Development and evaluation of controlled release pellets of diltiazem HCL

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Date
2007
Authors
Ur-Rahman, Nisar
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Abstract
A controlled release system was developed from coating drug layered pellets with a release rate controlling polymer film, using diltiazem as the model drug. The drug was layered onto inert pellets using bottom spray fluidized-bed coating system and subsequently coated with Eudragit NE40D alone or in combination with diltiazem. In vitro dissolution studies revealed that pellets coated with Eudragit or the dispersion of diltiazem powder in Eudragit sustained the release rate up to 12 hours. Dissolution studies of coated pellets also indicated that the release rate of the drug could be varied in a predictable manner by varying the coating thickness of polymer. Addition of 25% diltiazem powder with respect to the polymer dispe.r..s ion enhanced the release rates due to increased film permeability. Inclusion of 5% methyl cellulose or hydroxypropylmethyl cellulose, also increased the rate of drug release, but their utilization seemed to be unsuitable because they tended to cause agglomeration of the pellets during coating. The rate of drug release was reasonably independent of pH, agitation rate and ionic strength of buffers. Thermal treatment of coated pellets was essential to ensure complete film formation and hence constant drug release after different storage time. The rate of drug release was stable after storage at room temperature for 12 months. A new dispersion of polyvinyl acetate, Kollicoat SR30D (SR30) was also investigated as the rate controlling polymer. The coating of SR30 onto diltiazem-layered pellets was found to display desirable release rates at various coating-levels. The amount of plasticizers namely, propylene glycol or triethyl citrate and hydrophobic substance (magnesium stearate) in the coating formulation played a major role in controlling the release rate of drug from the coated pellets. Higher concentration of propylene glycol and magnesium stearate displayed slower rate of drug release in vitro. Blending the coated pellets with talc prior to curing or storage eliminated the agglomeration and film damage even at 60°C. The rate of drug release was reduced after thermal treatment of coated pellets at 60°C and invariable drug release profiles were achieved after the curing step. Scanning electron microscopic evaluation of pellets provided useful information on the 0" ~· !£'. integrity of the film formed. No distinct coating layer of drug and the polymer was identified at f;; f higher magnification. Eudragit-based coated pellets were chosen for in vivo bioequivalence f studies involving six healthy human volunteers in comparison with Herbesser SR capsules. The ~: ~: r two formulations were comparable in the extent of bioavailability under fasted conditions and f possessed almost similar release sustaining behaviour. A slightly faster rate of in vivo absorption was observed with test formulation. The presence of multiple peaks in the individual plasma concentration profiles of all the subjects were common in both test formulation and Herbesser SR. A satisfactory correlation was also established between in vivo and in vitro data for the two formulations. In addition, the gastrointestinal transit behaviour of test formulation and Herbesser SR was monitored using pellets of paracetamol and sulfasalazine as marker drugs. No significant difference was found in gastric emptying as well as small intestine transit times of the two preparations. For both test and reference formulations, approximately 14% of drug was absorbed when the pellets were in stomach. Whilst in the small intestine, the amount absorbed from the test formulation was approximately 50% and from Herbesser SR, was about 37%, whereas in the colon the respective amounts absorbed were 36% and 49%.
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