Dynamic deswelling studies of poly(n-vinyl-2-pyrrolidone/itaconic acid) hydrogels swollen in water and terbinafine hydrochloride solutions

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1 European Polymer Journal 38 (2002) Dynamic deswelling studies of poly(n-vinyl-2-pyrrolidone/itaconic acid) hydrogels swollen in water and terbinafine hydrochloride solutions Murat Sßen *,Olgun G uven Department of Chemistry, Polymer Chemistry Division, Hacettepe University, Beytepe, Ankara, Turkey Received 5 February 2001; received in revised form 30 July 2001; accepted 22 August 2001 Abstract Deswelling kinetics of water and terbinafine hydrochloride adsorbed poly(n-vinyl-2-pyrrolidone/itaconic acid) P(VP/IA) hydrogels were investigated. Hydrogels were prepared by irradiating the ternary mixture of VP/IA and crosslinking agent ethylene glycol dimethacrylate (EGDMA) in water by c-rays at ambient temperature. Hydrogels swelled in pure water and terbinafine hydrochloride (TER-HCl) solutions at room temperature and deswelling or water loss were investigated between 4 and 45 C temperature range and on human skin. The influence of IA content,% swelling, temperature and TER-HCl content on the water loss from gel matrix were investigated. Induction time for 80% water loss from hydrogel systems are found to increase from 9.6 to 21.2 h by increasing IA content in the gel system at 25 C and decreased by 11 h with addition of TER-HCl in the gel system. Kinetic analyses had shown that the basic properties affecting the water loss behavior of these hydrogels are the IA and TER-HCl content and temperature of the medium. Ó 2002 Elsevier Science Ltd. All rights reserved. Keywords: Hydrogel; Deswelling kinetics; Poly(N-vinyl-2-pyrrolidone/itaconic acid); Terbinafine hydrochloride 1. Introduction * Corresponding author. Tel.: ; fax: address: msen@hacettepe.edu.tr (M. Sßen). As early as 1950 attempts were made for the development of environmental sensitive materials in biomedical and biotechnological applications and as a result of these studies the past 25 years has shown that different type hydrogel systems can be used as biomaterials [1,2]. In more recent years a series of papers has been published by Saraydın,Karadag,G uven and Sßen who synthesized new hydrogels from the copolymers of acrylamide and N-vinyl-2-pyrrolidone and diprotic itaconic acid and maleic acid and showed that these hydrogels are biocompatible [3 5]. These authors also published that these polyelectrolyte hydrogels are potential adsorbents for biological agents and dyes,heavy metal ions and cationic drugs from aqueous solutions. The sensitivity of polyelectrolyte hydrogels on ph within a certain interval makes these systems suitable for various biomedical applications where ph responsiveness is required. The ph sensitivity also imparts additional advantages to these systems by providing close control of the release of drugs as compared with nonelectrolyte gels. The results of our previous study [6,7] indicated that polydiprotic acid contain hydrogel systems can be considered as potential carriers for the drug delivery systems and may be used especially for local therapeutic applications of cationic drugs. Recently,Sßen Uzun and G uven [7] also investigated the delivery of a positively charged antifungal drug terbinafine hydrochloride (TER-HCl) from maleic acid containing acrlyamide hydrogels. TER or TER-HCL is a topically and orally active allylamine antifungal agent which appears to act by preventing fungal ergesterol biosynthesis via specific and selective inhibition of fungal /02/$ - see front matter Ó 2002 Elsevier Science Ltd. All rights reserved. PII: S (01)

2 752 M. Sßen, O. G uven / European Polymer Journal 38 (2002) squale oxidase [8]. In standard in vitro suspectibility tests TER has demonstrated activity against a wide range of dermotophyte filamentous,dimorphic and dematiaceous fungi as well as yeasts. They investigated the usability of hydrogels for the controlled release of TER-HCl and influence of MA content and ph of the medium on the release properties of AAm/MA hydrogels. They observed that TER-HCl absorption capacity of hydrogels can be increased from 2 to 38 mg TER-HCl per gram dry gel with increasing amount of MA in the gel system [7]. More recent studies of Yakar [9] indicated that poly(n-vinyl-2-pyrrolidone/itaconic acid) P(VP/IA) hydrogels also can be considered as potential carrier system for the delivery of TER-HCl and may be used more effectively especially as local therapeutic trans dermal delivery (TDDS) applications of cationic drugs due to their higher drug adsorption capacities. In any application of a polymeric gel as a topical system like wound dressing or drug delivery system,one of the basic parameters determining applicability is the swelling and deswelling behavior. In previous publications from this laboratory,swelling behaviors of above mentioned copolymeric hydrogels were investigated in detail and relevant results have already been published elsewhere [10]. In this study,deswelling behavior of P(VP/IA) hydrogels and TER-HCl adsorbed P(VP/IA) hydrogels in 4 45 C temperature range and on human skin were investigated. The water loss kinetics and influence of IA and TER-HCl content and temperature of the medium on the release of water were examined. 2. Experimental 2.1. Chemicals The two monomers used in this study,namely VP and IA and cross-linking agent,egdma were obtained from Aldrich. TER-HCl was used after purification of the commercial drug Lamisil of Novarsis Company [7]. The water used in the preparation of hydrogels and swelling studies was deionized and doubly distilled Preparation of hydrogels Aqueous solutions containing 2 ml VP and 60,120, 180,and 240 mg IA were prepared in 1 ml of pure water corresponding to following compositions (VP/IA mole ratios,97.6:2.4,95.3:4.7,93.2:6.8,91.0:9.0). Every time 0.25% EGDMA (weight of EGDMA/weight of VP and IA) was added to these mixtures. Monomer solutions thus prepared were placed in PVC straws of 4 mm diameter and irradiated to 25 kgy in air at ambient temperature in Gammacell 220 type c irradiator at a fixed dose rate of 0.17 kgy/h Composition of gels Irradiated mixtures were dried in a vacuum oven at 315 K to constant weight and subjected to Soxhlet extraction with water as solvent. Uncross-linked polymer and/or residual monomer were removed with this extraction from the gel structure. Extracted gels were dried again in vacuum oven at 315 K to constant weight. The amount of uncross-linked MA was determined by titration of extract against NaOH (0.05 mol/l) to phenolphthalein end point Swelling and deswelling studies Dried hydrogels (3 4 mm thickness,4 mm diameter) were left to swell in distilled water at 25 C for two days. Similarly,dry gels were loaded with TER-HCl by immersion into aqueous solutions of drug (1.25 and 3.75 mg/ml) at 4 C for two days. Preliminary tests showed that two days is the minimum time to ensure complete swelling of gel and maximum loading of drug under prevailing experimental conditions. Swollen gels placed in an oven preset at a desired temperature and removed from the oven at regular intervals weighed and placed in the same oven. The measurements were continued until a constant weight was reached for each sample. The mass percentage swelling and % water in the gel during deswelling were calculated from the following equations: Swelling % ¼½ðm t m 0 Þ=m 0 Š100 ð1þ % Water ¼ ½ððm t m 0 Þ=m w Þ100Š ð2þ where m t is the weight of the swollen (deswollen) gel at time t and m 0 is the weight of dry hydrogel and m w is the weight of water in equilibrium swollen hydrogel. 3. Results and discussion 3.1. Composition of hydrogels When pure VP monomer has been irradiated with c- rays,polymerization and cross-linking reactions take place simultaneously. Total dose required for the onset of gelation was determined to be 3 kgy for pure VP and the sensitizing effect of water for the gelation of VP was very well demonstrated in our previous study [11]. In order to prepare mechanically stable IA containing hydrogels the ternary mixtures of VP/IA/H 2 O were needed to be irradiated to 25 kgy with gamma rays. In that study we showed that increasing mole percentage of IA in the initial mixture increases the amount of IA in the gel system but causes a decrease in the conversion from monomer to gel. This was explained to be due to the

3 M. Sßen, O. G uven / European Polymer Journal 38 (2002) Table 1 Mole percentages of diprotic acid,ia,in the feed compositions, in the gel systems and % gelation achieved Gel name Mole % of diprotic acid % Gelation In feed In gel P(VP/IA) P(VP/IA) P(VP/IA) P(VP/IA) chain transfer action of IA in the copolymerization with VP. In order to increase percentage conversion from monomer to gel and the amount of IA in the gel system in this study,we irradiated the ternary mixture of VP/IA/ water in the presence of cross-linking agent EGDMA. The % conversion and the amount of IA in the gel system increased approximately three fold as compared to EG- DMA free systems as reported in our previous study [6]. The percentage conversion and the amount of IA in the gel system are summarized in Table Swelling characteristics of hydrogels Fig. 1 represents the equilibrium degree of swelling (EDS) of P(VP/IA) hydrogels at 25 C in phosphate buffer solution from ph 2 to 9 at fixed ionic strength of I ¼ 0:1 [9]. Consistent with polyelectrolytic behavior, swelling of hydrogels was found to increase with ph. The solid curves in this figure represent the theoretical swelling curves of hydrogels. The construction of theoretical swelling curves are explained in detail in our recent work [12]. ph versus EDS curve of pure PVP hydrogels is also included in Fig. 1 for comparison. The experimental data points and theoretical curves are in very good accordance as it is seen from this figure. In all compositions the maximum extent of swelling were reached at ph 7,this being due to the complete dissociation of acidic groups of IA at this ph value. The first and second dissociation constants of IA are pk a1 ¼ 3:85,pK a2 ¼ 5:44 [13]. Since the two dissociation constants for IA are rather close,the consecutive swellings at these ph values overlap and only single-step swelling versus ph curves is observed. The change in EDS with ph has also been evaluated for the determination of average molecular weight between cross-links and the polymer solvent interaction parameter [14]. For the investigation of effect of drug loading on the EDS,hydrogels were also swollen in TER-HCl solutions. Percentage equilibrium mass swelling values of hydrogels in distilled water and in 1.25 and 3.75 mg/ml TER-HCl solution at ph 4.0 is given in Fig. 2. It is clearly seen from this figure that as a combined effect of increase in ionic strength of the solution and adsorption of TER in the gel system,and subsequent exclusion of water molecules,the EDS values show a sharp decrease and this effect becomes more pronounced at higher IA concentrations. When the concentration of drug in the swelling medium decreased from 3.75 to 1.25 mg/ml slight increase in the swelling values has been observed. An increase in ionic strength generally decreased the swelling because the difference in concentration of mobile ions between the gel and solution is reduced causing a decrease in the osmotic swelling pressure of these mobile ions inside the gel Deswelling of hydrogels For the investigation of deswelling kinetics of hydrogels,the loss of water with time was followed in the 4 45 C. Representative % water content versus time curves are given in Fig. 3. Fig. 3 depicts that the time required for almost complete dryness decreased approximately five times for every gel system by increasing temperature from 4 to 45 C. Fig. 1. Effect of ph on the equilibrium degree of swelling of P(VP/IA) hydrogels (solid curves are theoretical predictions). Fig. 2. Effect of TER-HCl on the equilibrium mass swelling of P(VP/IA) hydrogels.

4 754 M. Sßen, O. G uven / European Polymer Journal 38 (2002) Fig. 3. Variation of percentage water in the P(VP/IA) hydrogels with time,hydrogels initially swollen in pure water (deswelling temperatures are indicated on the figures). These curves indicate that due to increase of diffusion path with increasing of IA content lower water loss rates observed for hydrogels containing increasing amounts of IA at all temperatures. For a detailed comparison of deswelling behaviors, the time required for 50% and 80% water loss are considered. Fifty percent is the mid-value of deswelling and at 80% water loss,hydrogel systems almost reach dry state. The effect of IA content on the induction time values are given in Table 2. From a comparison of induction time values especially above 25 C it is seen that water loss behavior becomes almost independent of gel composition. This may be due to rapid loss of water from the subsurface layers at these high temperatures causing the formation of a skin at the surface retarding the further desorption of water Deswelling of TER-HCl adsorbed hydrogels As indicated above diprotic acid containing hydrogels may be used especially as local therapeutic transdermal delivery applications of cationic drug TER-HCl. For the investigation of TER-HCl on the deswelling behavior of hydrogels water loss was followed with time at 4 45 C temperature range. Variation of % water with time in these systems are given in Fig. 4. It is worth to note that presence of TER-HCl significantly reduced the EDS of these gels as was shown in Fig. 2. At first glance, one can notice that with the incorporation of TER-HCl into the hydrogels the time required to complete dryness is reduced and water loss becomes less dependent on the IA content of hydrogel system especially above 4 C. Reduced dependence of water loss on IA content can be explained again with relative insensitivity of water uptake capacity of hydrogels in TER-HCl solution. The relatively long times required for any extent of dryness at 4 C may be due to enhancement of some specific interactions between water and drug/hydrogel system at this temperature in addition to low driving force for desorption of water vapor. The variation of induction time for 50% and 80% water loss for TER-HCl adsorbed hydrogels are given in Table 2. For the investigation of drug concentration on the release of water from hydrogel systems,deswelling of hydrogels with TER-HCl loaded from 1.25 and 3.75 mg/ ml initial drug solution were investigated again in the 4 45 C. For 1.25 mg/ml drug loaded hydrogels the induction time values for 80% water loss at 25 C were found as 10.0,11.7,13.0,and 13.7 h for P(VP/IA)-1, P(VP/IA)-2,P(VP/IA)-3 and P(VP/IA)-4,respectively. These results are compared with the induction time values in Table 2 for 80% water loss from only water adsorbed hydrogels and TER-HCl adsorbed hydrogels from 3.75 initial solution as well. It was noticed that the water loss strongly depends on the presence of drug and IA content of the gels and induction time values of TER-HCl adsorbed hydrogels are very small compared with only water adsorbed systems. Very similar results were obtained for the other temperatures. This is probably due to lower affinity of

5 M. Sßen, O. G uven / European Polymer Journal 38 (2002) Table 2 Induction time values for 50% and 80% water loss from hydrogels Hydrogel Induction time (h) 50% water loss 80% water loss 4 C 25 C 37 C 45 C 4 C 25 C 37 C 45 C Swollen in distilled water P(VP/IA) P(VP/IA) P(VP/IA) P(VP/IA) Swollen in 3.75 mg/ml TER-HCl P(VP/IA) P(VP/IA) P(VP/IA) P(VP/IA) Fig. 4. Variation of percentage water in the TER-HCl adsorbed P(VP/IA) hydrogels with time (deswelling temperatures are indicated on the figures). water into hydrogel system in the presence of this cationic drug Release kinetics of water The study of water transport through hydrogels is important for the proper understanding of transport phenomena of aqueous solutes through these matrices. The release of drugs incorporated into hydrogels relies on the diffusion of water from these systems. In the trans dermal drug delivery systems higher drug loading is generally preferred for topical applications,the diffusion phenomena was therefore investigated for only maximum drug loading in this study. The diffusion coefficient of water can be calculated by various methods [15,16]. The short-time approximation method is used for the determination of diffusion coefficient of water. The shorttime approximation is valid for the initial 60% of deswelling. The diffusion coefficient of water from the cylindrical hydrogels is calculated by the following relation F ¼ M t =M 1 ¼ 4ðDt=pr 2 Þ 1=2 pðdt=pr 2 Þ ðp=3þðdt=pr 2 Þ 3=2 þ ð3þ

6 756 M. Sßen, O. G uven / European Polymer Journal 38 (2002) where, D is the diffusion coefficient, t the time and r the radius of cylindrical hydrogel sample. The diffusion coefficient of water was calculated from the slope of the lines of M t =M 1 vs. t 1=2. The results are listed in Table 3. The results obtained show that the diffusion coefficient is highly affected by the temperature and itaconic acid content of hydrogel system. From Table 3 it can be seen that the increase of temperature from 4 to 45 C causes an increase in the diffusion coefficient. However,the variation of diffusion coefficient is almost independent from IA content above 25 C in pure water and TER- HCl adsorbed hydrogels. Owing to the dependence of release rate on the geometry and thickness of the matrix and diffusion phenomena,the prediction of release kinetics of a prepared polymeric system is not easy and not absolutely correct. However,in order to estimate the release behavior of water from TER-HCl adsorbed hydrogels on human skin the release data in this study is used for the investigation of water loss kinetics and determination of initial water loss rate constant and order. We therefore analyzed water loss-time curves by introducing a wide Table 3 Diffusion coefficients of deswelling Hydrogel Diffusion coefficient (D) (m 2 /s) C 25 C 37 C 45 C Swollen in distilled water P(VP/IA) P(VP/IA) P(VP/IA) P(VP/IA) Swollen in 3.75 mg/ml TER-HCl P(VP/IA) P(VP/IA) P(VP/IA) P(VP/IA) range of mathematical relations by a computer program. For all gel systems studied,the best correlation with the deswelling data was observed by using the following variable order decay equation. y ¼ a þðb ð1 dþ þ cxd cxþ 1=ð1 dþ ð4þ where a and b are constants and c denote the release rate constant and d is the water loss order (decay). Here, y denotes the amount of water released from the gel at time t and x stands for the time. Water loss order was found between 0.49 and The variation of initial water loss rate constant with IA content and temperature are given Fig. 5a and b for pure water and TER- HCl adsorbed hydrogel systems. As can be seen from the figures for each hydrogel system the increase of temperature rapidly decreases the rate constant. However, the variation of rate constant is almost independent from IA content or swelling above 25 C. Loss of water from hydrogels in contact with human skin was also investigated and very similar loss trend has been observed with water loss at 25 C in open air. The water loss studies with TER-HCl adsorbed hydrogels on human skin could not be achieved yet due to uncertification of prepared hydrogel systems. On the other hand in order to obtain an idea about release rate of water from TER-HCl adsorbed hydrogels,the variation of pure water release rate constant with IA content at 25 C is compared with water release rates from TER-HCl adsorbed hydrogels in open air at 25 C (Fig. 5a). As can be seen from the figure the initial rate constant of water release from TER-HCl adsorbed hydrogels is slightly lower than the release rate constant at 25 C in open air and water release rate constant slightly decreases with IA content for TER-HCL adsorbed hydrogels. From a comparison of Fig. 5a and b we can expect similar water loss rates from TER-HCl adsorbed hydrogels on human skin as at 25 C in open air. To conclude,10 h induction time for 80% water loss at 25 C in open air for TER-HCl adsorbed hydrogel Fig. 5. Effect of IA content and temperature on the initial water loss rate constant of pure water (a) and TER-HCl (b) adsorbed P(VP/IA) hydrogels.

7 M. Sßen, O. G uven / European Polymer Journal 38 (2002) systems denotes that the P(VP/IA) hydrogels prepared in this study can be considered as potential carriers for the drug delivery systems and may be used especially for local therapeutic applications of cationic drugs as trans dermal delivery systems. By increasing the cross-link density of the gels by increasing the irradiation dose it would be possible to extend these induction times beyond those values reported here. Acknowledgements The authors gratefully acknowledge the support provided by the International Atomic Energy Agency through the Research contract no: 9076/R2. References [1] Peppas NA,Nicos AG. In: Peppas NA,editor. Hydrogels in medicine and pharmacy. Boca Raton: CRC Press; [2] Tsuruta T,Hayashi T,Kataoka K,Ishihara K,Kimura Y. Biomedical applications of polymeric materials. Boca Raton: CRC Press; [3] Karadag E,Saraydın D, Oztop HN,G uven O. Polym Adv Technol 1994;5:664. [4] Karadag E,Saraydın D,Cß etinkaya S,G uven O. Biomaterials 1996;17:67. [5] Saraydın D,Karadag E, G uven O. Polym Adv Technol 1994;6:719. [6] Sßen M,G uven O. Radiat Phys Chem 1999;55:113. [7] Sßen M,Uzun C,G uven O. Int J Pharma 2000;203:149. [8] Balfour JA,Faulds D. Drug 1992;43:259. [9] Yakar A. MS Thesis,Hacettepe University,Ankara,Turkey,2000. [10] Sßen M,Kantoglu O,G uven O. Polymer 1999;40:913. [11] G uven O,Sßen M. Polymer 1991;32:2491. [12] Sßen M,G uven O. Polymer 1998;39:1165. [13] Weast RC,editor. Handbook of chemistry and physics, 53rd ed. Ohio: The Chemical Rubber Co; [14] Sßen M,Yakar A,G uven O. Polymer 1999;40:2696. [15] Crank J. Mathematics of diffusion. New York: Academic Press; [16] Li Y,Tanaka J. J Chem Phys 1990;92:1365.