Influence of penetration enhancers on topical delivery of 5-aminolevulinic acid from bioadhesive patches

Objectives The inclusion 01 chemical penetration enhancers in a novel patch-based system for the delivery of 5-aminolevulinic acid (ALA) was examined in vitro and in vivo. Poor penetration of ALA has been implicated as the primary factor for low response rates achieved with topical ALA-based photodynamic therapy of thicker neoplastic lesions. such as nodular basal cell carcinomas.

Microneedle-based drug delivery systems: Microfabrication, drug delivery, and safety

Many promising therapeutic agents are limited by their inability to reach the systemic circulation, due to the excellent barrier properties of biological membranes, such as the stratum corneum (SC) of the skin or the sclera/cornea of the eye and others. The outermost layer of the skin, the SC, is the principal barrier to topically-applied medications. The intact SC thus provides the main barrier to exogenous substances, including drugs. Only drugs with very specific physicochemical properties (molecular weight <500 Da, adequate lipophilicity, and low melting point) can be successfully administered transdermally. Transdermal delivery of hydrophilic drugs and macromolecular agents of interest, including peptides, DNA, and small interfering RNA is problematic. Therefore, facilitation of drug penetration through the SC may involve by-pass or reversible disruption of SC molecular architecture. Microneedles (MNs), when used to puncture skin, will by-pass the SC and create transient aqueous transport pathways of micron dimensions and enhance the transdermal permeability. These micropores are orders of magnitude larger than molecular dimensions, and, therefore, should readily permit the transport of hydrophilic macromolecules. Various strategies have been employed by many research groups and pharmaceutical companies worldwide, for the fabrication of MNs. This review details various types of MNs, fabrication methods and, importantly, investigations of clinical safety of MN.

Designing photosensitizers for photodynamic therapy: strategies, challenges and promising developments

Photodynamic therapy (PDT) and photodynamic antimicrobial chemotherapy (PACT) are techniques that combine the effects of visible light irradiation with subsequent biochemical events that arise from the presence of a photosensitizing drug (possessing no dark toxicity) to cause destruction of selected cells. Despite its still widespread clinical use, Photofrin (R) has several drawbacks that limit its general clinical use. Consequently, there has been extensive research into the design of improved alternative photosensitizers aimed at overcoming these drawbacks. While there are many review articles on the subject of PDT and PACT, these have focused on the photosensitizers that have been used clinically, with little emphasis placed on how the chemical aspects of the molecule can affect their efficacy as PDT agents. Indeed, many of the PDT/PACT agents used clinically may not even be the most appropriate within a given class. As such, this review aims to provide a better understanding of the factors that have been investigated, while aiming at improving the efficacy of a molecule intended to be used as a photosensitizer. Recent publications, spanning the last 5 years, concerning the design, synthesis and clinical usage of photosensitizers for application in PDT and PACT are reviewed, including 5-aminolevulinic acid, porphyrins, chlorins, bacteriochlorins, texaphyrins, phthalocyanines and porphycenes. It has been shown that there are many important considerations when designing a potential PDT/PACT agent, including the influence of added groups on the lipophilicity of the molecule, the positioning and nature of these added groups within the molecule, the presence of a central metal ion and the number of charges that the molecule possesses. The extensive ongoing research within the field has led to the identification of a number of potential lead molecules for application in PDT/PACT. The development of the second-generation photosensitizers, possessing shorter periods of photosensitization, longer activation wavelengths and greater selectivity for diseased tissue provides hope for attaining the ideal photosensitizer that may help PDT and PACT move from laboratory investigation to clinical practice.

Optical coherence tomography is a valuable tool in the study of the effects of microneedle geometry on skin penetration characteristics and in-skin dissolution.

In this study, we used optical coherence tomography (OCT) to extensively investigate, for the first time, the effect that microneedle (MN) geometry (MN height, and MN interspacing) and force of application have upon penetration characteristics of soluble poly(methylvinylether-co-maleic anhydride, PMVE/MA) MN arrays into neonatal porcine skin in vitro. The results from OCT investigations were then used to design optimal and suboptimal MN-based drug delivery systems and evaluate their drug delivery profiles cross full thickness and dermatomed neonatal porcine skin in vitro. It was found that increasing the force used for MN application resulted in a significant increase in the depth of penetration achieved within neonatal porcine skin. For example, MN of 600 µm height penetrated to a depth of 330 µm when inserted at a force of 4.4 N/array, while the penetration increased significantly to a depth of 520 µm, when the force of application was increased to 16.4 N/array. At an application force of 11.0 N/array it was found that, in each case, increasing MN height from 350 to 600 µm to 900 µm led to a significant increase in the depth of MN penetration achieved. Moreover, alteration of MN interspacing had no effect upon depth of penetration achieved, at a constant MN height and force of application. With respect to MN dissolution, an approximate 34% reduction in MN height occurred in the first 15 min, with only 17% of the MN height remaining after a 3-hour period. Across both skin models, there was a significantly greater cumulative amount of theophylline delivered after 24 h from an MN array of 900 µm height (292.23 ± 16.77 µg), in comparison to an MN array of 350 µm height (242.62 ± 14.81 µg) (p < 0.001). Employing full thickness skin significantly reduced drug permeation in both cases. Importantly, this study has highlighted the effect that MN geometry and application force have upon the depth of penetration into skin. While it has been shown that MN height has an important role in the extent of drug delivered across neonatal porcine skin from a soluble MN array, further studies to evaluate the full significance of MN geometry on MN mediated drug delivery are now underway. The successful use of OCT in this study could prove to be a key development for polymeric MN research, accelerating their commercial exploitation.

Design, optimisation and characterisation of polymeric microneedle arrays prepared by a novel laser-based micromoulding technique.

PURPOSE:
Design and evaluation of a novel laser-based method for micromoulding of microneedle arrays from polymeric materials under ambient conditions. The aim of this study was to optimise polymeric composition and assess the performance of microneedle devices that possess different geometries.
METHODS:
A range of microneedle geometries was engineered into silicone micromoulds, and their physicochemical features were subsequently characterised.
RESULTS:
Microneedles micromoulded from 20% w/w aqueous blends of the mucoadhesive copolymer Gantrez® AN-139 were surprisingly found to possess superior physical strength than those produced from commonly used pharma polymers. Gantrez® AN-139 microneedles, 600 µm and 900 µm in height, penetrated neonatal porcine skin with low application forces (>0.03 N per microneedle). When theophylline was loaded into 600 µm microneedles, 83% of the incorporated drug was delivered across neonatal porcine skin over 24 h. Optical coherence tomography (OCT) showed that drug-free 600 µm Gantrez® AN-139 microneedles punctured the stratum corneum barrier of human skin in vivo and extended approximately 460 µm into the skin. However, the entirety of the microneedle lengths was not inserted.
CONCLUSION:
In this study, we have shown that a novel laser engineering method can be used in micromoulding of polymeric microneedle arrays. We are currently carrying out an extensive OCT-informed study investigating the influence of microneedle array geometry on skin penetration depth, with a view to enhanced transdermal drug delivery from optimised laser-engineered Gantrez® AN-139 microneedles.

Investigation of swelling and network parameters of poly (ethylene glycol)-crosslinked poly (methyl vinyl ether-co-maleic acid) hydrogels

he influence of poly(ethylene glycol) (PEG) plasticiser content and molecular weight on the physicochemical properties of films cast from aqueous blends of poly(methyl vinyl ether-co-maleic acid) was investigated using thermal analysis, swelling studies, scanning electron microscopy (SEM) and attenuated total reflectance (ATR)-Fourier transform infrared (FTIR) spectroscopy. FTIR spectroscopy revealed a shift of the CO peak from 1708 to 1731 cm-1, indicating that an esterification reaction had occurred upon heating, thus producing crosslinked films. Higher molecular weight PEGs (10,000 and 1000 Da, respectively), having greater chain length, producing hydrogel networks with lower crosslink densities and higher average molecular weight between two consecutive crosslinks. Accordingly, such materials exhibited higher swelling rates. Hydrogels crosslinked with a low molecular weight PEG (PEG 200) showed rigid networks with high crosslink densities and, therefore, lower swelling rates. Polymer:plasticizer ratio alteration did not yield any discernable patterns, regardless of the method of analysis. The polymer–water interaction parameter (?) increased with increases in the crosslink density. SEM studies showed that porosity of the crosslinked films increased with increasing PEG MW, confirming what had been observed with swelling studies and thermal analysis, that the crosslink density must be decreased as the Mw of the crosslinker is increased. Hydrogels containing PMVE/MA/PEG 10,000 could be used for rapid delivery of drug, due to their low crosslink density. Moderately crosslinked PMVE/MA/PEG 1000 hydrogels or highly crosslinked PMVE/MA/PEG 200 systems could then be used in controlling the drug delivery rates. We are currently evaluating these systems, both alone and in combination, for use in sustained release drug delivery devices.