Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1997-04-23
2000-11-28
Henley, III, Raymond
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
546194, A61K 31445, C07D21168
Patent
active
061536237
DESCRIPTION:
BRIEF SUMMARY
The present invention concerns extended release formulations comprising cisapride-(L)-tartrate, in particular for oral administration, the use thereof as a medicine, especially in treating gastro-intestinal disorders.
European Patent No. 0,076,530 discloses the gastroprokinetic agent cisapride and classic compositions thereof. Cisapride has the following structural formula: ##STR1##
The systematic chemical name of cisapride is cis-4-amino-5-chloro-N-[1-[3-(4-fluorophenoxy)propyl]-3-methoxy-4-piperidi nyl]-2-methoxybenzamide. Cisapride is a racemic mixture of two enantiomers. Cisapride has excellent gastro-intestinal motility stimulating properties and is reported to be devoid of antidopaminergic activity. Its utility in a variety of gastro-intestinal disorders has already been reported extensively.
Useful extended release formulations of cisapride for oral administration should release the active ingredient, i.e. cisapride, over a long period of 15 to 24 hours, that is through the whole gastro-intestinal tract with its varying pH values. However, the solubility of cisapride depends very much on the surrounding pH. The solubility of cisapride is the highest in a strongly acidic medium at pH 1 to 2, such as for example in gastric juice. The solubility diminishes rapidly when the pH of the (physiological) medium increases, for example in the intestines. An effective sustained release formulation of cisapride should therefore function not only in highly acidic but also in less acidic or neutral media. Moreover an extended release formulation should release the active ingredient as soon as the formulation is administered and should release the active ingredient in a constant manner, preferably following zero order to first order kinetics. This profile is desired because it provides relief to the patient very soon after administration and overdosing is avoided when administering the formulation for a consecutive time.
A solution to this problem was found in the use of (+)-cis-4-amino-5-chloro-N-[1-[3-(4-fluorophenoxy)propyl]-3-methoxy-4-pipe ridinyl]-2-methoxybenzamide [R(R*,R*)]-2,3-dihydroxybutanedioate (1:1)--referred to hereinunder as "cisapride-(L)-tartrate"--in a matrix formulation as described hereinafter. Cisapride-(L)-tartrate is the salt of racemic cisapride with (+)-L-tartaric acid and is exemplified in European Patent No. 0,076,530 as compound number 241.
An additional aspect of this invention is the fact that the production process for the present extended release formulations is very simple as is shown in the examples hereinunder. This is in contrast to the production processes known in the art for preparing extended release formulations.
In comparison with other salts of cisapride the salt form with [R(R*,R*)]-2,3-dihydroxybutanedioic acid, i.e. (+)-L-tartaric acid (the natural form of tartaric acid) shows a remarkably good solubility in water. Cisapride being a racemic mixture and L-tartaric acid being one single enantiomer, the resulting salt form is in principle a mixture of two diastereomeric salts: (+)-cisapride-(L)-tartrate and (-)-cisapride-(L)-tartrate.
Unexpectedly, it was shown that the salt cisapride-(L)-tartrate is a mixture of the diastereomers [(3R4S)(2R3R)] and [(3S4R)(2R3R)], that crystallize as a double salt in a 1:1 ratio. (This is confirmed by X-ray.) The (3R4S) and (3S4R) refer to the respective enantiomers of cisapride and the (2R3R) refers to the optically pure L-tartrate.
Unexpectedly, it was found that formulations containing cisapride-(L)-tartrate released cisapride in a racemic form, i.e. equal amounts of (+)-cisapride and (-)-cisapride or in other words the diastereomeric salt forms (+)-cisapride-(L)-tartrate and (-)-cisapride-(L)-tartrate unexpectedly have equal dissolution rates.
Moreover, it was also found that during the preparation of cisapride-(L)-tartrate no enrichment of one of the two diastereomeric salt forms could be detected.
Compositions according to the present invention comprise pharmaceutically acceptable carriers and excipients, such as fillers, e.g. lac
REFERENCES:
patent: 5057525 (1991-10-01), Van Daele
The Theory and Practice of Industrial Pharmacy; "Sustained Release Dosage Forms"; pp. 452-455 (1986).
Gilis Paul Marie Victor
Jans Eugene Marie Jozef
Ciambrone Coletti Ellen
Henley III Raymond
Janssen Pharmaceutic N.V.
LandOfFree
Cisapride extended release does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Cisapride extended release, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Cisapride extended release will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-1726107