The advantages of sustained release pharmaceutical compositions are well-known and their use is becoming more and more widespread. The methods used in this field of pharmaceutical industry are continuously developping. However the requirements raised against sustained release compositions are considerably higher and more severe than those raised against conventional pharmaceutical compositions. For this reason there is not yet known any process which can be applied for every active ingredient and meets all requirements. The preparation of sustained release pharmaceutical compositions from active ingredients having a relatively high therapeutical dose is particularly encountered with difficulties because the solid oral pharmaceutical compositions are of a limited size (the weight of a single dosage unit form can not be generally more than 0.8-1.0 g) and for this reason the known methods wherein the protracted effect was achieved with the aid of a relatively higher amount of auxiliary agents (the amount of the said auxiliary agent was approximately the same as that of the active ingredient) were applicable not at all or but to a very limited extent.
Sustained release pharmaceutical compositions corresponding to a relatively high single dosage unit of 100-500 mg can be prepared first of all in the form of matrix tablets. This is due to the fact that pharmaceutical compositions which have the lowest specific volume and may be hence most easily swallowed can be manufactured by pressing.
According to U.S. Pat. No. 2,895,881 waxes or fatty substances or hydrogenated castor oil can be used as release retarding agent in the preparation of matrix tablets. For this purpose glycerol monostearate (U.S. Pat. No. 2,993,839), a mixture of stearic acid and castor oil (U.S. Pat. No. 2,736,628), waxes, a mixture of waxes and water insoluble substances and mixture of waxes and hydrophylic polymers (U.S. Pat. Nos. 4,132,753, 3,402,240, 3,459,850 and 3,487,138) can also be applied. According to U.S. Pat. Nos. 2,987,445 and 3,317,394 water insoluble polymers, polyethylene and polymethyl-methacrylate and polivinyl chloride can be used as release retarding agent.
It is also known that a mixture of waxes and water insoluble polymers (U.S. Pat. No. 3,965,256), mixtures of polymers which readily swell in water and form mucus (U.S. Pat. No. 3,065,143), polymers forming complex with each other in water (carbopol; an acrylic acid polymerisate) and polyvinyl pyrrolidone (U.S. Pat. No. 3,458,622) and a mixture of carbopol and polyoxyethylene glycole (U.S. Pat. No. 3,634,584) can also be used as release retarding agent. In British Pat. No. 935,672 the use of protein derivatives while in U.S. Pat. No. 3,062,720 the use of water insoluble substances (e.g. talc, calcium sulfate, calcium hydrogen phosphate etc.) is reported. According to U.S. Pat. No. 3,905,508 a mixture of talc, ethyl cellulose and a metal stearate is used.
The matrix tablets disclosed in the said references comprise 10-70% of active ingredient. Sustained release tablets having a higher active ingredient content than the above value can only be prepared from active ingredients being poorly soluble in aqueous medium (to less than 1%).
According to the cited patent specifications matrix tablets are prepared by means of conventional granulating methods (by wet or dry granulation) or in the case of fatty substances by melting the said materials and encorporating the active ingredient into the liquid matrix material.