Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Patent
1995-03-21
1998-04-28
Nutter, Nathan M.
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
536 46, 536103, 514608, 514646, 514649, 514651, 514717, C08B 3716, A61K 4740, A61K 3163
Patent
active
057441650
DESCRIPTION:
BRIEF SUMMARY
This application is filed under 35 USC 371 as a continuation PCT/HU94/00014 filed May 18, 1994.
FIELD OF THE INVENTION
The invention relates to highly soluble, physiologically acceptable inclusion complexes of nimesulide-salts with cyclodextrins, to the preparation thereof, to pharmaceutical compositions containing the same as well as methods for their use.
More particularly, the invention relates to inclusion complexes of nimesulide alkali and alkaline earth salts of general formula (I) ##STR1## wherein A represents an alkali and/or alkaline earth ion; with cyclodextrins and cyclodextrin derivatives.
BACKGROUND OF THE INVENTION
non-steroidal antiinflammatory drug successfully used for the treatment of different painful inflammatory conditions and rheumatoid arthritis. It also possesses antipyretic activities (Belgian Patent No. 801812). Solutions of nimesulfide sodium salts were prepared from nimesulide with sodium carbonate in acetone and they were used without isolation as intermediates to prepare N-substituted nimesulide derivatives (Belgian Patent No. 801812). Probably due to the high pH value of their solutions, the nimesulide alkali and alkaline earth salts were not practical for use as pharmaceuticals. Recently, it has been confirmed that based on its mechanism of action in pain relief, nimesulide can also be considered to represent a new type of useful analgesic agent. Forsuch drugs a quick onset of action of the orally administered formulation is a very important factor.
Compared to other non-steroidal antiinflammatories, nimesulide has a favorable therapeutic index, minimal acute gastrointestinal toxicity and exhibits good general tolerability. It is chemically different from other drugs of its class because its functional acidic group is a sulfonanilide moiety.
Nimesulide is a very hydrophobic drug substance and is practically insoluble in water. Its aqueous solubility is about 0.01 mg/ml at room temperature. The very poor aqueous solubuility and wettability of the drug present problems for the preparation of pharmaceutical formulations with good release and non-variable bioavailability.
It is desirable to overcome the disadvantages connected with the very poor aqueous solubility and wettability in order to increase the aqueous solubility of nimesulide.
Nimesulide is a weak acid type compound; therefore its aqueous solubility in acidic medium, e.g., at the pH of the gastric juice, is particularly poor. Orally administered nimesulide is likely to be absorbed only in the lower part of the gastrointestinal tract. This probably explains the rather protracted onset of its biological effect, although other theories are possible to explain this observation.
Patent Applications PCT/IT91/00043 and DE 4116659 describe complexation of nimesulide with cyclodextrins, preferably with .beta.-cyclodextrin in about a 1:1 molar ratio, and faster absorption and higher plasma levels of nimesulide were shown in animal tests when compared with administration of nimesulide per se.
For solid complex preparation, three different known methods are exemplified: overnight, the preferred solvent being methylene-chloride; solution; and isolating the complex by evaporation under reduced pressure.
Method A is not acceptable for preparation of cyclodextrin (CD) compexes for pharmaceutical purposes. All organic solents form more or less stable complexes with cyclodextrins. Inclusion of methylene chloride by .beta.-cyclodextrin is invevitable in this case; consequently the product might contain a considerable amount of toxic chlorinated solvent. The chlorinated solvent can not be removed completely even by heating in vacuo at elevated temperature for hours. The toxic chlorinated solvent will be released only upon dissolution, e.g., in the gastric juice.
Method C is the oldest known method for preparation of drug/cyclodextrin-complexes, but the long stirring time, with the concomitant degradation makes this process technically obsolete. Method B seems to be the best, however, it is difficult to completely remove ammonia dur
REFERENCES:
patent: 4565807 (1986-01-01), Uekama et al.
M. Kurozumi, et al. "Inclusion Compounds of Non-Steroidal Antiinflammatory nd Other Slightly Water Soluble Drugs with .alpha.- and .beta.-Cyclodextrins in Powdered Form", Chem. Pharm. Bull. Vo. 23 (1975), pp. 3062-3068.
Cyclolab Cyclodextrin Research and Development Laboratory, Ltd.
Europharmaceutical, S.A.
Nutter Nathan M.
LandOfFree
Nimesulide salt cyclodextrin inclusion complexes does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Nimesulide salt cyclodextrin inclusion complexes, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Nimesulide salt cyclodextrin inclusion complexes will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-1530050