Research Article Formulation, Optimization and Evaluation of Novel Ultra-deformable Vesicular Drug Delivery System for an Anti-fungal Drug Devika Nayak, 1 Roshan M. Tawale, 2 Jesil Mathew Aranjani, 2 and Vamshi Krishna Tippavajhala 1,3 Received 26 November 2019; accepted 9 April 2020 Abstract. The present study is aimed at enhancing the skin penetration of ketoconazole by formulating it as transethosome. Ketoconazole-loaded transethosome formulations were prepared by conventional thin film evaporation and hydration method and were optimized using concentration of edge activator (span 80), ethanol and sonication time as factors and particle size, polydispersity index and entrapment efficiency as responses. The optimized formulation was further evaluated for in vitro diffusion, anti-fungal activity, ex vivo penetration and in vivo pharmacodynamic activity. The results of in vitro drug diffusion and ex vivo skin penetration studies demonstrated that the amount of drug diffused and penetrated through the skin was increased. Optimized transethosomes showed enhanced in vitro antifungal and in vivo pharmacodynamic activities against Candida albicans in Wistar albino rats when compared to conventional liposomes. Therefore, the developed ketocona- zole encapsulated transethosome formulation is capable of enhancing the skin penetration of the drug by overcoming the stratum corneum barrier function and acting as an effective drug delivery system for ketoconazole through the skin for its anti-fungal activity. KEY WORDS: transethosomes; transdermal drug delivery; skin penetration; ketoconazole. INTRODUCTION Liposomes are vesicular systems that have an aqueous internal environment bounded by the phospholipid bilayer formed when the phospholipids are dispersed into water (1). These are spherical and artificial vesicles that can be created from non-toxic natural phospholipids and cholesterol. It can entrap both lipophilic and hydrophilic drugs in its liposomal system (2). The drawback of liposomes is poor penetration of the drug to the deeper layers of the skin tissue. Therefore, to overcome the stratum corneum barrier, for the passage of drugs, a new drug delivery system has to be used (3). So in the early 1990s, novel lipid vesicles known as deformable or elastic (flexible) liposomes, also known as ultra-deformable vesicles (UDV), were developed. These are bilayer biocom- patible vesicular drug delivery systems that are used for many drugs for their biochemical, cosmetic and therapeutic pur- poses. The first group consists of deformable vesicles, such as transfersomes and non-ionic surfactant–based flexible vesi- cles. The second group comprised of penetration enhancer- containing vesicles, invasomes and ethosomes (4). Compared to conventional liposomes, deformable vesicles have higher entrapment efficiency and higher potential in skin perme- ation. Deformable liposomes also contain smaller vesicle sizes and higher elasticity because of the presence of edge activator. High elasticity and membrane hydrophilicity pro- mote vesicles to avoid fusion as well as aggregation due to osmotic stress, as these properties are difficult to achieve with conventional liposomes (5). Following the osmotic gradient, deformable liposomes penetrate deeper epidermis layers through lipid lamellar regions of stratum corneum, whereas conventional liposomes merge with the lipids of the skin, dehydrate and remain near the skin surface (2). Elastic liposomes were used as a successful carrier for the topical and transdermal deliveries of the anti-fungal drugs in various studies. Aggarwal et al. used deformable liposomes for the encapsulation of griseofulvin in dermal delivery for the treatment of dermatophytosis (6). Ultra-flexible lipo- somes of miconazole nitrate were used for the treatment of candiadiasis (7). Abdallah et al. used nystatin-loaded transfersomes for the transdermal drug delivery to penetrate poorly soluble drugs (8). Amphotericin B containing ultra- deformable liposomes was used for the treatment of cutane- ous infection and leishmaniasis (9). Bhalaria et al. used fluconazole-loaded ethosomes for the treatment of candidiasis to determine the clinical efficacy against marketed prepara- tion, liposomal gel and hydroethanolic drug solution (10). Song et al. used a novel carrier, i.e. transethosomes composed 1 Department of Pharmaceutics, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karna- taka, India. 2 Department of Pharmaceutical Biotechnology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India. 3 To whom correspondence should be addressed. (e–mail: krissrcm@gmail.com) AAPS PharmSciTech (2020) 21:140 DOI: 10.1208/s12249-020-01681-5 1530-9932/20/0000-0001/0 # 2020 American Association of Pharmaceutical Scientists