The influence of topical formulations on the permeation of 5-aminolevulinic acid and its n-butyl ester through excised human stratum corneum.
ABSTRACT The limited permeation of 5-aminolevulinic acid (ALA) through excised human stratum corneum could be improved by using 5-aminolevulinic acid-n-butyl ester (ABE). Furthermore drug permeation could be increased by choice of a permeation enhancing formulation. In this study, permeation of ALA and ABE was investigated from various formulations. In addition, differential scanning calorimetry (DSC) and wide angle X-ray diffraction (WAXD) experiments were performed in order to reveal an interaction between the tested formulations and stratum corneum lipid structure. Drug incorporation into Dolgit Mikrogel showed the highest increase in permeability with both ALA and ABE. Especially, ABE together with Dolgit Mikrogel was the most promising combination. Further permeation studies with poloxamer based ABE formulations, partially enriched with ibuprofen acid and medium chained triglycerides showed that both compounds promote permeation. The permeation coefficients of either drug from Excipial Creme and Basiscreme DAC were found to be very similar. These results were in accordance with those of DSC and WAXD experiments. Interaction between formulation and stratum corneum lipid structure resulting in an increased drug permeation only occurred after pretreatment with formulations enriched with ibuprofen acid. After pretreatment with Excipial Creme, Basiscreme DAC or Excipial Fettcreme stratum corneum structure and subsequently permeability remained unchanged. Nevertheless permeation of ALA from Excipial Fettcreme is slower than from the tested hydrophilic formulations and therefore believed to be influenced by the affinity of ALA to the vehicle and stratum corneum.
- [show abstract] [hide abstract]
ABSTRACT: Photodynamic therapy (PDT) is a new modality of skin cancer treatment. It involves the administration of photosensitizing drugs which, when localized in tumor tissue can produce its destruction by absorbing an adequate dose of light of an appropriate wavelength. A large number of photosensitizing agents have been tested in PDT experiments. Topical application of 5-aminolevulinic acid (5-ALA) followed by light irradiation is the most commonly used method. 5-ALA is a prodrug converted in situ via the heme cycle into protoporphyrin IX, an effective photosensitizer agent. Treatment of nonmelanoma skin cancers by PDT has met with varying degrees of success. In the case of 5-ALA, this therapy's main limitation is the poor penetration of 5-ALA into skin, due to hydrophilic and charge characteristics. However, the efficacy of 5-ALA-PDT may be improved by (a) development of adequate drug delivery systems; (b) use of enhancers of PpIX production and accumulation in target tissue, and (c) modifications of the 5-ALA molecule. Optimal timing, light sources, doses, and number of applications are also important factors for topical 5-ALA therapy and must be well defined. The aim of this review is to highlight recent progress in 5-ALA-PDT of skin cancer, and to present ways holding promise for its improvement.Pharmaceutical Research 01/2001; 17(12):1447-55. · 4.74 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: The aim of this work was to test in vitro and in vivo the efficacy of the derivatives of 5-aminolevulinic acid (ALA): hexyl-ALA (He-ALA), undecanoyl-ALA and R,S-2-(hydroximethyl)tetrahydropyranyl-ALA (THP-ALA) as pro-photosensitising agents. The compounds were assayed in a cell line derived from a murine mammary tumour, in tumour explants and after injection of the cells into mice. In vitro, undecanoyl-ALA and THP-ALA did not improve ALA efficacy in terms of porphyrin synthesis. On the other hand, half of the amount of ALA is required to obtain the same plateau amount of photosensitiser from He-ALA. However, this plateau value cannot be surpassed in spite of the four-times higher accumulation of ALA/He-ALA from the ALA derivative. This shows that He-ALA conversion to porphyrins but not He-ALA entry to the cells is limiting. Employing ionic exchange chromatography, we found that 80% of total uptake was He-ALA whereas only 20% was ALA. This suggests that the esterases, probably themselves regulated by the heme pathway, are limiting the conversion of ALA derivatives into porphyrins. A similar situation occurs with THP-ALA. Tumour explant porphyrin results correlate well with cell line data. However, i.p. injection of ALA derivatives to mice resulted in a lower porphyrin concentration in the tumour when compared to the administration of equimolar amounts of ALA, indicating that there should be retention of ALA derivatives either within the blood vessels in the initial phase of distribution and/or within the capillaries of the tumour.British Journal of Cancer 05/2004; 90(8):1660-5. · 5.08 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: Photodynamic therapy (PDT) using topical application of 5-aminolaevulinic acid (ALA) has been widely reported for the treatment of a variety of neoplastic and non-neoplastic cutaneous diseases. Although different formulations containing variable amounts of ALA have been applied in PDT, the dose-response relationships between transdermal ALA delivery and cutaneous protoporphyrin IX (PpIX) accumulation have not been studied. The objectives of this study were to investigate the effect of permeability barrier function, ALA concentration and formulation on the in vitro penetration of ALA through nude mouse skin and cutaneous PpIX formation at 2 h following a 2-h application of ALA to nude mouse skin in vivo, and to delineate the relationships in between. Results demonstrated that variations in barrier integrity, in addition to ALA concentration, profoundly influenced ALA delivery to generate PpIX. Saturable correlations were found to exist between PpIX concentrations in both the epidermis and dermis in vivo and its transdermal flux in vitro, and the relationships were well described by the Emax model. The established correlations based on pure aqueous solutions were applicable to different formulations containing hydroxypropylmethylcellulose as the gelling agent and ethylenediamine tetraacetic acid as the iron chelator. Moreover, incorporation of desferrioxamine, another iron chelator, in the formulation prolonged cutaneous PpIX accumulation in the skin in comparison with 3% ALA aqueous solution, but the peak PpIX levels were not increased. Application of a liposomal formulation resulted in similar prolongation in ALA-induced PpIX accumulation, as well as better epidermal targeting. Knowledge of the dose-response relationships and the effect of formulation is important for designing optimal formulations and treatment schedules for topical ALA-PDT.British Journal of Dermatology 06/2002; 146(5):853-62. · 3.76 Impact Factor