Compositions with controlled liberation

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention describes solid dispersed measured drug including a core with pharmacological agent dispersed in the first matrix for controlled liberation at relatively low speed; and coating covering the core and including the agent dispersed in the second matrix for controlled liberation at relatively high speed. The first matrix can be represented by cross-linked starch with high amylose content, and the second matrix can be represented by polyvinylacetate and polyvinylpyrrolidone mix. Solid measured drug is preferably a pill.

EFFECT: reduced administration frequency, relatively stable medicine concentration in organism for a given time period and reduced undesired side effect frequency and intensity due to reduction of high concentrations in plasma.

19 cl, 5 dwg, 4 tbl, 4 ex

 

The text descriptions are given in facsimile form.

1. Solid dosage form, comprising: a core comprising a pharmacological agent dispersed in a first matrix for controlled release, and a cover formed over the core, containing a pharmacological agent dispersed in the second matrix to con the controlled release in which the first matrix for controlled release contains cross-linked starch with a high content of amylose and/or the second matrix for controlled release includes a physical mixture of polyvinyl acetate polyvinylpyrrolidone and the initial rate of release of agent from the second matrix for controlled release of at least two times greater than the rate of release of the agent from the first matrix for controlled release when measured separately for each matrix material using a device USP type I, 50 mm phosphate, pH 6.8 and under stirring at 100 rpm

2. Dosage form according to claim 1, in which the rate of release of agent from the coating, at least three times the speed of release of the agent from the kernel.

3. Dosage form according to claim 2, in which the rate of release of agent from the coating, from 3 to 9 times the speed of release of the agent from the kernel.

4. Dosage form according to any one of the preceding paragraphs, having the following dissolution profile in vitro, measured using a device USP type I, 50 mm phosphate, pH 6.8 and with stirring from 50 to 150 rpm:

time (hrs.) the release agent, wt.%:

0-210-40
2-730-60
-12 50-80
2080-100

5. Dosage form according to claim 1, in which the weight ratio of the agent in the core of the agent in the coating is in the range from 0.6 to 2.

6. Dosage form according to claim 1, in which the agent is present in the core in an amount of from 30 to 70 wt.% from the overall composition of the kernel.

7. Dosage form according to claim 1, in which the correlation matrix of the coating agent in the coating is in the range from 0.7 to 4.

8. Dosage form according to claim 1 in which the polyvinyl acetate contained in the coating, has a molecular weight of from 100000 to 1000000.

9. Dosage form according to claim 1, in which the polyvinylpyrrolidone contained in the coating has a molecular weight in the range of from 10000 to 100000.

10. Dosage form according to claim 1, in which the coating further includes xanthan gum.

11. Dosage form according to claim 1, in which the weight ratio of the core to the coating is in the range from 0.2 to 0.5.

12. Dosage form according to claim 1, in which the first matrix for controlled release includes cross-linked starch with high amylose content and a second matrix for controlled release includes a physical mixture of polyvinyl acetate and polyvinylpyrrolidone.

13. Dosage form according to claim 1, in which the agent has a solubility in water of more than 500 g/L.

14. Dosage form according to claim 1, in which the agent will gain an ionisable group, and this group is at least an ionisable 90% in the gastric juice (0.1 M model HC1).

15. Dosage form according to claim 1, in which the agent is contained in the kernel, and the agent contained in the coating, is one and the same agent and is a tramadol.

16. Dosage form according to item 15, which is a pharmaceutical composition for oral administration once daily for controlled release of tramadol or its pharmaceutically acceptable salt, after providing unit receiving an average plasma concentration of at least 100 ng/ml within 2 hours of administration and continues to provide the average concentration in plasma, at least for 22 h after injection.

17. Dosage form according to item 16, in which the average maximum plasma concentration (Cmax) 2.2 times lower than the mean plasma concentration obtained 24 hours after administration (C24 hours).

18. Dosage form according to any one of p-17, which provides the concentration of tramadol in the plasma, which is after the time at which the observed maximum plasma concentration (Cmax)decreases linearly in logarithmic scale with a rate constant of visible final excretion (λz) component of 0.12 per hour.

19. Tablet, including dosage form according to any one of the preceding paragraphs.

PR is the priority points:

25.10.2002 according to claims 1 to 19;

10.10.2003 according to claims 1-19.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention concerns new nitrogen-containing heterocyclic derivatives represented by the formula (I): where symbols have the following meaning: R1 and R2 can be equal or different and denote H-, C1-C6-alkyl, C3-C14-cycloalkyl, C1-C6-alkyl-CO-, HO-CO-, C1-C6-alkyl-O-CO-, H2N-CO-, C1-C6-alkyl-HN-CO-, (C1-C6-alkyl)2N-CO-, C1-C6-alkyl-O-, C1-C6-alkyl-CO-O-, H2N-, C1-C6-alkyl-HN-, (C1-C6-alkyl)2N-, C1-C6-alkyl-CO-NH-, halogen, nitro, morpholine, pyrrolidin, imidazol or cyano; R3 and R4 can be equal or different and denote C1-C6-alkyl, C1-C6-alkyl-O-, (C1-C6-alkyl)2N- or halogen; R5 and R6 can be equal or different and denote H-, C1-C6-alkyl or halogen; R7 and R8 can be equal or different and denote H-, C1-C6-alkyl, HO-, C1-C6-alkyl-O- or halogen; R7 and R8 together can form oxo (O=); R9 denotes heterocyclic group -C1-C6-alkyl-CO-, which can be optionally substituted for at least one substitute selected out of a group b described further, where heterocyclic group is selected out of morpholine, piperazine, pyrrolidin, piperidine, thiomorpholine, azepine, diazepine, oxyazepine, decahydroquinoline, decahydroisoquinoline, hexahydroazepine or 2,5-diazabicyclo[2.2.1]heptane; R10, R11, R12 and R13 can be equal or different and denote H- or C1-C6-alkyl; group b: (1) HO, (2) C1-C6-alkyl-O-, (3) R101 R102N (where R101 and R102 can be equal or different and denote (i) H, (ii) C1-C6-alkyl), (4) halogen, (5) oxo (O=), (6) C3-C14-cycloalkyl, (7) phenyl, (8) pyrrolidine, (9) C1-C6-alkyl, which can be optionally substituted for HO, C1-C6-alkyl-O-, phenyl, C1-C6-alkyl-CO- or morpholine, (10) acyl, which can be optionally substituted for oxo (O=), where acyl is C1-C6-alkyl-CO- or heterocyclic -CO group, where heterocyclic group is imidazol, pyridine or pyrazine, (11) H2N-CO- and (12) C1-C6-alkyl-SO2; A denotes heterocycloalkyl group selected out of piperidine, pyrrolidine or hexahydroazepine; n is 0, or its pharmaceutically acceptable salts. The invention also concerns pharmaceutical composition and application of nitrogen-containing heterocyclic derivatives from each of pp. 1-11.

EFFECT: obtaining new biologically active compounds and pharmaceutical composition based on there, with inhibition effect on sodium channel activity.

16 cl, 226 ex, 32 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to the compounds of general formula I , where: X denotes (CR15R16)m-, where: m is 1, R15 and R16- hydrogen; R1 selected from the group consisting of

A-B selected from the group consisting of N-C, C-N, N-N and C-C; D-E selected from the group consisting of O-C, S-C and O-N. The compounds can be used for the treatment of disorders modulated by opiotic receptors, for example, pain and gastroenteric disorder. The method of pharmaceutical composition production and application of the compounds are described.

EFFECT: production of the new compounds for the treatment of disorders modulated by opiotic receptors.

41 cl, 2 tbl, 18 ex

FIELD: chemistry; obtaining of medicinal preparations.

SUBSTANCE: description is given of a compound with general formula where R1 represents a halogen, C1-C6alkyl, CF3, CF2H or cyano, R2 represents C1-C6alkyl, R3 represents 5- or 6 - member hetero-aryl, optionally substituted with one, two or three substitutes, chosen from a group, consisting of a halogen, C1-C6alkyl, C3-C6cycloalkyl, C1-C6alkylhalogen, C1-C6alkoxy, NR'R", or substituted with a 1-morpholinyl group or substituted with thiomorpholinyl groups, 1-oxothiomorpholinyl or 1,1-dioxothiomorpholinyl; R', R" independently represent hydrogen, C1-C6alkyl, (CH2)0,1-(C3-C6)cycloalkyl, R represents hydrogen as well as its pharmaceutical salts and the method of obtaining them. The invention also relates to use of the given amidazole derivatives for obtaining medicinal preparations and to medicinal preparations containing them, meant for prevention or treatment of damages, through the mGluR5 receptor, such as acute and/or chronic neurologic damages, primarily shock pain, or for treatment of chronic and sharp pain.

EFFECT: obtaining of new compounds, with useful biological properties.

40 ex

FIELD: chemistry.

SUBSTANCE: invention refers to benzamide 4-(phenyl-piperazin-methyl) derivatives of the general formula I in which R1 - aryl, heteroaryl, selected from the group which includes difuryl, pyridyl and thienyl; R2 - hydrogen or C1-12 alkyl. The methods of preparation of the compounds, pharmaceutical composition on their basis and application while preparing medicines are described.

EFFECT: compounds can be applied to treatment of pain and functional gastroenteric upset.

8 cl, 1 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel substituted derivatives of cyclohexan-1,4-diamine of the general formula (I): possessing binding property with ORLI receptors and showing homology to opioid μ-, κ- and δ-receptors. Compounds can be used for preparing drugs possessing analgesic effect. In the formula (I) R1 and R2 mean independently of one another (C1-C8)-alkyl, or residues R1 and R2 form in common a ring and mean -CH2-CH2NR6CH2CH2 or -(CH2)3-6 wherein R means (C1-C8)-alkyl; R3 means phenyl, naphthyl or 5-membered sulfur-containing heteroaryl wherein each of them is unsubstituted or monosubstituted with halogen atom, or unsubstituted phenyl added through saturated unsubstituted (C1-C4)-alkyl group; R4 means hydrogen atom (H), saturated (C1-C8)-alkyl or -C(X)R7 wherein X means oxygen (O) or sulfur (S) atom; R means H or (C1-C8)-alkyl either unsubstituted phenyl or phenyl substituted with halogen atom; R5 means (C3-C8)-cycloalkyl, adamantyl, aryl or 5-membered heteroaryl comprising 1-3 heteroatoms chosen from nitrogen, oxygen or sulfur and condensed with one or two benzene rings and wherein each of them is unsubstituted or monosubstituted with a substitute chosen from halogen atom, lower alkyl, lower alkoxy, hydroxy or benzyloxy; or -CHR11R12, -CHR11-CH2R12, -CHR11-CH2-CH2R12, -CHR11-CH2-CH2-CH2R12, -C(Y)R12 wherein Y means O or H2; R11 means H, saturated, linear or branched (C1-C7)-alkyl, saturated or unsaturated, linear or branched, mono- or multisubstituted either unsubstituted -C(O)O-(C1-C6)-alkyl; R12 means phenyl or 5-membered heteroaryl comprising 1-3 heteroatoms chosen from nitrogen, oxygen or sulfur condensed with one or two benzene rings each of them is unsubstituted or mono- or multisubstituted and wherein in values R11 and R12 substituted of alkyl, phenyl or heteroaryl are chosen from halogen atom, lower alkyl, lower alkoxy, hydroxy, trifluoromethyl or benzyloxy; or R4 and R5 form in common 5-membered nitrogen-containing heterocycle that represents unsaturated, monosubstituted lower alkoxycarbonyl-lower alkyl, halogen atom, or it is unsubstituted and condensed with benzene ring under condition that if R means substituted or unsubstituted phenyl and at least one R1 or R2 means (C1-C8)-alkyl then R4 can't mean alkyl, and R3 and R5 can't form in common heterocycle, or if R3 means unsubstituted phenyl and R1 and R2 mean in common -(CH2)5 then R4 means H or (C1-C8)-alkyl; Y means O, and R5 doesn't mean (C1-C6)-alkyl. Also, invention relates to a method for synthesis of compounds of the formula (I) and a drug.

EFFECT: valuable medicinal properties of compounds.

40 cl, 1 tbl, 94 ex

FIELD: medicine, pharmaceutical industry and technology, pharmacy.

SUBSTANCE: invention relates to a method for preparing a drug possessing analgesic, antipyretic and psychostimulating effect. The drug possessing analgesic, antipyretic and psychostimulating effect comprises paracetamol, propiphenazone and anhydrous caffeine as an active components, and starch, microcrystalline cellulose, magnesium stearate, copolyvidon, hydroxypropylmethylcellulose, sodium dodecyl sulfate, crospovidon and croscarmelose sodium as accessory substances taken in the definite ratio of components. Method for preparing a drug possessing analgesic, antipyretic and psychostimulating effect involves stirring sieved powders of paracetamol, propiphenazone, anhydrous caffeine and microcrystalline cellulose followed by wetting the prepared mixture with hydroxypropylcellulose solution and repeat stirring to uniform moisture distribution. Then method involves the successive granulation, drying, powdering prepared granules with a mixture of copolyvidon, dodecyl sodium sulfate, starch, croscarmelose sodium and magnesium stearate to obtain a homogenous mass followed by the tabletting process the prepared homogenous mass. The drug prepared by above described method is made as a tablet and possesses the high dissolving index and the high dosing precision.

EFFECT: improved preparing method of drug.

3 cl, 2 tbl, 1 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention describes a combination used in therapeutic, prophylactic or palliative treatment of pain. Proposed combination consists of the following components: (a) alpha-2-delta ligand chosen from habapentine, prehabaline, [(1R,5R,6S)-6-(aminomethyl)bicyclo[3.2.0]hept-6-yl]acetic acid, 3-(1-aminomethylcyclohezylmethyl)-4H-[1.2.4]oxadiazol-5-one, C-[1-(1H-tetrazol-5-ylmethyl)cycloheptyl]methylamine, (3S,4S)-(1-aminomethyl-3,4-dimethylcyclopentyl)acetic acid, (1α,3α,5α)-(3-aminomethylbicyclo[3.2.0]hept-3-yl)acetic acid, (3S,5R)-3-aminomethyl-5-methyloctanoic acid, (3S,5R)-3-methylheptanoic acid, (3S,5R)-3-amino-5-methylnonanoic acid and (3S,5R)-3-amino-5-methyloctanoic acid, or pharmaceutically acceptable salts of any of them, and (b) S,S-reboxetine or its pharmaceutically acceptable salt wherein alpha-2-delta ligand and S,S-reboxetine are taken in the range of ratio from 1:10 to 10:1 of mass parts. Proposed combination provides decreasing the dose of each substance that results to declining adverse effects and enhancing clinical utility of compounds. Also, invention describes using this combination and a set comprising this combination.

EFFECT: improved, enhanced and valuable properties of combinations.

8 cl, 3 ex

FIELD: organic chemistry, medicine, pharmacology.

SUBSTANCE: invention relates to compounds of the formula: , wherein variable value Y in ring is not obligatory and represents heteroatom chosen from nitrogen (N), oxygen (O) and sulfur (S) atoms under condition that N atom is trivalent and O or S atoms are bivalent; k means a whole number from 0 to 1; n means a whole number 0, 1 or 2; p means a whole number 0, 1 or 2; X means O or S atom; dotted lines represent a bond or its absence under condition that ring comprises only a single double bond and two adjoining lines are not a bond; R1, R2, R3 and R represent independently hydrogen atom (H), phenyl wherein indicated phenyl group is substituted optionally with one, two or three substitutes represented by (C1-C6)-alkyl, -SO3H, -N3, halogen atom, -CN, -NO2, -NH2, (C1-C6)-alkoxy-, (C1-C6)-thioalkoxy-, (C1-C6)-alkylamino-, (C1-C6)-dialkylamino-group, (C2-C6)-alkynyl, (C2-C6)-alkenyl; 5- or 6-membered heteroaryl comprising from 1 to 3 heteroatoms chosen from O, S and N atoms wherein indicated heteroaryl groups are substituted optionally and independently with one, two or three substitutes represented by (C1-C6)-alkyl, -SO3H, -N3, halogen atom, -CN, -NO2, -NH2, (C1-C6)-alkoxy- (C1-C6)-thioalkoxy-, (C1-C6)-alkylamino-, (C1-C6)-dialkylamino-group, (C2-C6)-alkynyl, (C2-C6)-alkenyl, or indicated groups R1, R2, R3 and R4 represent independently alkyl comprising from 1 to 4 carbon atoms, cycloalkyl comprising from 3 to 5 carbon atoms, -CH2CN, -CH2SR5, -CH2NR6R6, -COR5, -CH2OR5, -OR6, -SR6, -NR6R6, alkenyl comprising from 1 to 4 carbon atoms, alkynyl comprising from 1 to 4 carbon atoms, cycloalkyl comprising from 3 to 6 carbon atoms, fluorine atom, chlorine atom, bromine atom, iodine atom, -CF3 or -CN, oxygen atom bound by a double bond with ring carbon under condition that adjoining dotted line inside of ring means absence of a bond; R5 means H, -OR7, alkyl comprising from 1 to 4 carbon atoms, -CF3, cycloalkyl comprising from 3 to 6 carbon atoms, phenyl, phenyl substituted with one or two alkyl groups comprising from 1 to 4 carbon atoms, fluorine atom, chlorine atom, bromine atom, iodine atom or -CF3, either R5 represents 5- or 6-membered heteroaryl comprising from 1 to 3 heteroatoms chosen from O, S and N atoms, and 5- or 6-membered heteroaryl comprising from 1 to 3 heteroatoms chosen from O, S and N atoms substituted with one or two alkyl groups comprising from 1 to 4 carbon atoms, fluorine atom, chlorine atoms, bromine atom, iodine atom or -CF3; R6 means H, alkyl comprising from 1 to 4 carbon atoms, allyl, cycloalkyl comprising from 3 to 6 carbon atoms, phenyl, phenyl substituted with one or two alkyl groups comprising from 1 to 4 carbon atoms, fluorine atom, chlorine atom, bromine atom, iodine atom or -CF3, either R6 represents 5- or 6-membered heteroaryl comprising from 1 to 3 heteroatoms chosen from O, S and N atoms, either 5- or 6-membered heteroaryl comprising from 1 to 3 heteroatoms chosen from O, S and N atoms substituted with one or two alkyl groups comprising from 1 to 4 carbon atoms, fluorine atom, chlorine atom, bromine atom, iodine atom or -CF3; R7 means H, alkyl comprising from 1 to 4 carbon atoms, allyl, cycloalkyl comprising from 3 to 6 carbon atoms, phenyl, phenyl substituted with one or two alkyl groups comprising from 1 to 4 carbon atoms, fluorine atom, chlorine atom, bromine atom, iodine atom or -CF3; R1 and R2 or R2 and R3, or R3 and R4 can form in common a ring with corresponding carbon atoms to which they are bound; fragments represented by substitutes R1 and R2 or R2 and R3, or R3 and R4 have the following formulae (i): , (ii): , (iii): , (iv): or (v): - wherein m means a whole number from 0 to 3; R8 represents independently H, alkyl comprising from 1 to 6 carbon atoms, alkenyl comprising from 2 to 6 carbon atoms, alkynyl comprising from 2 to 6 carbon atoms, -SO3H, -N3, -CN, - NO2, F, Cl, Br, J atoms, -CF3, -COR9, -CH2OR9, -OR10, -SR10, (C1-C)-alkylamino- or (C1-C6)-dialkylamino-group wherein R9 means H, alkyl comprising from 1 to 6 carbon atoms, or -OR10 wherein R10 represents independently H or alkyl comprising from 1 to 6 carbon atoms. Also, invention relates to compounds of the formula: and , and to a method for activation of alpha2B- or alpha2C-adrenergic receptors. Invention provides synthesis of novel biologically active compound possessing activity as agonists of alpha-2B and alpha-2C-adrenergic receptors.

EFFECT: valuable medicinal properties of compounds.

34 cl, 5 tbl, 33 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention proposes an injection solution comprising the following components, wt.-%: butorphanol tartrate, 0.05-0.5; stabilizing agent, 1.6-5.4; chelating agent, 0.001-5.0, and water for injection, the balance. Invention provides decreasing concentration of active substance in preparing the equal pharmacological effect as compared with nalbuphine solution that allows reducing hazard effect of analgesic preparation on the body. The injection solution satisfies the quality index norm values for fitness period -3 years, not less.

EFFECT: improved and valuable medicinal and pharmaceutical properties of solution.

6 cl, 9 ex

FIELD: medicine, pharmacology.

SUBSTANCE: invention relates to new enantiomerically pure (-)3-((S)-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-thienyl)methyl)phenol, pharmaceutical composition containing the same having antagonistic activity in relates to μ- and/or δ-opioid receptors; methods for treatment of pain, cough, functional diarrhea, functional pain, heart diseases, emesis; method for receptor-mediated analgesia; method for amelioration, treatment and prevention of drug-mediated respiratory depression; method for screening of compounds suppressing opioid respiratory depression; pharmaceutical composition containing biologically active agent for treatment of pain, cough, functional diarrhea, functional pain, heart diseases, emesis, respiratory depression and claimed compound; and method for performance of reaction mediated with opioid receptors.

EFFECT: therapy of increased effectiveness.

17 cl, 6 dwg, 4 tbl, 7 ex

FIELD: medicine.

SUBSTANCE: claimed composition contains core including Rabeprasol or pharmaceutically acceptable salt thereof as acid secretion inhibitor in stomach and basic compound, intermediate coat coating the core, and overcoat applied on intermediate layer and containing water insoluble polymer and enterosoluble polymer. Also described is method for production of composition containing said preparation.

EFFECT: composition of prolonged storage time providing effective concentration of Rabeprasol in blood for long period of time.

16 cl, 5 dwg, 14 ex

FIELD: chemical-pharmaceutical industry, pharmacy.

SUBSTANCE: invention relates to solid medicinal formulations covered by enterosoluble envelope. Enterosoluble envelope represents a polymeric derivative as conglomerate of hydroxypropylcellulose and acetatephthalatecellulose in the presence of wax and Tween. Envelope has 1-10 layers and its mass is 0.1-10% of the solid pharmaceutical composition mass in the definite ratio of component in envelope. Also, invention represents methods for coating a pharmaceutical composition by such enterosoluble envelope. Invention provides the required disintegration of envelope for capsules as a whole and expanding assortment of active components among medicinal agents useful for applying the claimed cover and with inclusion to this enumeration of thermolabile medicinal immunobiological preparations.

EFFECT: improved and valuable properties of envelope, improved coating method.

9 cl, 7 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

The invention relates to pharmaceutical compositions cefuroxime aksetila in the form of particles
The invention relates to chemical-pharmaceutical industry, namely intersolubility shell of solid dosage forms having two layers, one of which contains a film-forming component, and a second plasticizer, dye and technological additives

The invention relates to the field of pharmacology, and relates to a composition containing diphosphonic acid

FIELD: medicine.

SUBSTANCE: invention claims oral compositions containing a single daily effective dose of active substance based on quinolone, containing a mix of at least quinolone derivatives in the form of a mix of a salt with free base, or a salt mix. The compositions educe 80% of active substance both in 0.1 N hydrochloric acid and in acetate poiser at pH 4.5 in the test using rotary-vane method according to USP XXIV at 50 rpm. at the temperature of 37°C for 1-4 hours.

EFFECT: sufficient therapeutic effect by administration one time daily.

13 cl, 7 ex

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