Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-12-21
2001-03-27
Henley, III, Raymond (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06207682
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a novel formulation containing (R)-1-(3-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-propyl)-3-piperidinecarboxylic acid or a pharmaceutically acceptable salt thereof, and to its use in the treatment and/or prophylaxis of certain disorders.
2. Description of the Related Art
WO 95/18793 and WO 97/22338 discloses inter alia (R)-1-(3-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-propyl)-3-piperidinecarboxylic acid or a pharmaceutically acceptable salt thereof, and the use of the compound to treat all painful, hyperalgesic and/or inflammatory conditions in which C-fibres play a pathophysiological role by eliciting neurogenic pain or inflammation. Further, it has been demonstrated that (R)-1-(3-(10,11 -Dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-propyl)-3-piperidinecarboxylic acid or a pharmaceutically acceptable salt thereof, is useful in reducing blood glucose and/or inhibiting the secretion, circulation or effect of insulin antagonizing peptides like CGRP or amylin.
The formulations containing (R)-1-(3-(10,11 -Dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-propyl)-3-piperidinecarboxylic acid or a pharmaceutically acceptable salt thereof, as suggested in WO 95/18793 and WO 97/22338, relate to formulations which are prepared by conventional techniques. The formulations mentioned appear in conventional forms, for example capsules, tablets, aerosols, solutions, suspensions or topical applications.
The half-life for (R)-1-(3-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-propyl)-3-piperidinecarboxylic acid is relatively short, and in order to control the release of the compound in such a manner that an effective concentration in the blood can be maintained over an extended period of time but also that the drug concentration in the blood remains relatively constant over an extended period of time, there exists a need for a modified release formulation for (R)-1-(3-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-propyl)-3-piperidinecarboxylic acid.
The use of modified release formulations will furthermore improve patient compliance as it reduces the numbers of dosages to be taken per day.
Thus one object of the present invention is to provide modified release formulations containing (R)-1-(3-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-propyl)-3-piperidinecarboxylic acid or a pharmaceutically acceptable salt thereof to reduce the fluctuations in plasma concentrations and thereby reduce any inconvenience therefrom.
To reduce plasma fluctuations it is necessary to provide modified release formulations with zero-order drug release. However, zero-order drug release is difficult to obtain for modified release products, especially for matrix tablets comprising hydroxypropylmethylcellulose, which is a polymer often used within modified release formulations.
SUMMARY OF THE INVENTION
It has now surprisingly been found that modified release formulations with zero-order drug release containing (R)-1-(3-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-propyl)-3-piperidinecarboxylic acid or a pharmaceutically acceptable salt thereof dispersed in a polymeric matrix comprising at least one release rate controlling polymer can be provided.
The present invention further provides modified release formulations with zero-order drug release wherein the polymeric matrix comprises a combination of a polyethylene oxide and a hydroxypropylmethylcellulose so that the in vitro dissolution rate is decreased compared to what is obtained with polyethylene oxide alone as the rate controlling polymer.
Furthermore, the present invention relates to modified release formulations comprising a combination of a polyethylene oxide and a hydroxypropylmethylcellulose making the in vitro zero-order dissolution profile independent of pH, indicating that the in vivo absorption also is zero-order and independent of pH.
The requirements of the dissolution profile for the formulation depends on the disorders to be treated and thereby by the ratio between the polymers used. For disorders having a relatively short treatment period, for example during the night, the dissolution rate should be higher than for disorders requiring once daily treatment. The in vitro dissolution profiles can be modified according to the actual requirement.
The present invention further provides a method of treating conditions or indications related to all painful, hyperalgesic and/or inflammatory conditions in which C-fibres play a pathophysiological role, e.g. neurogenic pain, neurogenic inflammation, migraine, neuropathy, itching and rheumatoid arthritis; urinary incontinence; angiogenesis as well as indications caused by or related to the secretion and circulation of insulin antagonizing peptides, e.g. non-insulin-dependent diabetes mellitus (NIDDM) and ageing-associated obesity, by administering an effective and/or a prophylactic amount of a modified release formulation containing (R)-1-(3-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-propyl)-3-piperidinecarboxylic acid or a pharmaceutically compound thereof to a patient in need thereof.
Furthermore, the present invention also provides the use of a modified release formulation containing (R)-1-(3-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-propyl)-3-piperidinecarboxylic acid or a pharmaceutically compound thereof in the manufacture of a medicament, for treating the above mentioned conditions or indications.
The present invention also provides a pharmaceutical composition for use in the treatment of the above mentioned conditions or indications which comprises a modified release formulation containing (R)-1-(3-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-propyl)-3-piperidinecarboxylic acid or a pharmaceutically compound thereof.
REFERENCES:
patent: 5783212 (1998-07-01), Fassihi et al.
patent: 2 152 940 (1985-08-01), None
patent: WO 95/18793 (1995-07-01), None
patent: WO 97/22338 (1997-06-01), None
Yang et al., Internation Journal of Pharmaceutics, vol. 155, pp. 219-229 (1997).
Andersen Tina Meinertz
Hjorth Thyge Borup
Jorgensen Kim Westi
Henley III Raymond
Novo Nordisk A S
Rozek, Esq. Carol E.
Zelson, Esq. Steve T.
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