Iontophoretic Delivery of 5-Aminolevulinic Acid (ALA): Effect of pH
- 150 Downloads
Purpose. To examine the iontophoretic delivery of ALA as a function of pH and to determine the principal mechanisms responsible for its electrotransport.
Methods. Anodal iontophoretic transport of ALA was measured as a function of its concentration and pH of the donor solution. Experiments were performed in vitro using skin excised from porcine ears as the membrane. To deduce mechanism, the concomitant transport of the electroosmotic marker, mannitol, was also assessed.
Results. ALA iontophoresis at pH 7.4 is a linear function of concentration over the range 1-100 mM. The mechanism was deduced to be electroosmosis. By reducing the pH from 7.4 to 4.0, the dominant mechanism of ALA transport was shifted from electroosmosis to electrorepulsion as the skin's net negative charge was progressively neutralized. However, the total delivery of the compound was not altered by lowering the pH suggesting that the increased electrorepulsive contribution was essentially balanced by the concomitantly reduced electroosmosis.
Conclusions. Significant ALA delivery at pH 7.4 can be achieved by increasing the drug concentration in the anodal formulation to 100 mM. Lowering the pH does not result in increased ALA transport. Alternative strategies are therefore required to maximize and optimize ALA delivery by iontophoresis.
Unable to display preview. Download preview PDF.
- 1.A. Marti, N. Lange, H. Van den Bergh, D. Sedmera, P. Jichlinski, and K. Kucera. Optimization of the formation and distribution of protoporphyrin IX in the urothelium: an in vitro approach. J. Urology 162:546-552 (1999).Google Scholar
- 2.K. Svanberg, T. Anderson, D. Killander, I. Wang, U. Stenram, S. Andersson-Engels, R. Berg, J. Johansson, and S. Svanberg. Photodynamic therapy of non-melanoma malignant tumours of the skin using topical δ-amino levulinic acid sensitization and laser irradiation. Br. J. Dermatol. 130:743-751 (1994).Google Scholar
- 3.S. Lang, R. Baumgartner, R. Struck, A. Leunig, R. Gutmann, and J. Feyh. Photodynamic diagnosis and therapy of neoplasms of the facial skin after topical administration of 5-aminolevulinic acid. Larynorhinootologie 74:85-89 (1995).Google Scholar
- 4.C. Fritsch, P. Lehmann, W. Stahl, K. W. Schulte, E. Blohm, K. Lang, H. Sies, and T. Ruzicka. Optimum porphyrin accumulation in epithelial skin tumours and psoriatic lesions after topical application of γ-aminolaevulinic acid. Br. J. Cancer 79:1603-1608 (1999).Google Scholar
- 5.J. C. Kennedy, R. H. Pottier, and D. C. Pross. Photodynamic therapy with endogenous protoporphyrin IX: Basic principles and present clinical experience. J. Photochem. Photobiol. B. 6: 143-148 (1990).Google Scholar
- 6.F. Cairnduff, M. Stringer, E. Hudson, D. Ashand, and S. Brown. Superficial photodynamic therapy with topical 5-aminolevulinic acid for superficial primary and secondary skin cancer. Br. J. Cancer 69:605-608 (1994).Google Scholar
- 7.F. S. De Rosa, J. M. Marchetti, J. A. Thomazini, A. C. Tedesco, and M. V. L. B. Bentley. A vehicle for photodynamic therapy of skin cancer: Influence of dimethylsulphoxide on 5-aminolevulinic acid in vitro cutaneous permeation and in vivo protoporphyrin IX accumulation determined by confocal microscopy. J. Control. Release 65:359-366 (2000)Google Scholar
- 8.A. Kim, P. G. Green, G. Rao, and R. H. Guy. Convective solvent flow across the skin during iontophoresis. Pharm. Res. 10:1315-1320 (1993).Google Scholar
- 9.R. R. Burnette and B. Ongpipattanakul. Caracterization on the permeselective properties of excised human skin during iontophoresis, J. Pharm. Sci. 76:765 (1987).Google Scholar
- 10.L. E. Rhodes, M. M. Tsoukas, R. R. Anderson, and N. Kollias. Iontophoretic delivery of ALA provides a quantitative model for ALA pharmacokinetics and PpIX phototoxicity in human skin. J. Inv. Dermatol. 108:87-91 (1997).Google Scholar
- 11.P. Glikfeld, C. Cullander, R. S. Hinz, and R. H. Guy. A new system for in vitro studies of iontophoresis. Pharm. Res. 5:443-446 (1988).Google Scholar
- 12.P. G. Green, R. S. Hinz, C. Cullander, G. Yamane, and R. H. Guy. Iontophoretic delivery of amino acids and amino acid derivatives across the skin in vitro. Pharm. Res. 8:1113-1120 (1991).Google Scholar
- 13.H. Oishi, H. Nomiyama, K. Nomiyama, and K. Tomokuni. Fluometric HPLC determination of δ-aminolevulinic acid (ALA) in the plasma and urine of lead workers: Biological indicators of lead exposure. J. Anal. Toxicol. 20:106-110 (1996).Google Scholar
- 14.R. C. Wester and H. I. Maibach. In vivo animal models for percutaneous absorption. In R. L. Bronaugh and H. I. Maibach (eds.), Percutaneous Absorption, Marcel Dekker, Inc, New York and Basel, 1989 pp. 221-238.Google Scholar
- 15.V. Merino, A. López, D. Hochstrasser, and R. H. Guy. Noninvasive sampling of phenylalanine by reverse iontophoresis. J. Control. Release 61:65-69 (1999).Google Scholar
- 16.G. Rao, P. Glikfeld, and R. H. Guy. Reverse iontophoresis development of a noninvasive approach for glucose monitoring. Pharm. Res. 10:1751-1755 (1993).Google Scholar
- 17.O. Siddiqui, M. S. Roberts, and A. E. Polack. The effect of iontophoresis and vehicle pH on the in-vitro permeation of lignocaine through human stratum corneum. J. Pharm. Pharmacol. 37:732-735 (1985).Google Scholar
- 18.P. G. Green, R. S. Hinz, A. Kim, F. C. Szoka, Jr., and R. H. Guy. Iontophoretic delivery of a series of tripeptides across the skin in vitro. Pharm. Res. 8:1121-1127 (1991).Google Scholar
- 19.R. R. Burnette and D. Marrero. Comparison between the iontophoretic and passive transport of thyrotropin releasing hormone across excised nude mouse skin. J. Pharm. Sci. 75:738-743 (1986).Google Scholar
- 20.J. B. Phipps and J. R. Gyory. Transdermal ion migration. Adv. Drug Del. Rev. 9:137-176 (1992).Google Scholar
- 21.M.J. Pikal The role of electroosmotic flow in transdermal iontophoresis. Adv. Drug Del. Rev. 9:201-237 (1992).Google Scholar
- 22.M. B. Delgado-Charro and R. H. Guy. Characterization of convective solvent flow during iontophoresis. Pharm. Res. 11:929-935 (1994).Google Scholar
- 23.V. Merino, A. López, Y. N. Kalia, and R. H. Guy. Electrorepulsion versus electroosmosis: effect of pH on the iontophoretic flux of 5-fluorouracil. Pharm. Res. 16:758-761 (1999).Google Scholar
- 24.D. Marro, R. H. Guy, and M. B. Delgado-Charro. Characterization of the iontophoretic permselectivity properties of human and pig skin. J. Control. Release 70:213-217 (2001).Google Scholar