(491c) Preparation of PVA-Borate Complexes for Tunable Controlled Release of Small Molecules

Borate cross-linked polyvinyl alcohol (PVA) has been extensively explored over the years for different applications. Due to their unique properties, borate cross-linked PVA could potentially be used for drug delivery applications. PVA-borate complexes have a very good adhesive property, which is being explored for topical applications¹. Another study has evaluated the potential of these complexes for photodynamic therapy of infected wounds². However, there are very few studies on understanding the controlled release of molecules from PVA-borate complexes.  

Here, we have studied the properties of PVA-borate films to evaluate their potential for controlled release of small molecules. The major focus of this work is to achieve tunable release rates of small molecules by modifying the method of preparing PVA-borate complexes. We have chosen two cationic drugs (toluidine blue [TB], methylene blue [MB]), one uncharged drug (lidocaine) and one anionic drug (eosin blue [EB]) as the model drugs for our study. Due to the polyelectrolyte nature of the PVA-borate complex, effect of charge and pH on tuning the release of the model drugs has been tested.

PVA-borate complex films containing the model drugs were formed by solvent casting method. PVA solution was mixed with the model drug (0.2 mg/mL for TB, MB and EB, 10 mg/mL for lidocaine) to form a uniform mixture. This mixture was cast in films at 60°C. Cross-linking was introduced by the addition of equal volume of boric acid solution to the dried films (0%, 1% and 2%). The pH (4, 7.4 and 10) was modulated during the preparation of the PVA-borate films. The cross-linked films were suspended in 30 mL of release media, which was maintained at a pH of 7.4. At predetermined time point’s 3 mL of the release media was removed and replaced with same volume of fresh release media.

Initially, release rates were assessed for PVA-borate complex films prepared at pH 7.4. From the release profiles of TB, MB, EB and lidocaine, it was observed that the release rates were lowered with the increase in boric acid concentration for positively charged molecules. However, for negatively charged EB, the faster release rates were observed with increase in boric acid concentration. For the uncharged lidocaine molecule, there was no change in the release profiles for the cross-linked and non cross-linked polymeric films. Based on these results, it can be inferred that there is possibly a charge-based interaction between the drug molecules and the PVA-borate complex films.

To further evaluate the effect of charge of the encapsulated molecule on its release rate from PVA-borate complex, the pH at which PVA-borate films were prepared was modulated (4 and 10). Hydrogen ions are known to act as shielding/counter ions to the polyelectrolyte PVA-borate complex. For the positively charged molecules, the rate of release was higher at pH 4 when compared to pH 7.4 and pH 10. This might due to the increase in concentration of the hydrogen ions at the lower pH. The hydrogen ions will compete the with charged drug molecules to interact with the polyelectrolyte PVA-borate complex, thereby restricting the interaction of charged drug molecules with the PVA-borate complex.

In case of eosin blue, there was no difference in the release profiles at pH 4. This might due the uncharged nature of eosin blue at pH 4. Eosin blue has a pKa of 4.8. Therefore, at pH 4, it will behave as a neutral molecule. This could a plausible explanation for the release profile of eosin blue at pH4. However, at pH 10, EB release profiles were similar to that obtained at pH 7.4. Therefore, charge of the eosin blue molecule plays an important role in determining the release profiles. In case of lidocaine, the release profiles at pH 4 were similar to that observed in pH 7.4. This could due to the uncharged nature of lidocaine in pH 4. Lidocaine has a pKa value of 7.6-8. Therefore, it remains uncharged in pH 4 and 7.4. However, at pH 10, lidocaine would acquire a negative charge. This correlates with the release profile observed at pH 10. The non cross-linked samples had a slower release when compared to the PVA-borate complex prepared at pH 10. Therefore, for lidocaine, the charge of the molecules regulates the release from the PVA-borate complex.

Cell viability studies, using A431 (Human epidermoid carcinoma) cell line, performed on PVA-borate complexes prepared at pH 7.4 showed no cytotoxicity. Studies are currently underway for evaluating the cytotoxicity of PVA-borate films prepared at pH 4 and 10.

References

1.            McCarron PA, Murphy DJ, Little C, McDonald J, Kelly OJ, Jenkins MG. Preliminary clinical assessment of polyvinyl alcohol-tetrahydroxyborate hydrogels as potential topical formulations for local anesthesia of lacerations. Acad Emerg Med. Apr 2011;18(4):333-339.

2.            Donnelly RF, Cassidy CM, Loughlin RG, et al. Delivery of Methylene Blue and meso-tetra (N-methyl-4-pyridyl) porphine tetra tosylate from cross-linked poly(vinyl alcohol) hydrogels: a potential means of photodynamic therapy of infected wounds. J Photochem Photobiol B. Sep 4 2009;96(3):223-231