Design and Development of Controlled/Sustained Release Formulations for Certain Newer drugs

The present thesis deals with the investigations carried out by the writer on the development and evaluation of oral sustained release formulations, namely, tablets and spheroids using a novel polysaccharide isolated from Delonix regia and to improve the pharmacotherapy associated with the selected drug candidates. The first chapter of the thesis deals a brief account of the trends in drug delivery systems and an introduction to oral drug delivery systems along with the detailed account of polymeric drug delivery based both on the design of the device and mechanism of drug release. A brief note on the hydrophilic matrices, polysaccharides used for hydrophilic matrices, single and multiple unit dosage forms, pellets and spheroids along with a literature review on the isolation of polysaccharides from plant sources and work done by earlier investigators on the development of sustained release formulations if any in the drug selected is also discussed. The scope and objectives of the present investigation along with the plan of work is presented in the second chapter of the thesis. The importance of polysaccharides in drug delivery systems and the need for the development of novel polysaccharide hydrogels is emphasized. The rationale for the development of sustained release drug delivery systems and advantages of these delivery systems for the selected drug candidates is also discussed. The third chapter gives a detailed account of the materials and the experimental techniques used for the isolation, characterization and toxicity studies on the novel polysaccharides isolated, preformulation studies, development and evaluation of oral sustained release tablets and spheroids, stability studies, bioanalytical method developed used for the estimation of the selected drugs in plasma and its validation. Bioavailability studies carried out on both rabbits and humans are described. The fourth chapter describes in detail the experimental results obtained in the present investigation along with a detailed discussion. The purification of the polysaccharide hydrogel and its characterization, preformulation studies, development and evaluation of sustained release tablets and spheroids, stability studies of the developed formulations, bioanalytical method development and its validation and pharmacokinetic evaluation of the selected drug candidates in humans and rabbits are well discussed. The fifth chapter gives the detailed bibliography. The following are the some of important findings of the present investigation; ◈ Water swellable polysaccharides were isolated from Artocarpus integrifolia, Tamarindus india, Moringa oleifera, and Delonix regia by hot water extraction followed by ethanol precipitation and evaluated for their suitability for preparing SR tablets. The polysaccharide isolated from Delonix regia was selected as the best among them based on in vitro studies. The antimicrobial and toxicity studies of the selected polysaccharide show that it does not have any toxicity. It has remarkable swelling character and hence suitable for sustained release purposes. ◈ The developed sustained release tablets have acceptable pharmaco-technical properties which indicate that the process can be used for the scale up studies and the drug release can be modulated significantly by varying the components of the matrix. ◈ The development of matrix spheroids with acceptable physicochemical and in vitro drug release justifies the application of this technique in the development of multiparticulate sustained drug delivery. ◈ The developed HPLC methods for the estimation of quetiapine fumarate (QF) and ondansetron hydrochloride (OH) in plasma are found to be accurate, precise, selective and linear and were used for the bioavailability and bioequivalence studies of developed formulations. ◈ A comparative bioavailability study of the developed SR tablets and the marketed IR tablets indicate that the SR tablets of the selected drugs are well absorbed and the extent of absorption is higher than that of the marketed IR tablets. The sustained and efficient drug delivery system developed in the present study could maintain plasma drug levels better which can overcome the drawbacks associated with the conventional therapy. ◈ The polysaccharide isolated from Delonix regia exhibits sustaining properties similar to that of the widely used polymer, namely, HPMC. ◈ The sustained release formulations of developed for the OH and QF using the polysaccharide isolated as release modifier are capable of sustaining the drug release in vivo in rabbits. The better absorption behavior of the developed SR tablets can overcome the drawbacks associated with the conventional therapy. ◈ The developed spheroids of the QF using HPMC as a release modifier and microcrystalline cellulose as spheronization enhancer were found to sustain the drug release