Govender, Thirumala.Ojewole, Elizabeth Bolanle.Jones, Elsabé.2015-09-212015-09-2120132013http://hdl.handle.net/10413/12475M. Pharm. University of KwaZulu-Natal, Durban 2013.The development of new chemical entities, novel drug delivery systems and alternative routes to deliver antiretrovirals (ARVs) are being explored to overcome the numerous limitations associated with HIV & AIDS drug therapy. Drug delivery via the buccal route has recently emerged as a promising alternative to delivery via the oral route. Drugs can directly enter the systemic circulation, bypass gastrointestinal degradation and first-pass hepatic metabolism, thereby increasing bioavailability. Although buccal permeation investigations with ARV drug solutions have confirmed their trans-buccal delivery potential, studies on their formulation into delivery systems are lacking. Rapid drug degradation of didanosine (DDI) in the gastrointestinal tract due to acid hydrolysis, together with the need for repetitive dosing, its short half-life, low oral bioavailability and dose-related toxicity, make DDI a suitable model ARV drug for buccal delivery. The aim of this study was therefore to design, evaluate and optimize the preparation of novel polymeric films for buccal delivery of DDI as a model ARV drug. Multipolymeric monolayered films (MMFs) with drugs and polymers of opposing solubilities will offer several advantages for the controlled release delivery of DDI via the buccal route. The first aim of this study was therefore to prepare DDI loaded films with polymers of opposing solubilities and to undertake extensive physico-chemical/mechanical and molecular modelling characterisations. MMFs were prepared via a simplified solvent casting/evaporation method and characterised in terms of drug content uniformity, in vitro drug release, in vitro permeation, histomorphology, mucoadhesivity, mechanical properties and surface pH. Uniform drug content (91–105 %) with low variability was obtained for all films. Co-blending of DDI, Hydroxypropyl methylcellulose (HPMC) and Eudragit®RS 100 (EUD) (1:1:10) was required to achieve controlled drug release. The buccal permeability potential of DDI from the MMFs was successfully demonstrated with a permeability coefficient of 0.72 ± 0.14 × 10−2cm/h and a steady state flux of 71.63 ± 13.54 μg/cm2h. Films had acceptable mucoadhesivity (2184 mN), mechanical strength (0.698 N/mm2) and surface pH (6.63). The co-blending-co-plasticization technique for preparation of MMFs containing EUD and HPMC was justified via static lattice molecular mechanics simulations (SLAS). The mechanism inherent to the mucoadhesive and drug release profile performance of the MMFs was also elucidated via SLAS wherein a close corroboration among the in vitro–in silico (IVIS) data was observed. These extensive physico-mechanical and molecular atomistic studies confirmed the use of MMFs containing DDI, HPMC and EUD as a buccal delivery system. A large portion of ARV limitations are related to inadequate drug concentrations reaching the site of action and low oral bioavailability. Recent developments in the field of buccal drug delivery show an increased interest towards nano-enabled drug delivery. The advantages of buccal drug delivery can be combined with that of the nanoparticulate delivery systems to provide a superior delivery system in terms of enhanced bioavailability and drug targeting. The second aim of the study was therefore to design, evaluate and optimize the preparation of novel nano-enabled polymeric films for buccal delivery of DDI as a model ARV drug. Solid lipid nanoparticles (SLNs) were prepared via a hot homogenization technique followed by ultrasonication and were characterized in terms of size, surface charge, morphology and drug entrapment efficiency (EE). Optimal parameters for preparation of the DDI loaded SLNs were identified before preparing and comparing the physico-mechanical properties of nano-enabled multipolymeric monolayered films (MMFs) to conventionally prepared MMFs. Glyceryl tripalmitate in combination with Poloxamer 188 as a surfactant was identified as being most suitable for preparation of DDI-loaded SLNs. Optimized particles exhibited a desired particle size (201 nm), polydispersity index (0.168), zeta potential (-18.8 mV) and formulation pH (5.5). Conventional and SLN entrapped MMFs were prepared via solvent casting/evaporation using EUD and HPMC in combination and characterised in terms of drug content, drug release, permeation, mucoadhesion and mechanical properties. Drug release from the nano-enabled films was higher, with 56 % released in the 1st hour as opposed to 20 % for the conventionally loaded MMFs. DDI was released from the buccal film and permeated across the mucosa as evidenced by steady state ix flux values of 71.63 ± 13.54 μg/cm2h and 74.39 ± 15.95 μg/cm2h, for the conventional and nano-enabled MMFs, respectively. SLNs did not adversely affect the flux and confirms the potential of DDI being delivered via the buccal route using nano-enabled MMFs. Conventional MMFs exhibited higher mucoadhesion (1425.00 ± 77.15 mN) and mechanical strength (0.6976 ± 0.064 N/mm2) than nano-enabled MMFs (914.33 ± 68.09 mN and 0.4930 ± 0.003 N/mm2). These physico-mechanical studies confirm the potential use of nano-enabled MMFs containing DDI-loaded SLNs as a buccal delivery system and serves as a platform for future formulation optimisation studies. These results confirm the feasibility of preparing films for buccal delivery of DDI as a model ARV drug that may ultimately lead to optimized drug therapy for HIV & AIDS patients.en-ZADrug delivery systems.Antiretroviral agents.Theses -- Pharmacy and pharmacology.Thesis