AAPS PharmSciTech (2021) 22: 121 Research Article Transdermal Permeation of Caffeine Aided by Ionic Liquids: Potential for Enhanced Treatment of Cellulite Audrey N. Hernandes, 1 Rodrigo Boscariol, 1 Victor M. Balcão, 1,2,3 and Marta M. D. C. Vila 1,3 Received 18 December 2020; accepted 8 February 2021 Abstract. Ginoid hydrolipodystrophy (HDLG) or “cellulite” involves alteration of the cutaneous relief and occurs in 80-90% of the female population. Several topical treatments are available with the use of substances capable of stimulating lipolysis, such as caffeine. However, the effectiveness of topical therapy is related to the processes of release and permeation of the active in skin cells. In this sense, ionic liquids, such as choline geranate, are considered to facilitate topical permeation agents. In this way, the aim of this research was to develop and evaluation of the effectiveness of a cosmetic product for topical treatment of cellulite with caffeine in association with choline geranate. The choline geranate was synthesized by the reaction between geranic acid and choline hydroxide [1: 2]. The gel was prepared using 2% Carpobol 940®, 5% caffeine, and 1% choline geranate. Preliminary and accelerated stability tests were performed by checking pH, spreadability, and organoleptic characteristics. The transdermal permeation capacity of caffeine in vitro was evaluated by the Franz cell permeation assay, and the gel cytotoxicity by the MTS method. To prove the efficacy in the treatment of cellulite, a pilot type 1 clinical trial was carried out. The formulation was considered stable and the product maintained your characteristics during 180 days of storage. The product showed moderate cytotoxicity and high skin permeation capacity. In the clinical trial, it showed results superior to the caffeine gel without ionic liquid. The developed gel favored the cutaneous permeation of caffeine, showing a promising product in the treatment of cellulite. KEY WORDS: ginoid hydrolipodystrophy; caffeine; choline geranate; permeation. INTRODUCTION Gynoid hydrolipodystrophy (GHLD), or cellulite, in its various degrees, is an alteration of the subcutaneous tissue, quite common in women. Approximately 95% of women will have some degree of cellulite at different moments in life, starting at puberty (1). Depending on the intensity of the established condition, this unsightly dermatosis may be responsible for important psychosocial disorders (2). The pathophysiology of cellulite is multifactorial, with a variety of causes including sexual dimorphism of subcutaneous connec- tive tissue, local circulatory and inflammatory abnormalities, and hormonal factors (3). These modifications result in the orange-peel aspect of the skin (4). The therapeutic options available for GHLD are numerous and complementary. They can vary from conventional modalities (topical applications and massages, intense pulsed light, acoustic waves, and radiofrequency) to minimally invasive approaches, such as subcision, laser therapy, and injections (5). However, among these, topical treatments are the most accessible ones to treat cellulite (6). Cosmetic formulations for topical applications have been developed, containing active ingredients with microvascular, lymphatic flow stimulatory, and lipolytic ef- fects. The ingredients more cited in the literature are methylxanthines (caffeine, theophylline, aminophylline), ret- inol, phosphatidylcholine, L-carnitine, ginkgo biloba, methyl nicotinate, menthol, camphor, and silicone (4). Caffeine (1,3,7-trimethylxanthine) is an alkaloid in the group of xanthines, commonly used in the topical treatment of cellulite because it prevents excessive accumulation of fat in cells. Caffeine exhibits several molecular actions, including the ability to act as a phosphodiesterase inhibitor, ryanodine, and adenosine receptor agonist, in addition to numerous cytoprotective properties through its antioxidant role, to- gether with the ability to inhibit carcinogenesis (7). However, the clinical efficacy of a drug applied topically depends not only on its pharmacological properties but also on its (bio)availability at the site of action. Hence, the transfer or release of the active agent from in vitro topical formulations 1 PhageLab - Laboratory of Biofilms and Bacteriophages, University of Sorocaba, Sorocaba, SP 18023-000, Brazil. 2 Department of Biology and CESAM, University of Aveiro, Campus Universitário de Santiago, P-3810-193, Aveiro, Portugal. 3 To whom correspondence should be addressed. (e–mail: victor.balcao@prof.uniso.br; marta.vila@prof.uniso) DOI: 10.1208/s12249-021-01956-5 ; published online April 1 2021 1530-9932/21/0300-0001/0 # 2021 American Association of Pharmaceutical Scientists, corrected publication 2021