Pharmaceutical formulations containing darifenacin

Details Pharmaceutical formulations containing darifenacin Pharmaceutical formulations containing darifenacin

1998-03-03

2000-08-22

Jordan, Kimberly

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Matrices

514422, 514966, A61K 914, A61K 3140

Patent

active

061068640

DESCRIPTION:

BRIEF SUMMARY
This is a National Phase filing under 35 U.S.C. .sctn.171 based on PCT/EP96/03719 having an international filing date Aug. 21, 1996.
This invention relates to pharmaceutical dosage forms of darifenacin and its pharmaceutically acceptable salts.
Darifenacin is (S)-2-{1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-dipheny l-acetamide and is disclosed in European Patent No 0388054, Examples 1B and 8, and is referred to therein as 3-(S)-(-)-(1-carbamoyl-1,1-diphenylmethyl)-1-[2-(2,3-dihydro-benzofuran-5- yl)ethyl]pyrrolidine. It is indicated in the treatment of urinary incontinence and irritable bowel syndrome and has the following structure: ##STR1##
Clinical investigations have shown a major metabolite of darifenacin to be the following 3'-hydroxyl derivative: ##STR2##
It appears that the metabolite is 6-fold less selective for muscarinic M3 receptors over M1 receptors in comparison with darifenacin, and so the metabolite is more likely than darifenacin to produce unwanted side-effects such as dry mouth, confusion and blurred vision.
It has now been found that delivering darifenacin and its pharmaceutically acceptable salts to the lower gastrointestinal tract (e.g. in a sustained release formulation) gives rise to a greater ratio of darifenacin to metabolite in the systemic circulation. This increases the bioavailability of darifenacin, which is likely to minimize any unwanted side-effects. This is surprising because a slower release rate normally leads to a slower delivery to liver enzymes and a greater degree of metabolism of an administered drug.
Thus, according to the present invention, there is provided a pharmaceutical dosage form adapted for administration to the gastrointestinal tract of a patient, comprising darifenacin, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant, diluent or carrier; characterized in that the dosage form is adapted to deliver at least 10% by weight of the darifenacin, or the pharmaceutically acceptable salt thereof, to the lower gastrointestinal tract of the patient.
The dosage forms of the invention may be of the sustained or delayed release type, and so release the darifenacin, or the pharmaceutically acceptable salt thereof, to the gastrointestinal tract of the patient over or after a sustained period of time following administration of the dosage form to the patient. However, when the dosage forms are administered rectally, conventional rectal formulations may be used.
By "lower gastrointestinal tract" is meant the portion of the gastrointestinal tract between the region of the ileo-caecal junction and the rectum inclusive.
"Patient" means primarily a human patient, although the formulations of the present invention may be useful in the treatment of non-human animals.
Preferably, the dosage forms of the invention are adapted to deliver at least 25%, and more preferably 50% by weight of the darifenacin, or the pharmaceutically acceptable salt thereof, to the lower gastrointestinal tract.
Preferably, no more than 90% by weight of the darifenacin, or the pharmaceutically acceptable salt thereof, is released 4 hours after dosing; more preferably no more than 90% by weight of the darifenacin, or the pharmaceutically acceptable salt thereof, is released 8 hours after dosing; and most preferably, no more than 90% by weight of the darifenacin, or the pharmaceutically acceptable salt thereof, is released 16 hours after dosing.
The conditions in the gastrointestinal tract are thought to be reproduced in vitro using Apparatus 1 described in USP XXII at page 1578, having baskets of 40 mesh (381 .mu.m apertures), a rotation speed of 100 rpm and a dissolution medium of water at 37.degree. C. Therefore, the sustained release formulations of the invention may be defined alternatively as a pharmaceutical dosage form adapted for administration to the gastrointestinal tract of a patient, comprising darifenacin, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant, diluent or carrier; characterized in t

REFERENCES:
patent: 5233053 (1993-08-01), Cross et al.

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