Jeanetta du Plessis

The influence of the physicochemical characteristics and pharmacokinetic properties of selected NSAID's on their transdermal absorption

The purpose of this study was to determine the plasma concentrations of selected NSAIDs after topical gel administration and to determine the influence of the physicochemical characteristics of these drugs on transdermal absorption. Plasma concentrations of the drugs were determined using high performance liquid chromatography. The logP values obtained from literature for piroxicam, ketoprofen, naproxen, ibuprofen and indomethacin, (1.8, 0.97, 3.22, 3.6 and 3.8, respectively) correlated with the area under the plasma-time curve (AUC) values. The AUC values determined were 527.00 (piroxicam) 269. 45 (ketoprofen) 258.65 (naproxen) 243.22 (indomethacin) and 88.09 (ibuprofen) microg/ml per h. It was concluded that the most reliable parameter for transdermal absorption was the lipophilic character of a drug (logP value). The molecular mass, solubility constraint and percentage unionized moiety can only be used in combination with other properties in the prediction of possible transdermal drug delivery.

The selection of non-steroidal anti-inflammatory agents for dermal delivery

An analysis has been conducted to show how the penetration of a selection of non-steroidal anti-inflammatory agents (NSAIDs) through the skin may be predicted. The calculations are based on physicochemical parameters that can be predicted using commercially available software. Where available the predictions compare favourably with the literature values. The bio-effectiveness of the NSAID will be a function of both its penetration through the skin and its potency. The variation in potency has also been considered. Most NSAIDs are carboxylic acids, therefore the pK(a) will be an important determinant in ionisation and hence permeation. pH partition behaviour into the skin has been considered together with the relative impact of decreased permeation but increased solubility with degree of ionisation.

Review of Natural Compounds for Potential Skin Cancer Treatment

Most anti-cancer drugs are derived from natural resources such as marine, microbial and botanical sources. Cutaneous malignant melanoma is the most aggressive form of skin cancer, with a high mortality rate. Various treatments for malignant melanoma are available, but due to the development of multi-drug resistance, current or emerging chemotherapies have a relatively low success rates. This emphasizes the importance of discovering new compounds that are both safe and effective against melanoma. In vitro testing of melanoma cell lines and murine melanoma models offers the opportunity for identifying mechanisms of action of plant derived compounds and extracts. Common anti-melanoma effects of natural compounds include potentiating apoptosis, inhibiting cell proliferation and inhibiting metastasis. There are different mechanisms and pathways responsible for anti-melanoma actions of medicinal compounds such as promotion of caspase activity, inhibition of angiogenesis and inhibition of the effects of tumor promoting proteins such as PI3-K, Bcl-2, STAT3 and MMPs. This review thus aims at providing an overview of anti-cancer compounds, derived from natural sources, that are currently used in cancer chemotherapies, or that have been reported to show anti-melanoma, or anti-skin cancer activities. Phytochemicals that are discussed in this review include flavonoids, carotenoids, terpenoids, vitamins, sulforaphane, some polyphenols and crude plant extracts.

Transdermal drug delivery enhancement by compounds of natural origin

The transdermal route of administration offers an alternative pathway for systemic drug delivery with numerous advantages over conventional routes. Regrettably, the stratum corneum forms a formidable barrier that hinders the percutaneous penetration of most drugs, offering an important protection mechanism to the organism against entrance of possible dangerous exogenous molecules. Different types of penetration enhancers have shown the potential to reversibly overcome this barrier to provide effective delivery of drugs across the skin. Although certain chemical and physical skin penetration enhancers are already employed by the pharmaceutical industry in commercially available transdermal products, some skin penetration enhancers are associated with irritating and toxic effects. This emphasizes the need for the discovery of new, safe and effective skin penetration enhancers. Penetration enhancers from natural origin have become popular as they offer several benefits over their synthetic counterparts such as sustainable mass production from a renewable resource and lower cost depending on the type of extraction used. The aim of this article is to give a comprehensive summary of the results from scientific research conducted on skin penetration enhancers of natural origin. The discussions on these natural penetration enhancers have been organized into the following chemical classes: essential oils, terpenes, fatty acids and polysaccharides.

Physico-chemical determinants of dermal drug delivery: effects of the number and substitution pattern of polar groups

The aim of this study was to investigate the effect of number and substitution pattern of -OH groups of a set of phenols on the in vitro permeation of heat-separated human epidermis. The diffusion was calculated from Log(D/x)=logk(p)-0.59logK(oct)+0.024 (D, diffusion coefficient; x, pathlength; k(p), permeability coefficient (cm/h); and K(oct), octanol-water partition coefficient). The main factors reducing D were the dipolar and hydrogen bonding capabilities of the permeants quantified as their Hansen partial solubility parameters delta(p) and delta(h). These parameters are significantly reduced by the degree of symmetry of the molecule, so that phloroglucinol (1,3,5-benzenetriol), with three -OH groups, diffuses more rapidly that phenol. When symmetry is absent, as in 1,2,4-benzenetriol, the number of -OH groups results in very slow diffusion. D/x (cm/h) was related to the combined solubility parameter delta(a) defined as radical(delta(p)(2)+delta(h)(2)) by: (D/x)=0.0024-0.000065delta(a) (n=7, R(2)=0.70, P=0.012).

Cutaneous tuberculosis overview and current treatment regimens

Tuberculosis is one of the oldest diseases known to humankind and it is currently a worldwide threat with 8-9 million new active disease being reported every year. Among patients with co-infection of the human immunodeficiency virus (HIV), tuberculosis is ultimately responsible for the most deaths. Cutaneous tuberculosis (CTB) is uncommon, comprising 1-1.5% of all extra-pulmonary tuberculosis manifestations, which manifests only in 8.4-13.7% of all tuberculosis cases. A more accurate classification of CTB includes inoculation tuberculosis, tuberculosis from an endogenous source and haematogenous tuberculosis. There is furthermore a definite distinction between true CTB caused by Mycobacterium tuberculosis and CTB caused by atypical mycobacterium species. The lesions caused by mycobacterium species vary from small papules (e.g. primary inoculation tuberculosis) and warty lesions (e.g. tuberculosis verrucosa cutis) to massive ulcers (e.g. Buruli ulcer) and plaques (e.g. lupus vulgaris) that can be highly deformative. Treatment options for CTB are currently limited to conventional oral therapy and occasional surgical intervention in cases that require it. True CTB is treated with a combination of rifampicin, ethambutol, pyrazinamide, isoniazid and streptomycin that is tailored to individual needs. Atypical mycobacterium infections are mostly resistant to anti-tuberculous drugs and only respond to certain antibiotics. As in the case of pulmonary TB, various and relatively wide-ranging treatment regimens are available, although patient compliance is poor. The development of multi-drug and extremely drug-resistant strains has also threatened treatment outcomes. To date, no topical therapy for CTB has been identified and although conventional therapy has mostly shown positive results, there is a lack of other treatment regimens.

The effect of hydrogen bonding on diffusion across model membranes: consideration of the number of H-bonding groups

The diffusion of a series of phenols across simple silicone membranes impregnated with either octanol or toluene was studied. These solvents are taken up and saturate the membrane. The presence of the solvents in a solid membrane allows them to interact with any permeant that cross the membrane. This membrane was used to simulate a bio-membrane, e.g. the skin, capable of hydrogen bonding with the permeant. As the number of H-bonding groups was increased the flux across both the octanol and toluene impregnated membranes decreased. However, deconvolution of the data showed that for the octanol impregnated membrane the diffusion coefficient (Dm) decreased significantly with the number of H-bonding groups. This was not the case for the toluene impregnated membrane. Furthermore the spatial configuration of the -OH groups around the aromatic ring had a significant effect on the decrease in Dm. These findings have considerable implications in understanding the absorption of permeants across bio-membranes capable of H-bonding.

In vitro anti-cancer effects of artemisone nano-vesicular formulations on melanoma cells

UNLABELLED Artemisone is a 10-amino-artemisinin derivative that is markedly superior in vitro and in vivo to current artemisinins against malaria and also possesses antitumor activity. In seeking to capitalise on the last property, we have examined the encapsulation of artemisone in nano-vesicular niosomes and solid lipid nanoparticles, and have evaluated efficacies of the free and encapsulated artemisone against human melanoma A-375 cells and effects on human keratinocytes (HaCaT). Artemisone is successfully encapsulated into the nano-vesicles with encapsulation efficiencies of 67±6% and 79±5%, and with average particle sizes being 211±10nm and 295±18nm respectively. The formulations displayed highly selective cytotoxicity towards the melanoma cells with negligible toxicity towards the normal skin cells. The artemisone-loaded nano-vesicles almost completely inhibited the melanoma cells compared to the free drug. The results overall suggest a potentially more useful therapeutic strategy that needs to be evaluated for the treatment of melanoma and other cancers. FROM THE CLINICAL EDITOR Apart from being an effective anti-malarial drug, a surprising action of artemisone also has antitumor activity. Nonetheless, its low water solubility and bioavailability has limited its clinical use. In this article, the authors enacapsulated artemisone in nano- vesicles and solid lipid nano-particles (SLNs). In-vitro studies confirmed the selective cytotoxicity towards melanoma cells. Further in-vivo and pre-clinical studies are awaited.

The effect of the nature of H-bonding groups on diffusion through PDMS membranes saturated with octanol and toluene

The permeation of a series of structurally related compounds across silicone membranes (PDMS) was studied. The PDMS was saturated either with toluene, to mimic a functionally inert barrier, or octanol, to mimic the polar/hydrogen bonding environment of the stratum corneum lipid barrier. Phenol, salicylic acid, benzoic acid, anisole, phenylethanol and benzyl alcohol were chosen in an attempt to relate permeation to their different H-bonding capabilities. The flux was lower through the octanol system suggesting retardation by polar/H-bonding interactions. Separation of the permeability coefficient into its thermodynamic (partition coefficient) and kinetic (diffusion coefficient) terms suggests that the effect of altering polarity within the membrane has a greater impact on the diffusion of permeant rather than its chemical potential within the membrane.

Dermal delivery of selected hydrophilic drugs from elastic liposomes: effect of phospholipid formulation and surfactants.

The effect of phospholipid formulation and choice of surfactant on skin permeation of selected hydrophilic drugs from elastic liposomes across human epidermal membrane has been studied. Sodium cholate and various concentrations of phosphatidylcholine were used for the preparation of liposomes namely hydrogenated phosphatidylcholine 90% (Phospholipon 90H), phosphatidylcholine 95% (Phospholipon 90G), phosphatidylcholine 78.6% (Phospholipon 80), and phosphatidylcholine 50% (Phosal PG). To investigate the effect of the surfactant, liposomes were prepared from 95% phosphatidylcholine (Phospholipon 90G) and various surfactants (sodium cholate, sodium deoxycholate, Span 20 (sorbitan monolaurate), Span 40 (sorbitan monopalmitate), Span 60 (sorbitan stearate) and Span 80 (sorbitan monooleate)). The vesicles were prepared by the conventional rotary evaporation technique. The film was hydrated with phosphate‐buffered saline (10 mL) containing 9, 2 and 2.5 mg mL−1 of methotrexate, idoxuridine and aciclovir, respectively. All formulations contained 7% ethanol. Homogenously‐sized liposomes were produced following extrusion through 100‐nm polycarbonate filters using Lipex Extruder. Particle size was characterized by transmission electron microscopy. Vertical Franz diffusion cells were used for the study of drug delivery through human epidermal membrane. For the three drugs, the highest transcutaneous fluxes were from elastic liposomes containing 95% phosphatidylcholine. In general, a higher flux value was obtained for liposomes containing sodium cholate compared with sodium deoxycholate. For the liposomes containing sorbitan monoesters, there was no clearly defined trend between alkyl chain length and flux values. Overall, transcutaneous fluxes of liposomal preparations of hydrophilic drugs were comparable with those from saturated aqueous solutions (P > 0.05).