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Acta Pharm. 58 (2008) 221229 10.2478/v10007-008-0006-3 Short communication SHAILESH T. PRAJAPATI1* LAXMANBHAI D. PATEL2 DASHARATH M. PATEL1 1Department of Pharmaceutics Shri Sarvajanik Pharmacy College Mehsana-384001, Gujarat, India of Pharmaceutics DDIT Pharmacy College, Nadiad-387001 Gujarat, India 2Department The purpose of the present study was to develop an optimized gastric floating drug delivery system (GFDDS) containing domperidone as a model drug. Box-Behnken design was employed in formulating the GFDDS with three polymers: hydroxypropyl methylcellulose K4M (HPMC K4M) (X1), Carbopol 934P (X2) and sodium alginate (X3), as independent variables. Floating lag time (FLT), total floating time (TFT), time required to release 50% of the drug (t50) and diffusion exponent (n) were selected as dependent variables. Seventeen formulations were prepared, dissolution data obtained was fitted to the power law and floating profiles were analyzed. HPMC loading was found to be significant for floating properties. Carbopol loading had a negative effect on floating properties but was found helpful in controlling the release rate of the drug. No significant effect of sodium alginate on floating properties was observed but it was important for gel formation. The quadratic mathematical model developed could be used to predict formulations with desired release and floating properties. Keywords: domperidone, floating matrix tablet, Box-Behnken design, GFDDS, release kinetics Accepted April 3, 2008 The real challenge in the development of a controlled drug delivery system is not just to sustain the drug release but also to prolong the presence of the dosage form in the stomach or the upper small intestine until all the drug is completely released in the desired period of time (12). The residence of a drug delivery system in the upper part of the gastrointestinal tract (GIT) can be accomplished by several drug delivery systems, such as intragastric floating systems (3), swelling and expandable systems (4), bioadhesive systems (5), modified shape systems (6), high density systems (7), delayed gastric emptying systems (8) and low density super porous systems (9). Domperidone is a synthetic benzimidazole compound that acts as a dopamine D2 receptor antagonist. Domperidone is also used as a prokinetic agent for treatment of up- *Correspondence, e-mail address: stprajapati@gmail.com per gastrointestinal motility disorders (10). It continues to be an attractive alternative to metoclopramide because it has fewer neurological side effects. Patients receiving domperidone or other prokinetic agents for diabetic gastropathy or gastroparesis should be also managing a diet, lifestyle, and other medications to optimize gastric motility (11). After oral administration, domperidone is rapidly absorbed from the stomach and the upper part of the GIT with fewer side effects (1214). It is a weak base with good solubility in acidic pH but significantly reduced solubility in alkaline medium. Such a weak base, formulated as an oral controlled release dosage form is exposed to environments of increasing pH with subsequent precipitation of poorly soluble free base within the formulation that is no longer capable of being released from the formulation (15). The present study involved the design of domperidone gastric floating matrix tablets by combining three polymers: HPMC K4M, Carbopol 934P and sodium alginate, and investigation of the combined effect of these polymers on the floating behavior and in vitro release pattern of the drug. EXPERIMENTAL Materials Domperidone was obtained as a gift sample (Mann Pharmaceutical Ltd., India). Hydroxypropyl methylcellulose K4M (HPMC K4M) and Carbopol 934P were received as gift samples from the Torrent Research Center (India). Sodium alginate (SA), sodium bicarbonate and lactose were purchased from S.D. Fine Chemicals (India). Methods Formulation design. DESIGN EXPERT 6.0.11 (STAT-EASE) demo version software was used for formulation design. The Box-Behnken design was used in the study. In this design, three factors were evaluated and experimental trials were performed in all 17 possible combinations. The amounts of HPMC K4M (X1), Carbopol 934P (X2) and SA (X3) were selected as independent variables. The floating lag time (FLT), total floating time (TFT) and times required for 50% of drug release (t50) and diffusion exponent (n) were selected as dependent variables. The experimental design with the corresponding formulations is outlined in Table I. The statistical model: Y = b0+b1X1 + b2X2 + b3X3 + b11X1 X1 + b22X2 X2 + b12X1 X2 + b23X2X3 + b13X1X3 + E incorporating interactive and polynomial terms was used to evaluate the responses, where Y is the dependent variable, b0 is the mean response of 17 runs and bi is the estimated coefficient for factor Xi. The main effects (X1, X2 and X3) represent the average result of changing 1 factor at a time from its low to high values. The interaction terms (X1X2, X2X3 and X1X3) show how the response changes when 2 factors are simultaneously changed. The polynomial terms (X1X1, X2X2, and X3X3) are included to investigate nonlinearity. Fabrication of domperidone floating tablets. Domperidone was mixed with the required quantity of HPMC K4M, Carbopol 934P, SA, sodium bicarbonate and lactose with a spatula in a mortar for 5 min. Isopropyl alcohol was added dropwise until a suitable mass for granulation was obtained. Then the wet mass was granulated through a sieve with 420 mm aperture size. The granules were dried at room temperature (35 °C) for 1 h and then blended with 5% polyethylene glycol 4000, 1% magnesium stearate and compressed on a 10-station rotary tablet compression machine (Rimek, India) using a 8-mm standard flat-face punch. The prepared tablets were round and flat with an average diameter of 8.0 ± 0.1 mm and a thickness of 2.8 ± 0.2 mm. In vitro buoyancy studies. The in vitro buoyancy was determined by floating lag times according to the method described by Rosa et al. (16). The tablets were placed in a 100-mL beaker containing 0.1 mol L1 HCl. The time required for the tablet to rise to the surface and float was taken as the floating lag time. The experiments were conducted in triplicate. In vitro dissolution studies. The release rate of domperidone from floating matrix tablets (n = 3) was determined according to British Pharmacopoeia (17) using the Dissolution Testing Apparatus 2 (paddle method). The dissolution test was performed using 900 mL of 0.1 mol L1 HCl, at 37 ± 0.5 °C and 50 rpm. A 5-mL sample was withdrawn from the dissolution apparatus hourly for 12 h, and the samples were replaced with fresh dissolution medium. The samples were filtered through a 0.45-mm membrane filter and diluted to a suitable concentration with 0.1 mol L1 HCl. Absorbance of these solutions was measured at 284 nm using a Shimadzu UV-1700 UV/Vis double-beam spectrophotometer (Japan). Cumulative drug release was calculated using the equation generated from Beer Lambert's calibration curve in the linearity range of 025 mg mL1. FLT and TFT of the tablets were measured during dissolution studies. The t50 and n were calculated based on the Korsmeyer and Peppas model (18). Statistical analysis. Statistical analysis of the Box-Behnken design batches was performed by multiple regression analysis using Microsoft Excel. To evaluate the contribution of each factor with different levels to the response, the two-way analysis of variance (ANOVA) was performed using the DESIGN EXPERT 6.0.11 (STAT-EASE) demo version software. To graphically demonstrate the influence of each factor on the response, the response surface plots were generated using the DESIGN EXPERT 6.0.11 (STAT-EASE) demo version software. RESULTS AND DISCUSSION In the present investigation, combinations of three polymers were studied using the Box Behken design. The mathematical models developed for all the dependent variables using statistical analysis software are shown in Equations (1)(4): FLT = 8.41 + 0.63X1 2.13X2 + 3.25X3 + 3.51X1X2 + 2.75X1X3 + + 1.25X2X3 5.95X1X1 + 7.55X2X2 + 3.32X3X3 R = 0.599582 (1) TFT = 5.98 + 4.6875X1 3.2625X2 0.21X3 4.47X1X2 6.92X1X3 2.35X2X3 + 3.40X1X1 0.65X2X2 + 1.72X3X3 R = 0.898329 t50 = 14.84 0.14X1 0.28X2 + 1.21X3 0.45X1X2 + 1.08X1X3 0.05X2X3 + 1.7425X1X1 + 1.87X2X2 0.66X3X3 R = 0.928214 n = 0.38 + 0.02X1 0.01X2 + 0.02X3 0.01X1X2 0.03X1X3 0.01X2X3 0.07X1X1 + 0.02X2X2 0.04X3X3 R = 0.845881 (4) (3) (2) The floating lag time for all tablets was found to be below 33 s regardless of the content of polymers used (Table I), indicating insignificant effect of the concentration of poTable I. Formulation and dissolution characteristics (response data) of batches in the Box-Behnken designa Batch B1 B2 B3 B4 B5 B6 B7 B8 B9 B10 B11 B12 B13 B14 B15 B16 B17 X1 (%) 10 20 30 10 10 20 30 10 20 30 20 20 30 20 20 20 20 X2 (%) 15 5 5 10 10 5 10 5 10 15 15 15 10 10 10 10 10 X3 (%) 25 15 25 15 35 35 35 25 25 25 15 25 15 25 25 25 25 FLT (s) 2±1 9±2 4±2 11 ± 2 5±2 3±2 26 ± 4 4±2 3±2 15 ± 3 33 ± 4 15 ± 4 3±1 24 ± 3 10 ± 2 6±2 12 ± 2 TFT (h) 2.5 ± 0.4 10.0 ± 0.4 24.0 ± 0.3 4.2 ± 0.3 5.3 ± 0.3 24.0 ± 0.3 5.6 ± 0.4 8.0 ± 0.4 2.5 ± 0.2 4.4 ± 0.1 3.6 ± 0.3 4.9 ± 0.2 24.0 ± 0.4 4.8 ± 0.2 6.8 ± 0.5 7.0 ± 0.4 4.2 ± 0.3 t50 (h) 13.1 ± 0.0 12.5 ± 0.1 13.3 ± 0.0 12.0 ± 0.1 11.9 ± 0.0 14.8 ± 0.1 14.7 ± 0.1 12.0 ± 0.0 15.8 ± 0.0 12.0 ± 0.0 12.8 ± 0.0 11.1 ± 0.0 11.3 ± 0.1 10.5 ± 0.0 15.0 ± 0.1 13.2 ± 0.1 13.2 ± 0.0 n 0.48 ± 0.02 0.57 ± 0.01 0.52 ± 0.03 0.60 ± 0.02 0.65 ± 0.07 0.52 ± 0.01 0.51 ± 0.01 0.39 ± 0.02 0.44 ± 0.01 0.52 ± 0.03 0.62 ± 0.02 0.47 ± 0.04 0.36 ± 0.06 0.50 ± 0.01 0.48 ± 0.04 0.70 ± 0.03 0.45 ± 0.02 t50 time requir ed to release 50% of drug, X1 amount of HPMC K4M, X2 amount of Carbopol 934P, X3 amount of sodium alginate. All batches contain 30 mg of domperidone, 10% sodium bicarbonate, 5% polyethylene glycol, 1% magnesium stearate, and a sufficient quantity of lactose to adjust the average mass of tablets to 180 mg. lymers (Table II). Lower value of the correlation coefficient (Eq. 1) clearly indicates that the response is independent of the factors studied. This was due to evolution and entrapment of carbon dioxide inside the hydrated polymeric matrices, resulting from the interaction between the gas generating agent (NaHCO3) and dissolution medium (0.1 mol L1 HCl, pH 1.2) which led to lowering of the density of matrices enabling the tablets to float. The results of TFT and t50 showed wide variations (Table I). From the results of multiple regression analysis, it was found that the dependent variables, TFT and t50, are strongly dependent on the independent variables (p < 0.05, Table II). The correlation coefficients indicate a good fit. Polynomial equations (Eq. 2 and 3) can be used to draw a conclusion after considering the magnitude of the coefficient and the mathematical sign it carries (positive or negative). As the amount of Carbopol 934P increased, TFT decreased; this may be due to high affinity of Carbopol toward water, which promotes water penetration into tablet matrices, leading to increased density. As the amount of HPMC K4M increased, TFT increased; this is because of increased gel strength of matrices, which prevents escape of evolved carbon dioxide from matrices, leading to decreased density. As the amount of SA increased, TFT decreased; this is because of the poor gelling strength of SA compared to HPMC K4M. This effect of polymer concentration is reflected in formulations B3, B6 and B13 (shown in Table I). As the amount of HPMC K4M Table II. Analysis of variance for dependent variables from the Box Behnken design Source FLT Regression Residual Total TFT Regression Residual Total t50 Regression Residual Total n Regression Residual Total SS sum of squares df degrees of freedom MS mean of square F Fischer's ratio SS 209.25 838.2794 1047.529 225.4207 19.1005 244.5212 47.83579 3.6995 51.53529 0.03816 0.020922 0.059081 df 6 10 16 9 7 16 9 7 16 9 7 16 MS 34.875 83.82794 F-value 0.416031 Probability 0.8524 a) b) c) d) Fig. 1. Response surface plot for the effect of polymer amount on a) floating lag time (FLT); b) total floating time (TFT); c) time required for 50% drug release (t50); d) diffusion exponent (n). X1 amount of HPMC K4M, X2 amount of Carbopol 934P; X3 amount of sodium alginate. 226 and Carbopol 934P increased, t50 decreased; this may be due again to high affinity of HPMC and Carbopol toward water, which promotes water penetration into tablet matrices, leading to solubilization of domperidone. As the amount of SA increased, t50 decreased; probably because of poor water affinity of SA compared to HPMC K4M and Carbopol 934P. To demonstrate graphically the effect of the amount of HPMC K4M and Carbopol 934P and SA, the response surface plots were generated for the dependent variables FLT, TFT, t50% and n (Fig. 1). Dissolution profiles of the developed formulations are compared in Fig. 2. The dissolution profiles were fitted with the power law equation given by Korsmeyer and Pappas (18). Although the type of polymer and its concentration had significant influence on TFT and t50 (p < 0.05, Table II), the diffusion exponent ranged from 0.386 to 0.695, indicating anomalous drug release involving a combination of swelling, diffusion and/or erosion of matrices. This might be due to poor water solubility of domperidone as well as different characteristics of polymers. Nonlinear relationship was obtained between the diffusion exponent and three independent variables. It was observed that as the concentration of HPMC K4M increased, diffusion exponent increased up to an intermediate value and decreased. Carbopol 934P concentration had no significant effect on the value of n. As the concentration of SA increased, the values of n decreased. Cumulative drug release (%) Time (h) Fig. 2. Comparative release profile of developed formulations. CONCLUSIONS HPMC K4M, Carbopol 934P and SA significantly affect TFT of the formulated GFDDS. When they are used in combination for developing GFDDS, high to moderate amount of HPMC K4M, low to moderate amount of Carbopol 934P and low to high amount of SA is to be used to achieve the desired TFT and release profile required for once daily formulations. Acknowledgments. Authors are thankful to Maan Pharmaceutical Pvt. Ltd (Mehsana, India) for providing gift sample of domperidone and Torrent research Center (Gandhinagar, India) for providing HPMC K4M and Carbopol 934P.
Acta Pharmaceutica – de Gruyter
Published: Jun 1, 2008
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