Bystrorazvarivayuschayasya dosage form that does not contain gelatin

 

(57) Abstract:

The invention relates to bistrotdepierrerue solid dosage form that dissolves in the mouth within sixty (60), more preferably thirty (30), most preferably ten (10) seconds. New sign of a solid dosage form in accordance with the invention is based on the fact that the composition essentially contains or does not contain gelatin derived from mammals. It is established that the use of certain modified starches in a concentration of from 20 to 90% of the mass. by weight of the solid dosage form provides dosage forms, which are mechanically and chemically stable and able to tolerate higher concentrations of active ingredient than bystrotverdeyuschie solid dosage forms based on gelatin. In addition, the solid dosage forms in accordance with the invention is obtained by removing the solvent, such as water, from a mixture containing the active ingredient, modified starch and forming a matrix agent, by freeze-drying. 8 C.p. f-crystals, 2 PL.

The technical field

The invention relates to farmacevticheskaya form essentially does not contain gelatin mammals and contains, at least one agent, forming a matrix (base) and modified with lactose starch.

Background of invention

The most common pharmaceutical dosage forms are tablets. The main disadvantage of tablets is poor compliance by patients regimens medication because of difficulty swallowing tablets and poor bioavailability of the active ingredient due to inefficient dissolving tablets. Therefore, in the medical community there is a need for quick-dissolving dosage forms. To overcome the shortcomings of tablets has been used a number of techniques, including the creation of effervescent tablets, razzhevyvaya tablets, the use of dispersing agents and agents that increase the absorbency.

Recently, using instant matrices on the basis of gelatin were prepared bystrotverdeyuschie dosage forms which release the active ingredient in the oral cavity. These dosage forms are well known and can be used to deliver a wide range of medicines. In most bystrotverdeyushchie dosage forms use gelatin as wear the governmental form, in order to prevent the destruction when removing from the packaging, but when hit in the mouth gelatin provides an immediate dissolution of the dosage form.

Gelatin BP (British Pharmacopoeia), which is normally used in such preparations, defined as the protein, obtained by partial hydrolysis of animal collagen tissues, such as skin, tendons, ligaments and bones. However, obtained from mammalian gelatin has a weak taste and, therefore, requires the use of such bystrotverdeyushchie dosage forms sweetening agents and flavoring substances to hide the taste of the active ingredient. When an ordinary animal gelatin is used upon receipt of such bystrotverdeyushchie dosage forms, it is necessary to heat the solution of gelatin in order to facilitate dissolution. This is the stage of heating increases the duration of the technological process and incurs costs on heating, thus increasing the total cost of the process.

Traditional manufacturing processes may require time keeping up to 48 hours. It is established that during this time the viscosity of the mixture on the basis of gelatin may increase, leading to technological enjoy the water, which can lead to shrinkage of the dosage form during normal storage period.

Another known issue with the quick-dissolving dosage forms on the basis of gelatin, is the lack of homogeneity and sedimentation liquid mixture during curing, as some mixtures include the active substance in the form of suspended particles. The use of gelatin derived from mammals, leads to the deposition of the active ingredient due to the low viscosity of gelatin derived from mammals. One of the advantages of the present invention is that by using the described modified starches largely overcome the problems of homogeneity and sedimentation associated with the use of gelatin derived from mammals.

Another advantage associated with the use of modified starches in recipes quick-dissolving dosage forms, based on the discovery that the dosage form with modified starch can contain a higher drug load. This is advantageous because for a given dose of the active ingredient dosage form with modified starch most other materials instead of gelatin in bystrotverdeyushchie dosage forms, but, although they can form solid products (reduced tendency to cracking and crushing), they usually slowly dispersed or form in the mouth sticky mass. It is now established that for the preparation of bystrotverdeyushchie dosage forms instead of gelatin mammals can be used modified starches.

Thus, the present invention provides a pharmaceutical composition for oral administration in the form of bistrotdepierrerue dosage form for fast release of the active ingredient in the oral cavity, characterized in that essentially does not contain gelatin composition comprises a modified starch and at least one agent, forming a matrix.

The invention creates the possibility of reducing or preferably exception of gelatin bystrotverdeyushchie dosage forms (BDLP). Modified starches can be used in BDLF as the main structure-forming agent with the formation of physically durable products, while maintaining the desirable characteristics of rapid dispersion products. With proper selection of the modified starch can p the time improved stability and physical strength of the dosage form. The modified starch can reduce or eliminate the content of sweetening agents, flavoring substances, which were previously used to improve the taste of the dosage form. The use of the material of Botanical origin instead of animal material also gives a positive effect by eliminating exposure to such agents as BSE.

Starch can be considered as the product of the condensation polymer of glucose. Such glucose components are present in the form anhydroglucose residues (AHP). If the processed starch or acids, or certain enzymes, it can be completely destroyed due to the hydrolysis of glycosidic linkages to its components glucose levels. Most of the starch consists of two types of glucose polymers, each of which has a wide size range of molecules:

(i) a molecule with a linear chain, called aminosol, which can contain up to 6000 units of glucose linked 1-4 bonds, and

(ii) a highly branched polymer called amylopectin, consisting of short chains (from 10 to 60 glucose units), the United -1 is -6 and the secondary hydroxyl group on carbon-2 and carbon-3. Such molecules have many hydroxyl groups, which give starch hydrophilic properties and lead to dispersive ability of the pigment starch when heated with water. However, these hydroxyl groups also have a tendency to be attracted to each other, forming hydrogen bonds between adjacent molecules of starch and preventing dissolution in cold water.

Natural starch can be modified by physical, chemical or enzymatic treatment to modify its properties or giving it new properties. The properties of these modified starches include the ratio of the solid components, the viscosity characteristics of gelatinization and cooking, resistance fall of viscosity under the action of acid, heat and/or mechanical shear, ionic and hydrophilic character.

A number of modified starches is commercially available and useful in the present invention, and includes:

Pre gelatinisation starches obtained by drying in the dryer or by extrusion:

Low viscosity starches obtained by controlled hydrolysis of glycosidic linkages;

Dextrins obtained by calcination of the dry starch in the presence of HB diluted acid to achieve the desired viscosity;

Oxidized starches, when oxidizing agents cause the introduction of carbonyl and carboxyl groups with depolymerization, leading to a reduced ability to conversion and gelatinization;

Enzyme modified starches, obtained by controlled enzymatic degradation to achieve the required physico-chemical properties;

Cross-linked starches, when bi - or polyfunctional reagents react with hydroxyl groups for cross-linking; examples of specific reagents are phosphorus oxychloride, trimetaphosphate sodium and epichlorohydrin; and

Stabilized starches, when the starch reacts with the agents simple or complex esterification in the presence of an alkaline catalyst with the formation of a wide range of products.

The level of technology

In U.S. patent No. 5120549 described bystrorazvarivayuschayasya dosage form, which is obtained by primary curing forming a matrix system, dispersed in the first solvent, and subsequent contact utverzhdenii matrix with a second solvent, which essentially can be mixed with the first solvent at a temperature of, the t is essentially insoluble in the second solvent, in the result, the first solvent is essentially removed, giving bistrotdepierrerue dosage form.

In U.S. patent No. 5079018 described bystrorazvarivayuschayasya dosage form containing a porous skeletal structure, are soluble in water, capable of hydration of the gel or foam material, which had been gidratirovana water, steel hard in the hydrated state using the amplifier stiffness and digidrirovanny liquid organic solvent at a temperature of approximately 0°C or below to leave a space instead of hydrating fluid.

In published international application no WO 93/12769 (PCT/JP 93/01631) described bistrotdepierrerue dosage form very low density, obtained by gelatinization with agar, water systems comprising forming the matrix elements and the active ingredient, and then removing the water by air under pressure or vacuum drying.

In U.S. patent No. 5298261 disclosed bystrorazvarivayuschayasya dosage form containing partially “explosion” matrix structure, which was subjected to vacuum drying at a temperature above the temperature of the collapse of the matrix. However, preferably the matrix, likovna international application no WO 91/04757 (PCT/US 90/05206) reveals bystrotverdeyuschie dosage forms, which contain effervescent dispersing agent prepared in such a way that it foams on contact with saliva, providing a fast dispersing dosage forms and the formation of a dispersion of the active ingredient in the oral cavity.

In U.S. patent No. 5595761 for use in the manufacture of quick-dissolving tablets offered support matrix in the form of particles containing:

the first polypeptide component having a full charge when it is in solution, for example, non-hydrolyzed gelatin;

the second polypeptide component having full charge of the same sign as the charge of the first polypeptide component when it is in solution, for example, gelatin hydrolysate; and

filler, and where the first polypeptide component and the second polypeptide component together comprise from about 2 to 20 wt%. support matrix in the form of particles and where the filler is from about 60 to 96% of the mass. support matrix in the form of particles; and

where the second polypeptide component has a solubility in aqueous solution greater than the solubility of the first polypeptide component, and where the mass (mass OTOs:1 to 1:14; and

where, when the supporting matrix is introduced into the aquatic environment supporting matrix disintegrates within less than 20 seconds.

In the publication EP-B-0690747 described particles containing the filler, forming a matrix, and at least one active ingredient uniformly distributed in the mass matrix, which is obtained by a process comprising a stage of a homogeneous pasty mixture with a viscosity below 1 PA·sec, measured at room temperature (15-20°C), of at least one active ingredient, a physiologically acceptable hydrophilic filler and water, extruding the obtained homogeneous mixture and cutting the extrudate with getting wet particles; freezing obtained particles as they are sinking under the action of gravity through a stream of inert gas at a temperature below 0°C; and drying the particles by freezing.

Australian patent # 666666 describes a pill from a variety of particles containing a mixture of fillers, in which the active substance is present in the form of microcrystals coated or optional microgranules coated. These tablets disintegrate in the mouth for only a short time, usually less than 60 is artesania and the introduction of the active material, which can quickly dissolve with saliva and which is obtained by freezing a solution of liquid ammonia containing liquid ammonia, soluble in liquid ammonia gel or foam material and amplifier the stiffness of the gel or foam material selected from the group comprising a monosaccharide, polysaccharide, or a combination thereof, and diamondale obtained in this way frozen material due to the fact that the material is forced to transfer ammonia from the frozen state in the gas leaving through the gaps in the raw material instead of frozen ammonia.

Published international application No. WO 93/13758 (PCT/US 92/07497) describes pills with high physical strength, which is obtained by mixing and compaction able to melt binders, fillers and pharmaceutically active agent in the tablet, the melting of the binder in the tablet, followed by curing of the binder. In one embodiment of the invention uses a dispersing agent to improve the speed dispersion tablets after oral administration. In another embodiment uses a volatile component with a porous tablets. Some versions of the image is dispergirujutsja porous tablets and a way to increase their physical strength by first pressing of tablets, and then evaporation of the volatile solid adjuvant, put into a pill to achieve the desired porosity.

Published international application No. WO 94/14422 describes a method of drying the frozen discrete elements, in which the solvent is removed under conditions where the solvent is evaporated from the solids through the liquid phase to the gas, and not by sublimation from solid to gas as by freeze-drying. This is achieved by vacuum drying at a temperature below the point of complete freezing of the composition in which the solvent (such as water) changes the phase.

Publication EP-0693281 (Lilly S. A.) relates to pharmaceutical preparations of fluoxetine or its acid additive salts, which are placed in dispersible tablets by direct compression. This link actually opens the sodium salt glycolate starch as a dispersing agent. Sodium salt of glycolate starch is used in this work in excess of 5 wt. -%, preferably in concentrations of between 9.5 and 17% of the mass. This link is in fact not disclosed bystrorazvarivayuschayasya solid dosage form that contains at least 20 wt. -%, at least real and, containing the active ingredient, modified starch and forming a matrix agent.

Publication EP-0599767 relates to a method for producing dispersible tablets of Diclofenac. The method is compressing the mixture containing granules comprising hydrophilic lubricating substance and disintegrity agent, the active ingredient and other excipients. Fillers are microcrystalline cellulose, corn starch and lactose. The examples also indicate the use of carboxymethyl amylum. This reference is not intended and does not disclose bistrotdepierrerue dosage form, which contains at least one active ingredient, at least one modified starch in a concentration of from 20 to 90% of the mass. based on the solid dosage form and at least one forming a matrix agent. Furthermore, the method described in this reference differs from the method of producing solid dosage forms of the present invention, where the solvent is removed from the mixture by freeze-drying.

Publication EP-0159631 (National Starch & Chemical Corporation) refers to the compression of the starches as binders for tablets or capsules. In this reference discloses the in operations tabletting, especially in case of direct extrusion, and are likely useful as binders, diluents, etc. during the filling of the capsules. This link is actually not expected or does not disclose the use of such modified starches in bystrotverdeyushchie solid dosage forms, which can be obtained by removing the solvent from mixtures containing the active ingredient, modified starch and forming a matrix agent.

Publication GB-2172006 relates to fillers for use in direct compression of tablets. This reference discloses the fillers, which is obtained by dispersing cellulose powder and powder hydroxypropylmethyl in aqueous solution and subsequent spray drying of the dispersion. This drug is described as useful for direct compression of tablets. If this is not offered or is not described bystrorazvarivayuschayasya solid dosage form that contains at least one modified starch concentrations from 20 to 90% of the mass. based on dosage form, and where the dosage form obtained by removing the solvent from the mixture containing the active ingredient, modified starch and forming a matrix agent.

Abstract in Chemical Abstracts under the title “Preparation of Emulsifying Agents for Pharmaceuticals, Cosmetics and Foods, Vol.110, No. 10, Abstract No. 82495, discloses modified starches as emulsifying agent in pharmaceutical preparations. In this work does not imply or not disclosed bystrorazvarivayuschayasya solid dosage form that contains at least one modified starch in a concentration of from 20 to 90% of the mass. race is, containing the active ingredient, modified starch and forming a matrix agent.

The invention

In the invention disclosed bystrorazvarivayuschayasya solid dosage form, designed for rapid release of the active ingredient in the oral cavity, characterized in that the solid dosage form essentially does not contain gelatin mammals and contains:

at least one active ingredient;

at least one modified starch in a concentration of from 20 to 90% of the mass. based on the specified solid dosage form; and

at least one forming a matrix agent,

where this solid dosage form obtained by removing solvent from a mixture containing specified active ingredient that is listed on modified starch and the specified forming a matrix agent.

In one variant of the invention, the solid dosage form contains at least one modified starch selected from the group comprising starches, hydroxyl groups are esterified, hydroxypropyl-dichromatic, enzyme modified starch, etc is purified starch.

In a preferred variant of the invention, the solid dosage form in accordance with the present invention contains from 50 to 90% of the mass. modified starch.

Although many specific examples of useful modified starches, their General characteristics in bistrotdepierrerue solid dosage form of the present invention is that they are readily soluble or dispersible in water at ordinary temperature. Another positive effect that is associated with modified starches useful in the present invention is that the mixture of the active ingredient, modified starch and forming a matrix agent is actually a constant viscosity within about 24 hours. The preferred solvent in accordance with the present invention is water. The preferred form the matrix agent is mannitol.

Bystrotverdeyuschie solid dosage forms in accordance with the present invention can also contain coloring agents, agents for improving taste and smell (corrigentov), fillers, a variety of therapeutic agents, etc. In one of the embodiments izobretennoe description of the invention

Used in the description and in the claims, the definition of “bystrorazvarivayuschayasya dosage form (BDLF)” refers to compositions which, when hit in the mouth dissolve/disperse in the range from 1 to 60 seconds, preferably from 1 to 30 seconds, more preferably from 1 to 10 seconds, and in particular from 2 to 8 seconds. Dosage form of the present invention is similar to the dosage form described in British patent No. 1548022, i.e. solid bistrotdepierrerue dosage form containing the mesh structure of the active ingredient and the water-soluble or dispersible in water media, which is inert towards the active ingredient, and a mesh structure obtained by sublimation of the solvent from the composition in the solid state, and this composition contains an active ingredient and a solution of the carrier in the solvent. The difference is that as the carrier modified starch is used instead of the usual gelatin derived from mammals.

Bystrorazvarivayuschayasya dosage form in accordance with the present invention may also contain, besides the active ingredient and the modified starch of the present invention, include materials derived from animal or vegetable proteins, such as gelatin, derived from mammals, dextrins and proteins of soybean seeds, wheat and psyllium; gums, such as Arabian gum, diatomaceous earth, agar and xanthan gum; polysaccharides; alginates; carboxymethylcellulose; carragenan; dextrans; pectins; synthetic polymers such as polyvinylpyrrolidone; and polypeptide/protein or polysaccharide complexes such as complexes of gelatin-Arabian gum.

Form the matrix agents suitable for use in the present invention include sugars such as mannitol, dextrose, lactose, galactose and trehalose; cyclic sugars such as cyclodextrin; inorganic salts such as sodium phosphate, sodium chloride and aluminum silicates; and amino acids, containing from 2 to 12 carbon atoms such as glycine, L-alanine, L-aspartic acid, L-glutamic acid, L-hydroxy-Proline, L-isoleucine, L-leucine and L-phenylalanine.

One or more forming the matrix agents may be introduced into the solution or suspension prior to curing. Forming a matrix agent may be present in addition to a surfactant or instead of the surface-active substances are the main ingredient within the solution, suspension or mixture. This is particularly useful in the case of active ingredients which are slightly soluble in water, and therefore should be suspended, not dissolved.

Secondary components such as preservatives, antioxidants, surfactants, agents that increase the viscosity, coloring agents, corrigentov, pH modifying agents, sweetening agents, or agents, taste masking can also be introduced into the composition. Suitable coloring agents are red, black and yellow iron oxides, dyes, FD & C, such as FD & C Blue No. 2 and FD & C Red No. 40. Suitable flavouring flavouring substances are mint, raspberry, licorice, orange, lemon, grapefruit, caramel, vanillic, cherry and grape flavouring flavouring additive, and combinations thereof. Suitable pH modifiers are citric acid, tartaric acid, phosphoric acid, hydrochloric acid, maleic acid and sodium hydroxide. Suitable sweetening agents include aspartame, Acesulfame K and thaumatin. Suitable taste masking agents are sodium bicarbonate, ion exchange resins, the compounds include cyclodextrin, adsorbents or mikroC 5 to 99.5% of the mass. solid components BDLF, normally from 20 to 90%, usually from 50 to 90%.

Every drug can be used as the active ingredient in the composition of the present invention. Examples of suitable drugs include, but are not limited to, medicines listed below:

Analgesics and anti-inflammatory agents: aloxiprin, auranofin, azapropazone, benorilate, diflunisal, etodolac, fenbufen, fenoprofen-calcium, flurbiprofen, ibuprofen, indometacin, Ketoprofen, meclofenamic acid, marennikova acid, nabumetone, naproxen, oxaprozin, oxyphenbutazone, phenylbutazone, piroxicam, sulindac.

Antihelmintic; albendazole, bephenium hydroxynaphthoate, cambendazole, dichlorophen, ivermectin, mebendazole, oxamniquine, oxfendazole, oxantel embonate, praziquantel, Pyrantel embonate, thiabendazol.

Antiarrhythmic agents: amiodarone-HCl, disopyramide, flecainide acetate, quinidine sulfate.

Antibacterial agents: benethamine penicillin, cinoxacin, ciprofloxacin-HCl, clarithromycin, clofazimine, cloxacillin, demeclocycline, doxycycline, erythromycin, ciprofloxacin, imipenem, nalidiksova acid, nitn, sulfafurazole, sulfamethoxazole, sulfapiridin, tetracycline, trimethoprim.

Anticoagulants: difenacoum dipyridamole, nicoumalone, phenindione.

Antidepressants: amoxapine, cycloidal, maprotiline-HCl, mianserin-HCl, nortriptyline-HCl, trazodone-HCl, trimipramine maleate.

Antidiabetic agents: acetohexamide, hlorpropamid, glibenclamide, gliclazide, glipizide, tolazamide, tolbutamide.

Anti-epileptic tools: reclamed, carbamazepine, clonazepam, ethotoin, Meton, methsuximide, methylphenobarbital, oxcarbazepine, paramethadione, phenacemide, phenobarbital, phenytoin, phensuximide, primidone, Altium, valbrona acid.

Antifungal agents: amphotericin, butoconazole nitrate, clotrimazole, econazole nitrate, fluconazole, flucytosine, griseofulvin, Itraconazole, ketoconazole, miconazole, natamycin, nystatin, sulconazole nitrate, terbinafine-HCl, terconazole, tioconazole, undecenoate acid.

Agents against gout: allopurinol, probenecid, sulfinpyrazone.

Antihypertensive agents: amlodipine, benidipine, durodie, diltiazem-HCl, diazoxide, felodipine, guanacasteca, indoramin, isradipine, Minoxidil, nicardipine-HCl, nifedipine, nimodipine, Phenoxyethanol-HCl, halofantrine-HCl, mefloquin-Hcl, proguanil-HCl, pyrimethamine, hemisulfate.

Caused agents: digidroergotamin mesilate, ergotamine tartrate, methysergide maleate, pizotifen maleate, sumatriptan succinate.

Protivopanikovye agents: atropine, benzhexol-HCl biperiden, ethopropazine-HCl, gostinstvo, hyoscyamin, mepenzolate, orphenadrine, oxyphencyclimine-HCl, tropikamid.

Antineoplastic agents and immunosuppressants: aminoglutetimid, amsacrine, azathioprine, busulfan, chlorambucil, cyclosporine, dacarbazine, estramustine, etoposide, lomustin, melphalan, mercaptopurine, methotrexate, mitomycin, mitotane, mitozantrone, procarbazine-HCl, tamoxifen citrate, testolactone.

Antiprotozoal agents: benznidazol, kliohinol, dechent, diethylacetanilide, diloxanide furoate, dinitolmide, furazolidone, metronidazole, nimorazole, nitrofurazone, Ornidazole, tinidazole.

Antithyroid agents: carbimazole, propylthiouracil.

Anxiolytics, sedatives, hypnotics and sedative agents: alprazolam, amylobarbitone, barbiton, bentazepam, bromazepam, bromperidol, brotizolam, butobarbital, carbromal, chlordiazepoxide, hlormetiazola, chlorpromazine, clobazam to canout, fluphenazine decanoate, flurazepam, haloperidol, lorazepam, lormetazepam, medazepama, meprobamate, methaqualone, midazolam, nitrazepam, oxazepam, pentobarbital, perphenazine pimozide, prochlorperazine, sulpiride, temazepam, thioridazine, triazolam, zopiclone.

Blockers: acebutolol, alprenolol, atenolol, labetalol, metoprolol, nadolol, oxprenolol, pindolol, propranolol.

Cardiac inotropic agents: amrinone, digitoxin, digoxin, enoximone, lanatoside With, methoxy.

Corticosteroids: beclomethasone, betamethasone, budesonide, cortisone acetate, desoximetasone, dexamethasone, fludrocortisone acetate, flunisolide, fluocortolone, fluticasone propionate, hydrocortisone, methylprednisolone, prednisolone, prednisone, triamcinolone.

Diuretics: acetazolamide, amiloride, bendrofluazide, bumetanide, chlorothiazide, chlorthalidone, ethacrynic acid, furosemide, metolazone, spironolactone, triamterene.

Enzymes

Agents against Parkinson's disease: parlodel mesilate, lisuride maleate.

Gastrointestinal agents: Bisacodyl, cimetidine, cisapride, Diphenoxylate-HCl, domperidone, famotidine, loperamide, mesalazin, nizatidine, omeprazole, ondansetron-HCl, ranitidine-Hcl, sulfasalazin the HCl, dimenhydrinate, flunarizin-HCl, loratadine, meclozine-HCl, oxatomide, terfenadine, triprolidine.

Agents that regulate lipid metabolism: bezafibrat, clofibrate, fenofibrate, gemfibrozil, probucol.

Local anesthetic agents:

Neuromuscular agents: pyridostigmine.

Nitrates and other agents against angina: amylnitrate, trinitroglycerin, the isosorbide dinitrate treatment, isosorbide Mononitrate, pentaerythritol TETRANITRATE.

Nutritional agents: beta-carotene, vitamin a, vitamin B2, vitamin D, vitamin E, vitamin K.

Narcotic analgesics: codeine, dextropropoxyphene, diamorphine, Dihydrocodeine, meptazinol, methadone, morphine, nalbuphine, pentazocine.

Oral vaccines are:

Vaccines designed to prevent or ameliorate symptoms of disease, of which the following are typical, but not exclusive:

influenza, tuberculosis, meningitis, hepatitis, whooping cough, polio, tetanus, diphtheria, malaria, cholera, herpes, typhoid, HIV, AIDS, measles, disease Lum, Travellers' diarrhea, hepatitis a, b and C, inflammation of the middle ear, Dengue fever, rabies, parainfluenza, rubella, yellow fever, dysentery, Legionnaires ' disease, toxoplasmosis, Q-lia, urinary tract infections, caused by E. coli, pneumococcal disease, mumps and chikungunya (fever).

Vaccines for the prevention or attenuation of symptoms of other painful syndromes, which are typical, but not exclusive, pathogenic microorganisms:

Vibrio species. Salmonella species, Bordetella species, Haemophilus species, Toxoplasmosis gondii, Cytomegalovirus, Chlamydia species, Streptococcal species, Norwalk Virus, Escherischia coli, Helicobacter pylori, Rotavirus, Neisseria gonorrhae, Neisseria meningiditis, adenovirus, the virus Epstein-Barr virus Japanese encephalitis, Pneumocystic carini, herpes simple, Clostridia species, respiratory syncytial virus, Klebsielia species, Shigella species, Pseudominas aeruginosa, parvovirus, Campylobacter species, Rickettsia, Varicella zoster, Yersinia species, the virus Ross River virus J. C., Rhodococcus equi, Moraxella catarrhalis, Borrelia burgdorferi and Pasteurella haemolytica.

Vaccine-related noncommunicable immunomodulatory painful conditions, such as local and systemic allergic conditions, such as polynosis, asthma, rheumaticky arthritis and cancer.

Vaccines for veterinary use, which aims to coccidiosis, Newcastle disease, enzootic pneumonia, Feline leukemia, atrophic rhinitis, erysipelas, disease foot and mouth, mumps, pneumonia, and other painful conditions and other Chida and recombinant drugs: insulin (review/dimeric/Monomeric forms), glucagon, growth hormone (somatotropin), polypeptides or derivatives thereof (preferably with a molecular weight of from 1000 to 300000), calcitonin and their synthetic modification, enkephalins, interferon (especially alpha-2-interferon for the treatment of common colds), LHRH and analogues (nafarelin, buserelin, solidex), GHRH (hormone-releasing hormone growth hormone, secretin, antagonists Bredikhina, GRF (growth hormone-releasing factor), THF, TRH (tireotropin releasing hormone), ACTH analogs, IGF (insulin-like growth factor), CGRP (peptide associated with calcitonin gene), trially natriurectic peptide, vasopressin and its analogues (DDAVP, lypressin), factor VIII, G-CSF (granulocyte-colony stimulating factor), EPO (erythropoietin).

Sex hormones: clomiphene citrate, danazol, levonorgestrel, medroxyprogesterone acetate, mestranol, methyltestosterone, norethisterone, norgestrel, estradiol, conjugated estrogens, progesterone, stanozolol, stilboestrol, testosterone, tibolone.

Products that destroy sperm: nonoxynol 9.

Stimulants: amphetamine, dexamfetamine, dexfenfluramin, fenfluramine, mazindol, pemoline.

The exact amount of active ingredient will depend on the selected drugs. Odsa weight of the composition dried dosage form.

The invention is additionally illustrated by the following examples which are illustrative and do not limit the invention. In the following examples BDLF obtained and tested in the absence of the active ingredient.

Amylogum CLS is a starch in which a hydroxyl group tarifitsirovana. He is a commercially available product of the company Avebe U.K., Ltd., South Huberside, England. Mannitol supplied by the company Roquette Ltd., Kent, England.

Starch is added to purified water and heated to 60°C under stirring. The mixture was incubated at 60°C for 10 minutes to dissolve and then cooled to room temperature. After sufficient cooling of the mixture mannitol is added and stirred until dissolved. The mixture is metered in blister packs of PVC/PVDC (PVC/PVdC) with a mass filling 500 mg. Received items frozen in a stream of cold gaseous nitrogen and then dried, gradually raising the temperature from -10°C to +20°C at a pressure of 0.5 mbar.

Perfectagel MPT is a phosphate hydroxypropylmethyl and is a commercially available product of the company Avebe U.K., Ltd.

Paselli MD10 represents Fe which tx2">The water is stirred using a handheld electric mixer and with stirring, add the starch and mannitol. For the starch does not require heating. The solution is stirred 1/5 hours to achieve equilibrium.

Dispersing dosage forms in the mouth is gently and quickly, and they have a sweet taste.

Avebe MD20 is an enzymatically modified starch, and is a commercially available product of the company Avebe U.K., Ltd.

Dosage forms of examples 1-4 provide rapid dispersion in the mouth in less than 10 seconds.

Used modified starches:

Paselli Easygel, which is a pre-gelatinizing dichromatic.

Paselli SA, which is a pre-gelatinizing acetylated dichromatic.

Paselli WA4, which is a pre-gelatinizing purified starch.

All of these modified starches are commercially available products of the company Avebe, U. K., Ltd.

The powders are mixed in a dry process and add into the funnel to mix purified water. Then the mixture is heated to 50°With usausa environment with continuous stirring. Viscosity measurements carried out in 1-3 hours mixing and after 22 hours using a viscometer of the khaak at 500 sec-1.

The Results:

No significant changes in viscosity during the 22-hour period. This property is very desirable in obtaining BDLF. This property improves the efficiency of obtaining and reduces losses due to waste.

Paselli BC is a pre-gelatinizing acetylated micromalthus, commercially available product of the company Croda Colloids Ltd. Cheshire, England.

Gelatin preparation

Gelatin and mannitol added to the funnel to mix purified water and heated to 60°C to dissolve. Then before dispensing the mixture is cooled to 25°C.

The preparation of modified starch

Mannitol and Paselli BC mixed dry and then gradually add in the funnel to mix purified water at ordinary temperature. The resulting mixture was then homogenized using a Silverson L4R (small head adapter) for about 1 minute.

The mixture is metered in blister packs of PVC/PVDC, diameter 16 mm, weight fill 500 mg, with a view gaseous nitrogen before freeze-drying by a gradual increase in temperature from -10 to +20°C at a pressure of 0.5 mbar.

The elements are placed, uncovered, in cells with stable conditions 40°C and relative humidity 75% for 20 hours, determining after this time, the diameter of the elements.

The Results:

You may notice that BDLF that use modified starch, have a 50% reduction of the shrinkage in comparison with the conventional BDLF containing gelatin. This is an unexpected and surprising result.

Example 7

Comparative gelatin BDLF relatively BDLF with modified starch

In an article entitled “Drug Delivery Products and the Zydis Fast Dissolving Dosage Form” (H. Seagers et al., J. Pharm Pharmacol., 1998) discusses the problems associated with highly water-soluble drugs in BDLF. Zydis® is a registered trademark of R. P. Scherer Corporation, Basking Ridge, N j, USA. N. Seagers with co-authors found that the dose of water-soluble drugs is usually limited to an upper value of approximately 60 mg per dosage form. The dose size is governed by the behavior of medicines during the process of freezing and drying characteristics. Can be obtained eutectic mixtures, which cannot adequately be frozen or can melt at higher the et to form an amorphous solid by freezing and that is a solid substance may “shrink” during the drying process due to ice sublimation and loss support structures.

The collapse of structures formed by water-soluble drugs, as you know, is reduced due to the inclusion of forming crystals of filler. These materials are also known as forming the matrix agents. These materials contribute to the crystallinity and, consequently, the stiffness of amorphous products. Another method involves the binding of a water-soluble compound with ion exchange resin with the formation of water-insoluble complex. Another method incorporates non-aqueous solution of the active ingredient in the pre-formed elements placebo-BDLF. The organic solvent is then evaporated, and recrystallized medication is deposited in the pores Zydis-matrix.

Another technique, which is known to overcome the problems associated with highly water-soluble active compounds, is the decrease of the ratio of drug to excipient and increase mass filling blister packs. This effectively weakens the influence of active soluble compounds at the same dose of medicine, but with a larger amount of filler. This possible solution has obvious disadvantages in that it requires greater if the capacity due to limitations in size.

It is also known that the solubility of the drug can be changed by regulating the pH. Reduced solubility, as is well known, facilitates the introduction of higher doses of active compounds in BDLF. One aspect of the present invention is based on the discovery that the use of essentially not containing gelatin BDLF, which use a modified starch, allows you to enter a greater number of water-soluble drugs, than in the case of conventional gelatin systems. This example is presented in order to show such an unexpected result.

In this example, three (3) highly water-soluble active ingredient were prepared in the form BDLF. The solubility of these active compounds in water are presented below:

Diclofenac-sodium - 1:30 water

Pravastatin-sodium - 1:3 water

Phenylpropanolamine-HCl - 1:2,5 water

In accordance with table 1 prepared the following sample.

Samples 1, 3 and 5 (samples containing gelatin) prepared by adding gelatin and mannitol funnel mix of purified water. The mixture is then heated to a temperature of 60°C(±1°C) to put gelatin and mannitol in rest the Ala. Each download before dispensing blister packaging incubated for at least one (1) hour. Samples 2, 4 and 6 (samples with modified starch is prepared by adding starch and mannitol in a clean, dry chemical glass and dry mixing with a spatula. Then to this mixture, add purified water and homogenized using a Silverson L4R - Small Head Adapter at half speed for two (2) minutes. To this solution add the specified active material and leave to dosing for at least one (1) hour. No heating of the downloads are required and not taken.

Each sample is dosed in 20 blister packs using the metering device Hamilton Microlab that puts 500 mg of a mixture of (±2%) in aluminum blister pockets. Blister packs then frozen at -110°C With liquid nitrogen at the time of 3.2 minutes. Frozen samples before freeze-drying stored at -25°C. Drying by freezing, make use of a temperature cycle from -10 to 10°C at 0.5 mbar. The samples are dried overnight on the day of manufacture.

After freeze-drying each package is extracted and Oslo noticeable when viewed BDLF and shows 90% of sample 1 clearly form cracks, while for sample 2 (containing modified starch) showed 0%. Sample 3 containing gelatin, shows 45-50% of cracking, whereas sample 4 on the basis of starch formulations, it does not crack.

Sample 5 containing 2.5% of the mass. phenylpropanolamine and 4% of the mass. gelatin gives the degree of cracking of 60-70%. This means that 60-70% 20 blister fillings for this sample crack and crumble when trying to extract from the blister pack. On the contrary, the use of starch in the sample 6 leads to the degree of cracking is only 10-20%.

This experience clearly shows that the use of modified starch in BDLF provides a higher content of highly water-soluble active compounds, which can be entered in BDLF without cracking and reduction of physical stability observed in the case of conventional gelatin preparations.

Example 8

Comparative

From the work carried out in example 7, it is obvious that the use of modified starch in BDLF provides a higher level of load of the dosage form in the absence of cracking and/or physical is to get BDLF on the basis of gelatin, containing the same active ingredient per dosage form. Essentially, this experiment was conducted in order to determine whether it is possible to prepare formulations on the basis of gelatin containing highly active soluble compounds, without melting (absorption of water vapor and falling physical stability and formation of cracks. Received the following medications:

These samples manufactured as described in example 7, except that the used filling 750 ml. After removing the samples from the stage of freeze-drying a visual inspection shows no samples with cracks. This example shows that the necessary larger dosing forms, when receiving bystrotverdeyushchie dosage forms used gelatin. This unexpected result has the advantage that smaller dosage forms that use modified starch, will improve patients ' adherence to regimens and reduce the cost of production.

Industrial applicability

The present invention relates to bystromenyayuschimsya dosage forms for oral administration. The advantages of Lublin funds. Currently, the most commercially popular form is soluble solid dosage form, which is prepared by introducing an aliquot of the suspension of therapeutic agent, solvent, gelatin and other fillers in the prior variance. The liquid is then frozen, and then the solvent is removed by sublimation, usually freeze-drying. The resulting tablets have an open porous matrix, which easily dissolves upon contact with saliva.

The conventional BDLF has some drawbacks, for example: 1) the use of gelatin derived from mammals; 2) limited load highly water-soluble active compounds in BDLF; 3) insufficient mechanical strength; 4) unpleasant taste; 5) inability to ensure homogeneity of the mixture; (6) inability to prevent the deposition of particles of the active substance; and (7) the minimum dissolved in cold water. The present invention is a step forward in the field BDLF due to the discovery that certain modified starches can be used for cooking BDLF, which have improved physical stability; unexpected ability to contain a higher load is echeveste to absorb moisture and subsequent shrinkage when compared with gelatin matrix systems); and a significant decrease in the deposition rate of active particles in the mixture.

It should be understood that the description and examples are illustrative and do not limit the present invention and that other embodiments of the invention within the essence and scope of the invention will be proposed qualified in this area specialists.

1. Bystrorazvarivayuschayasya solid dosage form intended for quick release of the active ingredient in the oral cavity, characterized in that the dosage form essentially free from gelatin and includes at least one active ingredient, b) at least one modified starch in a concentration of from 20 to 90 wt.% and in at least one forming a matrix agent, with the specified solid dosage form obtained by removing solvent from a mixture containing specified active ingredient that is listed on modified starch and the specified forming a matrix agent.

2. Bystrorazvarivayuschayasya solid dosage form under item 1, in which the specified modified starch selected from the group comprising starch, a hydroxyl group which tarifitsirovana, phosphate hydroof, gidroxiatilkrahmal, pre gelatinizing acetylated micromalthus and pre gelatinizing purified starch.

3. Bystrorazvarivayuschayasya solid dosage form under item 1, which contains from 50 to 90 wt.% the specified modified starch.

4. Bystrorazvarivayuschayasya solid dosage form under item 1, in which the modified starch is easily dissolved or dispersed in water at ambient temperature.

5. Bystrorazvarivayuschayasya solid dosage form under item 1, in which the mixture of the active ingredient, modified starch and forming a matrix agent is actually a constant viscosity over a period of approximately 24 hours

6. Bystrorazvarivayuschayasya solid dosage form under item 1, in which the preferred solvent is water.

7. Bystrorazvarivayuschayasya solid dosage form under item 1, in which the preferred form the matrix agent is mannitol.

8. Bystrorazvarivayuschayasya solid dosage form under item 1, which additionally may contain colouring agents, flavouring flavouring substances, fillers, a lot of therapist is of the solvent from the mixture preferably is carried out by drying, the freezing.



 

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