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Nariman Shahid,1,2 Alia Erum,1 Muhammad Zaman,3 Ume Ruqia Tulain,1 Qurat-ul-ain Shoaib,3 Abdul Majeed,4 Muhammad F Rasool,4 Imran Imran,5 Sultan Alshehri,6 Behnam Noorani,7 Faleh Alqahtani8 1College of Pharmacy, University of Sargodha, Sargodha, 40100, Pakistan; 2Akhtar Saeed College of Pharmaceutical Sciences, Lahore, 53720, Pakistan; 3Faculty of Pharmacy, University of Central Punjab, Lahore, 54782, Pakistan; 4Department of Pharmacy Practice, Faculty of Pharmacy, Bahauddin Zakariya University, Multan, 60800, Pakistan; 5Department of Pharmacology, Faculty of Pharmacy, Bahauddin Zakariya University, Multan, 60800, Pakistan; 6Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, 11451, Saudi Arabia; 7Department of Pharmaceutical Sciences, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX, 79106, USA; 8Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, 11451, Saudi ArabiaCorrespondence: Muhammad Zaman; Faleh Alqahtani Email dr.mzaman@ucp.edu.pk; afaleh@ksu.edu.saBackground: Ticagrelor (TG), an antiplatelet drug is employed to treat patients with acute coronary syndrome, but its inadequate oral bioavailability due to poor solubility and low permeability restricts its effectiveness.Purpose: This contemporary work was aimed to design a novel pH-sensitive nanocomposite hydrogel (NCH) formulation incorporating thiolated chitosan (TCH) based nanoparticles (NPs) of Ticagrelor (TG), to enhance its oral bioavailability for effectively inhibiting platelet aggregation.Methods: NCHs were prepared by free radical polymerization technique, using variable concentrations of chitosan (CH) as biodegradable polymer, acrylic acid (AA) as a monomer, N,N-methylene bisacrylamide (MBAA) as cross-linker, and potassium persulphate (KPS) as initiator.Results: The optimum hydrogel formulation was selected for fabricating NCHs, considering porosity, sol-gel fraction, swelling studies, drug loading capacity, and TG’s in vitro release as determining factors. Outcomes of the studies have shown that the extent of hydrogel swelling and drug release was comparatively greater at higher pH (7.4). Moreover, an amplifying trend was observed for drug loading and hydrogel swelling by increasing AA content, while it declined by increasing MBAA. The NCHs were evaluated by various physicochemical techniques and the selected formulation was subjected to in vivo bioavailability studies, confirming enhancement of bioavailability as indicated by prolonged half-life and multifold increase in area under the curve (AUC) as compared to pure TG.Conclusion: The results suggest that NCHs demonstrated a pH-responsive, controlled behavior along with enhanced bioavailability. Thus NCHs can be effectively utilized as efficient delivery systems for oral delivery of TG to reduce the risk of myocardial infarction.Keywords: nanocomposite, thiolated chitosan, biodegradable, bioavailability, free radical polymerization