Research Paper Taste Masking of Topiramate by Newer Range of Ion-Exchange Resin

Transcription

1 T.N. Patel, et.al. : Taste Masking of Topiramate by Newer Range of Ion-Exchange Resin 1105 International Journal of Pharmaceutical Sciences and Nanotechnology Volume 3 Issue 3 October - December 2010 Research Paper Taste Masking of Topiramate by Newer Range of Ion-Exchange Resin T.N. Patel 1,*, R.P. Patel 1, B.V. Patel 2 1 S. K. Patel College of Pharmaceutical Education and Research, Kherva, India. 2 ASTRON Research Limited, Ahmedabad, India. ABSTRACT: Topiramate, is an anti-epileptic drug used to treat partial onset seizures, or primary generalized tonicclonic seizures in children and adults. But its bitter taste became a critical issue which strongly demanded to mask the taste. Different types of ion exchange resins like Kyron T-104, Kyron T-114, Kyron T-134, Doshion P 542 were used to form complex with Topiramate. Ion exchange resin to drug ratio, effect of ph, effect of temperature, effect of resin soaking time, effect of stirring time on complex formation were optimized. Drug-resin complex was evaluated for swelling, particle size analysis and drug release from drug-resin complex. Developed taste masked drug candidate in this research work become eligible to formulate mouth disintegrating dosage form. KEY WORDS: Topiramate; taste masking; ion-exchange resin; Drug-resin complex; Kyron; Doshion Introduction The last two decades in the pharmaceutical industry have witnessed an avant-garde interaction among the fields of polymer and material science, resulting in the development of novel drug delivery systems. In recent years, considerable attention has been focused on developing new technology for the masking of bitter taste of drug. Today most of the drugs are unpalatable and unattractive in their natural state but modern pharmaceutical preparation present them to patient as colorful, flavorful formulation attractive to sight smell and taste. Topiramate (TOP) is an anti-epileptic class of drug used to treat partial onset seizures, or primary generalized tonic-clonic (Goodman & Gilman A, 2006) seizures in both children and adults. In children it is also indicated for treatment of Lennox-Gastaut syndrome (Rang & Dale M, 2007) (a disorder that causes seizures and developmental delays). Generally dose varies from 25 mg to 400 mg according to age of the patient. Doses above 400 mg/day (600, 800, or 1,000 mg/day) have not been shown to improve responses in dose-response studies in adults with partial onset seizures (Goodman & Gilman A, 2006). Topiramate is a white crystalline powder material with very bitter taste. IUPAC name is 2,3,4,5-Di-O- Isopropylidene-ß-D-Fructopyranose Sulfamate (Rang & Dale M, 2007), it s molecular formula is C 12 H 21 NO 8 S and * For correspondence: T.N. Patel, tanmay128@gmail.com molecular weight is It is most soluble in alkaline solutions containing sodium hydroxide or sodium phosphate, freely soluble in acetone, chloroform, dimethylsulfoxide, ethanol and sparingly soluble in water. Half-life of the drug is hours (Goodman & Gilman A, 2006). Selection of tasking masking approach (Koizumi et al., 1997) had become a very crucial and important issue. Varieties of the approaches were available like ionexchange resin (Anand et al., 2001; Koizumi et al., 1997), numbing the taste buds (Mennella et al., 2005), inclusion complexes with beta cyclodextrin (Fernandes & Veiga, 2002; Sjovall J., 1984) derivatives etc. Ion exchange resin proved a great role in masking of bitter taste. For this study, four different ion exchange resins were exercised and optimized by different ion-exchange resin to drug ratio. Finally, the taste masked drug was checked for taste sensation on human volunteer. Material and Method Material Topiramate was procured from Intas Pharmaceutical, Ahmedabad, Gujarat, India. Ion exchange resin; Kyron T- 104, Kyron T-114, Kyron T-134 were obtained as a gift sample from Corel Pharma Chem, Ahmedabad, Gujarat, India. Doshion P-542 was procured from Akhil Healthcare Ltd., Vadodara, Gujarat, India. All the reagents and chemical used were analytical grade. 1105

2 1106 International Journal of Pharmaceutical Sciences and Nanotechnology Volume 3 Issue 3 October-December 2010 Table 1 Compositions of different Drug-resin formulations. Drug/Resin Quantity for each tablet (mg) Topiramate Kyron T Kyron T Kyron T Doshion P Formulation of Drug-Resin Complex (DRC) Accurately weighed 30 gm of resin (table 1) was dispersed in a beaker containing 300 ml of demineralised water and allowed to swell for minutes. The ph of resin solution was adjusted to by using 1 M KOH. Accurately weighed 10 gm of Topiramate was added slowly and stirred for 3-4 hr. During stirring, ph of solution was measured frequently and adjusted to by using 1 M KOH. After 3-4 hr, the drug resin complex (DRC) was separated from dispersion by filtration and washed with three portions of 75 ml of demineralised water. Complex was dried and then evaluated for taste and drug-loading efficiency (Nanda et al., 2002). Optimization Effect of Drug-Resin Ratio on complex formation Ratio of drug to resin can greatly impact on complex formation and ultimately affects taste masking ability. It was necessary to find out the optimum drug to resin ratio. To optimize the ratio, different proportion of drug to resin was taken as mentioned in Table 1. As per different proportion, drug-resin complex was formed as shown in procedure which was mentioned earlier. Effect of ph on complex formation Seven batches were prepared by dispersing 3 gm of resin in 30 ml of demineralised water for 30 min. ph of all batches were adjusted up to 4, 5, 5.5, 6, 6.5, 7 and 8, respectively, by using 1 M KOH maintained at room temp. TOP (1 gram) was added to each mixture, and then common procedure as mentioned earlier was followed. Finally the drug-loading efficiency was estimated. Table 2 Effect of ph on drug loading efficiency. ph % Drug loading ± ± ± ± ± ± ± 1.03 Effect of temperature on drug loading Resin (3 gm) was dispersed into 30 ml of demineralised water, was stirred for 30 min. The ph of resin solution was adjusted to 7 and 1 gm drug was added and stirred for 4 hr at room temperature. The same process was performed at 40, 50, 60, 70 and 80 C using temperature-controlled magnetic stirring for 4 hr. The drug loading efficiency was estimated by using HPLC. Table 3 Effect of temperature on drug loading. Temperature ( o C) % Drug loading ± ± ± ± ± ± 1.63 Effect of soaking time of resin on drug loading Seven different batches of Kyron T-114 were prepared by soaking 3 gm of resin into 30 ml of demineralised water for 0, 10, 20, 30, 60, 90 and 120 minutes, respectively. The ph of all batches were adjusted to 7 and now one gm of TOP was added to each batch and stirred for 4 hr. Drug loading efficiency of swollen resin for different time period was determined. Table 4 Effect of resin soaking time on drug loading. Time (min) % Drug loading ± ± ± ± ± ± ± 1.51

3 T.N. Patel, et.al. : Taste Masking of Topiramate by Newer Range of Ion-Exchange Resin 1107 Effect of stirring time on drug loading Seven different batches of Kyron T-114 were prepared by soaking 3 gm of resin into 250 ml of demineralised water for 30 min. After adjusting the ph 7, 1 gm TOP was added with continuous stirring to resin dispersion and samples were withdrawn at regular intervals of 60 min up to 5 hr. Each sample was analyzed by using HPLC to find drug loading efficiency. Table 5 Effect of stirring time on drug loading. Time (hr) % Drug loading ± ± ± ± ± 1.43 Evaluation of Drug Resin Complex Taste Evaluation Taste was evaluated by recognized human volunteers panel. Volunteers in the age group of 20 to 30 years performed taste evaluation of DRC. The study protocol was explained and taste opinion was obtained from volunteers. In taste evaluation study, DRC equivalent to 50 mg of Topiramate was held in the mouth for 15 seconds by each volunteer and the bitterness level was recorded against pure drug. Table 6 Taste Evaluation of different DRC formulations. Resin Kyron T-134 Kyron T-114 Kyron T-104 Doshion P 542 Drug-Resin Ratio Bitterness Level 1:2 * 1:3 * 1:4 ** 1:2 *** 1:3 **** 1:4 **** 1:2 * 1:3 ** 1:4 ** 1:2 * 1:3 * 1:4 * Where, *: Extremely Bitter; **: Moderately Bitter; ***: Slightly Bitter & ****: Not Bitter Particle size analysis & Swelling study of resin and DRC The size was measured using an optical microscope (Labomed CX RIII, Ambala, India), and the mean particle size was calculated by measuring size of 200 particles with the help of a calibrated ocular micrometer (Fu et al., 2004). The slide containing Kyron T-114 resin particles was mounted on the stage of the microscope and diameter of at least 100 particles was measured using a calibrated optical micrometer. Photomicrographs (10 x magnifications) of resin and drug resin complex were taken in non-swelling as well as swelling conditions. Two gm of resin was taken in a 10 ml measuring cylinder. The initial height was noted and the volume was made up to 10 ml with distilled water. The cylinder was kept undisturbed and maximum swelling was recorded. Same procedure was repeated for 0.1 N HCl and Phosphate buffer ph 6.8 (salivary ph). Table 7 Particle size of non-swollen & swollen resin and DRC. Material Particle Size (µm) Non swollen Kyron T ± 3.5 Swollen Kyron T ± 3.7 Non swollen DRC 41 ± 3.9 Swollen DRC 53 ± 4.2 Drug release from DRC Drug release from DRC (1:4) in 0.1 N HCl was determined using a USP type II dissolution apparatus. Accurately weighed DRC equivalent to 50 mg of Topiramate was added to 900 ml 0.1 N HCl for 60 minutes (100 rpm, 37 C). A 10-ml sample was withdrawn, filtered and analyzed. Drug release from the DRC was also performed in 10 ml of ph 6.8 buffer solution (simulated saliva fluid) by adding 50 mg of the DRC to a test tube, shaken for 60 seconds, filtered and filtrate was assayed for drug (Augello et al., 2000). Table 8 Drug release data of DRC in 0.1N HCl. Time (min) % Drug Release ± ± ± ± ± ± ± ± ± 2.60

4 1108 International Journal of Pharmaceutical Sciences and Nanotechnology Volume 3 Issue 3 October-December 2010 Results and Discussion Effect of Drug-Resin Ratio on complex formation Table 1, shown earlier depicts four ion exchange resins, Kyron T-104, Kyron T-114, Kyron T-134, Doshion P 542 in different proportion. Drug to resins were used in different proportion like 1:2, 1:3 and 1:4 respectively. By taking all the proportion into consideration, Kyron T-114 shown best result compared to others. The optimized ratio for Drug:Kyron T-114 was 1:3 respectively. Effect of ph on Drug Loading Efficiency Above shown table 4 depicts the effect of ph of resin dispersion on the % drug loading. The complexation was enhanced with increasing ph from 4 to 7. A maximum of 91.21% drug loading was obtained at ph 7 (near to pka of Topiramate). As shown in Fig. 3, as ph increased above 7, the percentage drug loading decreased. The ph of the solution affects both solubility and the degree of ionization of drug and resin. The results can be attributed to the fact that Topiramate has a pka between 8.6 and 8.8 and hence will have maximum solubility and complete ionization in this range. The decreased complexation at lower ph is due to excess H + ions in the solution, which have more binding affinity to the COO - groups of resin and compete with the drug for binding (Augello et al., 2000). Effect of Temperature on Drug Loading Efficiency Efficient drug loading on Kyron T-114 occurred uniformly in the experimental temperature range of 27ºC to 80ºC as shown in table 5. Higher temperatures tend to increase the diffusion rate of ions by decreasing the thickness of exhaustive exchange zone. Topiramate is a water-soluble drug with a pka of 8.6 to 8.8 that has potential at operational ph to be completely ionized. The continuous stirring in process does not allow the development of thick exchange zones so temperature may not show any effect on Topiramate- Kyron T-114 complexation (Nanda et al., 2002). Effect of Resin Soaking Time on Drug Loading Results of effect of soaking time on drug loading are shown in Table 4. The results reveal that a 30-minute swelling time of Kyron T-114 in demineralised water gave the maximum Topiramate loading of 92.21% wt/wt. This may result of maximum swelling and hydrating properties of Kyron T-114 that affect the rate of ion exchange. Less drug-loading efficiency may be observed in unswollen resin matrix because the exchangeable groups of resin are latent and coiled toward the backbone. Effect of Stirring Time on Drug Loading The equilibrium ion exchange in solution occurs stoichiometrically and hence is affected by stirring time. The percentage drug loading (wt/wt) with a stirring time of 0.5 to 5 hr was observed from Table 5. Increasing the stirring time above 4 hr did not further increase the complexation values. Hence, 4 hr contact time between drug and resin could be optimized to equilibrate the ion exchange process to achieve maximum drug loading. This study indicated that the optimum ion exchange could be completed in a period of 4 hr. Taste Evaluation Taste evaluation of Drug-Resin Complex in volunteers confirmed that the taste of Topiramate was successfully masked by complexing it with Kyron T-114 with 1:3 ratio of drug to resin. All the volunteers had shown that DRC was tasteless and agreeable. Also the DRC was stable in salivary ph for a period of administration. The efficiency of resin could be checked by bitterness level of DRC. The bitterness level was divided into four different categories like extremely bitter, moderately bitter, slightly bitter and no bitter (table 8). Particle size analysis & Swelling study of Resin and DRC As described in table 2, the particle size of Kyron T114 in normal and swollen condition was measured microscopically. The mean particle size of Kyron T-114 particles was 30 ± 5 µm, which is in confirmation with the reported size (<75 µm), which presents an enormous surface area of ion exchange resin that is useful for taste masking. Substantially small size particles are difficult to process and particles greater than 200 µm have a tendency to fracture. Kyron T-114 is highly porous, and even though insoluble in water, it is capable of hydration (Augello et al., 2000). A higher degree of swelling is suggestion of the fact that on hydration, the resin is producing a swollen porous network structure that is capable of allowing the drug molecules to permeate /diffuse inside and also get complexed with the resin. Fig. 1 shows the photomicrograph of non swollen and swollen Kyron T 114 particles in distilled water while Fig. 2 shows the photomicrograph of non swollen and swollen DRC in distilled water.

5 T.N. Patel, et.al. : Taste Masking of Topiramate by Newer Range of Ion-Exchange Resin 1109 A B Where, A: Non-swollen Kyron T-114 & B: Swollen Kyron T-114 Fig. 1 Photomicrograph of non-swollen Kyron T-114 & swollen Kyron T-114. A B Where, A: Non-swollen DRC & B: Swollen DRC Fig. 2 Photomicrograph of non-swollen drug resin complex and swollen drug resin complex. Fig. 3 Effect of ph on drug loading efficiency.

6 1110 International Journal of Pharmaceutical Sciences and Nanotechnology Volume 3 Issue 3 October-December 2010 Drug Release from DRC Topiramate release from drug-resin complex was observed in average salivary ph of 6.8, and at gastric ph of 1.2, separately. In vitro drug release in average salivary ph of 6.8 was 2.39% (< 3%) within 60 seconds. The presence of exchangeable ions of ionizable electrolytes in the salivary fluid may be responsible for this release. The DRC is stable in salivary ph for a period of administration. Thus it provides better taste masking. At gastric ph (1.2), 90% of Topiramate were released within 10 minutes (table 3). The hypothesis that the drugrelease equilibrium, similar to drug loading, is highly dependent on the physiological ph can be applied for taste masking without affecting the dosage form characteristics. Conclusion In the present study, an attempt was performed to mask bitter taste of Topiramate by different Ion-exchange resin. Upon exercising with various Ion-exchange resin, Kyron T-114 (Cation exchange resin) with Drug-Resin ratio of 1:3 was found to offer best taste masking. This approach can be used for taste masking of bitter pharmaceutical ingredients and can make it eligible to formulate mouth disintegrating dosage form. Acknowledgement Authors are very much thankful to ASTRON Research Center, Ahmedabad, Gujarat, INDIA for permission and all facilities for successful completion of this research work. References Anand V, Raghupathi K, Garg S. Ion-Exchange resins: carrying drug delivery forward, Drug Discovery Today. 6: (2001). Augello M, Dell SM, Reier GE, Stamato HJ, DiMemmo LM, U.S. Patent, , Fernandes CM, Veiga FJ. Effect of hydrophobic nature of triacetyl-β-cyclodextrin on the complexation with nicardipine hydrochloride: physicochemical and dissolution properties of the kneaded and spray-dried complexes. Chem Pharm Bull (Tokyo). 50: (2002). Fu Y, Yang S, Jeong SH, Kimura S, Park K. Orally fast disintegrating tablets: developments, technologies, tastemasking, and clinical studies. Critical Reviews in Therapeutic Drug Carrier Systems. 21(6): (2004). Goodman L., Gilman A., Goodman & Gilman s the pharmacological basis of therapeutics 11: (2006). Koizumi K, Watanabe Y, Morita K, Utoguchi N. New method for preparing high porosity rapidly saliva soluble compressed tablets using mannitol with camphor, a subliming material. International Journal of Pharmaceutics, 152: (1997). Mennella J, Pepino Y, Reed D. Genetic and Environmental Determinants of Bitter perception and sweet perception, Journal of Pediatrics, 115(2): (2005). Nanda A, Kandarapu R, Garg S. An update on oral taste masking technologies for oral pharmaceuticals. Indian Journal Pharmaceutical Science, 64: (2002). Rang H. and Dale M., Rang & Dale's pharmacology, 6: (2007). Sjovall J. Methods for evaluating the taste of pediatrics formulations in children: A comparison between the facial hedonic method and the patients own spontaneous verbal judgement, European Journal of Pediatrics, 8: (1984).