Diprotic acid containing hydrogels and drug delivery systems

During the last decade many different kind of polymeric systems are proposed as drug carrier systems. One of these systems is poly-electrolyte polymers. Yoshida, et al. [27]

synthesized the thermo and pH responsive acryloyl-L- proline ether ester(A-ProOEt) co-polymers with methacryloyl-glycine(MA-Gly) and methacryllic acid to be design a novel biofunctional gel for application in colon delivery systems. Recently, Nakamae, et al. [28]

synthesized phosphate group containing metacryloyl-oxyethyl dihydrogen phosphate/N-isopropyl acrylamide co-polymeric hydrogels for the delivery of positively charged enzymes.

They recommended that this type of pH sensitive hydrogels should be ideal for delivering drugs to the small intestines, while avoiding release in the stomach. For the investigation of cationic drug adsorption and release behaviour of diprotic acid containing hydrogels prepared in this study, firstly MB was used as the model drug. The second part of the release studies has been performed with commercial drug terbinafine hydrochloride(TER-HCl). The experimental results are explained in details below.

3.4.1. Adsorption and controlled release behaviour of methylene blue

The amounts of total (specific and non-specific) MB uptake into one gram of dry PVP and P(VP/IA) hydrogels are given in Fig. 15. As can be seen from the figure the amount of total MB taken increased rapidly after an IA content of 2.0 (mole %). The reason of this increase was attributed to the increase of free volume available for diffusion and specific bonding of positively charged drug to completely ionized hydrogel.

In order to determine the amount of non-specific adsorbed MB, hydrogels are placed in pH7 phosphate buffer solution. Fig. 16 shows the release kinetics of non-specific adsorbed MB from PVP and P(VP/IA) hydrogels. While 99% of MB was released from PVP hydrogels this value decreased to 42.0% with increasing IA content in the gel system. The percentage release of MB at pH7 was calculated from the following equation

% Release = w w ^t x

total 100 (6)

FIG. 15. The variation of total and specific adsorbed adsorbed MB with IA content in the gel system.

FIG. 16. Release of non-specific MB from P(VP/IA) hydrogels at pH7.

where, wtis the weight of released MB at time t and wtotal is the total weight of specific and non-specific adsorbed MB in the gel system. The incomplete release of MB from P(PV/IA) hydrogels at pH7 was expected to be due to binding of the cationic MB to the polymer. The difference between the total and non-specific adsorbed MB is therefore taken to be equal to the amount of specific adsorbed MB in the hydrogel. The variations of specific adsorbed MB with IA concentration are plotted in Fig. 15.

Fig. 16 also shows that the release rate was higher for pure PVP hydrogel than P(VP/IA) hydrogels and the release rate decreased with the increase of IA content in the gel system This can be explained by the increase in the diffusional path due to high swelling of P(VP/IA) hydrogels.

The controlled release of specific adsorbed MB from P(VP/IA) hydrogels was investigated primarily at pH5.5. The drug release was followed until equilibrium and then hydrogel was transferred into MB free buffer at pH4 and after reaching new equilibrium to pH2. The percentage of release of MB with time at each hydrogel system is given in Figs 17–

19. The percentage releases of specific adsorbed MB at pH5.5, 4.0 and 2.0 were calculated from the following equation

% Release of specific adsorbed MB = w w ^t x

sp. 100 (7)

where, wt is the weight of released MB at time t and wsp. is the total weight of specific adsorbed MB in the gel system. As can be seen from Figs 17–19 the release rate decreased at pH5.5 and pH4 with increasing IA content in the gel system due to an increase of the diffusion path. Approximately 10.0% and 5.5% differences in the drug release were observed at 400 min between P(VP/IA)-1 and P(VP/IA)-3 hydrogels at pH5.5 and pH4.0, respectively.

However, the release of MB at pH2 was opposite in trend to the release at pH5.5 and pH4.0.

The release rate increased with increase of IA content in the gel system. The percentage of released MB from P(VP/IA)-3 hydrogel is approximately 14.0%, higher than that of P(VP/IA)-1 hydrogel at 400 min of release. As is known [29] the release of the drug may be influenced for two reasons. The first is the diffusion path of the drug in the network. As discussed previously a decrease on the cross-linking density causes to increase the swelling capacity and diffusion path. The second can be explained by the driving force concept for drug diffusion. The drug concentration in the gel defines the driving force for drug diffusion, which is due to the release rate increasing with the drug loading. The amount of drug concentration in P(PV/IA)-3 hydrogel is approximately 2.6 fold higher than that in P(VP/IA)-1 hydrogel when the release was completed at pH4.0. The Hydrogels were placed in pH2.0 buffer solution, hence, the release of MB from P(PV/IA)-3 hydrogel is much faster than P(VP/IA)-1 hydrogel.

Figs 17–19 also indicated that, the percentage releases of specific adsorbed MB for each hydrogel at individual pH values were approximately of the same magnitude. This could be explained by the same extent of ionization or protonization of hydrogel at each pH value.

Mathematically, it is known that, being independent of the diprotic acid concentration in the gel system, the percentage ionization is constant for each hydrogel at a certain pH. Variation of the specific adsorbed MB (%) and ionization with pH for P(VP/IA) hydrogels are given in Fig. 20. It was noticed that the adsorption of the drug depends on the pH and percentage of ionization obviously and compared with the theoretically plotted ionization curve of IA there is no drug release in pH 7 buffer which is due to the physically bonding of the positively charged MB to completely ionized hydrogel. On the other hand, 100% release was not observed at pH 2 as expected from theoretically plotted ionization curve (dashed line). The complete release of MB was observed at pH 1. The theoretical ionization versus pH curve in Fig. 20 is plotted by using the Ka1 and Ka2 values of pure itaconic acid. As can be seen from Fig. 20 there is a significant difference between theoretically plotted ionization curve and adsorbed MB (%) versus pH curves. This change may be due to the changes of the dissociation constants of IA in the gel/drug-phosphate buffer system.

In this study the preparation of P(VP/IA) hydrogels and their drug release behaviours have been investigated. It has been found that the specific and non-specific adsorption capacity of hydrogels both increase with increasing IA content in the gel system. This has been explained due to the incorporation of more specific acidic groups into the network and consequent higher swelling capacity of gels. The release studies show that one of the basic parameters affecting the drug release behaviour of P(VP/IA) hydrogels is the pH of the solution. To conclude, the hydrogels prepared in this study can be considered as potential

carriers for the drug delivery systems and may be used as especially local therapeutic applications of cationic drugs.