Journal of Pharmaceutical Negative Results ¦ Volume 13 ¦ Special Issue 9 ¦ 2022 1111 Nano-progesterone: An improvised therapeutic approach Gaurav K Jain 1 ,* Jagriti Sharma1, Nimesh Modi 2 , Tejas Kothari 2 , Nazeer Hasan 3 , Nitin Sharma 4 , Afsana Sheikh 3 , Amirhossein Sahebkar 5 , Prashant Kesharwani 3,6,7* 1 Center for Advanced Formulation Technology (CAFT), Delhi Pharmaceutical Science and Research University (DPSRU), Pushp Vihar, New Delhi- 110017, India 2 Corona Remedies Pvt. Ltd., Mondeal Business Park, "Corona House", Block C, S. G. Highway, Apex St, near Gurudwara, Thaltej, Ahmedabad, Gujarat-380059, India 3 Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi 110062, India 4 Pharmacy, Shri Ram Murti Smarak Institute of Medical Sciences, Bareilly, Uttar Pradesh 243202, India 5 Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran 6 Center for Transdisciplinary Research, Department Of Pharmacology, Saveetha Dental College, Saveetha Institute of Medical and Technical science, Chennai, India 7 University Institute of Pharma Sciences, Chandigarh University, Mohali, Punjab, India Email: drgkjain@gmail.com ; prashantdops@gmail.com DOI: 10.47750/pnr.2022.13.S09.157 Progesterone (PG) is a natural steroid secreted during the luteal phase by the corpus luteum. It is highly required for the release of oocytes, embryo implantation and retaining and maintaining pregnancy. However, due to hydrophobic nature, its biological half-life is extremely less due to which oral delivery of PG is near to impossible. To improve its efficiency and overcome such pitfalls researchers are developing novel drug delivery system (NDDS) for sustained delivery of PG. This review highlights the major hurdles of PG administration via oral route and the application of NDDS for the delivery of progesterone. Keywords: Progesterone, nano-progesterone, drug delivery system, hormone replacement therapy; drug delivery. 1. INTRODUCTION Oral progesterone (PG), available as synthetic and natural PG, is used to treat various acute or chronic gynaecological conditions including menorrhagia, amenorrhea, contraception, luteal support and to pregnant woman for maintenance of pregnancy [1,2] The use of synthetic PGs for luteal support and in pregnant woman is limited owing to their inherent androgenic activity [3]. The synthetic PGs results in reduced estrogenic benefits [4], adverse effects on the lipoprotein metabolism [5] and cardiovascular system [6] and teratogenicity [7]. Conversely, natural PG, devoid of androgenic activity, has no effect on lipoprotein metabolism or cardiovascular system or induce teratogenicity [7]. In addition, several reports suggest that natural PG has a favourable effect on blood vessels [8]. The major problem with natural PG is its poor oral bioavailability due to its unfavourable physico-chemical properties [9]. It is classified as Class ІІ drug by Biopharmaceutical Classification System (BCS) with high lipophilicity (Log P = 3.9) and very low aqueous solubility (10 mg/mL) [10]. Further, it also undergoes hepatic metabolism when given by oral route [11]. A higher dose of PG shows extensive side effects such as dizziness or somnolence. Recently, lipidic delivery systems [12], microemulsions [13], self-emulsifying delivery systems [15] and surfactants [16] have been used to enhance the solubility of PG. Although, these technologies demonstrated improved solubility of PG but there are few major concerns: (a) reduced stability of PG in lipids and of lipids themselves and (b) final product is oral softgel, which is second choice compared to tablets and (c) reduced likelihood of sustained release of PG [14,15] Presently, sustained release (SR) PG formulations are preferred due to reduce hepatic metabolism and improved patient compliance [16]. Nanotechnology has paved the path, circumventing the major hiccups in progesterone delivery. It has been long deemed the answer to conquer major issues due to its potential in analysing reams of issues, uncover potential benefits and predict effect [17–26]. The nanostructures could entrap or conjugate with the hydrophobic or hydrophilic therapeutic entities. This improves the solubility and bioavailability of the preparations. Controlled release, site specific drug delivery, ligand attachment, amelioration of drug resistance and most importantly enhanced survival and therapeutic window could be achieved upon utilization of novel drug delivery system [27–31]. We believe that novel algorithm with drugs can be translated into improved human health. Thus, the review emphasized the effective role of PG, their drawbacks and application in of novel drug delivery system in the delivery of progesterone.