in Example 1 and 5 g of calcium stearate were mixed with the resulting product, a rotary granulator was used at a pressure of 93 kg / punch and 丨. A 200 mg tablet containing 0.2 mg tamsulosin hydrochloride was manufactured at an initial hardness of 0 kp. Next, the ingots were placed under a temperature of 25 ° C / 75% R, and then heated and humidified in a constant temperature (Tabaiespec Co., Ltd., PR-35C) for 18 hours under a fixed humidity. They were then dried at 30 ° C and 40% R for 3 hours. The obtained ingots showed a hardness of 4.1 kp (η = 5) and an intraoral disintegration time of 15 seconds (η = 3). Furthermore, the result of content uniformity evaluation, CV% = 5.6%, proves that there is poor content uniformity. Comparative Example 2 First, 4 5.2 g of the enteric slow-release fine particles prepared in Example 1, 319.3 g of mannitol (Towa Kasei Co., Ltd.), and 79.7 g of lactose (Domomilk) were used to contain 50 g of maltose. (Hayashibara Co., Ltd., brand name: Sunmalt S) A 20% w / w aqueous solution was granulated in a first-class bed granulator (Freund Industries, unit-glatt) (the spray volume was 10 g / min. The air pressure of the spraying cloth is 1.5 kg / cm 2 -42- (37) (37) 200412245 minutes, the product temperature is 30 ° C, the inlet temperature is 60 ° C, and the spraying cycle is continuous spraying). After mixing 5 g of calcium stearate with this obtained product, a rotary granulator was used to produce 0.2 mg of tamsulosin hydrochloride at an ingot pressure of 96 kg / punch and an initial hardness of 1.0 kp. 200 mg of osmium tablets. Next, these ingots were placed at 25 ° C / 75% RH, and heated and humidified in a constant temperature oven (Tabaiespec Co., Ltd., PR-35C) for 18 hours under a fixed humidity. They were then dried at 30 ° C and 40% RH for 3 hours. The obtained ingots did not show a hardness of 3.7 kp (η = 5) and an intraoral disintegration time of 15 seconds (η = 3). Moreover, the result of content uniformity evaluation, CV% = 4.0%, proves that there is poor content uniformity. Experiment 1 (Quantitative analysis of particle size distribution) The particle size distribution of the slow-release fine particles obtained in Example 1 and the composition prepared in Examples 1 and 2 (Table 1) and the products prepared in Comparative Examples 1 and 2 (Table 2) The particle size distribution) is shown together with the particle size quantitative analysis distribution. -43- (38) 200412245 (38)

Table 1. Particle size distribution of slow-release fine particles and implementation of Example 1 Particle size distribution of components 1 and 2 and quantitative analysis of particle size distribution of slow-release fine particles Example 1 Example 1 Group Example 2 Composition Example Two groups of particle size distribution composition. Particle size distribution. Particle size distribution. Particle size distribution. Quantitative analysis distribution. Quantitative analysis distribution. Average particle size (micron) 165 393 204 30 On the mesh (%) 0 26.9 19.0 1.5 1.1 42 on the mesh (%) 0 29.7 22.4 5.1 6.2 60 on the mesh (%) 0 23.8 23.5 23.1 27.2 80 on the mesh (%) 14.4 9.8 18.2 31.5 43.4 100 on the mesh (%) 70.6 2.8 14.3 15.2 17.6 150 on the mesh ( %) 15.0 3.1 2.5 16.1 4.3 200 on the mesh (%) 0 1.5 0 5.1 〇 200 mesh passing (%) 0 2.5 0 2.5 〇 Ungranulated product ratio (%) 4.3 — 11.2

-44- (39) 200412245 (39)

Table 2. Particle size distribution and comparison of slow-release fine particles 1 Particle size distribution of the composition of columns 1 and 2 Spear particle size quantitative analysis distribution Slow-release fine particles Comparative Example 11 Comparative Example 11 Comparative Example 2 Comparative Example 12 The particle size of the product. The particle size of the product. The particle size of the product. The particle size distribution of the product. 2.1 42 on the mesh (%) 0 8.0 〇11.3 10.3 60 on the mesh (%) 〇13.8 〇17.8 19.3 80 on the mesh (%) 14.4 23.6 14.2 23.4 42.2 100 on the mesh (%) 70.6 18.9 70.9 12.8 4.9 150 on the mesh (% ) 15.0 17.8 14.4 13.8 4.9 200 on the mesh (%) 0 8.4 〇8.8 0 200 mesh passed (%) 0 4.9 0 9.0 0 Proportion of ungranulated products (%) 99.2 16.0

-45- (40) · (40) · 200412245 Most of the sustained-release fine particles are within the 80-1 00 mesh and the quantitative analysis of the particle size distribution of Examples 1 and 2 determines that most of the sustained-release fine particles are The distribution of the composition containing the sustained-release fine particles coated by granulation is shifted toward a large particle size. On the other hand, regarding the product distribution of Comparative Example 2, it can be confirmed that the apparent particle size is larger, but the quantitative analysis ratio of the particle size distribution may not necessarily be consistent with the product distribution. In particular, the quantitative analysis ratio of 80 to 100 meshes below which the ungranulated slow-release fine particles below would fall was 20% or more, and many un-granulated slow-release fine particles were observed. In addition, as a result of microscopic observation of the composition and the product ', many ungranulated slow-release fine particles were observed in the 80-150 mesh portion of the product of Comparative Example 2. On the other hand, almost no granulated sustained-release fine particles were observed for the composition of Example 1. For example, findings that support the above data were obtained even when observed through a microscope. It is known from these results that the sustained-release fine particles were completely granulated by the tinctures in the compositions of Comparative Examples 1 and 2. In addition, when the proportion of the ungranulated product is 4.3% (Example 1) and 11.2% (Example 2), the coefficients of variation are 2.2 · (CV%) and 2.1 · φ (CV%), respectively. ), And when the ratios of the ungranulated products were 99.2% (Comparative Example 1) and 16.0% (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 result shows that the coefficient of variation (CV%) as an index of content uniformity is larger and more than 3.5% of the allowable radon. Experiment 2 (dissolution experiment) The ingots obtained in Examples 1 and 2 and Comparative Examples 1 and 2 were subjected to a dissolution experiment -46- (41) (41) 200412245, and the results were compared with the dissolution rate when only slow-release fine particles were used. The experimental conditions were a paddle method of 100 rpm, and a 500 ml Japanese Pharmacopoeia Disintegration Test Method wide fluid (pH 1.2) and 2nd fluid (pH 6.8) were used as the experimental fluids. The experimental results show that after the initial dissolution experiment using the test fluid at pH 1.2 for up to 2 hours, in the examples, there is almost no difference in the dissolution rate between the slow-release fine particles and the ingot (the difference after 2 hours is 値0.7%), and even when the test fluid at pH 6.8 is used, the dissolution rate difference between slow-release fine particles and tablets is always less than 15 when the slow-release fine particles dissolve at 30%, 50%, and 80%. The percentages were 2.9%, 5.8%, and 5.1%, respectively. It was confirmed that the dissolution was not promoted when the ingots were made (Figures 1 and 2). On the other hand, in the comparative example, it can be seen that the dissolution rate is accelerated when making ingots compared to the slow-release fine particles (Figure 3, the number difference after 2 hours is 1 5.9% and 1 2.8% ). It can be judged that this is because it is different from the fact that the slow-release fine particles did not appear on the surface of the ingot in Example 1. In Comparative Examples 1 and 2, it was observed that the slow-release fine particles appeared on the surface of the ingot and therefore, As a result of the contact between the surface of the punch and the slow-release fine particles, the slow-release fine particles are damaged. Therefore, it can be confirmed that with the present invention, the sustained-release fine particles can be completely granulated by the tincture and the dissolution promoting phenomenon during ingot making can be avoided. Example 2 First, 2,609 g of mannitol (Towa Kasei Co., Ltd.) and 653 g of lactose (Domomilk) were pulverized in a pin mill pulverizer (42) (42) 200412245 (Hosokawa Micron). . This pulverized product and 307 g of the enteric slow-release fine granules prepared in Example 1 were used in a 20% w / w aqueous solution containing 400 g of maltose (Hayashibara Co., Ltd., brand name: Sunmalt S) in a first-class bed. Granulation is performed in a granulator (Freund Industries, FL0-5) (the spray volume is 100 g / min, the spray air pressure is 1.5 kg / cm2, the product temperature is 28 ° C, and the inlet temperature is 80 ° C. Cloth cycle: 20 seconds spraying and 30 seconds drying). After mixing 32 g of calcium stearate with the composition obtained, a rotary granulator was used to produce 0.1 mg of hydrochloric acid at a pressure of 100 kg / punching and an initial hardness of 1.0 kp. Tamsulosin 120 mg tablets. Next, the ingots were placed at 25 ° C / 70% RH, and stored in a constant temperature oven (Tabaiespec Co., Ltd., PR-35C) under a fixed humidity for 18 hours. They were then dried at 3 (TC and 40% RH for 3 hours. The resulting ingots had a hardness of 5.2 kp (n = 5), a friability of 0.6% (100 revolutions), and an oral cavity of 20 seconds. Disintegration time (η = 3). Furthermore, the content uniformity evaluation result, c V% = 2.2%, confirms that the ingot has good content uniformity. In addition, the results of the dissolution test on the obtained slow-release fine particles and ingot After using the test flow of ρ Η 1 · 2; the initial dissolution experiment for 2 hours, the dissolution rate difference between the slow-release fine particles and the ingot was 4.7%, and even with the test fluid of pH 6 · 8, When the dissolution rate of slow-release fine particles is 30%, 50%, and 80%, the difference in dissolution rate between slow-release fine particles and tablets is always less than 15%, which are 2.3%, 2.4%, and 1.4%, respectively. It can be confirmed that the dissolution during the manufacture of the ingot was not promoted. In addition, the same composition and the same manufacturing method as above were used to produce the tablets. The obtained tablets had a hardness of 5.6 kp (η = 5), 0.6 % Brittleness (43) (43) 200412245 Friability (100 revolutions) and oral disintegration time of 25 seconds (n = 3). Furthermore, the result of content uniformity evaluation, CV% = 2 · 5%. Like the above-mentioned discoverer, the results of the dissolution test and the lozenge are not revealed. Therefore, 'Using the present invention, it is possible to prepare a composition containing slow-release fine particles, and to prevent the As a result of partial segregation, uniformity of content can be ensured. In addition, it can be confirmed that reproducibility is obtained. Example 3 200 g of acetaminophen (Yoshitomi Fine Chemicals Co., Ltd.) and 60 g of hydroxypropylmethyl Cellulose (TC5E, Shin-Etsu Chemical Co., Ltd.) was dissolved in a mixture of 720 g of methanol and 720 g of dichloromethane. 300 g was introduced into a fluidized bed granulator (Freund Industries, unit-glatt) Celphere 102 (brand name, Asahi Kasei, with an average particle size of about 127 microns and a particle size of about 50 to about 150 microns) and applied this solution by side spraying (14 g / min spray volume, spray air The pressure is 3 kg / cm², the product temperature is 32 ° C, and the inlet temperature is 45 ° C) to obtain replenishing paracetamol particles. In addition, 48 g of ethyl cellulose (Nissin Chemistry Co.) and 12 g of propylmethyl Cellulose (TC5E 'Brand Name, Shin-Etsu Ch emical Co., L t d.) was dissolved in a mixture of 57 g of pure water and 1.08 g of methanol. 300 g of supplemental heat was introduced into a fluidized bed granulator (Freund Industries, uni-glatt). Paracetamol particles were applied by side spraying with this solution (spray volume 8 g / min, spray air pressure 3 kg / cm2, product temperature 38 ° C, inlet temperature 67 ° C) for sustained release Fine grain. 66 (44) (44) 200412245 grams of this slow-release fine particles and 314.25 grams of mannitol (Towa Kasei Co., Ltd.) pulverized by a pin mill pulverizer (Hosokawa Micron) were used. 67.5 grams of maltose (Hayashibara Co., Ltd., brand name · Sunma 11 S) 30% w / w aqueous solution was granulated in a first-rate bed granulator (Freund Industries, uni-glatt) (spray volume 15 g) / Min, spray air pressure 1.1 kg / cm2, product temperature 30 ° C, inlet temperature 38 ° C, spray cycle: 30 seconds spray to 30 seconds drying) to obtain the composition of the present invention. The proportion of ungranulated slow-release fine particles was 0.0%. After mixing 2.25 g of magnesium stearate with this resulting composition, a rotary granulator was used to produce 450 mg of 25 mg tonicol at a tabletting pressure of 25 kg / punch and an initial hardness of 2.0 kp. ingot. Then, the ingots were stored at 25 ° C / 75% RH, and stored in a constant temperature oven (Tabaiespec Co., Ltd., PR-gSC) for 24 hours under a constant humidity. They were then dried at 30 ° C and 40% RH for 3 hours. The obtained ingots exhibited a hardness of 3.5 kp (η = 5) and an intraoral disintegration time of 12 seconds (η = 1). Furthermore, as a result of content uniformity evaluation, CV% = 1.2%, it was confirmed that there was good content uniformity. In addition, 2.8 hours after the initial dissolution experiment (when the sustained-release fine particles are about 30% dissolved), 5 hours (when the slow-release fine particles are about 50% dissolved), and 9 hours (after the slow-release fine particles are dissolved) When the released fine particles are about 80% dissolved), when the dissolution rate of the slow-release fine particles and the ingot is compared and the difference is calculated, it is 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) (45) 200412245 Example 4 600 grams of tonicol (Yoshitomi Fine Chemicals Co., Ltd.) and 120 grams of hydroxypropyl methylcellulose (TC5E, Shin-Etsu Chemical Co ., Ltd.) was dissolved in a mixture of 1,440 g of methanol and 1,440 g of dichloromethane. Introduce 300 grams of table salt (Shin Nihon Salt Co., Ltd. EF-70 grade) in a fluidized bed granulator (Freund Industries, unit-glatt) with an average particle size of about 67 microns and a particle size of about 75 microns or less Person) and use this solution to apply by side spraying method (spray volume of 10 g / min, spray air pressure of 3 kg / cm2, product temperature of 33 ° C, inlet temperature of 55 t) to obtain replenishing paracetamol particle. In addition, 72 g of ethyl cellulose (Nissin Chemistry Co ·) and 8 g of hydroxypropylmethyl cellulose (TC5E, brand name, Shin-Etsu Chemical Co., Ltd.) were dissolved in 76 g of pure water and 1, 444 grams of methanol in a mixture. Introduce 400 grams of replenishing paracetamol particles into a fluidized bed granulator (Freund Industries, uni-glatt) and use this solution to apply by side spraying (the spray volume is 10 g / min, spray air The pressure is 3 kg / cm2, the product temperature is 39t, and the inlet temperature is 70 ° C) to obtain slow-release fine particles. Then 76.5 g of this slow-release fine granules and 393.4 g of mannitol (Towa Kasei Co., Ltd.) pulverized by a pin mill pulverizer (Hosokawa Micron) were used, containing 52.5 g of maltose (Hayashibara Co., L t d ., Brand name: Sunma 11 S) 20% w / w aqueous solution was granulated in a first-class bed granulator (Freund Industries, uni-glatt) (spray volume 15 g / min, spray air The pressure (1.0 kg / cm², product (46) (46) 200412245, temperature 29t :, inlet temperature 35 ° C, spraying cycle: 20 seconds spraying -40 seconds drying)) to obtain the composition of the present invention. The proportion of ungranulated slow-release fine particles was 10.8%. After mixing 2.6 g of magnesium stearate with the composition obtained, a rotary granulator was used to manufacture a heat supplement containing 25 mg at 50 kg / punching pressure and an initial hardness of 1.9 kp. Painful 3 50 mg tablets. Next, these ingots were placed at 25 ° C / 75% RH, and stored in a humidified oven (Tabaiespec Co., Ltd., PR-3 5C) under a fixed humidity for 24 hours. They were then dried at 30 ° C and 40% RH for 3 hours. The obtained ingots showed a hardness of 4.8 kp (η = 5), a friability of 1.23% (100 revolutions), and an intraoral disintegration time of 13 seconds (η = 1). Furthermore, as a result of content uniformity evaluation, CV% = 2.4%, it was confirmed that there was good content uniformity. In addition, 2.8 hours after the initial dissolution experiment (when the slow-release fine particles are about 30% dissolved), 5 hours (when the slow-release fine particles are about 50% dissolved), and 9.5 hours (after the slow-release fine particles are dissolved) When the released fine particles are about 80% dissolved), when comparing the dissolution rate of slow-release fine particles and tablets and calculating the difference, it is 5.5% after 2.8 hours, 3.5% after 5 hours, and after 9 · 5 hours At 3.1%, it was confirmed that the promotion of slow-release fine particle dissolution was prevented at all times. Example 5 1,200 grams of tonicol (Yoshitomi Fine Chemicals Co., Ltd.) and 120 grams of hydroxypropylmethyl cellulose (TC5E'Shin-Etsu Chemical Co., Ltd.) were dissolved in 2,640 In a mixture of g of methanol and 2,640 g of dichloromethane. In fluidized bed granulator (Freund (47) (47) 200412245

Industries, unit-glatt) introduced 300 grams of table 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 use this solution through the side Spray coating method (spray volume 16 g / min, spray air pressure 3 kg / cm2, product temperature 30 ° C, inlet temperature 75 ° C) to obtain replenishing painkiller particles. In addition, 45.9 grams of ethyl Cellulose (Nissin Chemistry Co.) and 5.1 g of hydroxypropylmethyl cellulose (TC5E, brand name, Shin-Etsu Chemical Co., Ltd.) were dissolved in a mixture of 45.8 g of pure water and 920.5 g of methanol. Introduce 300 grams of acetaminophen granules into a fluidized bed granulator (Freund Industries, uni-glatt) and apply this solution by side spraying (spray volume 8 g / min, spray air pressure) 2.5 kg / cm², product temperature 39t, inlet temperature 75 ° C) to obtain slow-release fine particles. Then 1 1 6.4 g of this slow-release fine particles and 5 4 2.7 g of mannitol (Towa Kasei Co., Ltd.) pulverized by a pin mill pulverizer (Hosokawa Micron) using 117 g of maltose (Hayashibara Co. , Ltd., 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 The pressure is 1.1 kg / cm2, the product temperature is 28 ° C, the inlet temperature is 351, and the spraying cycle: spraying in 20 seconds and drying in 40 seconds) to obtain the composition of the present invention. The proportion of ungranulated slow-release fine particles was 1.6%. After mixing 3.9 g of magnesium stearate with the resulting composition, use a rotary granulator at an ingot pressure of 200 kg / punch and a starting hardness of 1.9 kp (48) (48) 200412245 Manufactures 520 mg tablets containing 50 mg tonicol. Next, these ingots were placed at 25 ° C./75% RH, and stored under heating and humidification in a constant temperature box (Tabaiespec Co., Ltd., PR-35C) for 24 hours. They were then dried at 30 ° C and 40% RH for 3 hours. The obtained ingots exhibited a hardness of 6.4 kp (η: = 5), a friability of 1.13% (100 revolutions), and an intraoral disintegration time of 21 seconds (n = 1). In addition, as a result of content uniformity evaluation, CV% = 3.3%, which confirms that there is good content uniformity. In addition, 2.5 hours after the initial dissolution experiment (when the slow-release fine particles are about 30% dissolved), 5 hours (when the slow-release fine particles are about 50% dissolved), and 9.5 hours (after slow-release fine particles) When the released fine particles are about 80% dissolved), when comparing the dissolution rate of slow-release fine particles and tablets and calculating the difference, it is 8.8% after 2.5 hours, 6.3% after 5 hours, and 3.3 after 9.5 hours %, It can be confirmed that the promotion of slow-release fine particle dissolution can be prevented at any time. Example 6 40 g of ethyl cellulose (Nissin Chemistry Co.) was dissolved in a mixture of 380 g of methanol and 380 g of dichloromethane. 400 grams of table salt (Shin Nihon Salt Co., Ltd. EF-70 grade) was introduced into a fluidized bed granulator (Freund Industries, unit-glatt), with an average particle size of about 67 microns and a particle size of about 75 microns or less And) using this solution for coating by side spraying (6 g / min spray volume, 2 kg / cm² air pressure, product temperature 28 ° C, inlet temperature 60T :) to obtain tritium particles. Then, 1,200 grams of tonicol (Yoshitomi Fine Chemicals Co., Ltd.) and 1,200 grams of hydroxypropylmethyl cellulose (49) (49) 200412245 (TC5E, Shin-Etsu Chemical Co ·, Ltd.) was dissolved in a mixture of 2,640 g of methanol and 2,640 g of dichloromethane. Introduce 300 g of the above ingot cores into a fluidized bed granulator (Freund Industries, unit-glatt) and use this solution to apply by side spraying (spray volume 15 g / min, spray air pressure 3 kg) / Cm2, product temperature 30 ° C, inlet temperature 70 ° C) to get replenishing acetaminophen particles. In addition, 47.2 g of ethyl cellulose (Nissin Chemistry Co.) and 5.3 g of hydroxypropylfluorenyl cellulose (TC5E, brand name, Shin-Etsu Chemical Co., Ltd.) were dissolved in 49.9 g of pure water and 947.6 g Methanol mixture. Introduce 350 grams of acetaminophen particles into a fluidized bed granulator (Freund Industries, uni-glatt) and use this solution to apply by side spraying (jetting volume 8 g / min, spray air pressure) 2.5 kg / cm², product temperature 37 ° C, inlet temperature 75 ° C) to obtain slow-release fine particles. Then 1 1 6.4 g of this slow-release fine particles and 5 4 2.7 g of mannitol (Towa Kasei Co., Ltd.) pulverized by a pin mill pulverizer (Hosokawa Micron Co., Ltd.) containing 117 g A 30% w / w aqueous solution of maltose (Hayashibara Co., Ltd., brand name: Sunmalt S) was granulated in a first-class bed granulator (Freund Industries, uni-glatt) (spray volume 1 5 G / min, spray air pressure l. L kg / cm2, product temperature 30 ° C, inlet temperature 40 ° C, spray cycle: 20 seconds spray to -40 seconds drying) to obtain the composition of the present invention. The proportion of ungranulated slow-release fine particles was 3.9%. After mixing 3.9 g of magnesium stearate with the composition obtained, a rotary granulator was used to manufacture the pellets at an ingot pressure of 140 kg / punch and an initial hardness of 2.6 kp (50) (50) 200412245. 50 mg tablets for replenishing acetaminophen 5 20 mg tablets. Next, the ingots were placed at 25 ° C / 75% RH, and stored in a humidified oven (Tabaiespec Co., Ltd., PR-35C) under a fixed humidity for 24 hours. They were then dried at 30 ° C and 40% RH for 3 hours. The obtained ingots exhibited a hardness of 5.9 kp (η = 5), a friability of 1.64% (100 revolutions), and an intraoral disintegration time of 26 seconds (η = 1). Furthermore, as a result of content uniformity evaluation, CV% = 2.0%, it was confirmed that there was good content uniformity. In addition, 2.3 hours after the initial dissolution experiment (when about 30% of the slow-release fine particles are dissolved), 5.5 hours (when about 50% of the slow-release fine particles are dissolved), and 13.5 hours (after slow-release fine particles) When the released fine particles are about 80% dissolved), when the dissolution rate of the slow-release fine particles and the ingot is compared and the difference is calculated, it is 0.6% after 2.3 hours, 1.2% after 5.5 hours, and 13.5 hours. After 3.2%, it can be confirmed that the promotion of slow-release fine particle dissolution can be prevented at any time. Example 7 80 g of tamsulosin hydrochloride and 80 g of hydroxypropyl cellulose (TC5E, Shin-Etsu Chemical Co., Ltd.) were dissolved in a mixture of 304 g of pure water and 2,763 g of methanol . 400 grams of Celphere 102 (brand name, Asahi Kasei, average particle size of about 127 microns, particle size of about 50 to about 150 microns) were introduced into a fluidized bed granulator (Freund Industries, FLO-5) and borrowed using this solution Coating by side spraying method (spray volume of 100 g / min, spray air pressure of 4 kg / cm2, product temperature of 40 ° C, inlet temperature of 8 (TC) to obtain tamsulosin hydrochloride particles. (51) 200412245

In addition, 43.7 g of ethyl cellulose (Nissin Chemistry Co ·) and 12.3 g of hydroxypropyl methyl cellulose (TC5E, brand name, Shin-Etsu Chemical Co., Ltd.) were dissolved in 43.9 g of pure water and 83 3.4 G of methanol in the mixture. 400 g of tamsulosin hydrochloride particles were introduced into a fluidized bed granulator (Freund Industries, uni-glatt), and the solution was applied by a side spray method (the spray volume was 6 g / min, and the air was sprayed with air) The pressure is 4 kg / cm², the product temperature is 40 ° C, and the inlet temperature is 63 ° C) to obtain slow-release fine particles. The receiver ’was introduced into a fluidized bed granulator (Freund Industries, uni-glatt) with 300 g of this slow-release fine granule and used 90 g of Aquacoat (brand name, Asahi Kasei) and 180 g of Eudragit.

L30D55 (brand name, R0hm), 30 g Eudragit NE30D (brand name, R hm), and 300 g of pure water for coating (6 g / min spray volume, 3 kg / square spray air pressure) Cm, product temperature 40 ° C 'inlet temperature 75 · 51 :) to obtain enteric slow-release fine particles. Then, 9 2 · 5 g of these enteric slow-release fine particles, 5 6 · 2 g of mannitol (Towa Kasei Co., Ltd.) and 14 2 · 1 g were passed through a pin mill pulverizer. (Hosokawa Micron Co., Ltd.) pulverized lactose (DomomUk) and 72 grams of erythrose (Nikken Chemicals Co., L td.) Using 18 grams of copolyvinylpyrrolidone (bas FC ο., Brand name Kolhdon VA64) 5% w / w aqueous solution was granulated in a first-class bed granulator (Freund Industries, Uni-glatt) (liquid spray volume 15 g / min, spray air pressure 0.5 kg / cm2, product temperature 40. (:, inlet temperature 70 ° C, spraying cycle: 15 seconds spraying_30 seconds drying -57- (52) (52) 200412245 drying) to obtain the composition of the present invention. Ungranulated slow The proportion of fine particles released 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 tamsulosin hydrochloride at an initial hardness of 0.6 kp. 300 mg ingots. Next, the ingots were placed at 120 ° C and heated in a pattern oven (model No. MOV-112P, Sanyo Corporation). 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 revolutions), and an intraoral disintegration time of 27 seconds (η = 3). Furthermore, the content uniformity evaluation result, CV% = 1.6%, proved a good content uniformity. In addition, after 1 hour from the initial dissolution experiment (when about 30% of the slow-release fine particles were dissolved) ), After 2 hours (when the slow-release fine particles are about 50% dissolved), and after 6 hours (when the slow-release fine particles are about 80% dissolved), compare the dissolution rate of the slow-release fine particles and the tablets When calculating rates, it is 1.1% after 1 hour, 2 · 8% after 2 hours, and 9.4% after 6 hours. It can be confirmed that the promotion of slow-release fine particle dissolution can be prevented at any time. Example 8 1,200 g of nicardipine hydrochloride and 120 g of hydroxypropylmethyl cellulose (TC5E, Shin-Etsu Chemical Co., Ltd.) were dissolved in 4,800 g of methanol and 4,800 g of two In a mixture of methyl chloride, 300 g of silica (Silica Gel, Sigma, average particle size about 48 micrometers) was introduced into a fluidized bed granulator (Freund Industries, unit-glatt). M, particle size is about 75 microns or less) and apply this solution by side spraying method -58- 4 (53) (53) 200412245 (18 g / min spray volume, spray air pressure 3 Kg / cm2, product temperature 30 ° C, inlet temperature 70 ° C) to obtain nicardipine hydrochloride particles. In addition, 54 g of ethyl cellulose (Nissin Chemistry Co.) and 6 g of hydroxypropylmethyl cellulose (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 grams of nicardipine hydrochloride particles were introduced into a fluidized bed granulator (Freund Industries, uni-glatt), and the solution was applied by a side spray method (the spray volume was 8 g / min, and the air pressure of the spray cloth was applied). 2.5 kg / cm², product temperature 39 ° C, inlet temperature 75 ° C) to obtain slow-release fine particles. Then 60 g of this slow-release fine granules, 254.4 g of mannitol (Towa Kasei Co., Ltd.) and 63.6 g of lactose (Domomilk) pulverized by a pin mill pulverizer (Hosokawa Micron), and 12 g of red Moss (Nikken Chemicals Co., Ltd.) used a 5% w / w aqueous solution containing 8 g of copolyvinylpyrrolidone (BASF Co., brand name Kollidon VA64) in a first-class bed granulator (Freund Industries, uni- glatt) granulation (spray liquid volume 15 g / min, spray air pressure 0.5 kg / cm2, product temperature 39 ° C, inlet temperature 50 ° C, spray cycle: 5 seconds spray-1-5 seconds Bell drying) to obtain the composition of the present invention. The proportion of ungranulated slow-release fine particles was 7.9%. After mixing 2 g of magnesium stearate with this resultant composition ', a rotary granulator was used to manufacture a 400 mg tablet containing 20 mg of nicardipine hydrochloride tablet at an initial hardness of 0.6 kp. Next, place the ingots (54) (54) 200412245 at 130 ° C, heat in a pattern oven (model No. MOV-1 12P, Sanyo Corporation) for 10 minutes, and then at room temperature Cool for 30 minutes. The obtained ingots showed a hardness of 3.7 kp (η = 5), a friability of 0.1% (100 revolutions), and an intraoral disintegration time of 20 seconds (η = 3). Furthermore, the result of content uniformity evaluation, CV% = 1.1%, proved that there is good content uniformity. In addition, 0.5 hours after the initial dissolution experiment (when the slow-release fine particles are about 30% dissolved), 2 hours (when the slow-release fine particles are about 50% dissolved), and 5.5 hours (after When the slow-release fine particles are about 80% dissolved), when comparing the dissolution rates of slow-release fine particles and tablets and calculating the difference, it is 10.3% after 0.5 hours, 1 2.8% after 2 hours, and 5.5 hours The latter is 6.6%, and it can be confirmed that the promotion of slow-release fine particle dissolution can be prevented at any time. Example 9 80 g of tamsulosin hydrochloride and 80 g of hydroxypropyl cellulose (TC5E, Shin-Etsu Chemical Co., Ltd.) were dissolved in a mixture of 304 g of pure water and 2,7 3 6 g of methanol in. 400 g of Celphere 102 (brand name, Asahi Kasei, average particle size of about 127 microns, particle size of about 50 to about 150 microns) was introduced into a fluidized bed granulator (Freund Industries, FLO-5) and the solution was used Coating was performed by a side spray method (a spray volume of 100 g / min, a spray air pressure of 4 kg / cm2, a product temperature of 40 ° C, and an inlet temperature of 80 ° C) to obtain tamsulosin hydrochloride particles. In addition, 561.6 g of ethyl cellulose (Nissin Chemistry Co ·) and 158.4 g of hydroxypropyl methyl cellulose (TC5E, brand name, 60- (55) (55) 200412245 S hi η-Etsu C hemica 1 C ο ·, L td ·) was dissolved in a mixture of 5 6 4 g of pure water and 10, 7 1 6 g of methanol. Introduce 4,000 g of tamsulosin hydrochloride particles into a fluidized bed granulator (Freund Industries, FLO-5) and use this solution to apply by side spraying (spray volume 40 g / min, spray air The pressure is 4 kg / cm2, the product temperature is 40 ° C, and the inlet temperature is 54 ° C) to obtain slow-release fine particles. Next, 4,000 grams of this slow-release fine granules were introduced into a fluidized bed granulator (Freund Industries, FLO-5) and 800 grams of Aquacoat (brand name, Asa hi Ka s ei) containing 1,600 grams of Eudragit L30D55 was used. (Brand name, R0hm), 266.7 grams of Eudragit NE30D (brand name, R0hm), and a mixture of 5,3, 3 and 3 grams of pure water for coating (spray volume 60 g / min, spray air pressure 4.5 kg / cm2) , Product temperature 50 ° C, inlet temperature 84 ° C) to obtain enteric slow-release fine particles. Then, 392.7 g of these enteric slow-release fine particles, 2,540.2 g of mannitol (Towa Kasei Co., Ltd.), and 635.1 g of the pulverized product through a pin mill pulverizer (Hosokawa Micron Co., Ltd.) Domomilk uses a 20% w / w aqueous solution containing 400 g of maltose (Hay ashibara Co., Lt d., Brand name: Sunma 11 S) in a first-class bed granulator (Freund Industries, FLO- 5) Granulation (spray volume 100 g / min, spray air pressure 1.5 kg / cm2, product temperature 33 ° C, inlet temperature 48 ° C, spray cycle: 20 seconds spray -30 seconds (Dried) to obtain the composition of the present invention. The proportion of ungranulated slow-release fine particles was 1.1%. After further mixing 32 g of calcium stearate with the obtained composition of -61-(56) (56) 200412245, a rotary granulator was used to produce 0.4 mg of tanso hydrochloride at an initial hardness of 2.1 kp. Rosin tincture of 300 mg. Next, the ingots were placed at 25C / 75% RH, and then heated and humidified in a constant temperature box (Tabaiespec Co., Ltd., PR-35C) for 24 hours under a fixed humidity. They were then dried at 30 ° C and 40% RH for 3 hours. The obtained ingots showed a hardness of 4.1 kp (η = 5), a friability of 1.67% (100 revolutions), and an intraoral disintegration time of 20 seconds (η = 1). Furthermore, the result of content uniformity evaluation, CV% = 1.6%, proved that there is good content uniformity. In addition, 2 hours after the initial dissolution experiment (when the sustained-release fine particles are about 30% dissolved) '4 hours (when the slow-release fine particles are about 50% dissolved), and 8 hours (after the slow-release fine particles are dissolved) When the released fine particles are about 80% dissolved), when comparing the dissolution rate of slow-release fine particles and tablets and calculating the difference, it is 7.5% after 2 hours, 6.4% after 4 hours, and 1 after 8 hours 5%, it can be confirmed that the promotion of slow-release fine particle dissolution can be prevented at any time. Industrial Applicability The present invention relates to a composition containing slow-release fine particles, which can provide a contradictory function at first glance, that is, even if the tablets disintegrate and dissolve rapidly in the oral cavity, they still have a slow-release Sex. Furthermore, the present invention is characterized in that the phenomenon that the dissolution of the slow-release fine particles during ingot making under the ingot making pressure causes the dissolution of the drug to be promoted after the ingot can be suppressed, and even after the ingot is made, With good reproducibility, controlled dissolution is achieved as a design target for slow-release fine-particle formulations. In this way, the design of the slow-release fine-grained pharmaceutical preparation can be simplified, and therefore, it has the characteristics that it can ensure a good drug -62- (57) 200412245 > content uniformity. In addition, a composition containing slow-release fine particles can be presented. In the development of various kinds of rapid disintegrating tablets in the oral cavity, the process of rapidly disintegrating the tablets containing the slow-release fine particles into a product, especially in Industrial manufacturing steps, and moreover, the process of quality assurance has obvious utility. [Schematic description]

Fig. 1 shows the results obtained by dissolving the tablet and the slow-release fine particles of Example 1 in a dissolution experiment 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 obtained by dissolving the tablet and the slow-release fine particles of Example 1 in a dissolution experiment 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. Fig. 3 shows the results of the dissolution experiments of Comparative Examples 1 and 2 and the sustained-release fine particles by 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. -63-

Claims (1)

200412245 Λ Patent application scope 1. A composition containing sustained-release fine particles for rapid disintegration of tablets in the oral cavity, characterized in that it comprises sustained-release fine particles containing a drug and one or more selected from the group consisting of Tinctures: sugars and sugar alcohols, granulated products made by using a binder for rapid disintegration of tablets in the oral cavity, and the proportion of ungranulated slow-release fine particles in the overall composition is 0 to 1 5 %. 2. The composition containing slow-release fine particles for rapid disintegration of tablets in the oral cavity according to item 1 of the patent application scope, wherein the adhesive for the rapid disintegration of tablets in the oral cavity is one or more selected from the group consisting of the following Middle: Highly moldable sugars, water-soluble polymer substances, and low melting sugars. 3. The composition containing sustained-release fine particles for rapid disintegration of tablets in the oral cavity in item 2 of the scope of patent application, wherein the sugars and sugar alcohols are one or more selected from the group consisting of: low Moldable sugars, high melting sugars and low melting sugars. 4. The composition containing slow-release fine particles for rapid disintegrating tablets in the oral cavity, such as the scope of patent application No. 3, wherein the slow-release fine particles, tinctures, and the adhesive for fast disintegrating tablets in the cavity The mixing ratio of the agent is 1 to 50%, 20 to 98%, and 1 to 30%. 5. The composition containing sustained-release fine particles for use in the orally rapidly disintegrating tablet according to item 4 of the patent application, wherein the average particle size of the rapidly disintegrating fine particles is about 0.1 micrometer to about 3-50 micrometers. 6. The composition containing slow-release fine particles for rapid disintegration of tablets in the oral cavity according to item 5 of the patent application, wherein the slow-release fine particles include at least crystalline cellulose particles, drugs, and polymer substances. -64- (2) 200412245 7 · A composition containing slow-release fine particles for rapid disintegration of tablets in the oral cavity under item 6 of the patent application, wherein the drug is tamsulosin hydrochloride ° 8. For example, the composition containing sustained-release fine particles for rapid disintegration of tablets in the oral cavity under the scope of patent application No. 7, wherein the slow-release fine particles are enteric slow-release fine fez. 9. The composition containing slow-release fine particles for rapid disintegration of tablets in the oral cavity according to item 8 of the patent application, wherein the polymer substance is hydroxypropyl methylcellulose, ethyl cellulose, Eudragit L30D55, and Eudragit NE 3 0 D. 10. The composition containing slow-release fine particles for the rapidly disintegrating tablets in the oral cavity according to item 9 of the scope of patent application, wherein the binder for the rapidly disintegrating tablets in the oral cavity is one or more selected from the group consisting of the following In the group: maltose, trehalose, sorbitol, and maltitol. 11. An orally rapidly disintegrating tablet, which is composed of a composition containing slow-release fine particles as described in item 10 of the scope of patent application. 1 2. The orally rapidly disintegrating tablet according to item 11 of the scope of patent application, wherein the coefficient of variation (CV%) of the drug content as an index of content uniformity is 3.5% or less. 1 3. —A method for manufacturing a composition containing slow-release fine particles for rapidly disintegrating tablets in the oral cavity, characterized in that it comprises slow-release fine particles containing a drug and one or more selected from the group consisting of Tincture: sugars and sugar alcohols, granulated products made by using a binder for rapid disintegration of tablets in the oral cavity, and the proportion of ungranulated slow-release fine particles in the overall composition is 0 to 1 5 %. -65- (3) * (3) * 200412245 14. A method for producing a composition containing slow-release fine particles for rapid disintegration of oral tablets in the scope of application for item 13, wherein the oral tablet rapidly disintegrates tablets The binder used is one or more selected from the group consisting of high moldability sugars, water-soluble polymer substances, and low melting sugars. 15. The method for manufacturing a composition containing slow-release fine particles for rapid disintegration of tablets in the oral cavity according to item 14 of the patent application, wherein the sugar and sugar alcohol are one or more selected from the group consisting of : Low-mold sugars, high-melting sugars and low-melting sugars. 16. The method for manufacturing a composition containing slow-release fine particles for rapid disintegration of tablets in the oral cavity according to item 15 of the scope of patent application, wherein the slow-release fine particles, tincture, and the rapid disintegration in the oral cavity The mixing ratio of the binder for the ingot is 1 to 50%, 20 to 98%, and 1 to 30%. 17 · The method for manufacturing a composition containing slow-release fine particles for rapid disintegration of tablets in the oral cavity according to item 16 of the scope of patent application, wherein the average particle size of the fast-disintegrating fine particles is about 0.1 micrometer to about 350 Microns. 1 8 · A method for producing a composition for sustained disintegration of 0 tablets, such as rapid disintegration in the oral cavity, according to item 17 of the scope of patent application, wherein the sustained-release fine particles include at least crystalline cellulose particles, drugs, and polymers substance. 19 · A method for producing a composition containing slow-release fine particles for rapid disintegration of tablets in the scope of patent application No. 18, wherein the drug is tamsulosin hydrochloride. 20 · A method for producing a composition containing sustained-release fine particles for rapid disintegration of tablets in the scope of patent application No. 19, wherein the slow-release fine particles are enteric slow-release fine particles. -66-(4) (4) 200412245 2 1 · A method for manufacturing a composition containing slow-release fine particles for rapid disintegration of tablets in the oral cavity, such as in the scope of patent application No. 20, wherein the polymer substance is hydroxypropyl Methylcellulose, ethylcellulose, Eudragit L30D55, and Eudragit NE30D 02. A method for producing a composition containing slow-release fine particles for rapid disintegration of tablets in the oral cavity, such as in the scope of patent application No. 21, wherein the The binder for the fast disintegrating tablets in the oral cavity is one or more selected from the group consisting of maltose, trehalose, sorbitol, and maltitol. 23 · —A method for manufacturing a fast-disintegrating tablet in the oral cavity, the fast-disintegrating tablet in the oral cavity is composed of a composition prepared by the method described in Item 22 of the patent application, and the sustained-release fine particles. 24. The method for manufacturing an intraoral cavity according to item 23 of the patent application, wherein the drug-containing variation system (C V%) which is an index of content uniformity is 3.5% or less. -67-