IE60877B1 - An injection solution of the salt of thioctic acid with trometamol and/or amino acids - Google Patents

An injection solution of the salt of thioctic acid with trometamol and/or amino acids

Info

Publication number
IE60877B1
IE60877B1 IE361888A IE361888A IE60877B1 IE 60877 B1 IE60877 B1 IE 60877B1 IE 361888 A IE361888 A IE 361888A IE 361888 A IE361888 A IE 361888A IE 60877 B1 IE60877 B1 IE 60877B1
Authority
IE
Ireland
Prior art keywords
acid
trometamol
thioctic acid
salt
injectable solution
Prior art date
Application number
IE361888A
Other versions
IE883618L (en
Original Assignee
Asta Medica Ag
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
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First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=6341895&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=IE60877(B1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Asta Medica Ag filed Critical Asta Medica Ag
Publication of IE883618L publication Critical patent/IE883618L/en
Publication of IE60877B1 publication Critical patent/IE60877B1/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/385—Heterocyclic compounds having sulfur as a ring hetero atom having two or more sulfur atoms in the same ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Engineering & Computer Science (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Dermatology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

Injectable solution of the thioctic acid salt with trometamol and/or with basic amino acids.

Description

This invention relates to an injectable solution of the thioctic acid salt of trometamol and/or of basic amino acids. The salt-forming acid/base pair is in the molar ratio of thioctic acid : trometamol = 1 : 1.1 to 3.2 and/or thioctic acid : basic amino acid = 1 : 1.1 to 2.
Thioctic acid (ar-liponic acid) is chemically a 1,2-dithiacyclopentane-3-valeric acid: (CH2 C00H Thioctic acid is a product of cell metabolism and is therefore found in many plants and animal organisms. It acts as one of the coenzymes in the oxidative decarboxylation of pyruvate and other α-keto acids.
Thioctic acid has long been used in the treatment of various diseases, inter alia liver diseases, liver damage due to mushroom poisoning and diabetic and alcoholic polyneuropathy, a change in the peripheral nerves accompanying metabolic diseases.
Therapy with thioctic acid is mainly carried out by means of injection solutions, especially in the initial stage of the treatment.
Thioctic acid has, however, the disadvantage that it is only sparingly soluble in water and in the usual solvents used for the preparation of products for injection and is also chemically not sufficiently stable since the S-S bond is split relatively easily to give rise to free ions which in the course of time lead to intramolecular polymerisation. The salts of these acids are generally used as they are more readily soluble.
Various salt formers for thioctic acid cause symptoms of incompatibility when the solution is injected, such as headache, flushes, respiratory distress and sensations of burning at the site of injection.
Another disadvantage is that the solutions used for injection have little stability with various salt formers as they tend to form cloudiness and precipitates.
According to a general medical-pharmaceutical rule, solutions which become cloudy in the course of storage must be regarded as decomposed and must no longer be used.
It was therefore an object of this invention to provide injectable solutions of thioctic acid salts which have good compatibility and at the same time good storage stability.
It was found that injectable solutions having the desired improved properties may be obtained by using the thioctic acid salt of trometamol and/or of basic amino acids in which the salt forming acid-base pair is present in a molar ratio of thioctic acid : trometamol = 1 : l.i to 3.2 and/or thioctic : basic amino acid = 1 : 1.1 to 2. The salt of thioctic acid with trometamol (2-amino-2-hydroxymethyl-propane-1,3-diol) in the molar ratio of 1 : l and its preparation are described in DE-OS 1 695 358. This salt is a yellow crystalline powder which has a melting point of 120’C and is highly soluble in water and hot alcohol. A 0.1 M agueous solution has an almost neutral pH of 6.5. Trometamol is a known pharmaceutical agent which acts both as plasma buffer and as intracellular buffer.
Salts of thioctic acid with amino acids are known from French Patent No.4 630 M and from Spanish Patents 313 056 and 365 246. The salts are prepared by equimolar reactions of thioctic acid and amino acids so that their 1% aqueous solutions have a neutral pH.
It is known from the state of the art (DE-OS 1 056 784, DE-OS 1 047 991) to prepare storage stable injectable solutions of salts of thioctic acid which are at a physiological or slightly alkaline pH. In contrast to the known injectable solutions with their disadvantageous properties, the highly compatible solutions prepared according to the invention have a basic pH of from 7.6 to about 8.8.
A base such as, for example, NaOH may optionally be added to obtain the basic pH. The good compatibility is surprising since in the known salt of thioctic acid with ethylene diamine an increase in the amino content results in poor compatibility of the injectable preparation.
A preferred embodiment is the preparation of an injectable solution consisting of the thioctic acid salt of trometamol and/or of basic amino acids in which the acid-base pair is present in a molar ratio of thioctic acid : trometamol = 1 : 1.4 to 2.8 and/or thioctic acid : basic amino acid = 1 : 1.2 to 1.4. A particularly preferred embodiment is an injectable solution in which the molar ratio of thioctic acid : trometamol = 1 : 2.4. In a preferred embodiment of the salt of thioctic acid with a basic amino acid, the amino acid of the salt is L-lysine or L-arginine. The corresponding mixed salt consisting of thioctic acid : troroetamol : basic amino acid may be used in similar manner. The thioctic acid may be present either in the racemic D,L form or as enantiomer.
Other conventional pharmaceutical auxiliaries such as, for example, benzyl alcohol, propylene glycol, ethanol, glycerol, sorbitol, mannitol, liquid polyethylene glycols (types 200-600), tetraglycol (glycofurolR) or butylene glycol (1,3-butanediol) may be used for preparing the injectable solutions according to the invention.
The solutions are prepared by stirring thioctic acid and the basic amino acid and/or troroetamol in water until the reaction mixture dissolves. The solution is then made up to the required volume with water, filtered, introduced into ampoules and sterilized with superheated steam at 121*C. Another advantage of the invention is that this enables the solution to be sterilized after its introduction into ampoules, which dispenses with the need for the complicated and cost intensive procedure of aseptic filling of the ampoules, and the process of preparing the formulation is therefore safer and more reliable.
The following Examples serve to illustrate the invention: 250 g of Thioctic acid are dissolved in 9 litres of water for injection purposes together with 352.3 g of trometamol with stirring. The solution is made up to 10 litres with water for injection purposes and then filtered through a membrane filter of pore size 0.2 pm with glass fibre preliminary filter. The filtrate is introduced in 2 ml portions into 2 ml ampoules.
The ampoules are sterilised in superheated steam at 121*C for 15 minutes.
One ampoule contains 50 mg of thioctic acid in the form of the trometamol salt in 2 ml of injection solution. 250 g of thioctic acid are dissolved together with 278.6 g of L-lysine monohydrate in 9 litres of water for injection purposes with stirring. The solution is made up to 10 litres with water for injection purposes and then filtered through a membrane filter of pore size 0.2 Mm with glass preliminary filter. The filtrate is introduced in 2 ml portions into 2 ml ampoules. The ampoules are sterilised in superheated steam at 121*C for 15 minutes.
One ampoule contains 50 mg of thioctic acid in the form of the L-lysine salt in 2 ml of injection solution.

Claims (9)

1. 1. Patent Claims 1.Injectable solution of the thioctic acid salt of trometamol and/or of basic amino acids, characterised in that the salt forming acid/base pair is present in a 5 molar ratio of thioctic acid : trometamol = 1 : 1.1 to 3.2 and/or thioctic acid : basic amino acid = 1 : 1.1 to 2, and optionally together with other conventional pharmaceutical auxiliary substances. 2.Injectable solution according to Claim 1, characterised 10 in that the salt forming acid/base pair is present in a molar ratio of thioctic acid : trometamol = 1 : 1.4 to
2.8.
3.Injectable solution according to Claim 1, characterised in that the salt-forming acid/base pair is present in a 15 molar ratio of thioctic acid : basic amino acid 1 : 1.2 to 1.4.
4.Injectable solution according to Claims 1 and 3, characterised in that the basic amino acid is L-lysine or L-arginine. 20
5. Injectable solution according to Claims 1 to 4, characterised in that the salt-forming acid/base pair is prepared from thioctic acid/trometamol and basic amino acid.
6.A process for the preparation of an injectable solution 25 according to Claims 1 to 5, characterised in that thioctic acid together with trometamol and/or a basic amino acid is dissolved in water for injection purposes with stirring, filtered through a membrane filter of pore size 0.2 μτη and filled into ampoules and finally sterilized in superheated steam at 121®C for 15 minutes. (
7. . An injectable solution according to claim 1, substantially as hereinbefore described and exemplified. < 5
8.. A process according to claim 6 for the preparation of an injectable solution, substantially as hereinbefore described and exemplified.
9. . An injectable solution whenever prepared by a process claimed in a preceding claim.
IE361888A 1987-12-04 1988-12-02 An injection solution of the salt of thioctic acid with trometamol and/or amino acids IE60877B1 (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
DE3741152 1987-12-04

Publications (2)

Publication Number Publication Date
IE883618L IE883618L (en) 1989-06-04
IE60877B1 true IE60877B1 (en) 1994-08-24

Family

ID=6341895

Family Applications (1)

Application Number Title Priority Date Filing Date
IE361888A IE60877B1 (en) 1987-12-04 1988-12-02 An injection solution of the salt of thioctic acid with trometamol and/or amino acids

Country Status (7)

Country Link
EP (1) EP0318891B1 (en)
AT (1) ATE70974T1 (en)
DE (1) DE3867445D1 (en)
ES (1) ES2038733T3 (en)
GR (1) GR3003517T3 (en)
IE (1) IE60877B1 (en)
PT (1) PT89144B (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9107889B2 (en) 2005-08-04 2015-08-18 Encrypta Gmbh Compositions comprising an NO donor and a dithiolane and their use for improvement of sexual function

Families Citing this family (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0382066A3 (en) * 1989-02-09 1992-01-08 ASTA Medica Aktiengesellschaft Use of dihydroliponic acid as an analgetic, antiphlogistic and/or cytoprotective agent
EP0812590A3 (en) * 1989-11-09 1999-06-09 ASTA Medica Aktiengesellschaft Use of R-alpha lipoic acid for cytoprotection
PT95827B (en) * 1989-11-09 1997-11-28 Asta Medica Ag PROCESS FOR THE PREPARATION OF PHARMACEUTICAL COMPOSITIONS FOR COMBATING RETROVIRUS, CONTAINING AS ACTIVE INGREDIENTS ACIDS CARBOXYLS WITH SULFUR
DK0530446T3 (en) * 1991-07-05 1998-09-23 Asta Medica Ag Use of sulfur-containing carboxylic acids for the control of pathophysiologically conditioned excitation disorders
DE9213914U1 (en) * 1992-10-15 1992-12-03 Asta Medica AG, 6000 Frankfurt Ampoule and infusion solution of thioctic acid in the form of the water-soluble salts of thioctic acid
DE29506604U1 (en) * 1995-04-25 1995-06-14 Asta Medica Ag, 01277 Dresden Ready infusion set
DE69734734D1 (en) * 1996-07-05 2005-12-29 Us Gov Health & Human Serv SATURATED 1,2-DITHIACHETEROCYCLIC COMPOUNDS CONTAINING ANTIVIRAL PHARMACEUTICAL PREPARATIONS
DE19806354B4 (en) * 1998-02-10 2004-09-16 Bdd Group Holding Ag Use of α-lipoic acid or its physiologically tolerable salts for the treatment of LDL hypercholesterolemia
DE10159245A1 (en) * 2001-12-03 2003-06-18 Degussa Stable, acidic, aqueous solution containing alpha-lipoic acid (derivatives), process for their preparation and their use
CN1853626B (en) * 2005-04-29 2010-10-06 上海医药工业研究院 Zinc sulfate freeze-dried preparation for injection
IT1399923B1 (en) 2010-05-11 2013-05-09 Cbb Net S A PROCEDURE FOR THE PREPARATION OF SALTS OF THE ACID (R) ALPHA-LIPOIC THEIR FORMULATION AND USE IN PHARMACEUTICAL COMPOSITIONS IN THE FORM OF TABLETS THAT CONTAIN THEM
EP2389931A1 (en) * 2010-05-21 2011-11-30 Raw Materials Internatinal LLC Pharmaceutical aqueous compositions comprising lipoic acid as an antioxidant
ITMI20111452A1 (en) * 2011-07-29 2013-01-30 Istituto Biochimico Naz Sav Io Srl BASIC SOLUTION OF ALPHA-LIPOIC ACID AND ITS USES
IT202000009577A1 (en) 2020-04-30 2021-10-30 Fatro Spa INJECTABLE LIPOIC ACID FORMULATIONS FOR THE TREATMENT OF OXIDATIVE STRESS AND METABOLIC DISORDERS

Family Cites Families (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1056784B (en) * 1956-05-24 1959-05-06 Istituto Sieroterapico Italian Process for the preparation of stable injection solutions of 6,8-thioctic acid
DE1047991B (en) * 1957-11-20 1958-12-31 Nordmark Werke Gmbh Process for the production of chemically stable, non-toxic, sterile injection solutions from thioctic acid
DE1095991B (en) * 1959-05-09 1960-12-29 Chemiewerk Homburg Zweignieder Process for the preparation of a stable and injectable solution containing 1,2-dithia-cyclopentane-3-valeric acid
FR4630M (en) * 1965-06-09 1966-11-28
ES323195A1 (en) * 1966-02-17 1966-12-01 Ferrer Labor Tris (hydroxymethyl) aminomethane theophylline acetate
DE1617740B1 (en) * 1967-09-25 1971-11-04 Pfrimmer & Co J Method of stabilizing alpha-lipoic acid
ZA716628B (en) * 1970-10-15 1972-06-28 Richardson Merrell Spa Composition and method for treatment of hepatic disease and mental fatigue
DE2629845A1 (en) * 1976-07-02 1978-01-05 Geb Graze Erika Graze Infusion or injection for restoring cellular energy metabolism - contg. glucose-(1)-phosphate with potassium, magnesium and/or amino acids
GB1504767A (en) * 1976-08-23 1978-03-22 Beecham Group Ltd Antibiotic compositions
DE3217315C2 (en) * 1982-05-08 1986-05-22 Gödecke AG, 1000 Berlin Medicinal preparations containing oxicam derivatives

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9107889B2 (en) 2005-08-04 2015-08-18 Encrypta Gmbh Compositions comprising an NO donor and a dithiolane and their use for improvement of sexual function

Also Published As

Publication number Publication date
PT89144B (en) 1993-05-31
GR3003517T3 (en) 1993-03-16
EP0318891A1 (en) 1989-06-07
IE883618L (en) 1989-06-04
PT89144A (en) 1989-12-29
ATE70974T1 (en) 1992-01-15
ES2038733T3 (en) 1993-08-01
DE3867445D1 (en) 1992-02-13
EP0318891B1 (en) 1992-01-02

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