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Novel lipidic materials to enhance the transdermal delivery of tenofovir.

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The global burden of HIV and AIDS coupled with the limitations of current oral tenofovir (TNF) administration drives the need to develop strategies such as the use of alternate routes of administration to improve drug therapy. Transdermal drug delivery (TDD) offers numerous advantages and is an attractive alternative for the systemic delivery of TNF. Although the inherent protective barrier property of skin is one of the major challenges in the design of TDD systems, the use of chemical permeation enhancers (CPEs) such as fatty acids (FA) and their esters or the use of nano drug delivery systems have the potential to overcome this limitation. To date there are no reports on TDD permeation enhancement strategies or a nanoemulgel (NEG) as a TDD formulation for TNF. Novel lipidic approaches that reversibly decrease the barrier properties of the skin as well as the use lipid based nano drug delivery systems such as NEGs to enhance the TDD of TNF remain to be investigated. The broad aim of this study was therefore to explore the potential of novel lipid-based strategies for enhancing transdermal permeation of TNF. The specific research aims of this study were to: (1) Synthesize and characterize novel biocompatible dendritic ester derivatives of unsaturated FAs (UFAs) and explore their potential as promising permeation enhancers for the transdermal delivery of TNF. (2) Evaluate the novel application of UFA esters of cholesterol as promising transdermal permeation enhancers using TNF as a model drug. (3) Synthesize and characterize novel biocompatible mono, di and tri-ester derivatives of FAs and explore their potential as promising transdermal permeation enhancers using TNF as a model drug. (4) Explore the potential of novel linolenic acid based heterolipid, LLA1E (a novel transdermal permeation enhancer), as an oily phase in the development of a nanoemulgel for the transdermal drug delivery of TNF. UFAs [palmitoleic (PA), linoleic (LA), linolenic (LLA) and arachidonic acid (AA)] were used to synthesize novel dendritic ester derivatives [PA1E, LA1E, LLA1E and AA1E]. The structural features of the biosafe derivatives were confirmed by FTIR, NMR (1H and 13C) and HRMS. All synthesized novel dendritic ester derivatives at 1% w/w were found to be more effective enhancers with LLA1E being identified as the most superior with an ER of 6.11 at 2% w/w. Histomorphological analysis displayed no significant loss in the integrity of the skin and also indicated that TNF utilized both the transcellular and intercellular route of transport, with the drug and enhancer treatment having no permanent effects on the epidermis. Therefore these novel dendritic ester derivatives of UFAs can be considered as effective transdermal permeation enhancers for TNF. The TDD potential of TNF using UFA esters of Cholesterol (Chol) viz., oleate, linoleate and linolenate, as CPEs showed that all Chol UFA esters at 1% w/w were found to be more effective enhancers when compared to their respective parent FAs and saturated FAs counterparts. Cholesteryl linolenate (Chol-LLA) showed the most superior performance with the greatest ER of 5.93 being achieved at a concentration of 2% w/w. The histomorphological and transepithelial electrical resistance (TEER) evaluations displayed no damage to the integrity of the epidermis and skin exposure to the permeation enhancer had only temporary effects on its barrier property. Therefore Chol UFA esters can be considered as new CPEs for exploitation in transdermal formulations for various classes of drugs. The synthesized mono, di and tri-ester derivatives were non-toxic and displayed better transdermal permeation enhancement capabilities as compared to their respective parent FAs. The in vitro permeation results showed that the mono oleate derivative (MOAPE) displayed the greatest ER for TNF (5.87) at 1% w/w. Histological investigations of the rat skin treated with MOAPE revealed fluidization of the stratum corneum. Histological and TEER studies revealed no significant change to the viable epidermis of the skin after 1% MOAPE exposure. The TEER findings also suggested that the permeation enhancement effects of MOAPE were not permanent and showed a return towards original skin integrity after removal of the enhancer formulation. These findings therefore indicate that the novel mono ester derivative of OA (MOAPE) adds to the pool of CPEs available to formulation scientists and can be safely incorporated into TDD systems for several classes of drugs. LLA1E served as an effective oily phase in the formulation of nanoemulsions (NEs). TNF loaded nanoemulsions (TNEs) were prepared and incorporated into TNF nanoemulgels (TNEGs) which were subsequently evaluated for their ex vivo transdermal permeation efficacy. TNEs had a mean globule diameter (MGD) of 129.06 ± 3.35 nm, polydispersity index (PDI) of 0.192 ± 0.038 and zeta potential (ZP) of 20.9 ± 2.02 mV with an incorporation efficiency of 91.94 ± 0.84%. There was no significant change is these properties after incorporation of TNEs into a hydrogel as MGD, PDI and ZP of TNEGs were found to be 136.13 ± 5.21 nm, 0.182 ± 0.020 and -20.9 ± 2.08 mV respectively. Ex vivo permeation studies showed that the TNEG significantly enhanced the TNF permeation by 39.65-fold, with a cumulative amount of 1866.54 ± 108.62 μ -2. Histological and TEER assessments showed no permanent effects on the skin by TNEG. Therefore, this novel TNEG nanosystem has the potential of further translation into clinical trials for optimal treatment alternatives for HIV/AIDs patients. The findings of this study therefore identified and developed novel lipid based approaches that were successful in reversibly decreasing the barrier of the skin and was able to promote the transdermal delivery of TNF. Novel lipid based strategies such as dendritic ester derivatives of UFAs; UFA esters of cholesterol; mono, di and tri-ester derivatives of FAs and TNF loaded NEGs therefore have the potential of enhancing TDD of TNF. This study has therefore made significant contributions towards improving TDD and TNF therapy for optimal treatment alternatives for HIV/AIDs patients.


Doctoral Degree. University of KwaZulu-Natal, Durban.