| Summary: | Thesis (M.Pharm.)--University of the Witwatersrand, Faculty of the Health Sciences, 2013. === The oral route presents the most convenient, least invasive and thus the most widely used route for the administration of drugs but displays inherent impediments, related to both the drugs used and the gastrointestinal tract itself, resulting in diminished bioavailability of drugs. Additionally, development of new drug molecules is difficult, expensive, time-consuming and their approval and success is not guaranteed. Development of novel controlled Multiparticulate Oral Drug Delivery Systems (MODDS) aims to address these issues by employing existing drugs and enhancing their oral bioavailibility and safety, thus improving clinical efficacy in many disease states. Multiparticulate drug delivery systems are specialized controlled drug delivery systems that comprise of many discrete units, each loaded with a fraction of the total dose and each possessing the ability to release entrapped drug independently, thus preventing dose dumping and allowing diverse applications within a single dosage form. However, novel drug delivery systems possess disadvantages in that they may be expensive, difficult to reproduce on a large-scale and frequently use synthetic polymers that may not be disintegrated nor excreted to a sufficient extent in vivo. Starch, a natural polymer, is widely available, inexpensive, and biocompatible and can be modified in various ways. Starch is thus available in several forms and compositions, including commercial multiparticulates, allowing it to be used for the development of an effective controlled MODDS.
The essential aim of the study was to functionalize the inert, inexpensive, commercially available, food-grade multiparticulates derived from sago or tapioca starch and employ the multiparticulates as a Starch-Based Platform (SBP) in a MODDS. Following characterization of both starch-based multiparticulates, the sago multiparticulates were selected as the SBP and preliminary optimization of drug entrapment employing diphenhydramine (DPH) as the model drug was conducted using a Box-Behnken experimental design. The pre-optimized formulation displayed superior Drug Entrapment Efficiency (DEE= 59.354%, R2=0.9257 when compared to the predicted DEE), but demonstrated poor control of drug release. Thus, alternate drugs displaying varying physicochemical characteristics were evaluated and sulfasalazine (SSZ) was ultimately selected as the model drug for the study.
Various modifications of the SBP were attempted with epichlorohydrin-facilitated crosslinking followed by SSZ loading and finally secondary epichlorohydrin crosslinking conferring the best control of drug release coupled with satisfactory drug entrapment and excellent SBP structural stability. The formulation procedure was optimized using a Face Centered Central Composite Design by evaluating the effects of varying the drug loading time (DLT) and secondary crosslinking time (CLT) on the responses of DEE and Mean Dissolution Time (MDT). The optimum formulation conditions was established as DLT=8 hours and CLT=8 hours with predicted DEE and MDT of 40.78% and 171.696 minutes, respectively. Formulation, scaling up and analysis of the optimized SBP revealed that gelatinization and crosslinking had occurred throughout the SBP resulting in incorporation of SSZ into the structure of the SBP, both at the surface and at the core of the SBP. Experimental DEE values for the optimized and scaled-up formulations demonstrated close correlation to the predicted DEE with R2 values of 0.9813 and 0.9893, respectively. The modifications imparted during optimization caused coalescence of the surface starch granules and resulted in a decrease in surface area and porosity of the SBP. This in turn affected the drug release resulting in MDT values of 163.972 and 166.011 minutes, which translated into R2 values of 0.9550 and 0.9669 for the optimized and scaled-up formulations, respectively. Drug release from the optimized SBP formulation was found to fit the Higuchi model best with Quasi-fickian diffusion occurring in simulated gastric fluid and anomalous drug transport in simulated intestinal fluid resulting in an overall anomalous drug transport mechanism of drug release.
In vivo SSZ release throughout the gastrointestinal tract was determined directly by measuring plasma SSZ concentrations and indirectly by measuring the plasma concentrations of 5-Acetyl Salicylic Acid (5-ASA) and N-Acetyl-5-ASA and displayed general correlation to the in vitro SSZ behavior determined previously. Furthermore, the in vivo SSZ release of the optimized SBP formulation was compared to a conventional commercially available SSZ formulation, Salazopyrin® with the optimized SBP formulation displaying superior SSZ release characteristics and a vast improvement in the bioavailability of SSZ compared to Salazopyrin®.
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