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

Abstract

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 C_max 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

Acknowledgments

The authors extend their appreciation to the research supporting Project (No: RSP-2019/110) at King Saud University for funding and supporting this research work The support of Navegal Laboratories (Pvt) Industrial state Hattar Haripur Pakistan is also appreciated and acknowledged for providing the facility for tablet manufacturing and characterizations. We are also very grateful to Heather C. Radford (University of Texas at Austin, USA) for her support to thoroughly check this manuscript for grammatical mistakes.

Disclosure

The authors report no conflicts of interest in this work.