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Engineering of Naproxen Loaded Polymer Hybrid Enteric Microspheres for Modified Release Tablets: Development, Characterization, in silico Modelling and in vivo Evaluation

Authors Hameed HA, Khan S, Shahid M, Ullah R, Bari A, Ali SS, Hussain Z, Sohail M, Khan SU, Htar TT

Received 23 September 2019

Accepted for publication 13 December 2019

Published 7 January 2020 Volume 2020:14 Pages 27—41


Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 2

Editor who approved publication: Dr Qiongyu Guo

Hajra Afeera Hameed,1 Shahzeb Khan,1–3 Muhammad Shahid,4 Riaz Ullah,5 Ahmed Bari,6 Syed Saeed Ali,6 Zahid Hussain,7 Muhammad Sohail,8 Shafi Ullah Khan,9 Thet Thet Htar9

1Department of Pharmacy, University of Malakand, Chakdara, Khyber Pakhtunkhwa 18800, Pakistan; 2Discipline of Pharmaceutical Sciences, School of Health Sciences, University of KwaZulu-Natal, Durban 4000, South Africa; 3Division of Molecular Pharmaceutics and Drug Delivery, College of Pharmacy, The University of Texas at Austin, Austin, TX, USA; 4Department of Pharmacy, Sarhad University of Science and Information Technology, Peshawar, Khyber Pakhtunkhwa, Pakistan; 5Medicinal, Aromatic & Poisonous Plants Research Center (MAPPRC), College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia; 6Central Laboratory, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia; 7Department of Pharmaceutics and Pharmaceutical Technology, College of Pharmacy, University of Sharjah, Sharjah 27272, United Arab Emirates; 8Department of Pharmacy, COMSATS University Islamabad, Abbottabad 22060, Pakistan; 9School of Pharmacy, Monash University Malaysia, Bandar Sunway, Subang Jaya 47500, Malaysia

Correspondence: Shahzeb Khan
Department of Pharmacy, University of Malakand, Dir Lower KPK, Pakistan

Background: Naproxen (NP) is a non-steroidal anti-inflammatory drug with poor aqueous solubility and low oral bioavailability, which may lead to therapeutic failure. NP causes crucial GIT irritation, bleeding, and peptic and duodenal ulcers.
Purpose of the study: This study aimed to engineer and characterize polymer hybrid enteric microspheres using an integrated (experimental and molecular modelling) approach with further development to solid dosage form with modified drug release kinetics and improved bioavailability.
Materials and methods: NP loaded polymer hybrid enteric microspheres (PHE-Ms) were fabricated by using a modified solvent evaporation technique coupled with molecular modelling (MM) approach. The PHE-Ms were characterized by particle size, distribution, morphology, crystallinity, EE, drug-polymer compatibility, and DSC. The optimized NP loaded PHE-Ms were further subjected to downstream procedures including tablet dosage form development, stability studies and comparative in vitro-in vivo evaluation.
Results: The hydrophobic polymer EUD-L100 and hydrophilic polymer HPMC-E5 delayed and modified drug release at intestinal pH while imparting retardation of NP release at gastric pH to diminish the gastric side effects. The crystallinity of the NP loaded PHE-Ms was established through DSC and P (XRD). The particle size for the developed formulations of PEH-Ms (M1-M5) was in the range from 29.06 ±7.3–74.31 ± 17.7 μm with Span index values of 0.491–0.69, respectively. The produced NP hybrid microspheres demonstrated retarded drug release at pH 1.2 and improved dissolution at pH 6.8. The in vitro drug release patterns were fitted to various release kinetic models and the best-followed model was the Higuchi model with a release exponent “n” value > 0.5. Stability studies at different storage conditions confirmed stability of the NP loaded PHE-Ms based tablets (P<0.05). The molecular modelling (MM) study resulted in adequate binding energy of co-polymer complex SLS-Eudragit-HPMC-Naproxen (−3.9 kcal/mol). In contrast to the NP (unprocessed) and marketed formulations, a significant increase in the Cmax of PHE-MT1 (44.41±4.43) was observed.
Conclusion: The current study concludes that developing NP loaded PHE-Ms based tablets could effectively reduce GIT consequences with restored therapeutic effects. The modified release pattern could improve the dissolution rate and enhancement of oral bioavailability. The MM study strengthens the polymer-drug relationship in microspheres.

Keywords: naproxen, hybrid microspheres, molecular modelling, dissolution, bioavailability, modified-release tablets

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