Composition containing fine dispersed long releasing particles for quick-disposable in buccal cavern tablets

FIELD: medicine, in particular composition for quick-disposable in buccal cavern tablets.

SUBSTANCE: claimed composition contains granulated product of fine dispersed long releasing particles, comprising drug and fillers selected from group including sugars and sugar alcohols together with binder, wherein content of non-granulated fine dispersed long releasing particles is 0-15 %. Method for production of such tablets is also disclosed.

EFFECT: pharmaceutical composition with accelerated degradation.

24 cl, 9 ex, 3 dwg

 

The scope of the invention

The present invention relates to compositions comprising fine particles with a slow release for bystrorazvivajushchihsja in cheek (buccal) cavity tablets. In more detail, the present invention relates to compositions comprising fine particles with a slow release for bystrorazvivajushchihsja in the buccal cavity of tablets, characterized in that it comprises the product of the granulation of fine particles with a slow release and one or two or more fillers selected from the group consisting of sugars or sugar alcohols, granulated with the binder for bystrorazvivajushchihsja in the buccal cavity of tablets, and the fact that the ratio in the form of fine particles with a slow release throughout the composition is from 0 to 15%.

Background of invention

The term “fine particles with a slow release” of the present invention means fine particles, which contain the drug proposed for different types of treatment with a slow release, and have an average particle diameter of approximately from 0.1 μm to 350 μm. The term “different types of treatment with slow release” means treatment that provides quality “sametingsvalget”, which is well known in the pharmaceutical industry. As examples may be given treatment, giving the gradual release of the drug, treatment, giving the solubility in the intestinal tract, treatment, giving the solubility in the intestinal tract, treatment, giving prolonged release, treatment, giving the release, which is a combination of the above types, etc. in Addition, particles which have a solubility in the intestinal tract, called the “enteric fine particles with a slow release”.

You have developed various types of decaying in the buccal cavity of the tablets, so that they are easy to take, even without water, people with weak swallowing effort, including older people, children, etc. moreover, the demand in recent years the range of drugs has led to the need to ensure the function of slow release for bystrorazvivajushchihsja in the buccal cavity of the tablets.

The first generation bystrorazvivajushchihsja in the buccal cavity of tablets, for example, “TidesTM” (“ZydisTM”delivered on the market R.P.Scherer etc., known as pharmaceutical preparations that are obtained by lyophilization. Such bystrorazvivajushchiesja in the buccal cavity of the tablet first generation mainly produced by lyophilization or special is a pressing drying with the use of a solution or suspension of the drug. Thus, it needed a way of getting in the liquid state, and was not discussed providing functions slow release.

There are various bystrorazvivajushchiesja in the buccal cavity of tablets of the second generation, including those that use action dezintegriruetsja agents (patent laying Japan Kokai No.Hei 10-182436, international publication WO 98/02185 etc), which are characterized in that the saccharide of high moldability is applied by spraying in the form of a coating and/or granularit as binders for saccharide of low moldability and which can be wetted and dried, when necessary strength tablets (international publication WO 95/20380, corresponding to U.S. patent 5576014 and the Japan patent 312141), etc. and get them to pelletizing. To resolve the apparent contradictory problems of maintenance functions slow release data for bystrorazvivajushchihsja in the buccal cavity of the second generation tablets, you must ensure that bystrorazvivajushchiesja in the buccal cavity of tablets containing fine particles were processed to give slow release, for example, coated with polymer. However, although attempts were made just to mix fine particles that have been processed for slow released the I, with filler for bystrorazvivajushchihsja in the buccal cavity of tablets and tablet to the mix, during the tabletting process was segregation due to the difference in the apparent specific gravity and the difference in yield strength between the filler and fine particles with a slow release. The term “segregation”used in this description, is a state where fine particles with a slow release is not evenly distributed in the filler, and segregation occurs when they are distributed unevenly. Segregation can be confirmed by determination of content uniformity drug, which include tablets, after receiving them. For example, you can say that if the coefficient of variation (CV%) number of drugs, which are presented next, is from 0 to 3.5%, that segregation does not occur, and if the coefficient of variation exceeds 3.5%, the segregation occurs. The reason for this segregation are various problems. For example, there are problems: (1) tabletroute pressure propagating directly on the fine particles with a slow release due to contact between the outer surface of the punch and fine particles with a slow release during tabletting Il is direct contact between the fine particles with a slow release, leads to the destruction of the fine particles with a slow release and promotion of dissolution after both of them were obtained tablets, (2) the degree of destruction of the fine particles with a slow release varies with the degree of segregation and, therefore, controlled dissolution, which is the planned purpose of the preparation of the fine particles with a slow release, is not realized with good reproducibility after there were obtained tablets, (3) there are fluctuations in the number of fine particles with a slow release contained in one tablet, and it is impossible to guarantee the uniformity of content medicines, etc.

In international publication WO 00/24379 described an invention relating to a method for producing spherical fine particles, which can be used to obtain pharmaceutical controlled release, which can be easily taken using a special method of drum granulation. This publication provides a method of obtaining, including special drum granulation data spherical fine particles, and it is shown that the dissolution is controlled by covering the shell of the spherical fine particles, and that such spherical tanked spermie particles can be used in bystrorazvivajushchihsja in the buccal cavity tablets. However, studies have confirmed that various of the above problems continue to exist, and the goal is not achieved when bystrorazvivajushchiesja in the buccal cavity of the tablet simply contain spherical fine particles that have not been processed to achieve a slow release. Moreover, in the aforementioned publication does not describe or specify a specific means for solving these problems.

Thus, at the moment this tool is unknown and there is a need to bystrorazvivajushchihsja in the buccal cavity tablets, including fine particles with a slow release, in which after receiving tablets inhibited promotion dissolution of the medicinal product resulting from the destruction of the fine particles with a slow release under the action of tabletiruemogo pressure when getting a tablet, and even after obtaining tablets with good reproducibility is implemented controlled dissolution, which is the planned purpose of the preparation of the fine particles with a slow release, and which is guaranteed homogeneous content medicines.

Description of the invention

Under these circumstances, attention has been focused on bystrorazvivajushchihsja the buccal cavity tablets, including fine particles with a slow release were investigated methods that prevent segregation of the fine particles with a slow release and filler used in bystrorazvivajushchihsja in the buccal cavity tablets, which is a source of various problems. As a result of repeated sets of experiments were completed successfully the present invention, it was found that the segregation of the fine particles with a slow release and filler can be prevented by obtaining the product of the granulation comprising fine particles with a slow release, some of which are aggregated together during this method of granulation, using the method of granulation, where the entire surface or part of the surface of the individual fine particles with a slow release coated filler. The term “granulation” here relates to the production of particles or powder, the size and shape of which are visually homogeneous. In the subsequent detailed studies it was found that the segregation of the fine particles with a slow release and filler is prevented, when the ratio in the form of fine particles with a slow release throughout on ucaeoy ultimately the composition is from 0 to 15%. Assume that usually the easy segregation occurs as a result of increasing the difference in the apparent specific gravity between fine particles and filler and deterioration of the fluidity of the fine particles, etc. when so aggregated multiple particles. However, it was completely unexpected that it is possible not only to guarantee the uniformity of content upon receipt of the tablets, but also to neutralize the pressure during tableting by eliminating direct contact between the outer surface of the punch and fine particles with a slow release or between fine particles with a slow release, and to achieve good reproducibility of the controlled dissolution, which is the goal.

Thus, the present invention relates to:

1. compositions comprising fine particles with a slow release for bystrorazvivajushchihsja in the buccal cavity of tablets, characterized in that it comprises the product of the granulation of fine particles with a slow release containing the drug, and one or two or more fillers selected from the group consisting of sugars and sugar alcohols, together with the binder for bystrorazvivajushchihsja in the buccal cavity of tablets, and t is m the ratio in the form of fine particles with a slow release throughout the composition is from 0 to 15%,

2. compositions comprising fine particles with a slow release for bystrorazvivajushchihsja in the buccal cavity of the tablets of the above paragraph 1, where the binder for bystrorazvivajushchihsja in the buccal cavity of tablets is one or two or more substances selected from the group consisting of saccharides with high plasticity, water-soluble polymeric compounds and saccharides with a low melting point,

3. compositions comprising fine particles with a slow release for bystrorazvivajushchihsja in the buccal cavity of tablets on the above paragraph 2, where the sugar or sugar alcohol is one or two or more selected from the group consisting of saccharides with low plasticity, saccharides with a high melting point and saccharides with a low melting point,

4. compositions comprising fine particles with a slow release for bystrorazvivajushchihsja in the buccal cavity of tablets on the above item 3, where the ratio of the fine particles with a slow release, filler and binders for bystrorazvivajushchihsja in the buccal cavity of the tablets ranges from 1 to 50%, from 20 to 98% and from 1 to 30%, respectively,

5. compositions comprising fine particles with a slow, visualaid the tion for bystrorazvivajushchihsja in the buccal cavity of tablets on the above item 4, where the average particle diameter bystrorazvivajushchihsja fine particles is from about 0.1 μm to about 350 μm,

6. compositions comprising fine particles with a slow release for bystrorazvivajushchihsja in the buccal cavity of tablets on the above paragraph 5, where fine particles with a slow release consist of at least particles of crystalline cellulose, drugs and polymeric substances,

7. compositions comprising fine particles with a slow release for bystrorazvivajushchihsja in the buccal cavity of tablets on the above item 6, where the drug is tamsulosin hydrochloride,

8. compositions comprising fine particles with a slow release for bystrorazvivajushchihsja in the buccal cavity of tablets on the above item 7, where fine particles with a slow release are soluble in the intestine fine particles with a slow release,

9. compositions comprising fine particles with a slow release for bystrorazvivajushchihsja in the buccal cavity of tablets on the above item 8, wherein the polymeric substance is a hypromellose, ethylcellulose, Eudragit L30D55 and Eudragit NE30D,

10. com is osili, including fine particles with a slow release for bystrorazvivajushchihsja in the buccal cavity of tablets on the above item 9, where the binder for bystrorazvivajushchihsja in the buccal cavity of tablets is one or two or more selected from the group consisting of maltose, trehalose, sorbitol and maldita,

11. bystrorazvivajushchimsja in the buccal cavity tablets consisting of a composition comprising fine particles with a slow release on the above item 10,

12. bystrorazvivajushchimsja in the buccal cavity tablets, according to the above item 11, wherein the coefficient of variation (CV%) number of drugs, which is a measure of the uniformity of the content is 3.5% or less

13. method for producing a composition comprising fine particles with a slow release for bystrorazvivajushchihsja in the buccal cavity of tablets, characterized in that it comprises the product of the granulation of fine particles with a slow release containing the drug, and one or two or more fillers selected from the group consisting of sugars or sugar alcohols, together with the binder for bystrorazvivajushchihsja in the buccal cavity of tablets, and the fact that the ratio of ungranulated tonkodispersnykh particles with a slow release throughout the composition is from 0 to 15%,

14. method for producing a composition comprising fine particles with a slow release for bystrorazvivajushchihsja in the buccal cavity of tablets on the above item 13, where the binder for bystrorazvivajushchihsja in the buccal cavity of tablets is one or two or more substances selected from the group consisting of saccharides with high plasticity, water-soluble polymeric compounds and saccharides with a low melting point,

15. method for producing a composition comprising fine particles with a slow release for bystrorazvivajushchihsja in the buccal cavity of tablets on the above item 14, where the sugar or sugar alcohol is one or two or more selected from the group consisting of saccharides with low plasticity, saccharides with a high melting point and saccharides with a low melting point,

16. method for producing a composition comprising fine particles with a slow release for bystrorazvivajushchihsja in the buccal cavity of tablets on the above item 15, where the ratio of the fine particles with a slow release, filler and binders for bystrorazvivajushchihsja in the buccal cavity of the tablets ranges from 1 to 50%, from 20 to 98% and from 1 to 30%, respectively,

17. the way to receive the deposits of the composition, including fine particles with a slow release for bystrorazvivajushchihsja in the buccal cavity of tablets on the above item 16, where the average particle diameter bystrorazvivajushchihsja fine particles is from about 0.1 μm to about 350 μm,

18. method for producing a composition comprising fine particles with a slow release for bystrorazvivajushchihsja in the buccal cavity of tablets on the above paragraph 17, where fine particles with a slow release consist of at least particles of crystalline cellulose, drugs and polymeric substances,

19. method for producing a composition comprising fine particles with a slow release for bystrorazvivajushchihsja in the buccal cavity of tablets on the above paragraph 18, where the drug is tamsulosin hydrochloride,

20. method for producing a composition comprising fine particles with a slow release for bystrorazvivajushchihsja in the buccal cavity of tablets on the above paragraph 19, where fine particles with a slow release are soluble in the intestine fine particles with a slow release,

21. method for producing a composition comprising fine particles with Zam is Clennam release for bystrorazvivajushchihsja in the buccal cavity of tablets on the above paragraph 20, where the polymeric substance is a hypromellose, ethylcellulose, Eudragit L30D55 and Eudragit NE30D,

22. method for producing a composition comprising fine particles with a slow release for bystrorazvivajushchihsja in the buccal cavity of tablets on the above, paragraph 21, where the binder for bystrorazvivajushchihsja in the buccal cavity of tablets is one or two or more selected from the group consisting of maltose, trehalose, sorbitol and maldita,

23. the method of obtaining bystrorazvivajushchihsja in the buccal cavity of tablets, consisting of a composition comprising fine particles with a slow release, above, paragraph 22, and

24. the method of obtaining bystrorazvivajushchihsja in the buccal cavity of tablets on the above paragraph 23, wherein the coefficient of variation (CV%) number of drugs, which is a measure of the uniformity of the content is 3.5% or less.

“Binder for rapidly decaying in the buccal cavity” tablets of the present invention means commonly used binder, with the binder, which is especially useful for obtaining bystrorazvivajushchihsja in the buccal cavity of tablets, and a variety of chosen in relation to the “filler” this is subramania. The details are described below, including options for implementation.

“The form of fine particles with a slow release” in the present invention means fine particles with a slow release, which does not include granulated product, when fine particles with a slow release granularit with filler using binders for bystrorazvivajushchihsja in the buccal cavity of tablets. In addition, the ratio in the form of fine particles with a slow release” is calculated by the following formulas using values from the definition of the diameter distribution of the particles to fine particles with a slow release and the quantitative ratio of the diameter of the particles of the composition including fine particles with a slow release, using the following methods:

The ratio in the form of fine particles with a slow release (%)=G1+Σ(Gi+1-(Pi-Gi))

In this specification, assessment Σ [get] calculated from i=1 and the definition of values up to the moment when the point before (Gi+1-(Pi-Gi) becomes negative.

P1: the ratio of the fine particles with a slow release on the sieve with a minimum size of about what verste within the diameter distribution of the particles to fine particles with a slow release (except where it is 0%).

P2: the ratio of the fine particles with a slow release on the sieve with the second minimum hole size in the range of the diameter distribution of the particles to fine particles with a slow release (except where it is 0%). The third, fourth and so on refers to P3, R4and so forth, and they, as a whole, presented in the form of Pi.

G1: value quantitative ratio of the diameter distribution of the particles of the composition on the sieve with the same hole size for P1.

G2: value quantitative ratio of the diameter distribution of the particles of the composition on the sieve with the same hole size for P2; the third, fourth and so on belong to the G3, G4and so forth, and they, as a whole, represented in the form Gi.

“The value in the form of particles with a slow release throughout the composition was adjusted to 15% or less in the present invention means in other words that the ratio of fine particles with a slow release is low, i.e. most of the fine particles with a slow release contained in each granulated product. Moreover, this also means that is controlled by the segregation of the fine particles with slow you what order his and filler.

“Product of the granulation” in the present invention means a product granulation consisting of fine particles with a slow release, filler and binders for bystrorazvivajushchihsja in the buccal cavity of tablets, granulation product, which does not include fine particles with a slow release determine, in part, as “product of the granulation, which does not include fine particles with a slow release". That is, in the particular form of the composition according to the present invention is a mixture of the product of the granulation”, “in the form of fine particles with a slow release” and “product of the granulation, which does not contain fine particles with a slow release”.

In addition, the rapidly decaying in the buccal cavity of the tablet in the present invention are tablets, for which time decomposition in the buccal cavity is from 0 to 2 minutes, preferably from 0 to 1 minute, and they may be such as described in international publication WO 98/02185, international publication WO 95/20380, patent laying Japan Kokai No. Hei 10-182436, application for U.S. patent No. 10/142081 (corresponding to international patent application number PCT/JP 02/04481) etc.

In addition, the “promotion dissolution of fine particles with C the slow release ingibirovalo” and “controlled dissolution, which is the purpose [of the fine particles with a slow release] is implemented in the present invention means that there are no differences between the dissolution rate of the fine particles with a slow release and dissolution rate bystrorazvivajushchihsja in the buccal cavity of tablets. Specifically, when carried out tests on the solubility of fine particles with a slow release and bystrorazvivajushchihsja in the buccal cavity of tablets and compare the dissolution of drugs from fine particles with a slow release, the difference between the dissolution rate of the fine particles with a slow release and dissolution rate bystrorazvivajushchihsja in the buccal cavity of the tablets ranges from 0 to 15% for each time of dissolution, when the dissolution of the medicinal product fine particles with a slow release of approximately 30%, approximately 50% and approximately 80%. If fine particles with a slow release are soluble in the intestine fine particles with a slow release, the above estimation can not be performed under conditions of a pH of 1.2, in this case, the difference between the rate of dissolution of the enteric fine particles with a slow released the eat and the rate of dissolution bystrorazvivajushchihsja in the buccal cavity tablets two hours after the start of the dissolution experiment is from 0 to 10%.

In addition, the “reproducibility” means that you are getting the same results, for example, even for bystrorazvivajushchihsja in the buccal cavity of the tablets obtained in different cases, when the difference between the dissolution bystrorazvivajushchihsja in the buccal cavity of the tablet and dissolution of fine particles with a slow release, the components of these pills are compared as described above.

In addition, the coefficient of variation (CV%) number of drugs in the present invention is the uniformity of the content. Conduct the following tests on homogeneity and expect [CV%] according to the following formula:

CV% = (average deviation of each content)/(average content)×100

“CV%average of from 0 to 3.5%, can be viewed as a lack of segregation with minor fluctuations in the content of drug in the resulting tablets, and you can say, “guaranteed the uniformity of content of the medicinal product”. Moreover, the CV%in excess of 3.5%can be seen as segregation with large fluctuations in the content of the medicinal product, and you can say that “uniformity of content is bad”. In this regard, “CV%average of from 0 to 3.5%” is the appropriate range of coefficient of variation on the present and the finding, number, which acts as necessary for quality assurance and indicates that get a song with a constant content of the medicinal product.

Further, the composition including fine particles with a slow release of the present invention, and method of reception according to the present invention will be described in detail.

There are no specific restrictions for medicines used in the present invention, while he is an active component that requires a slow-release, which is effective in the treatment or which is effective in the prevention. Examples of such drugs are hypnotics sedatives, hypnotics agents, anti-anxiety drugs, antiepileptic drugs, antidepressants, drugs against Parkinson's disease, psihonevroticheskih drugs, drugs for the Central nervous system, local anesthetics, muscle relaxants skeletal, drugs for autonomic nervous system, antipyretic analgesic anti-inflammatory agents, antispasmodics, medicines against dizziness, cardiotonic, medicines against arrhythmia, diuretics, antihypertensive drugs is, vasoconstrictors, vasodilators, drugs for the circulatory system, medicines against hyperlipidemia, promoting breathing medicines, remedies against cough expectorants, antitussive expectorants, bronchodilators, anti-diarrhoeal agents, drugs for controlling intestinal function, drugs for peptic ulcer, stomach remedies, antacids, laxatives, bile, gastrointestinal drugs, adrenal cortical hormones, hormones, urogenital drugs, vitamins, hemostatic, medicines for liver diseases, medicines used for gout, medicines used in diabetes, antihistamines, antibiotics, antimicrobial agents, drugs used in malignant tumors, chemotherapy drugs, multisymptom cough and cold remedies, food & health tools, medicines for osteoporosis, etc. are Examples of such medicines are anti-inflammatory, antipyretic antispasmodics or analgesics, such as indomethacin, diclofenac, diclofenac sodium, codeine, ibuprofen, phenylbutazone, oxyphenbutazone, MEP is rizal, aspirin, hidename, acetaminophen, aminopyrine, phenacetin, butylscopolamine bromide, morphine, atomically, pentazocine, fenoprofen calcium, naproxen, celecoxib, valdecoxib, tramadol etc., Antirheumatic drugs, such as etodolac etc., TB drugs such as isoniazid, ethambutol chloride etc., drugs for the circulatory system, such as isosorbide nitrate, nitroglycerine, nifedipine, barnidipine hydrochloride, nicardipine hydrochloride, dipyridamole, amrinone, indenolol hydrochloride, hydralazine hydrochloride, hydrochlorothiazide methyldopa, furosemide, spironolactone, guanethidine nitrate, resperin, amosulalol hydrochloride, lisinopril, metoprolol, pilocarpin, tasosartan etc., psihonevroticheskih drugs, such as chlorpromazine hydrochloride, amitriptyline hydrochloride, nemonapride, haloperidol, operon hydrochloride, perphenazine, diazepam, lorazepam, chlordiazepoxide, adinazolam, alprazolam, methylphenidate, milnacipran, paroxetine, risperidone, sodium valproate, etc., an antiemetic such as metoclopramide, ramosetron hydrochloride, granisetron hydrochloride, ondansetron hydrochloride, azasetron hydrochloride etc., antihistamines such as chlorpheniramine maleate, diphenhydramine hydrochloride, etc., vitamins, such as thiamine nitrate, tocopherol hydrochlo the ID, SikhoteAlin, pyridoxal phosphate, kobamamid, ascorbic acid, nicotinamide, etc., medication against gout, such as allopurinol, colchicine, probename etc., drugs against Parkinson's disease such as levodopa, selegiline, etc., hypnotics sedatives, such as amobarbital, bramwellmacfa, midazolam, chloralhydrate etc., antineoplastic agents in malignant tumors, such as fluorouracil, carmofur, aclarubicin hydrochloride, cyclophosphamide, thiotepa etc., antiallergic drugs, such as pseudoephedrine, terfenadine, etc., antidepressants, such as phenylpropanolamine, ephedrine etc., medicines used to treat diabetes, such as acetanilid, insulin, tolbutamide, desmopressin, glipizid etc., diuretics such as hydrochlorothiazide, polythiazide, triamteren etc., bronchodilators such as aminophylline, formoterol fumarate, theophylline, etc., anti-cough, such as codeine phosphate, noscapine, dimemorfan phosphate, dextromethorphan etc., antiarrhythmic drugs, such as guanidine nitrate, digitoxin, propafenone hydrochloride, procainamide, etc., surface anesthetics, such as aminomethylbenzoic, lidocaine, dibucaine hydrochloride, etc., antiepileptic drug tools such as phenytoin, tosucceed, primidone, etc., synthetic corticosteroids, such as hydrocortisone, prednisolone, triamcinolone, betamethasone, etc. and medicines for the digestive tract, such as famotidine, ranitidine hydrochloride, Dymatize, sucralfate, sulpiride, teprenone, plaunotol, 5-aminosalicylic acid, sulfasalazine, omeprazole, lansoprazole etc., drugs for the Central nervous system, such as indeloxazine, idebenone, tiaprid hydrochloride, livermere hydrochloride, homopentameric calcium etc., agents for the treatment of hyperlipidemia, such as pravastatin sodium, simvastatin, lovastatin, pravastatin, atorvastatin, etc. antibiotics, such as ampicillin phthalidyl hydrochloride, cefotetan, josamycin etc., national Department of standardization of therapeutic agents such as tamsulosin hydrochloride, doxazosin mesilate, terazosin hydrochloride, etc., Antiasthmatic drugs, such as pranlukast, zafirlukast, albuterol, ambrosa, budesonide, levalbuterol etc., agents - derived prostaglandin I to improve peripheral circulation, such as velopress sodium, etc., antithrombotic tools, antihypertensives, agents for the treatment of heart failure, agents for the treatment of various diabetic complications, agents for the treatment of peptic ulcers, agents for cured the skin I ulcers, agents for treatment of hyperlipidemia [here note: it was mentioned earlier], anti-asthmatic agents [here note: it was mentioned earlier], and so the Drug can be used in free form or in the form of any salt that is pharmaceutically acceptable.

Moreover, the present invention may include medicines that do not require slow release. In addition, you can use one drug or a combination of two or more drugs. There are no special restrictions to the amount of that drug until it is a number, which is usually effective for treatment, but preferably it is 50 wt.% or less, preferably 20 wt.% or less translated into a lot of pills. For example, when it exceeds 50 wt.% in terms of the mass of the tablet, the ratio of the fine particles is high and the pelleted with filler will be unsatisfactory.

These medicines are means of treatment with a slow release and contains fine particles with a slow release in the form of small particles, for which the release of drug is controlled by the usual methods described below. There are no special restrictions to di the meter particles to fine particles with a slow release, while it is located within the range that does not cause the feeling of sand in the buccal cavity. Generally preferred is a diameter from about 0.1 microns to about 350 microns, more preferably, from about 5 μm to 250 μm and, more preferably, from about 50 microns to 250 microns in average particle diameter. If it is less than 0.1 μm, it will be difficult to provide slow release using modern pharmaceutical technology, whereas if it is more than 350 μm, it will cause a very uncomfortable feeling, like the feeling of sand in the buccal cavity.

Moreover, fine particles with a slow release of the present invention can be obtained in the usual way. For example, fine particles with a slow release can be obtained by the process of granulation by mixing or liquid by way of drum granulation after adding the polymer solution to drug and microcrystalline cellulose as described in Japanese publication No. Hei 7-721129 (corresponding to U.S. patent No. 4772475) and in international publication WO 00/24379, or fine particles with a slow release can be obtained by layering and coating drug over particle commercial microcrystalline the cellulite, tighten the PS (avicel particles, Asahi Kasei, brand Celphere 102 and so on) as the core using conventional coating methods such as a coating in the fluidized bed, drum liquefied coating, etc. and then further coated with a polymer substance for the formation of films with controlled-release (Avicel Jiho, No.40, p.16-33, Asahi Kasei Corp.). In addition, you can also use regular crystalline filler with a size of approximately 1 μm to approximately 150 μm, in particular, crystalline lactose, granulated sugar, table salt, corn starch, silicon dioxide (silica gel), etc. taking into account the size of the fine particles with a slow release (from approximately 0.1 to approximately 350 μm). Pre-coating of water-soluble polymeric substance is not water-soluble polymeric substance, etc. can also be used to round the edges of the filler, which in this case becomes the core. In addition, it is also possible to obtain fine particles with a slow release by spray drying of a solution or suspension of drug and polymer material with suitable equipment, such as spray drying, etc. Examples of solvents used for obtaining such fine particles with decreasing the major release, are water, organic solvent, etc. are Examples of organic solvents are alcohols, in particular methanol, ethanol, propanol, isopropanol, etc., halogenated alkanes, in particular, dichloromethane, chloroform, chlorate, trichloroethane, carbon tetrachloride, etc., ketones, in particular acetone, methyl ethyl ketone, etc., NITRILES, in particular acetonitrile, etc. and hydrocarbons, in particular n-hexane, cyclohexane, etc. you Can use a single solvent or a mixture in an appropriate ratio such two or more organic solvents, and they can also be used as a mixture with water in a suitable percentage.

Need a polymeric substance that is used to obtain fine particles with a slow release, can be selected according to the intended application. Examples are not water-soluble polymer soluble in the gastric tract polymers soluble in the intestinal tract polymers, wax-like substances, etc. are Examples of water insoluble polymers are not soluble in water simple cellulose ether, such as ethylcellulose, Aquacoat (trademark, Asahi Kasei), etc. that are not water-soluble copolymers of acrylic acid such as a copolymer of acrylate-methyl methacrylate-ammonium chloride ethyl methacrylate (for example, brand Eudrgit RS, Rhm), dispersion of a copolymer of methyl methacrylate-ethyl acrylate (for example, trade name: Eudragit NE30D, Rhm) and so on and so forth. Examples soluble in the intestinal tract of the polymers are soluble in the intestinal tract polyvinyl derivatives, such as diethylaminoacetate polyvinylacetal etc., soluble in the intestinal tract copolymers of acrylic acid such as a copolymer of methyl methacrylate-butyl methacrylate-dimethylaminoethylmethacrylate (for example, the trade mark Eudragit E, Rhm) and so on and so forth. Examples soluble in the intestinal tract of the polymers are soluble in the intestinal tract derivatives of cellulose such as acetate-succinate of hydroxypropylmethylcellulose, phthalate of hydroxypropylmethylcellulose, phthalate of hydroxyethylmethylcellulose, karboksimetiltselljuloza etc., soluble in the intestinal tract copolymers of acrylic acid such as a copolymer of methacrylic acid-methyl methacrylate (for example, trade name: Eudragit L100, Eudragit S, both from), a copolymer of methacrylic acid-ethyl acrylate (for example, trade name: Eudragit L100-55, Eudragit L30D55,and so on and so forth. Examples of wax-like substances are solid oils and fats, such as gidrirovannoe castor oil, gidrirovannoe coconut oil, fat, etc., higher fatty acids, such as terinova acid, lauric acid, myristic acid, palmitic acid, etc., and higher alcohols such as cetyl alcohol, stearyl alcohol, etc. Among them, a copolymer of methacrylic acid-ethyl acrylate is preferred to ensure solubility in the intestinal tract and pH-independent water-insoluble polymer, in particular ethylcellulose is preferred to provide a slow-release, whereby the drug is released gradually. For controlled dissolution, you can use one or a suitable combination of two or more of these polymeric substances.

In addition, if necessary, can also be added plasticizer. Examples of such a plasticizer is triacetin, triethylcitrate, dibutylsebacate, acetylated monoglyceride, dispersion of a copolymer of acrylate-methacrylate (for example, the trade mark Eudragit NE30D, Rhm), and preferred are triacetin and dispersion of a copolymer of acrylate-methyl methacrylate.

In addition, water-soluble polymers, sugars, salts, etc. can be mixed with the above polymeric substances such as water-insoluble polymers, soluble in the intestinal tract polymers soluble in the intestinal tract polymers, etc. or wax-like substances, etc. are Examples that is their substances are hydroxypropylcellulose, the hypromellose, polyvinylpyrrolidone, polyvinyl alcohol, etc. as the water-soluble polymer substances. Examples of sugars include maltose, ▫ maltitol, etc. and examples of the salts is sodium chloride, etc. the Number used here of the polymer and the saccharide can be adjusted as required to control the dissolution rate of the drug. In addition, you can use one or a combination of two or more of these polymers and sugars. Incidentally used herein, water-soluble polymeric substances, sugars and salt added for easily controlled dissolution of drugs from fine particles with a slow release and should be distinguished from those used in obtaining the compositions of the present invention.

There is no special limitation to be used in the present invention a “filler”until he is a pharmaceutically acceptable alcohol or sugar alcohol. Examples of sugars or sugar alcohols are carbohydrates with a low plasticity described in international publication WO 95/20380. Specific examples include xylitol, aritra, glucose, mannitol, sucrose and lactose. Among them, mannitol, lactose and aritra are preferred. In addition, you can use one or ethnie two or more of these sugars. In this description of the “saccharide with a low plasticity” means a saccharide, which, for example, demonstrates the hardness of the tablet is less than 2 kp when 150 mg of saccharide tabletirujut at a tabletting pressure of 10 to 50 kg/cm2using punch with a diameter of 8 mm (citing WO 95/20380, corresponding to U.S. patent No. 5576014, Japan patent No. 3122141). In addition, can be selected sugar with high melting temperature and sugar with a low melting point, specified in the application for U.S. patent No. 10/142081 (corresponding to the application for international patent number PCT/JP 02/04481).

There is no special limitation to be used in the present invention, the saccharide with a low melting point, as long as it is pharmaceutically acceptable and is a saccharide with a low melting point listed in the application for U.S. patent No. 10/142081 (corresponding to the application for international patent number PCT/JP 02/04481) and has a relatively lower melting temperature compared to drugs and sugars with a high melting point used in the present invention, but saccharide with a melting point from about 80 to about 180°is the preferred and saccharide [melting point] about 90 to 150°is preferable. Examples of such Saha the IDA are glucose (monohydrate, melting point 83°C), xylitol (melting point 93°C), trehalose (dihydrate, melting point 97°C), sorbitol (hydrate, melting point slightly less than 100°C), maltose (melting point 102°C), sorbitol (melting point 110°C), aritra (melting point 122°C), glucose (melting point 146°) ▫ maltitol (melting point 150°C), mannitol (melting point 166°C), sucrose (melting point of approximately 170° (C), etc. Can be used alone or two or more saccharides selected from the constituents of this group. Among these sugars are preferred one or two or more saccharides selected from glucose, xylitol, trehalose, sorbitol, maltose, eritria, maldita and their hydrates. Ideal are trehalose, maltose, aritra or ▫ maltitol, particularly trehalose and/or aritra, because these sugars are themselves only weakly hygroscopic and, therefore, they are easy to deal with. You can use one or a combination of two or more of these sugars. These sugars can also be used in the form of a hydrate. When the hydrate and the anhydride of the saccharide have different melting points, respectively, as required, must be set the temperature of the heating.

Used in infusion is eating the invention of the “saccharide with a high melting point” is a saccharide with a high melting point, listed in the application for U.S. patent No. 10/142081 (corresponding to the application for international patent number PCT/JP 02/04481). This is a saccharide, a melting point different from the melting temperature used in the present invention, the saccharide with a low melting point by 10°or more, even more preferably, it is a saccharide, a melting temperature that differs by 20°With or more. Taking into account the difference between the temperature at which installed the heating device and the temperature of the tablets representing the heated object is preferred to be selected saccharides with a greater difference in their melting points. Specifically, given xylitol (melting point 93°C), trehalose (dihydrate, melting point 97°C), sorbitol (hydrate, melting point slightly less than 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°C), mannitol (melting point 166°C), sucrose (melting point of approximately 170°C), lactose (melting point 202° (C) etc. Can be used alone or two or more saccharides selected from the constituents of this group. Illustration of a saccharide is in high melting temperature visually duplicates the saccharides with a low melting point, but as the “saccharide with a high melting point selected in the translation of the relative relationship with a saccharide with a low melting point, it does not choose the same sugars. “Sugars with a high melting point and saccharides with a low melting point” of the present invention selects, as required, taking into account the chemical properties of drugs that will be used, i.e. the stability of the medicinal product in relation to temperature. When transaction completed and the case of the “saccharide with a high melting point” and “saccharide with a low melting point” is described in concrete terms, xylitol, trehalose, sorbitol, aritra, glucose, ▫ maltitol, mannitol, sucrose, lactose, and their hydrates can be used as the “saccharide with a high melting point”, when glucose (monohydrate, melting point 83° (C) is used as the “saccharide with a low melting point”used in the present invention. Moreover, 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) is used as the “saccharide with a low melting point”, usage is used in the present invention. Glucose, ▫ maltitol, mannitol, sucrose or lactose can be used as the “saccharide with a high melting point, when eritra (melting point 122° (C) is used as the “saccharide with a low melting point”used in the present invention. In addition, mannitol, sucrose or lactose can be used as the “saccharide with a high melting point”, when ▫ maltitol (melting point 150° (C) is used as the “saccharide with a low boiling point” in the present invention. Additionally, lactose can be used as the “saccharide with a high melting point”, when sucrose (melting point of approximately 170° (C) is used as the “saccharide with a low melting point” in the present invention. “Saccharide with a high melting point” is chosen, as described, as necessary in accordance with the type of saccharide used in the present invention. When selecting saccharides such that there is a greater difference between their melting temperature, “saccharide with a high melting point”preferably represents 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. Their ispolzuut suitable quantities as one of the sugars or a mixture of two or more as it is required.

Sugars with high plasticity listed in international publication WO 95/20380, saccharides with a low melting point listed in the application for U.S. patent No. 10/142081 (corresponding to the application for international patent number PCT/JP 02/04481) or water-soluble polymer substance is chosen as binders for bystrorazvivajushchihsja in the buccal cavity tablets”used in the present invention. For example, the as saccharides with high plasticity maltose (preferably powder, malt syrup (maltose content of 83% or higher)), trehalose, sorbitol or ▫ maltitol, maltose and trehalose are preferred. In this description of the “saccharide with a high plasticity” means a saccharide, showing the hardness of the tablets 2 kp or more when 150 mg of saccharide tabletirujut at a tabletting pressure of 10 to 50 kg/cm2using punch with a diameter of 8 mm (citing WO 95/20380 (corresponding to U.S. patent No. 5576014, Japan patent No. 2122141). The above saccharides with a low melting point is given as saccharides with a low melting point. In addition, as water-soluble polymeric substances listed hydroxypropylcellulose, hypromellose, polyvinylpyrrolidone, copolyvidone, polyvinyl alcohol, etc. Can and is to use one or a combination of two or more binders for bystrorazvivajushchihsja in the buccal cavity of tablets”. Preferred are hydroxypropylcellulose, hypromellose or copolyvidone with low hygroscopicity, taking into account the environment during storage as the initial substance and a pharmaceutical preparation, and copolyvidone is ideal.

In addition, the “binder for bystrorazvivajushchihsja in the buccal cavity” tablets of the present invention may be one or two or more substances selected from the group consisting of “saccharides with high plasticity”, “saccharides with a low melting point” and “water-soluble polymeric substances”.

I. “Filler”: saccharide with a low plasticity, “binder for bystrorazvivajushchihsja in the buccal cavity pills: saccharide with high plasticity or water-soluble polymeric substance,

II. “Filler”: saccharide with a high melting point, “binder for bystrorazvivajushchihsja in the buccal cavity of tablets: the saccharide with a low melting point,

III. “Filler”: saccharide with a high melting point, “binder for bystrorazvivajushchihsja in the buccal cavity of tablets: the saccharide with a low melting point and a water-soluble polymeric substance, and

IV. “Filler”: saccharide with a high melting point and a saccharide with a low the melting point, “binder for bystrorazvivajushchihsja in the buccal cavity pills: water-soluble polymeric substance or a saccharide with high plasticity;

given as specific embodiments of the present invention regarding the selection of the above “filler” and “binders for bystrorazvivajushchihsja in the buccal cavity of tablets”. As a specific illustration IV is preferred that aritra was selected as the “saccharide with a low melting point, lactose and/or mannitol were selected as the “saccharide with a high melting point”, and ▫ maltitol additionally choose as binders for bystrorazvivajushchihsja in the buccal cavity tablets (the“saccharide with a high plasticity”), or to aritra was selected as the “saccharide with a low melting point, lactose and/or mannitol were selected as the “saccharide with a high melting point”, and copolyvidone additionally choose as binders for bystrorazvivajushchihsja in the buccal cavity tablets (“water soluble polymer”).

The number of “filler”used in the present invention, regulate, as required in accordance with the dose of the drug and/or size of the tablet. This added amount is adjusted, as required shall be by increasing the number of “filler”used in the present invention, when the dose of the drug is small, and by reducing the amount of “filler”used in the present invention, when the dose of the medicinal product is great, etc. to obtain pellets of the desired size. Usually, it is preferable from 20 to 1000 mg, more preferably from 50 to 500 mg and more preferably from 100 to 400 mg per tablet. There is a possibility that a thorough granulation cannot be realized if the amount of added filler is less than 20 mg. moreover, the amount of filler to the amount of saliva in the buccal cavity is too large, when [the amount of added filler] exceeds 1000 mg, and will create a strange feeling when he is in his mouth.

The number of binders for bystrorazvivajushchihsja in the buccal cavity of tablets, which are used in the present invention is usually preferably ranges from 0.5 to 50 wt.%, more preferably, from 1 to 30 wt.%, even more preferably, 1 to 20 wt.% from the mass of “filler”used in the present invention. If it is less than 0.5 wt.% by weight of the filling, there is a possibility that its function as binders will not be fully implemented. In addition,if more than 50 wt.% from the mass of “filler”, there is a possibility that you will encounter many problems, including slow-motion destruction, etc. and you will not get good properties when used bystrorazvivajushchejsja in the buccal cavity of the tablet. Although the ratio of the fine particles with a slow release”, “filler” and “binders for bystrorazvivajushchihsja in the buccal cavity of tablets will not be completely specified using percentages are illustrated: the corresponding ratio is preferably from 1 to 50%, from 20 to 98% and from 1 to 30%, more preferably from 1 to 20%, from 60 to 98% and from 1%to 20%.

In addition to the filler and binder substance for bystrorazvivajushchihsja in the buccal cavity tablets”as used in the present invention, it is possible to add various additives, which are pharmaceutically acceptable and are used as auxiliary additives. Such additives can be mixed with the filler in the granulating fine particles with a slow release, or they can be used in the form of a mixture with a composition of the present invention in the manufacture of tablets. Examples of such additives are dezintegriruetsja substances, acidic flavor additives, foaming agents, artificial sweeteners, flavors, lubricants, to acitelli, stabilizers, etc. you Can use one or a combination of two or more such additives. In addition, there are no specific limitations to the added amount, until it is a number, usually pharmaceutically used specialists in this area, and is within the range which does not adversely affect the results of the present invention.

Examples dezintegriruetsja agents include starches such as corn starch, etc., carmellose calcium, partially alpha-converted starch, crosspovidone, substituted lower derivatives of hydroxypropylcellulose, etc. Examples of acidic flavorings are citric acid, tartaric acid, malic acid and so on, examples of blowing agents are sodium bicarbonate, etc. are Examples of artificial sweeteners include saccharin sodium, glycyrrhizinate of dicale, aspartame, stevia, cormatin etc. are Examples of perfumes are lemon, lemon-lime, orange, menthol, etc. Examples of lubricants are magnesium stearate, calcium stearate, esters of sucrose and fatty acid, polyethylene glycol, talc, stearic acid, etc. are Examples of the dyes include food dyes such as yellow food dye No. 5, red food dye No. 2, blue food dye No. 2, and so on, food is replac; red iron oxide, etc. Stabilizers choose to use drugs after conducting various tests. If necessary, you can add one or a combination of two or more of such additives in a suitable amount.

The techniques of the method of obtaining a composition comprising fine particles with a slow release of the present invention, in particular the conditions for obtaining, etc. will now be described in detail.

Next, a method of obtaining a composition comprising fine particles with a slow release for bystrorazvivajushchihsja in the buccal cavity of the tablets of the present invention, will be described using (a) the stage of obtaining fine particles with a slow release, including the number of drugs that are effective in terms of treatment or prevention, and with which the dissolution rate of such drugs is controlled, and (b) stage, through which fine particles with a slow release” and “filler” granularit together with binder for bystrorazvivajushchihsja in the buccal cavity pills.

Stage (a): a Method of obtaining fine particles with a slow release.

Fine particles with a slow release get the regular ways the AMI, as previously noted. There are no particular limitations to this method, and it can be selected, as required, until it is this that is the purpose of the controlled dissolution. For example, the drug layer and coated on a commercial particles of crystalline cellulose, crystalline lactose, granulated sugar, salt, silicon dioxide and so on, is additionally coated with a membrane on such particles using a binder such as hydroxypropylcellulose, etc. and then polymeric substances such as water-insoluble polymeric substance soluble in the stomach polymeric substance soluble in the intestine polymeric substance, a wax-like substance, etc. to obtain fine particles with a slow release. It is also possible to layering and coating of polymeric substances such as water-insoluble polymeric substance soluble in the stomach polymeric substance soluble in the intestine polymeric substance, a wax-like substance, etc. together with the medicinal product on the commercial particles of crystalline cellulose, crystalline lactose, granulated sugar, salt, silicon dioxide, etc. to obtain fine particles with a slow release. Fine part of the s delayed release also get way granulation by mixing or drum granulation fluidized bed and after adding a solution of a polymeric substance to drug medium and microcrystalline cellulose. The above coating can optionally be carried out for such fine particles with a slow release, and, if necessary, they can be given the function of dissolution in the intestine by using coating layer of enteric polymer base. To cover the shell, for example, choose granulator fluidized bed. The temperature and then the volume of the sprayed liquid, the amount of sprayed air, etc. are set so that the temperature of the product ranged from about 40°With up to about 60°in the case of coatings using water and from about 30°With up to about 60°when using an organic solvent. The concentration of the drug, the percentage and number of polymeric substances etc. that are used to cover, can be adjusted, as required, in accordance with the desired rate of dissolution.

Stage (b): Method of granulating

There are no specific limitations to the method of granulation of the present invention, while it is a method in which fine particles with a slow release granularit with “filler” and “binder for bystrorazvivajushchihsja in the buccal cavity of tablets”. Example is, granulation in the fluidized bed, granulation by mixing, drum granulation, etc. can be selected as such a method of granulation. Among them, preferred in translation performance is way granulation in the fluidized bed. The way in which the solution “binders for bystrorazvivajushchihsja in the buccal cavity of tablets, which is used in the present invention, dissolved and/or suspended in a pharmaceutically acceptable solvent is sprayed on the mixture of fine particles with a slow release and a “filler” for the manufacture of particles and obtain the “composition”can be selected for the method of granulation in the fluidized bed. At this point fine particles with a slow release should be covered with a “filler”. The conditions for obtaining preferable are, for example, the product temperature from about 25°With up to about 40°and a water content of from about 0.2 to about 5%. In addition, it is preferable granulation with periodic spraying. “Periodic spraying” means intermittent spraying and represents the atomization method for granulating, for example, repeated cycles of sputtering for 10 seconds with the following drying for 30 seconds. In addition, such a cycle may be set as required for manufacturing. Additionally, while spray - drying time can be selected appropriately. Also can be pelletized after adding the above auxiliary additives, as required.

“Filler” may be a commercial product used as such. When the average particle diameter of the filler is larger than the average particle diameter of the fine particles with a slow release, is preferable to “filler” was crushed using a suitable grinding device, such as mobile mill, mill samples, pin mill, etc. to facilitate granulation particles with a slow release. It is preferable to “binder for bystrorazvivajushchihsja in the buccal cavity of the tablets was dissolved in water to obtain a solution, when it represents a saccharide of high moldability. The concentration of this fluid should be, for example, from 10 to 40 wt.%, more preferably from 20 to 30 wt.% to increase to the limit of the binding force of the binder for bystrorazvivajushchihsja in the buccal cavity of tablets. If the concentration of water is lower than 10 wt.%, the volume of liquid will be too large and the procedure will take longer than the belts, whereas if the concentration of the liquid above 40 wt.%, the procedure will be completed in a shorter period of time, and therefore will be difficult to maintain the cycle - time spray - drying time.

In addition, a composition including fine particles with a slow release of the present invention, can be used in bystrorazvivajushchihsja in the buccal cavity tablets and this method comprises: (C) stage tabletting compositions obtained in stage (b), and (d) the stage of wetting and drying of the tablets obtained in stage (C), if necessary. In addition, when the composition is chosen above the saccharide with a high melting point and a saccharide with a low melting point, you can choose the method comprising (d’) stage of heating the tablets obtained in stage (C), and (e) cooling stage after stage (d’). Stage (d) can also be carried out after steps (d) and (e).

Stage (C): Method tabletting

“Tableting” carried out in the usual ways. There are no particular limitations while this way we obtain a pellet-shaped with at least the minimum pressure required to maintain the shape of the tablets. This “tableting” can be implemented using, for example, conventional tabletiruemogo device, for example, Autonomous tabletroute what about the device or rotary tabletiruemogo devices, etc., after adding the above “composition” necessary additions, starting with lubricants such as magnesium stearate, etc. in Addition, of the above songs can also be obtained tablets using tabletiruemogo device with an external lubricant. It is preferable tabletroute pressure is usually from about 25 to 800 kg/kick, more preferably, from about 50 to 500 kg/shock, and, most preferably, from about 50 to 300 kg/punch.

Stage (d): Method of moistening and drying

When the saccharide, which is the “binder for bystrorazvivajushchihsja in the buccal cavity of tablets used in the method of granulation is amorphous and there is a reduction of the strength of the tablets obtained by the method of tabletting due to absorption of moisture, that is when the “binder for bystrorazvivajushchihsja in the buccal cavity tablets”used in the present invention is a saccharide of high moldability, and are maltose, sorbitol or trehalose is preferred to apply the following method of moistening and drying:

“Hydration is carried out in combination with the drying process, which is a process that follows the process of hydration. There are no specific limitations to the method, n is ka he is such wherein the saccharide “binders for bystrorazvivajushchihsja in the buccal cavity tablets”used in the present invention, crystallizes from the amorphous material. Terms such a “hydrate” is defined by the visible critical relative humidity of the mixture, including containing medicinal fine particles with a slow release, “binder for bystrorazvivajushchihsja in the buccal cavity tablets”used in the present invention, and “filler”. Hydration is usually carried out at least to the critical relative humidity of a mixture. For example, from about 30 to about 100% relative humidity is preferred and, more preferably, from about 50 to about 90% relative humidity as humidity. As the temperature for a given period of time, the preferred temperature is from about 15 to about 50°and, more preferably, from about 20 to about 40°C. as the wetting time is preferred period of from one to 48 hours and, more preferably, from 12 to 24 hours.

There are no particular restrictions for “drying”, as she represents the way in which moisture is removed, absorbed in SWL is ininii. Usually as conditions for drying the preferred temperature is from about 10 to about 100°S, more preferably from about 20 to about 60°and, most preferably, from about 25 to about 40°C. as the drying time is preferred period of from thirty minutes to 10 hours and, more preferably, from 1 to 4 hours.

Stage (d’): a Method of heating

“Heating” in the present invention is carried out in the usual ways, and there are no particular limitations, as long as it is a method in which a molded product obtained in stage (C), can be brought to a temperature which at least represents a melting temperature above the “saccharide with a low melting point”. The “heat” can be implemented, for example, using a ventilated oven. Temperature conditions chosen, as required, depending on the type of saccharide with a low melting point”, and there are no specific restrictions as they represent the melting temperature of the “saccharide with a low melting point”used in the present invention, or higher and the melting point of the “saccharide with a high melting point or lower. When used in isout “saccharide with a low melting point”, used in the present invention, it ranges from approximately 80 to approximately 180°preferably from about 90 to about 150°C. Temporary conditions chosen, as required depending on the type of saccharide, desired strength tablets, characteristics of decomposition in the buccal cavity, but usually the time is from 0.5 to 120 minutes, preferably from 1 to 60 minutes, more preferably from 2 to 30 minutes.

Stage (e): cooling Method

“Cooling” in the present invention is carried out in the usual ways, and there are no particular limitations, as long as it is a way in which the saccharide with a low melting point used in the present invention, cures after melting. The specified cooling can be performed, for example, when leaving at room temperature or when stored in an atmosphere with a low temperature, such as in the refrigerator, etc.

The following is an example of a method of obtaining a composition comprising fine particles with a slow release for bystrorazvivajushchihsja in the buccal cavity of the tablets of the present invention: original drug layer and is applied in the form of a coating on particles of commercial crystalline cellulose (e.g., Celphere 102) using p is thedamage binders (for example, hydroxypropylmethylcellulose) in the granulator fluidized bed etc. Fine particles with a slow release get with additional coating with a mixture of water insoluble polymeric substances (for example, ethylcellulose) and the water-soluble polymer (e.g. hypromellose), as required, using a granulator fluidized bed, etc. to obtain the desired dissolution. The data is then finely dispersed particles and sugars (e.g. mannitol) granularit in peremejayutsya mode (for example, the cycle of spraying for 10 seconds, and then drying for 30 seconds) together with the binder for bystrorazvivajushchihsja in the buccal cavity of the tablets (such as maltose) using a granulator fluidized bed and so on, to obtain a composition comprising fine particles with a slow release for bystrorazvivajushchihsja in the buccal cavity of the tablets of the present invention.

Bystrorazvivajushchiesja in the buccal cavity of the tablet, including fine particles with a slow release, can be obtained by adding auxiliary additives, if necessary, for example, a suitable lubricant such as magnesium stearate, etc. to compositions comprising fine particles with the slow visvobodi the Institute of economy and management, used for bystrorazvivajushchihsja in the buccal cavity of the tablets of the present invention, and obtain tablets using tabletiruemogo device.

Brief description of drawings

Figure 1 presents the results of experiments on the dissolution of tablets and fine particles with a slow release of example 1 using 1-th fluid tests the solubility of the Pharmacopoeia of Japan.

Figure 2 presents the results of experiments on the dissolution of tablets and fine particles with a slow release of example 1 using the 2nd fluid for tests on the solubility of the Pharmacopoeia of Japan.

Figure 3 presents the results of experiments on the dissolution of tablets and fine particles with a slow release of comparative examples 1 and 2 using the 1st fluid for tests on the solubility of the Pharmacopoeia of Japan.

Description of the preferred embodiments

The present invention will be described below using examples, but the interpretation of the present invention is not limited to these examples.

The methods for determining the quality of a composition comprising fine particles with a slow release.

[Determination of the distribution of the particle diameter of the fine particles with a slow release and composition, Lucaya fine particles with a slow release]

The diameter of the particles was determined using the measuring instrument of the diameter distribution of the particles sieve type (Seishin Enterprise Co., Ltd., Robot Sifter) using sieves with holes 30, 42, 60, 80, 100, 150, 200 and 250 mesh.

[Quantitative determination of the ratio of the diameter of the particles of the composition including fine particles with a slow release]

The composition remaining on the sieves with each of the above sizes of holes, allocate and determine the proportion of each fraction. Given that the total quantity is equal to 100%, calculate the ratio relating to the quantitative value on each sieve, and it serves as a proportion of the diameter of the particles. In addition, the quantitative distribution of the particle diameters was obtained, with the proportion of the diameter of particles in the order of the size of the hole each sieve. In this regard, to determine the quantitative result can be used any way, yet contained the medicinal product is meticulously extracted from the composition, and the determination carried out by method of determining appropriate for each drug.

[The value in the form of fine particles with a slow release]

Determine the distribution of particle diameter for fine particles with a slow release of the quantitative distribution of the particle diameter of the composition, including fine particles with a slow release, and calculated using the following formula:

The ratio in the form of fine particles with a slow release (%)=G1+Σ(Gi+1-(Pi-Gi))

In this specification, assessment Σ [get] calculated from i=1 and estimating the value up until the point before (Gi+1-(Pi-Gi)) becomes negative.

P1: the ratio of the fine particles with a slow release on the sieve with a minimum hole size in the range of the diameter distribution of the particles to fine particles with a slow release (except where it is 0%). That is, it is equal to 15.0% 150 mesh in the following examples.

P2: the ratio of the fine particles with a slow release on the sieve with the second minimum hole size in the range of the diameter distribution of the particles to fine particles with a slow release (except where it is 0%). That is, it is 70,6% on 100 mesh, in the following examples. The third, fourth and so on refers to P3, R4and so forth, and they, as a whole, presented in the form of Pi.

G1: value quantitative ratio of the diameter distribution of the particles of the composition on the sieve with the same hole size, Thu and for P 1. That is, it is 2.5% to 150 mesh in the following examples.

G2: value quantitative ratio of the diameter distribution of the particles of the composition on the sieve with the same hole size for P2. That is, it is 14.3% on 100 mesh, in the following examples, third, fourth and so on belong to the G3, G4and so on, and they as a whole are presented in the form Gi.

For example, if the distribution results are as follows:

The distribution of particle diameter for fine particles with a slow releaseQuantitative distribution of the particle diameter of the composition of example 1
on 30 mesh (%)019,0
42 mesh (%)022,4
60 mesh (%)023,5
80 mesh (%)14.4V18,2
100 mesh (%)70,614,3
150 mesh (%)15,02,5
on 200 mesh (%)00
200 mesh passing (%)00

ratio (%) in the form of fine particles with a slow release

=G1 +Σ(Gi+1-(Pi-Gi))

=Gi+(G2-(P1-G1))+(G2-(P2-G2))+.......

=2,5+(14,3-(15-2,5)+(18,2-(70,6-14,3))+(23,5-(14,4-18,2))=2,5+(+1,8)+(-38,1)

If the numbers in parentheses are negative, this means that fine particles with a slow release have a particle diameter that is at least 1 order of magnitude greater due to granulation. [Therefore], there are no subsequent assessment and

=2,5+(+1,8)=4,3

The methods for determining the quality bystrorazvivajushchihsja in the buccal cavity tablets

[Study of hardness] Determination is performed using the Vickers hardness of the tablets Lanigera (Schleuniger) (Schleuniger Co., Ltd). The study was conducted for 5 tablets and lead the average value. The hardness of the tablets are in the form of the force required for crushing tablets (units kp). A higher number indicates a stronger pill.

[The fragile] the Determination is carried out with the use of the tester fragility (model PTFR A Pharma Test Co.). The fragility install using 6 tablets. She is presented as the percentage of weight loss pills after rotation for 100 times at a speed of 25 revolutions/minute. A smaller value indicates a more durable surface tablets.

[Studies of decomposition in the buccal cavity] Adult healthy men placed the tablet on this is the overarching invention in its buccal cavity without any water in the buccal cavity and defined time, which tablet is fully decomposed and dissolved only by saliva.

[Research content uniformity] Quantitatively determined the content of the drug in each of 10 tablets and represented as the coefficient of variation (CV%) number of drugs on the above formula.

[Solubility studies] study was performed using a test solubility method No. 2 in accordance with the revised version of the Pharmacopoeia of Japan

Example 1

Eighty grams of the hydrochloride tamsulosin and 80 g hydroxypropylmethylcellulose (TC5E, Shin-Etsu Chemical Co., Ltd.) was dissolved in a mixture of 304 g of purified water and 2736 g of methanol. Four thousand grams of Celphere 102 (trademark, Asahi Kasei, the average particle diameter of about 127 μm, a particle diameter of from about 50 to about 150 μm) were introduced in the granulator fluidized bed (Freund Industries, FLO-5) and covered by this solution using the method of lateral spraying (spraying liquid volume 100 g/min, spraying air pressure of 4 kg/cm2the product temperature 40°C, the temperature at the inlet 80° (C) to obtain particles of tamsulosin hydrochloride. Separately 533 g of ethyl cellulose (Nissin Chemistry Co.) and 187 g of hydroxypropylmethylcellulose (TC5E, Shin-Etsu Chemical Co., Ltd.) was dissolved in a mixture 698 g of purified water and 22582 g of methanol. Four thousand grams of net assets the TIC hydrochloride tamsulosin was introduced in the granulator, fluidized bed (Freund Industries, FLO-5) and covered by this solution using the method of lateral spraying (spraying liquid volume 40 g/min, spraying air pressure of 4 kg/cm2the temperature of the product 50°C, water inlet temperature 60° (C) to obtain fine particles with a slow release. Four thousand grams of these particles with a slow release was introduced in the granulator, fluidized bed (Freund Industries, FLO-5) and covered with a mixture of 2000 g of Aquacoat (trademark, Asahi Kasei), 4000 g of Eudragit L30D55 (trademark), 667 g of Eudragit NE30D (trade mark,and 6667 g of purified water (spraying liquid volume 40 g/min, spraying air pressure of 4 kg/cm2the product temperature 40°C, water inlet temperature 60° (C) to obtain soluble in the intestine of the fine particles with a slow release.

Then 368 g data soluble in the intestine of the fine particles with a slow release, 2560 g mannitol (Towa Kasei Co., Ltd.) and 640 g of lactose (Domomilk) were granulated (spraying liquid volume of 200 g/min, spraying air pressure of 1.5 kg/cm2the temperature of the product 29°C, the temperature at the inlet 80°With the cycle of spraying consisted of 10 seconds of spray - 30 seconds drying) with aqueous 40 wt.% a solution containing 400 g of maltose (Hayashibara Co., Ltd., brand: Sunmalt S) in the granulator with pseudoo is defined layer (Freund Industries, FLO-5) to obtain the compositions of the present invention.

After additional mixing 32 g of calcium stearate with the obtained composition was given 200 mg tablets containing 0.2 mg of tamsulosin hydrochloride in tablet tabletirujut a pressure of 100 kg/shock and the initial hardness of 1.0 kp using a rotary tabletiruemogo device. Then these tablets was kept for 18 hours under heating and humidifying at 25°C/75% relative humidity using a thermostatted chamber at constant humidity (Tabaiespec Co., Ltd., PR-35C). Then they were dried for 3 hours at 30°C and 40% relative humidity. The resulting tablets showed a hardness of 5.9 kp (n=5), the fragility of 0.8% (100 rpm) and disintegration time in the buccal cavity 20 seconds (n=3). Moreover, the evaluation of content uniformity CV%=2.1% of confirms that there is a good uniformity of content.

Comparative example 1

Originally 319,3 g mannitol (Towa Kasei Co., Ltd) and 79,7 g of lactose (Domomilk) were granulated (spraying liquid volume of 10 g/min, spraying air pressure of 1.5 kg/cm2the product temperature 30°C, water inlet temperature 60°With the cycle of spraying: continuous spraying with water to 20 wt.% a solution containing 50 g of maltose (Hayashibara Co., Ltd., brand: Sunmalt S) in the granulator, fluidized bed (Freund Industries, uni-glatt). P the following mix of 45.2 g soluble in the intestine of the fine particles with a slow release of example 1 and 5 g of calcium stearate with the received product received 200 mg tablets containing 0.2 mg of tamsulosin hydrochloride in tablet tabletirujut pressure of 93 kg/shock and the initial hardness of 1.0 kp using a rotary teletrauma machine. Then, these tablets was kept for 18 hours under heating and humidifying at 25°C/75% relative humidity using a thermostatted chamber at constant humidity (Tabaiespec Co., Ltd., PR-35C). Then they were dried for 3 hours at 30°C and 40% relative humidity. The resulting tablets had a hardness of 4.1 cu (n=5) and disintegration time in the buccal cavity 15 seconds (n=3). Moreover, the evaluation results of content uniformity was CV%=5.6%for tablets had poor uniformity of content.

Comparative example 2

Initially, 45,2 g soluble in the intestine of the fine particles with a slow release obtained in example 1, 319,3 g mannitol (Towa Kasei Co., Ltd.) and 79,7 g of lactose (Domomilk) were granulated (spraying liquid volume of 10 g/min, spraying air pressure of 1.5 kg/cm2the product temperature 30°C, water inlet temperature 60°With the cycle of spraying: continuous spraying with water to 20 wt.% a solution containing 50 g of maltose (Hayashibara Co., Ltd., brand: Sunmalt S) in the granulator, fluidized bed (Freund Industries, uni-glatt). After mixing 5 g of calcium stearate with the obtained product was received 200 mg tablets is, containing 0.2 mg of tamsulosin hydrochloride in tablet tabletirujut pressure 96 kg/shock and the initial hardness of 1.0 kp using a rotary teletrauma machine. Then these tablets was kept for 18 hours under heating and humidifying at 25°C/75% relative humidity using a thermostatted chamber at constant humidity (Tabaiespec Co., Ltd., PR-35C). Then they were dried for 3 hours at 30°C and 40% relative humidity. The resulting tablets had a hardness of 3.7 cu (n=5) and disintegration time in the buccal cavity 15 seconds (n=3). Moreover, the evaluation results of content uniformity was CV%=4.0 percent, tablets had poor uniformity of content.

Experiment 1 (Quantitative characteristics using a distribution of particle diameters)

The distribution of the particle diameter of the fine particles with a slow release obtained in example 1, and the distribution of particle diameters as well as quantitative distribution using particle diameter of the composition obtained in examples 1 and 2 (table 1)and the product obtained in comparative examples 1 and 2 (table 2), are presented together.

Table 1.

The distribution of the particle diameter of the fine particles with a slow release and distribution is of particle diameter and distribution of particle diameter of the compositions of examples 1 and 2
The distribution of particle diameter for fine particles with a slow releaseDiameter distribution of the particles of the composition of example 1Quantitative distribution of the particle diameter of the composition of example 1Diameter distribution of the particles of the composition of example 2Quantitative distribution of the particle diameter of the composition of example 2
The average particle diameter µm165393--204--
on 30 mesh (%)026,919,01,51,1
42 mesh (%)029,722,45,16,2
60 mesh (%)023,823,523,127.2
80 mesh (%)14.4V9,818,231,543,4
100 mesh (%)70,62,814,315,217,6
150 mesh (%)15,03,12,516,14,3
on 200 mesh (%)01,505,10
200 mesh passing (%)02,502,50
The ratio of ungranulated product (%)----4,3--11,2

td align="left"> 60 mesh (%)
Table 2.

The distribution of the particle diameter of the fine particles with a slow release and distribution of particle diameter and distribution of particle diameter of the products of comparative examples 1 and 2
The distribution of particle diameter for fine particles with a slow releaseDiameter distribution of the particles of the product of example 1Quantitative distribution of the particle diameter of the product of example 1Diameter distribution of the particles of the product of example 2Quantitative distribution of the particle diameter of the product of example 2
The average particle diameter µm165179--196--
on 30 mesh (%)0the 4.703,12,1
42 mesh (%)08,0011,310,3
013,8017.819,3
80 mesh (%)14.4V23,614,223,442,2
100 mesh (%)70,618,970,912,8of 21.2
150 mesh (%)15,017,814.4V13,8a 4.9
on 200 mesh (%)08,408,80
200 mesh passing (%)0a 4.909,00
The ratio of ungranulated product (%)----99,2--16,0

Most of the fine particles with a slow release was in the range of from 80 to 100 mesh and the results of the quantitative ratio of the diameter distribution of the particles in examples 1 and 2 demonstrate that the vast majority of the fine particles with a slow release coated filler by granulation and distribution of the composition including fine particles with a slow release, is shifted in the direction of the larger diameter particles. On the other hand, as for the races is determining the product in comparative example 2, it was confirmed that the apparent diameter of the particles is large, but in proportion to the diameter of the particles is not the same in the desired extent with the distribution of the product. In particular, the quantitative ratio to range from 80 to 100 mesh, under which fall in the form of fine particles with a slow release, is 20% or higher, and observed that many fine particles with a slow release are not granulated.

Separately, a lot of the fine particles with a slow release that were not granulated, was observed in part of the product 80-150 mesh of comparative example 2 microscopic observation and composition of the product. On the other hand, was not almost observed in the form of fine particles with a slow release for the composition of example 1. Thus, even using microscopic observations were findings that support the above data. Therefore, these results confirm that fine particles with a slow release were carefully granular with filler in the compositions of examples 1 and 2. In addition, the coefficient of variation, when the ratio of ungranulated product amounted to 4.3% (example 1) and 11.2% (example 2), was equal to 2.2 (CV%) and 2.1 (CV%), sootvetstvenno is, while the coefficient of variation in the case when the ratio of ungranulated product amounted to 99.2% (comparative example 1) and 16.0% (comparative example 2), was equal to 5.5% (CV%) and 4.0 (CV%), respectively. Thus, if the ratio of ungranulated product is 16% or higher, the results indicate that the coefficient of variation (CV%), an index of the content uniformity is large and exceeds the permissible value of 3.5%.

Experiment 2 (experiment dissolution)

Experiments on solubility was carried out on the tablets obtained in example 1 and comparative examples 1 and 2, and the results were compared with the dissolution rate themselves the fine particles with a slow release. Experimental conditions were set at 100 rpm with a paddle method and the experimental liquids used the 1st fluid (pH of 1.2) and 2nd fluid (pH 6.8) testing method of decomposition of the Pharmacopoeia of Japan.

In the experiment the sample liquid test with a pH of 1.2 almost not there was a difference (difference in values in two hours 0.7%) between the dissolution rate of the fine particles with a slow release and tablets for a period of time up to two hours after the start of the experiment on solubility, and even for liquids for testing with pH 6.8, the difference in dissolution rate between the fine particles with a slow release and the tablet was always less than 15% of 2.9%to 5.8% and 5.1% for each time of dissolution, when the degree of dissolution of the fine particles with a slow release was 30%, 50% and 80%, respectively, confirming that dissolution is not promoterwise at reception of tablets (figure 1 and 2). On the other hand, there was an accelerated rate of dissolution upon receipt of the tablets when compared with fine particles with a slow release in the comparative examples (Fig 3, the difference in values in two hours, or 15.9% and 12.8%). It is concluded that this is because in contrast to the fact that the presence of fine particles with a slow release on the surface of the tablet was not confirmed in example 1, fine particles with a slow release was observed on the surface of the tablet in comparative examples 1 and 2, and therefore, fine particles with a slow release was destroyed as a result of contact between the surface of the punch and fine particles with a slow release.

Therefore, it was confirmed that by the present invention, fine particles with a slow release carefully granularity with filler, and p is motherofone dissolution during the manufacture of the tablets can be excluded.

Example 2

Originally 2609 g mannitol (Towa Kasei Co., Ltd.) and 653 g of lactose (Domomilk) were crushed using a pin grinding device (Hosokawa Micron). This crushed product and 307 g soluble in the intestine of the fine particles with a slow release obtained in example 1 was granulated (spraying liquid volume 100 g/min, spraying air pressure of 1.5 kg/cm2the temperature of the product 28°C, the temperature at the inlet 80°With the cycle of spraying consisted of 20 seconds of spray - 30 seconds drying) with an aqueous 20 wt.% a solution containing 400 g of maltose (Hayashibara Co., Ltd, brand: Sunmalt S) in the granulator, fluidized bed (Freund Industries, FLO-5) to obtain the compositions of the present invention. After mixing 32 g of calcium stearate with the obtained composition was obtained 120 mg tablets containing 0.1 mg of tamsulosin hydrochloride in tablet tabletirujut a pressure of 100 kg/shock and the initial hardness of 1.0 kp using a rotary tabletiruemogo device. Then these tablets were stored for 18 hours under heating and humidifying at 25°C/75% relative humidity using a thermostatted chamber at constant humidity (Tabaiespec Co., Ltd., PR-35C). Then they were dried for 3 hours at 30°C and 40% relative humidity. The resulting tablets had a hardness of 5.2 kp (n=5), the fragility of 0.6% (100 rpm)and disintegration time in the buccal cavity 20 seconds (n=3). Moreover, the evaluation results of content uniformity gave CV%=2.2%, and confirming that the tablets have good uniformity of content. In addition, tests on dissolution for fine particles with a slow release and the obtained tablets was confirmed that the difference in dissolution rate between the fine particles with a slow release and a tablet was 4.7% in two hours after the start of the test for solubility using the fluid for testing, having a pH of 1.2, and even when using fluid for testing, having a pH of 6.8, the difference in dissolution rate between the fine particles with a slow release and the tablet was always less than 15% from 2.3%to 2.4% and 1.4% for each time of dissolution, when the degree of dissolution of the fine particles with a slow release was 30%, 50% and 80%, respectively, indicating that dissolution is not promoterwise during tableting.

Separately received tablets using the same compositions and the same manner as previously described. The resulting tablets had a hardness of 5.6 kp (n=5), the fragility of 0.6% (100 rpm) and disintegration time in the buccal cavity 25 seconds (n=3). In addition, the evaluation results of content uniformity showed a CV%=2,5%. As the above light is to be placed, the results of the tests of solubility revealed no differences between fine particles with a slow release and a tablet. Thus, by the present invention receive a composition including fine particles with a slow release, and therefore guaranteed the uniformity of content as a result prevent segregation between fine particles with a slow release and filler. In addition, it was confirmed that receive reproducible results.

Example 3

Three hundred grams of acetaminophen (Yoshiyomi Fine Chemicals Co., Ltd.) and 60 g of hydroxypropylmethylcellulose (TC5E, Shin-Etsu Chemical Co., Ltd.) was dissolved in a mixture of 720 g of methanol and 720 g of dichloromethane. Three hundred grams of Celphere 102 (trademark, Asahi Kasei, the average particle diameter of about 127 μm, a particle diameter of from about 50 to about 150 μm) were introduced in the granulator fluidized bed (Freund Industries, uni-glatt) and covered with a solution using the method of lateral spraying (spraying liquid volume 14 g/min, spraying air pressure of 3 kg/cm2the temperature of the product 32°C, the temperature at the inlet 45° (C) to obtain particles of acetaminophen. Separately, 48 g of ethyl cellulose (Nissin Chemistry Co.) and 12 g of hydroxypropylmethylcellulose (TC5E, Shin-Etsu Chemical Co., Ltd.) was dissolved in a mixture of 57 g of purified water and 1083 g of methanol. Three hundred gramme the particles of acetaminophen was introduced in the granulator, fluidized bed (Freund Industries, uni-glatt) and covered by this solution using the method of lateral spraying (spraying liquid volume of 8 g/min, spraying air pressure of 3 kg/cm2the temperature of the product 38°C, the temperature at the outlet 67° (C) to obtain fine particles with a slow release. Sixty-six grams of the data of the fine particles with a slow release and 314,25 g mannitol (Towa Kasei Co., Ltd.), which was crushed using a pin grinding device (Hosokawa Micron), granulated (spraying liquid volume 15 g/min, spraying air pressure of 1.1 kg/cm2the product temperature 30°C, the temperature at the inlet 38°With the cycle of spraying consisted of 30 seconds of spray - 30 seconds drying) with an aqueous 30 wt.% a solution containing 67,5 g maltose (Hayashibara Co., Ltd, brand: Sunmalt S) in the granulator, fluidized bed (Freund Industries, uni-glatt) to obtain the compositions of the present invention. The ratio in the form of fine particles with a slow release amounted to 0.0%. After additional mixing 2.25 g of magnesium stearate with the obtained composition was obtained 450 mg tablets containing 25 mg of acetaminophen per tablet, when tabletirujut pressure of 25 kg/shock and the initial hardness of 2.0 kp using a rotary tabletiruemogo device. Then these tablets were kept for 24 hours is in heat and moisture at 25° C/75% relative humidity using a thermostatted chamber at constant humidity (Tabaiespec Co., Ltd., PR-35C). Then they were dried for 3 hours at 30°C and 40% relative humidity. The resulting tablets showed a hardness of 3.5 kp (n=5) and disintegration time in the buccal cavity 12 seconds (n=1). Moreover, as a result of assessment uniformity the contents of CV%=1.2% of confirms that there is good uniformity of content. In addition, when comparing the dissolution of fine particles with a slow release tablets 2.8 hours after the start of dissolution tests (a time when there is about 30%dissolution of fine particles with a slow release), after 5 hours (the time when there is about 50%dissolution of fine particles with a slow release) and 9 hours (a time when there is about 80%dissolution of fine particles with a slow release) and calculated the difference, it was 4.9% after 2.8 hours, and 4.6% after 5 hours and 2.5% after 9 hours, confirming that the promotion of the dissolution of fine particles with a slow release is not permitted at any time.

Example 4

Six hundred grams of acetaminophen (Yoshiyomi Fine Chemicals Co., Ltd.) and 120 g of hydroxypropylmethylcellulose (TC5E, Shin-Etsu Chemical Co., Ltd.) was dissolved in a mixture of 1440 g of methane is a and 1440 g of dichloromethane. Three hundred grams of table salt (Shin Nihon Salt Co., Ltd., classification EF-70, average particle diameter of approximately 67 μm, a particle diameter of 75 μm or less) were introduced in the granulator fluidized bed (Freund Industries, uni-glatt) and covered by this solution using the method of lateral spraying (spraying liquid volume of 10 g/min, spraying air pressure of 3 kg/cm2the temperature of the product 33°C, the temperature at the inlet 55° (C) to obtain particles of acetaminophen.

Separately, 72 g of ethyl cellulose (Nissin Chemistry Co.) and 8 g of hydroxypropylmethylcellulose (TC5E, Shin-Etsu Chemical Co., Ltd.) was dissolved in a mixture of 76 g of purified water and 1444 g of methanol. Four hundred grams of the particles of acetaminophen was introduced in the granulator, fluidized bed (Freund Industries, uni-glatt) and covered by this solution using the method of lateral spraying (spraying liquid volume of 10 g/min, spraying air pressure of 3 kg/cm2the temperature of the product 39°C, water inlet temperature 70° (C) to obtain fine particles with a slow release.

Then of 76.5 g data fine particles with a slow release and 393,4 g mannitol (Towa Kasei Co., Ltd.), which was crushed using a pin grinding device (Hosokawa Micron), granulated (spraying liquid volume 15 g/min, spraying air pressure of 1.0 kg/cm2the temperature of the product 29°C, the temperature is at the entrance 35° With the cycle of spraying consisted of 20 seconds of spraying 40 seconds drying) with an aqueous 20 wt.% a solution containing 52,5 g maltose (Hayashibara Co., Ltd, brand: Sunmalt S) in the granulator, fluidized bed (Freund Industries, uni-glatt) to obtain the compositions of the present invention. The ratio in the form of fine particles with a slow release was 10.8%.

After additional mixing 2.6 g of magnesium stearate with the obtained composition was obtained 350 mg tablets containing 25 mg of acetaminophen per tablet, when tabletirujut pressure of 50 kg/shock and the initial hardness of 1.9 kp using a rotary tabletiruemogo device. Then these tablets was kept for 24 hours under heating and humidifying at 25°C/75% relative humidity using a thermostatted chamber at constant humidity (Tabaiespec Co., Ltd., PR-35C). Then they were dried for 3 hours at 30°C and 40% relative humidity. The resulting tablets showed a hardness of 4.8 kp (n=5), the fragility of 1.23% (100 rpm) and disintegration time in the buccal cavity 13 seconds (n=1). Moreover, the evaluation of content uniformity CV%=2.4% of confirms that there is good uniformity of content. In addition, when comparing the dissolution of fine particles with a slow release and tablets through 2.8 hours after the start of the tests for RA is the creation (time, when there is about 30%dissolution of fine particles with a slow release), after 5 hours (the time when there is about 50%dissolution of fine particles with a slow release) and after 9.5 hours (a time when there is about 80%dissolution of fine particles with a slow release) and calculated the difference, it was 5.5% after 2.8 hours, 3.5% after 5 hours and 3.1% after 9.5 hours, confirming that the promotion of the dissolution of fine particles with a slow release is not permitted at any time.

Example 5

Originally 1200 g of acetaminophen and 120 g of hydroxypropylmethylcellulose (TSAI, Shin-Etsu Chemical Co., Ltd.) was dissolved in a mixture 2640 g of methanol and 2640 g of dichloromethane. Three hundred grams of table salt (Shin Ninon Salt Co., Ltd., classification EF-70, average particle diameter of approximately 67 μm, a particle diameter of 75 μm or less) were introduced in the granulator fluidized bed (Freund Industries, uni-glatt) and covered by this solution using the method of lateral spraying (spraying liquid volume 16 g/min, spraying air pressure of 3 kg/cm2the product temperature 30°C, water inlet temperature 75° (C) to obtain particles of acetaminophen.

Separately to 45.9 g of ethyl cellulose (Nissin Chemistry Co.) and 5.1 g of hydroxypropylmethylcellulose (TC5E, Shin-Etsu Chemical Co., Ltd.) was dissolved in a mixture of 48.5 gocasino water and 920,5 g of methanol. Three hundred and forty grams of the particles of acetaminophen was introduced in the granulator, fluidized bed (Freund Industries, uni-glatt) and covered by this solution using the method of lateral spraying (spraying liquid volume of 8 g/min, spraying air pressure of 2.5 kg/cm2the temperature of the product 39°C, water inlet temperature 75° (C) to obtain fine particles with a slow release. Then 116,4 g data fine particles with a slow release and 542,7 g mannitol (Towa Kasei Co., Ltd.), which was crushed using a pin grinding device (Hosokawa Micron), granulated (spraying liquid volume 15 g/min, spraying air pressure of 1.1 kg/cm2the temperature of the product 28°S, inlet temperature 35°With the cycle of spraying consisted of 20 seconds of spray - 40 seconds drying) with an aqueous 30 wt.% a solution containing 117 g of maltose (Hayashibara Co., Ltd, brand: Sunmalt S) in the granulator, fluidized bed (Freund Industries, uni-glatt) to obtain the compositions of the present invention. The ratio in the form of fine particles with a slow release was 1.6%.

After additional mixing of 3.9 g of magnesium stearate with the obtained composition was obtained 520 mg tablets containing 50 mg of acetaminophen per tablet, when tabletirujut pressure of 200 kg/shock and the initial hardness of 1.9 kp the BL is reattaching the rotary tabletiruemogo device. Then these tablets was kept for 24 hours under heating and humidifying at 25°C/75% relative humidity using a thermostatted chamber at constant humidity (Tabaiespec Co., Ltd., PR-35C). Then they were dried for 3 hours at 30°C and 40% relative humidity. The resulting tablets showed a hardness of 6.4 kp (n=5), the fragility of 1.13% (100 rpm) and disintegration time in the buccal cavity, comprising 21 second (n=1). Moreover, the evaluation of content uniformity CV%=3.3% of confirms that there is good uniformity of content. In addition, when comparing the dissolution of fine particles with a slow release tablets 2.8 hours after the start of dissolution tests (a time when there is about 30%dissolution of fine particles with a slow release), after 5 hours (the time when there is about 50%dissolution of fine particles with a slow release) and after 9.5 hours (a time when there is about 80%dissolution of fine particles with a slow release) and calculated the difference, it was 8.8% after 2.8 hours, and 6.3% after 5 hours and 3.3% after 9 hours, confirming that the promotion of the dissolution of fine particles with a slow release is not permitted at any time.

Example 6

Forty-gra the MOU ethyl cellulose (Nissin Chemistry Co.) was dissolved in a mixture of 380 g of methanol and 380 g of dichloromethane. Four hundred grams of table salt (Shin Nihon Salt Co., Ltd., classification EF-70, average particle diameter of approximately 67 μm, a particle diameter of 75 μm or less) were introduced in the granulator fluidized bed (Freund Industries, uni-glatt) and covered by this solution using the method of lateral spraying (spraying liquid volume 6 g/min, spraying air pressure of 2 kg/cm2the temperature of the product 28°C, water inlet temperature 60° (C) to obtain the particle core. Then 1200 g of acetaminophen (Yoshiyomi Fine Chemicals Co., Ltd.) and 1200 g of hydroxypropylmethylcellulose (TC5E, Shin-Etsu Chemical Co., Ltd.) was dissolved in a mixture 2640 g of methanol and 2640 g of dichloromethane. Three hundred grams of the above core particles were introduced into the granulator fluidized bed (Freund Industries, uni-glatt) and covered by this solution using the method of lateral spraying (spraying liquid volume 15 g/min, spraying air pressure of 3 kg/cm2the product temperature 30°C, water inlet temperature 70° (C) to obtain particles of acetaminophen.

Separately to 47.2 g of ethyl cellulose (Nissin Chemistry Co.) and 5.3 g of hydroxypropylmethylcellulose (TC5E, Shin-Etsu Chemical Co., Ltd.) was dissolved in a mixture of 49.9 g of purified water and 947,6 g of methanol. Three hundred and fifty grams of the particles of acetaminophen was introduced in the granulator, fluidized bed (Freund Industries, uni-glatt) and covered by this solution using the method of the side spray (spray volume of the liquid 8 g/min, spray air pressure of 2.5 kg/cm2the temperature of the product 37°C, water inlet temperature 75° (C) to obtain fine particles with a slow release. Then 116,4 g data fine particles with a slow release and 542,7 g mannitol (Towa Kasei Co., Ltd.), which was crushed using a pin grinding device (Hosokawa Micron), granulated (spraying liquid volume 15 g/min, spraying air pressure of 1.1 kg/cm2the product temperature 30°C, the temperature at the inlet 40°With the cycle of spraying consisted of 20 seconds of spray - 40 seconds drying) with an aqueous 30 wt.% a solution containing 117 g of maltose (Hayashibara Co., Ltd, brand: Sunmalt S) in the granulator, fluidized bed (Freund Industries, uni-glatt) to obtain the compositions of the present invention. The ratio in the form of fine particles with a slow release 3.9%.

After additional mixing of 3.9 g of magnesium stearate with the obtained composition was obtained 520 mg tablets containing 50 mg of acetaminophen per tablet, when tabletirujut pressure of 140 kg/shock and the initial hardness of 2.6 kp using a rotary tabletiruemogo device. Then these tablets was kept for 24 hours under heating and humidifying at 25°C/75% relative humidity using a cooled camera is s at a constant humidity (Tabaiespec Co., Ltd., PR-35C). Then they were dried for 3 hours at 30°C and 40% relative humidity. The resulting tablets showed a hardness of 5.9 kp (n=5), the fragility of 1.64% (100 rpm) and disintegration time in the buccal cavity 26 seconds (n=l). Moreover, the evaluation of content uniformity CV%=2,0% confirms that there is good uniformity of content. In addition, when comparing the dissolution of fine particles with a slow release and tablets via 2.3 hours after the start of the dissolution tests (a time when there is about 30%dissolution of fine particles with a slow release), in 5.5 hours (a time when there is about 50%dissolution of fine particles with a slow release) and after 13.5 hours (a time when there is about 80%dissolution of fine particles with a slow release) and calculated the difference, it was 0.6% after 2.3 hours, and 1.2% after 5.5 hours and 3.2% after 13.5 hours, confirming that the promotion of the dissolution of fine particles with a slow release is not permitted at any time.

Example 7

Eighty grams of the hydrochloride tamsulosin and 80 g hydroxypropylmethylcellulose (TSAI, Shin-Etsu Chemical Co., Ltd.) was dissolved in a mixture of 304 g of purified water and 2736 g of methanol. Four thousand grams of Celphere 102 (trademark, Asahi Kasei, the medium is nd a particle diameter of approximately 127 microns, particle diameter from about 50 to about 150 μm) were introduced in the granulator fluidized bed (Freund Industries, FLO-5) and covered by this solution using the method of lateral spraying (spraying liquid volume 100 g/min, spraying air pressure of 4 kg/cm2the product temperature 40°C, the temperature at the inlet 80° (C) to obtain particles of tamsulosin hydrochloride.

Separately 43,7 g ethyl cellulose (Nissin Chemistry Co.) and 12.3 g hydroxypropylmethylcellulose (TC5E, Shin-Etsu Chemical Co., Ltd.) was dissolved in a mixture 43,9 g of purified water and 833,4 g of methanol. Four hundred grams of the particles of tamsulosin hydrochloride was injected into the granulator fluidized bed (Freund Industries, uni-glatt) and covered by this solution using the method of lateral spraying (spraying liquid volume 6 g/min, spraying air pressure of 4 kg/cm2the product temperature 40°C, the temperature at the inlet 63° (C) to obtain fine particles with a slow release.

Then 300 g data fine particles with a slow release was introduced in the granulator, fluidized bed (Freund Industries, uni-glatt) and covered with a mixture of 90 g of Aquacoat (trademark, Asahi Kasei), 180 g of Eudragit L30D55 (trademark), 30 g of Eudragit NE30D (trade mark,) and 300 g of purified water (spraying liquid volume 6 g/min, spraying air pressure in the Ghost 3 kg/cm 2the product temperature 40°C, inlet temperature of 75.5° (C) to obtain soluble in the intestine of the fine particles with a slow release. Then of 92.5 g data soluble in the intestine of the fine particles with a slow release, 568,2 g mannitol (Towa Kasei Co., Ltd.) and to 142.1 g of lactose (Domomilk), which were then ground using a pin grinding device (Hosokawa Co., Ltd.) and 72 g of Eretria (Nikken Chemicals Co., Ltd.) was granulated (spraying liquid volume 15 g/min, spraying air pressure of 0.5 kg/cm2the product temperature 40°C, water inlet temperature 70°With the cycle of spraying consisted of 15 seconds spray - 30 seconds drying) with aqueous 5 wt.% a solution containing 18 g of copolyvidone (BASF Co., trademark Kollidon VA64) in the granulator, fluidized bed (Freund Industries, uni-glatt) to obtain the compositions of the present invention. The ratio in the form of fine particles was 3.0%.

After additional mixing 7.2 g of calcium stearate with the obtained composition was 300 mg tablet contains 0.4 mg of tamsulosin hydrochloride in the tablet, when the initial hardness of 0.6 kp using a rotary tabletiruemogo device. Then these tablets were heated for 13 minutes at 120°using programmable microwave oven (model No.MOV112P, Sanyo Corporation), and then Oh what was Adali at room temperature for 30 minutes.

The resulting tablets showed a hardness of 6.8 kp (n=5), the fragility of 0.28% (100 rpm) and disintegration time in the buccal cavity 27 seconds (n=1). Moreover, the evaluation of content uniformity CV%=1.6% of confirms that there is good uniformity of content. In addition, when comparing the dissolution of fine particles with a slow release tablets within 1 hour after start of the dissolution tests (a time when there is about 30%dissolution of fine particles with a slow release), 2 hours (the time when there is about 50%dissolution of fine particles with a slow release) and after 6 hours (the time when there is about 80%dissolution of fine particles with a slow release) and calculated the difference, it was 1.1% after 1 hour, a 2.8% after 2 hours and 9.4% after 6 hours, confirming that the promotion of the dissolution of fine particles with a slow release is not permitted at any time.

Example 8

Originally 1200 g of the hydrochloride of nicardipine and 1200 g of hydroxypropylmethylcellulose (TSAI, Shin-Etsu Chemical Co., Ltd.) was dissolved in a mixture of 4800 g of methanol and 4800 g dichloromethane. Three hundred grams of silicon dioxide (Silica gel, Sigma, average particle diameter of approximately 48 μm, a particle diameter of about 75 μm or less) was introduced granulator fluidized bed (Freund Industries, uni-glatt) and covered with a solution using the method of lateral spraying (spraying liquid volume 18 g/min, spraying air pressure of 3 kg/cm2the product temperature 30°C, water inlet temperature 70°C) to obtain particles of the hydrochloride of nicardipine.

Separately, 54 g of ethyl cellulose (Nissin Chemistry Co.) and 6 g of hydroxypropylmethylcellulose (TSAI, Shin-Etsu Chemical Co., Ltd.) was dissolved in a mixture of 57 g of purified water and 1083 g of methanol. Three hundred grams of the particles of the hydrochloride of nicardipine was introduced in the granulator, fluidized bed (Freund Industries, uni-glatt) and covered by this solution using the method of lateral spraying (spraying liquid volume of 8 g/min, spraying air pressure of 2.5 kg/cm2the product temperature 39°C, water inlet temperature 70° (C) to obtain fine particles with a slow release.

Sixty grams of the data of the fine particles with a slow release, 254,4 g mannitol (Towa Kasei Co., Ltd.) and 63.6 g of lactose (Domomilk), which were then ground using a pin grinding device (Hosokawa Micron), and 12 g of Eretria (Nikken Chemicals Co., Ltd.) was granulated (spraying liquid volume 15 g/min, spraying air pressure of 0.5 kg/cm2the temperature of the product 39°C, water inlet temperature 50°With the cycle of spraying consisted of 5 seconds spray - 15 seconds drying) with aqueous 5 wt.% a solution containing 8 g of copolyvidone (BSF Co., trademark Kollidon VA64) in the granulator, fluidized bed (Freund Industries, uni-glatt) to obtain the compositions of the present invention. The ratio in the form of fine particles was 7.9%.

After additional mixing 2 g of magnesium stearate with the obtained composition was obtained 400 mg tablets containing 20 mg of the hydrochloride of nicardipine a tablet, when the initial hardness of 0.6 kp using a rotary tabletiruemogo device. Then these tablets were heated for 10 minutes at 130°using programmable microwave oven (model No.MOV-112P, Sanyo Corporation). Then they were cooled at room temperature for 30 minutes. The resulting tablets showed a hardness of 3.7 kp (n=5), the fragility of 0.1% (100 rpm) and disintegration time in the buccal cavity 20 seconds (n=1). Moreover, the evaluation of content uniformity CV%=1.1% of confirms that there is good uniformity of content. In addition, when comparing the dissolution of fine particles with a slow release tablets after 0.5 hours after the start of dissolution tests (a time when there is about 30%dissolution of fine particles with a slow release), 2 hours (the time when there is about 50%dissolution of fine particles with a slow release) and after 5.5 hours (the time, when there is about 80%dissolution of fine particles with a slow release) and calculated the difference, it was 10.3% after 0.5 hour, to 12.8% in 2 hours and 6.6% after 5.5 hours, confirming that the promotion of the dissolution of fine particles with a slow release is not permitted at any time.

Example 9

Eighty grams of the hydrochloride tamsulosin and 80 g hydroxypropylmethylcellulose (TC5E, Shin-Etsu Chemical Co., Ltd.) was dissolved in a mixture of 304 g of purified water and 2736 g of methanol. Four thousand grams of Celphere 102 (trademark, Asahi Kasei, the average particle diameter of about 127 μm, a particle diameter of from about 50 to about 150 μm) were introduced in the granulator fluidized bed (Freund Industries, FLO-5) and covered by this solution using the method of lateral spraying (spraying liquid volume 100 g/min, spraying air pressure of 4 kg/cm2the product temperature 40°C, the temperature at the inlet 80° (C) to obtain particles of tamsulosin hydrochloride.

Separately 561,6 g ethyl cellulose (Nissin Chemistry Co.) and of 158.4 g hydroxypropylmethylcellulose (TC5E, Shin-Etsu Chemical Co., Ltd.) was dissolved in a mixture of 564 g of purified water and 10716 g of methanol. Four thousand grams of the particles of tamsulosin hydrochloride was injected into the granulator fluidized bed (Freund Industries, FLO-5) and covered by this solution using the method side is asplenia (spraying liquid volume 40 g/min, spray air pressure of 4 kg/cm2the product temperature 40°C, the temperature at the inlet 54° (C) to obtain fine particles with a slow release.

Then 4000 g data fine particles with a slow release was introduced in the granulator, fluidized bed (Freund Industries, FLO-5) and covered with a mixture of 800 g of Aquacoat (trademark, Asahi Kasei), 1600 g of Eudragit L30D55 (trademark), USD 266.7 g of Eudragit NE30D (trade mark,) and 5333 g of purified water (spraying liquid volume 60 g/min, spraying air pressure of 4.5 kg/cm2the temperature of the product 50°C, the temperature at the inlet 84° (C) to obtain soluble in the intestine of the fine particles with a slow release.

Then 392,7 g data soluble in the intestine of the fine particles with a slow release, 2540,2 [g] mannitol (Towa Kasei Co., Ltd.) and 635,1 g of lactose (Domomilk), which were then ground using a pin grinding device (Hosokawa Co., Ltd)was granulated (spraying liquid volume 100 g/min, spraying air pressure of 1.5 kg/cm2the temperature of the product 33°C, the temperature at the inlet 48°With the cycle of spraying consisted of 20 seconds of spray - 30 seconds drying) with an aqueous 20 wt.% a solution containing 400 g of maltose (Hayashibara Co., Ltd., brand: Sunmalt S) in the granulator with pseudoo is defined layer (Freund Industries, FLO-5) to obtain the compositions of the present invention. The ratio in the form of fine particles was 1.1%.

After additional mixing 32 g of calcium stearate with the obtained composition was 300 mg tablet contains 0.4 mg of tamsulosin hydrochloride in the tablet, when the initial hardness of 2.1 kp using a rotary tabletiruemogo device. Then these tablets was kept for 24 hours under heating and humidifying at 25°C/75% relative humidity using a thermostatted chamber at constant humidity (Tabaiespec Co., Ltd., PR-35C). Then they were dried for 3 hours at 30°C and 40% relative humidity.

The resulting tablets showed a hardness of 4.1 kp (n=5), the fragility of 1,67% (100 rpm) and disintegration time in the buccal cavity 20 seconds (n=1). Moreover, the evaluation of content uniformity CV%=1.6% of confirms that there is good uniformity of content. In addition, when comparing the dissolution of fine particles with a slow release tablets 2 hours after start of the dissolution tests (a time when there is about 30%dissolution of fine particles with a slow release), 4 hours (time when there is about 50%dissolution of fine particles with a slow release) and after 8 hours the (time, when there is about 80%dissolution of fine particles with a slow release) and calculated the difference, it was 7.5% after 2 hours, to 6.4% after 4 hours and 1.5% after 8 hours, confirming that the promotion of the dissolution of fine particles with a slow release is not permitted at any time.

Industrial applicability

The present invention relates to compositions comprising fine particles with a slow release to ensure that the sight is a contradictory functions that tablets have a slow release, even though they quickly decompose and dissolve in the buccal cavity. In addition, the present invention differs in that it gives you the ability to inhibit the promotion of dissolution of the medicinal product after receiving the tablets, which was a result of the destruction of the fine particles with a slow release when tabletirujut the pressure at which receive the pills and implement controlled dissolution, which is the designed purpose of the preparation of the fine particles with a slow release, with good reproducibility, even after receiving tablets. Therefore, it is easier to develop a pharmaceutical preparation of the fine particles with a slow high what opozdaniem, and additionally there exists a distinctive feature to make it possible to guarantee good content uniformity of the drug. In addition, it is possible to create a composition including fine particles with a slow release, which will have a profound impact on the range bystrorazvivajushchihsja in the buccal cavity of tablets being received bystrorazvivajushchihsja in the buccal cavity of tablets containing fine particles with a slow release, in the form of the product, particularly at the stage of industrial production and, additionally, at the stage of quality assurance.

1. The composition including fine particles with a slow release for bystrorazvivajushchihsja in the buccal cavity of tablets, characterized in that it comprises the product of the granulation of fine particles with a slow release containing the drug, and one, or two, or more fillers selected from the group consisting of sugars and sugar alcohols, together with the binder for bystrorazvivajushchihsja in the buccal cavity of tablets, and the fact that the ratio in the form of fine particles with a slow release throughout the composition is from 0 to 15%.

2. The composition including fine particles with a slow release for bystrorazvivajushchihsja in the buccal cavity of tablets according to claim 1, where the binder for bystrorazvivajushchihsja in the buccal cavity of tablets is one or two or more substances selected from the group consisting of saccharides with high plasticity, water-soluble polymeric compounds and saccharides with a low melting point.

3. The composition including fine particles with a slow release for bystrorazvivajushchihsja in the buccal cavity of tablets according to claim 2, where the sugar or sugar alcohol is one or two or more substances selected from the group consisting of saccharides with low plasticity, saccharides with a high melting point and saccharides with a low melting point.

4. The composition including fine particles with a slow release for bystrorazvivajushchihsja in the buccal cavity of tablets according to claim 3, where the ratio of the fine particles with a slow release, filler and binders for bystrorazvivajushchihsja in the buccal cavity of the tablets ranges from 1 to 50%, from 20 to 98% and from 1 to 30%, respectively.

5. The composition including fine particles with a slow release for bystrorazvivajushchihsja in cheek oral tablets according to claim 4, where the average particle diameter bystrorazvivajushchihsja fine particles is from approximately 0.1 to approximately 350 microns.

<> 6. The composition including fine particles with a slow release for bystrorazvivajushchihsja in the buccal cavity of tablets according to claim 5, where fine particles with a slow release consist of at least particles of crystalline cellulose, drug substance and polymeric substance.

7. The composition including fine particles with a slow release for bystrorazvivajushchihsja in the buccal cavity of tablets according to claim 6, where the drug is tamsulosin hydrochloride.

8. The composition including fine particles with a slow release for bystrorazvivajushchihsja in the buccal cavity of tablets according to claim 7, where fine particles with a slow release are soluble in the intestine fine particles with a slow release.

9. The composition including fine particles with a slow release for bystrorazvivajushchihsja in the buccal cavity of the tablet of claim 8, where the polymeric substance is a hypromellose, ethylcellulose, Eudragit L30D55 and Eudragit NE30D.

10. The composition including fine particles with a slow release for bystrorazvivajushchihsja in the buccal cavity of tablets according to claim 9, where the binder for bystrorazvivajushchihsja in the buccal cavity of tablets is is th one, or two or more substances selected from the group consisting of maltose, trehalose, sorbitol and maldita.

11. Bystrorazvivajushchiesja in the buccal cavity of a tablet consisting of a composition comprising fine particles with a slow release of claim 10.

12. Bystrorazvivajushchiesja in the buccal cavity pills to claim 11, characterized in that the coefficient of variation (CV%) number of drugs, which is a measure of the uniformity of the content is 3.5% or less.

13. A method of obtaining a composition comprising fine particles with a slow release for bystrorazvivajushchihsja in the buccal cavity of tablets, characterized in that it comprises the product of the granulation of fine particles with a slow release containing the drug, and one, or two or more fillers selected from the group consisting of sugars or sugar alcohols, together with the binder for bystrorazvivajushchihsja in the buccal cavity of tablets, and the fact that the ratio in the form of fine particles with a slow release throughout the composition is from 0 to 15%.

14. A method of obtaining a composition comprising fine particles with a slow release for bystrorazvivajushchihsja in the buccal cavity of tablets indicated in paragraph 13, where the binder for quick is decaying in the buccal cavity of tablets is one, or two or more substances selected from the group consisting of saccharides with high plasticity, water-soluble polymeric compounds and saccharides with a low melting point.

15. A method of obtaining a composition comprising fine particles with a slow release for bystrorazvivajushchihsja in the buccal cavity of tablets 14, where the sugar or sugar alcohol is one or two or more substances selected from the group consisting of saccharides with low plasticity, saccharides with a high melting point and saccharides with a low melting point.

16. A method of obtaining a composition comprising fine particles with a slow release for bystrorazvivajushchihsja in the buccal cavity of tablets indicated in paragraph 15, where the ratio of the fine particles with a slow release, filler and binders for bystrorazvivajushchihsja in the buccal cavity of the tablets ranges from 1 to 50%, from 20 to 98% and from 1 to 30%, respectively.

17. A method of obtaining a composition comprising fine particles with a slow release for bystrorazvivajushchihsja in the buccal cavity of tablets of clause 16, where the average particle diameter bystrorazvivajushchihsja fine particles is from approximately 0.1 to approximately 350 microns.

18. The method of obtaining the composition, vklyuchayuschimisya particles with a slow release for bystrorazvivajushchihsja in the buccal cavity of tablets of 17, where fine particles with a slow release consist of at least particles of crystalline cellulose, drugs and polymeric substances.

19. A method of obtaining a composition comprising fine particles with a slow release for bystrorazvivajushchihsja in the buccal cavity tablets p, where the drug is tamsulosin hydrochloride.

20. A method of obtaining a composition comprising fine particles with a slow release for bystrorazvivajushchihsja in the buccal cavity of the tablets of claim 19, where fine particles with a slow release are soluble in the intestine fine particles with a slow release.

21. A method of obtaining a composition comprising fine particles with a slow release for bystrorazvivajushchihsja in the buccal cavity of the tablets of claim 20, where the polymeric substance is a hypromellose, ethylcellulose, Eudragit L30D55 and Eudragit NE30D.

22. A method of obtaining a composition comprising fine particles with a slow release for bystrorazvivajushchihsja in the buccal cavity of tablets of item 21, where the binder for bystrorazvivajushchihsja in the buccal cavity of tablets is one or two or more substances selected from the group SOS is oasa from maltose, trehalose, sorbitol and maldita.

23. The method of obtaining bystrorazvivajushchihsja in the buccal cavity of tablets, consisting of a composition comprising fine particles with a slow release, p.22.

24. The method of obtaining bystrorazvivajushchihsja in the buccal cavity of tablets of item 23, wherein the coefficient of variation (CV%) number of drugs, which is a measure of the uniformity of the content is 3.5% or less.



 

Same patents:

The invention relates to the field of pharmaceutical industry, namely pharmaceutical compositions for the manufacture of tablets and prolonged action, in particular tablets for sublingual application, and to methods of producing such compositions

The invention relates to a solid molded dosage form for controlled release of nimesulide for oral administration

The invention relates to medicine, in particular to pharmaceutical preparations containing peptides

The invention relates to solid pharmaceutical preparative forms with controlled release based on sulfoalkyl ether cyclodextrin (SAE-CD)

The invention relates to the field of pharmaceutical chemistry and relates to a composition extended release, containing a physiologically active substance or its salt, oximately acid or its salt and a biodegradable polymer or its salt with improved bioavailability

The invention relates to the field of pharmaceutical industry and relates antihyperlipidemic and antihyperlipidemics funds

The invention relates to the field of pharmaceutics

The invention relates to pharmaceutical compositions cefuroxime aksetila in the form of particles

The invention relates to the field of pharmaceutical industry and relates to dosage forms with anti-TB activity

The invention relates to peptide compositions with delayed release, representing a compound (I) containing the compound (A) formula

and the polymer containing lactide links, glycolide links and links tartaric acids - which are found in the polymer at the next sootnoshenii: lactide units constitute from about 71% to about 73%, glycolide links from about 26% to about 28%; and the parts of tartaric acid from about 1% to 3%, and the amino group of the compound (a) relate ionic bond with the carboxyl groups of the acid units of the polymer; the particles of compound I, an average size of from about 10 microns to about 100 microns; pharmaceutical composition with delayed release and two methods of treatment of various diseases, including the introduction to the patient an effective amount of compound A, or microparticles

The invention relates to the field of medical genetics

FIELD: medicine, in particular composition for quick-disposable in buccal cavern tablets.

SUBSTANCE: claimed composition contains granulated product of fine dispersed long releasing particles, comprising drug and fillers selected from group including sugars and sugar alcohols together with binder, wherein content of non-granulated fine dispersed long releasing particles is 0-15 %. Method for production of such tablets is also disclosed.

EFFECT: pharmaceutical composition with accelerated degradation.

24 cl, 9 ex, 3 dwg

Up!