- Email: [email protected]
A nanoemulsion based drug delivery system for PDT: Development and clinical application of BF-200 ALA
Abstracts / Photodiagnosis and Photodynamic Therapy 17 (2017) A4–A78
Oral ODe-032 A nanoemulsion based drug delivery system for PDT: Development and clinical application of BF-200 ALA B. Novak 1,∗ , T. Dirschka 2,3 , C. Morton 4 , U. Reinhold 5 , M. Foguet 1 , B. Schmitz 1 , R.M. Szeimies 6 , H. Lübbert 1 1
Biofrontera, Hemmelrather Weg 201, Leverkusen, Germany 2 CentroDerm, Hans-Fangmann-Straße, Wuppertal, Germany 3 Faculty of Health, University Witten-Herdecke, Alfred-Herrhausen-Straße, Witten, Germany 4 Stirling Community Hospital, NHS Forth Valley, Livilands Gate, Stirling, UK 5 Dermatology Center Bonn Friedensplatz, Bonn, Germany 6 Klinikum Vest, Dept of Dermatology and Allergology, Dorstener Straße, Recklinghausen, Germany
The efficacy of 5-aminolevulinic acid (ALA) PDT for epidermal neoplasias is associated with effective formation and distribution of the photosensitizer Protoporphyrin IX (PpIX). To remove epidermal cancers, the sensitizer should reach the proliferative basal layer or hair follicles and remove the neoplastic cells located there [1,2]. Both commonly used drugs to drive epidermal PpIX formation (aminolevulinic acid and its methyl ester) are not sufficiently lipophilic to pass lipid membranes without specific transporters [3]. While the ALA-methylester is slightly more stable in an aqueous environment [4], it is disadvantageous in terms of PpIX formation 5. While the contrary has long been discussed [6], newer literature shows that the selectivity for tumor cells may even be lower [5,7]. While ALA may thus be the preferred precursor, its use in practice was long hampered by its instability in aqueous environments [8]. BF-200 is an oil-in-water nanoemulsion containing phosphatidylcholine-coated lipid vesicles at a nanometer scale [9]. Combining ALA it with the nanoemulsion greatly increased the stability of ALA. Here, we report both the preclinical and the clinical trials conducted with BF-200 ALA for its development in the treatment of cutaneous neoplasia. ALA in this nanoscale lipid vesicle formulation displayed superior penetration into porcine skin when compared to a methyl-ALA formulation. To further investigate the penetration enhancing capacity of BF-200 on ALA we established organotypic cultures from eyelid skin. This preparation retains the skin at the natural air-liquid interface and allows the topical application of drugs. PpIX formation and distribution were measured microscopically in slices and quantitatively in tissue lysates of the same specimen. Using this system we compared PpIX formation after application of BF-200 ALA and a galenic standard formulation containing twice the ALA concentration. We found that PpIX formation after application of BF-200 ALA was more rapid and more abundant than after application of the standard formulation. Three phase III clinical studies were conducted to demonstrate clinical efficacy and safety of BF-200 ALA together with red light at 635 nm in a total of 779 patients with 4–8 mild to moderate lesions of actinic keratosis. In two studies PDT was applied to AK lesions only, while a third study employed field treatment. All studies used red light LED illumination sources (∼635 nm). Furthermore, a 278 patient study comparing BF-200 ALA with MAL in the treatment of non-aggressive BCC showed high efficacy of BF-200 ALA in this indication as well.
A17
BF-200 ALA constitutes a stabilized and penetration-enhancing formulation for use in PDT. The presented preclinical data and data from phase III trials demonstrate very high efficacy and excellent safety and cosmetic outcome. References [1] V. Ratushny, M.D. Gober, R. Hick, T.W. Ridky, J.T. Seykora, J. Clin. Invest. 122 (2) (2012) 464–472. [2] M. Kasper, V. Jaks, D. Hohl, R. Toftgard, J. Clin. Invest. 122 (2) (2012) 455–463. [3] P. Uehlinger, M. Zellweger, G. Wagnieres, L. Juillerat-Jeanneret, B.H. Van den, N. Lange, J. Photochem. Photobiol. B 54 (1) (2000) 72–80. [4] M. Kaliszewski, M. Kwasny, A. Juzeniene, P. Juzenas, A. Graczyk, L.W. Ma, et al., J. Photochem. Photobiol. B 87 (2) (2007) 67–72. [5] R. Schulten, B. Novak, B. Schmitz, H. Lubbert, Naunyn Schmiedebergs Arch. Pharmacol. (2012). [6] C. Fritsch, B. Homey, W. Stahl, P. Lehmann, T. Ruzicka, H. Sies, Photochem. Photobiol. 68 (2) (1998) 218–221. [7] B. Novak, R. Schulten, H. Lubbert, Naunyn Schmiedebergs Arch. Pharmacol. 384 (6) (2011) 583–602. [8] Y. Wu, Y.H. Li, X.H. Gao, H.D. Chen, J. Drug Target. 21 (4) (2013) 321–327. [9] T. Maisch, F. Santarelli, S. Schreml, P. Babilas, R.M. Szeimies, Exp. Dermatol. 19 (8) (2010) e302–e305.
http://dx.doi.org/10.1016/j.pdpdt.2017.01.038 Oral ODe-033 Photodynamic antifungal therapy M. Venturini ∗ , P.G. Calzavara-Pinton Department of Dermatology, University of Brescia, Brescia, Italy The growing resistance against antifungal drugs has renewed the search for alternative treatment modalities, and antimicrobial photodynamic therapy (PDT) seems to be a potential candidate. Preliminary findings have demonstrated that dermatophytes [1] and yeasts [2] can be effectively sensitized in vitro and in vivo by administering photosensitizers (PSs) belonging to four chemical groups: phenothiazine dyes, porphyrins and phthalocyanines, as well as aminolevulinic acid, which, while not a PS in itself, is effectively metabolized into protoporphyrin IX. Besides efficacy, PDT has shown other benefits. First, the sensitizers used are highly selective, i.e., fungi can be killed at combinations of drug and light doses much lower than that needed for a similar effect on keratinocytes. Second, all investigated PSs lack genotoxic and mutagenic activity [3]. Finally, the hazard of selection of drug resistant fungal strains has been rarely reported. We will review the studies published to date on antifungal applications of PDT, with special focus on yeast, and will present our experience in this area of research, which has the potential to make a significant impact in future treatment of fungal infections. References [1] T.G. Smijs, S. Pavel, Photochem. Photobiol. 87 (2011) 2–13. [2] B.J. Zeina, et al., Br. J. Dermatol. 144 (2001) 274–278. [3] G.F. Bertoloni, et al., Microbios 71 (1992) 33–46.
http://dx.doi.org/10.1016/j.pdpdt.2017.01.039
Oral ODe-032 A nanoemulsion based drug delivery system for PDT: Development and clinical application of BF-200 ALA B. Novak 1,∗ , T. Dirschka 2,3 , C. Morton 4 , U. Reinhold 5 , M. Foguet 1 , B. Schmitz 1 , R.M. Szeimies 6 , H. Lübbert 1 1
Biofrontera, Hemmelrather Weg 201, Leverkusen, Germany 2 CentroDerm, Hans-Fangmann-Straße, Wuppertal, Germany 3 Faculty of Health, University Witten-Herdecke, Alfred-Herrhausen-Straße, Witten, Germany 4 Stirling Community Hospital, NHS Forth Valley, Livilands Gate, Stirling, UK 5 Dermatology Center Bonn Friedensplatz, Bonn, Germany 6 Klinikum Vest, Dept of Dermatology and Allergology, Dorstener Straße, Recklinghausen, Germany
The efficacy of 5-aminolevulinic acid (ALA) PDT for epidermal neoplasias is associated with effective formation and distribution of the photosensitizer Protoporphyrin IX (PpIX). To remove epidermal cancers, the sensitizer should reach the proliferative basal layer or hair follicles and remove the neoplastic cells located there [1,2]. Both commonly used drugs to drive epidermal PpIX formation (aminolevulinic acid and its methyl ester) are not sufficiently lipophilic to pass lipid membranes without specific transporters [3]. While the ALA-methylester is slightly more stable in an aqueous environment [4], it is disadvantageous in terms of PpIX formation 5. While the contrary has long been discussed [6], newer literature shows that the selectivity for tumor cells may even be lower [5,7]. While ALA may thus be the preferred precursor, its use in practice was long hampered by its instability in aqueous environments [8]. BF-200 is an oil-in-water nanoemulsion containing phosphatidylcholine-coated lipid vesicles at a nanometer scale [9]. Combining ALA it with the nanoemulsion greatly increased the stability of ALA. Here, we report both the preclinical and the clinical trials conducted with BF-200 ALA for its development in the treatment of cutaneous neoplasia. ALA in this nanoscale lipid vesicle formulation displayed superior penetration into porcine skin when compared to a methyl-ALA formulation. To further investigate the penetration enhancing capacity of BF-200 on ALA we established organotypic cultures from eyelid skin. This preparation retains the skin at the natural air-liquid interface and allows the topical application of drugs. PpIX formation and distribution were measured microscopically in slices and quantitatively in tissue lysates of the same specimen. Using this system we compared PpIX formation after application of BF-200 ALA and a galenic standard formulation containing twice the ALA concentration. We found that PpIX formation after application of BF-200 ALA was more rapid and more abundant than after application of the standard formulation. Three phase III clinical studies were conducted to demonstrate clinical efficacy and safety of BF-200 ALA together with red light at 635 nm in a total of 779 patients with 4–8 mild to moderate lesions of actinic keratosis. In two studies PDT was applied to AK lesions only, while a third study employed field treatment. All studies used red light LED illumination sources (∼635 nm). Furthermore, a 278 patient study comparing BF-200 ALA with MAL in the treatment of non-aggressive BCC showed high efficacy of BF-200 ALA in this indication as well.
A17
BF-200 ALA constitutes a stabilized and penetration-enhancing formulation for use in PDT. The presented preclinical data and data from phase III trials demonstrate very high efficacy and excellent safety and cosmetic outcome. References [1] V. Ratushny, M.D. Gober, R. Hick, T.W. Ridky, J.T. Seykora, J. Clin. Invest. 122 (2) (2012) 464–472. [2] M. Kasper, V. Jaks, D. Hohl, R. Toftgard, J. Clin. Invest. 122 (2) (2012) 455–463. [3] P. Uehlinger, M. Zellweger, G. Wagnieres, L. Juillerat-Jeanneret, B.H. Van den, N. Lange, J. Photochem. Photobiol. B 54 (1) (2000) 72–80. [4] M. Kaliszewski, M. Kwasny, A. Juzeniene, P. Juzenas, A. Graczyk, L.W. Ma, et al., J. Photochem. Photobiol. B 87 (2) (2007) 67–72. [5] R. Schulten, B. Novak, B. Schmitz, H. Lubbert, Naunyn Schmiedebergs Arch. Pharmacol. (2012). [6] C. Fritsch, B. Homey, W. Stahl, P. Lehmann, T. Ruzicka, H. Sies, Photochem. Photobiol. 68 (2) (1998) 218–221. [7] B. Novak, R. Schulten, H. Lubbert, Naunyn Schmiedebergs Arch. Pharmacol. 384 (6) (2011) 583–602. [8] Y. Wu, Y.H. Li, X.H. Gao, H.D. Chen, J. Drug Target. 21 (4) (2013) 321–327. [9] T. Maisch, F. Santarelli, S. Schreml, P. Babilas, R.M. Szeimies, Exp. Dermatol. 19 (8) (2010) e302–e305.
http://dx.doi.org/10.1016/j.pdpdt.2017.01.038 Oral ODe-033 Photodynamic antifungal therapy M. Venturini ∗ , P.G. Calzavara-Pinton Department of Dermatology, University of Brescia, Brescia, Italy The growing resistance against antifungal drugs has renewed the search for alternative treatment modalities, and antimicrobial photodynamic therapy (PDT) seems to be a potential candidate. Preliminary findings have demonstrated that dermatophytes [1] and yeasts [2] can be effectively sensitized in vitro and in vivo by administering photosensitizers (PSs) belonging to four chemical groups: phenothiazine dyes, porphyrins and phthalocyanines, as well as aminolevulinic acid, which, while not a PS in itself, is effectively metabolized into protoporphyrin IX. Besides efficacy, PDT has shown other benefits. First, the sensitizers used are highly selective, i.e., fungi can be killed at combinations of drug and light doses much lower than that needed for a similar effect on keratinocytes. Second, all investigated PSs lack genotoxic and mutagenic activity [3]. Finally, the hazard of selection of drug resistant fungal strains has been rarely reported. We will review the studies published to date on antifungal applications of PDT, with special focus on yeast, and will present our experience in this area of research, which has the potential to make a significant impact in future treatment of fungal infections. References [1] T.G. Smijs, S. Pavel, Photochem. Photobiol. 87 (2011) 2–13. [2] B.J. Zeina, et al., Br. J. Dermatol. 144 (2001) 274–278. [3] G.F. Bertoloni, et al., Microbios 71 (1992) 33–46.
http://dx.doi.org/10.1016/j.pdpdt.2017.01.039