Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1994-07-11
1997-01-14
Burn, Brian M.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
424468, 424470, 424472, 424471, 424482, 424501, A61K 3104
Patent
active
055940137
DESCRIPTION:
BRIEF SUMMARY
INTRODUCTION
This introduction is a 371 of PCT/GB93/00055, filed Jan. 12, 1993, and published as WO93/13773 Jul. 22, 1993.
1. Technical Field
The present invention relates to pharmaceutical compositions containing nifedipine and to a process for the preparation thereof. In particular the present invention relates to a slow release pharmaceutical formulation containing nifedipine which provides for a regular and prolonged release pattern upon administration and, in its most preferred form, may be administered once a day. The invention also relates to a process for the preparation thereof.
2. Background to the Invention
The drug nifedipine is currently used in the form of rapid release and comparatively slow release pharmaceutical dosage forms for the treatment, respectively, of acute angina and chronic hypertension. It appears that, for the acute treatment of angina, it is desirable quickly to attain relatively high nifedipine concentrations in plasma and this requirement is currently served by a preparation consisting of a solution of nifedipine in low molecular weight polyethylene glycol contained within soft gelatin capsules. For the treatment of hypertension it appears that it is more desirable to maintain plasma nifedipine concentrations within a much lower concentration range. Modified release preparations of the substance are available for this purpose, although they mostly still require multiple daily doses to be taken which is both a clinical disadvantage in that symptomatic control of the condition may not be optimised and a disadvantage from the patient's point of view. The inconvenience of taking a dosage more than once per day may affect compliance with the dosage regime, also leading to poor clinical performance.
The reason for the two significantly different types of formulation is that nifedipine per se is very poorly soluble in water. Because of this many of the patent specifications on controlled release systems of nifedipine describe means of actually enhancing, rather than suppressing, the solubility of nifedipine.
Thus, in European Patent No. 0047899 (corresponding to Canadian Patent No. 1180277) control of the dissolution of nifedipine is achieved by processing the material to give it a large specific surface area of 0.5 to 6m.sup.2 /g. The specification discloses the production of fine nifedipine crystals by grinding and screening but not by any other means.
Similarly, in PCT/EP85/00481 the control of nifedipine dissolution is achieved by limiting its specific surface area to 0.1 to 0.42m.sup.2 /g and coating the nifedipine crystals, in admixture with an equal quantity of a filler, onto inert spheroids by means of suitable binders.
Further enhancement of the dissolution of nifedipine is achieved by processing the material to form a solution adsorbed onto a solid base (as in British Patent No. 1,456,618), or to form a solid solution (also known as a co-precipitate) with high molecular weight polyethylene glycol (European Patent Application No. 0220760) or an ester or ether of polyethylene glycol (European Patent Application No. 0249587) or with other selected materials, including polyvinylpyrrolidone (British Patent No. 1,579,818).
This ability of polyvinylpyrrolidone to enhance the solubility characteristics of certain materials by forming coprecipitates with them is now fairly well documented. It is also generally accepted that in order to form such coprecipitates the amount of polyvinylpyrrolidone used must be in excess of the amount of active material.
In our European Patent No. 385582 we describe pharmaceutical compositions in which polyvinylpyrrolidone in an amount less than the amount of nifedipine actually significantly slows the dissolution of nifedipine from the finished solid dosage form. More specifically, EP 385582 discloses a pharmaceutical composition which comprises particles of a finely divided pharmaceutically acceptable water soluble carrier coated with microparticles of nifedipine, the majority of which have a particle size of 100 micrometers or less, in the presen
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Sugimoto, I., et al., "Dissolution and absorption of nifedipine from nifedipine-polyvinylpyrroidone coprecipitate", Drug Development and Industrial Pharmacy, 6(2):137 (1980).
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Burn Brian M.
Ethical Pharmaceuticals Limited
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