Development of levamlodipine long-acting patches based on an ion-pair strategy: Investigation of the mechanism for reducing skin irritation.

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  • Additional Information
    • Source:
      Publisher: Elsevier/North-Holland Biomedical Press Country of Publication: Netherlands NLM ID: 7804127 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1873-3476 (Electronic) Linking ISSN: 03785173 NLM ISO Abbreviation: Int J Pharm Subsets: MEDLINE
    • Publication Information:
      Original Publication: Amsterdam, Elsevier/North-Holland Biomedical Press.
    • Subject Terms:
      Transdermal Patch* ; Skin*/drug effects ; Skin*/metabolism ; Administration, Cutaneous*; Rabbits ; Animals ; Swine ; Humans ; Skin Absorption ; Delayed-Action Preparations ; Skin Irritancy Tests ; Male ; Erythema/chemically induced ; Erythema/prevention & control ; Myristates/chemistry
    • Abstract:
      The aim of this study was to develop a long-acting transdermal patch of levamlodipine (LAM) using an ion-pair strategy to reduce the skin irritation induced by topical application of LAM and explore the mechanism underlying the improvement of skin irritation. The formulation was optimized through porcine in vitro transdermal experiments and rabbit in vivo skin irritation tests. The obtained formulation consisted of poly (2-Ethylhexyl acrylate-co-N-Vinyl-2-pyrrolidone-co-N-(2-Hydroxyethyl) acrylamide) (PENH) as the adhesive matrix, 13.00 % levamlodipine-sorbic acid ion-pair complex (LAM-SA) (w/w), and 10 % isopropyl myristate (IPM) (w/w), with a patch thickness of 70 μm, achieving an erythema index of 188 for rabbit skin and 117-187 for human skin (264 for rabbit skin and 110-260 for human skin in the absence of sorbic acid (SA)). In vivo rabbit and human skin erythema analysis and H&E staining verified that the optimized ion-pair patch effectively reduced skin irritation. Drug distribution experiments in the skin, ATR-FTIR, and molecular simulation were used to characterize the mechanism by which the ion-pair reduced skin irritation. Excessive accumulation of LAM in the epidermis induced secondary structural changes in keratin, resulting in skin barrier damage and inflammatory response. The formation of the LAM-SA ion pair altered physicochemical properties of LAM, reducing drug retention in the epidermis and, thereby, reducing skin irritation. This study demonstrated the potential of the ion-pair strategy to improve the safety of transdermal drug delivery system (TDDS) and provided a means for reducing skin irritation caused by the active pharmaceutical ingredient (API) itself.
      Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
      (Copyright © 2024 Elsevier B.V. All rights reserved.)
    • Contributed Indexing:
      Keywords: Ion-pair strategy; Levamlodipine; Permeation enhancers; Skin irritation; Transdermal patch
    • Accession Number:
      0 (Delayed-Action Preparations)
      0RE8K4LNJS (isopropyl myristate)
      0 (Myristates)
    • Publication Date:
      Date Created: 20240923 Date Completed: 20241009 Latest Revision: 20241009
    • Publication Date:
      20241010
    • Accession Number:
      10.1016/j.ijpharm.2024.124703
    • Accession Number:
      39312986