Available online at wwwscholarsresearchlibrarycom Scholars Research Library Der Pharmacia Lettre, 215, 7 (3):114-123 (http://scholarsresearchlibrarycom/archivehtml) ISSN 975-571 USA CODEN: DPLEB4 Feasibility of using natural gums for development of sustained release matrix tablet of itopride Nandita Deb, Suresh V Kulkarni and Ashok Kumar P Department of Pharmaceutics, Sree Siddaganga College of Pharmacy, Tumkur, Karnataka, India ABSTRACT The objective of this research work was to check feasibility of using natural gums for development of sustained release matrix tablets of Itopride in view to improve patient compliance and therapeutic action Matrix tablets were prepared by direct compression method by using natural polymers like xanthan gum, guar gum, karaya gum, locust bean gum, neem gum as matrix forming agent and excipients such as magnesium stearate, MCC, PVP and talc were used The dissolution medium consisted of 9 ml of 1 N HCl for first 2 hours and then 74 phosphate buffer for remaining 1 hours All the tablet formulations showed acceptable pharmacokinetic properties and complied with in-house specifications for tested parameters Stability studies were performed for optimised formulation as per ICH guidelines which show that formulations were stable after three months of short term stability studies The formulation was optimized on the basis of acceptable tablet properties and in-vitro drug release Formulation F-6 was successfully sustained the release of drug upto 12 hours The kinetic treatment of selected optimized formulation shows that the regression coefficient for zero-order kinetics were found to be higher when compared with those of the first-order kinetics, indicating that drug release from all the formulations followed zero-order kinetics and the n value lies between 76-85 (Korsmeyer-Peppas model) demonstrating that the mechanism controlling the drug release was Anomalous (non-fickian) diffusion Optimized formulation was tested for their compatibility with Itopride by FT-IR studies, which revealed that there is no chemical interaction occurred with polymer and other excipients The drug release profile of the best formulation was well controlled and uniform throughout the dissolution studies Keywords: Xanthan gum, Guar gum, Karaya gum, Locust bean gum, Neem gum, Magnesium stearate, MCC, PVP, Talc, Matrix tablets, Direct compression method, Sustained release INTRODUCTION The oral route is the most often used for administration of drugs Tablets are the most popular oral formulations available in the market and are preferred by patients and physicians alike In required to be administered in multiple doses and therefore have several disadvantages [1] Extended release formulations are preferred for such therapy because they maintain uniform drug levels, reduce dose and side effects, better patient compliance, and increase safety margin for high potency drugs [2] Itopride hydrochloride is an oral prokinetic agent used in the treatment of gastric motility disorder It is benzamide derivative, absorbed from gastrointestinal tract Itopride hydrochloride activates the gastrointestinal motility through synergism of its dopamine D 2 - receptor antagonistic action and its acetylcholine esterase-inhibitory action In addition to these actions, itopride has an antiemetic action, which is based on its dopamine D 2 -receptor antagonistic action The short biological half-life (6 hrs), 6 % bioavailability and dosage frequency more than once a day (5 mg tid) makes the itopride hydrochloride an ideal candidate for the controlled drug delivery systems [3, 4] 114
The matrix tablets composed of drug and the release retarding material offers the simplest approach in designing an extended release system [5] MATERIALS AND METHODS The chemicals used in this study were pure drug like Itopride ( Symed labs,hyderabad) and polymers like Xanthan gum, Guar gum, Karaya gum, Locust bean gum, Neem gum (SD Fine Chem Limited, Mumbai) and other excipients like Magnesium stearate, MCC, PVP, Talc, (Yarrowchem Products, Mumbai) Preparation of matrix tablets The drug and excipients of table 1 were passed through a 6 # size mesh prior to the preparation of the dosage form The entire ingredient are weighed separately and mixed thoroughly for 1 mints to ensuring uniform mixing in geometrical ratio 5 mg of the powder mix was accurately weighed and fed into the die of ten station rotary tablet machine (Shakti Pharmatech Pvt Ltd Ahmedabad) and compressed at 6±5 Kg/cm 2 compression force using 12 mm flat punches Evaluation of matrix tablets [6] The matrix tablets of itopride hydrochloride were evaluated for pre compression parameters such as angle of repose, % compressibility index, and post compression parameters such as hardness (Monsanto hardness tester), weight variation, content uniformity, percentage friability (Roche friabilator), thickness (Vernier caliper) Drug content of matrix tablets was determined by weighing and finely grinding 1 tablets of each batch Aliquot of this powder equivalent to 15 mg of itopride hydrochloride was accurately weighed, suspended in approximately 5 ml of phosphate buffer ph 74 and shaken for 15 min final volume was adjusted to 1 ml with phosphate buffer and filtered The suitable dilutions were made and absorbance recorded at 256 nm In-vitro release[7] In-vitro drug release studies were carried out using USP XXII dissolution apparatus type II (Electrolab, Mumbai, India) at 5 rpm The dissolution medium consisted of 9 ml of ph 12 for first two hrs and ph 74 phosphate buffers for next 1 hrs, maintained at 37 + 5 C The drug release at different time intervals was measured using an ultraviolet visible spectrophotometer (Labindia, Mumbai, India) at 256 nm The study was performed in triplicate Kinetic study [8] The release of drug from extended release dosage form is regulated by several processes These are extraction or diffusion of drug from matrix and erosion of matrix, alternatively the drug may be dissolved in the matrix material and then released by diffusion through membrane In some cases, drug may be released by osmotic process Different kinetic equations (Zero order, First order, Higuchi and Korsemeyer Peppas equation) were applied to interpret the release rate from the tablet matrix Fourier Transform Infrared Spectroscopy (FTIR) study[9] FTIR spectra of the selected formulation were taken and compared with the spectrum of pure drug The characteristic peaks of drug were checked in the formulation spectra Table 1: Tablet composition of Itopride sustained release matrix tablets prepared with different release retardant natural matices (F-1 to F-12) FORMULATION F1 F2 F3 F4 F5 F6 F7 F8 F9 F1 F11 F12 CODE DRUG 15 15 15 15 15 15 15 15 15 15 15 15 XANTHAN GUM 3 - - - - 15 15 15 - - 15 - GUAR GUM - 3 - - - - - 15 15 15-15 LOCUST BEAN GUM - - 3 - - 15 - - 15 - - - KARAYA GUM - - - 3 - - 15 - - 15 - - NEEM GUM - - - - 3 - - - - - 15 15 MCC 1 1 1 1 1 1 1 1 1 1 1 1 PVP 25 25 25 25 25 25 25 25 25 25 25 25 MAGNESSIUM STEARATE 1 1 1 1 1 1 1 1 1 1 1 1 TALC 5 5 5 5 5 5 5 5 5 5 5 5 ( -) indicates NIL RESULTS AND DISCUSSION All the batches were evaluated for pre and post compression parameters and found within acceptable limits The 115
Carr s Index (Compressibility) of the powders was in the range of 854 ± 75 to 1163 ± 163 The angles of repose of the powders were in the range of 2419 ± 141 to 2945 ± 152, which indicate a good flow property of the powders Here the angle of repose was found to be below 4 o C this shows that the reasonable flow property of powders The results are given in (table-2&3) The hardness of the tablets was found to be in the range of 57 ± 33 to 69 ± 24 It was within the range of monograph specification Thicknesses of the tablets were found to be in the range of 356 ± 12 to 39 ± 12 The friability of the tablets was found to be less than 1% and it was within the range of standard specification The results are given in (table-4) Prepared tablets were evaluated for weight variation and the results are given in table 4 Percentage deviation from the average weight was found to be within the prescribed official limits The drug content for all the batches was found to be in the range of 9879 to 198 The results are given in (table-4) The drug release at different time intervals was measured using an UV spectrophotometer (Labindia, Mumbai, India) at 256 nm The results were evaluated for 12 hrs As per the results of dissolution study formulations F-1, F-2, F-3, F-4, F-5, F-6, F-7, F-8, F-9, F-1, F-11 and F-12, showed 9827, 9826, 9827, 9826, 9827, 9828, 9645, 9462, 9463, 9644, 9645, and 9278 respectively This showed that the drug release from the tablet was sustained for 1 to 12 hrs The results are given in (table5&6) Table 2: Granules properties of formulations F1 to F6 of Itopride sustained release matrix tablets PARAMETERS FORMULATION CODE F1 F2 F3 F4 F5 F6 Angle of repose 252±132 2622 ± 178 2715±154 2419±141 252±171 2715±154 Loose bulk Density 284±4 262±3 254±2 299±6 324±4 296±4 (LBD)(g/ml) Tapped bulk density (TBD) 295±19 269±15 276±18 289±14 322±11 284±11 (g/ml) Compressibility 146±131 1123±151 165±144 971±133 1163±163 119±126 index (%) Table 3: Granules properties of formulations F7 to F12 of Itopride sustained release matrix tablets PARAMETERS Angle of repose FORMULATION CODE F7 F8 F9 F1 F11 F12 2622±178 2945±152 2812±157 2564±121 2422±132 2715±141 Loose bulk Density 262±3 294±9 279±6 276±6 254±5 284±4 (LBD)(g/ml) Tapped bulk density (TBD) 289±14 235±12 295±16 296±12 273±13 322±11 (g/ml) Compressibility 971±133 12±148 1156±78 994±164 854±75 1163±163 index (%) 116
Table 4: Tablet properties of formulations F1 to F12 of Itopride sustained release matrix tablets Formulation Code Thickness (mm) Hardness (Kg/cm 2 ) Parameters Friability (%) Weight Variation (mg) Drug content (%) F-1 356 ± 12 59 ± 11 15 ± 17 4993±915 9912 F-2 363 ± 17 66 ± 22 2 ± 45 4989±998 9912 F-3 371 ± 3 58 ± 14 31 ± 28 4979±978 9899 F-4 379 ± 7 6 ± 7 22 ± 12 4995±991 165 F-5 382 ± 12 6 ± 38 4 ± 34 4995±991 9998 F-6 389 ± 1 67 ± 19 45 ± 28 4992±985 994 F-7 39 ± 12 69 ± 24 32±9 4991±919 19 F-8 366 ± 17 57 ±33 52±2 4979±999 9879 F-9 37 ± 148 69 ± 12 28±1 4985±983 152 F-1 376 ± 151 63 ±45 41±6 4998±897 9999 F-11 38 ± 165 58 ± 12 39±4 4986±959 198 F-12 386±129 66 ± 37 49± 8 4991±987 18 Each value represents as mean±sd of three determinants Table 5: Percentage drug release of formulations (F1 F6) Time (hrs) FORMULATION CODE F-1 F-2 F-3 F-4 F-5 F-6 1 132 78 132 96 174 168 2 251 187 2594 2956 3318 1869 3 2967 359 3875 4843 4422 2419 4 3334 4423 5149 5396 5152 3871 5 3879 5152 576 6545 6484 466 6 4244 6122 6849 7457 7275 5938 7 4427 6851 782 8367 8547 6669 8 5937 8182 8791 9277 997 7397 9 7453 8552 946 9463 9281 8728 1 8367 8916 9645 9826 9644 946 11 9639 9461 9827-9827 9826 12 9827 9826 - - - 9828 Table 6: Percentage drug release of formulations (F7 - F12) Time (hrs) FORMULATION CODE F-7 F-8 F-9 F-1 F-11 F-12 1 15 15 132 24 114 144 2 2232 2413 3137 2775 251 3137 3 2787 315 459 448 3329 424 4 4842 4482 5211 5394 3698 468 5 5396 5213 5941 6666 4967 5395 6 663 5941 6488 7276 632 634 7 732 731 7275 84 733 733 8 7821 7278 7642 8913 764 7278 9 855 7823 8368 999 992 7461 1 8916 8731 981 941 9281 85 11 9461 998 9281 943 9463 8551 12 9645 9462 9463 9644 9645 9278 117
DRUG RELEASE PROFILE %CDR 12 1 8 6 4 2 F-1 F-2 F-3 F-4 F-5 F-6 2 4 6 8 TIME(HRS) 1 12 14 Figure1: In Vitro release Profile of F-1 to F-6 Formulations 12 DRUG RELEASE PROFILE 1 8 F-7 % CDR 6 4 2 2 4 6 8 1 12 14 TIME(HRS) F-8 F-1 F-11 F-12 Figure2: In Vitro release Profile of F-7 to F-12 Formulations Different models like Zero order, First order, Higuchi s and Peppas or Korsemeyer et al s plots were drawn The regression coefficient (R 2 ) value for Zero order, First order, Higuchi s and Peppas or Korsemeyer et al s plots (Figure36-39 ) for best formulation F-6 were found to be 98, 867, 963, and 953 respectively The slope (n) value of Peppas or Korsemeyer et al s plots for best formulation F-6 were found to be 83 The n value lies between 76-85 (korsemeyer-peppas model) demonstrating that the mechanism controlling the drug release was Anomalous (non-fickian) diffusion Thus orally sustained itopride matrix tablets, delivers the drug through a complex mixture of diffusion, swelling and erosionthe regression coefficient for zero-order kinetics were found to be higher when compared with those of the first-order kinetics, indicating that drug release from all the formulations followed zero-order kinetics The results are given in (table-7&8) 118
Table 7: Model fitting for formulation F-6 Time(hrs) % CDR Log of % drug unreleased Log time SQRT Log % CDR 1 168 192123 1 122539 2 1869 191143 313 1414214 127169 3 2419 1879726 477121 173251 1383635 4 3871 1787389 626 2 1587823 5 466 173191 69897 223668 1663323 6 5938 168739 778151 244949 177364 7 6669 1522574 84598 2645751 18246 8 7397 1415474 939 2828427 186955 9 8728 114487 954243 3 194914 1 946 732393 1 3162278 1975891 11 9826 24549 141393 3316625 1992376 12 9828 235528 179181 346412 1992465 12 ZERO ORDER KINETICS y = 85286x + 4868 R² = 981 1 8 %CDR 6 4 2 2 4 6 8 1 12 14 TIME(HRS) Figure3: Zero order kinetic of in vitro release data of formulation F -6 FAST ORDER KINETICS LOG OF % DRUG UNRELEAS 25 2 15 1 5 y = -161x + 23871 R² = 8675 2 4 6 8 1 12 14 TIME (HRS) Figure4: First order kinetic of in vitro release data of formulation F -6 119
12 1 8 HIGUCHI PLOT y = 3952x -34943 R² = 9639 %CDR 6 4 2 5 1 15 2 25 3 35 4 SQRT TIME Figure5: Higuchi plot of in vitro release data of formulation F -6 25 2 PEPPAS MODEL LOG %CDR 15 1 5 2 4 6 8 1 12 LOG TIME Figure6: Peppas model of in vitro release data of formulation F -6 Table 8: Correlation coefficients of different kinetic models for sustained release matrix tablet of Itopride FORMULATION ZERO RDER FIRST ORDER HIGUCHI PEPPAS R 2 R 2 R 2 R 2 n value F1 989 84 975 991 812 F2 99 778 995 974 799 F3 995 843 978 997 842 F4 99 778 969 993 832 F5 993 771 974 99 798 F6 98 867 963 953 839 F7 999 775 99 978 859 F8 997 799 983 983 849 F9 98 67 987 961 761 F1 865 845 912 987 845 F11 987 798 843 798 798 F12 789 745 877 899 792 Drug polymer interaction was checked by comparing the IR spectra of the formulations with the IR spectra of the pure drug There was no significant change in the functional groups between the IR spectrums of the pure drug and 12
also no additional peaks were seen in the selected formulations (figures: 7-12) This confirms that no interaction between drug and excipients Figure 7: FT-IR of Itopride Figure 8: FT-IR of Xanthan gum Figure 9: FT-IR of Locust bean gum 121
Figure 1: FT-IR of Itopride+Xanthan gum Figure 11: FT-IR of Itopride+Locust bean gum Figure 12: FT-IR of Optimised Formulation F6 Stability Study: Stability studies were carried out on selected formulations (F6) as per ICH guidelines There was no significant changes in drug content, physical stability, hardness, friability and drug release (Table 9-11) for the selected 122
formulation F-6 after 9 days at 4 C ± 5 / 75% ± 5% RH Therefore the main objective of the study to design and evaluate the matrix tablets of a Itopride drug using natural polymers as a retardant was achieved Table 9: Physical appearance of all optimised formulation with excipients after stability studies F6 Temp and relative humidity Days Parameters 15 3 45 6 75 9 4 C± 5 C / 75% ± 5% RH No change in physical appearance Physical appearance Table 1: Percentage Drug content of the optimised formulation prepared with, locust bean gum and xanthan gum after stability period NO of Days %Drug content 994 3 989 6 987 9 986 Table 11: In vitro % drug release of F6 after the stability period Time in hr F6 At day After 9 days 1 168 158 2 1869 1744 3 2419 2356 4 3871 376 5 466 455 6 5938 5837 7 6669 6568 8 7397 7289 9 8728 8627 1 946 936 11 9826 9715 12 9827 9726 CONCLUSION All the tablet formulations showed acceptable pharmacotechnical properties like hardness, friability, thickness, weight variation, drug content uniformity etc and complied with in house specifications for tested parameters To develop sustained release matrix tablet the polymer were used individually and in combination Among all, the xanthan gum and locust bean gum (1:1) release almost all amount of drug incorporated in the period of 12 hrs Thus, formulation F-6 was found to be the most promising formulation on the basis of acceptable tablet properties and invitro drug release REFERENCES [1] YW Chien Novel drug delivery systems Marcel Dekker, New York, 1992, 2 nd ed, 139-146 [2] SP Vyas, RK Khar Controlled drug delivery: Concept and advantages Vallabh Prakashan, Delhi, 22, 155-195 [3] S Gupta, V Kapoor, B Kapoor JK Science: J of Medical Education and Res, 24, 6, 16-18 [4] P Chippa, AM Pethe, S Upadhyay, A Tekade J of Pharm Res, 29, 2, 8, 144-8 [5] RV Nellore, GS Rekhi, AS Hussain, LG Tilman, LL Augsburger J Cont Rel, 1998, 5, 247-5 [6] Remington The science and practice of pharmacy 2th ed Vol1 New York: Lippincott Williams and Wilkins; 2 : 93 [7] United State Pharmacopoeia 23, The National Formulary 18 Asian Edition MD: United States Pharmacopeial Convention, Inc; 1995, 2648 [8] B Biswas, Md Safiqu Islam, F Begum, Abu Shara Shamsur Rouf Dhaka Univ J Pharm Sci, 28,7,1,39-45 [9] AA Bodke, P Zurao, AV Chandewar, SB Jaiswal Der Pharmacia Lettre, 21, 2,1,329-335 123