Tablet subjecting for rapid decomposition in buccal pocket and method for its preparing

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to a tablet decomposing rapidly in the buccal pocket and comprising a medicinal agent, excipient and saccharide with relatively lower melting point than that of a medicinal agent and excipient. Tablet is made by uniform mixing saccharide with low melting point with tablet mass to form bridge between particles of named medicinal agent and/or excipient through melting product followed by hardening mentioned saccharide with low melting point. Except for, invention relates to a method for making tablet decomposing rapidly in buccal pocket and comprising a medicinal agent, excipient and saccharide with relatively lower melting point than that of medicinal agent and excipient. Method involves: (a) the parent components of tablet comprising a medicinal agent, excipient and saccharide with relatively lower melting point that that of a medicinal agent and excipient are pressed under low pressure to provide the required tablet form; (b) pressed product obtained after stage (a) is heated to temperature when saccharide with low melting point is melted; (c) melted product obtained after stage (b) is cooled to temperature when melted saccharide with low melting point is hardened. Invention represents a tablet decomposing rapidly in buccal pocket and having the tablet strength providing its using in tablet-making machines for dosed formulations and giving the possibility for making tablet using common tablet-making machines, and to a method for making tablets. Except for, invention represents a tablet decomposing rapidly in buccal pocket being this table as compared with common tablets has enhanced tablet strength and improved frangibility without prolonged decomposing time in buccal pocket, and a method for tablet making.

EFFECT: improved making method.

63 cl, 4 tbl, 1 dwg, 21 ex

 

This invention relates to the creation of tablets fast dezintegriruetsja in the buccal pocket containing a drug, a diluent and a saccharide with a relatively lower melting point than the drug and diluent, which is obtained by evenly mixing the saccharide with a low melting point with a tablet weight so as to form a bridge between the particles of the medicinal product and/or diluent through the product of melting and then solidification of the saccharide with a low melting point. In addition, this invention relates to a method of manufacturing tablets fast dezintegriruetsja in the buccal pocket containing a drug, a diluent and a saccharide with a relatively lower melting point than the drug and diluent, which consists of (a) the method by which the tablet starting materials comprising a drug, a diluent and a saccharide with a relatively lower melting point than the drug and diluent, is pressed under low pressure required to create the form of a tablet, (b) the method by which the extruded product obtained by the method (a)is heated at least to a temperature at which the mentioned saccharide with a low melting point is melted, and (C) of the method, the cat the rum extruded product, obtained by the method (b)is cooled at least to a temperature at which the molten saccharide with a low melting point solidifies.

In recent years, developed a number of tablets fast dezintegriruetsja in the buccal pocket that older people and children can use without water. For example, in the technical description of the Avenue of the international preliminary application WO 95/20380 (corresponding to U.S. patent 5576014, Japan patent No. 3122141) describe the tablet quickly desintegrators in the buccal pocket, obtained by granulation of the saccharide with a low plasticity with a saccharide with high plasticity and then pressing casting the obtained granulation product using a conventional tablet press machine. The above invention is characterized by the fact that the saccharide with high plasticity as a binder spray and cover and/or granularit with the saccharide with a low plasticity; also present invention, in the case which you can make hydration and drying, if you want extra strength tablets. As saccharides with low plasticity consider lactose, mannitol, glucose, sucrose, xylitol and the like, and maltose, ▫ maltitol, sorbitol, lactosucrose and the like are considered as sugars with high plasticity. In addition, technical Avenue international is Oh provisional application WO 99/47124 describe the tablet, quickly desintegrators in the buccal pocket, which is obtained by hydration and drying the molded product after extrusion granulation product, which is obtained by dissolving and/or suspendirovanie of saccharide, which can be amorphous, pharmaceutically acceptable solvent, and spraying and coating and/or granulation of the product on the medicinal product and/or a saccharide, or after pressing amorphous saccharide, which is obtained by dissolving and/or suspendirovanie drug, diluent and saccharide, which becomes amorphous, pharmaceutically acceptable solvent, and spray drying the resulting solution and/or suspension. This invention is characterized by the fact that the pressing is carried out using a saccharide, which can move in the amorphous state, and then extruded product moisturize and dried in order to link the tablet to the original substance, such as a drug and a saccharide, and the like. That is, this invention is particularly pressing medicinal product, diluent and saccharide, which can move in the amorphous state, after pressing a sugar capable of becoming amorphous transitions in amorphous state and then crystallized in the tablet in the wetting and drying DL is increasing the strength of the tablets. In the above invention mannitol, ▫ maltitol, aritra, xylitol and the like is considered as a saccharide (crystalline saccharide), lactose, sucrose, glucose, sorbitol, maltose, trehalose, lactic, fructose and the like considered as the saccharide, which can become amorphous (saccharide, which crystallizes in the wetting and drying after the transition in amorphous state). It turned out that using the described methods provide sufficient for practical use strength tablets, although there are some important problems, however, considering the fact that, compared with conventional pharmaceutical tablets for oral administration, tablets turned out to be to some extent below, in particular, when used automatic device for packaging dosage forms, there remains a need to further increase the strength of the tablets and reduce brittleness.

In addition, in patent Kokai Japan No. 11-35451 describe the tablet, desintegrators in the buccal pocket, and a method of its production, characterized by the fact that the medicinal active ingredient, a saccharide and a substance with a low melting point such as polyethylene glycol and the like, are mixed, the resulting mixture tabletirujut under low pressure and the obtained tablets was heated to a temperature at which cited aloe substance with a low melting point is melted and then cooled. However, there is no description or instructions for special ways to increase tablet strength and reduce brittleness tablets fast dezintegriruetsja in the buccal pocket containing the drug and a saccharide, which is the main component raw materials of pharmaceutical drug. In addition, technical Avenue international preliminary application WO 93/13758 (corresponds to the Japan patent No. 2640570) consider the method of manufacturing tablets high strength, comprising (a) a method in which a water-soluble binder, capable of melting at least 1 filler and a pharmaceutically active agent are mixed and pressed into a tablet, (b) the method by which the above-mentioned water-soluble binder, capable of melting, melt in the aforementioned tablet, and (C) the manner in which the above-mentioned water-soluble binder, capable of melting and hardens. According to the described method, it was found that the melting point of water-soluble binders, able to melt, usually is 38~62°C. Therefore, there is a possibility to further improve the stability properties of a pharmaceutical product, as there is a possibility that the strength and disintegration time of the tablets in the buccal pocket will be the change in the re-melting binder in the time period when a pharmaceutical drug, which use the binder with the specified melting temperature, store in a place that is not properly ventilated in the summer and so on. In addition, there is a tendency to slow dissolution in the buccal pocket and a prolonged time of disintegration in the buccal pocket when using polymers, such as polyethylene glycol and the like, and a hydrophobic filter, such as an ester of sucrose and the like, which are described as water-soluble binders, able to melt. Therefore, from a medical point of view, there remains a need for further development of new methods of production which will increase tablet strength and reduce the fragility of the tablets, or to improve the stability properties of a pharmaceutical product, including the disintegration time in the buccal pocket, and there remains a need in the tablets fast dezintegriruetsja in the buccal pocket, obtained by the developed methods.

Incidentally in U.S. patent 6083438 (corresponding to patent-Japan Kokai No. 11-113525) describe the invention with respect to the filler for direct tableting, which was obtained by heating at a temperature at which two specific saccharide be eutectic, such as eritra and sorbitol, and the like is, and then by cooling and pulverization of the obtained product, and the tablets obtained with the same filler. This invention represent the production technology of the above-mentioned filler by granulation of the melt, which selects the polyol, which is eutectic with erythritol, with the aim of introducing the tablet for conventional oral administration. However, in the above-mentioned publication is not described or represented tablet fast dezintegriruetsja in the buccal pocket having a porous structure, which is obtained by forming a bridge between the particles through the product of melting and solidification of the saccharide with a low melting point only after tabletting under low pressure.

Under the described circumstances, the result of intensive research, the applicants have successfully completed this invention by the prior art that (1) sugars, low plasticity, i.e. sugars that act as filler and do not function as a binder, are sugars, which increase the strength of the tablets through the education interparticle bridge between particles of the medicinal product and/or diluent in the heat treatment so that the particles themselves firmly glued to each other (for example, aritra), to the ome, (2) sugars, which do not pass into the amorphous state, i.e. sugars that act as filler and do not function as a binder, are sugars, which increase the strength of the tablets, forming heat treatment “interparticle” the bridge between the particles of the medicinal product and/or diluent so that the particles themselves firmly sticking with each other (for example, aritra and ▫ maltitol), and, in addition, (3) tablet fast dezintegriruetsja in the buccal pocket, with increased tablet strength and reduced fragility can be quickly made for example, by pressing product granulation, which is obtained using two saccharide with different temperatures of melting points, for example, by spraying, to apply and to pelletize the “saccharide with a low melting point” as a binding substance on the “saccharide with a high melting point, and then heating to melt only the “saccharide with a low melting point, and education “interparticle bridge between the particles of drug and/or “saccharide with a high melting point” through the product of melting and solidification of the “saccharide with a low melting point so that particles themselves firmly sticking with each other.

That is, the present invention is:

1. pill fast disintegrity Sousa in the buccal pocket, containing a drug, a diluent and a saccharide with a relatively lower melting point than the above-mentioned drug and the above-mentioned diluent, which is obtained by evenly mixing the saccharide with a low melting point with a tablet weight and in which is formed bridges between the particles of the above-mentioned medicinal product and/or the above-mentioned diluent through the product of melting and then solidification of the saccharide with a low melting point

2. pill fast desintegrators in the buccal pocket, by the above claim 1, in which the saccharide with a low melting point is a saccharide, a melting point which is at least 10°C lower than the melting point of drug and diluent,

3. pill fast desintegrators in the buccal pocket on the above items 1 or 2, in which the saccharide with a low melting point is one or two or more saccharides selected from the group consisting of xylitol, trehalose, maltose, sorbitol, eritria, glucose, maldita, mannitol, sucrose, and their hydrates,

4. pill fast desintegrators in the buccal pocket, according to any one of above 1 to 3, in which the number of saccharide with a low melting point is from 0.5 to 25%, wt./wt., from drugs and/and and diluent,

5. pill fast desintegrators in the buccal pocket, according to any one of above 1 to 4, in which, in addition, added binder,

6. pill fast desintegrators in the buccal pocket, according to any one of the above 1 through 5 in which the diluent is a saccharide with a relatively higher melting point than that of the saccharide with a low melting point in the above paragraphs. 1 through 4,

7. pill fast desintegrators in the buccal pocket, by the above claim 6, in which the saccharide with a high melting point in the above item 6, represents one or two or more saccharides selected from the group consisting of xylitol, trehalose, maltose, sorbitol, eritria, glucose, maldita, mannitol, sucrose, lactose, and their hydrates,

8. pill fast desintegrators in the buccal pocket on the above claim 7, in which the saccharide with a high melting point on the above 7 represents one or two or more saccharides selected from the group consisting of mannitol, sucrose, lactose, and their hydrates,

9. pill fast desintegrators in the buccal pocket, according to any one of above 1 to 8, in which the saccharide with a low melting point is a trehalose and/or aritra, and a saccharide with a high melting point is a mannitol and/or l is ctsu,

10. pill fast desintegrators in the buccal pocket, by the above claim 9, in which the saccharide with a low melting point is aritra, and a saccharide with a high melting point is a mannitol,

11. pill fast desintegrators in the buccal pocket, according to the above item 5, in which the saccharide with high plasticity and/or water-soluble polymer is part of binders,

12. pill fast desintegrators in the buccal pocket, in the above-mentioned item 11, in which the binder is a ▫ maltitol and/or copolyvidone,

13. pill fast desintegrators in the buccal pocket, according to any one of above 1 to 12, in which the porosity is 10 to 80%,

14. pill fast desintegrators in the buccal pocket, according to the above item 13, in which the porosity is 20 to 50%,

15. pill fast desintegrators in the buccal pocket, according to any one of the above 1 through 14, in which the hardness of the tablets is 3 kPa or higher and the fragility is 1% or less

16. pill fast desintegrators in the buccal pocket, according to the above item 15, in which the hardness of the tablets is 4 kPa or higher and the fragility of 0.8% or less

17. pill fast desintegrators in the buccal pocket, according to the above item 16, which fragility is 0.5% or less

18. pill fast desintegrators in the buccal pocket, according to any one of above 1 to 17, in which the amount of added drug is at least an effective amount, from the point of view of treatment and is not more than 80%, by weight. by weight of the tablet,

19. method for the production of tablets fast dezintegriruetsja in the buccal pocket containing a drug, a diluent and a saccharide with a relatively lower melting point than the above-mentioned drug and the above-mentioned diluent, which includes: (a) the method by which the original tablet materials/ includes drug, a diluent and a saccharide with a relatively lower

melting point than the above-mentioned drug and the above-mentioned diluent, is pressed under low pressure required to maintain the form of tablets, (b) the method by which the extruded product obtained by the method (a), is heated at least to a temperature at which the saccharide with a low melting point will melt, and (C) the method by which the extruded product obtained by the method (b)is cooled at least to a temperature at which the molten saccharide with a low melting point solidifies,

20. method for the production of tablets fast detente arouses in the buccal pocket, by the above claim 19, in which by method (a) above to claim 19, a drug, a diluent and a saccharide with a relatively lower melting point than the above-mentioned drug and the above-mentioned diluent, physically mixed to obtain a tablet of source materials

21. method for the production of tablets fast dezintegriruetsja in the buccal pocket, by the above claim 19, in which by method (a) above claim 19, saccharide with a low melting point are dissolved and/or suspended in a pharmaceutically acceptable solvent and sprayed as a binder for coating and/or granulation, to obtain a tablet of source materials

22. method for the production of tablets fast dezintegriruetsja in the buccal pocket, by the above claim 19, in which by method (a) above claim 19, saccharide with a low melting point is mixed with the medication and the diluent in the form of particles and/or powder and carry out granulation, using a solution of a binder, to obtain a tablet of source materials

23. method for the production of tablets fast dezintegriruetsja in the buccal pocket, by the above claim 19, in which by method (a) above claim 19, tablet feedstock Presswood pressure tableting from 25 to 800 kg/stamp,

24. method for the production of tablets fast dezintegriruetsja in the buccal pocket, by the above claim 19, in which by method (b) above p.19 heating was carried out at a temperature between the melting point of the saccharide with a low melting point and melting point drug and diluent,

25. method for the production of tablets fast dezintegriruetsja in the buccal pocket, by the above claim 19, which additionally includes the method (d), by which the extruded product is humidified and dried,

26. method for the production of tablets fast dezintegriruetsja in the buccal pocket, above A.25, in which the method (d) above A.25 applied between (a) and (b) on or after the method (s).

The tablet of the present invention, quickly dezintegriruetsja in the buccal pocket, characterized by the fact that it contains a drug, a diluent and a saccharide with a relatively lower melting point than the above-mentioned drug and the above-mentioned diluent, or tablet contains a drug and a saccharide with a relatively lower melting point than the above-mentioned drugs, and only a saccharide with a relatively low melting point melts and hardens, and forms a bridge over the obtained products is melting and solidification, especially in the case when the tablet has a porous structure. With regard to the different tablets fast dezintegriruetsja in the buccal pocket, which were developed, this feature improves the strength and fragility of the tablets, when compared with conventional tablets fast dezintegriruetsja in the buccal pocket, when creating a porous structure, the tablet of the present invention, quickly dezintegriruetsja in the buccal pocket, exhibits excellent effects, characterized by the ability to improve tablet strength (3 kPa or higher, preferably 4 kPa or higher) and to maintain a low fragility (1% or less, preferably of 0.8% or less, more preferably 0.5% or less) tablets, made mainly the same type of saccharide, at the same time keeping the fast disintegration in the buccal pocket (approximately less than 1 minute, preferably less than 40 seconds, more preferably less than 30 seconds).

Used in this invention, the expression “tablet fast dezintegriruetsja in the buccal pocket, implies a tablet which disintegrates in the buccal pocket in less than 1 minute (preferably approximately less than 40 seconds, more preferably less than 30 seconds) basically just saliva, no drinking after water when taking the pill.

Used in this invention, the term “RA is nomemo” means the state, when the saccharide with a low melting point uniformly distributed in the whole tablet, that is, in a state where there is no any “non-distribution”. The drawing shows some aspects, however, this invention is not limited to these aspects.

The term “education interparticle bridge” in this invention means a state where the particles of the medicinal product and/or diluent are attached to each other through the product of melting and solidification of a saccharide with a relatively lower melting point than the drug and diluent.

The expression of the present invention “form of the pill is maintained” means that essentially not made any “cracks” or “defects” in the pharmaceutical tablet for oral administration, usually with manual production.

“Melting point” of the saccharide of the present invention means the temperature at which the used in this invention, the saccharide with a low melting point begins to melt.

“Heat” in this invention means bringing the temperature of the saccharide with a low melting point used in the present invention, prior to its melting point or higher.

“Cooling” in this invention means bringing the temperature of the saccharide with a low melting point used in the present invention,prior to its melting point or lower to set.

The tablet of the present invention, quickly dezintegriruetsja in the buccal pocket, and method of its manufacture will now be described in detail.

For medicines used in the present invention, there is no restriction, since it is an active component that is efficient from the point of view of treatment, or active ingredient, which is effective as prevention. Examples of the pharmaceutically active component are hypnotics sedatives, noninducible agents, anti-anxiety remedies, antiepileptic drugs, antidepressants, antiparkinsonian drugs, psihonevroticheskih tools, medicines, acting mainly on the Central nervous system, mestnoanesteziruyuschie funds, muscle relaxants, drugs that act primarily on the autonomic nervous system, antipyretic analgesic antiphlogistic, antispasmodic remedies, anti-vertigo, Karbinci, antiarrhythmic agent, diuretics, antihypertensive drugs, vasoconstrictors, vasodilators, drugs that act on the circulatory system, anti-hyperlipidemia, an agent stimulating breath, antitussives, expectorants media is TBA, antitussive expectorants, bronchodilators, anti-diarrhoeal remedies, medicines that control bowel function, means acting on peptic ulcers, medications that increase the functional activity of the stomach, antacids, laxatives, cholagogue, drugs acting on the gastro-intestinal tract, adrenal cortical hormones, hormones, medicines for urinary system, vitamins, hemostatic tools, medicines used for liver diseases, the tools used for gout, medicines used in diabetes, anti-histamine drugs, antibiotics, antibacterial drugs, anticancer drugs, chemotherapy tools, tools used presentano cold, bracing means protivostoyanie medicines and current like that. Examples of medicines are anti-inflammatory, antipyretic antispasmodics or analgesics, such as indomethacin, diclofenac, diclofenac sodium, codeine, ibuprofen, phenylbutazone, oxyphenbutazone, Marisol, aspirin, hidename, acetaminophen, aminopyrine, phenacetin, butylscopolamine bromide, morphine, atomically, pentazocine, venapro the Yong calcium, naproxen, celecoxib, valdecoxib, tramadol and the like; anti-rheumatic drugs, such as etodolac and the like; anti-TB drugs such as isoniazid, ethambutol chloride and the like; drugs that act on the circulatory system, such as isosorbide nitrate, nitroglycerine, nifedipine, barnidipine hydrochloride, nicardipine hydrochloride, dipiridamol, amrinone, indenolol hydrochloride, hydralazine hydrochloride, hydrochlorothiazide methyldopa, furosemide, spironolactone, guanethidine nitrate, resperin, amosulalol hydrochloride, lisinopril, metoprolol, pilocarpin, tasosartan and the like; psihonevroticheskih medicines, such as chlorpromazine hydrochloride, amitriptyline hydrochloride, nemonapride, haloperidol, operon hydrochloride, perphenazine, diazepam, lorazepam, chlordiazepoxide, adinazolam, alprazolam, methylphenidate, milnacipran, paroxetine, risperidone, sodium valproate, and the like; antiemetics such as metoclopramide, ramosetron hydrochloride, granisetron hydrochloride, ondansetron hydrochloride, azasetron hydrochloride and the like; anti-histamine drugs such as chlorpheniramine maleate, diphenhydramine hydrochloride, and the like; vitamins such as thiamine nitrate, tocopherol hydrochloride, SikhoteAlin, pyridoxal phosphate, Cobham the Ministry of foreign Affairs, ascorbic acid, nicotinamide, and the like; protivopodagricakih drugs, such as allopurinol, colchicine, probename and the like; drugs used in Parkinson's disease such as levodopa, selegiline, and the like; hypnotics sedatives, such as amobarbital, bramwellmacfa, midazolam, chloral hydrate; antitumor drugs, such as fluorouracil, carmofur, aclarubicin hydrochloride and the like; antiallergic drugs such as putidaredoxin, terfenadine, and the like; antidepressants such as phenylpropanolamine, ephedrine and the like; medicines used to treat diabetes such as acetanilid, insulin, tolbutamide, desmopressin, glipizide and the like; diuretics, such as hydrochlorothiazide, polythiazide, triamteren and the like; bronchodilators such as aminophylline, formaterror, theophylline and the like; antitussives such as codeine phosphate, noscapine, dimemorfan phosphate, dextromethorphan, and the like; antiarrhythmic drugs such as quinidine nitrate, digitoxin, propafenone hydrochloride, procainamide, and the like; surface-anaesthetics, such as aminomethylbenzoic, lidocaine, dibucaine guy is rochloride and the like; antiepileptic drugs such as phenytoin, tosucceed, primidone, and the like; synthetic corticosteroids such as hydrocortisone, prednisolone, triamcinolone, betamethasone and the like; drugs acting on the gastrointestinal tract, such as famotidine, ranitidine hydrochloride, Dymatize, sucralfate, sulpiride, teprenone, plaunotol, 5-aminosalicylic acid, sulfasalazin, omeprazole, lansoprazole, and the like; drugs acting on the Central nervous system, such as indeloxazine, idebenone, tiaprid hydrochloride, livermere hydrochloride, calcium homopentameric and the like; means used for the treatment of hyperlipidemia, such as pravastatin nitri, simvastatin, lovastatin, pravastatin, atorvastatin, and the like; antibiotics, such as ampicillin falselikecresid, cefotetan, josamycin and the like; national Department of standardization therapeutic agent, such as tamsulosin, doxazosin mesilate, terazosin hydrochloride and the like; anti-asthma drugs, such as pranlukast, zafirlukast, albuterol, ambrosa, budesonide, levalbuterol and the like; drugs, prostaglandin derivatives I to improve peripheral circulation, such as velopress sodium and the like; antithrombotic, the hypothesis is sunye means for heart failure, means for treatment of various complications of diabetes, medicines for peptic ulcer treatment, drugs for the treatment of skin ulcers, means for treatment of hyperlipidemia, anti-asthma drugs, and the like. You can use the drug in free form or in the form of any salt, which is farmacevtichesky acceptable. In addition, you can apply 1 or 2 or more drugs.

Regarding the number mentioned medicines there is no restriction, since it is this quantity that is usually used for treatment, but at least it is an effective amount and is not more than 80%, wt./wt., weight of the tablet, preferably, at least an effective amount, from the point of view of treatment and is not more than 70%, wt./wt., weight of the tablet. According to this invention, achieved sufficient strength tablet while maintaining the porous structure and therefore, it becomes possible to increase the number of drugs that add depending on the weight of the tablet. In addition, if the particle diameter of the medicinal product is great, there is a “feeling of sand in the disintegration in the buccal pocket and therefore, the preferred average particle diameter of 250 μm or less. If the one particle diameter of the medicinal product is 250 μm or more, typically this product is used after grinding to a particle size average diameter of from about 1 to 200 microns, preferably after grinding to the size of an average particle diameter of approximately from 5 to 100 μm, more preferably after grinding to the size of an average particle diameter of from 5 to 30 μm, using the appropriate device for grinding, such as hammer crusher, sample mill and jet mill and the like.

In addition, when the drug of the present invention is a tool with a bitter taste and/or poor fluidity, it can be mixed with a pharmaceutically acceptable carrier, which reduces the bitter taste of the medicine or may improve the fluidity of the medicinal product. Examples of the said carrier is a polymeric substance comprising a water-insoluble polymers, polymers soluble in the stomach, the polymer soluble in the intestine, wax-like substances and similar substances. Examples of water-insoluble polymers are simple water-insoluble cellulose ether, such as ethylcellulose, aquacoat (trade name, Asahi Kasei), and the like, water-insoluble copolymers of acrylic acid such as a copolymer of chloride acrylate-methyl methacrylate-trimethylammonium-ethyl methacrylate (for example, trade name: AUD the agit RS (Eudragit), Eudragit RS30D, Rohm), a copolymer of methyl methacrylate-ethyl acrylate (e.g., Eudragit NE30D, Rohm), and the like. Examples of polymers that are soluble in the stomach, are soluble in the stomach derivatives of polyvinyl, such as polyvinylacetal-diethylaminoacetate and the like, soluble in the stomach copolymers of acrylic acid such as a copolymer of methyl methacrylate-butylmethacrylate-dimethylaminoethylmethacrylate (for example, trade name Eudragit E, Rohm), and the like. Examples of enteric polymers are soluble in the intestine derivatives of cellulose such as acetate-succinate of hydroxypropylmethylcellulose, phthalate of hydroxypropylmethylcellulose, phthalate of hydroxymethylcellulose, karboksimetiltselljuloza and the like, soluble in the intestine copolymers of acrylic acid such as a copolymer L, methacrylic acid (for example, trade name: Eudragit L, Rohm), a copolymer LD, methacrylic acid (for example, trade name: Eudragit L30D-55, Rohm), and the like. Examples of wax-like substances are solid oils and fats, such as gidrirovannoe castor oil, gidrirovannoe coconut oil, tall oil and the like, higher fatty acids such as stearic acid, lauric acid, myristic acid, palmitic acid and the like, higher alcohols, such the AK cetyl alcohol, stearyl alcohol and the like. If the pH-independent water-insoluble polymer is preferred, more preferred are a simple water-insoluble cellulose ether or water-insoluble copolymer of acrylic acid, and particularly preferred are ethylcellulose (in the ideal case, Aquacoat (trade name water dispersion of ethyl cellulose) or a copolymer of an acrylate-methyl methacrylate-chlorinated trimethylammoniumchloride (in the ideal case, Eudragit RS30D (trade name)) is particularly preferred. If necessary, the carrier of the present invention can also be added plasticizer. Examples of the above-mentioned plasticizer is triacetin, triethylcitrate, dibutylsebacate, acetylated monoglyceride, Eudragit NE30D (trade name of Rohm) and the like. In addition, the fluidity of medicines that should not have a bitter taste or odor, can be improved, and in addition to the above polymeric substances such as water-insoluble polymers, which are soluble in the stomach polymers, enteric polymers, and the like or wax-like substances and the like, in this case, as the carrier can be used water-soluble polymers, sugars and stuff like that. Examples of the media being printed are the camping water-soluble polymers, such as hydroxypropylcellulose, hypromellose, polyvinylpyrrolidone, copolyvidone, polyvinyl alcohol and the like. If necessary, the number used in the invention device can be adjusted depending on how bitter or how much liquid is a drug. However, typically the carrier is from 5 to 300%, wt/wt., preferably from 10 to 100%, wt./wt., more preferably from 20 to 100%, wt./wt. on the drug. If the drug is famotidine, the media is 20-100%, wt./wt., preferably 30-50%, wt./wt. on famotidine. In addition, when the present invention use a drug with a long release, it is preferable that appropriate treatment with slow release means (for example, a link to the Japan patent No. Hei 7-72129) was carried out by

conventional ways, so that there were obtained particles, depending on which controlled release of drugs. In addition, as the tablet of the present invention disintegrates and dissolves in the buccal pocket, the drug can be absorbed in the buccal pocket if it is a medicine that is absorbed by the mucous membrane of the buccal karma is on.

Relatively used in this invention diluent, there are no special restrictions, as it has a relatively higher melting point than the saccharide, which forms the product of melting and solidification used in this invention, and it quickly desintegrated in the buccal pocket, if the above-mentioned diluent to form a tablet. As examples of the saccharides with a relatively higher melting point than that of the saccharide used in the present invention, inorganic substances such as anhydrous calcium phosphate, bicrystalline calcium carbonate, calcium silicate and the like, crystalline cellulose (e.g., trade name: avicel (Avicel) Asahi Kasei), and the like. Sugars with a high melting point are preferred. Sugars with a temperature difference of melting points, at least 10°C, preferably sugars with a temperature difference of melting points, at least 20°from the saccharide with a low melting point, used in this invention are the saccharide with a high melting point used in this invention. The choice of saccharides with a greater difference in melting points is preferred, taking into account the difference between the projected temperature of the heating device and is the temperature of the tablets, which is heated.

If necessary, the amount of diluent used in the present invention, adjusted in accordance with the dose of the drug and/or size of the tablet, and there are no special restrictions, as the “saccharide with a low melting point”used in this invention forms a bridge between the particles of the medicinal product and/or diluent so that you can retain the shape of the tablets made from the drug and diluent. If you want this added amount is adjusted to obtain a tablet of the desired size, increasing the added amount if the dose of the drug is small, reducing the added amount when the dose of the drug is large, and so forth, but typically ranges from 20 to 1000 mg, preferably 50-500 mg, more preferably 100-400 mg per 1 tablet. In addition, the number ranges from 10 to 99.5%, wt./wt., preferably from 20 to 95%, wt./wt. by weight of the tablet. The ratio of mixture of the diluent used in the present invention, the “saccharide with a low melting point”used in this invention is preferably from 99.5:0.5 to 75:25, more preferably from 98:2 to 80:20.

There are no special restrictions regarding when harida with a low melting point, used in this invention (also referred to hereinafter as the “saccharide”as it is pharmaceutically acceptable and has a relatively lower melting point than the drug and diluent used in the present invention, and it supports the shape of the tablets in the melting and solidification. However, the sugars with a melting point of approximately 80-180°are the preferred and more preferred are sugars with a melting point of approximately 90-150°C. Examples of the above-mentioned saccharides are glucose (megahydrate, melting point 83°C), xylitol (melting point 93°C), trehalose (dihydrate, melting point 97°C), sorbitol (hydrate, melting point less than 100°C), maltose (melting point 102°) sorbitol (melting point 110°C), aritra (melting point 122°C), glucose (melting point 146°C) ▫ maltitol (melting point 150°C), mannitol (melting point 166°C), sucrose (melting point of approximately 170°). As such saccharide use one, two or more saccharides selected from the group consisting of glucose, xylitol, trehalose, sorbitol, maltose, eritria, maldita, mannitol, sucrose, and their hydrates. Preferred are one or two or more saccharides selected from the group consisting of glucose, xylitol, is regalos, sorbitol, maltose, eritria, maldita and their hydrates. Trehalose, maltose, aritra or ▫ maltitol, which are easily adjustable, as mentioned sugars hardly absorb moisture, are perfect, and trehalose and/or aritra are particularly ideal. The saccharides of the present invention optionally, you can choose, given the chemical properties of used drug, i.e. medicinal product stability relative to temperature. In addition, you can use one saccharide, or a combination of two or more saccharides. In addition, it also is possible to use these sugars in the form of hydrates. If there is a difference between the melting points of hydrated and anhydrous forms were Saarela, should be chosen accordingly the temperature of the heating.

If required, the amount of saccharide (the“saccharide with a low melting point”used in this invention, regulate in accordance with the dose of the drug and/or size of the tablet, with no special restrictions, as a bridge between particles of the medicinal product and/or diluent through the product of melting and solidification of the saccharide with a low melting point so as to keep the shape of tablets made from drugs and dilute the I am. If necessary, it added the correct number so that there was obtained a tablet of the desired size by increasing the amount of diluent used in the present invention, if the dose of the drug is small, reducing the amount of diluent used in this invention, if the dose of the drug is large, and the like. Therefore, the number of “saccharide with a low melting point”used in this invention is usually from 0.5 to 25%, wt./wt., preferably 2-20%, wt./wt., more preferably 5-10%, wt./wt. depending on the mass of the medicinal product and/or diluent used in the present invention, or 2-20%, wt./wt., mass of the pharmaceutical product.

Xylitol (melting point 93°C), trehalose (dihydrate, melting point 97°C), sorbitol (hydrate, melting point below 100°C), maltose (melting point 102°C), sorbitol (melting point 110°C), aritra (melting point 122°C), glucose (melting point 146°C) ▫ maltitol (melting point 150°), mannitol (melting point 166°C.), sucrose (melting point of approximately 170° (C) and lactose (melting point 202° (C) and the like are presented as a saccharide with a relatively higher melting point than the saccharide with a low point of plaul the tion, used in this invention, Examples of the above-mentioned saccharide is one or two or more saccharides selected from the group consisting of xylitol, trehalose, hydrate sorbitol, maltose, sorbitol, eritria, glucose, maldita, mannitol, sucrose, lactose, and their hydrates. As described in special terms, xylitol, trehalose, sorbitol, aritra, glucose, ▫ maltitol, mannitol, sucrose, lactose, and their hydrates can be used as the “saccharide with a high melting point, whereas glucose (monohydrate, melting point 83° (C) is used as the “saccharide with a low melting point”used in this invention. In addition, sorbitol, aritra, glucose, ▫ maltitol, mannitol, sucrose, lactose, and their hydrates can be used as the “saccharide with a high melting point”, when xylitol (melting point 93° (C) or trehalose (dihydrate, 97° (C) apply, as the “saccharide with a low melting point”used in this invention. Glucose, ▫ maltitol, mannitol, sucrose or lactose can be used as the “saccharide with a high melting point, whereas eritra (melting point 122° (C) is used as the “saccharide with a low melting point”used in the present invention. In addition, mannitol, sucrose and lactose can be used as the “saccharide with a high melting point”, while molytic (melting point 150° (C) used is as the “saccharide with a low melting point” in this invention. In addition, the lactose can be used as the “saccharide with a high melting point, whereas sucrose (melting point of approximately 170° (C) primeniaut as the “saccharide with a low melting point” in this invention. When necessary, the “saccharide with a high melting point” must be selected as described, in accordance with the type of saccharide used in the present invention. When choosing saccharides in order to have a greater difference between their melting points, the “saccharide with a low melting point” is preferably one or two or more saccharides selected from the group consisting of glucose, maldita, mannitol, sucrose and lactose, and more preferably from mannitol, sucrose and lactose. These sugars are used in an appropriate amount of one saccharide or a mixture of two or more saccharides, as required. If the difference between the melting point of the “saccharide with a high melting point” is small, there is a possibility that the “saccharide with a low melting point”used in this invention, and “saccharide with a high melting point” will work together to melt and harden in the tablet, and the sugars contained in the tablet form “interparticle” the bridge, resulting in an increase in the strength of the tablets above the necessary strength so that it will not be quickly disintegrates in the buccal ka the Manet. Thus, the choice of saccharides with a greater temperature difference between the melting points is preferred from the viewpoint of the production of tablets fast dezintegriruetsja in the buccal pocket. Preferably the difference of the melting points is 10°s or higher, more preferably 20°C or higher.

There are no particular limitations on the binder, while receiving a constant concentration of particles so that is not observed phenomenon sorting or sticking during tableting, and improved ductility when granularit drug, diluent and “saccharide with a low melting point and, in addition, other optional fillers that are required. “Saccharide with a high plasticity” or water-soluble polymer are the examples mentioned binders. In the description of the “saccharide with a high plasticity” means a saccharide, which shows the hardness of the tablets 2 kPa or more when 150 mg of saccharide tabletirujut under a tabletting pressure of 10 to 50 kg/cm2using a stamp with a diameter of 8 mm (mentioned in WO 95/20380 (corresponding to U.S. patent 5576014, Japan patent 3122141)). Maltose, ▫ maltitol, sorbitol and the like are considered as mentioned saccharide. It is preferable ▫ maltitol, even when heating and melting of OK is called crystal. Examples of water-soluble polymers are hydroxypropylcellulose, hypromellose, polyvinylpyrrolidone, copolyvidone, polyvinyl alcohol and the like. Taking into account the environment in which to store the raw materials and pharmaceutical drug, hydroxypropylcellulose, hypromellose and copolyvidone with a low ability to absorb moisture are preferable, and copolyvidone is perfect.

There are no particular limitations on the number of “saccharide with a high plasticity” or water-soluble polymer added to the “saccharide with a low melting point”, while receiving a constant concentration of particles so that not observe the phenomenon of sorting or sticking during tableting, and improved ductility when granularit drug, diluent and “saccharide with a low melting point and, in addition, the required pharmaceutical excipients in addition to binders. Generally this amount is from 0.5 to 20%wt./wt. Preferably the number of “saccharide with a high plasticity” is 2-20%, wt./wt., more preferably 2-10%, wt./wt. The amount of water-soluble polymer is preferably from 0.5 to 5%. wt./wt., more preferably from 0.5 to 3% wt./wt.

PR is pactically is when combining the “saccharide with a low melting point” of the present invention, the “saccharide with a high melting point and binders choose aritra as the “saccharide with a low melting point”, lactose and/or mannitol is chosen as the “saccharide with a high melting point and ▫ maltitol choose as binders (the“saccharide with a high plasticity”), or aritra chosen as the “saccharide with a low melting point” of the present invention, lactose and/or magnet chosen as the “saccharide with a high melting point and, in addition, choose copolyvidone as a binder (“water soluble polymer”).

There are no restrictions for pharmaceutical excipients in addition to the diluent and the binder used for the present invention because they relate to a variety of excipients that are pharmaceutically acceptable and are used as additives. Examples of the above-mentioned fillers are disintegrator, acidic flavoring agents, foaming agents, synthetic sweeteners, flavoring agents, lubricants, coloring agents, stabilizers and the like. Use one of the above pharmaceutical fillers, or a combination of two or more of these fillers.

Examples of disintegrators are corn starch, calcixerollic on ricemills, palynology alcohol and the like. Examples of acidic flavoring agents are citric acid, tartaric acid, malic acid and the like. Examples of foaming agents are sodium bicarbonate, and the like. Examples of synthetic sweeteners are saccharin sodium, glycyrrhizinate of dicale, aspartame, stevia, cormatin and the like. Examples of flavors include lemon, lime, orange, menthol and the like. Examples of lubricants are magnesium stearate, calcium stearate, sucrose esters of fatty acids, polyethylene glycols, talc, stearic acid and the like. Examples of coloring agents include food dyes such as yellow food dye No. 5, red food dye No. 2, blue food dye # 2 and

the like; food lacquer dye; red iron oxide and the like. The stabilizers are selected via medicines after conducting various tests. If necessary, one of these additives, or a combination of two or more additives are added in an appropriate amount. There are no particular restrictions on the quantity added of the pharmaceutical filler as the filler included in the list of commonly used in the trade of pharmaceutical products.

Processes, especially conditions is proizvodstva and the like included in a method for the production of tablets of the present invention, quickly dezintegriruetsja in the buccal pocket, will be described in detail below.

Method for the production of tablets of the present invention, quickly dezintegriruetsja in the buccal pocket, consists of (a) the method by which the tablet starting materials comprising a drug, a diluent and “saccharide with a relatively lower melting point than the drug and diluent, is pressed under low pressure required to maintain the shape of the tablet, (b) the method by which the extruded product obtained by the method (a), is heated at least to a temperature at which the above-mentioned saccharide with a low melting point will melt, and (C) the way in which the extruded product obtained by the method (b)is cooled at least to a temperature at which the molten saccharide with a low melting point will harden.

Method (a): compaction Method

There are no restrictions regarding the “tablet starting materials of this invention as a drug, a diluent and a saccharide with a relatively lower melting point than the drug and diluent are able, when they pharmaceutically evenly dispersed. The above-mentioned “tablet starting materials can be obtained using Fizicheskaya, drying spray or a number of methods of granulation, such as granulation in the fluidized bed granulation by mixing, granulation during processing in the drum, and the like. Of the following methods granulation in the fluidized bed is preferred from the viewpoint of productivity. For example, by granulation in fluidized bed “tablet starting materials” produced by atomization of the solution of the “saccharide with a low melting point”used in this invention as a binder, dissolved and/or suspended in a pharmaceutically acceptable solvent, pharmaceutical diluent, in order to apply and/or be pelletized. It also provides a way to obtain “tablet starting materials”in which the “saccharide with a low melting point” is mixed with drug and/or diluent in the form of particles and/or powder, and granularit using the solution of the “saccharide with a high plasticity” or water-soluble polymer. In this case, for example, the drug add-on way “tablet starting materials” pharmaceutically

prepare uniform mixing with the product of the granulation containing the “saccharide with a low melting point”used in this invention, the way in which “tabla is full-time source materials produced by atomization of the solution of the “saccharide with a low melting point”, used in this invention as a binder substances dissolved and/or suspended in a pharmaceutically acceptable solvent, a mixture of drug and diluent to apply and/or be pelletized and so on. It also provides a way to obtain “tablet starting materials”, according to which the “saccharide with a low melting point” is mixed with the drug and diluent in the form of particles and/or powder and granularit using the solution of the “saccharide with a high plasticity” or water-soluble polymer. In addition, the drug can be used in the form of particles medicines with improved fluidity or in the form of particles, bitter taste which is masked, obtained by spray drying according to the method of technical Avenue international preliminary application WO 02/02083A1 (application for U.S. patent, series No. 90/896820: the claimed priority to provisional patent application U.S. series, No. 60/215292).

In this invention the pressing can be performed using conventional methods, while there are no special restrictions as “pressing” is a method by which the shape of the pill is maintained at a lower pressure threshold required to keep the form of tablets, or higher. Referred to the pressing can

to carry out after mixing the lubricant and the like with the aforementioned “tablet source materials using a conventional tablet press machine, such as a device for the manufacture of individual tablets or rotary tabletirovanija machine and the like. In this case, the pressure for tabletting is usually 25~800 kg/die, preferably 50~500 kg/stamp, more preferably 50~300 kg/stamp.

Method (b): Method of heating

In this invention, “heat” is carried out by conventional methods, and there are no special restrictions because “the heat” is a way by which the extruded product obtained by the method (a)may be brought to a temperature which, at least, is the melting point of the “saccharide with a low melting point”used in this invention. In addition, this invention also includes heating, in which the part is used in the present invention the sugar melts and blends. Called the process of “heating” can be performed using, for example, the Plenum. When necessary, the temperature conditions are selected depending on the type of saccharide with a low melting point”used in this invention, and usually there are no special restrictions, because the temperature value corresponds to the melting point of the “saccharide with a low melting point”, used in this invention, or is higher and corresponds to the melting point of the diluent or is below. When using the “saccharide with a low melting point”used in this invention, the temperature

approximately 80 to 180°C, preferably from 90 to 150°C. Temporary conditions optionally selected depending on the type of saccharide required strength tablets, implementation of disintegration in the buccal pocket and the like, but usually the time is from 0.5 to 120 minutes, preferably from 1 to 60 minutes, more preferably from 2 to 30 minutes. In addition, the processes of “heating” and “cooling” can also be carried out after the processes of “wetting and drying”, which are described below.

Method (C): cooling Method

In this invention, cooling was performed using conventional methods and for methods there are no special restrictions as a way of “cooling” is that used in the present invention, the saccharide with a low melting point is solidified after melting. Named “cool”, for example, can be performed at room temperature or in a low temperature environment such as a refrigerator and the like.

The method of wetting and drying, as described below, should PR is changing, if used in this invention, the saccharide with a low melting point, which melts and solidifies when cooled, becomes amorphous and there is a reduction of the strength of the tablet when it absorbs moisture, that is, if consumed glucose, sorbitol, maltose or trehalose as the saccharide used in the present invention. It is possible to obtain a solid tablet when using the process of wetting and drying in order crystallized saccharide, which becomes amorphous when heated. In addition, you can also use the method, which can stably maintain a state of transition in amorphous, such as how to obtain a consistent farmacevticheskogo drug by sealing inside of packaging material, made of waterproof material.

In this invention, there are no restrictions regarding the “wetting”as “hydration” is the way used in this invention saccharide crystallizes after the transition to the amorphous state, if the hydration is carried out in combination with the drying. Mentioned a way to “hydrate” is selected on the basis of the observed critical relative humidity of the medicinal product, the saccharide with a low melting point, and time is of avatele, used in this invention. Typically, however, the hydration is carried out until the observed critical relative humidity or to a higher. For example, humidity 30-100% RH (relative humidity), preferably 50-90% RH. The temperature during this process corresponds 15-50°C, preferably 20-40°C. the processing Time is from 1 to 36 hours, preferably from 12 to 24 hours.

There are no particular restrictions regarding the “drying”as “drying” is a means by which to remove the water that was absorbed during hydration. Usually called “drying” is carried out at 10-100°C, preferably 20-60°With, in particular when 25-40°C. the processing Time is from 0.5 to 5 hours, preferably from 1 to 3 hours.

The tablet of the present invention, quickly dezintegriruetsja in the buccal pocket, obtained by the described method has a porous structure. The porous structure means that typically, the porosity of approximately 20%to 80%, preferably from 20 to 50%, more preferably from 30 to 50%. It is possible that through education of the bridge over the product of melting and solidification of the saccharide remains porous structure and retained the ability to quickly disintegrates in the buccal pocket, and also achieved tableto the Naya strength and fragility, which withstand automated packaging dosage forms on the machines.

Brief description of drawings

Figure 1 is a schematic drawing showing the position of the saccharide before and after the heat treatment of the tablets of the present invention, without limiting the present invention represented by the drawings.

Figure 1(A) is a schematic drawing showing the situation before and after the heat treatment, when the “saccharide with a low melting point” (saccharide of low melting point) in the tablet is uniformly mixed with a diluent, such as the “saccharide with a high melting point” (saccharide high melting point) and the like.

Figure 1(B) is a schematic drawing showing the position after heating. It turned out that the “saccharide with a low melting point” (saccharide of low melting temperature) of the present invention, which melts/freezes contacts between particles of a diluent, such as the “saccharide with a high melting point” (saccharide high melting point) and the like, and as a result improves physical strength. When described applies to the tablet whole, it manifests as improving strength tablets. In this case, the uniformly mixed means that even if the status is and when each component is present in the form of particles and is not uniformly dispersed in the whole tablet is in a state where each component is uniformly dispersed, which was observed at the level of particles.

Description of the preferred aspects

Hereinafter the invention is explained in more detail as examples, but this invention is not limited to the following examples. In addition, the following examples of the present invention evaluate the strength, friability and disintegration time of tablets, but, as it turned out, that adding drugs have little effect on these parameters of the assessment, the examples also include the results obtained with those tablets, which did not contain the drug.

Evaluation methods

Methods for evaluation of tablets of the present invention, quickly dezintegriruetsja in the buccal pocket, described below.

[Research hardness] Determination was carried out using a hardness tester tablets Slaunger ((Schleuniger) Schleuniger Co., Ltd). Testing was performed with 5 tablets and presents average values. The hardness of the tablets was determined by the power required for crushing tablets (units kPa). Higher values indicate a stronger pill.

[The fragile] Determination was carried out, is using the abrasion tester (model PTFR-A, Pharma Test Co.) Fragility was determined using the pill 6, Fragility was determined by weight loss pills in percent after 100 cycles a circular motion at a speed of 25 revolutions per minute. Lower values indicate a more durable surface tablets.

[Testing disintegration in the buccal pocket] the Tablet of the present invention placed inside the buccal pocket healthy adult males in the absence of any water inside their oral cavity and determine the time until the tablet is completely not desintegrated and dissolved by saliva.

[Porosity] the porosity of the tablets was calculated by the following formula (I) and represented the average of five tablets.

(V: volume pills, W: weight of the tablet, R.: specific weight of the powder constituting the pill)

[Experiment 1] Confirmation of melting when heated, the saccharide and the changes in its crystalline form.

(Method)

After careful crushing trehalose (Hayashibara Co., Ltd.), maltose (trade name of carmalt-(Sunmalt-S), Hayashibara Co. Ltd.,), sorbitol, sucrose, mannitol (Towa kasei Co., Ltd.), erythrite (Hayashibara Co., Ltd.), xylene (Towa kasei Co., Ltd.) as saccharides in a mortar and through a punch press them was transferred into a glass bowl and perform heat treatment for 5 minutes at 140°using PECs is software controlled (model No. MOV-112P, Sanyo).

The melting of the saccharide was confirmed visually. After cooling the molten saccharide to room temperature its SKOV was crushed using a mortar and punch press, the measurements were performed using differential scanning calorimeter (hereinafter DSC) and assessed the crystalline form.

In addition, maltose watered during the night under conditions of 25°C and 75% RH using a thermostated vessel at a constant humidity (Tabaiespec Co., Ltd., OR-35C), and were determined using DSC. Then received a physical mixture of mannitol/maltose (9/1) and mannitol/trehalose (9/1) and were determined using DSC before heat treatment after heat treatment and once carried out the moisture after the heat treatment, in order to evaluate the crystalline form.

(The results)

It was determined melting trehalose, maltose, sorbitol, xylitol and eritria when heated. On the other hand, was not confirmed melting sucrose and mannitol. Among the saccharides, which were melted, the endothermic peak coming from the crystals of trehalose and maltose, disappeared, confirming the transition to the amorphous state. In addition, when the recrystallization of sugar that goes into an amorphous state as a result of moisture, amorphous saccharide is also installed. In contrast, the crystallization of xylitol and er is TRITA has been confirmed, because there were the same endothermic peak as before heating. Disappeared only peak of the “saccharide with a low melting point”used in this invention, confirming the transition to the amorphous state, in the case of each physical mixture of mannitol/maltose; mannitol/trehalose. In addition, the peak used in this invention the “saccharide with a low melting point” appeared after moistening, confirming that took place recrystallization.

(Discussion)

The melting of the sugars used in this experiment was estimated was heated at 140°C. As a result, the observed melting with saccharides with a low melting point, whereas there have been no changes with saccharides with a high melting point”. In addition, because only an endothermic peak saccharides with a low melting point would disappear when heated physical mixtures, it was found that melted only “saccharides with a low melting point”. It appeared that only the “saccharide with a low melting point can melt and particles “saccharide with a low melting point” is able to stick.. in Addition, it was found that when melting the sugar goes into the amorphous state, he recrystallizes when wet. Therefore, it appears that the improvement in stability can be realized by Krista the implementation, if the saccharide with a low melting point becomes amorphous state and a probability that the strength will decrease and the like due to moisture absorption during storage and so on.

[Experiment 2] Research on improving the strength of the model of tablets (mannitol/maltose)

(Method)

Model tablet And (in the future, the tablet (A) was prepared as follows: first, 450 g of mannitol were sieved through a sieve (20 mesh), and then granulated using a granulator for treatment in the fluidized bed, with 250 g of an aqueous solution of maltose (20% wt./wt.) as the binder. Then, to the obtained granulation product was added to 0.5% magnesium stearate and mixed, and tablets, approximately 200 mg per 1 tablet, made using a rotary tablet press machine. If necessary, adjust the pressure tableting, to obtain the strength tablets 1 kPa, and it was approximately 0.1 t/stamp. Tablet And was heated and/or humidified as described below (group 1: only thermoablative, group 2: watered after heat treatment, group 3: thermoablative after moistening and again made). The treatment conditions for each method was heat treatment for 5 minutes at 140°using furnace with software control (model MOV-112P, Sanyo) and processing hydrated is eat, includes moisture for 18 hours at 25°C and 75% RH using a temperature-controlled chamber with constant humidity (Tabaiespec, PR-35C) and then drying for 3 hours at 30°C and 40% RH.

In addition, if necessary, evaluated crystalline form for each way, carrying out the determination using DSC. In addition, the stability of the tablets group 1 was evaluated at 25°C and 60% RH.

(The results)

The higher strength tablet And approximately 4 times observed only when heated (group 1), but the decrease in strength was noted (table 1) in the definitions of sustainability (25°C, 60% RH), which is understandable. When determining tablets And using DSC was performed after heat treatment, it was confirmed that the maltose enters amorphous state, and suggested that the absorption of moisture amorphous maltose was the cause strength reduction. Determination by DSC on tablets, which was moistened (group 2) for the crystallization of maltose, which is passed in the amorphous state, but crystallization was not observed. In addition, the crystallization of maltose was observed during the initial hydration of the group of tablets. Peak coming from the crystals maltose, disappeared after she was subjected to heat treatment, confirming that the fusion of maltose also took place in this tablet. In addition, the crystal is tion maltose were not observed, when maltose was moistened again.

Table 1
Changes in the strength of the tablets of the present invention (kPa).
 Tablet A (group 1)
Before thermal processing1,2
After heat treatmentthe 5.7
1 hour after storage at 25°60%0,3
2 hours0,1
4 hours0,3
8 hours0,0
24 hours0,2
120 hours0,2

(Discussion)

Increase strength by heat treatment was observed with tablet A. it Appears that the observed increase in strength, obviously, was the result of stable adhesion of particles “saccharide with a high melting point” as a result of the melting of the “saccharide with a low melting point”, since the peak of maltose crystals disappeared at definitions by DSC (group 3).

Was confirmed resilience in the face of 25°C and 60% RH, as maltose, which is converted to an amorphous state, has low to eticheskuyu relative humidity, and there is a probability that the strength will fall upon the absorption of moisture. As a result, the observed decrease in strength tablets (group 1). An attempt is made to hydrate pellets, which were heat treated to increase the critical relative humidity and to improve the stability and crystallization of maltose (group 2). However, the peak coming from the crystals maltose, was not observed and occurred almost no crystallization. As shown in experiment 1, the crystallization was observed with the physical mixture and therefore it was found that crystallization was slow with the creation of surface area is relatively small tablets. Therefore, it is possible to provide a pharmaceutical preparation which increase the strength of the tablets can be maintained, if used maltose as the saccharide of the present invention, for example by sealing in moisture-proof packaging material.

[Experiment 3] Research on improving the strength of the model of tablets (mannitol/trehalose, mannitol/aritra)

(Method)

Model tablets and received the following way: first 450 g of mannitol were sieved through a sieve (20 mesh), and then granulated using a granulator for treatment in the fluidized bed, with 250 g of an aqueous solution of trehalose (model tablet In, in the future, t is bleda) or an aqueous solution of Eretria (model tablet, in the future, tablet) (20% wt./wt.) as the binder. Then, to the obtained granulation product was added to 0.5% magnesium stearate and mixed, and tablets, approximately 200 mg per 1 tablet, made using a rotary tablet press machine. If necessary, adjust the pressure tableting, to obtain the strength tablets 1 kPa, and it was approximately 0.1 t/stamp for tablets and approximately 0.25 t/stamp for tablet S. the Model of the tablet was heated and/or humidified as described below (group 1: only thermoablative, group 2: watered after heat treatment, group 3: watered). Conditions of heat treatment for the pills were In 9 minutes at 140°and the conditions for heat treatment for tablets were 5 minutes at 140°and moisture conditions were the same as in experiment 2. Resistance strength, friability and disintegration time in the buccal pocket investigated tablets, when left at 25°C and 60% RH were evaluated for up to 24 hours. In addition, were determined using DSC and, if necessary, evaluated crystalline form for each method.

(The results)

The increase in strength of 2.5-8 times observed when heated as tablets, and C (Tables 2 and 3). When investigated crystalline form, using DSC, this time trehalose tablets In advance the eh amorphous, and aritra tablets was crystalline. When investigated the stability of the tablets at 25°C and 60% RH, in the case of tablets In the observed temporary reduction in strength, which is believed to be a consequence of the absorption of moisture (table 2, group 1). However, it was almost full recovery of these strength reduction for 24 hours. The fact that it was accompanied by the crystallization of trehalose, confirmed by DSC. There was no strength reduction, indicating stability in the case of tablets group 2, which was moistened after heat treatment to enhance crystallization. In addition, crystallization, almost the same as the crystallization group 2 tablets were valid for tablets group 3, which was done by only wetting, which is the usual method of production. Therefore, when considering the results of heat treatment/treatment-hydration tablets compared to single treatment with hydration, it turns out that probably received the tablet with excellent properties. As aritra tablets is crystalline, it happened almost no absorption of moisture, and he was almost stable at 25°C and 60% RH (table 3). Therefore, moisturizing after heating (group 2) were not conducted. Eritra is a crystalline saccharide and therefore had not been pastinacella increase the strength alone of hydration (table 3, group 3).

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Table 2
Properties of the tablets of the present invention (pill)
Processing groupGroup 1Group 2Group 3
 Strength (kPa)Friability (%)Vivo (sec)Strength (kPa)Friability (%)Vivo (sec)Strength (kPa)Friability (%)Vivo (sec)
Before heating0,84,80130,84,80130,84,813
After heating6,40,66236,40,6623
After wetting5,90,88283,21,5817
25°60%

1 hour
5,2---the 5.7 -3,1---
2 hours1,6----5,9----3,1----
4 hours1,5----6,2----3,4----
8 hoursa 4.9----6,1----3,1----
24 hours5,60,92205,20,90272,5of 1.5720

Table 3
Properties of the tablets of the present invention (pill)
Processing groupGroup 1Group 3
 Strength (kPa)Friability (%)Vivo (sec)Strength (kPa)Friability (%)Vivo (sec)
Before heating2,1of 1.34242,1of 1.3424
After heating5,2 0,8130
After wetting2,31,0332
25°60% 1 hour4,6----3,4----
2 hoursthe 5.7----3,6----
4 hours7,5----2,6----
8 hours4,0----2,9~---
24 hours4,60,72452,51,0020

(Discussion)

Trehalose is a saccharide with high plasticity, which becomes amorphous. As a result of the experiment revealed that trehalose is easily crystallized at 25°C and 60% RH and under conventional conditions of wetting and drying. In addition, as soon as trehalose formed crystals, it was stable at 25°C and 60% RH. Therefore, trehalose is a saccharide useful for obtaining tablets fast disintegrity the workers in the buccal pocket, when using heat treatment.

Eritra is a crystalline saccharide with a low plasticity. Eritra is a saccharide that is not functioning as a binder in the usual ways, but the present invention was achieved success in improving the strength of the tablets as a result of fusion, as mentioned saccharide has a low melting point. Because its source is a crystalline sugar, does not require crystallization when wet, and the like, and eritra is also helpful to improve performance.

Example 1 (Above experiment 3, the tablet, 1)

After sifting 450 g mannitol (Towa kasei Co., Ltd.) through a sieve (20 mesh) was used to granulation using a pellet mill for processing in the fluidized bed (Ohkawara Seisakujo) with 250 g of an aqueous solution of trehalose (Hayashibara Co., Ltd.) (20% wt./about.) as the binder. Then 0.5% magnesium stearate was mixed with the product of the granulation and tablets ((φ 8,5mm, 10,2 R), weighing 200 mg 1 tablet strength tablets of 0.8 kPa (n=5)), were under pressure from tabletirovanija approximately 0.1 t/stamp using a rotary tablet press machine. Then the tablets were heated for 9 minutes at 140°s using the oven with software control (model MOV-112P, Sanyo) and then left for 30 minutes at room Tempe is the atur. The disappearance of the endothermic peak coming from the crystals of trehalose, was confirmed at the moment using DSC, proving that trehalose was amorphous. Then the obtained tablets were humidified at 25°C/75% RH and kept for 18 hours in wet conditions, using a thermostatic chamber at constant humidity (Tabaiespec Co., Ltd., PR-35C). Then the tablets were dried for 3 hours at 30° (humidity 40%)to obtain a tablet of the present invention. The resulting tablets showed the strength of 6.4 kPa (n=5), the fragility of 0.66% (100 cycles), the disintegration time in the buccal pocket - 20 seconds (n=1) and the porosity of 30.6%. In addition, the research results obtained tablets using DSC was discovered endothermic peak coming from the crystals of trehalose, indicating that trehalose was crystalline.

Comparative example 1 (the Above experiment 3, the tablet, group 3)

Tablets, which were grained and alloy preformed as in example 1, was moistened with 25°C/75% RH and kept for 18 hours in wet conditions, using a thermostatic chamber at constant humidity (Tabaiespec Co., Ltd., PR-35C) without heating. Then the tablets were dried for 3 hours at 30° (humidity 40%). The resulting tablets showed the strength of 3.2 kPa (n=5), the fragility of 1.53% (100 cycles), the disintegration time in the buccal pocket - 17 seconds (n=1, and the porosity of 30.6%. On the basis of the obtained results revealed that the tablet of the present invention has excellent properties in terms of strength and fragility, while maintaining a short disintegration time in the buccal pocket compared to the tablets obtained only by wetting and drying.

Example 2 (Above experiment 3, the tablet, 1)

After sifting 450 g mannitol (Towa kasei Co., Ltd.) through a sieve (20 mesh) was used to granulation using a pellet mill for processing in the fluidized bed (Ohkawara Seisakujo) with 250 g of an aqueous solution of Eretria (Hayashibara Co., Ltd.) (20% wt./about.) as the binder. Then 0.5% magnesium stearate was mixed with the product of the granulation and tablets ((φ 8.5 mm, 10,2 R), weighing 200 mg 1 tablet strength tablets of 1.0 kPa (n=5)received under the pressure of tabletirovanija approximately 0.25 t/stamp using a rotary tablet press machine. Then the tablets were heated for 2 minutes at 140°s using the oven with software control (model MOV-112P, Sanyo), and then left for 30 minutes at room temperature to obtain a tablet of the present invention. The resulting tablets showed a strength of 5.2 kPa (n=5), the fragility 0,81% (100 cycles), the disintegration time in the buccal pocket - 30 seconds (n=1) and the porosity of 25.5%.

Comparative example 2 (the Above experiment 3, the tablet, the group 3)

Tablets, which were grained and alloy preformed as in example 2, was moistened with 25°C/75% RH and kept for 18 hours in wet conditions, using a thermostatic chamber at constant humidity (Tabaiespec Co., Ltd., PR-35C) without heating. Then the tablets were dried for 3 hours at 30° (humidity 40%). The resulting tablets showed the strength of 2.3 kPa (n=5), the fragility - of 1.03% (100 cycles), the disintegration time in the buccal pocket - 32 seconds (n=1) and the porosity of 25.5%. Based on these results, it was established that the tablet of the present invention has excellent properties in terms of strength and fragility, while maintaining a short disintegration time in the buccal pocket compared to the tablets obtained only by wetting and drying.

Example 3

The suspension was obtained by mixing 1500 g of famotidine, 2000 aquacoat (trade name of Asahi Kasei), 150 g of triacetin and 700 g of purified water. The resulting suspension was dried by spraying at a rate of spraying of 30 g/minute, the temperature of the input - 120°C and the rotation speed of the disk 8000 rpm using spray drying (Ohkawara Kakoki Co., Ltd., L-8)to obtain particles of famotidine. In this case, the average particle diameter was 91 μm. Separately 4578,6 g mannitol (Towa kasei Co., Ltd.), 60 g of aspartame (Ajinomoto Co., Ltd.) and 165,2 g flavouring powder peppermint (So Hasegwa Co., Ltd) was grained with 15% wt./wt., aqueous solution containing 244,2 g maltose (Hayashibara Co., Ltd., trade name - carmalt-S (Sunmalt-S)) in the granulator for treatment in the fluidized bed (Freund Industry Co., Ltd, FLO-5). After mixing 574,8 g of the obtained particles famotidine and 40 g of calcium stearate with 3385,2 g of the obtained granulation product was received tablets weighing 200 mg, containing 20 mg of famotidine per 1 tablet using a rotary tablet press machine. Then the obtained tablets were humidified at 25°C/75% RH and kept for 24 hours in wet conditions, using a thermostatic chamber at constant humidity (Tabaiespec Co., Ltd., PR-35C). Then the tablets were dried for 3 hours at 30°C and 40% RH.

The obtained tablets were heated for 2 minutes at 140°s using the oven with software control (model MOV-112P, Sanyo Co., Ltd.), and left for 30 minutes at room temperature, to obtain tablets of the present invention. The resulting tablets showed strength - of 5.9 kPa (n=5), the fragility of - 0.14% (100 cycles), the disintegration time in the buccal pocket - 15 seconds (n=1) and the porosity of 25.5%.

Comparative example 3

Tablets were obtained by granulating, pelletizing, moisturising and zasilanie as in example 3. Tablets obtained without heating, showed the strength to 3.7 kPa (n=5), fragility is 0.38% (100 cycles), the disintegration time in the buccal pocket - 15 seconds (n=1) and the porosity of 25.5%. the and the basis of the obtained results clearly the tablet of the present invention has excellent properties in terms of strength and fragility, while maintaining a short disintegration time in the buccal pocket compared to the tablets obtained only by wetting and drying.

Example 4

After sifting 450 g mannitol (Towa kasei Co., Ltd.) through a sieve (20 mesh) was used to granulation using a pellet mill for processing in the fluidized bed (Ohkawara Seisakujo) with 250 g of an aqueous solution of maltose (trade name of carmalt-S, Hayashibara Co., Ltd.) (20% wt./about.) as the binder. Then 0.5% magnesium stearate was mixed with the product of the granulation and tablets ((φ 8.5 mm, 10,2 R), 200 mg 1 tablet strength tablets of 1.2 kPa (n=5)received under the pressure of tabletirovanija approximately 0.15 t/stamp using a rotary tablet press machine. Then the tablets were heated for 5 minutes at 140°s using the oven with software control (model MOV-112P, Sanyo), and then left for 30 minutes at room temperature to obtain a tablet of the present invention. The resulting tablets showed the strength of 6.9 kPa (n=5), the fragility of 0.39% (100 cycles), the disintegration time in the buccal pocket 22 seconds (n=1) and the porosity of 35.6%.

Example 5

After sifting 475 g mannitol (Towa kasei Co., Ltd.) through a sieve (20 mesh) was used to granulation using a pellet mill for processing in pseudouridine the layer (Ohkawara Seisakujo) with 125 g of an aqueous solution of maltose (trade name of carmalt-S, Hayashibara Co., Ltd.) (20% wt./about.) as the binder. Then 0.5% magnesium stearate was mixed with the product of the granulation and tablets ((φ 8.5 mm, 10,2 R), weighing 200 mg 1 tablet strength tablets of 1.0 kPa (n=5)received under the pressure of tabletirovanija approximately 0.1 t/stamp using a rotary tablet press machine. Then the tablets were heated for 5 minutes at 140°s using the oven with software control (model MOV-112P, Sanyo), and then left for 30 minutes at room temperature to obtain a tablet of the present invention. The resulting tablets showed the strength of 7.8 kPa (n=5), the fragility of 0.67% (100 cycles), the disintegration time in the buccal pocket - 23 seconds (n=1) and the porosity 33,2%.

Example 6

After sifting 400 g mannitol (Towa kasei Co., Ltd.) through a sieve (20 mesh) was used to granulation using granulator for treatment in the fluidized bed (Ohkawara Seisakujo) with 500 g of an aqueous solution of maltose (trade name of carmalt-3, Hayashibara Co., Ltd.) (20% wt./about.) as the binder. Then 0.5% magnesium stearate was mixed with the product of the granulation and tablets ((φ 8.5 mm, 10,2 R), weighing 200 mg 1 tablet strength tablets of 0.9 kPa (n=5)received under the pressure of tabletirovanija about 0.03 t/stamp using a rotary tablet press machine. Then the tablets were heated for 5 minutes at 140°With, use what I bake with software control (model MOV-112P, Sanyo), and then left for 30 minutes at room temperature to obtain a tablet of the present invention. The resulting tablets showed the strength of 4.4 kPa (n=5), the disintegration time in the buccal pocket - 20 seconds (n=1) and the porosity of 42.7%.

Example 7

After sifting 490 g mannitol (Towa kasei Co., Ltd.) through a sieve (20 mesh) was used to granulation using a pellet mill for processing in the fluidized bed (Ohkawara Seisakujo) with 67 g of an aqueous solution of maltose (trade name of carmalt-S, Hayashibara Co., Ltd.) (15% wt./about.) as the binder. Then 0.5% magnesium stearate was mixed with the product of the granulation and tablets ((φ 8.5 mm, 10,2 R), weighing 200 mg 1 tablet strength tablets of 0.8 kPa (n=5)received under a tabletting pressure of approximately 0.1 t/stamp using a rotary tablet press machine. Then the tablets were heated for 10 minutes at 140°s using the oven with software control (model MOV-112P, Sanyo), and then left for 30 minutes at room temperature to obtain a tablet of the present invention. The resulting tablets showed the strength of 3.9 kPa (n=5), the disintegration time in the buccal pocket - 20 seconds (n=1) and the porosity of 29.3%.

Example 8

After sifting 450 g mannitol (Towa kasei Co., Ltd.) through a sieve (20 mesh) was used to granulation using a pellet mill for processing in the fluidized bed (Ohkawara Seisakujo) with 333 g aq is the solution of Eretria (Hayashibara Co., Ltd.) and maldita (Hayashibara Co., Ltd.) (7,5% wt./about. each, 15% wt./about. in General) as binders. Then 0.5% magnesium stearate was mixed with the product of the granulation and tablets ((φ 8.5 mm, 10,2 R), weighing 200 mg 1 tablet strength tablets of 0.9 kPa (n=5)received under the pressure of tabletirovanija roughly 0.04 t/stamp using a rotary tablet press machine. Then the tablets were heated for 10 minutes at 120°s using the oven with software control (model MOV-112P, Sanyo), and then left for 30 minutes at room temperature to obtain a tablet of the present invention. The resulting tablets showed the strength of 4.8 kPa (n=5), the fragility of 0.3% or less (100 cycles), the disintegration time in the buccal pocket - 20 seconds (n=1) and the porosity is 32.2%.

Example 9

After sifting 450 g of lactose (Freund Industry Co., Ltd.) through a sieve (20 mesh) was used to granulation using granular for treatment in the fluidized bed (Ohkawara Seisakujo) with 250 g of an aqueous solution of maldita (Hayashibara Co., Ltd.) (20% wt./about.) as the binder. Then 0.5% magnesium stearate was mixed with the product of the granulation and tablets ((φ 8.5 mm, 10,2 R), weighing 200 mg 1 tablet strength tablets of 0.9 kPa (n=5), were under pressure tableting about 0.03 t/stamp using a rotary tablet press machine. Then the tablets were heated for 2.5 mi the ut at 160° With using the oven with software control (model MOV-112P, Sanyo), and then left for 30 minutes at room temperature to obtain a tablet of the present invention. The resulting tablets showed the strength of 5.6 kPa (n=5), the fragility of 0.3% or less (100 cycles), the disintegration time in the buccal pocket 27 seconds (n=1) and the porosity was 42.1%.

Example 10

After sifting 900 g mannitol (Towa kasei Co., Ltd.) through a sieve (20 mesh) was used to granulation using a pellet mill for processing in the fluidized bed (Ohkawara Seisakujo) with 400 g of an aqueous solution of Eretria (Hayashibara Co., Ltd.) (20% wt./about.) and 133,3 g of an aqueous solution of maldita (Hayashibara Co., Ltd.) (15% wt./about.) as binders. Then 1% of ester

sucrose fatty acid (Mitsubishi-Called Foods) was mixed with the product of the granulation and tablets ((φ 8.5 mm, 9,0 R), weighing 200 mg 1 tablet strength tablets of 0.4 kPa (n=5)) was done using a rotary tablet press machine. Then the tablets were heated under the conditions shown in table 4, using the oven with software control (model MOV-112P, Sanyo), and then left for 30 minutes at room temperature, to obtain tablets of the present invention (porosity 34,1%). Values of porosity obtained tablets are also presented in Table 4.

Table 4
Conditions of heat treatment and properties of the tablets of example 10
The Processing Temperature./ Time 5 min10 min20 min30 min60 min
120°CStrength (kPa)3,35,65,65,05,5
 Friability (%)0,310,170,120,080,15
 The disintegration time in the buccal pocket (s)1217161716
130°Strength (kPa)4,66,26,4  
 Friability (%)0,390,240,23  
 Time

Disintegration in the buccal pocket (s)
131620  
140°Strength (kPa)6,37,6   
 Friability (%)0,150,10    
 The disintegration time in the buccal pocket (s)1329   

Example 11

After sifting 250 grams of acetaminophen (Yoshitomi Fine Chemicals) and 200 g mannitol (Towa kasei Co., Ltd.) through a sieve of 24 mesh) was used to granulation using a pellet mill for processing in the fluidized bed (Ohkawara Seisakujo), by spraying 200 g of an aqueous solution of Eretria (Hayashibara Co., Ltd.) (20% wt./about.) and 66.7 g of an aqueous solution of maldita (Hayashibara Co., Ltd.) (15% wt./about.) as binders. Then 1% of an ester of sucrose fatty acid (Mitsubishi-Called Foods) was mixed with the product of the granulation and did pills ((φ 8.5 mm, 9 R), weighing 200 mg 1 tablet strength tablets of 0.4 kPa (n=5)using a rotary tablet press machine. Then the tablets were heated for 10 minutes at 120°s using the oven with software control (model MOV-112P, Sanyo), and then left for 30 minutes at room temperature to get 1 tablet of the present invention. The resulting tablets showed the strength of 6.9 kPa (n=5), fragility - 0,23% or less (100 cycles), the disintegration time in the buccal pocket 26 seconds (n=1) and the porosity of 29.6%.

Example 12

After sifting 250 g of calcium carbonate (Nitto Funka Kogyo) and 200 g of mannitol (Toma kasei Co., Ltd.) che is ez sieve (24 mesh) the product was made in a mixer with a vertical rotor and added 40 g of water and mixed. After sieving the mixture through a sieve of 16 mesh) was used to granulation using a pellet mill for processing in the fluidized bed (Ohkawara Seisakujo), by spraying 200 g of an aqueous solution of Eretria (Hayashibara Co., Ltd.) (20% wt./about.) and 66.7 g of an aqueous solution of maldita (Hayashibara Co., Ltd.) (15% wt./about.) as binders. Then 1% of an ester of sucrose fatty acid (Mitsubishi-Called Foods) was mixed with the obtained granulation product and received tablets ((φ 9.5 mm, 11,4 R), weighing 400 mg 1 tablet strength tablets of 0.4 kPa (n=5)using a rotary tablet press machine. Then the tablets were heated for 10 minutes at 130°s using the oven with software control (model MOV-112P, Sanyo), and then left for 30 minutes at room temperature, to obtain tablets of the present invention. The resulting tablets showed the strength of 4.6 kPa (n=5), the fragility - of 0.48% (100 cycles), the disintegration time in the buccal pocket 25 seconds (n=1) and the porosity of 44.9%.

Example 13

After sifting 450 g mannitol (Towa kasei Co., Ltd.) and 40 g of Eretria (Hayashibara Co., Ltd.) through a sieve (20 mesh) was carried out by granulation using a pellet mill for processing in the fluidized bed (Ohkawara Seisakujo), with 200 g of an aqueous solution copolyvidone (Kollidon VA64, BASF) (5% wt./about.) as the binder. Then 0.5% magnesium stearate was mixed with the granulation product and received tablets is ((⊘ 8.5 mm, 10,2 R), weighing 200 mg 1 tablet strength tablets of 0.6 kPa (n=5)using a rotary tablet press machine. Then the tablets were heated for 10 minutes at 120°s using the oven with software control (model MOV-112P, Sanyo), and then left for 30 minutes at room temperature to obtain a tablet of the present invention. The resulting tablets showed the strength of 7.3 kPa (n=5), the fragility of 0.20% (100 cycles), the disintegration time in the buccal pocket - 18 seconds (n=1) and the porosity ratio of 36.9%.

Example 14

After sifting 475 g mannitol (Towa kasei Co., Ltd.) and 15 g of Eretria (Hayashibara Co., Ltd.) through a sieve (20 mesh) was carried out by granulation using a pellet mill for processing in the fluidized bed (Ohkawara Seisakujo), with 200 g of an aqueous solution of copolyvidone (Kollidon VA64, BASF) (5% wt./about.) as the binder. Then 0.5% magnesium stearate was mixed with the product of the granulation and did pills ((φ 8.5 mm, 10,2 R), weighing 200 mg 1 tablet strength tablets 0,7 kPa (n=5)using a rotary tablet press machine. Then the tablets were heated for 10 minutes at 120°s using the oven with software control (model MOV-112P, Sanyo), and then left for 30 minutes at room temperature to obtain a tablet of the present invention. The resulting tablets showed the strength of 6.2 kPa (n=5), fragility is 0.37% (100 cycles), the time design the integration in the buccal pocket 15 seconds (n=1) and the porosity of 36.7%.

Example 15

After sifting 350 grams of acetaminophen (Yoshitomi Fine Chemicals), 100 g mannitol (Towa kasei Co., Ltd.) and 40 g of Eretria (Hayashibara Co., Ltd.) through a sieve (20 mesh) was carried out by granulation using a pellet mill for processing in the fluidized bed (Ohkawara Seisakujo), with 200 g of an aqueous solution of copolyvidone (Kollidon VA64, BASF) (5% wt./about.) as the binder. Then 0.5% magnesium stearate was mixed with the obtained granulation product and received tablets ((φ 8.5 mm, 10,2 R), weighing 200 mg 1 tablet strength tablets of 0.8 kPa (n=5)using a rotary tablet press machine. Then the tablets were heated for 10 minutes at 120°s using the oven with software control (model MOV-112P, Sanyo), and then left for 30 minutes at room temperature, to obtain tablets of the present invention. The resulting tablets showed the strength of 8.3 kPa (n=5), fragility - 0,36% (100 cycles), the disintegration time in the buccal pocket - 31 seconds (n=1) and the porosity was 31.0%.

Comparative example 4

After sifting 360 g mannitol (Towa kasei Co., Ltd.) through a sieve (20 mesh) was carried out by granulation using a pellet mill for processing in the fluidized bed (Ohkawara Seisakujo), with 200 g of an aqueous solution of maldita (Hayashibara Co., Ltd.) (20% wt./about.) as the binder. Then 0.5% magnesium stearate was mixed with the obtained granulation product and received the tablet and ((⊘ 8.5 mm, 10,2 R), weighing 200 mg 1 tablet strength tablets to 4.6 kPa (n=5) under a tabletting pressure of approximately 0.1 t/stamp using a rotary tablet press machine. Then the tablets were heated for 2 minutes at 140°s using the oven with software control (model MOV-112P, Sanyo), and then left to cool for 30 minutes at room temperature.

The resulting tablets showed the strength of 4.0 kPa (n=5) and the porosity of 22.8%. Did not observe any increase strength by heat treatment at the temperature of melting maldita (150°C) or below.

Comparative example 5

Granulation in a vertical granulator was carried out using 50 g water 800 g of mannitol. After drying the product of granulation 15 g of PEG6000 and 0.3 g of magnesium stearate was added to 284,7 g of the product of the granulation and received tablets ((φ 8.5 mm, 10,2 R), weighing 200 mg 1 tablet strength tablets of 0.4 kPa (n=5) under a tabletting pressure of approximately 0.1 t/stamp using a rotary tablet press machine. Then the tablets were heated for 1 hour at 70°s using the oven with software control (model MOV-112P, Sanyo), and then left for 30 minutes at room temperature. The resulting tablets showed the strength of 5.1 kPa (n=5), fragility is 0.37% (100 cycles), the disintegration time of the tablets in the buccal pocket - 60 seconds or more is (n=1) and the porosity of 22.8%. On the basis of the obtained results revealed that although the tablets that were obtained by melting PEG6000, which is used as a binder, had the same strength as the product of the present invention, the disintegration time in the buccal pocket was much more and they are not possessed properties quickly dezintegriruetsja tablets.

Comparative example 6

After sifting 490 g mannitol (Towa kasei Co., Ltd.) through a sieve (20 mesh) was carried out by granulation using a pellet mill for processing in the fluidized bed (Ohkawara Seisakujo), with 200 g of an aqueous solution of copolyvidone (Kollidon VA64, BASF) (5% wt./about.) as the binder. Then 0.5% magnesium stearate was mixed with the obtained granulation product and produced tablets ((φ 8.5 mm, 10,2 R), weighing 200 mg 1 tablet strength tablets of 0.8 kPa (n=5)using a rotary tablet press machine. Then the tablets were heated for 10 minutes at 120°s using the oven with software control (model MOV-112P, Sanyo), and then left to cool for 30 minutes at room temperature. The resulting tablets showed the strength of 1.1 kPa (n=5) and the porosity of 36.5%. Did not observe any increase strength by heat treatment in the case of tablets, which did not contain eritra.

The tablet of the present invention, quickly dezintegriruetsja in the buccal pocket, Hara is marked almost the same properties, as usual oral pharmaceutical tablet having a higher pellet durability, in particular keeping a low fragility, without prolonging the time of disintegration in the buccal pocket in comparison with conventional tablets fast dezintegriruetsja in the buccal pocket. So the tablet can be used with automatic machines for dosage forms. Pill fast desintegrators in the buccal pocket, can also be used with drugs that are administered in large doses. In addition, as in the case of normal oral pharmaceutical tablets, the tablet of the present invention, quickly desintegrators in the buccal pocket, you can take without dissolution in the buccal pocket or it can be taken along with water. In addition, the tablet of the present invention can be used after dissolving in water and the like in a Cup and so on.

The tablet of the present invention, quickly dezintegriruetsja in the buccal pocket, which is produced using a conventional tablet press machines, and how you can get it you can apply for a wide range of drugs and therefore are very popular in the pharmaceutical industry.

1. Tablet fast dezintegriruetsja in the buccal pocket comprising a drug, a diluent and a saccharide with a relatively lower point of the melt is to be placed, than the drug and diluent, which is obtained by evenly mixing the saccharide with a low melting point with a tablet weight and in which is formed bridges between the particles of the medicinal product and/or diluent through the product of melting and then solidification of the saccharide with a low melting point.

2. Tablet fast dezintegriruetsja in the buccal pocket according to claim 1, in which the saccharide with a low melting point is a saccharide, a melting point which is at least 10°C lower than the melting point of drug and diluent.

3. Tablet fast dezintegriruetsja in the buccal pocket according to claim 1 or 2, in which the saccharide with a low melting point represents one, or two, or more saccharides selected from the group consisting of xylitol, trehalose, maltose, sorbitol, erotica, glucose, maldita, mannitol, sucrose, and their hydrates.

4. Tablet fast dezintegriruetsja in the buccal pocket according to claim 1, in which the number of saccharide with a low melting point is 0.5 - 25% wt./wt. in relation to the number of the medicinal product and/or diluent.

5. Tablet fast dezintegriruetsja in the buccal pocket according to claim 1, in which, in addition, the added binder.

6. Tablet fast dezintegriruetsja in the buccal pocket according to claim 1 in which the diluent is the Wallpaper saccharide with a relatively higher melting point, than the saccharide with a low melting point according to claim 1.

7. Tablet fast dezintegriruetsja in the buccal pocket, according to claim 6, in which the saccharide with a high melting point represents one, or two, or more saccharides selected from the group consisting of xylitol, trehalose, maltose, sorbitol, eritria, glucose, maldita, mannitol, sucrose, lactose, and their hydrates.

8. Tablet fast dezintegriruetsja in the buccal pocket, according to claim 7, in which the saccharide with a high melting point represents one, or two, or more saccharides selected from the group consisting of mannitol, sucrose, lactose, and their hydrates.

9. Tablet fast dezintegriruetsja in the buccal pocket, according to claim 6, in which the saccharide with a low melting point is a trehalose and/or aritra, and a saccharide with a high melting point is a mannitol and/or lactose.

10. Tablet fast dezintegriruetsja in the buccal pocket, according to claim 9, in which the saccharide with a low melting point is aritra, and a saccharide with a high melting point is a mannitol.

11. Tablet fast dezintegriruetsja in the buccal pocket, according to claim 5, in which the saccharide with high plasticity and/or water-soluble polymer is a part of the binder.

12. Tablet fast dezintegriruetsja in the buccal pocket, according to claim 11, in which the binder is from the Oh ▫ maltitol and/or copolyvidone.

13. Tablet fast dezintegriruetsja in the buccal pocket according to claim 1, in which the porosity is 10 to 80%.

14. Tablet fast dezintegriruetsja in the buccal pocket, item 13, in which the porosity is 20 to 50%.

15. Tablet fast dezintegriruetsja in the buccal pocket according to claim 1, in which the hardness of the tablets is 3 kPa or higher and the fragility is 1% or less.

16. Tablet fast dezintegriruetsja in the buccal pocket, § 15, in which the hardness of the tablets is 4 kPa or higher and the fragility of 0.8% or less.

17. Tablet fast dezintegriruetsja in the buccal pocket, in P16, in which fragility is 0.5% or less.

18. Tablet fast dezintegriruetsja in the buccal pocket according to claim 1, in which the amount of added drug is at least an effective amount, from the point of view of treatment and is not more than 80% wt./wt. weight of the tablet.

19. Tablet fast dezintegriruetsja in the buccal pocket comprising a drug, a diluent and a saccharide with a relatively lower melting point than the drug and diluent, and a binder, in which the saccharide with a low melting point and binder are uniformly mixed together in the tablet, the formation of bridges between particles of the medicinal product and/or diluent through the product PLA is ing and hardening of the saccharide with a low melting point.

20. Tablet fast dezintegriruetsja in the buccal pocket according to claim 19, in which the saccharide with a low melting point is a saccharide, a melting point which is at least 10°C lower than the melting point of drug and diluent.

21. Tablet fast dezintegriruetsja in the buccal pocket according to claim 19 or 20, in which the saccharide with a low melting point represents one, or two, or more saccharides selected from the group consisting of xylitol, trehalose, maltose, sorbitol, erotica, glucose, maldita, mannitol, sucrose, and their hydrates.

22. Tablet fast dezintegriruetsja in the buccal pocket according to claim 19, in which the number of saccharide with a low melting point is 0.5 - 25% wt./wt. in relation to the number of the medicinal product and/or diluent.

23. Tablet fast dezintegriruetsja in the buccal pocket according to claim 19, in which the binder is a saccharide and/or a water-soluble polymer with high plasticity, demonstrating the hardness of 2 kPa or more when 150 mg of saccharide tabletirujut under a tabletting pressure of 10 to 50 kg/cm, using a die with a diameter of 8 mm

24. Tablet fast dezintegriruetsja in the buccal pocket according to claim 19, in which the diluent is a saccharide with a relatively higher melting point than that of the saccharide with a low point PL is the effect on p.19.

25. Tablet fast dezintegriruetsja in the buccal pocket, paragraph 24, in which the saccharide with a high melting point represents one, or two, or more saccharides selected from the group consisting of xylitol, trehalose, maltose, sorbitol, eritria, glucose, maldita, mannitol, sucrose, lactose, and their hydrates.

26. Tablet fast dezintegriruetsja in the buccal pocket, A.25, in which the saccharide with a high melting point represents one, or two, or more saccharides selected from the group consisting of mannitol, sucrose, lactose, and their hydrates.

27. Tablet fast dezintegriruetsja in the buccal pocket according to claim 19, in which the saccharide with a low melting point is a trehalose and/or aritra, and a saccharide with a high melting point is a mannitol and/or lactose.

28. Tablet fast dezintegriruetsja in the buccal pocket, item 27, in which the saccharide with a low melting point is aritra, and a saccharide with a high melting point is a mannitol.

29. Tablet fast dezintegriruetsja in the buccal pocket according to claim 19 or 23, in which the saccharide and/or a water-soluble polymer with high plasticity represents maltose, ▫ maltitol, sorbitol, hydroxypropylcellulose, hypromellose, polyvinylpyrrolidone, copolyvidone or polyvinyl alcohol.

30. Tablet is a, quickly dezintegriruetsja in the buccal pocket, in clause 29, in which the saccharide and/or a water-soluble polymer with high plasticity represents ▫ maltitol and/or copolyvidone.

31. Tablet fast dezintegriruetsja in the buccal pocket according to claim 19, in which the saccharide with a low melting point is aritra, saccharide with a high melting point is a lactose and/or mannitol and saccharide with high plasticity represents ▫ maltitol, or a saccharide with a low melting point is aritra, saccharide with a high melting point is a lactose and/or mannitol and water-soluble polymer with high ductility is copolyvidone.

32. Tablet fast dezintegriruetsja in the buccal pocket according to claim 19, in which the porosity is 10 to 80%.

33. Tablet fast dezintegriruetsja in the buccal pocket, p, in which a porosity is 20 to 50%.

34. Tablet fast dezintegriruetsja in the buccal pocket according to claim 19, in which the hardness of the tablets is 3 kPa or higher and the fragility is 1% or less.

35. Tablet fast dezintegriruetsja in the buccal pocket, § 34, in which the hardness of the tablets is 4 kPa or higher and the fragility of 0.8% or less.

36. Tablet fast dezintegriruetsja in the buccal pocket, p in which the fragility of 0.5% who do less.

37. Tablet fast dezintegriruetsja in the buccal pocket according to claim 19, in which the amount of added drug is at least an effective amount, from the point of view of treatment and is not more than 80% wt./wt. weight of the tablet.

38. Tablet fast dezintegriruetsja in the buccal pocket according to claim 19, in which the saccharide with a low melting point is a saccharide, which becomes amorphous when heated and then humidified and dried.

39. Tablet fast dezintegriruetsja in the buccal pocket, § 38, in which the saccharide with a low melting point, which becomes amorphous when heated, is glucose, sorbitol, maltose or trehalose.

40. Tablet fast dezintegriruetsja in the buccal pocket containing (1) a drug, (2) lactose and/or mannitol, (3) aritra and (4) ▫ maltitol, in which the hardness of the tablets is 3 kPa or higher friability is 1% or less and the porosity is about 30 - 50%, or containing the drug, (2) lactose and/or mannitol, (3) aritra and (4) copolyvidone, in which the hardness of the tablets is 3 kPa or higher friability is 1% or less and porosity is about 30 - 50%.

41. Method for the production of tablets fast dezintegriruetsja in the buccal pocket containing a drug, a diluent and a saccharide with otnositel the lower melting point, than the drug and diluent, which includes: (a) stage, in accordance with which the original tablet materials, including a drug, a diluent and a saccharide with a relatively lower melting point than the drug and diluent, is pressed under low pressure required to maintain the form of tablets, (b) stage, in which the extruded product obtained in stage (a), is heated at least to a temperature at which the saccharide with a low melting point will melt, and (C) stage in accordance with which the extruded product obtained by the method (b)is cooled at least to a temperature at which the molten saccharide with a low melting point solidifies.

42. Method for the production of tablets fast dezintegriruetsja in the buccal pocket, paragraph 41, in which during stage (a) drug, a diluent and a saccharide with a relatively lower melting point than that of medicines called and called diluent, physically mixing, to obtain a pellet raw materials.

43. Method for the production of tablets fast dezintegriruetsja in the buccal pocket, paragraph 41, in which during stage (a) the saccharide with a low melting point are dissolved and/or suspended in a pharmaceutically acceptable process is the and sprayed as a binder for coating and/or granulation, to obtain a pellet feedstock.

44. Method for the production of tablets fast dezintegriruetsja in the buccal pocket, paragraph 41, in which during stage (a) the saccharide with a low melting point is mixed with the medication and the diluent in the form of particles and/or powder and carry out granulation, using a solution of a binder, to obtain a pellet raw materials.

45. Method for the production of tablets fast dezintegriruetsja in the buccal pocket, paragraph 41, in which during stage (a) tablet source material is pressed under pressure tableting 25 - 800 kg/stamp.

46. Method for the production of tablets fast dezintegriruetsja in the buccal pocket, paragraph 41, in which during stage (b) the heating is carried out at a temperature between the melting point of the saccharide with a low melting point and melting point drug and diluent.

47. Method for the production of tablets fast dezintegriruetsja in the buccal pocket, paragraph 41, which, in addition, includes means (d)for which the extruded product is humidified and dried.

48. Method for the production of tablets fast dezintegriruetsja in the buccal pocket, p, in which stage (d) is applied between the stage (a) and stage (b) or after stage (C).

49. Method for the production of tablets fast dezintegriruetsja in the buccal pocket containing drug among the STV, the diluent and a saccharide with a relatively lower melting point than the drug and diluent, which comprises (a) stage, in accordance with which the original tablet materials, including a drug, a diluent, a saccharide with a relatively lower melting point than the drug and diluent, and a binder is pressed under low pressure required to maintain the form of tablets, (b) stage, in which the extruded product obtained in stage (a), is heated at least to a temperature at which the saccharide with a low melting point will melt, and (C) stage, in which the extruded product obtained in stage (b)is cooled at least to a temperature at which the molten saccharide with a low melting point solidifies.

50. Method for the production of tablets fast dezintegriruetsja in the buccal pocket, § 49, in which during stage (a) drug, a diluent and a saccharide with a relatively lower melting point than the drug and diluent, and a binder physically mixed to obtain a pellet raw materials.

51. Method for the production of tablets fast dezintegriruetsja in the buccal pocket, § 49, in which during stage (a) the saccharide with a low point is Lavinia and the binder is dissolved and/or suspended in a pharmaceutically acceptable solvent and sprayed as a binder for coating and/or granulation, to obtain a pellet feedstock.

52. Method of manufacturing tablets fast dezintegriruetsja in the buccal pocket, § 49, in which during stage (a) § 49 saccharide with a low melting point is mixed with the medication and the diluent in the form of particles and/or powder and carry out granulation using a mortar binder containing saccharide with high plasticity and/or water-soluble polymer, to obtain a pellet raw materials.

53. Method for the production of tablets fast dezintegriruetsja in the buccal pocket, § 49, in which during stage (a) tablet source material is pressed under pressure tableting 25 - 800 kg/stamp.

54. Method for the production of tablets fast dezintegriruetsja in the buccal pocket, § 49, in which during stage (b) the heating is carried out at a temperature between the melting point of the saccharide with a low melting point and melting point drug and diluent.

55. Method for the production of tablets fast dezintegriruetsja in the buccal pocket on any of PP-54, where the saccharide with a low melting point represents one, or two, or more saccharides selected from the group consisting of xylitol, trehalose, maltose, sorbitol, eritria, glucose, maldita, mannitol, sucrose, and their hydrates.

56. Method for the production of tablets, quickly de is integrated into the buccal pocket on any of PP-54, where the saccharide with a high melting point represents one, or two, or more saccharides selected from the group consisting of xylitol, trehalose, maltose, sorbitol, eritria, glucose, maldita, mannitol, sucrose, lactose, and their hydrates.

57. Method for the production of tablets fast dezintegriruetsja in the buccal pocket on any of PP-54, where the binder is a saccharide and/or a water-soluble polymer with high plasticity, demonstrating the hardness of 2 kPa or more when 150 mg of saccharide tabletirujut under a tabletting pressure of 10 to 50 kg/cm, using a die with a diameter of 8 mm

58. Method for the production of tablets fast dezintegriruetsja in the buccal pocket on any of PP-54, where the saccharide and/or a water-soluble polymer with high elasticity are maltose, ▫ maltitol, sorbitol, hydroxypropylcellulose, hypromellose, polyvinylpyrrolidone, copolyvidone or polyvinyl alcohol.

59. Method for the production of tablets fast dezintegriruetsja in the buccal pocket in § 58, where the saccharide, and a water-soluble polymer with high plasticity represent ▫ maltitol and/or copolyvidone.

60. Method for the production of tablets fast dezintegriruetsja in the buccal pocket, § 49, where the saccharide with a low melting point is aritra, saccharide with a high melting point, not only is em a lactose and/or lures, and saccharide with high ductility is ▫ maltitol, or a saccharide with a low melting point is aritra, saccharide with a high melting point is a lactose and/or attracts, a water-soluble polymer is copolyvidone.

61. Method for the production of tablets fast dezintegriruetsja in the buccal pocket, § 49, which in the case when the saccharide with a low melting point is a saccharide, which becomes amorphous when heated, additionally includes a step (d), and according to which the extruded product is humidified and dried.

62. Method for the production of tablets fast dezintegriruetsja in the buccal pocket, p, in which the saccharide with a low melting point, which becomes amorphous when heated, is glucose, sorbitol, maltose or trehalose.

63. Method for the production of tablets fast dezintegriruetsja in the buccal pocket, item 62, in which stage (d) is applied between the stage (a) and stage (b) or after stage (C).



 

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