Solid dosage form for oral administration of pharmaceutically active substances that have adverse organoleptic properties
(57) Abstract:Usage: in medical practice. The essence of the invention: solid pharmaceutical form, preventing adverse organoleptic properties of active substances, contains a core with an active substance coated with a polymer membrane, soluble at pH 5 and above. Dosage form contains one or more pharmaceutically acceptable organic acids. The acid may be: fumaric, citric, ascorbic and wine. The shell of the nucleus can be made of the following polymers: a copolymer of methacrylic acid and methyl methacrylate or ethyl methacrylate, talatalatat cellulose phthalate of oksipropilmetiltselljulozy, polyvinylacetate, shellac, activatestatusnotifications, carboxymethylcellulose, trimellitates cellulose and a copolymer of maleic acid and a derivative of phthalic acid. 6 C.p. f-crystals, 3 tables. The invention relates to dosage forms containing the composition, which mask the taste of orally injected drugs.Oral introduction of solid dosage forms, e.g. tablets, often causing problem swallowing in patients, especially in children and the elderly. For Wallpaper is bletcham, which quickly dissolved in the mouth or in full spoon of water, and a bag (sachet) with monodose, the contents of which are dissolved or suspended in a glass of water.However, unfortunately, many drugs have an unpleasant, bitter or irritating taste and, therefore, it is necessary to mask the taste. For taste masking particles medication may be covered with a membrane, which prevents the release of medicines into the water (if it is in water before swallowing) and in the oral cavity during swallowing, but releases the drug after ingestion.The most suitable membranes for this purpose are impervious to water and saliva, but which dissolve under the action of the environment of the gastrointestinal tract. Among the most acceptable membranes can lead those that are composed of polymers that are insoluble in water or in an acid environment, but soluble at pH 5, i.e. in the environment of the gastrointestinal tract. However, the pH of the saliva is also higher than this value, so that a partial dissolution of the membrane with the subsequent occurrence of an unpleasant taste may begin in the mouth.For example, the famous oral preparation consisting of a core containing the drug with NC in water 
Now it was discovered that this difficulty can be eliminated or minimized by the addition of acidic substances to the oral input pharmaceutical forms, so the acid compounds are dissolved with the establishment of a microenvironment around the coated particles, which prevents the dissolution of the polymers made from the membrane. Consequently remains masking taste in the mouth when you cover the drug.According to the invention offers a solid dosage form for oral administration consisting of a core containing the active substance and coated with a polymer membrane, which is soluble only at a pH of 5 or above. At this dosage form contains a pharmaceutically acceptable organic acid to reduce or prevent dissolution of the membrane in the oral cavity. The acid number 1-20% by weight of the total form.The core may be, for example, by the medicine, for example, in crystalline form, or it may be granules containing the drug.The form can be prepared by coating a core with a polymer that forms a polymer membrane, and adding acidic compounds.As the organic acid lekarstvi wine.The polymer shell of the nucleus can be made from a group of polymers comprising a copolymer of methacrylic acid and methyl methacrylate or ethyl methacrylate, talatalatat cellulose phthalate of hydroxypropylmethylcellulose, polyvinylacetate, shellac, accentuated the hypromellose, carboxymethylcellulose, trimellitates cellulose or a copolymer of maleic acid and a derivative of phthalic acid.As the active substance form can contain, for example, an antibiotic or ibuprofen. The kernel size can be in the range of 100-1200 mm. Preferably the size of the kernel is 200-700 μm. Dosage form may be in the form of tablets or pouch (sachet).The invention provides masking of the taste of the medicine contained in pharmaceutical formulations by coating a polymer membrane, which is soluble only at a pH of 5 or above. When this acidic compound reduces or prevents the dissolution of the membrane in the oral cavity.According to the invention, the drug will be released only when the covered core (e.g., particles) pass through the stomach and reach the intestines where the pH is 6 or higher (this happens quickly, osobennaya is that can be obtained masking the taste of the action by using a membrane that is insoluble at high pH (above 5) and soluble at low pH (1.2 to 1.5), such as, for example, Eudragit E; it is insoluble in the oral cavity (and therefore has a beneficial effect on the masking of taste and soluble in the intestinal tract. However, if the movement of the dosage form is particularly fast, which may be particles of small size and an empty stomach, there is a risk of incomplete dissolution of the membrane and also incomplete absorption of the medication.The invention also differs from that described in the patent EP-A-O 101 418, where the substance, for example, carbohydrates and polysaccharides, are added to compositions containing cover the drug, for example, semi-permeable and independent of pH membranes. These substances prevent or provide slowly allocation of drugs through the membrane, whereas in the present invention the acidic substances prevent the dissolution of the membrane covering the drug, not the dissolution of drugs.The invention is particularly suitable for medication with particularly unpleasant taste or that can irritate the mouth; as illustrative, but not ogranichivaya, cimetidine, carboxymethylcysteine, thiopropyl, dextromethorphan hydrobromide, codeine and its salts, 5-aminosalicylic acid, macrolides, and antibiotics such as penicillin and its derivatives, erythromycin and its complex or simple esters (for example, roxithromycin), cephalosporin and tetracyclines. Before coating, it is advisable to pelletize the medication, although granulation is not significant.However, the granulation is useful for optimizing the particle size distribution of the particles and can be essential when using known dry (seal) or wet technology.Preferably the core (for example, containing the drug in crystalline or granular form) has a size in the range from 50, 100 or 200 µm to 1500, 1200, or 700 μm. The preferred interval size is 100-1200 μm, preferably 200-700 μm.For masking the unpleasant taste of the medicine it is covered by a membrane consisting of polymers mentioned above, having pH-dependent solubility, and more specifically, polymers, insoluble in the acid environment and soluble at pH 5 or higher.Cover the drug in these polymers can be carried out by a known method is 3 415 758 and 3 341 416 and in the European patent 0038585.the floor in the trays to cover, as shown in the examples of the Italian patent 929112 and canadian patent 879042.the floor in the liquefied layer, as shown in the examples in U.S. patent 3 186 827 and 3 253 944 D. E. Wurster.Coated granules drugs are very thin and irregular and, therefore, have a large surface area. Due to the fact that the membrane has only a few micrometers thickness even at high mass percentage of the membrane, so within a short time, during which all or some portion of the particles remains fully or partially in the mouth, dissolution or swelling, even partial, of the membrane may occur with subsequent release of unpleasant taste.Now it was discovered that this difficulty can be eliminated or minimized in accordance with the invention, if the recipe is to add an acidic substance in such quantity to maintain the microenvironment at pH below 5 during the stage of passage through the oropharyngeal cavity. Obviously, more acidic microenvironment better, although an excess of the acid itself can give a bad taste.It was found that the optimum amount of acid varies in head is to be placed. As illustrative, but not limiting examples of acidic compounds can lead fumaric, citric and tartaric acids.Compositions of the invention may be in a pharmaceutical form that is easy to give to children, the elderly and patients with difficulty swallowing. Examples are formulations of pills and a sack with monodose. Examples of tablets are tablets that can be chewed or which dissolve in the mouth or quickly desagregirutee (e.g., one minute) in small quantities (tablespoon) water pouches with monodose can be given directly or suspended in a small amount of water (e.g. 20-50 ml).Example 1.(A) Preparation of the granulate
Put 2000 of roxithromycin in a laboratory mixer, mixed with an aqueous solution consisting of 257 g of polyethylene glycol 6000 and 600 g of purified water.Granularit on the 600 µm sieve and dry the granules at a temperature of approximately 45oC. Use fractions between 500 and 210 μm.(B) Coating the granules in the liquefied layer.Placed 350 g of Eudragit L 100-55, 121 g IH sodium hydroxide, 122,1 g of talc, 36 g of triethylcitrate, of 57.8 g Ozernoy perfumes and 1910 g of purified water in a vessel made of stainless Bunny insert Worcester, and sprayed a pre-prepared suspension via atomizer.Dried granules at a temperature of about 50oC sifted through a sieve 600 micron.The selection of the coated granules is determined in artificial juices in accordance with the method described in USP XXII (blade stirrer, 200 rpm./min, see table. 1
(C) Preparation of tablets
Put 346,8 g microcrystalline cellulose, 66 g Kollidon CL, 18 g of sodium saccharin, 90 g of fumaric acid, 6 g of lauryl sodium, 12 g of Aerosil, 30 g strawberry perfumes, 12 g of magnesium stearate and 451,2 g of granulate (B) in a cubic mixer.Stirred for 20-25 min and pressed.Tablet weight 172 mg contains 60 mg of roxithromycin.The formulation of these tablets was studied, it was shown that they disintegrate in less than 30 s in a tablespoon of water or directly in the mouth. To maintain masking the taste is added fumaric acid, which supports the microenvironment at pH lower than that at which dissolves the membrane.The resulting protection is satisfactory, indeed, as can be seen from the data presented in paragraph (C), the allocation under relatively acidic pH is low, therefore, unpleasant taste l is giant will be released in the intestinal tract, when will be achieved this pH, as shown by tests on bioavailability.Example 2.(A) Preparation of the granulate
Put 1400 g of ibuprofen in a laboratory mixer and mixed with a solution composed of 210 g of 95% ethanol and 37 g of ethyl cellulose.Granularit on a sieve of 500 μm and dried granulate with approximately 45oC. Use the fraction between 500 and 210 μm.(B) Coating the granules of coacervation
Prepare a solution of 1870 g of purified water, 100 g phthalate cellulose acetate and 25.7 sodium bicarbonate.Prepare a solution containing 600 g of sodium sulfate in 2800 g of purified water. Placed in a container of pre-cooked solution phthalate cellulose acetate, a solution of 1500 grams of sodium sulfate and 600 granulate (A). Stirred for about 5 minutes and add the remaining solution of sodium sulfate.Filtered the obtained microcapsules and washed with water until, until you remove the sodium sulfate. Dried microcapsules at approximately the 50oC for 3-4 h and sieved through a sieve 600 micron.Determine the allocation of the coated granules in artificial juices in accordance with the method described in USP XXII (blade stirrer, 150 rpm./min, see table. 2.Stirred for 20-25 min and pressed.One tablet weighing 40 6,5 mg contains 200 mg of ibuprofen.Formulation of tablets examined by the method of example 1, to obtain rapid disintegration in the mouth or in a tablespoon of water and add fumaric acid to maintain the microenvironment at acidic pH.Example 3.(A) Preparation of the granulate
Put 2000 erythromycin in laboratory mixer and stirred for about 20 min with 1380 g of an aqueous solution of 15% hydroxypropylmethylcellulose. Granularit through a sieve 720 μm and dried in an oven at approximately 40oC for 15-20 hUse fraction between 500 and 210 μm.(B) Coating the granules in the liquefied layer
Put 550 g of granulate (A) (500-210 ám) UNI Glatt container with liquefied layer with insert Wurster, and is sprayed through an atomizer 7140 g of a solution having the following composition: 428,7 g phthalate of hydroxypropylmethylcellulose, 21,3 g plasticizers 1340 g of ethyl alcohol, 5350 g of methylene chloride.Dried is renal determine in artificial juices in accordance with the methodology described in USP XXII (blade stirrer, 100 rpm./min, see table. 3
(C) Preparation of bags with montazemi.In a cubic mixer placed 2490 g of sorbitol, 165 g xanthan resin, 18 g of PVP K 30, 1.5 g of saccharin sodium, 37,5 g of citric acid, 112,5 g grapputo odorants, 22,5 g of talc, 0.4 g of sodium docusinate and 873 g of the granules (B).Stirred for 20-25 min and divided into bags made of paper (aluminium) non-toxic polyethylene and sealed.One 2400 g package monodose contains 250 mg of erythromycin.Similarly to the procedure in examples 1 and 2 in the composition of the package add citric acid to preserve acidic pH and, therefore, mask the taste in the oropharyngeal cavity.Similar results to maintain taste masking produced by adding acids in the finished recipe when replacing erythromycin a cephalosporin or penicillin and their derivatives. 1. Solid dosage form for oral administration of pharmaceutically active substances that have adverse organoleptic properties, consisting of a core containing the active substance coated with a polymer shell, characterized in that it further comprises a pharmaceutically prier 5 and above.2. Form p. 1, characterized in that as organic acids it contains one or more acids selected from the group: fumaric, citric, ascorbic and wine.3. Form PP.1 and 2, characterized in that the polymer shell is made of polymers selected from the group comprising a copolymer of methacrylic acid and methyl methacrylate or ethyl methacrylate, talatalatat cellulose, flatheadlibertybell, polyvinylacetate, shellac, accentuated the hypromellose, carboxymethylcellulose, trimellitates cellulose or a copolymer of maleic acid and a derivative of phthalic acid.4. Form PP.1 to 3, characterized in that the active substance it contains an antibiotic or ibuprofen.5. Form PP.1 to 4, characterized in that the kernel size is in the range of 100 to 1200 μm.6. Form under item 5, characterized in that the kernel size is in the range of 200 to 700 μm.7. Form PP.1 to 6, characterized in that it is made in the form of tablets or pouch (sachet).
FIELD: medicine, in particular composition for quick-disposable in buccal cavern tablets.
SUBSTANCE: claimed composition contains granulated product of fine dispersed long releasing particles, comprising drug and fillers selected from group including sugars and sugar alcohols together with binder, wherein content of non-granulated fine dispersed long releasing particles is 0-15 %. Method for production of such tablets is also disclosed.
EFFECT: pharmaceutical composition with accelerated degradation.
24 cl, 9 ex, 3 dwg
FIELD: medicine, pharmacy.
SUBSTANCE: invention relates to a pharmaceutical composition that comprises internal lipophilic matrix and external hydrophilic matrix in the mass ratio of lipophilic and hydrophilic matrices from 100:0.5 to 100:20. The internal lipophilic matrix consists of substances with melting point below 90oC and comprises at least partially an active component as globules. As an active component the composition comprises mesalazine - 5-aminosalicylic acid in the concentration up to 95 wt.-%. Lipophilic matrix is dispersed in external hydrophilic matrix. The composition can comprise optionally other excipients. Also, invention describes a method for preparing the composition. Invention provides sustained-release of mesalazine from first phases after administration and more homogenous pattern of release as compared with conventional systems.
EFFECT: improved properties of composition.
11 cl, 5 ex
FIELD: medicine, pharmacy.
SUBSTANCE: invention relates to a medicinal formulation with the constant rate for releasing a medicinal substance, core of medicinal formulation and to a method for providing relieved release of medicinal substance. Medicinal formulation comprises medicinal substance-containing layer and semi-permeable wall and expanding layer. A layer promoting to moving forward is placed between semi-permeable wall and medicinal substance-containing layer and the content of medicinal substance is at least 20% of the total layer mass containing a medicinal substance. Invention provides releasing practically all amount of medicinal substance from medicinal formulation to medium for it applying.
EFFECT: improved and valuable medicinal and pharmaceutical properties of medicinal formulation.
12 cl, 13 dwg, 8 ex
FIELD: medicine, cardiology, pharmacy.
SUBSTANCE: invention relates to carvedilol-containing pharmaceutical composition that is used for treatment and/or prophylaxis of hypertension, cardiac insufficiency or stenocardia. The composition comprises carvedilol or its pharmaceutically acceptable salt and one or some adjuvants. Carvedilol is distributed in adjuvants as a molecular dispersion. Adjuvants are not surface-active substance and/or non-ionogenic surface-active substance. The concentration of adjuvants exceeds 5 wt.-%. Also, invention describes a method for preparing the composition and pharmaceutically acceptable solid formulation for oral administration. Compositions of the present invention provide the enhancing solubility of carvedilol and level of its absorption in lower regions of intestine.
EFFECT: improved and valuable pharmaceutical properties of composition.
17 cl, 9 ex
FIELD: pharmaceutical industry.
SUBSTANCE: invention provides oral-administration beta-histin-based controlled-release solid preparation prepared by granulating active ingredient from melt with fat component added followed by mixing thus obtained granulate with hydrophilic polymer and conventional excipients. Invention enables preparation of pharmaceutical dosage form with appropriate beta-histin release profile allowing reduction of daily drug intake to single dose, whereas concentration of active ingredient is kept constant within therapeutical dose limits.
EFFECT: facilitated therapeutical treatment.
4 cl, 14 ex
SUBSTANCE: the present innovation deals with pharmaceutical composition of bactericidal action. The composition suggested contains ciprofloxacin in the form of hydrochloride monohydrate, maltodextrin as a binding substance, sodium carboxymethyl starch as a disintegrating agent, silica gel, a lubricant at quantities mentioned in its formula. Ciprofloxacin tablets should be obtained due to pressing technique by applying the stage of moisture granulation. If necessary, the surface of tablets should be covered with a hydroxypropylmethylcellulose-based water-soluble membrane. Simultaneous application of maltodextrin as a binding substance and sodium carboxymethyl starch as a disintegrating agent enables to obtain ciprofloxacin-containing tablets of sufficient strength and quick release of active ingredient.
EFFECT: higher efficiency of application.
6 cl, 6 ex, 9 tbl
FIELD: pharmaceutical industry, medicine.
SUBSTANCE: invention relates to human insulin drug with activity of 100 IU/ml, including cartridge forms. Drug contains active ingredient, glycerol as isotonic agent, conserving agent and water, wherein it contains human insulin substance of high purity with residual proteolysis activity not more than 0.005 adsorption units, sodium chloride as additional isotonic agent, m-cresol as conserving agent, and additionally sodium dihydrogenphosphate dihydrate or disodium hydrogenphosphate heptahydrate as substance with buffer capacity and pH 6.9-7.8.
EFFECT: human insulin drug of short action with increased physiological activity and physical and chemical storage stability.
6 ex, 1 tbl
FIELD: pharmaceutical industry, medicine.
SUBSTANCE: invention relates to human insulin drug of durable action. Drug contains human insulin substance of high purity, protamine sulfate, zinc chloride, glycerol, m-cresol, phenol, sodium dihydrogenphosphate dihydrate or disodium hydrogenphosphate heptahydrate, sodium chloride, and water and has residual proteolysis activity not more than 0.005 adsorption units.
EFFECT: human insulin drug of durable action with increased physiological activity and physical and chemical storage stability.
4 ex, 1 tbl
FIELD: pharmaceutics, medicine.
SUBSTANCE: the present innovation deals with cardiotherapy for treating and preventing coronary deficiency. The preparation is designed as a plate (film) consisted of three layers, each of them is manufactured out of co-polymer of vinyl pyrrolidone, acrylamide and nitroglycerin-containing ethylacrylate; moreover, internal layer additionally contains solid fat - cacao oil, and weight ratio for the sum of external layers to internal corresponds to 1 : 1. The suggested preparation could additionally contain brilliant green dyestuff. The preparation should be manufactured out of pre-obtained mixture of nitroglycerin and copolymer in solution of alcohol and water followed by layer-by-layer forming three-layer film due to spreading the mixture onto solid bottom plate and drying at 30-50 C. The innovation provides higher adhesion to gingival mucosal surface, decreased side action, improved bioavailability and stability of therapeutic effect.
EFFECT: higher efficiency of therapy.
3 cl, 3 ex
FIELD: pharmaceutical industry.
SUBSTANCE: invention discloses solid oral dozed pharmaceutical form of hydrocodon with controlled release. Pharmaceutical form comprises analgetically effective amount of hydrocodon or pharmaceutically acceptable salt thereof and controlled-release material. Pharmaceutical forms of hydrocodon are suitable to be administered once a day and provides early commencement of therapeutical effect, which lasts at least about 24 h.
EFFECT: enhanced analgetic action.
44 cl, 3 tbl, 3 ex
FIELD: medicine, pharmacy.
SUBSTANCE: invention proposes a composition comprising as active components pyridoxine hydrochloride and doxylamine succinate and a disintegrating agent that provide the following dissolving pattern: 20-90% of the total amount of each component among pyridoxine hydrochloride and doxylamine succinate are dissolved in 5-120 min. The composition is made preferably as a tablet with an enterosoluble envelope. The tablet has a core comprising pyridoxine hydrochloride and doxylamine succinate, and inactive excipients also. The composition is used in treatment of nausea, vomiting being especially in pregnancy. The composition provides rapid and simultaneous release of synergetic pair of indicated active components.
EFFECT: improved and valuable properties of composition.
24 cl, 2 dwg, 9 tbl, 3 ex