Photosensitiser delivery for photodynamic therapy. Part 1: Topical carrier platforms

Photodynamic therapy (PDT) is a medical treatment in which a combination of a photosensitising drug and visible light causes destruction of selected cells. Due to the lack of true selectivity of preformed photosensitisers for neoplastic tissue and their high molecular weights, PDT of superficial skin lesions has traditionally been mediated by topical application of the porphyrin precursor 5-aminolevulinic acid (ALA). Objective: This article aims to review the traditional formulation-based approaches taken to topical delivery of ALA and discusses the more innovative strategies investigated for enhancement of PDT mediated by topical application of ALA and preformed photosensitisers. Methods: All of the available published print and online literature in this area was reviewed. As drug delivery of agents used in PDT is still something of an emerging field, it was not necessary to go beyond literature from the last 30 years. Results/conclusion: PDT of neoplastic skin lesions is currently based almost exclusively on topical application of simple semisolid dosage forms containing ALA or its methyl ester. Until expiry of patents on the current market-leading products, there is unlikely to be a great incentive to engage in design and evaluation of innovative formulations for topical PDT, especially those containing the more difficult-to-deliver preformed photosensitisers.

Autoradiographic and scintillation analysis of 5-aminolevulinic acid permeation through epithelialised tissue: Implications for topical photodynamic therapy of superficial gynaecological neoplasias

Purpose. Aminolevulinic acid (5-ALA) diffusion through both keratinised and non-keratinised tissue, used as a model tissue substrates, was evaluated, together with the depth of permeation and the concentration achieved following delivery from bioadhesive patch and proprietary cream formulations. Materials and Methods. Moisture-activated, bioadhesive patches loaded with 5-ALA at concentrations of 19.0, 38.0 and 50.0 mg cm(-2) and an o/w cream (20% w/w 5-ALA) were radiolabelled with C14 5-ALA and applied to excised human vaginal tissue and porcine skin. After 1, 2 and 4 h, tissue was sectioned in two orientations and the 5-ALA concentration at specific depths determined using autoradiography and liquid scintillation counting (LSC). Results. The stratum corneum was a significant barrier to 5-ALA permeation, with concentrations in tissue dependent on application time and drug loading. 5-ALA was detected at 6 mm using autoradiography after 2 h, with LSC showing phototoxic concentrations at 2.375 mm after 4 h of application. Inclusion of oleic acid and dimethyl sulphoxide in bioadhesive patches increased 5-ALA significantly in neonate porcine tissue, but only for patches cast from blends containing 5% w/w oleic acid. Conclusions. The bioadhesive patch described delivered 5-ALA to depths of at least 2.5 mm in tissue types indicative of vulval skin, suggesting that photodynamic therapy of deep vulval intraepithelial neoplasia is feasible using this means of bioadhesive 5-ALA delivery.

An examination of the rheological and mucoadhesive properties of poly(Acrylic acid) organogels designed as platforms for local drug delivery to the oral cavity

This study examined the rheological/mucoadhesive properties of poly (acrylic acid) PAA organogels as platforms for drug delivery to the oral cavity. Organogels were prepared using PAA (3%, 5%, 10% w/w) dissolved in ethylene glycol (EG), propylene glycol (PG), 1,3-propylene glycol (1,3-PG), 1,5-propanediol (1,5-PD), polyethylene glycol 400 (PEG 400), or glycerol. All organogels exhibited pseudoplastic flow. The increase in storage (G') and loss (G '') moduli of organogels as a function of frequency was minimal, G '' was greater than G '' (at all frequencies), and the loss tangent <1, indicative of gel behavior. Organogels prepared using EG, PG, and 1,3-propanediol (1,3-PD) exhibited similar flow/viscoelastic properties. Enhanced rheological structuring was associated with organogels prepared using glycerol (in particular) and PEG 400 due to their interaction with adjacent carboxylic acid groups on each chain and on adjacent chains. All organogels (with the exception of 1,5-PD) exhibited greater network structure than aqueous PAA gels. Organogel mucoadhesion increased with polymer concentration. Greatest mucoadhesion was associated with glycerol-based formulations, whereas aqueous PAA gels exhibited the lowest mucoadhesion. The enhanced network structure and the excellent mucoadhesive properties of these organogels, both of which may be engineered through choice of polymer concentration/solvent type, may be clinically useful for the delivery of drugs to the oral cavity.

A two compartment in vitro release model for the testing of HIV microbicide formulations

BACKGROUND: In vitro release testing of vaginal formulations is usually performed in a one-compartment model (OCM) where the release medium, usually comprising pH-adjusted water, an aqueous surfactant solution or a solvent-water solution, provides sink conditions throughout the release experiment. Although this model is useful in evaluating the effect of formulation parameters upon release, it rarely reflects in vivo conditions. Here we report use of a two-compartment diffusion cell model (TCM, comprising a small volume donor, a large volume receptor, and separated by a model epithelial membrane) to more closely mimic in vivo vaginal release and tissue absorption following administration of a UC781 vaginal ring.

METHODS: Macaque-sized matrix silicone elastomer vaginal rings containing 100mg UC781 were prepared by injection molding, and in vitro release testing performed using both OCM (20mL simulated vaginal fluid, SVF) and TCM (5mL SVF in donor cell and variable quantities of Tween 80; silicone elastomer membrane; 100mL 3:2 ethanol/water in receptor cell). In the TCM, drug levels were measured by HPLC in both donor and receptor cells, representing fluid and tissue levels respectively. Rings containing 100mg UC781 and 10% w/w Tween 80 were also manufactured and tested.

RESULTS: The amount of UC781 released from rings was significantly influenced by the choice of release model. Greatest release (56mg/14 days) was measured in the ethanol/water OCM, compared with no measurable release into SVF only. Increasing the concentration of Tween 80 in the SVF medium (1, 3 and 5% w/w) led to increased UC781 release (11, 16 and 18mg, respectively), demonstrating that vaginal fluid solubility of UC781 may be rate-determining in vivo. In the TCM, UC781 accumulates in the receptor cell medium over time, despite not being measured in the donor medium containing the ring device. Incorporation of Tween 80 directly into the ring provided enhanced release in both donor and receptor cells.

CONCLUSIONS: Release of UC781 was influenced by the choice of release medium and the inclusion of Tween 80 in the ring. Although use of SVF-only in the OCM indicated no measurable UC781 release from rings, data from the TCM confirms that UC781 is not only released but is also capable of penetrating across the model epithelial membrane. The TCM may therefore provide a more representative in vitro release model for mimicking in vivo absorption.

Comparison of a novel spray congealing procedure with emulsion-based methods for the micro-encapsulation of water-soluble drugs in low melting point triglycerides

The particle size characteristics and encapsulation efficiency of microparticles prepared using triglyceride materials and loaded with two model water-soluble drugs were evaluated. Two emulsification procedures based on o/w and w/o/w methodologies were compared to a novel spray congealing procedure. After extensive modification of both emulsification methods, encapsulation efficiencies of 13.04% tetracycline HCl and 11.27% lidocaine HCl were achievable in a Witepsol (R)-based microparticle. This compares to much improved encapsulation efficiencies close to 100% for the spray congealing method, which was shown to produce spherical particles of similar to 58 mu m. Drug release studies from a Witepsol (R) formulation loaded with lidocaine HCl showed a temperature-dependent release mechanism, which displayed diffusion-controlled kinetics at temperatures similar to 25 degrees C, but exhibited almost immediate release when triggered using temperatures close to that of skin. Therefore, such a system may find application in topical semi-solid formulations, where a temperature-induced burst release is preferred.

Hexyl Aminolaevulinate Is a More Effective Topical Photosensitiser Precursor than Methyl Aminolaevulinate and 5-Aminolaevulinic Acids When Applied in Equimolar Doses

Aminolaevulinic acid (ALA) is known to poorly penetrate into thick lesions, such as nodular basal cell carcinomas Short chain ALA esters, possessing increased lipophilicity relative to their hydrophilic parent, have previously been shown to be highly efficient at inducing protoporphyrin IX (PpIX) production in cell culture, at equimolar concentrations. In contrast, in vitro skin permeation and in vivo animal studies, which up to now have compared prodrugs on a % w/vv basis, have failed to demonstrate such benefits For the first time, equimolar concentrations of ALA, methyl-ALA (m-ALA) and hexyl-ALA (h-ALA) have been incorporated into an o/w cream preparation. In vitro penetration studies into excised porcine skin revealed that increased levels of h-ALA, compared to ALA and m-ALA were found in the upper skin layers, at all drug loadings studied. Topical application of the formulations to nude murine skin in vivo, revealed that creams containing h-ALA induced significantly higher levels of peak PpIX fluorescence (F-max = 289.0) at low concentrations compared to m-ALA (F-max = 159.2) and ALA (F-max = 191 9). Importantly, this study indicates that when compared on an equimolar basis, h-ALA has improved skin penetration, leading to enhanced PpIX production compared to the parent drug and m-ALA (C) 2010 Wiley-Liss, Inc and the American Pharmacists Association J Pharm Sci 99 3486-3498, 2010

Moisture-Activated Rheological Structuring of Nonaqueous Poloxamine–Poly(Acrylic Acid) Systems Designed as Novel Biomedical Implants

This study reports the formulation/characterisation of novel polymeric platforms designed to behave as low-viscosity systems in the nonaqueous state, however, following uptake of aqueous ?uids, exhibit rheological structuring and mucoadhesion. The rheological/mechanical and mucoadhesive properties of platforms containing poly(acrylic acid) (PAA, 1%, 3%, 5%, w/w) and poloxamines (Tetronic 904, 901, 704, 701, 304), both in the absence and presence of phosphate buffered saline (PBS, pH 7.4) are described. With the exception of Tetronic 904, all formulations exhibited Newtonian ?ow in the nonaqueous state, whereas, all aqueous formulations displayed pseudoplastic ?ow. The consistency and viscoelastic properties were dependent on the concentrations of PAA and PBS and Tetronic grade. PBS signi?cantly increased the consistency, viscoelasticity and mucoadhesion, reaching a maximum at a de?ned concentration of PBS that was dependent on PAA concentration and Tetronic grade. Formulations containing Tetronic 904 exhibited greatest consistency and elasticity both prior to and after dilution with PBS. Increasing PAA concentration enhanced the mucoadhesive properties. Prolonged drug release of metronidazole was observed from formulations containing 10% (w/w) PBS, 3% and, particularly, 5% (w/w) PAA. It is suggested that the physicochemical properties of formulations containing 3% or 5% (w/w) PAA and Tetronic 904, would render them suitable platforms for administration to body cavities.

Freeze-dried, mucoadhesive system for vaginal delivery of the HIV microbicide, dapivirine: Optimisation by an artificial neural network

Dapivirine mucoadhesive gels and freeze-dried tablets were prepared using a 3 x 3 x 2 factorial design. An artificial neural network (ANN) with multi-layer perception was used to investigate the effect of hydroxypropyl-methylcellulose (HPMC): polyvinylpyrrolidone (PVP) ratio (XI), mucoadhesive concentration (X2) and delivery system (gel or freeze-dried mucoadhesive tablet, X3) on response variables; cumulative release of dapivirine at 24 h (Q(24)), mucoadhesive force (F-max) and zero-rate viscosity. Optimisation was performed by minimising the error between the experimental and predicted values of responses by ANN. The method was validated using check point analysis by preparing six formulations of gels and their corresponding freeze-dried tablets randomly selected from within the design space of contour plots. Experimental and predicted values of response variables were not significantly different (p > 0.05, two-sided paired t-test). For gels, Q(24) values were higher than their corresponding freeze-dried tablets. F-max values for freeze-dried tablets were significantly different (2-4 times greater, p > 0.05, two-sided paired t-test) compared to equivalent gets. Freeze-dried tablets having lower values for X1 and higher values for X2 components offered the best compromise between effective dapivirine release, mucoadhesion and viscosity such that increased vaginal residence time was likely to be achieved. (C) 2009 Elsevier B.V. All rights reserved.