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 acidsInfo
- 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
Links
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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Dermatology (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (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.
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)
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)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5334612A (en) * | 1988-11-09 | 1994-08-02 | Asta Pharma Aktiengesellschaft | Pharmaceutical compositions containing as active substance sulphur-containing carboxylic acids and their use in combating retroviruses |
EP0382066A3 (en) * | 1989-02-09 | 1992-01-08 | ASTA Medica Aktiengesellschaft | Use of dihydroliponic acid as an analgetic, antiphlogistic and/or cytoprotective agent |
ES2115589T3 (en) * | 1989-11-09 | 1998-07-01 | Asta Medica Ag | MEDICATION CONTAINING R-ALPHA-LIPONIC ACID OR S-ALPHA-LIPONIC ACID AS AN ACTIVE SUBSTANCE. |
EP0530446B1 (en) * | 1991-07-05 | 1998-01-28 | ASTA Medica Aktiengesellschaft | Use of sulfur containing carboxylic acids for combatting pathophysiologic excitatory 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 |
AU737038B2 (en) * | 1996-07-05 | 2001-08-09 | Government Of The United States Of America, As Represented By The Secretary Of The Department Of Health And Human Services, The | Anti-viral pharmaceutical compositions containing saturated 1,2-dithiaheterocyclic compounds and uses thereof |
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)
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 |
-
1988
- 1988-11-28 DE DE8888119790T patent/DE3867445D1/en not_active Expired - Lifetime
- 1988-11-28 EP EP88119790A patent/EP0318891B1/en not_active Expired - Lifetime
- 1988-11-28 ES ES198888119790T patent/ES2038733T3/en not_active Expired - Lifetime
- 1988-11-28 AT AT88119790T patent/ATE70974T1/en not_active IP Right Cessation
- 1988-12-02 IE IE361888A patent/IE60877B1/en not_active IP Right Cessation
- 1988-12-02 PT PT89144A patent/PT89144B/en not_active IP Right Cessation
-
1992
- 1992-01-03 GR GR910402255T patent/GR3003517T3/el unknown
Cited By (1)
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 |
---|---|
IE883618L (en) | 1989-06-04 |
ES2038733T3 (en) | 1993-08-01 |
ATE70974T1 (en) | 1992-01-15 |
PT89144B (en) | 1993-05-31 |
DE3867445D1 (en) | 1992-02-13 |
EP0318891A1 (en) | 1989-06-07 |
PT89144A (en) | 1989-12-29 |
GR3003517T3 (en) | 1993-03-16 |
EP0318891B1 (en) | 1992-01-02 |
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Legal Events
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MK9A | Patent expired |