Mucoadhesive drug carrier based on interpolymer complex of poly(vinyl pyrrolidone) and poly(acrylic acid) prepared by template polymerization

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Abstract

To develop a new mucoadhesive drug carrier, poly(vinyl pyrrolidone) (PVP)/poly(acrylic acid) (PAA) interpolymer complexes were prepared by the template polymerization of acrylic acid using PVP as a template polymer. Fourier transform infrared results showed that the interpolymer complexes were formed by hydrogen bonds between the carboxyl groups of PAA and the carbonyl groups of PVP. The adhesive forces of the PVP/PAA interpolymer complexes were higher than that of commercial Carbopol 971. Moreover, the adhesive force and the release rate can be controlled by changing the mole ratios of PVP and PAA. The release rates of ketoprofen from the PVP/PAA interpolymer complexes showed pH-dependency, and were slower at lower pH. The release rate of ketoprofen from the complex seemed to be mainly controlled by the dissolution rate of the complex above a pKa of PAA (4.75) and by the diffusion rate below the pKa. The prepared complex appears to be an adequate carrier for the mucoadhesive drug delivery system.

Introduction

Many different kinds of polymers have been investigated for their potential use as a platform to deliver a drug in an efficient and a controlled manner. In recent years, drug delivery systems using mucoadhesive drug carriers have gained increasing importance, since they can adhere to mucosal surfaces of the gastrointestinal tract [1], [2], and thereby increase therapeutic efficacy [3]. Typical polymers that have been used as mucoadhesive drug carriers include poly(acrylic acid) (PAA), poly(methacrylic acid), carboxymethyl cellulose, and hydroxypropyl methylcellulose [4], [5]. Of these, PAA and its lightly crosslinked commercial forms, Carbopol and Polycarbophil, usually exhibit strong mucoadhesive properties, and also appear to be biocompatible [6]. However, PAA has some limitations as a mucoadhesive drug carrier including its high water solubility. High water solubility critically limits its use as a mucoadhesive drug carrier, since it may be dissolved before the drug is delivered across the membrane [7]. To solve this problem, many studies have been conducted to prepare copolymers or interpolymer complexes [8], [9], [10], [11], [12], [13], [14], [15], [16]. Strong intermolecular forces, such as hydrogen bonds, can connect the component polymers in the interpolymer complex [12], [13], and these may result in different physico–chemical characteristics from each component polymer. We undertook to prepare the interpolymer complexes of PAA with a methoxy poly(ethylene glycol), methoxy poly(ethylene glycol) macromer and poloxamer for application as mucoadhesive drug carriers [8], [9], [10]. Complex formation was attributed to hydrogen bonding between the carboxyl group of PAA and the ether group of the methoxy poly(ethylene glycol), methoxy poly(ethylene glycol) macromer or poloxamer. This study was conducted as part of a continuing effort to prepare a new mucoadhesive drug carrier using poly(vinyl pyrrolidone) (PVP) as a template polymer. Similar hydrogen bonding between the carbonyl groups of PVP and the carboxyl groups of PAA were expected.

The objectives of this work were to control the water solubility of PAA and to maintain or improve the mucoadhesive property of PAA for its application as a transmucosal drug delivery (TMD) system. To control the water solubility of PAA, the interpolymer complexes with various ratios of PVP and PAA were prepared by polymerizing acrylic acid in the presence of PVP as a template without a crosslinking agent. To characterize the new interpolymer complex its spectroscopic properties, thermal properties, adhesive forces, viscosities, and the release rates of ketoprofen, a model drug, were evaluated.

Section snippets

Materials

PVP with number average molecular weight (Mn) of 25K was provided by BASF (Ludwigshafen, Germany). 2,2′-Azobisisobutyronitrile (AIBN) and acrylic acid were purchased from the Junsei Chemical (Tokyo, Japan) and acrylic acid was used after removing its inhibitor using a disposable inhibitor remover column purchased from Aldrich (Milwaukee, WI, USA). All other chemicals were of reagent grade and were used without further purification.

Synthesis of PVP/PAA interpolymer complexes

As shown in Fig. 1, PVP/PAA interpolymer complexes were

FT-IR study of the complexes

The PVP/PAA interpolymer complexes were prepared by the template polymerization of acrylic acid in the presence of PVP using various monomer molar ratios of PVP to PAA (1/1, 1/4, 1/8 and 1/16). The complexation between PVP and PAA via hydrogen bonding was confirmed by the shift of the carbonyl absorption bands of PAA and PVP by FT-IR. As is shown by Fig. 2, the carbonyl absorption band of PAA at 1712 cm−1 was shifted to a higher wave number near 1730 cm−1. The carbonyl absorption band of PVP at

Conclusions

We have shown that PVP formed an interpolymer complex with PAA by hydrogen bonding. The complex had greatly reduced water solubility at lower pH and improved the mucoadhesive force requirements of a transmucosal drug delivery system. The adhesive force and the release rate may be controlled by changing the mole ratio of PVP and PAA. The prepared complex appears to be a suitable carrier for transmucosal drug delivery systems. Especially, it can be applied for gastric delivery system due to

Acknowledgments

This research was supported in part by the fund provided by Korean Ministry of Public Health and Welfare (HMP-00-PT-21700-0016).

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