Solid nanoemulsion as antigen and immunopotentiator carrier for transcutaneous immunization.
Imiquimod, a toll-like receptor 7 (TLR7) agonist, is an active pharmaceutical ingredient (API) established for the topical treatment of several dermal cancerous and precancerous skin lesions. Within this work, the immunostimulatory effect of imiquimod is further exploited in a transcutaneous immunization (TCI) approach based on a solid nanoemulsion (SN) formulation. SN contains a combination of imiquimod with the model peptide antigen SIINFEKL as a novel approach to omit needle and syringe and optimize dermal antigen administration. Excipients including sucrose fatty acid esters and the pharmaceutically acceptable oils MCT (middle chain triglycerides), avocado oil, jojoba wax and squalene are high pressure homogenized together with the antigen SIINFEKL. Freeze drying was performed to eliminate water and to achieve spreadable properties of the formulation for dermal administration. The influence of the different oil components was assessed regarding in vitro drug permeation in a Franz diffusion cell model using a murine skin setup. In vivo performance in terms of cytotoxic T-cell response was assessed in a C57BL/6 mouse model. Whereas Aldara® cream contains imiquimod in a dissolved state, the SN formulations carry the active in a suspended state. This resulted in a reduction of imiquimod permeation across murine skin from the SN when compared to Aldara® cream. In spite of this permeation rate reduction, each SN induced an in vivo immune response by specific T-cell lysis. A stabilized solid nanosuspension containing squalene/tocopherol exhibited a significantly higher performance (p⩽0.05) in comparison with Aldara® cream. MCT based SN exerted an in vivo effect comparable to Aldara®. In conclusion, anhydrous highly dispersed vehicles containing imiquimod in a submicron particle size distribution can represent promising formulations for TCI. The choice of the oil component has a strong influence on SN performance, independent of in vitro drug permeation.
Biopharmaceutics and Pharmaceutical Technology, Johannes Gutenberg University, 55128 Mainz, Germany.
Karsten
K
Gogoll
Third Department of Medicine (Hematology, Oncology and Pneumology), Johannes Gutenberg University Medical Center, 55131 Mainz, Germany.
Pamela
P
Stein
Department of Pharmaceutical Sciences, College of Pharmacy, The University of Michigan, 428 Church Street, Ann Arbor, MI 48109, USA.
K D
KD
Lee
Institute of Zoology, Johannes Gutenberg University, 55128 Mainz, Germany.
Philipp
P
Arnold
Biopharmaceutics and Pharmaceutical Technology, Johannes Gutenberg University, 55128 Mainz, Germany.
Tanja
T
Peters
Institute of Immunology, Johannes Gutenberg University Medical Center, 55131 Mainz, Germany.
Hansjörg
H
Schild
Third Department of Medicine (Hematology, Oncology and Pneumology), Johannes Gutenberg University Medical Center, 55131 Mainz, Germany.
Markus
M
Radsak
Biopharmaceutics and Pharmaceutical Technology, Johannes Gutenberg University, 55128 Mainz, Germany. Electronic address: langguth@uni-mainz.de.
Peter
P
Langguth
D000276:Adjuvants, Immunologic / Q000008:administration & dosage* / Q000737:chemistry; D000279:Administration, Cutaneous; D000634:Aminoquinolines / Q000627:therapeutic use*; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002626:Chemistry, Pharmaceutical; D016503:Drug Delivery Systems; D006801:Humans; D000077271:Imiquimod; D007114:Immunization; D007801:Langerhans Cells / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D049329:Nanostructures / Q000008:administration & dosage* / Q000737:chemistry; D009821:Oils / Q000737:chemistry; D011230:Precancerous Conditions / Q000188:drug therapy*; D012878:Skin Neoplasms / Q000188:drug therapy*; D014611:Vaccination
D000276:Adjuvants, Immunologic; D000634:Aminoquinolines; D000970:Antineoplastic Agents; D009821:Oils; D000077271:Imiquimod
Cytotoxic T-cell response; Dermal drug delivery; Imiquimod; Laurocapram; Squalene; Transcutaneous immunization