A New Method for Percutaneous Drug Delivery by Thermo‐Mechanical Fractional Injury

• Published in: Lasers in surgery and medicine Vol. 52; no. 1; pp. 61 - 69
• Main Authors: Shavit, Ronen, Dierickx, Christine
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.01.2020
• Subjects: Administration, Cutaneous; Adult; Aged; Aminolevulinic Acid; diffusion; Drug delivery; Drug delivery systems; Drug Delivery Systems - methods; Female; Fluorescence; Good Manufacturing Practice; Humans; Lasers; Levulinic acid; Levulinic Acids - administration & dosage; Male; Microemulsions; Middle Aged; Penetration; percutaneous drug delivery; percutaneous permeation; Permeability; Photochemotherapy - methods; Photodynamic therapy; Photosensitization; Photosensitizing Agents - administration & dosage; Protoporphyrin; Protoporphyrin IX; Pulse duration; Skin; Skin Absorption; thermomechanical fractional injury; tixel; transepidermal drug delivery; Israel; diffusion; percutaneous permeation; thermomechanical fractional injury; tixel; transepidermal drug delivery; percutaneous drug delivery
• ISSN: 0196-8092; 1096-9101; 1096-9101
• DOI: 10.1002/lsm.23125

Background and Objectives Percutaneous drug delivery (PDD) is a means of increasing the uptake of topically applied agents into the skin. Successful delivery of a photosensitizer into the skin is an important factor for effective photodynamic therapy. To evaluate the efficacy of pretreatment by thermomechanical fractional injury (TMFI) (Tixel®, Novoxel®, Israel) at low‐energy settings in increasing the permeability of the skin to a known hydrophilic‐photosensitizer medication, 5‐amino‐levulinic‐acid hydrochloride (ALA) in compounded 20% ALA gel. To compare the effect of TMFI on ALA permeation into the skin in compounded gel to three commercial photosensitizing medications in different vehicles: ALA microemulsion gel, methyl‐amino‐levulinic‐acid hydrochloride (MAL) cream, and ALA hydroalcoholic solution. Study Design/Materials and Methods Five healthy subjects were treated in two separate experiments and on a total of 136 test sites, with four topical photosensitizer preparations as follows: compounded 20% ALA gel prepared in a good manufacturing practice (GMP)‐certified pharmacy (Super‐Pharm Professional, Israel), 10% ALA microemulsion gel (Ameluz®, Biofrontera Bioscience GmbH, Leverkusen, Germany), 16.8% MAL cream (Metvix®, Galderma, Lausanne, Switzerland), and 20% ALA hydroalcoholic solution (Levulan Kerastick®, DUSA Pharmaceuticals, Inc., Wilmington, MA, USA). The dermal sites were pretreated by Tixel® (Novoxel® Ltd., Israel) prior to topical drug application. One site was untreated to serve as control. Protoporphyrin IX (PpIX) fluorescence intensity readouts were taken immediately and 1, 2, 3, 4, and 5 hours posttreatment. Results The highest average PpIX fluorescence intensity measurements were obtained for the compounded 20% ALA gel following pre‐treatment by TMFI at 6 milliseconds pulse duration. After 2 and 3 hours, TMFI‐treated sites exhibited an increased hourly rate in readouts of FluoDerm units, which were 156–176% higher than the control rates (P ≤ 0.004). TMFI pre‐treatment did not enhance the percutaneous permeation of either ALA or MAL following the microemulsion gel, hydroalcoholic solution, and cream applications. Conclusions Pretreatment with low‐energy TMFI at a pulse duration of 6 milliseconds increased the percutaneous permeation of ALA linearly over the first 5 hours from application when the compounded 20% ALA gel was used. Formulation characteristics have substantial influence on the ability of TMFI pretreatment to significantly increase the percutaneous permeation of ALA and MAL. Lasers Surg. Med. © 2019 Wiley Periodicals, Inc.