MSc (Med),Dept of Pharmacy and Pharmacology, Faculty of Health Sciences, University of the Witwatersrand / Pain is the net effect of multidimensional mechanisms that engage most parts of the central
nervous system (CNS) and the treatment of pain is one of the key challenges in clinical medicine
(Le Bars et al., 2001; Miranda et al., 2008). Polypharmacy is seen as a barrier to analgesic
treatment compliance, signifying the necessity for the development of fixed dose combinations
(FDCs), which allow the number of tablets administered to be reduced, with no associated loss in
efficacy or increase in the prevalence of side effects (Torres Morera, 2004). FDCs of analgesic
drugs with differing mechanisms of nociceptive modulation offer benefits including synergistic
analgesic effects, where the individual agents act in a greater than additive manner, and a
reduced occurrence of side-effects (Raffa, 2001; Camu, 2002).
This study aimed at producing a novel, rate-modulated, fixed-dose analgesic formulation for the
treatment of mild to moderate pain. The fixed-dose combination (FDC) rationale of paracetamol
(PC), tramadol hydrochloride (TM) and diclofenac potassium (DC) takes advantage of previously
reported analgesic synergy of PC and TM as well as extending the analgesic paradigm with the
addition of the anti-inflammatory component, DC.
The study involved the development of a triple-layered tablet delivery system with the desired
release characteristics of approximately 60% of the PC and TM being made available within 2
hours to provide an initial pain relief effect and then sustained zero-order release of DC over a
period of 24 hours to combat the on-going effects of any underlying inflammatory conditions. The
triple-layered tablet delivery system would thus provide both rapid onset of pain relief as well as
potentially address an underlying inflammatory cause.
The design of a novel triple-layered tablet allowed for the desired release characteristics to be
attained. During initial development work on the polymeric matrix it was discovered that only
when combined with the optimized ratio of the release retarding polymer polyethylene oxide
(PEO) in combination with electrolytic-crosslinking activity, provided by the biopolymer sodium
alginate and zinc gluconate, could the 24 hour zero-order release of DC be attained. It was also
necessary for this polymeric matrix to be bordered on both sides by the cellulosic polymers
containing PC and TM. Thus the application of multi-layered tableting technology in the form of a
triple-layered tablet were capable of attaining the rate-modulated release objectives set out in the
study. The induced barriers provided by the three layers also served to physically separate TM
and DC, reducing the likelihood of the bioavailability-diminishing interaction noted in United
States Patent 6,558,701 and detected in the DSC analysis performed as part of this study.
The designed system provided significant flexibility in modulation of release kinetics for drugs of
varying solubility. The suitability of the designed triple-layered tablet delivery system was
confirmed by a Design of Experiments (DoE) statistical evaluation, which revealed that
Formulation F4 related closest to the desired more immediate release for PC and TM and the
zero-order kinetics for DC. The results were confirmed by comparing Formulation F4 to typical
release kinetic mechanisms described by Noyes-Whitney, Higuchi, Power Law, Pappas-Sahlin
and Hopfenberg. Using f1 and f2 fit factors Formulation F4 compared favourably to each of the
criteria defined for these kinetic models.
The Ultra Performance Liquid Chromatographic (UPLC) assay method developed displayed
superior resolution of the active pharmaceutical ingredient (API) combinations and the linearity
plots produced indicated that the method was sufficiently sensitive to detect the concentrations of
each API over the concentration ranges studied. The method was successfully validated and
hence appropriate to simultaneously detect the three APIs as well as 4-aminophenol, the
degradation product related to PC.
Textural profile analysis in the form of swelling as well as matrix hardness analysis revealed that
an increase in the penetration distance was associated with an increase in hydration time of the
tablet and also an increase in gel layer thickness. The swelling complexities observed in the
delivery system in terms of both the PEO, crosslinking sodium alginate and both cellulose
polymers as well as the actuality of the three layers of the tablet swelling simultaneously suggests
further intricacies involved in the release kinetics of the three drugs from this tablet configuration.
Modified release dosage forms, such as the one developed in this study, have gained widespread
importance in recent years and offer many advantages including flexible release kinetics and
improved therapy and patient compliance.
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:wits/oai:wiredspace.wits.ac.za:10539/8733 |
| Date | 17 September 2010 |
| Creators | Hobbs, Kim Melissa |
| Source Sets | South African National ETD Portal |
| Language | English |
| Detected Language | English |
| Type | Thesis |
| Format | application/pdf, application/pdf |
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