Browsing by Author "Rambharose, Sanjeev Kumar."

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Enhancing the buccal permeability potential of model ARV drugs : permeability and histo-morphological evaluations.
(2013) Rambharose, Sanjeev Kumar.; Govender, Thirumala.; Ojewole, Elizabeth Bolanle.
Buccal delivery of antiretroviral (ARV) drugs may overcome disadvantages such as low bioavailability due to extensive first pass effects and gastrointestinal degradation associated with the oral route. However, the small mucosal surface area and low membrane permeability are challenges to buccal drug permeation. Identification of new permeation enhancers as well as new permeation enhancing strategies have been shown to overcome these limitations, thereby delivering adequate amounts of drug through the buccal mucosa. Polymeric excipients with previously reported mucoadhesive and controlled release properties could also possess additional buccal permeation enhancing effects and may therefore serve as multifunctional excipients in a buccal drug delivery system. Therefore the aims of this study were: 1) to identify and compare the buccal permeability potential of tenofovir (TNF) and didanosine (ddI). 2) to identify the buccal permeation effects of potential multifunctional excipients ie. carboxymethylcellulose (CMC), sodium alginate (SA), polyacrylic acid (PAA) and polyethylene glycol (PEG) for TNF and ddI, and 3) to identify the buccal permeation potential of saquinavir (SQV) and assess the effect of high-energy ball milling on its permeability. All in vitro permeation studies across porcine buccal mucosa were performed using vertical Franz diffusion cells with TNF, ddI and SQV being quantified using UV spectrophotometry at 262 nm, 250 nm and 239 nm respectively. The histomorphological evaluations were undertaken by light microscopy (LM) and Transmission Electron Microscopy (TEM). Ball milling of SQV samples for 1, 3, 15 and 30 hours was performed in a high-energy planetary mill. The integrity of the buccal mucosa was assessed by transepithelial electrical resistance (TEER) measurements using a Millicell ERS meter connected to a pair of chopstick electrodes. Both TNF and ddI were able to permeate the buccal mucosa in a concentration-dependent manner. A higher permeability was observed for ddI (Flux = 181.62 ± 23.62 μg/cm2h) as compared to TNF (Flux = 102.10 ± 19.80 μg/cm2h). The permeation of these drugs in the absence of enhancers was attributed to passive diffusion via the paracellular route with transcellular route being an additional possibility for ddI. The addition of PAA, SA, CMC and PEG increased the permeability of TNF whilst only PEG was able to increase the permeability of ddI. The effect of these polymeric excipients appeared to be dependent on their ionic charges as well as that of the respective drugs. Permeability enhancement ratios for ddI and TNF were 1.63 and 1.74 respectively with PEG (0.5 %w/v) and CMC (0.5 %w/v) respectively. A maximum enhancement ratio of 2.13 for TNF was achieved with 4 %w/v PEG. Furthermore PEG was identified as the optimal permeation enhancer for TNF and ddI. Histological investigations revealed no significant loss in cellular integrity for mucosa treated with either TNF or ddI alone or when coupled with PEG as an enhancer. The differences in histomorphological changes in response to TNF and ddI alone could support the greater permeation observed with ddI. The histological findings proved useful in assessing the effects of drug and enhancer on mucosal integrity and provided insight into permeation pathways across the mucosa. Selective polymeric excipients therefore provide an effective means to increase the penetration of ddI and TNF. Their previously reported mucoadhesive and controlled release properties coupled with their permeation enhancing effects shown in this study highlight their potential use as multifunctional excipients for the design of buccal drug delivery systems. SQV, a candidate for buccal drug delivery, is limited by its poor solubility. Therefore, Aim 3 identified the effects of high energy ball milling on the buccal permeability of SQV and compared it’s enhancing effect to the conventional use of common chemical enhancers together with unmilled SQV i.e. ethylenediaminetetraacetic acid (EDTA), sodium lauryl sulphate (SLS), PEG and beta cyclodextrin (ß-cyclodextrin). Unmilled SQV was able to permeate through the buccal mucosa with a flux of 3.99 ± 0.11μg/cm2h. Ball milling of SQV at all the time periods led to an increase in its permeability with optimal enhancement obtained at 15 hours with an enhancement ratio of 2.61. The enhanced permeability of the milled SQV samples was attributed to a contribution of various factors such as solubility, particle size, surface area, crystallinity, morphology and the formation of solid dispersions. The chemical permeation enhancers were also able to increase the permeability of unmilled SQV across the buccal mucosa, with SLS achieving the greatest enhancement ratio of 1.75. However, ball milling of SQV without any chemical permeation enhancers displayed to a greater enhancement ratio (2.61) as compared to the best permeation enhancer SLS at 0.5 %w/v (1.75). Histological investigations revealed no significant loss in cellular integrity for mucosa treated with either unmilled or milled SQV samples. The presence of larger intercellular spaces in the treated tissue suggests that SQV also uses the paracellular route of transport in combination with the transcellular route across the mucosa. High energy ball milling of SQV is therefore an effective approach for increasing buccal permeability when formulating SQV for a buccal delivery system, as compared to incorporating common chemical enhancers studied at 0.5% w/v for this purpose. The findings in this study will therefore contribute to formulation optimization strategies for the development of novel buccal delivery systems for ARV drugs, thereby optimising treatment of patients with HIV and AIDS.
Novel lipidic materials to enhance the transdermal delivery of tenofovir.
(2017) Rambharose, Sanjeev Kumar.; Govender, Thirumala.
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 μg.cm -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.