PHARMACEUTICAL COMPOSITION CONTAINING LORNOXICAM AND A DISODIUM SALT OF EDTA

COMPOSITION PHARMACEUTIQUE CONTENANT DU LORNOXICAM ET UN SEL DISODIQUE D'ETHYLENEDIAMINETETRAACETATE

English Abstract

A pharmaceutical composition is disclosed which contains lornoxicam and a
disodium salt of EDTA.

French Abstract

L'invention concerne une composition pharmaceutique contenant du lornoxicam et un sel disodique de l'acide éthylènediamine tétracétique.

Claims

CLAIMS:
1. A pharmaceutical composition for parenteral or ophthalmic application
containing Lornoxicam or a pharmaceutically acceptable salt thereof and a
disodium
salt of EDTA.
2. The pharmaceutical composition according to claim 1, characterised by the
fact that the disodium salt of EDTA is used in concentrations of 0.1 to 5 mg
per 10
ml of solution.
3. The pharmaceutical composition according to claim 1, characterised by the
fact that the disodium salt of EDTA is used in concentrations of 0.25 to 4 mg
per 10 ml of solution.
6

Description

CA 02264626 1999-02-26WO 98109654 PCTIEP97I04742PHARMACEUTICAL COMPOSITION CONTAINING LORNOXICAM AND ADISODIC SALT OF EDTAA clear pharmaceutical composition for parenteral application is disclosed whichcontains 6-chloride-4-hydroxy—2-methyl-N—2—pyridyl-2H-thieno-[2,3—e]-1 ,2-thiazine-carboxamide—1,1-dioxide (Lornoxicam) or a pharmaceutically acceptablesalt thereof.Lornoxicam is a non—steroidal anti—inflammatory substance and can be used totreat acute and chronic pain conditions accompanied by inflammatory processes,e.g. post—operative pain, arthritis, rheumatism, injuries to soft parts, etc.Non-steroidal anti—inflammatory drugs (NSAlDs) are usually only slightly solubleand partly nearly insoluble in water. This insolubility causes serious problems inthe formulation of such compounds for solutions for parenteral or ophthalmicapplication, especially for intravenous application.Solubility can, for example, be enhanced through salt formation or complexing ofthe active substance.Lornoxicam is an NSAID of extremely low solubility, which is in liquidformulations additionally unstable, numerous side products resulting fromoxidation and hydrolytic dissociation. The stability of the liquid formulation can beincreased by lyophylisation. However, liquid formulations derived from thelyophylisate are significantly turbid. Thus parenteral or ophthalmic solutionsproduced in this way are useless.The application of EDTA and its salts to stabilise solutions of pharmaceuticallyapplicable compounds is known. They are especially used for the complexing ofmetal ions such as copper, iron or manganese ions, which cause or accelerateCA 02264626 1999-02-26oxidation of pharmaceutically active substances.Surprisingly, it has now turned out that the addition of small quantities of disodicsalt of EDTA can prevent clouding of solutions of lyophylised Lomoxicam. Acomparative stability analysis of Lomoxicam lyophylisate formulations with andwithout disodic EDTA conducted over a period of 3 years has shown that thiseffect exerts no impact on the chemical stability of the active substance as far asoxidation reactions are concerned. In contrast to disodic salt of EDTA, calciumsodium salt of EDTA has been shown to exert no influence on the clouding ofLornoxicam solutions.The subject of the invention disclosed herein are, therefore, pharmaceuticalcompounds for parenteral or ophthalmic application which contain Lomoxicam ora pharmaceutically acceptable salt thereof and a disodic salt of EDTA.According to the present invention, disodic salt of EDTA is used to preventclouding of solutions, which contain lyophylised Lomoxicam.Other methods such as filtering of the solution, addition of ascorbic acid orsodium bisulphite or addition of a complexing agent such as Polyvidone 17 PFwere not able to prevent clouding of the solution.Solving in organic solvents or mixtures thereof such as propylene glycol,polyethylene glycol, etc. reduces clouding of solutions but must be excluded dueto the pain that occurs as a consequence of hyperosmolality when such solutionsare injected.Disodic salt of EDTA is added in very small quantities, i.e. approx. 0.1 — 5 mg perml of solution, preferably 0.25 - 4 mg per 10 ml of solution.Solutions thus produced are characterised by turbidity levels of 3 - 12 and,CA 02264626 1999-02-26therefore, classified as clear solutions according to Ph. Eur. and suitable forparenteral and ophthalmic application.CA 02264626 1999-02-26Example 1Standard formulationLomoxicam 8 mgMannitol 100 mgTrometamol 2 mgSolved in 2 ml water ad inj.The clearness of the solution was determined by application of the followingprocedures:a) Ph. Eur. procedureThe sample is compared, in diffuse daylight and against a black background, withwater or a reference substance.b) Nephelometric analysisThe sample is measured in a monochromatic ray of light with a wavelength of564 nm, a glass cell of standardised opacity being used for reference purposes.The turbidity levels determined in the standard formulation in reconstitutedsolution were 140 — 200. According to Ph. Eur., only solutions with turbidity levelsbelow 70 -— 100 are classified as clear.Example 2Lornoxicam 8 mgMannitol 100 mgTrometamol 12 mgDisodic salt of EDTA 0.05 mg — 0.8 mgSolved in 2 ml water ad inj.Solutions of this type of Lomoxicam lyophylisate formula in reconstituted solutionwere characterised by turbidity levels of 3-12.CAExample 3LornoxicamMannitolTrometamolDisodic calcium salt of EDTA02264626 1999-02-268 mg100 mg12 mg0.05 — 0.8 mgSolutions of this type of Lornoxicam lyophylisate formula in reconstituted solutionwere characterised by cloudiness levels of 160 — 340.Example 4Comparative stability data after a storage period of 36 months of Lornoxicamlyophylisate formulations produced according to the basic formulas indicated inexample 1 (without disodic salt of EDTA) and example 2 (with disodic salt ofEDTA).Test parametersFormulation withoutdisodic salt of EDTA‘Content of activesubstance 8.44 mgOxidation productsCompound A < 0.1 %Compound B 0.2 %Formulation withdisodic salt of EDTA"8.44 mg0.1 %0.2 %* Lornoxicam 8 mg; Mannitol 100 mg; Trometamol 12 mg.** Lornoxicam 8 mg; Mannitol 100 mg; Trometamol 12 mg; disodic salt of EDTA0.2 mg.CA 02264626 1999-02-26Compound A: N-(2-amino-pyridyl) oxalic acidCompound B: 5—chlorine—3—sulphinothiopene—2-carboxylic acid