Nanoemulgel using a bicephalous heteolipid as a novel approach to enhance transdermal permeation of tenofovir
CHAPTER 6 CONCLUSION
CHAPTER 6
Conclusion Chapter 6 CHAPTER 6
CONCLUSION 6.1 General conclusions
Due to its increasing prevalence, HIV and AIDS is one of the most serious public health diseases worldwide. Although TNF is considered the most successful ARV to treat and prevent HIV and AIDS, its current oral administration has numerous limitations which negatively impact on the effective treatment/management of the disease. The current HIV and AIDS crisis coupled with limitations of oral TNF therapy therefore drive the need for identifying innovative drug delivery approaches. Drug delivery scientists have thus explored the use of novel drug delivery systems and alternate routes of drug administration for TNF. Although TDD offers an attractive alternative for the systemic delivery of drugs, this route has not been explored for the delivery of TNF. Despite the advantages of TDD, the barrier properties of the skin limit the applicability of this route. The use of FAs as transdermal CPEs has been advocated to efficiently decrease the barrier properties of the skin. FA esters have shown greater promise as transdermal permeation enhancers than their respective parent material. Therefore, the modification of existing FA CPEs to produce novel FA derivatives that display superior performance is highly desirable. Another strategy that has emerged as an effective means of promoting TDD is the use of biocompatible nanomaterials. NEGs have unique characteristics that promote enhanced drug permeation via the transdermal route and have therefore been used for the TDD of various classes of drugs.
However, to date there is no report on the formulation of NEG for transdermal delivery of TNF.
The broad aim of this study was to explore the potential of lipid-based strategies for enhancing transdermal permeation of TNF. The specific research aims of this study were therefore: (1) to synthesize and characterize novel biocompatible dendritic ester derivatives of UFAs and explore their potential as promising permeation enhancers for the transdermal delivery of TNF. (2) To evaluate the novel application of UFA esters of cholesterol as promising transdermal permeation enhancers using TNF as a model drug. (3) To 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) To 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.
In order to achieve aim 1, the objectives were to:
i) Synthesize novel ester dendritic derivatives of palmitoleic (PA), linoleic (LA), linolenic (LLA) and arachidonic acid (AA) and characterize the derivatives using FTIR, NMR (1H and 13C) and HRMS techniques.
ii) Determine the lipophilicity and pH responsiveness as well as the in vitro biosafety of the novel ester derivatives.
iii) Explore the in vitro potential of the novel UFA ester derivatives as transdermal permeation enhancers for TNF and assess the effects of the enhancer treatment on the skin using transepithelial electrical resistance as well as light and transmission electron microscopy.
To achieve aim 2, the objectives were to:
i) Synthesize cholesterol ester derivatives of oleic (OA), linoleic (LA), linolenic (LLA), Lauric (LuA), Palmitic (PA) and stearic acid (SA) and characterize the derivatives using FTIR, NMR (1H and 13C) techniques as well as determining their lipophilicity.
ii) Explore the in vitro potential of the cholesterol ester derivatives as transdermal permeation enhancers for TNF and assess the effects of the enhancer treatment on the skin using transepithelial electrical resistance and light microscopy.
To achieve aim 3, the objectives were to:
i) Synthesize novel mono, di and tri-ester derivatives of FAs bearing β-alanine t-butyl ester head group using oleic (OA), linoleic (LA), linolenic (LLA) and stearic acid (SA) and characterize the derivatives using FTIR, NMR (1H and 13C) and HRMS techniques.
ii) Determine the lipophilicity and the in vitro biosafety of the novel ester derivatives.
iii) Explore the in vitro potential of the novel ester derivatives as transdermal permeation enhancers for TNF and assess the effects of the enhancer treatment on the skin using transepithelial electrical resistance and light microscopy.
Conclusion Chapter 6 To achieve aim 4, the objectives were to:
i) To determine the optimal ratio of surfactant and co-surfactant (Smix) to oil (LLA1E) by constructing pseudo-ternary phase diagrams.
ii) Evaluate the TNF NE and TNF NEG in terms of mean globule diameter, polydispersity index, zeta potential, viscosity, morphology and stability.
iii) Explore the ex vivo potential of the novel TNF nanoemulgel to enhance the transdermal delivery of TNF and assess the effects of the nano formulation on the skin using transepithelial electrical resistance and light microscopy.
The main conclusions generated from the research data are summarised below:
1. Aim 1:
• Novel ester dendritic derivatives of palmitoleic (PA), linoleic (LA), linolenic (LLA) and arachidonic acid (AA) were successfully synthesized and their physical characteristics were confirmed using FTIR, NMR (1H and 13C) and HRMS techniques.
• All the derivatives synthesized in this study had a higher lipophilicity as compared to their respective parent UFA. This is a desirable property as the greater the lipophilic nature of an enhancer, the greater the permeability across the skin. The MTT assay results showed that none of the synthesized UFA ester dendritic derivatives were toxic against the HeLa cell line. The percentage cell viability between 85 to 95% for all derivatives across the concentration ranges studied with no dose dependent trends observed. These findings therefore suggest that the use of the synthesized UFA ester dendritic derivatives in biological studies would be safe. Further, all the synthesized UFA ester dendritic derivatives consist of tertiary nitrogen in their structure and their potential to show pH dependency were proven experimentally. This pH dependent property may attract attention, especially in pH based drug targeting. It therefore contributes to widening the pool of novel biocompatible excipients for drug delivery applications in addition to their use as transdermal chemical permeation enhancers.
• All synthesized UFA ester dendritic derivatives at 1% w/w were found to be more effective enhancers as compared to their parent UFAs, with LLA1E being identified as the most superior (ER = 5.31). Further, the concentration effect study revealed that at 2%
w/w LLA1E had a greater ER (6.11) as compared to its parent (ER = 3.85). The