Multifunctional polyvinylpyrrolidinone-polyacrylic acid copolymer hydrogels for biomedical applications
Introduction
Hydrogels are becoming increasingly important materials for pharmaceutical applications. They are used in a variety of applications including diagnostic, therapeutic, and implantable devices such as catheters (Whitbourne, 1994) biosensors, artificial skin, controlled release drug delivery systems (Graham, 1990, Ravichandran et al., 1997, Risbud et al., 2000, Varshosaz and Koopaie, 2002, Akhgari et al., 2005) and contact lenses (Shoji et al., 1997). Hydrogels have been widely used in such applications because of their biocompatibility with the human body. In addition to this, hydrogels resemble natural living tissue more than any other class of synthetic biomaterial due to their high water content and soft consistency which makes them similar to natural tissue (Ratner and Hoffman, 1976).
The selection of hydrogels used in such pharmaceutical processes depends on the characteristics of the gel and on the application of the drug or protein. Hydrogels have several important characteristics that play an important role in drug diffusion including ionisation of the gel, swelling ratio, and specific mesh or pore size. Functional groups along the polymer chain can also react to the external environment for example temperature (Aikawa et al., 1998, Kono et al., 1999a, Kono et al., 1999b), ionic strength (Peppas and Wright, 1998, Bales et al., 2000, Rodríguez et al., 2003) of the swelling agent (Ende and Peppas, 1996, Yaung and Kwei, 1997, Peppas et al., 2000, Bures and Peppas, 2000) or a combination of two or more factors (Jones, 1999, Alvarez-Lorenzo and Concheiro, 2002). Aikawa et al. (1998) investigated the effects of pH and temperature on hydrogel formation of polyvinylacetal diethylaminoacetate (AEA) and drug release from these polymers. Scanning electron microscope (SEM) observations suggested that AEA in solution becomes a hydrogel when the pH changes from 4 to 7.4, and that temperature change also accelerates network formation in the hydrogel.
The swelling ratio is also a very important parameter as it describes the amount of water that is contained within the hydrogel at equilibrium and is a function of the network structure, crosslinking ratio, hydrophilicity, and ionisation of the functional groups. Swelling ratio may be calculated from swelling studies and can be used to determine the molecular weight between crosslinks and the mesh size of the hydrogel. The mesh or pore size is the space available for drug transport (Peppas and Wright, 1998).
Many pharmaceutical systems are essentially made up of a polymeric carrier hosting the active agent inside a three dimensional network. They are often prepared as particulate systems, especially in the case of oral administration, since these forms present remarkable advantages over the single unit devices. The easier dispersion inside the stomach results in an appreciable reduction of local drug concentration that is usually responsible for gastric irritation (Grass et al., 2000). The use of hydrogels as carriers for these active agents has been studied, as well as methods for controlling their release. Ravichandran et al. (1997) studied a polyvinylpyrrolidinone-acrylic acid-polyethylene glycol copolymer and performed drug release experiments in simulated gastric fluids. It was found that the drug was released in an ordered fashion, and that modification of the crosslink density of the polymeric matrix could be used to achieve desirable drug release profiles. Lyons et al. (2006) compared the use of fillers within the polymer matrix to slow drug dissolution and reduce the cost of the overall drug delivery system. It was found that agar significantly reduced the release rate of the active agent, and as agar is biocompatible and relatively cheap it would have potential in commercial products. Friend (2005) puts forward a review of several methods of controlling the release of active agents in the gastro intestinal tract. Some of these methods include time-based delivery systems, pH based systems using enteric coatings, and combinations of both amongst others. Akhgari et al. (2005) also discusses the use of polymer coatings over the pellets that contained drug. It was also found that these coatings delayed the release of the active agent, thus allowing site specific drug release. Varshosaz and Koopaie (2002) analysed the release of an active agent from a crosslinked PVOH polymer and found that the crosslink density of the hydrogel affected the release of the drug used, i.e. there was a significant decrease in drug release as the percentage of crosslinking agent was increased. However, Devine et al. (2005) combined the use of a hydrogel for use as a lubricious coating with its ability to carry drug, and analysed the drug release from a lubricious coating with potential as a medical device coating. It was found that by varying the length of the crosslink chains the release of the active agent could by varied.
This work is a continuation of the work on the development of a novel co-polymer for use in biomedical applications. Here a series of PVP-PAA copolymers were analysed for their potential as a multifunctional hydrogel. Soxhlet extraction was carried out to determine the extractable content of the hydrogels and to ascertain which co-polymer composition may prove useful as a drug delivery device. The encapsulation of both aspirin and paracetamol within the polymer matrix was shown using Fourier transform infrared spectroscopy and the release of these active agents was determined using the USP XXV Basket method for drug dissolution. Selected hydrogels were subjected to preliminary cytotoxicity and genotoxicity testing to establish their suitability for use in the body.
Section snippets
Preparation of samples
The hydrogels investigated in this work were prepared by free-radical polymerisation. The monomers used were N-vinylpyrrolidinone (NVP, Lancaster synthesis) and acrylic acid (AA, Merck-Schuchardt, Germany). The polymers tested had monomeric feed ratios of 100 wt.% NVP, 90 wt.% NVP/10 wt.% AA, 80 wt.% NVP/20 wt.% AA and 70 wt.% NVP/30 wt.% AA. These polymers were analysed both with and without the incorporation of crosslinking agents. The crosslinking agents used in this work were using ethylene glycol
Preparation of samples
Copolymers of both NVP and NVP/AA were photopolymerised using Irgacure® 184 as a photoinitiator. These samples were cured on a silicone moulding, and prior to use dried for 24 h in a vacuum oven. Visual inspection of the samples prepared in this study showed no significant differences to those prepared in previous work (Devine and Higginbotham, 2003).
The addition of aspirin did not affect the curing rate of the polymer; however, it was found that paracetamol slowed the curing process. Therefore
Conclusions
In this work we have evaluated the potential of polyvinylpyrrolidinone-polyacrylic acid copolymers developed in our laboratory for use as multifunctional hydrogels in biomedical applications. We have shown that the extractable content of these hydrogels is relatively low, allowing these hydrogels to be used in applications where this is advantageous. We have demonstrated that the dissolution profile of active agents from these polymers vary depending upon the dissolution media used. Finally
Acknowledgments
This work has been funded by both the National Development Plan and the European Union Structural Fund.
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