Elsevier

Polymer

Volume 47, Issue 11, 17 May 2006, Pages 3845-3855
Polymer

Drug diffusion in hydrophobically modified N,N-dimethylacrylamide hydrogels

https://doi.org/10.1016/j.polymer.2006.03.096Get rights and content

Abstract

The use of hydrophobically modified hydrogels for drug release was investigated. Copolymers of N,N-dimethylacrylamide and 2-(N-ethyl-perfluorooctanesulfonamido) ethyl acrylate (FOSA) were prepared by free-radical polymerization. The drug release rates, dynamic swelling behavior, and pH sensitivities of copolymers ranging in composition from 0 to 30 mol% FOSA were studied. Pheniramine maleate, an ocular antihistamine, was used as the model drug substance. Hydrogels of DMA produced with increasing amounts of FOSA had a decreased equilibrium media content and exhibited a slower drug release rate. Early-time, late-time and Etters approximation drug diffusion coefficients ranged from 0.4×10−3 to 12.3×10−3 mm2/min. The diffusion of the drug model was less sensitive to pH of the buffered media over the range of pH 4–8, but increasing the media pH slowed the permeability slightly by decreasing the swellability of the hydrogel. The power law exponent (n≈0.5) and the swelling interface number (Sw≫1) suggested that the drug release mechanism from these hydrogels was Fickian and not swelling controlled. These novel thermoprocessible hydrogels have potential to be used as controlled ocular drug delivery devices (e.g. contact lenses or ocular inserts).

Introduction

A hydrogel is a network of polymer chains that absorbs and retains a significant amount of water (>20%). The water content in the hydrogels depends on the hydrophilicity of the chains and degree of crosslinking in the network [1]. The behavior of water within the hydrogel is important to understand because it dominates the physical and transport properties of the hydrogel. It has been reported that hydrogels contain three ‘types’ of water: free water, intermediate water, and bound water [2]. Free water can move through the network without significant attractive or repulsive interactions with the polymeric network. Bound water is joined to the polymer through hydrogen bonds, and intermediate water is thought to exchange with the bound and free water. When polymers are highly hydrophilic they typically contain a greater proportion of bound water; therefore, the hydrophilicity of the polymer can significantly affect the swelling and transport behavior of the hydrogel.

In their dehydrated state, hydrogels are not very different from common polymers. However, hydrated hydrogels are unique, because they can have the structural integrity of a solid and still exhibit the diffusive transport properties of a liquid [3]. These attributes make hydrogels attractive for use as biomedical devices, e.g. transdermal patches and implants. They can be either chemically crosslinked with irreversible bonds or physically crosslinked with reversible bonds depending on the monomers, polymerization method, and the application [4]. Recent research has focused on synthesizing and characterizing hydrogels that exhibit particular mechanical properties such as strength and modulus, environmental responsiveness to temperature, electric field, pH or ionic strength, and mass transport control that can be ‘tuned’ to achieve very specific pharmacological applications. For example, a well constructed hydrogel can help to reduce toxic ‘burst’ effects of a drug, protect fragile drugs in their dosing environment and allow location-specific dosing [5]. Hydrogels comprised of monomers such as 2-hydroxyethyl methacrylate (HEMA), N-vinyl pyrrolidone (NVP), vinyl alcohol (VA), ethylene oxide (EO), ethylene glycol (EG), and methyl methacrylate (MMA) have been generally well studied [1], but research continues to improve and optimize hydrogel properties.

One particular monomer that has received much attention is N,N-dimethylacrylamide (DMA), which can be polymerized into a highly hydrophilic and biocompatible hydrogel. However, even when chemically crosslinked, poly(DMA) exhibits rather low mechanical strength. To overcome this deficiency, DMA can be copolymerized with a hydrophobic monomer, and the glass transition temperature and water sorption and desorption kinetics of the hydrogel can be modified by changing the structure, location, or concentration of the hydrophobic group [6]. Therefore, hydrophobically modified hydrogels are of significant interest because their properties can be ‘tuned’. Related studies have shown that 5–30 wt% of the hydrophobic monomer MMA can be copolymerized with DMA to achieve an optimal balance between mechanical strength and water content [7]. Equilibrium water contents from 70 to 97% and Young's modului from ∼0 to 0.5 MPa were achievable by varying the MMA concentration. DMS has been used for contact lenses [8], [9], [10], because of its optical transparency, low modulus of elasticity and high oxygen permeability. Unfortunately, those hydrogels phase-separate, where poly(DMS) separates from the hydrophilic phase and polar solvents. That obstacle can be overcome by using fluorinated side chain siloxanes with terminal –CF2–H in copolymers of N-vinyl pyrrolidone and DMA. Such transparent hydrogels demonstrated low modulus while maintaining high water content and oxygen permeability. Therefore, the use of comonomers containing perfluoro side chains with DMA has proved promising for improving poly(DMA) properties.

Hogen-Esch and co-workers [11], [12], [13], [14], [15] demonstrated that the introduction of physical crosslinks from a hydrophobic fluorocarbon monomer such as 2-(N-ethyl-perfluorooctanesulfonamido) ethyl acrylate (FOSA) can modify the rheological and physical properties of acrylamide copolymers and conceivably control drug diffusion. That is an exciting prospect because these copolymers are thermally processable [8], which is attractive for exploiting manufacturing processes such as extrusion and injection molding, and this would enable a mechanically robust DMA-based hydrogel to be used as an effective drug delivery system. Similar hydrophilic/hydrophobic systems for controlling the diffusion of both large and small drug molecules and adjust these systems to exhibit zero-order, first-order, or bimodal release are reported in the literature [16], [17], [18], [19].

Although DMA copolymers with significant concentrations of FOSA have been studied and characterized [8], [20], [21], [22], the effects of FOSA on drug diffusion have not been specifically investigated. If FOSA can be used to improve or modify the properties of DMA-based hydrogels, these materials could have a significant potential for drug delivery applications based on contact lenses or ocular inserts. In order for these materials to be seriously considered for use in vivo, they must exhibit stable behavior in environments of different pH. The objective of the present work was to determine the effect of the hydrophobic comonomer, FOSA, on controlling the drug diffusion rate and/or drug diffusion mechanism in DMA-based hydrogels.

Section snippets

Materials and polymer preparation

The two monomers N,N-dimethylacrylamide (DMA) (Sigma–Aldrich, St. Louis, MO) and 2-(N-ethyl-perfluorooctanesulfonamido) ethyl acrylate (FOSA) (3 M, St Paul, MN) were used to prepare the polymers for this study. The structures of these monomers are shown in Fig. 1. Copolymers of DMA and FOSA were prepared according to previously reported methods by free-radical polymerization using 2,2′-azo-bis-isobutyrylnitrile as the initiator and 1,4-dioxane as the solvent [6]. Previous work showed that

Media penetration velocity and equilibrium media content

Fig. 2, Fig. 3 show the effect of the copolymer composition and the media pH on the dynamic swelling behavior of the copolymers. As the concentration of FOSA in the copolymer increased, the rate of sorption and the equilibrium water content decreased. This is not surprising since DMA is hydrophilic and the FOSA hydrophobic, so that the equilibrium swelling capacity of the hydrogel was expected to decrease as the proportion of DMA decreased [18]. Fig. 2 shows the media sorption profiles for each

Conclusions

The physically crosslinked hydrogel copolymer comprised of a hydrophilic monomer (DMA) and a hydrophobic monomer (FOSA) has proven to be effective in controlling the desorption rate of a drug substance from its matrix. Copolymerizing the FOSA with the DMA-based hydrogels decreased (1) the media penetration velocity through the hydrogels, (2) the change in hydrogel volume during swelling, (3) the equilibrium media content in the hydrogels, (4) and the drug diffusion rate through the hydrogels.

Acknowledgements

The authors thank Dr Jun Tian for participating in stimulating research discussions and contributing his technical expertise. Pfizer Global Research and Development is acknowledged for providing laboratory facilities to conduct these experiments. Partial support of this work was provided by the Petroleum Research Fund of the American Chemical Society, Grant No. 36649-AC7.

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