Original Article IMPROVED CHARACTERISTICS OF GLIBENCLAMIDE AS TRANSETHOSOME VESICULAR SYSTEM: PHYSICOCHEMICAL, SOLUBILITY AND IN VITRO PERMEATION STUDY NURUL ARFIYANTI YUSUF 1,6 , MARLINE ABDASSAH 2 , IYAN SOPYAN 2 , RACHMAT MAULUDIN 3 , I. MADE JONI 4,5 , ANIS YOHANA CHAERUNISAA 2* 1 Doctoral Program, Faculty of Pharmacy, Padjadjaran University, Jalan Raya Bandung-Sumedang Km 21, Jatinangor-45363, West Java, Indonesia. 2 Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Padjadjaran University, Jalan Raya Bandung-Sumedang Km 21, Jatinangor-45363, West Java, Indonesia. 3 School of Pharmacy, Institut Teknologi Bandung, Jalan Ganesha No. 10, Bandung-40132, West Java, Indonesia. 4 Department of Physics, Faculty of Mathematics and Natural Sciences, Universitas Padjadjaran, Jalan Raya Bandung-Sumedang Km 21, Jatinangor-45363, West Java, Indonesia. 5 Functional Nano Powder University Center of Excellence (FiNder U CoE), Universitas Padjadjaran, Jalan Raya Bandung-Sumedang Km 21, Jatinangor-45363, West Java, Indonesia. 6 Sekolah Tinggi Ilmu Farmasi Makassar, Jalan Perintis Kemerdekaan Km. 13,7, Makassar-90242, South Sulawesi, Indonesia * Corresponding author: Anis Yohana Chaerunisaa; * Email: anis.yohana.chaerunisaa@unpad.ac.id Received: 27 Aug 2023, Revised and Accepted: 14 Oct 2023 ABSTRACT Objective: Transethosome as a vesicular system offers high skin permeation; therefore, it is expected to improve the solubility and permeability of the poorly soluble drug glibenclamide. The study aimed to optimize the effect of lipid and surfactant concentration as well as sonication time on the physical characteristics of glibenclamide-loaded transethosomes. Methods: The transethosomes were prepared by solvent evaporation method. An experimental Box-Behnken design optimized the formula by assessing particle size, polydispersity index, zeta potential, and entrapment efficiency as response parameters. Further characterizations were conducted by determining the morphology by TEM, chemical interaction by FTIR, thermal behavior by DSC, as well as solubility improvement by using in vitro drug release and permeation study. Results: The result showed that the optimal formula was that with the lipid composition of 75 mg of soya lecithin, 5 mg of tween 80 as surfactant at a sonication time of 18.79 min. The responses were particle size of 166.8±5.3 nm, polydispersity index of 0.463±0.1, zeta potential of-44.7±2.2 mV, and entrapment efficiency as much as 87.18±3.8%. Glibenclamide-loaded transethosomes exhibited a spherical morphology with no visible aggregation. FTIR study revealed no chemical interactions between Glibenclamide and the excipients. Solubility and in vitro drug release tests showed a significant increase of Glibenclamide from transethosome (p<0.05) compared with that as a bulk powder. Conclusion: Overall, the optimized glibenclamide-loaded transethosomes designed with Box Behnken resulted in improved physicochemical characteristics and increased solubility and drug release compared with that from ethosomes and bulk powder comparison, which will be promising for Glibenclamide to be formulated as transdermal drug delivery. Keywords: Glibenclamide, Transethosome, Box-behnken, Transdermal © 2024 The Authors. Published by Innovare Academic Sciences Pvt Ltd. This is an open access article under the CC BY license (https://creativecommons.org/licenses/by/4.0/) DOI: https://dx.doi.org/10.22159/ijap.2024v16i1.49245 Journal homepage: https://innovareacademics.in/journals/index.php/ijap INTRODUCTION Glibenclamide is a second-generation sulfonylurea used as an oral antidiabetic for hyperglycemic patients that increases endogenous insulin release and lowers serum glycogen levels. According to the Biopharmaceutical Classification System (BCS), Glibenclamide is classified as class II with low solubility in water with good permeability [1, 2]. Glibenclamide has a plasma half-life (t 1/2 ) of about 4-6 h, with the first cross-metabolism in the liver as much as 50% [3]. Patient adherence becomes very important in using Glibenclamide due to its long consumption period. Mishra et al. showed that transdermal administration of Glibenclamide microcapsules increased the bioavailability and provided longer hypoglycemic effects than oral administration [4]. Transdermal would become a promising alternative route of administration for BCS II drugs [4]. It provides significant advantages, such as controlled drug release, reduced dose frequency, and improved patient adherence. It is also reported to improve bioavailability, reduce side effects, and avoid first-hand metabolism [5- 7]. Accordingly, the limitation of the transdermal system is the ability of drug molecules to penetrate and reach the action site due to the presence of stratum corneum (SC) as the outermost layer of the skin, which acts as the main barrier for drug delivery into the skin [8, 9]. The vesicular system has been developed to overcome the stratum corneum's barrier effect. This system works by mechanisms of vesicular fusion, disrupting the lipid stratum corneum or increasing lipid fluidity between cells [10]. Conventional vesicular systems such as liposomes have been the potential approaches to achieve better skin penetration due to the encapsulation of various bioactive compounds, thereby increasing physicochemical stability, reducing skin irritation side effects, and increasing topical absorption [8, 10- 13]. It has been considered to increase tissue permeation despite their limited penetration into the systemic circulation [14-16]. When liposomes do not penetrate the skin deeply, they remain confined to the upper layer of the stratum corneum [17–20]. One way to overcome this problem is by utilizing the concept of drug carriers or manipulating the vesicles to increase the penetration [21]. Transethosome, first introduced by Song et al., is derived from liposomes characterized by a high ethanol content and an edge activator in the formulation. A transethosome is a new vesicle system containing ethanol, surfactant, and phospholipids, equal to the transfersome and ethosomal systems [22]. Transfersome is a vesicular system that can deform after skin penetration [23]. It offers the ability to overcome the difficulty of drug penetration into the skin by changing its shape to pass through the intracellular stratum corneum [24]. The ethosomes, first developed by Touitou et al., represent the third generation of elastic lipid vesicular carriers with relatively high ethanol content [25]. Transethosomes have the advantage of a combination between transfersomes and ethosomes. Ethanol in transethosomes stabilizes the vesicles and increases their softness and the ability to load lipophilic drugs [25]. In the transethosome system, edge activators, such as surfactants, also implement ethanol composition, which increases drug entrapment efficiency and penetration potential. Another advantage of transethosomes is their better stability [26]. International Journal of Applied Pharmaceutics ISSN- 0975-7058 Vol 16, Issue 1, 2024