WO2008120070A2 - 2(hydroxyéthyle)triméthylammonium thioctate (choline thioctate) possédant une action hépatoprotectrice, hypoammoniémique et détoxique, procédé de production de cette substance et composition pharmaceutique basée sur ladite substance - Google Patents

2(hydroxyéthyle)triméthylammonium thioctate (choline thioctate) possédant une action hépatoprotectrice, hypoammoniémique et détoxique, procédé de production de cette substance et composition pharmaceutique basée sur ladite substance Download PDF

Info

Publication number
WO2008120070A2
WO2008120070A2 PCT/IB2008/000727 IB2008000727W WO2008120070A2 WO 2008120070 A2 WO2008120070 A2 WO 2008120070A2 IB 2008000727 W IB2008000727 W IB 2008000727W WO 2008120070 A2 WO2008120070 A2 WO 2008120070A2
Authority
WO
WIPO (PCT)
Prior art keywords
thioctate
choline
hepatoprotective
hydroxyethyl
trimethylammonium
Prior art date
Application number
PCT/IB2008/000727
Other languages
English (en)
Other versions
WO2008120070A3 (fr
Inventor
Ivan Ivanovych Novik
Original Assignee
Aktsionerne Tovarystvo Vidkrytogo Typu «Galychfarm»
Tovarystvo Z Obmezhenoyu Vidpovidalnistyu «Instytut Fito-Himichnyh Tehnologij»
Vidkryte Aktsionerne Tovarystvo «Kyivmedpreparat»
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Aktsionerne Tovarystvo Vidkrytogo Typu «Galychfarm», Tovarystvo Z Obmezhenoyu Vidpovidalnistyu «Instytut Fito-Himichnyh Tehnologij», Vidkryte Aktsionerne Tovarystvo «Kyivmedpreparat» filed Critical Aktsionerne Tovarystvo Vidkrytogo Typu «Galychfarm»
Publication of WO2008120070A2 publication Critical patent/WO2008120070A2/fr
Publication of WO2008120070A3 publication Critical patent/WO2008120070A3/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D339/00—Heterocyclic compounds containing rings having two sulfur atoms as the only ring hetero atoms
    • C07D339/02—Five-membered rings
    • C07D339/06—Five-membered rings having the hetero atoms in positions 1 and 3, e.g. cyclic dithiocarbonates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D339/00—Heterocyclic compounds containing rings having two sulfur atoms as the only ring hetero atoms
    • C07D339/02—Five-membered rings
    • C07D339/04—Five-membered rings having the hetero atoms in positions 1 and 2, e.g. lipoic acid

Definitions

  • the invention relates generally to medicine and chemical and pharmaceutical industry, and more particularly to a new physiologically active substance 2(hydroxyethyl)trimethylammonium thioctate (choline thioctate) which displays hepatoprotective, hypoammoniemic and detoxic activity, to a method for its production and to pharmaceutical compositions based thereon.
  • 2(hydroxyethyl)trimethylammonium thioctate choline thioctate
  • hepatoprotectors include substances of both vegetable and synthetic origins which exert a differently directed effect on metabolic processes.
  • a structural and pharmacological analog to choline thioctate is choline chloride - a choline derivative (2-oxyethyltrimethylammonium hydroxide), which is a lipotropic substance preventing severe liver diseases from occurring during its atheroma.
  • Choline chloride is used in medicine included in hepatoprotective drugs to treat liver diseases. It is also included in combined feed for farm animals. Its disadvantages include an insufficiently high level and limited spectrum of specific activity.
  • thioctic acid plays a substantial role in regulating metabolic processes in the liver. As a coenzyme, it takes part in carbohydrate or protein metabolism, and it is one of the important components of the antioxidant system of organism.
  • Thioctic acid plays an important role in ⁇ -keto acid oxidative decarboxylation reactions including pyruvic acid transformation into acetyl-CoA which will enter the Krebs cycle. A complex oxidation process of thioctic acid results in the formation of 3 ATP molecules this increasing significantly a cell energy potential.
  • Thioctic acid activates the oxidation processes of fatty acids in mitochondrions this, in addition provides the cell with energy, reducing the content of substrates therein for triglyceride synthesis and preventing thereby fatty (adipose) degeneration of the liver and hyperlipidemia from developing.
  • liver diseases The main reasons for a wide use of thioctic acid to treat liver diseases are as follows:
  • Nitrogen oxide synthesis inhibition by hepatocytes the prevention and reduction of disorders of the rheological properties and vascular disorders.
  • the study conducted has shown the prospects of providing a complex physiologically active substance based on choline base and thioctic acid, a further use of which, in particular, as hepatoprotector, improves substantially a patient's quality of life.
  • hepatoprotective drugs Legalon, Karsil, Siliborum in the form of tablets, capsules, pellets and others which contain as their active ingredients flavonoids extracted from seeds of variegated thistle. These drugs are used to treat acute hepatitis, hepatocirrhosis, in supporting therapy of chronic diseases of the liver. When using these drugs, undesirable side effects in the form of laxative action, allergic reactions of skin tissues are reported.
  • hepatoprotective drug Essentialle contains natural "essential" phospholipids - diglyceride esters of cholinephosphoric acid and unsaturated fatty acids (linolic, linoleic, and others) along with vitamins (pyridoxine, cyanocobalamin, nicotinamide, pantothenic acid).
  • Essentialle is used in the form of 5-mL and 10-mL ampoules which contain respectively 250 mg and 1000 mg of "essential" phospholipids, 2.5 mg and 5 mg of pyridoxine hydrochloride, 10 ⁇ g and 15 ⁇ g of cyanocobalamin, 25 mg and 100 mg of nicotinamide, 1.5 mg and 3 mg of sodium pantothenate, as well as in the form of capsules which contain 175 mg of "essential" phospholipids, 3 mg of thiamine, 3 mg of riboflavin, 3 mg of pyridoxine hydrochloride, 3 mg of cyanocobalamin, 15 mg of nicotinamide and 3.3 mg of alpha- tocopherol acetate.
  • the drug is useful to treat chronic hepatitis, degeneration and cirrhosis of the liver, as well as to treat liver involvement associated with diabetes, alcoholism and others. Undesirable side effects in the form of dyspeptic disorders are reported.
  • hepatoprotective drug which contains as its active ingredient 2-phenyl-3-carbetoxy-4-dimethylaminomethyl-5-oxibenzofuran hydrochloride (vinboron, phenicaberan) and helps to preserve the liver ravine structure.
  • Hepabene in the form capsules, which is a combined drug and contains extracts from medicinal herbs including variegated thistle with at least 22 mg of silibinin per capsule (4).
  • Hepabene in the form of infusion solution, which contains a 5% solution of amino acids, which are the most suitable for the organism including arginine (5).
  • Zixorin which is used in the form of capsules to treat functional hyperbilirubinemia in patients with chronic diffuse diseases of the liver, to treat jaundice caused by enzymopathies and benign intrahepatic cholestasis (6).
  • Drag Hepatofalk which contains choline orotate as its active ingredient. It is used to treat toxic liver disorders (including alcoholic and drug disorders), acute and chronic hepatitis of various ethiology and hepatocirrhosis as a supporting therapy (7).
  • a drag Lipovitan which contains choline tartrate as its active ingredient and is used to treat toxic liver disorders (8).
  • arginine amide derivatives Known in the art is a method for producing arginine amide derivatives, the method comprising: activating N-acylarginine or a salt thereof; the acylation thereby of amines of formula NH 2 R in an organic solvent medium at the presence of a base; and liberating the target product, wherein dimethyl formamidinium chloride is used as the activating agent (10).
  • 6-aminocapronic acid glutamate a substance which displays antifibrinolytic, anti-inflammatory and antimicrobial activity
  • the method comprising: dissolving glutamic acid and 6-aminocapronic acid in water; adding an activated charcoal to the resulting solution while stirring; filtering the resulting solution of 6-aminocapronic acid glutamate salt; cooling the filtrate for the purpose of further isolating a precipitate; and filtering, washing and drying the resulting crystalline precipitate - 6-aminocapronic acid glutamate salt.
  • a target product yield is 86% (11).
  • the most similar to a method in accordance with the present invention is the method for producing a water-soluble salt L-arginine L-glutamate, the method comprising: dissolving L-arginine base in water, adding L-glutamic acid, while stirring, to the resulting L-arginine base solution up to pH 6.6 to 6.8; filtering the resulting water solution of L-arginine L-glutamate; introducing the water solution of L-arginine L-glutamate in ethanol till precipitation (at a filtrate wate ⁇ ethanol ratio of 1:(9.76-10.24); filtering and washing the resulting precipitate of L-arginine L- glutamate; drying L-arginine L-glutamate under vacuum at temperature not higher than 60 0 C for 4 to 5 hours. (12)
  • the disadvantages of the prototype method include the complexity and a long duration of the manufacturing process, necessity to comply with strict temperature and time conditions.
  • an object of the present invention is to provide a new physiologically active substance choline thioctate which, displaying hepatoprotective, hypoammoniemic and detoxic activity, possesses a higher level and a wider spectrum of specific activity.
  • Another object of the present invention is to provide a method for producing a new chemical substance displaying hepatoprotective, hypoammoniemic and detoxic activity, which method, thanks to the sequence of process steps, the selection of process conditions and parameters, enables a substance with a higher level and a wider spectrum of specific activity to be produced while simplifying, and shortening the duration of, the manufacturing process.
  • Yet another object of the present invention is to provide pharmaceutical compositions based on a new physiologically active substance choline thioctate in various dosage forms.
  • the assigned object is achieved by that, in accordance with the present invention, 2(hydroxyethyl)trimethylammonium thioctate (choline thioctate) of formula
  • the assigned object is achieved by that, in accordance with the present invention, in a method for producing 2(hydroxyethyl)trimethylammonium thioctate (choline thioctate), the method comprises: dissolving a base and an organic acid in polar solvents and further isolating the target product, choline base is used as the base, thioctic acid is used as the organic acid, water and/or ethanol is/are used as the polar solvent(s), and the target product is isolated by removing the solvent by any method known to those skilled in the art.
  • the method comprises: dissolving a base and an organic acid in polar solvents and further isolating the target product, choline base is used as the base, thioctic acid is used as the organic acid, water and/or ethanol is/are used as the polar solvent(s), and the target product is isolated by removing the solvent by any method known to those skilled in the art.
  • a pharmaceutical composition containing an active ingredient and one or more pharmaceutically suitable carriers or solvents contains as the active ingredient 2(hydroxyethyl)trimethylammonium thioctate (choline thioctate) of formula
  • the technical result of implementing the present invention is the provision of a new physiologically active chemical substance 2(hydroxyethyl)trimethylammonium thioctate (choline thioctate) which displays hepatoprotective, hypoammoniemic and detoxic activity, the development of a method for producing the same which method ensures a higher level and a wider spectrum of specific activity while simplifying, and shortening the duration of the manufacturing process, as well as the provision of pharmaceutical compositions based on a new physiologically active substance 2(hydroxyemyl)trimethylammonium thioctate (choline thioctate) in various dosage forms the use whereof results in diversifying the range of hepatoprotective drugs.
  • Example 1 To a mixture of 0.8497 g (0.004125 moles) of thioctic acid (calculated with reference to the substance of 100%) in ethanol add 0.5 g (0.004125 moles) of choline base (calculated with reference to the dried substance of 100%) and stir till a clear solution. To produce the target product (choline thioctate), distillate ethanol out of the solution and dry the resulting precipitate under vacuum.
  • Example 2 To a suspension of 0.8497 g (0.004125 moles) of thioctic acid (calculated with reference to the substance of 100%) in water add 0.5 g (0.004125 moles) of choline base (calculated with reference to the substance of 100%) and stir till a clear solution. To produce the target product (choline thioctate), freeze- drying the solution.
  • Example 3 Proceed as in Example 2. To produce the target product (choline thioctate), dry the solution by spray drying.
  • Example 4 To a mixture of 0.5722 g (0.004125 moles) of choline hydrochloride (calculated with reference to the substance of 100%) in ethanol add 0.165 g (0.004125 moles) of sodium hydroxide (calculated with reference to the substance of 100%). Filter a sodium chloride precipitate, add 0.8497 g (0.004125 moles) of thioctic acid (calculated with reference to the substance of 100%) to the filtrate and stir till a clear solution. To produce the target product (choline thioctate), distillate ethanol out of the solution and dry the resulting precipitate under vacuum.
  • Example 5 To a mixture of 0.8497 g (0.004125 moles) of thioctic acid (calculated with reference to the substance of 100%) in ethanol, add 0.165 g (0.004125 moles) of sodium hydroxide (calculated with reference to the substance of 100%) and mix. To the resulting solution of sodium thioctate, add 0.5722 g (0.004125 moles) of choline hydrochloride (calculated with reference to the substance of 100%). Filter a sodium chloride precipitate. To produce the target product (choline thioctate), distillate ethanol out of the solution and dry the resulting precipitate under vacuum.
  • Example 6 Proceed as in Example 2 at a thioctic acid / choline base molar ratio of 1:1 to 1.2). To the resulting water solution of the target product, add pharmaceutically suitable adjuvants to produce an injection solution by any method known to those skilled in the art.
  • Example 7 To pharmaceutically suitable adjuvants, add, while stirring, a concentrated water solution of choline thioctate produced in accordance with Example 2, then granulate, then granulate, dry and tablet or capsulate by any method known to those skilled in the art.
  • a new physiologically active substance 2(hydroxyethyl)trimethylammonium thioctate (choline thioctate) is produced, which substance displays hepatoprotective, hypoammoniemic and detoxic activity.
  • the selection of conditions and parameters ensure the attainment of the object of the present invention.
  • the salt-forming reaction in producing choline thioctate occurs the most effectively in both polar solvents because of their specific properties (they perform a solvent function and a reaction medium function concurrently) and reagents - choline base and thioctic acid. It is to be understood that the present invention is not limited by selected ratios of solvents and choline base.
  • the methods to produce choline thioctate by the prototype method failed to produce the target product because of that the output substance dissolves not only in water but also in ethanol, which is used as a salt-forming agent in producing L- arginine L-glutamate.
  • the easiness of performing the salt-forming reaction, as well as its output reagents of a sufficient purity level which are used in an equivalent quantity ensure a high level of purity and stability of not only the target product but also pharmaceutical compositions when these solutions are used (a step of isolating the target product in a dry form is excluded thereby the manufacturing cycle is simplified significantly).
  • the temperature conditions of salt-forming do not influence on product purity and are only limited the freezing point and boiling point of solvents which are used as a reaction medium. Only the pre-determined parameters of target product concentration determine a solvent quantity for salt-forming.
  • choline thioctate based pharmaceutical compositions are produced in the form of tablets, capsules, powders, injection solutions, infusion solution concentrates, and other dosage forms.
  • An active substance was selected by means of the pharmacological screening of a number of complex compounds produced and of a comparative pharmacological assessment with respect to Glutarginum (injection dosage form). Preliminary screening studies of pharmacological activity of the complexes were conducted for the existence of their hepatoprotective action.
  • compositions Nos. 1 to 5 which contain, in 1 niL:
  • Composition No. 1 10.0 mg of choline base + 17.0 mg of ⁇ -lipoic (thioctic) acid with 0.4 % of sodium chloride;
  • Composition No. 2 14.4 mg of arginine base + 17.0 mg of ⁇ -lipoic (thioctic) acid; Composition No. 3: 10.0 mg of choline base + 17.0 mg of ⁇ -lipoic (thioctic) acid; Composition No. 4: 9.98 mg of choline base + 10.16 mg of nicotinic acid; Composition No.
  • composition No. 3 The administration of test specimens to rats revealed their marked hepatoprotective activity. The highest (100%) effect was observed when composition No. 3 was administered.
  • Composition No. 1 that, in addition to choline and lipoic acid, contained a 0.4 % solution of sodium chloride, exhibited a slightly lower activity (83.3%). The rest of the test compositions and Glutarginum were second to them in specific activity level.

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Toxicology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne la médecine ainsi que l'industrie chimique et pharmaceutique, et plus particulièrement une nouvelle substance physiologiquement active, 2(hydroxyéthyle)triméthylammonium thioctate (choline thioctate), qui possède une action hépatoprotectrice, hypoammoniémique et détoxique. L'invention concerne en outre un procédé de production de ladite substance et des compositions pharmaceutiques basées sur celle-ci. La mise en œuvre technique de cette invention permet d'obtenir une nouvelle substance chimique physiologiquement active, 2(hydroxyéthyle)triméthylammonium thioctate (choline thioctate) qui présente une action hépatoprotectrice, hypoammoniémique et détoxique. Elle permet également d'obtenir un procédé de production de cette substance, ledit procédé garantissant un niveau élevé et un spectre élargi de l'activité spécifique tout en simplifiant et en raccourcissant la durée du processus de fabrication. Enfin, l'invention fournit des compositions pharmaceutiques basées sur la nouvelle substance physiologiquement active 2(hydroxyéthyle)triméthylammonium thioctate (choline thioctate) dans diverses formes de dosage, dont l'utilisation débouche sur une gamme diversifiée de médicaments hépatoprotecteurs.
PCT/IB2008/000727 2007-03-30 2008-03-17 2(hydroxyéthyle)triméthylammonium thioctate (choline thioctate) possédant une action hépatoprotectrice, hypoammoniémique et détoxique, procédé de production de cette substance et composition pharmaceutique basée sur ladite substance WO2008120070A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
UAA200703481 2007-03-30
UAA200703481A UA86441C2 (ru) 2007-03-30 2007-03-30 (2-гидроксиэтил)триметиламмония тиоктат (холина тиоктат), имеющий гепатопротекторное, гипоаммониемическое и детоксицирующее действие, способ его получения, фармацевтическая композиция на его основе

Publications (2)

Publication Number Publication Date
WO2008120070A2 true WO2008120070A2 (fr) 2008-10-09
WO2008120070A3 WO2008120070A3 (fr) 2008-12-31

Family

ID=39808755

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2008/000727 WO2008120070A2 (fr) 2007-03-30 2008-03-17 2(hydroxyéthyle)triméthylammonium thioctate (choline thioctate) possédant une action hépatoprotectrice, hypoammoniémique et détoxique, procédé de production de cette substance et composition pharmaceutique basée sur ladite substance

Country Status (2)

Country Link
UA (1) UA86441C2 (fr)
WO (1) WO2008120070A2 (fr)

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010147962A1 (fr) 2009-06-15 2010-12-23 Encore Health, Llc Esters de choline
US7914815B2 (en) 2000-08-16 2011-03-29 Encore Health, Llc Method for delivery of pharmaceuticals for treating or preventing presbyopia
US7935332B2 (en) 2000-08-16 2011-05-03 Encore Health, Llc Presbyopia treatment by lens alteration
US8147816B2 (en) 2000-08-16 2012-04-03 Encore Health, Llc Presbyopia treatment by lens alteration
US8647612B2 (en) 2008-03-05 2014-02-11 Encore Health, Llc Dithiol compounds, derivatives, and treatment of presbyopia
US8697109B2 (en) 2000-08-16 2014-04-15 Encore Health, Llc Caged mercaptan and seleno-mercaptan compounds and methods of using them
US8795706B2 (en) 2000-08-16 2014-08-05 Encore Health, Llc Methods of treating ocular diseases using derivatives of lipoic acid
US9044439B2 (en) 2008-03-05 2015-06-02 Encore Health, Llc Low dose lipoic and pharmaceutical compositions and methods
US9161931B2 (en) 2008-03-05 2015-10-20 Encore Health, Llc Dithiol compounds and treatment of presbyopia using said compounds
WO2019150341A1 (fr) * 2018-02-05 2019-08-08 Cellixbio Private Limited Combinaison d'un agent antimuscarinique ou d'un agent anticholinergique et d'acide lipoïque et ses utilisations
US11426381B2 (en) 2014-03-03 2022-08-30 Novartis Ag Lipoic acid choline ester compositions and methods of use

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1077039A (en) * 1965-10-21 1967-07-26 Henry Eugene Jean Marie Meunie A choline derivative and therapeutic compositions containing it
WO1999055331A1 (fr) * 1998-04-25 1999-11-04 Skw Trostberg Aktiengesellschaft Utilisation de l'acide alpha-lipoique pour la diminution de l'appetit et/ou la reduction du poids corporel

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1077039A (en) * 1965-10-21 1967-07-26 Henry Eugene Jean Marie Meunie A choline derivative and therapeutic compositions containing it
WO1999055331A1 (fr) * 1998-04-25 1999-11-04 Skw Trostberg Aktiengesellschaft Utilisation de l'acide alpha-lipoique pour la diminution de l'appetit et/ou la reduction du poids corporel

Cited By (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9284305B2 (en) 2000-08-16 2016-03-15 Encore Health, Llc Methods of treating ocular diseases using derivatives of lipoic acid
US7935332B2 (en) 2000-08-16 2011-05-03 Encore Health, Llc Presbyopia treatment by lens alteration
US8795706B2 (en) 2000-08-16 2014-08-05 Encore Health, Llc Methods of treating ocular diseases using derivatives of lipoic acid
US8147816B2 (en) 2000-08-16 2012-04-03 Encore Health, Llc Presbyopia treatment by lens alteration
US10039743B2 (en) 2000-08-16 2018-08-07 Novartis Ag Method of treating presbyopia using dithiol compounds and their derivatives
US9567314B2 (en) 2000-08-16 2017-02-14 Encore Health Llc Dithiol compounds, derivatives, and uses therefor
US8747829B2 (en) 2000-08-16 2014-06-10 Encore Health, Llc Presbyopia treatment by lens alteration of disulfide bonds and reduction
US7914815B2 (en) 2000-08-16 2011-03-29 Encore Health, Llc Method for delivery of pharmaceuticals for treating or preventing presbyopia
US8697109B2 (en) 2000-08-16 2014-04-15 Encore Health, Llc Caged mercaptan and seleno-mercaptan compounds and methods of using them
US9204996B2 (en) 2000-08-16 2015-12-08 Encore Health, Llc Presbyopia treatment by lens alteration
US9044439B2 (en) 2008-03-05 2015-06-02 Encore Health, Llc Low dose lipoic and pharmaceutical compositions and methods
US8647612B2 (en) 2008-03-05 2014-02-11 Encore Health, Llc Dithiol compounds, derivatives, and treatment of presbyopia
US9517225B2 (en) 2008-03-05 2016-12-13 Encore Health, Llc Low dose lipoic acid pharmaceutical compositions and methods
US9161931B2 (en) 2008-03-05 2015-10-20 Encore Health, Llc Dithiol compounds and treatment of presbyopia using said compounds
US9326970B2 (en) 2009-06-15 2016-05-03 Encore Health Llc Choline esters
WO2010147962A1 (fr) 2009-06-15 2010-12-23 Encore Health, Llc Esters de choline
US8410162B2 (en) 2009-06-15 2013-04-02 Encore Health Llc Choline esters
EP2442645A4 (fr) * 2009-06-15 2013-03-06 Encore Health Llc Esters de choline
EP2442645A1 (fr) * 2009-06-15 2012-04-25 Encore Health, Llc Esters de choline
EP2821405A1 (fr) * 2009-06-15 2015-01-07 Encore Health, LLC Esters de choline pour le traitement de la cataracte et de la presbytie
US11426381B2 (en) 2014-03-03 2022-08-30 Novartis Ag Lipoic acid choline ester compositions and methods of use
WO2019150341A1 (fr) * 2018-02-05 2019-08-08 Cellixbio Private Limited Combinaison d'un agent antimuscarinique ou d'un agent anticholinergique et d'acide lipoïque et ses utilisations
JP2021512876A (ja) * 2018-02-05 2021-05-20 セリックス バイオ プライヴェート リミテッドＣｅｌｌｉｘ Ｂｉｏ Ｐｒｉｖａｔｅ Ｌｉｍｉｔｅｄ 抗ムスカリン薬又は抗コリン作動薬及びリポ酸の組合せ物並びにその使用

Also Published As

Publication number Publication date
UA86441C2 (ru) 2009-04-27
WO2008120070A3 (fr) 2008-12-31

Similar Documents

Publication Publication Date Title
WO2008120070A2 (fr) 2(hydroxyéthyle)triméthylammonium thioctate (choline thioctate) possédant une action hépatoprotectrice, hypoammoniémique et détoxique, procédé de production de cette substance et composition pharmaceutique basée sur ladite substance
US5728735A (en) Pharmaceutical composition containing R-α-lipoic acid or S-α-lipoic acid as active ingredient
AU694125B2 (en) Anti-stress, anti-impairment and anti-aging drug and process for manufacturing thereof
DE4218572A1 (de) Synergistische Kombination von Arzneimitteln enthaltend als Wirkstoff alpha-Liponsäure, Dihydroliponsäure, deren Metaboliten sowie die oxidierten und reduzierten Enantiomere der alpha-Liponsäure wie die R-alpha-Liponsäure oder S-alpha-Liponsäure sowie Metaboliten der alpha-Liponsäure mit den Vitaminen A, B1-6, B12, C und E
DE102005022276A1 (de) Derivate von Dihydroxyphenylalanin
EP2046773A1 (fr) Lipoate de metformine r-(+) utilisé comme antidiabétique contre l'hyperglycémie diabétique et les complications diabétiques
US20030078231A1 (en) Orthomolecular sulpho-adenosylmethionine derivatives with antioxidant properties
WO2012144938A2 (fr) Composition de protecteurs des encéphalopathies hépatiques aiguës et chroniques et méthode de traitement de celles-ci
WO2007063095A1 (fr) Utilisation de sels de zinc de l’acide liponique pour le traitement de troubles du metabolisme lipidique
JPS5857397A (ja) 安定なｓ−アデノシルメチオニン誘導体、その製法及びそれを活性成分として含む治療用組成物
DE10151764A1 (de) Kombination von Liponsäure und Glutamin in Lebens- und Arzneimitteln
CN102803243A (zh) 二硫辛酸哌嗪酯及含有二硫辛酸哌嗪酯的药物组合物
US7202270B2 (en) Convenient stable non-hygroscopic crystalline solid forms of racemic and chiral LA-plus salts: process for their manufacture and uses
DE10022856A1 (de) Therapeutische Kombination von Liponsäure und C1-Donoren zur Behandlung von Störungen des Zentralen Nervensystems
JPS62190190A (ja) Ｌ−カルニチンのホスホリルアルカノ−ルアミド誘導体類およびその医薬組成物
DE4327462A1 (de) Neue N-Acetyl-p-Aminophenol-Derivate zur Bekämpfung von Schmerzzuständen
DE60113808T2 (de) Therapeutikum oder Prophylaktikum für Lebererkrankungen, enthaltend ein Diaminotrifluorethylpyridin-Derivat
WO2006042728A2 (fr) Utilisation de sels d'ammonium stables de l'acide lipoique dans le traitement de troubles diabetiques et autres troubles
ES2709651T3 (es) Solución básica de ácido alfa lipoico y sus usos
CN105407884A (zh) 降低甘油三酯、总胆固醇和低密度脂蛋白血液浓度的方法
CA3143112A1 (fr) Promedicamenta base de succinate, compositions contenant le promedicament de succinate et utilisations associees
DE2116629A1 (en) 4-thiazolidinecarboxylic acid derivs - with in vivo thiol liberating activity
DE4331168A1 (de) Kombination von N-Acetyl-p-Aminophenol mit schwefelenthaltenden Carbonsäuren, wie z. B. alpha-Liponsäure und deren Derivate, zur Bekämpfung von Schmerzzuständen
WO2002083703A1 (fr) Composition a base d'un polyphosphate de s-adenosyl-l-methionine et utilisations d'un tel polyphosphate
Jay et al. Methods and pharmaceutical compositions for decorporation of radioactive compounds

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 08719373

Country of ref document: EP

Kind code of ref document: A2

NENP Non-entry into the national phase in:

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 08719373

Country of ref document: EP

Kind code of ref document: A2