Transdermal Delivery and Cutaneous Targeting of Antivirals using a Penetration Enhancer and Lysolipid Prodrugs

• Published in: Pharmaceutical research 2014-04, Vol.31 (4), p.1071-1081
• Main Authors: Diblíková, Denisa, Kopečná, Monika, Školová, Barbora, Krečmerová, Marcela, Roh, Jaroslav, Hrabálek, Alexandr, Vávrová, Kateřina
• Format: Article
• Language: English
• Subjects: 2-Aminopurine - administration & dosage; 2-Aminopurine - analogs & derivatives; 2-Aminopurine - chemistry; Administration, Cutaneous; Antiviral agents; Antiviral Agents - administration & dosage; Antiviral Agents - chemistry; Antiviral drugs; Biochemistry; Biomedical and Life Sciences; Biomedical Engineering and Bioengineering; Biomedicine; Drug delivery; Drug delivery systems; Drug Delivery Systems - methods; Epidermis; Female; HIV; Human immunodeficiency virus; Humans; Liposomes; Medical Law; Organ Culture Techniques; Pharmaceutical sciences; Pharmacology/Toxicology; Pharmacy; Phosphonates; Prodrugs; Prodrugs - administration & dosage; Prodrugs - chemistry; Research Paper; Skin; Skin Absorption - drug effects; Skin Absorption - physiology; Stratum corneum; Transdermal medication
• ISSN: 0724-8741; 1573-904X
• DOI: 10.1007/s11095-013-1228-8

Purpose In this work, we investigate prodrug and enhancer approaches for transdermal and topical delivery of antiviral drugs belonging to the 2,6-diaminopurine acyclic nucleoside phosphonate (ANP) group. Our question was whether we can differentiate between transdermal and topical delivery, i.e. , to control the delivery of a given drug towards either systemic absorption or retention in the skin. Methods The in vitro transdermal delivery and skin concentrations of seven antivirals, including ( R )- and ( S )-9-[2-(phosphonomethoxy)propyl]-2,6-diaminopurine (PMPDAP), ( S )-9-[3-hydroxy-2-(phosphonomethoxy)propyl]-2,6-diaminopurine (( S )-HPMPDAP), its 8-aza analog, and their cyclic and hexadecyloxypropyl (HDP) prodrugs, was investigated with and without the penetration enhancer dodecyl-6-(dimethylamino)hexanoate (DDAK) using human skin. Results The ability of ANPs to cross the human skin barrier was very low (0.5–1.4 nmol/cm 2 /h), and the majority of the compounds were found in the stratum corneum, the uppermost skin layer. The combination of antivirals and the penetration enhancer DDAK proved to be a viable approach for transdermal delivery, especially in case of ( R )-PMPDAP, an anti-HIV effective drug (30.2 ± 2.3 nmol/cm 2 /h). On the other hand, lysophospholipid-like HDP prodrugs, e.g. , HDP-( S )-HPMPDAP, reached high concentrations in viable epidermis without significant systemic absorption. Conclusions By using penetration enhancers or lysolipid prodrugs, it is possible to effectively target systemic diseases by the transdermal route or to target cutaneous pathologies by topical delivery.