Drug form desintegrating in oral cavity

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions relates to field of pharmaceutics. Claimed is method of obtaining drug form, which include: a) placement inside depression of friable material, including at least approximately 5 wt % of at least one hydrated salt and pharmaceutically active agent, and where at least one hydrated salt is characterised by temperature of dehydration from 20 to 120°C; b) heating friable material in depression to temperature higher than said temperature of dehydration of at least one hydrated salt for time period sufficient for fusion of material with formation of aggregate, and heating is performed by radio-frequency or microwave heating; and c) cooling aggregate in depression until aggregate hardens in dosed form. Friable material can additionally contain carbohydrate. Claimed is drug form, obtained by said method. In order to obtain drug form, which includes external edible part and internal part, disintegrating in oral cavity, said friable material is placed inside depression in preliminarily created external edible form, with depression having required shape and volume, sufficient for placement of part of drug form, disintegrating in oral cavity.

EFFECT: method makes it possible to create dosed drug forms avoiding production stage of pressing, which in its turn improves integrity of particles, which contain pharmaceutically active agent and are sensitive to forces of compression.

16 cl, 3 tbl, 2 ex

 

BACKGROUND of INVENTION

Drugs intended for oral administration, are normally supplied in solid form as tablets, capsules, pills, karamela or granules. Tablets are swallowed whole, razdevayutsya mouth or dissolved in the mouth. Soft tablets, which razdevayutsya or dissolved in the mouth, often applied in cases when prescribing pills to swallow whole is inappropriate. In the case of chewable tablets their chewing helps the disintegration of the components of the tablet particles in the process of disintegration of the tablet and can increase the rate of absorption in the digestive tract. Soft tablets also have an advantage in cases where it is desirable to ensure the availability of the active ingredient topically in the mouth or in the throat, with the aim of providing local and/or systemic absorption. Soft tablets are also used to facilitate medication in children and elderly patients. Soft tablets, which disintegrate in the mouth before swallowing, especially useful for a patient of childhood as a dosage form for improving compliance in children.

To date, found that the disintegrating in the oral dosage form can be created and the mixture comprising at least one active agent and at least one gidratirovannuyu salt. This method allows you to create dosage forms (such as tablets) bypassing the production stages of extrusion or lyophilization, which, in turn, improves the safety of particles containing pharmaceutically active agent, coated or subjected to a process of masking of taste, in the manufacturing process of the medicinal product.

BRIEF description of the INVENTION

In one aspect of the present invention is described disintegrating in oral dosage form, comprising from about 5% to about 40% by weight of at least one hydrated salt and a pharmaceutically active agent, and at least hydrated salt is characterized by the temperature of dehydration from approximately 20 to approximately 120°C.

The present invention also describes a method of obtaining a disintegrating in oral dosage form, comprising the following steps: a) providing a sheet for packaging units product with the deepening of the desired shape and size sufficient to accommodate the mentioned dosage form; b) placement within the recess of the installed quantity of bulk material, comprising at least 5% by weight of at least the ne hydrated salts and pharmaceutically active agent, and where the aforementioned at least one hydrated salt is characterized by the temperature of dehydration in the range of about 20 to 120°C; (c) heating the material placed in the cavities, to a temperature above the temperature of dehydration mentioned at least one hydrated salt, over a period of time sufficient for fusing the material together with the formation of the unit, and (d) cooling the aggregate material within the recesses so that the Assembly becomes solid form suitable for use dosage form, dissolving in the mouth.

The present invention also describes a dosage form, consisting of external edible parts, and disintegrating in the oral cavity part, and the outer edible portion comprises disintegrating in the oral cavity part, thus disintegrating in the oral cavity part contains at least 5 wt%. at least one hydrated salt plus pharmaceutically active agent, where the above-mentioned hydrated salt is characterized by the temperature of dehydration in the range of about 20 to 120°C;

The present invention also describes a method of obtaining a dosage form consisting of external edible parts, and parts of the disintegrating in the oral cavity, including the following steps: a) creating EXT is it edible parts, with the deepening of the desired shape and size sufficient to accommodate the disintegrating in the oral cavity is part of the mentioned dosage form; b) placement within the recess of the installed quantity of bulk material, comprising at least 5% by weight, of at least one hydrated salt and a pharmaceutically active agent, and where the aforementioned at least one hydrated salt is characterized by the temperature of dehydration in the range of about 20 to 120°C; (c) heating the material placed in the cavities, to a temperature above the temperature of dehydration mentioned at least one hydrated salt, over a period of time, sufficient for fusing the material together with the formation of the unit, and (d) cooling the aggregate material within the recesses so that the Assembly becomes solid form suitable for use dissolving oral dosage form.

Other distinctive features and advantages of the present invention will be clear from the text of the detailed description of the invention and its formula.

DETAILED description of the INVENTION

It is assumed that the expert based on this description, will be able to use the present invention in its maximum volume. The following specific embodiments of the image is etenia can be considered only as examples, which in no way limit disclose the essence of the present invention application.

All technical and scientific terms used herein, unless otherwise given their definition, have a common value, understood by any professional working in the field, which is the ratio of the present invention. In addition, all publications, applications for patent, patents and other mentioned here literary links grouped together in the form of a list. Everything used here is the percentage, unless there are other refinements are listed by weight.

Disintegrating in the oral dosage form

Disintegrating in the oral dosage form described in this application for the invention, includes at least one gidratirovannuyu salt and a pharmaceutically active agent, and as an optional add-ons include one or more carbohydrate compounds, gas-forming substances, flavorings and other ingredients.

In one of the embodiments of the invention disintegrating in the oral dosage form has a hardness of less than 6.8 kg/cm2(15 kgf/cm2), and less than 4.5 kg/cm2(10 kgf/cm2and less than 2.3 kg/cm2(5 kgf/cm2). In one of the embodiments of the invention to disintegrating in the oral cavity of dozer the bathroom dosage form to increase its hardness is applied a sufficient amount of energy for a sufficiently long period of time. In one of the embodiments of the invention to disintegrating in the oral dosage form of energy is applied in the form of heat or electromagnetic radiation such as microwave radiation. Depending on the composition of the disintegrating dosage forms, in one of the embodiments of the invention, the heating can be carried out from a temperature in the range of room temperature to 100°C or higher for a period of time sufficient to effect melting and/or solidification.

In one of the embodiments of the invention disintegrating in the oral dosage form demonstrates the strength of less than 2% (or less than 1%, or less than 0.5%) after application of energy to the bulk material with the aim of creating a disintegrating dosage form that is the second stage of the process. Discussion the strength of the disintegrating in oral dosage forms is represented in the US Pharmacopoeia 1995, str, 1981.

In one of the embodiments of the invention disintegrating in the oral dosage form is intended to disintegrate in less than 60 seconds after the language, for example, less than 45 seconds, or less than 30 seconds, or less than 15 seconds

Hydrated salt

Disintegrating in the oral cavity is cartenna form or part of the disintegrating in the oral dosage form contains at least one gidratirovannuyu salt. Examples of hydrated salts include the hydrate of sodium sulfate, hydrate of sodium carbonate, hydrate of calcium chloride, hydrate of sodium hydrogen phosphate, and mixtures thereof, but are not limited to these compounds. In one variant of the invention, the hydrated salt has a molecular weight in the range from about 150 to 400 daltons, such as, for example, in the range of about 200 to 350 daltons. In one variant of the invention, the dosage form contains from about 5% to 40% by weight of at least one gidratirovannuyu salt, for example, from about 5% to 20% salt by weight.

Carbohydrate

In one of the embodiments of the invention disintegrating in the oral dosage form includes at least one carbohydrate, comprising at least 40% by weight. Examples of carbohydrates include, among others, sugars such as dextrose, dextrose monohydrate, lactose, glucose, fructose, maltodextrin, isomalt, sucrose, dried corn syrup, and mannose; carbohydrate alcohols, such as sugar alcohols, such as hydrogenated starch hydrolysates, for example, sorbitol, lactitol, xylitol, erythritol, mannitol and polyols, and mixtures thereof. In some embodiments the invention, the dosage form comprises at least 40% by weight, as, e.g. the, at least 60% by weight of at least one carbohydrate.

In one of the embodiments of the invention the weight ratio mentioned at least one hydrated salt and the above-mentioned at least one carbohydrate varies approximately from a ratio of 1:4 to 1:30, or from about 1:9 to 1:20.

Water-insoluble fillers

In one of the embodiments of the invention disintegrating in the oral dosage form/part essentially does not contain the directly compressible water-insoluble filler. Water-insoluble excipients include microcrystalline cellulose, microcrystalline cellulose for direct compression, cellulose, water-insoluble cellulose, starch, corn starch and modified starches. As described in this embodiment of the invention, the wording "essentially does not contain" means a content of less than 2%, for example, less than 1% or no.

Pharmaceutically active agent

Dosage form comprising the subject matter of the present invention, includes at least one pharmaceutically active agent. The term "pharmaceutically active agent" refers to a substance (e.g., a compound)which has received the permission or approval of Department for quality control pexeva the products and pharmaceuticals USA, The European medicines Agency or any of their successors, as a means for oral administration in the treatment of pathological conditions or diseases. Used pharmaceutically active agents include analgesics, anti-inflammatory and antihistamine, antibiotics (e.g., antibacterial, antiviral and antifungal agents), antidepressants, antidiabetics, antispasmodic, tools, suppress the appetite, bronchodilatory, cardiovascular medicinal agents (e.g., statins), agents for the treatment of Central nervous system, cough drops, decongestants, diuretics, expectorants, agents for the treatment of diseases of the gastrointestinal tract, anesthetics, mucolytics, muscle relaxants, medicines for treatment of osteoporosis, stimulants, nikotinsoderzhaschie tools and sedatives, but not limited to the above substances.

Examples of agents used to treat gastrointestinal tract include, among others, the following substances: antacids such as aluminium-containing active ingredients (e.g., aluminum carbonate, aluminum hydroxide, carbonate dihydroxyaluminum sodium aluminum phosphate), bicarbonates active ingredients (for example, al is mint bismuth, carbonate of bismuth, subcarbonate bismuth, subgallate bismuth and subnitrate bismuth), calcium-containing active ingredients (e.g., calcium carbonate), glycine, magnesium-containing active ingredients (e.g., magaldrate, magnesium silicates, magnesium carbonate, glycinate magnesium, magnesium hydroxide, magnesium oxide, magnesium trisilicate), phosphate-containing active ingredients (e.g., aluminum phosphate or calcium phosphate), contain potassium, active ingredients (e.g., potassium bicarbonate), sodium active ingredients (e.g., sodium bicarbonate), and silicates; laxatives, such as softening the stool laxatives (e.g., docusinate) and laxatives stimulant actions (e.g., Bisacodyl); H2 antagonists of receptors, such as famotidine, ranitidine, cimetidine and nizatidine; proton pump inhibitor such as omeprazole and lansoprazole; means for protection of epithelial cells of the gastrointestinal tract (the protectors), such as sucralfate and misoprostol; prokinetic, such as prucalopride; antibiotics, active against H. pylori, such as clarithromycin, amoxicillin, tetracycline, and metronidazole; Antidiarrhoeal agents such as bismuth subsalicylate, kaolin, Diphenoxylate and loperamide; glycopyrrolate; analgesics, such as mesalamine; antiemetics, such as ondansetron, cyclizine, diphenhydramine, dipenhydramine, meclizine, promethazine, and hydroxyzine; probiotic bacteria, including, among others, lactic acid bacteria; lactase; racecadotril; and carminative drugs, such as polydimethylsiloxane (for example, Dimethicone and simethicone, including disclosed in U.S. patent 4906478, 5275822 and 6103260), their isomers and pharmaceutically acceptable salts and proletarienne forms (e.g., esters).

Examples of anesthetic, anti-inflammatory and fever-reducing drugs include, among others, non-steroidal anti-inflammatory drugs (NSAIDs)such as propionic acid derivatives (e.g., ibuprofen, naproxen, Ketoprofen, flurbiprofen, fenbufen, fenoprofen, indoprofen, fluprofen, pirprofen, carprofen, oxaprozin, pranoprofen, suprofen) and cyclo-oxygenase inhibitors such as celecoxib; acetaminophen; acetylsalicylic acid; derivatives of acetic acids such as indomethacin, diclofenac, sulindac, tolmetin; derivatives of Funambol acid, such as mefenamovaya acid, meclofenamic acid and floranova acid; derivatives of biphenylcarboxylic acid, such as diflunisal and flufenisal; and oxicam, such as piroxicam, sudoxicam, isoxicam and meloxicam; their isomers and pharmaceutically acceptable salts and proletarienne form.

Examples of ant is histaminic tools and decongestants include, among others, bromopheniramine, chlorcyclizine, dexbrompheniramine, bromhexin, phenindamine, Pheniramine, pyrilamine, thonzylamine, tripolidine, ephedrine, phenylephrine, pseudoephedrine, phenylpropanolamine, chlorpheniramine, dextromethorphan, diphenhydramine, doxylamine, astemizole, terfenadine, Fexofenadine, nafazolina, Oxymetazoline, montelukast, propylhexedrine, triprolidine, clemastine, acrivastine, promethazine, examination, mequitazine, buclizine, Bromhexine, ketotifen, Bastin, oxatomide, Xylometazoline, loratidine, desloratidine and cetirizine; their isomers and pharmaceutically acceptable salts and proletarienne form.

Examples of the antitussive and means salt include, among others, diphenhydramine, dextromethorphan, noscapine, chlophedianol, menthol, benzonatate, Ethylmorphine, codeine, acetylcysteine, carbocisteine, Ambroxol, alkaloids of belladonna ordinary, Sabrina, guaiacol and guaifenesin; their isomers and pharmaceutically acceptable salts and proletarienne form.

Examples of muscle relaxants include, among others, cyclobenzaprin, chlorzoxazone, metaxalone, orphenadrine and Methocarbamol; their isomers and pharmaceutically acceptable salts and proletarienne form.

Examples of stimulants include, among others, caffeine.

Examples of sedatives include, among others, hypnotics, such as antihistamines the courthouse square (for example, diphenhydramine), eszopiclone and zolpidem and their pharmaceutically acceptable salts and proletarienne form.

Examples of funds that suppress appetite, include, among others, phenylpropanolamine, phentermine and diethylcathinone and their pharmaceutically acceptable salts and proletarienne form.

Examples of anesthetics (for example, in the treatment of sore throat) include, among others, dicloran, benzocaine and pectin and their pharmaceutically acceptable salts and proletarienne form.

The relevant examples of statins include, among others, atorvastin, rosuvastin, lovastin, lovastin, simvastatin, atorvastatin, pravastatin and their pharmaceutically acceptable salts and proletarienne form.

In one variant of the invention, the pharmaceutically active agent included in the composition of the disintegrating in the oral dosage form selected from the group of drugs, such as phenylephrine, dextromethorphan, pseudoephedrine, acetaminophen, ibuprofen, Ketoprofen, loperamide, famotidine, calcium carbonate, simethicone and menthol and their pharmaceutically acceptable salts and proletarienne form.

In one variant of the invention, the pharmaceutically active agent is selected from the group of drugs, such as phenylephrine, dextromethorphan, pseudoephedrine, chlorpheniramine, methocarbomal, chlophedianol, ascorbic acid, menthol, pectin,dyclonine and benzocaine and their pharmaceutically acceptable salts and proletarienne form.

As discussed above, pharmaceutically active agents described in this application for the invention, may also be present in the form of pharmaceutically acceptable salts such as acid/anionic or alkali/cationic salts. Pharmaceutically acceptable acidic/anionic salts include, among others, acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, edetate calcium, camsylate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, estolate, Eilat, fumarate, gluceptate, gluconate, glutamate, picolylamine, hexylresorcinol, geranamine, hydrobromide, hydrochloride, hydroxysafrole, iodide, isetionate, lactate, lactobionate, malate, maleate, mandelate, mesilate, bromide, methylnitrate, methyl sulfate, mukat, napsylate, nitrate, pamoate, Pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, subacetate succinate, sulfate, tannat, tartrate, teoclate, tosylate and triethiodide. Pharmaceutically acceptable alkali/cationic salts include, among others, of an aluminum salt, benzathine, calcium, chloroprocaine, choline, diethanolamine, Ethylenediamine, lithium, magnesium, meglumine, potassium, procaine, sodium and zinc.

As discussed above, pharmaceutically active agents described in this application for the invention, may also be present in the form of prodrugs pharmaceutically active agent. In General, the e prodrugs will be functional derivatives of pharmaceutically active agent, which are easily converted in vivo to the desired pharmaceutically active agent. Conventional procedures for the selection and preparation of appropriate derivatives proletarienne forms are described, for example, in the book "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985. In addition to the salts of the present patent application provides for the use of esters, amides and other security or derivative forms of the described compounds.

In cases when the pharmaceutically active agents in accordance with the present invention have at least one chiral center, they may accordingly exist as enantiomers. In cases when the pharmaceutically active agents possess two or more chiral centers, they may additionally exist as diastereomers. You must understand that all such isomers and mixtures thereof fall within the scope of the present invention. Moreover, some of the crystalline forms of the pharmaceutically active agents may be in the form of polymorphic crystalline modifications, which, as implied, are also covered by the scope of the present invention. In addition, some of the pharmaceutically active agents may form a solvate with water (i.e. hydrates) or common organic solvents, and such solvate are also covered by part nastojasih the invention.

In one variant of the invention, the pharmaceutically active agent or agents are present in the dosage form in a therapeutically effective amount, which is the number that causes the desired therapeutic effect upon oral administration and can be easily determined by the expert. As we all know, when determining such amounts must be taken into account this assigned pharmaceutically active agent, its characteristics bioavailability, dosage, age and weight of the patient, and other factors.

Pharmaceutically active agent can be in various forms. For example, the pharmaceutically active agent can be dispersed at the molecular level, for example, be melted inside of the dosage form, or may be in the form of particles, which, in turn, can be coated or not coated. If the pharmaceutically active agent is in the form of particles (either coated or not coated), then typically the average particle size varies approximately in the range from 1 to 2000 microns. In one of the embodiments of the invention, such particles are crystals with an average particle size of from about 1 to 300 microns. In another embodiment of the invention the particles are what I granules or pellets with an average particle size of from about 50 to 2000 microns, as, for example, from about 50 to 1000 microns, or from about 100 to 800 microns.

If the pharmaceutically active agent has an unpleasant taste, as we all know this pharmaceutically active agent can be coated masking the taste of the shell. Examples of appropriate masking the taste of the membranes described in U.S. patent 4851226, in U.S. patent 5075114 and in U.S. patent 5489436. Can also be used commercially available pharmaceutically active agents with masked taste. For example, particles acetaminophen encapsulated in a shell of ethyl cellulose or other polymers by a process koatservatsii can be used within the present invention. Encapsulated using koatservatsii acetaminophen can be purchased on commercial terms, the company Eurand America, Inc. (Vandalia, Ohio) or the company Circa Inc. (Dayton, Ohio).

Before applying masking the taste of the shell pharmaceutically active agent may be pure crystalline form or granular form. The milling technology can be used to improve the flow characteristics or size of the particles of pharmaceutically active agent to facilitate its extrusion and subsequent coverage by the shell. Suitable binders used in the granulation technology, including the Ute, among others, starch, polyvinylpyrrolidone, polymethacrylates, hypromellose and hydroxypropylcellulose. Particles comprising a pharmaceutically active(e) agent(s)can be created by using cohanoschi pharmaceutically active agents with the corresponding particles of the substrate by well-known specialists granulation method. Examples of such a method of granulating include, among others, wet granulation, high shear rate and granulation in fluidized bed", such as rotary granulation in fluidized bed", the details of which are disclosed in the book “theory and Practice of Industrial Pharmacy", 3rd edition, Chapter 11, Lachman, Leon et. al, 1986.

As discussed above, one of the benefits described here disintegrating in the oral dosage form/part is the ability to incorporate modified particles containing a pharmaceutically active agent, such as particles with masked taste, coated granules or coated beads, which are usually sensitive to the effects of compressive forces applied in the manufacturing process. Traditionally used for the manufacture of tablets compression can have on coated particle effects that can compromise the properties of the covering shell (for example, mo is to officeroute masking the taste or the ability of the agent to be released). In one of the embodiments of the invention disintegrating in the oral dosage form includes covered in gel and fluid-filled granules, which may contain flavouring, active ingredient, or a mixture thereof. In one of the embodiments of the invention filled with gel granules are covered with materials that include, among others, hydrocolloids such as acacia, alginates, agar, guar gum, carob tree, carageenan, carboxymethylcellulose, gum packaging, resin acacia, tragakant, pectin, xanthan gum, 'gellan, gelatin, maltodextrin, galactomannan, pustular, laminarin, scleroglucan, inulin, Whelan, ramsan, zoogen, methylan, chitin, cyclodextrin, chitosan, polyvinylpyrrolidone, cellulose derivatives, sucrose, starch and the like, and derivatives and mixtures thereof) and plasticizing substance (such as propylene glycol, glycerin, or a mixture thereof). Because in one of the embodiments of the invention disclosed here dosage form is not subject to stage compression gel-coated fluid-filled pellets will decay with the lowest probability.

In one of the embodiments of the invention disintegrating in the oral dosage form/part incorporates the coated particles with modified release (i.e. particles containing Myung is our least one pharmaceutically active agent, which transmits properties of modified release). Used herein the term "modified-release" should be applied to the modified release or dissolution of the active agent in a solvent medium, such as liquid contents of the gastrointestinal tract. Types of modified release include, among others, extended release or delayed release. In General, dosage forms with modified release are created in order to make the active agents are available over an extended period of time after they are received, thereby to reduce the frequency of use in comparison with the reception of the same active agent(s) in a traditional dosage form dosage forms with modified release also allow the use of combinations of active agents, which may differ from each other by the duration of its effect. In one variant of the invention, the dosage form contains one pharmaceutically active agent that is released immediately, and an additional active agent or the second part of the same active agent with modified release.

In one of the embodiments of the invention f is matemticas active agent is covered with a combination of water-insoluble, forming a film of a polymer (such as, among others, cellulose acetate or ethylcellulose) and the water-soluble polymer (such as, among others, povidone, polymethacrylic copolymers, which are sold under the trade name Eudragit E-100 by the company Rohm America, and hydroxypropylcellulose). In one of the embodiments of the invention, the ratio of water-insoluble, film forming polymer with a water-soluble polymer is approximately equal to 50 to 95% of the quantity of water-insoluble polymer and from about 5 to 50% water-soluble polymer, with the weight ratio of the particles covered with masking the taste of the sheath is approximately 5 to 40%.

In one of the embodiments of the invention one or more of the active ingredient or part of the pharmaceutically active agent can be associated with ion exchange resin for taste masking pharmaceutically active agent, or for delivery of the active agent by a modified release.

In one variant of the invention, the pharmaceutically active agent which can dissolve when coming in contact with liquids, such as water, acid gastric juice, intestinal juice, and the like. In one of the embodiments of the invention the characteristics of the solubility of the pharmaceutically active agents is a, part of the disintegrating in oral dosage forms that meet the specifications of the United States Pharmacopeia(USP), typical tablets, containing pharmaceutically active agent with immediate-release. For example, acetaminophen tablets in USP 24 specifies that in phosphate buffer with a pH of 5.8, using USP apparatus 2 (paddles) at 50 rpm, at least 80% of the acetaminophen contained in the dosage form is released from it within 30 minutes after taking, and for tablets ibuprofen USP 24 specifies that in phosphate buffer with a pH of 7.2, using USP apparatus 2 (paddles) at 50 rpm, at least 80% of ibuprofen contained in the dosage form, released from it within 60 minutes after the dose. Cm. USP 24, Version 2000, 19-20 and 856 (1999). In another embodiment, the invention features the solubility of the pharmaceutically active agent modified: for example, controlled, maintained, extended, slow, renegotiated, linger, and the like.

Effervescent mixture

In one of the embodiments of the invention disintegrating in the oral dosage form further comprises one or two effervescent mixture. In one variant of the invention, the effervescent mixture include one of the substances group is s, consisting of sodium bicarbonate, potassium bicarbonate, calcium carbonate, magnesium carbonate, sodium carbonate and one member of the group consisting of citric acid, oxenfree acid, fumaric acid, tartaric acid, phosphoric acid, and alginic acid.

In one variant of the invention, the combined amount of effervescent mixtures in disintegrating in the oral dosage form comprise from about 0.1 to 20% by weight, such as from about 2 to 10% by weight of the total weight of the disintegrating dosage forms.

Other ingredients

Disintegrating in the oral dosage form may contain other commonly used ingredients, including other fillers, dry binders, such as polyvinylpyrrolidone and the like; sweeteners such as aspartame, Acesulfame potassium, sucrose and saccharin; sliding substances, such as magnesium stearate, stearic acid, talc, and waxes; preservatives; flavorings; leavening agents, antioxidants; podnikatel, such as, among others, citric acid, axentra acid, tartaric acid, ascorbic acid, fumaric acid; surfactants; supernatrual; flavoring and aroma additives; antioxidants; preservatives; thickening agents and coloring agents.

The example is suitable sweeteners for use in the dosage form include, among others, synthetic or natural sugar, Sucralose, saccharin, sodium saccharinate, aspartame, Acesulfame K or Acesulfame, Acesulfame potassium, thaumatin, glycyrrhizin, dihydrochalcones, alitum, miraculin, monellin, stevioside, and mixtures thereof.

Examples of superdisintegrants include, among others, croscarmellose sodium, sodium salt starch glycolate and cross-linked povidone (crospovidone). In one of the embodiments of the invention disintegrating in the oral dosage form comprises about 5% by weight of such superdisintegrants.

Examples of suitable flavors and aromas include, among others, essential oils, including distilled, extracted by solvents or by cold pressing of chopped flowers, leaves, peeled or turned into pulp whole fruit containing a mixture of alcohols, esters, aldehydes and lactones; essences, including either diluted solutions of essential oils, or mixtures of synthetic chemicals blended to mimic the natural smells of fruits (e.g. strawberry, raspberry and blackcurrant); artificial and natural smells of beer and spirits (e.g. brandy, whiskey, rum, gin, sherry, port wine, and wine; tobacco, coffee, tea, cocoa and mint; fruit juices, including juice, squeezed from the washed and imennyh fruit, such as lemon, orange and lime; mint; ginger; cinnamon; cocoa; vanilla; licorice; menthol; eucalyptus; anise seed, nuts (such as peanuts, coconut, hazelnut, chestnut, walnut and walnut Cola); almonds; raisins; and powder, flour or parts of plant materials, including parts of tobacco plants (for example, the genus Nicotiana, in quantities that do not generate significant, can have a therapeutic effect, nicotine levels).

Examples of antioxidants include, among others, tocopherol, ascorbic acid, sodium pyrosulfite, butylhydroxytoluene, bottled hydroxyanisol, ethylenediaminetetraacetic acid and its salts. Examples of preservatives include, among others, citric acid, tartaric acid, lactic acid, xiantao acid, acetic acid, benzoic acid and sorbic acid.

Examples of thickeners include, among others, pectin, polyethylene oxide and carageenan. In one of the embodiments of the invention, the thickeners are used in amounts comprising from about 0.1% to 10% by weight.

Test raspadaemost

In one of the embodiments of the invention disintegrating in the oral dosage form/part meets the criteria for tablets, disintegrating in the oral cavity, listed in the Control Protocol for the quality control of Isaevich products and medicines of the USA, published in April 2007, incorporated herein by reference. In one of the embodiments of the invention disintegrating in the oral dosage form/part of the object of the present invention, is the corresponding dual definition disintegrating oral tablets, including the following criteria: 1) that the solid dosage form is one that contains a drug substance and quickly, usually within seconds, decays, if you put it on the language and 2) such is considered a solid dosage form for oral administration, which rapidly disintegrates in the oral cavity and is characterized by the time raspadaemosti in vitro, approximately 30 seconds or less, based on the results of test raspadaemost based on the method developed for specific medical supplies in accordance with the requirements of the Pharmacopoeia of the United States (USP).

In order to determine raspadaemost in vitro for this dosage form should be used test designed for tablets, not coated, in accordance with the USP30-NF25 (as the immersion liquid is water). Briefly, a single unit dose of the medication is placed in each of six glass tubes baskets app is RA, when this water (the temperature of which is maintained at 37±2°C) is used as the immersion liquid. During raspadaemosti take the largest of the six measurements of the time required for complete disintegration of the appropriate dosage forms/parts. In one of the embodiments of the invention the time raspadaemosti in vitro for disintegrating in the oral dosage form/part is less than about 30 seconds, namely less than about 15 seconds.

In one of the embodiments of the invention, where the disintegrating in the oral cavity inner part combined with an edible outer part, the time of the destruction of the outer edible portion in vitro is at least ten times, namely, at least 50 fold or at least 100 times longer period than the time of the destruction of parts of the disintegrating in the oral cavity.

Hardness test

Hardness is a term used in the field and describing the amount of force required to break the tablet in diameter, and is measured using a device for determining a Schleuniger hardness according to the method described in the book Leiberman et al., Pharmaceutical Dosage Forms - Tablets, Volume 2, 2nd ed., Marcel Dekker Inc., 1990, p. 213-217, 327-329. For testing the hardness of a single unit dose of the medication is placed in a steel chamber device is, determining the hardness of the tablets, and the steel piston exerts pressure on the medical form up until it will not break, while the applied force and is the result of measuring the hardness. Usually examine 5 units/pieces for each sample of the dosage form in order to obtain the average value of the hardness, expressed in pounds-force. In one of the embodiments of the invention, the dosage form has a hardness of less than 2.3 kg/cm3(5 kgf/cm3), as, for example, such as less than 0.9 kg/cm3(2 kgf /cm3), as, for example, such as less than 0.7 kg/cm3(/1.5 kgf/cm3).

Additional test for hardness disintegrating in the oral dosage form/part of the object of the present invention is based on using the texture analyzer TA-XT2i, equipped with a flat probe with a diameter of 7 mm and is configured to measure compression forces and report on the results, expressed in grams. The probe makes movements at a rate of 0.5 mm per second on the depth of penetration equal to 2 millimeters. Registers the maximum value of compressive strength. In one of the embodiments of the present invention the measured force registered for disintegrating in the oral dosage form/part manufactured in accordance with the tvii with the principles of the present invention, mostly varied from approximately 700 g to about 6000 g and to a maximum level of 10000,

In one of the embodiments of the present invention the bulk material (e.g. powder) slightly lovers at the stage of heating. As a result, the particle size of the hydrate is reduced, requiring less heat for fusing the agglomerate and achieve the same degree of hardness.

Manufacturing and packaging disintegrating in oral dosage forms

(a) Sheet packing unit product

Pharmaceutical dosage forms such as pills, capsules, tablets and the like, may be Packed leaves, such as blister packaging. In one of the embodiments of the present invention blister pack consists of a multilayer sheet material having pockets containing dosage forms. A typical blister package include packaging, having a layer of metal foil, through which the user of the packaging must squeeze the tablet, tearing the foil. In U.S. patent No. 4158411 discussed this blister pack. Blisters, having an open top to accommodate pharmaceutical tablets are manufactured in the form of flexible sheets of plastic or aluminium-containing material. An additional layer of paper maps is on, having perforated areas discoid shape can cover the open top of the blister packs on top of each dosage form. The foil layer covers the layer of cardboard, holding areas discoid shape, designed for extrusion, in the right place. To open the package, the user must press on the blister and push the tablet through the foil, while removing the perforated sections of the cardboard layer.

Another type of blister packaging has a perforation between the partial units of the blister so that the user can separate the individual dose from packaging before opening them. In U.S. patent No. 4398634 illustrated blister pack of this type. Part of the blister is limited razrabotchikami flat, plastic sheet, soldered to one another in special areas on the perimeter of the part. These sites, located on the periphery of each part of the blister, forming pockets unsealed areas, which determine the location of the blisters, located in the Central part of each piece blister pack. Weakened areas in the sealed zones allow the user to divide the blisters on individual units, removing them from the packaging. After separation unit, the user breaks her through the layers of plastic, so that a fault line runs through the blister, for whom Holocene access to the dosage form. The incision is located on the corner of the unit blister pack, easy tearing.

Another type of blister packaging includes individual units, which after separation of the discover tab for opening the blister. In U.S. patent No. 5046618 describes this type of blister packaging. Blister pack of this type is formed from a sheet of material having formed therein cells and essentially flat, closing them, the second sheet. This blister pack has two rows of blisters, each blister unit is separated from adjacent units by perforations. A tear strip is separated series of perforations, going between the tear strips and blister units. To open the package, the user lifts an individual unit from the packaging: this tear-off strip is still attached to the unit. This tear-off strip must be removed to gain access to the eye, located in the unsealed region in the area of the unit blister. After the tear strip has been removed, the user grasping area, removes the covering sheet and pulling it back, discloses pharmaceutical form. Suitable materials for the creation of blister cells to use in order to describe the present invention include, among others, polyvinyl chloride (PVC), polyvinylidene is Lorig (PVDC), aluminum and polychlorotrifluoroethylene (PCTFE).

There are a variety of technological equipment, which can be used for manufacturing blister packaging, including the use of a press for hermetic packaging produced by the company Uhlmann Packaging Systems under model number UPS4, and a rotary device for packaging Bosch Packaging Group Minneapolis, Minnesota, USA, and sold under model numbers TLT TLT 1400 and 2800.

Sheet packaging units product may consist of a sheet having one or more recesses (e.g., from 2 to 12, for example, from 2 to 6)containing dosage forms, which are located, for example, rows or columns. Sheet packaging units product can include multiple packing units, with each unit package includes one recess and the sheet covering this deepening. The set of break lines may be included between adjacent packing unit, so that the user of the package can tear the package along a line break to separate packing units.

Deepening in the packaging and dosage forms, found in these depressions can essentially be of any shape. For example, dosage forms can be in the form of tablets in the form of a disc, oblong capsules, square what's pills, hemispheres or truncated cones. The shape of the recesses include a rounded, oblong, polygonal, triangular cavities or made in the form of stars in the plane of the sheet of the blister.

Moreover, the sides and bottom of the recesses may determine the form in the form of surfaces of revolution around a vertical axis perpendicular to the rim surrounding each of the recesses. For example, the indentations may have a curved, bowl-shaped form. If the dosage form has the form of a disk, it may have the edge on the walls of the cavities, in which such a dosage form is placed. Edge and the wall will determine the rounded region of the coaxial contact with the vertical axis of the recess. The edge of such disc-shaped dosage form may form an angle of contact with the walls of the recess. Rounded contact area prevents shifts dosage forms inside the blister and also the occurrence of the damage associated with such shifts. Sheet packaging units product must have a significant ability to be deformed in order to be able to break it and extract from it disintegrating in the oral dosage form without causing dosage form of any damage. Form sheet packaging units product must also be such that its gap and removing asparaguses in oral dosage forms could be produced without causing damage dosage form. In one of the embodiments of the present invention, the angle (obtuse) tilt the bottom surface blisters in relation to the angle of inclination of its side wall is greater than 90°, for example, more than 110°.

(b) Production using a sheet of packaging units product

Disintegrating in the oral dosage form can be manufactured using a variety of methods. In one of the embodiments of the present invention disintegrating in the oral dosage form is manufactured by a method comprising the following steps: (a) providing a sheet for packaging units product having at least one recess required shape and size sufficient to accommodate the mentioned dosage form; (b) placement within the recess of the installed quantity of bulk material, comprising at least 5% by weight of at least one hydrated salt and a pharmaceutically active agent, and where mentioned hydrated salt is characterized by the temperature of dehydration in the range of about 20 to 120°C; (c) optionally sealing the bulk material within the recess; (d) heating the material placed in the recess to a temperature above the temperature of dehydration mentioned at least one hydrated salt, for p is the period of time sufficient for fusing the material together with the formation of the unit, and (e) cooling the aggregate material within the recesses so that the Assembly becomes solid form suitable for use dosage form, dissolving in the mouth.

In one embodiment of the present invention to the sheet packaging units product (e.g., blister packs) before adding granular material is added to the moving substance. This moving substance may be liquid or solid, or integrated into the material used to create the sheet of packaging units product. Suitable sliding substances include, among others, solid sliding substances, such as magnesium stearate, starch, calcium stearate, aluminum stearate, talc, hydrogenated vegetable oil, sodium fumarate, glyceryl begent, stearic acid, or liquid sliding substances, including, among others, simethicone, lecithin, vegetable oil, olive oil or mineral oil. In certain embodiments of the implementation of the present invention the moving substance is added in a percentage by weight of the disintegrating in oral dosage forms, not exceeding 5%, for example, less than 2%, or, for example, less than 0.5%.

Granular material, preferably in solid form, is the aka as a powder or consisting of solid particles agglomerate, placed in at least one of the recesses of the sheet of packaging units product. In one embodiment of the present invention the bulk material can be defined as a material having an angle of repose of 20 to 44 degrees. In the monograph Terzaghi "theoretical Soil Mechanics in Engineering Practice", Wiley, New York, 1948), the angle of repose is defined as the angle between the horizontal and the slope of the heap of soil material (or powder), dropped from some height. In embodiments implementing the present invention is defined as a constant angle with respect to horizontal, educated conocephalinae a bunch of material. This bunch is formed from a point above the horizontal, by means of two flat glass plates, separated from each other by at least a distance of 1.3 cm (½ inch), allowing the material to paricipates over the edge.

The bulk material is mainly brought in specially designated slots located on the surface of the pallet for product placement, which can serve as a blister pack, as described above. The materials for each unit of packaging, heated to the temperature higher than the temperature of dehydration of at least one hydrated salt, over a period of time sufficient for fusing the material together with images of the drug unit, resulting in a single dosage form suitable for handling, extraction of deepening sheet packaging units product (such as a blister) and ingestion. In one of the embodiments of the present invention other components remain firm and retain their physical properties, including hardness (for example, the temperature of the rest of the content of the recesses in the heating process must be above the dehydration temperature, but below the melting point and temperature of decomposition of other ingredients of the dosage form, including pharmaceutically active agent). The heating time depends on at least one hydrated salt and sizes disintegrating in oral dosage forms or parts should be sufficient, as the temperature for fusing and stabilizing the output of the dosage form. In some cases, the active ingredients may be more sensitive to temperature increase, requiring different minimum temperatures and longer heat-up times.

Acceptable sources of heat include radiant heater, conductive heating, convective heating, radio frequency heating, ultrasonic, microwave heating or laser. In one of the embodiments of the present invention the rate the temperature and the cooling time are what possible connection of carbohydrates or carbohydrate granules with a hydrated salt by a bridge of communication with the formation of solid dosage forms. In one of the embodiments of the present invention a portion of carbohydrate (e.g., carbohydrate granules) is dissolved with the release of water from the hydrated salt and then, after recrystallization, generates the United bridge connection of the crystal structure at the microscopic level. In one of the embodiments of the present invention, the temperature during cooling down from a level approximately equal to 25°C, to a temperature of about 0°C, the time required for cooling is about 10 to 60 seconds. In General, the higher the temperature in the cooling process, the longer the cooling time. In one of the embodiments of the present invention, the cooling is carried out at room temperature (25°C) for more than five minutes.

(c) Production using edible outer part

Disintegrating in the oral dosage form may also be incorporated within a single edible outer part, such as caramel. In one of the embodiments of the present invention caramel is a Lollipop, formed during the cooling of the boiling sugar solution. In another VA who ianthe implementation of the present invention the sugar part is the product of the compression processing with a hardness of at least 15 kgf, as, for example, at least 20 kgf. In one of the embodiments of the present invention adding disintegrating in the oral dosage form is in a pre-made edible outer portion. In one of such embodiments of the present invention the outer shell of caramel or extruded candy is made as edible outer portion, is added to a fixed quantity of a granular material containing at least one active ingredient and dosage form is heated to a temperature and for time period above, required for the formation of disintegrating in the oral cavity preformed part, which is then packaged in blister, bag or bottle. In one of the embodiments of the present invention is an edible outer portion substantially is sealed in order to hold the material during heating or fusing. In these embodiments, the implementation of the present invention is a considerable degree of sealing can be achieved due to the formation of a circle, oval or other geometric shapes, made in the form of, but not limited to the following: triangle, star, moon, etc. and having an inner hollow portion, enough to fill material. This form puts the I to the surface with the purpose of retention of the material. This surface may be suitable for holding any flat shapes, including, among others, made of plastic, metal or composite materials. This can also be achieved using a pre-made sheet of packaging units product; can be applied negative embossing to transfer logo, picture or identifying information product after heating and fusing of the dosage form. Alternatively, the dosage form may be processed by laser or be subjected to printing for aesthetic (geometric shapes, letters, colors, etc) or provide identification (product name, reference doses, and so on).

In one of the embodiments of the present invention the outer part of the caramel is created using universal line for the production of caramel stuffed or hard-boiled, comprising the sequential stretching of the caramel mass, its rolling, followed by cutting and stamping, using special molds. In one of the embodiments of the present invention the outer part of the caramel contains one or more sugars selected from the group comprising isomalt, sucrose, dextrose, corn syrup, lactitol and hydrogenerating hydrolyzed starch. In one of the in the of options for the implementation of the present invention caramel part contains at least 50% (as for example, at least 75%, such as at least 90%) by weight of sugars.

In one of the embodiments of the present invention dosage form consisting of an edible outer part and the inner disintegrating in the oral cavity parts, covered with sugar or film-coated, designed for dosage forms with immediate-release. To produce such a dosage form, stage, following after fusing (heat and subsequent cooling dosage forms should include a coating film or a sugar shell using a specialized setup for the application shell.

In one of the embodiments of the present invention is an edible outer portion contains a pharmaceutically active agent and disintegrating in the oral dosage form contains the same pharmaceutically active agent. In one of the embodiments of the present invention is an edible outer portion contains a pharmaceutically active agent and disintegrating in the oral dosage form contains different from the first pharmaceutically active agent. In one of the embodiments of the present invention is an edible outer portion decays with rate at least 10 times greater than the decay rate of the disintegrating into strips and mouth dosage forms, as, for example, at least 20 times greater. In one of the embodiments of the present invention disintegrating in oral dosage part meets the requirements for control on the quality of the food and drug USA to tablets, disintegrating in the oral cavity. In one of the embodiments of the present invention disintegrating in oral dosage unit contains pharmaceutically active agent, affecting the upper respiratory tract, such as pseudoephedrine, dextromethorphan, cetirizine, diphenhydramine and chlorpheniramine, and edible outer portion contains menthol.

The use of disintegrating in oral dosage forms

In one of the embodiments of the present invention is claimed method of treatment of pathological conditions, namely, the method comprising oral administration of the above dosage forms, where the form includes a dose of the pharmaceutically active agent effective for the treatment of this pathological condition. Examples of such conditions include, among others, the pain (such as headaches, migraines, sore throat, cramps, back pain and myalgia), fever, inflammation, pathological conditions of the upper respiratory tract (as in the example, cough and stuffy nose), infections (such as bacterial and viral infections), depression, diabetes, obesity, disorders of the cardiovascular system (such as increased levels of cholesterol, triglycerides, and blood pressure), pathological conditions of the gastrointestinal tract, such as nausea, diarrhea, irritable bowel syndrome and increased flatulence), sleep disorders, osteoporosis and nicotine dependence.

In one of the embodiments of the present invention is disclosed a method of treatment of diseases of the upper respiratory tract, where the pharmaceutically active agent is selected from the group comprising Prilepin, cetirizine, loratidine, Fexofenadine, diphenhydramine, dextromethorphan, chlorpheniramine, chlophedianol and pseudoephedrine.

EXAMPLES

Separate embodiments of the present invention are illustrated by the following examples. The present invention is not limited to the specific scope of these examples.

Example 1: the disintegrating in the oral cavity preformed mixture of immediate-release of loratidine

(a) Cold forming blister packing

Using a machine for the manufacture of blisters Bosch TLT 1400 rotary device for thermal packing) is the unwinding of a roll of aluminium-containing material is material for the manufacture of blisters and his step-by-step movement in the direction of the transfer case installation where under the action of compressed air and/or vacuum in the rolled material are formed depressed shallow round depressions with a diameter of 1.6 cm (5/8 inch)bearing the identifier printed trade name of the product.

The resulting mesh fabric, the step moves to a distributing plant, where tableted dosage form described below in example 2, is distributed formed on the grooves.

(b) a Preformed mixture

Disintegrating in the oral cavity preformed mixture of immediate-release of loratidine includes the ingredients listed in table 1, and is manufactured as follows.

Table 1
The granulated mixtureg/Batchmg Tablet
Dextrose monohydrate87,711052,5
The hydrate of sodium hydrogen phosphate*9,74116,9
Sucralose USP0,607,2
Flavor1,12 the 13.4
Loratidine0,8310,0
Total100,01200,0
*Chemical formula: Na2HPO4·7H2O

Dextrose monohydrate, Sucralose and flavoring agents sifted through a 30 mesh sieve and placed in a plastic bottle 500 ml and mixed for 5 minutes. Also added loratadin and hydrate of sodium hydrogen phosphate and mixed for another 3 minutes. The mixture is then filled pre-formed recesses blisters mentioned in example 1.

(c) Packing blisters

Forming blisters pins and hammers used to form recesses for the subsequent filling of bulk material, contain a small amount of injection ports for introducing from about 0.1 to 5 mg of soybean lecithin on the surface of the blister after formation of the recess, which will facilitate subsequent retrieval of the dosage form. Formed the template for blisters from example 1, the next step is moving in the direction of the packing plant, where it is closed by a cover foil. The material for the cover otkatyvaetsya roll and the hermetically prepaid who is using heat and mechanical pressure, the resulting product is enclosed in the cavity of the blister. Sealed blister is placed in a convection oven heated to 55°C for 15 minutes.

Sealed roll material, the step moves to the installation for the production perforations. Installation for the production perforations uses blade sharp knives for applying perforations through the rolled material, resulting in a blister card with a special eye to facilitate its opening. Finally, the rolled material is pushed to the plant, where the cutting of the rolled material on individual blister cards, each of which contains 6 disintegrating in oral dosage forms.

The cavity of the blister is then cooled to 0°C for 5 minutes and Packed. Further pills are extracted from the cavity of the blister and ingested as a single individual doses.

Example 2: production of external edible annular part with fused inner part of the disintegrating in the mouth tablets

(a) the Manufacture of external edible annular part

All materials listed below in table 2, manually sifted through a sieve with a pore size of 30. One and a half (1,5) kg of the resulting mixture is placed in a V-shaped mixer with a capacity of 4 quarts and mixed for 5 minutes.

Table 2
IngredientsThe weight percent (in/in)Weight (mg)
Sorbitol550
A compressible starch*92,75927,5
Menthol110
The aroma of peppermint0,55
Magnesium stearate0,757,5
TOTAL1001000
* Comes on commercial terms firm Domino Specialty Ingredients, Baltimore, MD

Four hundred (400) grams of the resulting mixture is extracted from the mixer and subjected to compression processing using a rotary tablet press at a speed of 60 rpm using a 1.9 cm (3/4 inch) device for ring-shaped tablets for the manufacture of flat rings having an empty Central part of the $ 1.3 cm (½ inch) and weighing 1000 mg, and tverdostyu limits not less than 6.8 kg/cm 2(15 kgf/cm2) and a thickness of about 0.5 cm (0.20 per inch).

(b) the Manufacture of internal disintegrating in the mouth parts

Disintegrating in the oral cavity preformed mixture of immediate-release of loratidine includes the ingredients listed in table 3, and is manufactured as follows.

Table 3
The granulated mixtureg/Batchmg Tablet
Dextrose monohydrate86,67433,3
The hydrate of sodium hydrogen phosphate*9,6248,1
Sucralose USP0,63
Flavor1,125,6
Loratidine210
Total100500
*Na2HPO4·7H2O

Dextrose monohydrate, Sucralose and aromatizata the s sifted through a sieve of 30 mesh, placed in a plastic bottle 500 ml and mixed for 5 minutes. Also added loratadin and hydrate of sodium hydrogen phosphate and mixed for another 3 minutes.

(c) the Manufacture of external edible annular part with fused inner part of the disintegrating in the mouth tablets

External edible annular portion described in paragraph (a), is placed in the formed cavity of the blister. 500 mg of the mixture described in paragraph (b), then fill a void in the Central part of the ring, and the blister is sealed. Sealed blister is placed in a convection oven heated to 55°C, for 15 minutes. The cavity of the blister is then cooled to 0°C for 5 minutes. Further pills are extracted from the cavity of the blister and ingested as a single individual doses.

Means that despite the fact that the disclosure of the present invention is accompanied by a detailed description, the above description was intended to illustrate but not to limit the scope of this invention, which is defined by the range of the attached claims. Other aspects, advantages and modifications identified above mentioned claims.

1. The method of obtaining dosage forms, including:
a) placing inside the deepening of the bulk material, comprising (i) m is Nisha least about 5 wt.% at least one hydrated salt and a pharmaceutically active agent, and where at least one hydrated salt is characterized by the temperature of dehydration from 20 to 120°C;
b) heating the granular material in the recess to a temperature exceeding the temperature of dehydration of at least one of the mentioned hydrated salt over a period of time sufficient for fusing the material together with the formation of the unit, and the heating is carried out by radio frequency or microwave heating; and
c) cooling the Assembly in the recess prior to the solidification unit dosage form.

2. The method according to claim 1, in which at least one hydrated salt selected from the group consisting of hydrate of sodium sulfate, hydrate of sodium carbonate, hydrate of calcium chloride, hydrate of sodium hydrogen phosphate, and mixtures thereof.

3. The method according to claim 1, in which dosage form comprises from 5 to 40 wt.% at least one hydrated salt.

4. The method according to claim 1, in which the aforementioned bulk material further comprises at least one carbohydrate.

5. The method according to claim 4, in which at least one carbohydrate selected from the group consisting of dextrose, dextrose monohydrate, lactose, glucose, fructose, isomalt, sucrose, mannose, maltose, maltodextrin, dried corn syrup, hydrogenated starch hydrolysates, lactitol, xylitol, mannitol, at the hands of Eritrean is Itala and sorbitol, as well as mixtures thereof.

6. The method according to claim 4, in which at least one carbohydrate is a dextrose monohydrate.

7. The method according to claim 1, in which the dosage form contains at least 40% of at least one carbohydrate.

8. The method according to claim 4, in which the weight ratio of at least one hydrated salt and at least one carbohydrate is from 1:4 to 1:20.

9. The method according to claim 1, in which the bulk material is compacted in said recess prior to heating.

10. The method according to claim 1, in which recesses are blister packaging.

11. The method according to claim 1, which uses radio frequency heating.

12. The method according to claim 1, wherein the cooling is carried out at room temperature.

13. Dosage form obtained according to the method according to claim 1.

14. Dosage form according to item 13, which mentions the bulk material further comprises at least one carbohydrate.

15. A method of obtaining a dosage form comprising an external edible part and the inner part, disintegrating in the oral cavity, where the method includes the following stages:
a) creating an outer edible form, with the deepening of the desired shape and size sufficient to accommodate a portion of the dosage form, disintegrating in the oral cavity;
b) placing inside the deepening of the bulk material, including the surrounding (i) at least 5 wt.% at least one hydrated salt (ii) a pharmaceutically active agent, and where at least one hydrated salt is characterized by the temperature of dehydration from 20 to 120°C;
c) heating the granular material in the recess to a temperature exceeding the temperature of dehydration of at least one of the mentioned hydrated salt over a period of time sufficient for fusing the material together with the formation of the unit, and the said heating is carried out by radio frequency or microwave heating; and
d) cooling the Assembly in the recess prior to the solidification unit dosage form.

16. The method according to clause 15, which referred to the bulk material further comprises at least one carbohydrate.



 

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17 cl, 3 dwg, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a pharmaceutical composition for the correction of cerebrovascular disease accompanying cardiovascular diseases which contains the active ingredients presented by atorvastating or pharmaceutically acceptable salt thereof and nicergolin in the therapeutically effective amounts.

EFFECT: pharmaceutical composition is characterised by high stability and bioavailability.

8 cl, 8 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to an oral solid dosage form containing a therapeutically effective amount of aliskiren or its pharmaceutically acceptable salt wherein an active ingredient makes more than 46 wt % of total weight of the oral dosage form. The oral dosage form is presented in the form of a tablet or a film-coated tablet, and contains an internal phase containting aliskiren or its pharmaceutically acceptable salt, an excipient, a binding agent and a disintegrant, and an external phase containing a disintegrant, an excipient, a glidant and a lubricant.

EFFECT: invention provides administration of the active ingredient aliskiren in the small oral dosage form; it is characterised by an acceptable disintegration time.

32 cl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, more specifically to an agent to be used for treating arterial hypertension and congestive cardiac failure. A pharmaceutical composition contains ramipril, a combination of sodium bicarbonate and arginine as a stabiliser, lactose monohydrate, microcrystalline cellulose, hypromellose, sodium croscarmellose, glidant and a lubricant and optionally a dying agent. A method for preparing the pharmaceutical composition involves moisturising of a mixture of ramipril, lactose monohydrate, microcrystalline cellulose, sodium bicarbonate, and optionally the dying agent in a solution of hypromellose and arginine, granulation, drying, dry granulation, addition of sodium croscarmellose, glidant and the lubricant, and tableting of the prepared mixture. The pharmaceutical composition in the form of a solid dosage form is characterised by decreased formation of all impurities, including ramiprilate and diketopiperazine ramipril, fast release of the active substance, high strength and storage stability of the quality characteristics guaranteed within more than 2 years of shelf life.

EFFECT: preparing the agent for treating arterial hypertension and congestive cardiac failure.

11 cl, 2 tbl, 12 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to medicine, namely pharmacy and may be used for creating an oral solid dosage form. The dosage form contains a pharmaceutically acceptable salt of an alkaline-earth metal of 5-methyk-(6S)-tetrahydrofolic acid and granules containing progestogen, oestrogen and microcrystalline cellulose. What is also presented is a pharmaceutical kit for females for providing the concentrations or treating the diseases, conditions or symptoms associated with endogenous oestrogen deficiency.

EFFECT: group of inventions provides the good storage stability of tetrahydrofolic acid, and at the same time provides rapid and reliable release of oestrogen and progestogen being parts of the composition.

13 cl, 3 dwg, 4 tbl, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of medicine and deals with combined pharmaceutical composition, which possesses anti-tuberculosis action. Composition is made in form of solid drug form, which contains combination of levofloxacin, protionamide, pyrazinamide, ethambutol hydrochloride and pyridoxine hydrochloride ad active ingredient, and pharmaceutically acceptable auxiliary substances.

EFFECT: composition is characterised by high therapeutic activity.

10 cl, 2 tbl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to tablet, which is decomposed in mouth, containing D-mannite, active ingredient, disintegrating preparation, selected from crospovidone and carmellose, lubricant, selected from sodium stearylfumarate and sucrose esters of fatty acids, binding agent and starch. D-mannite has average size of particles larger than 30 mcm and specific surface larger than 0.40 m2/g.

EFFECT: claimed tablet has time of decomposition in oral cavity within 30 seconds, excellent sensation in oral cavity and sufficient strength, as a result of which tablet is not decomposed in the process of distribution.

28 cl, 1 dwg, 12 tbl, 51 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to chemical-pharmaceutical industry and represents a pharmaceutical composition containing: {1S-[1α,2α,3β(1S*,2R*),5β]}-3-(7-{[2-(3;4-difluorophenyl)cyclopropyl]amino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl)-5-(2-hydroxyethoxy)cyclopentane-1,2-diol; an excipient representing mixed mannitol and dibasic calcium phosphate dihydrate; a binding agent representing hydroxypropyl cellulose; a disintegrant representing sodium starch glycolate; and one or more lubricating agents.

EFFECT: invention provides preparing the composition of the active compound possessing high stability and high bioavailability of the active agent.

12 cl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to chemical-pharmaceutical industry and represents a drug preparation containing 97.0-59.5 wt % of naltrexone base, 0.5-3.0 wt % of corticosteroid specified in triamcinolone, betamethasone or dexamethasone, 2.0-37.0 wt % of a nitrogen-containing polymer composition and 0.2-0.5 wt % of stearic acid or magnesium stearate. The nitrogen-containing polymer composition contains N-vinylpyrrolidone and 2-methyl-5-vinylpyridine copolymer or a salt of branched oligomers hexamethylene diamine and guanidine, and polyvinylpyrrolidone. The drug preparation may be used in addictology for treating the alcohol- or opioid-dependent patients.

EFFECT: invention provides prolonged and uniform naltrexone release with a lower probability of the implant rejection caused by an inflammatory response.

2 cl, 3 ex, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutics and medicine, namely a stable pharmaceutical composition of a water-soluble salt of vinorelbine. The composition contains approximately 56 wt % of a diluent, approximately 2.5 wt % of a binding agent, approximately 5 wt % of a disintegrant, approximately 0.25 wt % of a flow agent and approximately 0.5 wt % of a lubrication agent. The water-soluble salt of vinorelbine is preferentially vinorelbine ditartrate.

EFFECT: pharmaceutical composition is preferentially presented in the form of a gelatine capsule or a tablet.

5 cl, 6 ex, 12 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to pharmacology and medicine. The group of inventions involves pharmaceutical compositions containing 5-azacytidine for the oral introduction wherein the compositions release a cytidine analogue substantially in stomach, a method of treating an individual suffering a disease associated with abnormal cell proliferation which involves the oral introduction of the pharmaceutical composition into the individual, using 5-azacytidine for preparing the pharmaceutical composition for treating the disease associated with abnormal cell proliferation.

EFFECT: invention provides higher clinical effectiveness.

9 tbl, 9 ex, 23 dwg

FIELD: medicine, pharmacy.

SUBSTANCE: invention proposes new tablets with size less 3 mm with sustained-releasing the opioid analgesic drug for 30 min in the amount above 75%. Invention provides opioid for oral intake with taking into account individual necessity of patient due to selection of required amount of mictotablets by dispenser.

EFFECT: valuable properties of tablet, expanded assortment of medicinal formulations of opioid analgesics.

19 cl, 4 tbl, 4 ex

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