Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Patent
1996-06-11
1998-05-26
Geist, Gary
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
514601, 514886, 564 89, A61K 3118
Patent
active
057565465
DESCRIPTION:
BRIEF SUMMARY
This is the U.S. National Stage Application of PCT/BE95/00055 filed Jun. 16, 1995 now WO95/34533 published Dec. 21, 1995.
The present invention relates to a water-soluble nimesulide salt and its preparation, an aqueous solution containing it, nimesulide-based combinations with cyclodextrins, and the uses of these nimesulide salt
As is known, nimesulide, also known under the name of N-(4-nitro-2-phenoxyphenyl)methanesulfonamide or 4-nitro-2-phenoxymethanesulfonanilide, is a well known medication employed in the treatment of inflammatory diseases or disorders, such as, for example, rheumatic disorders and acute inflammations. However, it has the disadvantage of being very poorly soluble in water, and this opposes its use in some galenic applications such as drinkable and injectable solutions and some other oral preparations, such as effervescent tablets or granules. Furthermore, it is known that nimesulide salts in solution which are known so far, in particular the sodium salt, impose a relatively alkaline pH of which it is necessary to be aware when they are formulated in an injectable form. Moreover, the sodium salt of nimesulide, although soluble, has the disadvantage of releasing sodium ions therewith, which are often contraindicated. It is also known, in accordance with patent applications WO91/17774 and 94/02177, to be able to complex nimesulide with cyclodextrins but, in fact, the latter allow only a moderate increase in the solubility in water of nimesulide which is not in salt form, that is to say of the order of approximately 0.05 mg/ml (value determined by a solubility diagram), that is 5 times the solubility of nimesulide (0.01 mg/ml).
The aim of the present invention is to overcome these disadvantages and to provide a nimesulide salt which is highly soluble in water, which can be used especially for the preparation of drinkable or injectable solutions of nimesulide while preserving the pharmacological and/or therapeutic antiinflammatory applications of acidic nimesulide.
To this end, in accordance with the invention, the salt consists of the product of reaction of nimesulide and of L-lysine.
The salt advantageously contains approximately 1 mole of L-lysine per mole of nimesulide.
In accordance with an advantageous embodiment an aqueous solution of said salt of nimesulide is provided in combination with L-arginine, the weight ratio of the nimesulide salt to the L-arginine being advantageously approximately 1/1.
The invention also relates to nimesulide-based combinations in order to appreciably increase further the water-solubility of nimesulide in comparison with the nimesulide-L-lysine salt.
With this in mind, nimesulide and L-lysine are combined, in accordance with the invention, with at least one cyclodextrin, in the form of a mixture of these compounds, of a mixture of the nimesulide-L-lysine salt with cyclodextrin, of a nimesulide-cyclodextrin complex mixed with L-lysine or else of a nimesulide-L-lysine-cyclodextrin complex.
According to another advantageous embodiment of the invention the cyclodextrin is chosen from the group including .alpha.-, .beta.- and .gamma.-cyclodextrins, their hydrates, their derivatives and their mixtures.
Finally, the invention also relates to the preparation of the abovementioned nimesulide salt and to its applications and to the applications of the aqueous solution containing it and of the abovementioned combinations.
According to one embodiment, nimesulide and L-lysine are dissolved in methanol and the methanol is removed from the mixture thus obtained by conventional methods such as concentration by evaporation, followed by filtration, the methanol employed for dissolving the nimesulide being heated preferably to a temperature close to its boiling point, advantageously to a temperature of 54.degree. to 64.degree. C.
As just explained, the water-soluble nimesulide salt of the present invention consists of the product of reaction of nimesulide with the amino acid L-lysine in its non-salt monohydrate form. This salt of nimesulide and L-lysine or nimesulide-L-lys
REFERENCES:
patent: 3840597 (1974-10-01), Moore et al.
patent: 4983628 (1991-01-01), Frenette et al.
patent: 5019563 (1991-05-01), Hunter et al.
Delneuville Isabelle
Geczy Joszef
Neven Philippe
Piel Geraldine
Pirotte Bernard
Geist Gary
Padmanabhan Sreeni
LandOfFree
Water-soluble nimesulide salt and its preparation, aqueous dolut does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Water-soluble nimesulide salt and its preparation, aqueous dolut, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Water-soluble nimesulide salt and its preparation, aqueous dolut will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-1960766