Patents Assigned to LEK, tovarna, farmacevtskih in Kemicnih . . .
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Publication number: 20030175348Abstract: There is disclosed a method for stabilizing active substances that are unstable in acidic medium, unstable when stored for longer periods of time in the presence of water and at the same time sensitive to heating, by means of anhydrous granulation of active substances and dried pharmaceutically acceptable auxiliary substances for the preparation of pellet cores or granules. All pharmaceutically acceptable auxiliary substances employed are dried before use so that their weight loss at drying is less than 1.0% of the total weight of the pharmaceutically acceptable auxiliary substance, preferably less than 0.5%. Organic solvents used in process of anhydrous granulation should contain less than 0.2% of water. A novel pharmaceutical formulation with controlled release of active substances that are unstable in acidic medium, unstable when stored for longer periods of time in the presence of water and at the same time sensitive to heating, is disclosed as well.Type: ApplicationFiled: March 28, 2003Publication date: September 18, 2003Applicant: LEK, TOVARNA FARMACEVTSKIH IN KEMICNIH IZDELKOV, D.D.Inventors: Bojan Kofler, Ljubomira Barbara Rebic, Judita Sirca, Peter Venturini
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Patent number: 6576258Abstract: There is disclosed a method for stabilizing active substances that are unstable in acidic medium, unstable when stored for longer periods of time in the presence of water and at the same time sensitive to heating, by means of anhydrous granulation of active substances and dried pharmaceutically acceptable auxiliary substances for the preparation of pellet cores or granules. All pharmaceutically acceptable auxiliary substances employed are dried before use so that their weight loss at drying is less than 1.0% of the total weight of the pharmaceutically acceptable auxiliary substance, preferably less than 0.5%. Organic solvents used in process of anhydrous granulation should contain less than 0.2% of water. A novel pharmaceutical formulation with controlled release of active substances that are unstable in acidic medium, unstable when stored for longer periods of time in the presence of water and at the same time sensitive to heating, is disclosed as well.Type: GrantFiled: January 12, 2000Date of Patent: June 10, 2003Assignee: Lek, Tovarna Farmacevtskih In Kemicnih Izdelkov, D.D.Inventors: Bojan Kofler, Ljubomira Barbara Rebi{haeck over (c)}, Judita {haeck over (S)}irca, Peter Venturini
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Patent number: 6489318Abstract: Disclosed are novel ethylidene derivatives of tricyclic carbapenems of the formula I wherein the ring marked C and X have the meaning as in the description, in the form of pure diastereoisomers and in the form of pure geometric isomers. Novel ethylidene derivatives of tricyclic carbapenems of the formula I are used as inhibitors of the action of the enzyme &bgr;-lactamase and/or as antibiotics in human and veterinary medicine. Also disclosed are pharmaceutical formulations for the treatment of bacterial infections of human and animal organisms comprising as an active ingredient a therapeutically effective amount of an ethylidene derivative of tricyclic carbapenems of the formula I in the form of an acid, a pharmaceutically acceptable salt or ester thereof and optionally in a combination with a &bgr;-lactam antibiotic, and usual pharmaceutically acceptable carriers and auxiliary substances.Type: GrantFiled: June 10, 1999Date of Patent: December 3, 2002Assignee: LEK, tovarna farmacevtskih in kemicnih izdelkov, d.d.Inventors: Anton {haeck over (C)}opar, Toma{overscore (z)} {overscore (S)}olmajer, Borut An{haeck over (z)}i{haeck over (c)}, Tadeja Kuzman, Toma{overscore (z)} Mesar, Darko Kocjan
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Patent number: 6268502Abstract: An improved process of synthesis of 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl-1H-benzimidazole (omeprazole) by oxidation of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]thio]benzimidazole with 3-chloroperoxy-benzoic acid in ethyl acetate wherein omeprazole is poorly soluble, at a temperature between −10° C. and 5° C. is disclosed. The second step is a purification of the crude product by dissolution and reprecipitation of the final product.Type: GrantFiled: August 30, 2000Date of Patent: July 31, 2001Assignee: LEK, Tovarna Farmacevtskih in Kemicnih Izdelkov. D.D.Inventors: Nata{haeck over (s)}a Hafner Mila{haeck over (c)}, Darja Jereb
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Patent number: 6042847Abstract: Described is a novel three-phase pharmaceutical form with constant and controlled release of an amorphous active ingredient stabilized with polymers for a single daily peroral application, which is especially suitable for active ingredients existing in amorphous form or in one or more polymorphous forms, which exhibit poor solubility in crystal form depending on the polymorphous form, particle size and the specific surface area of the active ingredient. The active ingredient can be used in its amorphous or any polymorphous form, which in the process of the preparation of the three-phase pharmaceutical form according to the invention is converted into the amorphous form. The three-phase pharmaceutical form with constant and controlled release of an amorphous active ingredient for a single daily peroral application contains a core consisting of a first and a second phase and a coating representing the third phase.Type: GrantFiled: November 12, 1997Date of Patent: March 28, 2000Assignee: LEK, Tovarna farmacevtskih in Kemicnih Izdelkov, d.d.Inventors: Janez Kerc, Ljubomira Barbara Rebic, Bojan Kofler
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Patent number: 5853720Abstract: The present invention discloses a new process for the purification of vancomycin hydrochloride by combining preparative chromatography on a silica gel column and the precipitation with ethanol from a salt-water-ethanolic solution without intermediary filtering, whereby the chromatographic purity of the product is improved.The chromatography is carried out on a column containing a silica gel stationary phase and an alkaline water-methanolic mobile phase at defined pH, mobile phase flow and temperature as well as the amount and concentration of vancomycin hydrochloride. The process is distinguished by the yield and chromatographic purity of the obtained product of about 93% area.Vancomycin hydrochloride purified according to the present invention is useful for peroral as well as parenteral administration since the portion of impurities it contains is for one third smaller than in hitherto available product.Type: GrantFiled: July 28, 1997Date of Patent: December 29, 1998Assignee: LEK, tovarna farmacevtskih in kemicnih izdelkov, d.d.Inventors: Zlatko Pflaum, Robert Turkalj
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Patent number: 5854390Abstract: The present invention discloses a new method for the purification of vancomycin hydrochloride by preparative HPLC (method of displacement chromatography), whereby the chromatographic purity of the product is essentialy improved.The chromatography is performed on a reverse stationary phase with a mobile phase consisting of an organic or inorganic acid or of a buffer with possible additives, with different displacing agents, at a defined pH and temperature as well as the amount and concentration of vancomycin hydrochloride.The process is distinguished by the excellent yield and exceptional chromatographic purity 95.5% area of the obtained product and, besides, it represents an ecologically irreproachable process.The vancomycin hydrochloride purified according to the present invention is useful for all types of application since the portion of impurities it contains is for one third lower than in hitherto known commercially available products.Type: GrantFiled: July 28, 1997Date of Patent: December 29, 1998Assignee: LEK, tovarna farmacevtskih in kemicnih izdelkov, d.d.Inventors: Rok Grahek, Andrej Bastarda
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Patent number: 5840714Abstract: Inclusion Complexes of Racemic Ibuproxam and of Optically Active Ibuproxam with Cyclodextrin Derivatives, Process for the Preparation Thereof, Pharmaceutical Preparations Containing these Inclusion Complexes or Containing Optically Active S-(+)-Ibuproxam, and Use ThereofThere are disclosed novel inclusion complexes of racemic ibuproxam and of optically active S-(+)-ibuproxam with hydrophilic and hydrophobic cyclodextrin derivatives and, in the case of optically active S-(+)-ibuproxam, also with .beta.-cyclodextrin alone. Further a process for preparing S-(+)-ibuproxam and inclusion complexes of racemic ibuproxam and of optically active S-(+)-ibuproxam with hydrophilic and hydrophobic derivatives of .beta.-cyclodextrin and, in the case of optically active S-(+)-ibuproxam, also with .beta.-cyclodextrin alone, is disclosed.Disclosed are also pharmaceutical compositions containing these inclusion complexes or optically active S-(+)-ibuproxam.Type: GrantFiled: February 20, 1996Date of Patent: November 24, 1998Assignee: LEK, tovarna farmacevtskih in kemicnih izdelkov, d.d.Inventors: Janko Zmitek, Katarina Verhnjak, Darja Fercej-Temeljotov, Mateja Kovacic, Anton Lavric, Breda Bole-Vunduk
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Patent number: 5824652Abstract: Heterocyclic acyldipeptides of the formula I ##STR1## wherein Z represents an oxygen or sulphur atom or a --CH.sub.2 -group;R.sub.1, R.sub.2 and R.sub.3 individually represent hydrogen or certain organic groups;R.sub.4 and R.sub.5, which are identical or different, represent an OR.sub.6 or NHR.sub.6 group, wherein R.sub.6 is hydrogen or certain organic groups;Y represents a --CH.sub.2 --, .dbd.CH-- or .dbd.N-- group;A represents a --(CH.sub.2).sub.3 -- group when Y is --CH.sub.2 --, the two rings being transcondensed, or a ##STR2## wherein R.sub.7 represents H, F, Br, Cl, nitro, or certain organic groups when Y is .dbd.CH-- or .dbd.N--; and their pharmaceutically acceptable salts are provided. These heterocyclic acyldipeptides and their salts are useful as active compounds in medicaments having immunostimulatory and antitumor activity.Type: GrantFiled: January 4, 1996Date of Patent: October 20, 1998Assignees: Univerza v Ljubljani, Fakulteta za naravoslovje in technologijo, Oddelek za farmacijo, LEK, tovarna farmacevtskih in kemicnih izdelkov, d.d.Inventors: Danijel Kikelj, Elizabeta Suhadolc, Alenka Rutar, Slavko Pecar, Alesa Puncuh, Uros Urleb, Vesna Leskovsek, Gasper Marc, Marija Sollner, Ales Krbavcic, Gregor Sersa, Srdjan Novakovic, Lucka Povsic, Anton Stalc
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Patent number: 5789597Abstract: There is disclosed a process for the preparation of compounds having ACE inhibitory action of the formula ##STR1## wherein R has the meanings as in claim 1, wherein the stereospecific amino acid N-?1-(S)-ethoxycarbonyl-3-phenylpropyl!-L-alanine is carboxylically activated with a thionyl chloride derivative wherein at least one chlorine atom is replaced by the residue of a heterocyclic ambident compound such as imidazole, benzimidazole, 2-methylimidazole or triazole, especially chlorothionylimidazole or thionyldiimidazole, in the presence of an organic solvent to the intermediate novel compound A or to the intermediate novel compound B and the obtained intermediate compound is reacted with an amino acid, preferably in the monosilylated form, most preferably in the disilylated form. Disclosed are also novel compounds useful as starting materials or intermediates in the present process.Type: GrantFiled: February 15, 1996Date of Patent: August 4, 1998Assignee: LEK, tovarna farmacevtskih in kemicnih izdelkov, d.d.Inventors: Sonia Serra Mortes, Alberto Palomo Coll, Rok Zupet
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Patent number: 5614199Abstract: Described is a new process for the preparation of alkali clavulanate from an aqueous solution of crude clavulanic acid, which is obtained in a conventional manner after the fermentation with a clavulanic-acid-producing microorganism, extracted with an ethyl acetate solution of a hydrophobic .beta.-CD derivative such as heptakis-(2,3,6-tri-O-acetyl)-.beta.-CD in at least equimolar ratio with regard to clavulanic acid. The resulting novel inclusion complexes of clavulanic acid and hydrophobic .beta.-CD derivative in a molar ratio about 1:1 are isolated, purified and then converted with an alkali base or alkali alkanoate to the desired alkali clavulanate, which is isolated. Furthermore, there are described new inclusion complexes of clavulanic acid and of its pharmaceutically acceptable alkali salts both with hydrophilic .beta.-CD derivatives and with hydrophobic .beta.Type: GrantFiled: June 6, 1995Date of Patent: March 25, 1997Assignee: LEK, tovarna farmacevtskih in kemicnih izdelkov, d.d., LjubljanaInventors: Janko Zmitek, Darja Fercej-Temeljotov, Katarina Verhnjak, Sonja Kotnik, Mateja Kovacic
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Patent number: 5608052Abstract: Described is a new process for the preparation of alkali clavulanate from an aqueous solution of crude clavulanic acid, which is obtained in a conventional manner after the fermentation with a clavulanic-acid-producing microorganism, extracted with an ethyl acetate solution of a hydrophobic .beta.-cyclodextrin derivative such as heptakis-(2,3,6-tri-O-acetyl)-.beta.-cyclodextrin in at least equimolar ratio with regard to clavulanic acid. The resulting novel inclusion complexes of clavulanic acid and hydrophobic .beta.-cyclodextrin derivative in a molar ratio about 1:1 are isolated, purified and then converted with an alkali base or alkali alkanoate to the desired alkali clavulanate, which is isolated. Furthermore, there are described new inclusion complexes of clavulanic acid and of its pharmaceutically acceptable alkali salts both with hydrophilic .beta.-cyclodextrin derivatives and with hydrophobic .beta.Type: GrantFiled: June 6, 1995Date of Patent: March 4, 1997Assignee: LEK, tovarna farmacevtskih in kemicnihInventors: Janko Zmitek, Darja Fer cej-Temeljotov, Katarina Verhnjak, Sonja Kotnik, Mateja Kova ci c
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Patent number: 5519012Abstract: Novel inclusion complexes of racemic 1,4-dihydropyridines and enantiomers thereof of the formula ##STR1## wherein R represents a phenyl group, substituted with nitro, trifluoromethyl, difluoromethoxy group or with one or two halo atoms (especially chlorine),R.sub.1 and R.sub.2, if the same, represent methyl groups and if one of them has the meaning of a 2-aminoethoxymethyl or cyano group, the other represents a methyl group,R.sub.3 and R.sub.4, if different, stand each time for a hydrogen, linear or branched C.sub.1 -C.sub.6 -alkyl, 2-methoxyethyl, 1-(phenylmethyl)-3-piperidinylphenyl, styryl, furyl, piperidino, 4-diphenylmethyl-1-piperazinylethyl, 5-phenyl-3-pirazolyloxy, 1-phenyl-methyl-3-pyrrolidinyl group or a group of the formula ##STR2## or, if the same, stand each time C.sub.1 -C.sub.4 alkyl group, and of acid addition salts thereof with methyl-.beta.-cyclodextrin, hydroxy-ethyl-.beta.-cyclodextrin or hydroxypropyl-.beta.Type: GrantFiled: December 16, 1994Date of Patent: May 21, 1996Assignee: LEK, tovarna farmacevtskih in kemicnih izdelkov, d.d., LjubljanaInventors: Darja Fercej-Temeljotov, Janko Zmitek, Breda Husu-Kovacevic, Sonja Kotnik, Zdenka Jerala-Strukelj
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Patent number: 5480885Abstract: A method of treating psychosis including administering an antipsychotically effective amount of an ergolinyl derivative of 2-propinylamine of the formula I ##STR1## wherein, R.sub.1, R.sub.2, and R.sub.3 independently represent a hydrogen atom or a straight-chain or branched-chain C.sub.1 -C.sub.6 alkyl group, X represents a hydrogen or a halogen atom, Z represents a carbonyl or methylene group, and C.sub.9 - - - -C.sub.10 represents a single or a double, diastereomeric forms, racemates and acid addition salts thereof.Type: GrantFiled: December 2, 1993Date of Patent: January 2, 1996Assignee: Lek, Tovarna Farmacevtskih in KemicnihInventors: Rudolf Rucman, Breda Bole-Vunduk, Magdalena Ocvirk, Bogomila Lavric, Igor Krisch
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Patent number: 5389654Abstract: There is disclosed a process for the preparation of 3-ethyl 5-methyl (.+-.) 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyri dine-dicarboxylate monobenzenesulphonate (amlodipine benzenesulphonate) of formula ##STR1## wherein 3-ethyl 5-methyl (.+-.) 2-[2-(N-tritylamino)-ethoxymethyl]-4-(2-chlorophenyl)-1,4-dihydro-6-methyl -3,5-pyridinedicarboxylate is reacted with benzenesulphonic acid in a methanolic or an aqueous methanolic medium at a temperature from 20.degree. C. to the reflux temperature and the title compound is isolated and purified.Amlodipine benzene sulphonate is a valuable anti-ischaemic and anti-hypertensive agent.Type: GrantFiled: November 10, 1993Date of Patent: February 14, 1995Assignee: LEK, tovarna, farmacevtskih in Kemicnih . . .Inventors: Borut Furlan, Anton Copar, Alenka Jeriha
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Patent number: 4769465Abstract: A new, technologically easily feasible process for the preparation of 2-(N-benzyl-N-methylamino)ethyl methyl 2,6-dimethyl-4(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate, comprising a partrial hydrolysis of dimethyl 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate in an inert organic solvent at a temperature between room temperature and the reflux temperature of the reaction mixture with an aqueous solution of alkali hydroxide and the reaction of the obtained 3-methoxycarbonyl-2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-5-car boxylic acid either with N-(2-hydroxyethyl)-N-benzyl-methylamine in the presence or absence of an organic solvent in the presence of N,N'-dicyclohexylcarbodiimide at a temperature of between 25.degree. and 120.degree. C. or with N-(2-haloethyl)-N-benzyl-methylamine in the presence of an inert organic solvent and of a proton acceptor at a temperature of between 25.degree. and 140.degree. C.Type: GrantFiled: May 14, 1986Date of Patent: September 6, 1988Assignee: LEK, tovarna farmacevtskih in kemicnih izdelkov, n.sol.o.Inventors: Ljubo Antoncic, Iztok Jazbec, Darko Kocjan, Ivana Krivec
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Patent number: 4467093Abstract: In the process for preparing 4-(2'-nitrophenyl-2,6-dimethyl)-3,5-dicarbmethoxy-1,4-dihydropyridine of the formula ##STR1## 2-nitrobenzaldehyd-diacetate, methyl acetoacetate and ammonia are reacted in the presence of an inert organic solvent, such as methanol, and in the presence or absence of an organic base, such as pyridine, at a temperature of between 20.degree. and 150.degree. C. The compound is a valuable medicine for the treatment of angina pectoris.Type: GrantFiled: July 27, 1982Date of Patent: August 21, 1984Assignee: LEK, Tovarna Farmacevtskih in Kemicnih Izdelkov, N.Sol.O.Inventors: Branko Jenko, Igor Langof
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Patent number: 4440772Abstract: Medicine containing salts of ergotaminine, ergosinine, ergocryptinine, ergocristinine, and ergocorninine and use for treating arterial hypertension, heart insufficiency, heart arrhythmia or cephalalgia.Type: GrantFiled: June 2, 1981Date of Patent: April 3, 1984Assignee: LEK, tovarna farmacevtskih in kemicnih izdelkov, n.sol.o.Inventors: Nebojsa Djordjevic, Rudolf Rucman, Suncica Jovanovic, Breda Bole-Vunduk, Tone Lavric, Boza Lavric, Cvetka Gruskovnjak, Ana Kocjan, Hermina Krmelj
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Patent number: 4354940Abstract: Sodium alumoglucoheptonate, process of preparing from sodium glucoheptonate and sodium aluminate, and use of sodium alumoglucoheptonate as a sequestering agent.Type: GrantFiled: July 9, 1981Date of Patent: October 19, 1982Assignee: LEK, tovarna farmacevtskih in kemicnih izdelkov, n.sol.o.Inventors: Peter Suhac, Natasa Hafner-Milac, Bozidar Dolenc
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Patent number: 4304929Abstract: Preparation of 4-(n-hexadecylamino)-benzoic acid or salt thereof employing as catalyst quaternary ammonium or phosphonium salt.Type: GrantFiled: March 7, 1980Date of Patent: December 8, 1981Assignee: LEK tovarna farmacevtskih in kemicnih izdelkov, n.sol.o.Inventors: Branko Jenko, Natasa Hafner-Milac, Joza Habjan, Anton Prosen, Igor Langof