Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Patent
1998-05-21
2000-10-03
Spear, James M.
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
424468, 424474, 424475, 5147722, 5147723, A61K 922, A61K 932
Patent
active
061269700
DESCRIPTION:
BRIEF SUMMARY
CROSS-REFERENCE TO RELATED APPLICATIONS
This application is based upon PCT Application Ser. No. PCT/EP 96/05346, filed Nov. 26, 1996, which claims priority from European Patent Application Ser. No. 95.203.309.0, filed on Dec. 1, 1995.
The present invention concerns pharmaceutical dosage forms comprising cisapride-(L)-tartrate or a precursor form thereof, contained in a porous structure consisting essentially of one or more polymers which are insoluble or practically insoluble in water or gastrointestinal fluids and wherein the pores of the porous structure comprise a substance soluble in water or gastrointestinal fluids adjacent to the surface of the dosage form. The present invention is further concerned with processes for preparing such pharmaceutical dosage forms and with the use of these pharmaceutical dosage forms as a medicine, especially in treating gastrointestinal disorders, more particularly gastro-oesophagal reflux disease.
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 gastrointestinal 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. It is currently being marketed as a medicine to treat the symptoms of gastro-oesophagal reflux disease, dyspepsia and other conditions which are related to impaired gastrointestinal motility.
The present dosage forms of cisapride call for an intake of cisapride tablets at least twice a day. A more patient-friendly intake regimen and consequently a intake regimen which would enhance patient compliance, would be a once-daily dosing frequency. A dosage form allowing once-daily intake of cisapride is provided with the sustained-release formulation of the present invention.
The terms "sustained-release", "extended-release" and "slow-release" are to be considered as synonyms in the context of the present invention.
Useful extended-release formulations of cisapride for oral administration should release the active ingredient, i.e. cisapride, over a long period of from 12 to 30 hours, preferably from 15 to 24 hours, that is throughout the whole gastrointestinal 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 upon consecutive administration the formulation.
A solution to the problem of very pH-dependent solubility of cisapride 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". 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.
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 w
Ciambrone Coletti Ellen
Janssen Pharmaceutica N.V.
Spear James M.
LandOfFree
Cisapride sustained 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 sustained release, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Cisapride sustained release will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-192582