Enhanced topical delivery of chlorhexidine digluconate for improved skin antisepsis

Abstract

Chlorhexidine digluconate (CHG) is a cationic bisbiguanide that has been used extensively for the past half century as a topical antiseptic, due to its ability to effectively kill surface bacteria with minimal reports of resistance. However, bacteria are understood to reside in deeper skin layers, skin furrows and follicular appendages that harbour the ability to cause skin and soft tissue infections (SSTIs), particularly where the stratum corneum barrier is compromised, such as at the site of a surgical incision. CHG permeates poorly into human skin due to its physicochemical properties, which lie outside of the “ideal” limits for topical and transdermal drug delivery and therefore it is unlikely to be able to target bacteria in deeper skin layers without permeation enhancement.
The purpose of this thesis was to enhance the depth permeation of CHG into skin for enhanced topical skin antisepsis. Both chemical and physical methods of permeation enhancement were explored. Previously it had been found that a topical skin pre-treatment with a G3 PAMAM-NH2 dendrimer significantly enhanced the permeation of CHG in vitro. This thesis began by creating a physically stable and clinically acceptable topical gel formulation that co-formulated CHG and a G3 PAMAM-NH2 dendrimer together in a one-step application for practicality purposes. This co-formulation (containing 4% CHG and 1 mM G3 PAMAM-NH2) was found to significantly enhance the depth permeation of CHG within porcine skin compared to the commercial benchmark Hibiscrub® (contains 4% w/v CHG; p <0.05). Permeation enhancement was initially characterised using Franz-type diffusion cell and tape stripping studies, considered the “gold standard” technique for quantifying dermal drug penetration. The systematic creation, characterisation and successful co-formulation of the drug and dendrimer within a topical gel formulation are novel developments.
The potential disadvantages of the tape stripping technique utilised in Chapter 3 were explored and the results from the tape stripping studies were confirmed by repeating in vitro studies and visualising treated skin samples using Time-of-Flight Secondary Ion Mass Spectrometry (ToF-SIMS) in Chapter 4. This method has been used to image topical drug distribution and co-localisation of the drug with endogenous skin components. The method was developed further by transforming the data semi-quantitatively, which reduced the subjectivity of image interpretation. The study found that CHG, when combined with a G3 PAMAM-NH2 dendrimer was able to permeate past the superficial stratum corneum skin barrier and was able to reside within deeper skin layers without significant permeation through full thickness porcine skin.
The mechanism of action of the PAMAM dendrimer mediated enhancement of CHG within the co-formulation was explored. Results from this study indicated that occlusive effects and a reduction in surface tension were the likely mechanistic contributions of the G3 PAMAM-NH2 dendrimer. It appears as though the PAMAM dendrimer exerted its enhancement effects within the co-formulation without altering the stratum corneum barrier. This may correlate to a lack of skin irritation, which is advantageous when considering irritation has prevented the commercial use of many chemical permeation enhancers.
A physical method of CHG permeation enhancement was explored for the first time. A solid microneedle 10 second pre-treatment (750 µm, 36 needle array) was found to enhance the depth permeation of CHG within porcine skin. This permeation enhancement effect was considered to be equivalent to the enhancement effect provided by the 4% CHG-1 mM PAMAM co-formulation regarding CHG depth permeation, however equivalence did not align when considering homogeneity of drug distribution across the skin.
In conclusion, the permeation of CHG was successfully enhanced using both a chemical and physical method of permeation enhancement. The gel formulation improved CHG delivery compared to the commercial Hibiscrub® solution, even without the addition of the chemical enhancer, indicating the significance of vehicle effects on the ability to enhance drug permeation into skin. This enhancement effect was statistically significant with the addition of the PAMAM dendrimer at clinically relevant concentrations (p <0.05). The results from this thesis suggest that a reduction in surface tension and an increase in occlusion were predominant in CHG mediated permeation enhancement, which has significantly positive implications when considering the clinical acceptability of this formulation compared to chemical permeation enhancers used in the past, which exhibit unacceptable levels of skin irritation.