| Summary: | ABSTRACT:Tuberculosis (TB) is a leading killer of young adults worldwide and the global scourge of multi-drug resistant
tuberculosis is reaching epidemic proportions. A number of novel drug delivery systems incorporating the
principle anti-tuberculosis (anti-TB) agents have been fabricated that either target the site of TB infection or
reduce the dosing frequency with the aim of improving patient outcomes; however, there is a requisite to
manufacture an oral system, which directly addresses issues of unacceptable rifampicin (RIF) bioavailability
recently reported in a number of fixed-dose combinations (FDCs). There is an urgent need to segregate the
delivery of RIF and isoniazid (INH) upon co-administration, such that INH is not released in the stomach owing
to the induction of accelerated hydrolysis of RIF in acidic medium to the poorly absorbed insoluble 3-formyl
rifamycin SV in the presence of INH. The fabrication of a polymeric once-daily oral multiparticulate fixed-dose
combination of the principal anti-TB drugs, which attains segregated delivery of RIF and INH for improved RIF
bioavailability, could be a step in the right direction in addressing issues of treatment failure due to
administration of poor quality FDCs and patient non-compliance.
Novel approaches were implemented for the fabrication of an oral multiparticulate system for differentiated
release of RIF and INH in the gastrointesinal tract. The envisaged system comprised INH-loaded enterosoluble
multiparticulate entities for targeted delivery of the INH to the small intestine and reconstitutable
multiparticulate entities incorporating the poorly water-soluble RIF and appropriate gel-forming hydrophilic
suspending agents, which were required to disintegrate rapidly in tepid water to form a gel network suspending
RIF and the INH-loaded enterosoluble multiparticulates. The dry dispersible multiparticulate system may be
reconstituted immediately prior to administration to the patient for once-daily dosing as a compliancepromoting
tool.
The design of a novel anti-TB drug delivery system hinged on preformulatory investigations and preliminary
experimental activities to yield a sufficient database to allow for the selection of the qualitative composition of a
prototype formulation. The aforementioned activities initiated the systematic identification of an innovative
method for formulating enterosoluble multiparticulates demonstrating the required enteric-release properties.
The novelly-formed multiparticulates, referred to as ‘enterospheres’, were obtained by inducing separation
(‘salting-out’) of a pH-sensitive poly (methacrylic acid-co-ethylacrylate) copolymer as a polymer-rich enteric
film and ionotropically cross-linking the internal enterosphere matrix. Rational selection of appropriate
suspending agents for design of reconstitutable multiparticulates resolved in the identification of a synergistic
hydrophilic sodium starch glycolate-kappa carrageenan combination, duly characterised by physicomechanical
analyses. The gel-forming composite system attained ease of dispersal and the formation of a three-dimensional
supporting network possessing the essential properties for extemporaneous use.
Statistical experimental design, implementing response surface methodology, was pivotally instituted on the
multiparticulate forms for the identification of critical formulation and processing variables for the development
of the optimum enterosoluble and reconstitutable multiparticulate systems for delivery to the patient as the
preferred multiparticulate two-drug FDC. Because there was an unequivocal relationship between the
properties of a cross-linked enterospheres and their structure in such a way that both characteristics could not
be considered in an isolated way, in-depth analyses on drug-free and drug-loaded enterospheres was
systematically undertaken.
Of principle concern in this study was the attainment of segregated gastrointestinal delivery of RIF and INH in
order to address issues of unacceptable RIF bioavailability on co-administration with INH. The proposed United
States Pharmacopoeial (USP) high performance liquid chromatographic (HPLC) and colorimetric method, and
a proposed regressional analysis of ultraviolet (UV) spectrophotometric absorbance data were employed to
resolve RIF and INH release from the optimum multiparticulate system at simulated gastric pH for comparison
with the release profiles of anti-TB FDCs commercially available in South Africa.
Ultimately, in keeping up to speed with future trends, this dissertation addressed innovations in nanotechnology,
with particular reference to anti-TB nanosystems. The novelly identified method for enterosphere manufacture
was adapted with a view to nanosizing the salted-out and cross-linked architecture, for controlled delivery of
anti-TB drugs to the patient, in the bid to promote patient adherence.
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