Complex Hydrogels Composed of Chitosan with Ring-opened Polyvinyl Pyrrolidone as a Gastroretentive Drug Dosage Form to Enhance the Bioavailability of Bisphosphonates

Chia-Yu Su,Der-Zen Liu,Yu-Ting Yu,Hsiu-O Ho,Ying-Chen Chen,Ming-Thau Sheu,Fang-Ching Chao

doi:10.1038/s41598-018-26432-2

Chia-Yu Su, Der-Zen Liu + Show 5 more

Open Access

https://doi.org/10.1038/s41598-018-26432-2

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Abstract

Complex hydrogels formed with chitosan (CS) and ring-opened polyvinyl pyrrolidone (roPVP) as a swellable mucoadhesive gastroretentive drug dosage form (smGRDDF) were prepared and characterized. CS/roPVP hydrogels were produced by blending CS with roPVP obtained by basic treatment of PVP. Effects of the heating time and NaOH concentration employed for preparing roPVP, and CS molecular weights (Mws), and roPVP/CS ratios on the swelling ability of the resultant hydrogels were characterized. Rheological characteristics were further examined. Results demonstrated that roPVP obtained in a 0.5 M NaOH solution heated to 50 °C for 4 h was suitable for producing complex hydrogels with CS. At a roPVP/CS ratio of 20:1, hydrogels composed of three different Mws of CS possessed optimal swelling and mucoadhesive abilities and rheological properties. In vitro dissolution revealed sustained drug release. A pharmacokinetic study exhibited that the plasma profile of alendronate followed a sustained manner with 3-fold enhancement of the oral bioavailability. In conclusion, the smGRDDF composed of CS/roPVP complex hydrogels was successfully developed and is potentially applicable to improve the clinical efficacy of bisphosphonates.

Highlights

Various combined gastroretentive mechanisms have been reported to enhance gastroretentive capabilities[7,8,9]
We previously reported the combination of hydroxyethyl cellulose (HEC) and sodium carboxymethyl cellulose to improve the extent of swelling and floating of GRDDFs for losartan[11], and the combination of HEC, chitosan (CS), and sodium bicarbonate[12]
When heating treatment of PVP was increased to 8 h at 100 °C, the swelling of complex hydrogels formed with low-molecular weights (Mws) (LMw) CS only lasted for 2 h and began to dissolve in simulated gastric acid, while swelling of complex hydrogels formed with both medium-Mw (MMw) and high-Mw (HMw) CS maintained their diameter at 12 h with a 1.8-fold increase without dissolution

Summary

Introduction

Various combined gastroretentive mechanisms have been reported to enhance gastroretentive capabilities[7,8,9]. CS gels with improved mechanical strength can be formed by chemical cross-linking with a cross-linker such as glutaraldehyde[19,20] and glyoxal[21] or physical cross-linking as ionically cross-linked CS with different multivalent phosphates, namely pyrophosphate (Pyro) and tripolyphosphate (TPP)[22] and in polyionic complexes of positively charged CS with a negatively charged natural polymer like alginate or a synthetic one like polylactic acid These chemically or physically cross-linked CS hydrogels swell and have intragastric-floating characteristics that prolong retention of the GRDDF in the stomach. Polyionic complex hydrogels of CS with ring-opened (ro)PVP possessing a combination of mucoadhesive and swelling capabilities to prolong gastric retention times of alendronate in the upper part of the GI tract with a sustained drug release pattern were developed and characterized. With these superior properties for such a novel swellable mucoadhesive (sm)GRDDF system, the active ingredient (alendronate sodium) with an absorption window located in the upper GI tract is expected to be continually and sustainably released upstream of the stomach and passed through the absorption region in the upper GI tract resulting in enhanced BA

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