PHARMA SCIENCE MONITOR AN INTERNATIONAL JOURNAL OF PHARMACEUTICAL SCIENCES FORMULATION AND IN-VITRO EVALUATION OF MUCOADHESIVE BUCCAL TABLET OF DOMPERIDONE Rahul B. Patel *, K. R. Patel, M. R. Patel, N. M. Patel Shri B. M. Shah College of Pharmaceutical Education & Research, College Campus, Dhansura Road, Modasa, Dist. Sabarkantha, 383350, Gujarat, India. ABSTRACT The object of this research work is to design efficacious and prolonged release buccal tablet of Domperidone. It is Anti-emetic agent. It has very low bioavailability 15%. It undergoes first pass metabolism that lowering bioavailability. Direct access to the systemic circulation bypasses drug from the hepatic first pass metabolism, leading to high bioavailability. Moreover, the buccal route is easily accessible, has a good patient compliance and can be used in patients who can t swallow. Bilayer buccal tablet was prepared by using mucoadhesive polymers combination of HPMC K4M and Carbopol 934P, by direct compression method using HP-β-CD as solubility enhancer and ethyl cellulose as backing layer. The formulation was optimized by 32 full factorial statistical designs by selecting independent variables, Ratio of polymer as factor X 1 and Concentration of polymer as factor X 2. The prepared formulations were evaluated for various evaluation studies. Statistical analysis as well as kinetic studies performed. Statistical study showed that both factors X 1 and X 2 had significant effect on dependable variables Q 8 (P=0.000), Mucoadhesive strength (P=0.000) and Swelling index (P=0.00).By using HP-β-CD with drug in complex formation enhance the solubility of drug, as well as dissolution of tablet, Formulation D1 was selected as an optimum formulation as it shows more similarity in dissolution profile with theoretical profile (f 2 = 72.43 and f 1 = 1.24). The optimized formulation D1 had given release of 92.28% after 8hrs and it had optimum swelling, mucoadhesive property and permeation from buccal mucosa. It also had desired drug release kinetic and found to be stable for the period of 1 month. Keywords: HydroxyPropyl-β-Cyclodextrine, HPMC K4M, Carbopol 934P, Ethyl cellulose, 3 2 factorial designs. INTRODUCTION The buccal region of the oral cavity is an attractive target for administration of the drug of choice, particularly in overcoming deficiencies associated with the latter mode of administration. Problems such as high first-pass metabolism and drug degradation in the gastrointestinal environment can be circumvented by administering the drug via the buccal route. Moreover, rapid onset of action can be achieved relative to the oral route and the formulation can be removed if therapy is required to be discontinued. It is also www.pharmasm.com IC Value 4.01 2532
possible to administer drugs to patients who unconscious and less co-operative. To prevent accidental swallowing of drugs adhesive mucosal dosage forms were suggested for oral delivery, which included adhesive tablets, adhesive gels, adhesive patches and many other dosage forms with various combinations of polymers, absorption enhancers. In addition to this, studies have been conducted on the development of controlled or slow release delivery systems for systemic and local therapy of diseases in the oral cavity. [1] Domperidone is a dopamine receptor (D2) antagonist. It is used as an antiemetic agent for short-term treatment of nausea and vomiting of various etiologies. It is also used for its prokinetic actions. It is rational to formulate the mucoadhesive dosage form of Domperidone as it is known to have a low oral bioavailability due to extensive first-pass effect. Sudden death may occur when Domperidone is administered intravenously in high doses. The plasma half-life of Domperidone is 7 hrs. It has a low molecular weight (425.92) and no objectionable taste. These make it an appropriate candidate for being incorporated into the mucoadhesive formulation. [2-3] Systematic optimization techniques have frequently been employed for the design and development of pharmaceutical dosage forms. Embodying the use of appropriate experimental designs, generation of polynomial relationships and optimum search methods, generally using pertinent software. Factorial designs (FDs), where all the factors are studied in all possible combinations, are considered to be the most efficient in estimating the influence of individual variables (main effects) and their interactions using minimum experimentation. An FD for two factors at three levels each (3 2 ) is considered. Identical to a two-factor composite design. The aim current study was to develop and optimize the mucoadhesive buccal tablet of Domperidone for buccal delivery. A computer-aided optimization process using a 3 2 FD was employed to investigate the effect of two independent variables, i.e. ratio of polymer (Carbopol 934P: HPMC K4M) (X 1 ) and concentration of polymers (Carbopol and HPMC K4M) (X 2 ). [4] MATERIAL AND METHOD Materials Domperidone was a gift sample from CADILA Pharmaceuticals Pvt. Ltd. (Ahmadabad, India), HP-β-CD from Triveni interchem pvt. Ltd., Methocel K4M and ethyl cellulose by www.pharmasm.com IC Value 4.01 2533
Colorcon Asia Pvt. Ltd. (Goa, India), Carbopol 934P from M/s Lobe Chemie Ltd. (Mumbai, India) and lactose and magnesium stearate from ACME Chemicals. Were procured from commercial sources. All other chemicals used in the study were of analytical grade. Compatibility study [5] This study has been done to check whether there is any compatibility related problems are associated with drug and excipients used for the formulation of tablet. The drug and excipients must be compatible with one another to produce a product that is stable, efficacious, attractive and easy to administer and safe. If the excipients are new and not been used in formulations containing the active substance, the compatibility studies are of paramount importance. The IR spectral analysis of a drug and other excipients were taken using Press pellet technique (using KBr). The IR spectra s were determined by using Shimadzu FTIR 8400 S. All the spectra were recorded in the range of 400 4000 cm 1. Differential Scanning Calorimeter (DSC) Thermo grams were obtained by using differential scanning calorimeter at a heating rate 20 C/min over a temperature range of 50-300 C by using instrument Differential Scanning Calorimeter. The sample was hermetically sealed in an aluminum crucible. Thermo grams of drug and formulation were compared for any disappearance or shifting in characteristic peak of drug melting point. Formulation of Inclusion Complex Preparation of Physical mixture (PM): Equimolar physical mixtures were prepared by blending exact weighed amounts of drug and HP-β-CD until homogenous mixture is obtained. Preparation of inclusion complex by kneading method (KM): In this method the equimolar physical mixture (1:1) was prepared as discussed above and then slowly 1.5 times of water to the total weight of physical mixture was added slowly during continuous kneading. The mixture is kneaded for about 1 hour to get the paste. Then this paste was allowed to dry at room temperature for 24 hour and then the dried powder sieved to get uniform particle size distribution. In vitro dissolution study of prepared inclusion complex: www.pharmasm.com IC Value 4.01 2534
In vitro dissolution study of inclusion complex was conducted using USP dissolution apparatus II at 50 rpm, using 500 ml phosphate buffer ph 6.8 as a dissolution media maintaining at 37 ± 0.5 0 C. Quantity of inclusion complex equivalent to 10 mg of drug was taken. 5 ml Sample were withdrawn at time intervals of 5, 10, 20, and 30 up to 60 min. and filtered through a 45µm filter paper, diluted and assayed at 284 nm using UV/ Visible double beam spectrometer. The volume of dissolution fluid was adjusted to 500 ml by replacing each 5 ml aliquot withdrawn with 5 ml of phosphate buffer. Selection of drug: HP-β-CD ratio has been carried out by preparing inclusion complex of different ratio like 1:1, 1:2, molecular ratio and enhancement of solubility, which is proved as a best for the improvement of solubility. Preparation of Bilayer Buccal Tablets: Buccal tablets were composed of two layers i.e., Core layer and Backing layer, Core layer contains drug complex made by inclusion complexation, different mucoadhesive Polymers, Lactose, Talc, Magnesium stearate and Aspartame as a sweetener. This layer weighed about 100mg. Backing layer contains water impermeable compound, ethyl cellulose. The weight of this layer was 50 mg. Therefore total weight of the tablet was 150 mg. Preparation: Direct double compression technique was employed for the formulation. In this technique, first intermediate layer was formed and blend of second layer was placed on first intermediate layer and compressed to get bilayer tablet. Compositions of the core layer contains drug, mucoadhesive polymers. Pre-Compression Evaluation Parameters [6-7] Bulk Density: Weigh accurately 25g of powder, which was previously passed through 20# sieve and transferred in 100 ml graduated cylinder. Carefully level the granules without compacting, and read the unsettled apparent volume (V 0 ). Calculate the apparent bulk density in gm/ml by the following formula Tapped bulk density: Bulk density (Eq. 2.1) www.pharmasm.com IC Value 4.01 2535
Weigh accurately 25 g of granules, which was previously passed through 20# sieve and transfer in 100ml graduated cylinder. Then mechanically tap the cylinder containing the sample by raising the cylinder and allowing it to drop under its own weight using mechanically tapped density tester that provides a fixed drop of 14± 2mm at a nominal rate of 300 drops per minute. Tap the cylinder for 500 times initially and measure the tapped volume (V 1 ) to the nearest graduated units, repeat the tapping an additional 750times and measure the tapped volume (V 2 ) to the nearest graduated units. If the difference between the two volumes is less than 2% then final the volume (V 2 ). Calculate the tapped bulk density in gm/ml by the following formula: Tapped Density (Eq. 2.2) Carr s Index: The Compressibility Index of the granules blend was determined by Carr s compressibility index. It is a simple test to evaluate the BD and TD of a granules and the rate at which it packed down. The formula for Carr s Index is as below: Carr s Index (Eq. 2.3) Hausner s Ratio: The Hausner s ratio is a number that is correlated to the flow ability of a granular material. Hausner s Ratio (Eq. 2.4) www.pharmasm.com IC Value 4.01 2536
TABLE 1: EFFECT OF CARR S INDEX AND HAUSNER S RATIO ON FLOW PROPERTY Carr s Index (%) Flow Character Hausner s Ratio < 10 Excellent 1.00 1.11 11 15 Good 1.12 1.18 16 20 Fair 1.19 1.25 21 25 Passable 1.26 1.34 26 31 Poor 1.35 1.45 32 37 Very poor 1.46 1.59 >38 Very, very poor >1.60 Angle of repose: The flow characteristics are measured by angle of repose. Improper flow of powder is due to frictional forces between the particles. These frictional forces are quantified by angle of repose. Angle of repose is defined as the maximum angle possible between the surface of a pile of the powder and the horizontal plane. Where, h = Height of pile. r = Radius of the base of the pile. θ = Angle of repose (Eq. 2.5 TABLE 2: EFFECT OF ANGLE OF REPOSE (Θ) ON FLOW PROPERTY Sr. No. Angle of Repose (θ) Type of Flow 1 < 20 0 Excellent 2 20 0-30 0 Good 3 30 0-34 0 Passable 4 >35 0 Very poor 3 2 full factorial design A 3 2 randomized full factorial design was employed in the present study. In this design 2 factors were evaluated, each at 3 levels, and experimental trials were performed for all 9 possible combinations. The ratio of polymer (Carbopol:HPMC K4M) (X 2 ) and concentration of polymers Carbopol and HPMC K4M (X 2 ) were chosen as independent variables in 3 2 full factorial design, while Q 8 (% drug release after 8 hours), swelling www.pharmasm.com IC Value 4.01 2537
index, Mucoadhesive strength were taken as dependent variables. The composition of factorial design batches (D1-D9) is shown in Table 4.10 and Table 4.11. The prepared formulations were evaluated for assay, friability and hardness and in vitro release study. Statistical treatment was carried out to the factorial design batches using design expert DX8 stat ease software. TABLE 3: CODING OF VARIABLE TABLE Actual Values Coded Values X 1 = ratio of polymers (Carbopol : HPMC K4M) X 2 = concentration of polymer (Carbopol and HPMC K4M) -1 1:2 10% 0 1:1 15% 1 2:1 20% Evaluation of Prepared Tablets: [8] Weight Variation: Twenty tablets were selected at random, weighed and the average weight was calculated. Not more than two of the individual weights should deviate from the average weight by more than 7.5 % as per IP. TABLE 4: OPTIMIZE FORMULATIONS OF BILAYER BUCCAL TABLET Ingredients R1 R2 R3 R4 R5 R6 R7 R8 R9 Ingredients (mg) Domperidone+HP-β- CD(10mg drug) 37 37 37 37 37 37 37 37 37 Carbopol 934P 3.33 5 6.66 5 7.5 10 6.66 10 13.34 HPMC-K4M 6.66 5 3.33 10 7.5 5 13.34 10 6.66 Lactose 49 49 49 44 44 44 39 39 39 Magnesium Stearate 1 1 1 1 1 1 1 1 1 Talc 1 1 1 1 1 1 1 1 1 Aspartame 2 2 2 2 2 2 2 2 2 Backinglayer:-Ethyl Cellulose 50 50 50 50 50 50 50 50 50 Total weight in mg 150 150 150 150 150 150 150 150 150 www.pharmasm.com IC Value 4.01 2538
Friability: For each formulation, pre weighed tablet sample (20 tablets) were placed in the Roche friabilator which is then operated for 100 revolutions. The tablets were deducted and reweighed. Conventional compressed tablets that loose <1% of their weight are considered acceptable. Hardness: Hardness was measured by using Monsanto hardness tester. For each batch ten tablets were tested. It is measured in Kg/ cm 2 unit. Content Uniformity: Twenty tablets were weighed and powdered in a glass mortar. Quantity of powder equivalent to 10 mg of Domperidone was accurately weighed and transferred to 100 ml ph 6.8 phosphate buffers in volumetric flask. From the resulting solution 10 ml of the sample was withdrawn and adjusted final volume in volumetric flask up to 100 ml using ph 6.8 phosphate buffers. The solution was analyzed at λ max value of 284 nm by using UV-Visible spectrophotometer. The content of drug was calculated from calibration curve. In Vitro Swelling or Swelling Index: This test was carried out by using Petri dishes having 10 ml of phosphate buffer of ph 6.8 and tablet was placed in Petri dish. The initial weights of the drug loaded tablets in each batch were determined (W 0 ) using an electronic balance. Tablets from each batch were removed at different time intervals (1, 2, 3, 4, 6 and 8 hrs), wiped with filter paper to remove excess water from the tablet surface, and then reweighed (W 1 ). The swelling index (% w/w) was determined from the following relationship and plotted against time. The experiment was performed in triplicate. (Eq.4) Swelling index (Eq. 2.6) In Vitro Residence time test: The in vitro residence time is one of the most important physical parameters of buccal tablet. A buccal tablet was pressed over the excised goat buccal mucosa for 30 sec after previously being secured on a glass slide and was immersed in a beaker containing 500 www.pharmasm.com IC Value 4.01 2539
ml of ph 6.8 isotonic phosphate buffer, at 37±0.2 C. One stirrer was fitted at a distance of 5 cm from the tablet and rotated at 25 rpm. The time for complete erosion or detachment of the tablet from the mucosa was recorded. Surface ph measurement: The buccal tablets were first allowed to swell by keeping them in contact with 5 ml of ph 6.8 phosphate buffer for 2 hrs. The surface ph was then found by bringing a combined glass electrode near the surface of the tablets and allowing the reading to stabilize for at least 1 min. The measurements were taken in triplicate for each batch of the buccal tablet. In Vitro Mucoadhesive strength test: Figure 1 Modified Mucoadhesive Strength Tester Mucoadhesive strength of the buccal tablets was measured by using the modified physical balance. The test assembly was fabricated as shown in schematic presentation (Figure 1). This method involves the use of goat buccal mucosa as the model mucosal www.pharmasm.com IC Value 4.01 2540
membrane. The fresh goat buccal mucosa was purchased from slaughter house and it was then washed in isotonic phosphate buffer ph 6.8. The two sides of the balance were balanced with a 5 gm weight on the right hand side. A piece of fresh membrane was glued to a support (glass block) with cyanoacrylate adhesive. The block was then lowered into the glass container, which was then filled with isotonic phosphate buffer ph 6.8 kept at 37± 1 C, such that the buffer just reaches the surface of mucosal membrane, and keeps it moist. This was then kept below the left hand setup of the balance. The test mucoadhesive tablet was glued with the same adhesive to a rubber block hanging on the left hand side and the balance beam raised with the 5 gm weight on the right pan was removed off the weight. This lowered the rubber block along with the tablet over the mucosa with a weight of 5 gm. The balance was kept in this position for 3 minutes and then slowly water was added to the plastic container in the right pan by pipette. The detachment of two surfaces was obtained. Weight of water was measured. Then the Mucoadhesive strength of tablet was calculated. Three tablets were tested on each goat buccal mucosal membrane. After each measurement, the tissues were gently and thoroughly washed with phosphate buffer ph 6.8 and left for 5 minutes before the next experiment. Fresh membrane was used for each batch of tablets. The experiment was performed in triplicate. In Vitro Dissolution study: The USP type II rotating paddle method was used to study the drug release from the bilayer tablet. The dissolution medium consisted of 500 ml of ph 6.8 phosphate buffer. The release study was performed at 37 ± 0.5 C, with a rotation speed of 50 rpm. The backing layer of the buccal tablet was attached to the glass slide with cyanoacrylate adhesive. The disk was placed at the bottom of the dissolution vessel. Aliquots were withdrawn at regular time intervals and replaced with fresh medium to maintain sink conditions. The samples were filtered, made appropriate dilutions with phosphate buffer and were thereafter analyzed spectrophotometrically at λ max value of 272 nm using a Shimadzu UV-Visible1800 double-beam spectrophotometer. Cumulative percentage drug release was calculated using an equation obtained from a calibration curve which was www.pharmasm.com IC Value 4.01 2541
developed in the range of 5-35µg/ml for ph-6.8 phosphate buffer. The experiment was performed in triplicate. Ex vivo permeation study Figure 2 Franz Diffusion Cell The fresh goat buccal mucosal membrane was obtained from slaughter house. It was than excised by removing the underlying connective and adipose tissue and was equilibrated at 37 ± 1.0 C for 30 min in ph 6.8 isotonic phosphate buffer. The buccal epithelium was carefully mounted in between the two compartments of Franz Diffusion Cell. Tablets were stuck to the mucosa in the donor side containing ph 6.8 phosphate buffers. Receiver medium was 20 ml of ph 6.8 phosphate buffer maintained at 37 ± 0.5 C under gentle stirring. From the receiver compartment, 5 ml aliquots were collected at predetermined time intervals and replaced by an amount of fresh buffer. The samples removed were filtered, diluted and analyzed at λ max value of 284 nm using a Shimadzu UV-Visible 1800 www.pharmasm.com IC Value 4.01 2542
double-beam spectrophotometer. The schematic representation of Franz diffusion apparatus was displayed in Figure 2. KINETIC TREATMENT ON DRUG RELEASE [9] Different mathematical models may be applied for describing the kinetic of the drug release process from the formulation matrix; the most suited being the one which best fits the experimental results. The kinetic of Domperidone release from tablets was determined by finding the best fit of the dissolution data (drug release Vs time) to distinct models: Zero order [eq.2.7], first order [eq.2.8], Higuchi [eq. 2.9], and Korsmeyerpeppas model [eq. 2.10]. Q t = k 0 t. (Eq. 2.7) Q t = Q (1 e k1t ). (Eq. 2.8) Q t = k H t 1/2. (Eq. 2.9) Q t /Q = k KP t n. (Eq. 2.10) Where, k 0 = Zero order rate constant expressed as concentration/time & t is the time. k 1 = First order constant. k H = Constant reflecting the design variables of the system. Q t = Amount of drug released in time t. Q 0 = Initial amount of drug in tablet. Qt/Q = Fraction of drug release. k KP = Release rate constant. n = Diffusion release exponent indicative of the drug release mechanism Accelerated Stability Study[10] Stability testing of drug products begins as a part of drug discovery and ends with demise of compound or commercial product. FDA and ICH specifies the guidelines for stability testing of new drug products, as a technical requirement for registration of pharmaceuticals for human use (ICH Q1C Guidelines). The samples of optimized batch were kept at 40 C temperature and 75% RH (Relative Humidity) for one month in HDPE bottle. Then samples were withdrawn and analyzed for physical evaluation and in-vitro dissolution study. www.pharmasm.com IC Value 4.01 2543
RESULTS & DISCUSSION Interference Study: FT-IR Spectroscopy: Overlapping of IR spectra indicate no significant difference in characteristic peak at wave numbers of the drug in presence of the excipients given in figure 3 & table5. 150 %T 100 50 0-50 3023.52 3017.73 3099.71 2941.54 2819.06 3500 2500 Overlay spectra 2138.16 1716.70 1695.49 1705.13 1688.73 1750 1629.90 1545.03 1487.17 1490.06 1246.06 1341.54 1276.92 Figure 3 Overlapping of FTIR spectra 1250 1144.79 1147.68 1062.81 Domperidone Formulation 832.31 732.01 664.50 750 500 1/cm TABLE 5: VIBRATION FREQUENCY OF FT-IR SPECTRA OF DOMPERIDONE Sr. No. Functional Group Frequency (cm -1 ) drug formulation 1 N-H stretching 3108 3120 4 C=O stretching 1717 1720 5 N-H Bending 1684 1684 7 C-O 1250 1250 www.pharmasm.com IC Value 4.01 2544
Upon comparing the IR spectra of the formulation with that of the pure drug (figure 5.1), it was noticed that the characteristic peaks of the pure drug were also present in the sample spectra revealing the inert nature of the carrier used for formulation. Overlapping of IR spectra indicate no significant difference in characteristic peak at wave numbers of the drug in presence of the excipients. DSC study: Figure 4 DSC study of drug Figure 5 DSC study of drug complex www.pharmasm.com IC Value 4.01 2545
From the study of DSC it was concluded that length of peak of drug was decrease and width was increase in formulation it means solubility of drug was increased. Evaluation of Domperidone Buccal Tablets: Precompression Evaluation Parameters: TABLE 6: PRECOMPRESSION EVALUATION OF FORMULATED INCLUSION COMPLEX AND EXCIPIENTS Parameter Angle of repose( 0 ) bulk density (g/ml) Tap density (g/ml) Hausner s ratio Carr s Index (%) D1 26.28±0.2 0.494±0.05 0.565±0.04 1.14±0.07 12.57±0.04 D2 24.30±0.5 0.510±0.04 0.582±0.02 1.14±0.05 12.37±0.05 D3 27.14±0.3 0.515±0.02 0.593±0.05 1.15±0.04 13.15±0.03 D4 23.65±0.4 0.526±0.05 0.583±0.02 1.11±0.03 9.83±0.07 D5 25.22±0.2 0.534±0.02 0.602±0.03 1.13±0.02 11.30±0.03 D6 25.13±0.5 0.495±0.05 0.567±0.06 1.15±0.05 12.70±0.04 D7 24.19±0.6 0.498±0.03 0.560±0.04 1.13±0.06 11.07±0.02 D8 27.11±0.4 0.527±0.04 0.583±0.05 1.11±0.07 9.60±0.06 D9 25.32±0.6 0.493±0.04 0.575±0.07 1.17±0.05 14.26±0.05 Post-compression Evaluation Parameters:- Tablets of each formulation were evaluated for parameters such as thickness, diameter, weight variation, hardness, friability and drug content in given table. Batch Code TABLE 7: POST COMPRESSION EVALUATION OF FORMULATED INCLUSION COMPLEX AND EXCIPIENTS Thickness (mm)±sd Weight variation (mg)±sd Hardness (Kg/cm 2 )±SD Friability (%)±SD Drug content (mg)±sd Surface ph±sd 2.03±0.03 149±0.27 5.2±0.22 0.63±0.05 9.79±0.04 6.75±0.02 D2 2.05±0.05 149±0.90 5.4±0.14 0.55±0.02 9.75±0.15 6.73±0.05 D3 2.02±0.07 151±0.75 5.5±0.19 0.52±0.05 9.92±0.30 6.66±0.06 D4 2.14±0.08 150±0.35 5.6±0.34 0.57±0.03 9.97±0.12 6.68±0.04 D5 2.05±0.02 147±0.85 5.4±0.15 0.56±0.05 9.99±0.36 6.62±0.05 D6 2.02±0.03 148±0.30 5.6±0.20 0.61±0.12 9.86±0.14 6.70±0.02 D7 2.05±0.04 149±0.37 5.3±0.28 0.54±0.10 9.95±0.31 6.65±0.07 D8 2.11±0.06 148±0.63 5.2±0.32 0.60±0.05 9.94±0.15 6.68±0.03 D9 2.03±0.04 151±0.72 5.4±0.21 0.54±0.08 9.82±0.06 6.77±0.01 www.pharmasm.com IC Value 4.01 2546
In-Vitro Drug Release Study: TABLE 8: IN-VITRO DISSOLUTION STUDY OF FACTORIAL BATCHES D1- D9 Time(hr.) D1 D2 D3 D4 D5 D6 D7 D8 D9 1 38.02 36.25 33.22 34.11 33.75 31.26 33.58 29.66 26.64 2 51.22 43.55 41.74 42.99 40.14 38.16 39.43 35.12 33.66 3 58.13 51.10 49.45 49.82 49.97 48.68 48.18 44.72 40.23 4 64.75 61.39 58.12 55.83 57.05 55.03 53.64 51.74 47.03 5 74.46 68.04 63.49 66.16 61.16 59.49 65.20 56.34 56.03 6 81.59 77.24 71.94 69.83 71.37 67.00 71.17 65.43 62.63 7 86.65 83.86 81.53 77.62 79.71 74.06 77.55 73.72 67.86 8 92.28 89.65 87.30 87.80 84.74 82.60 85.41 80.65 76.16 The release of Domperidone from buccal tablets varied according to the ratio and concentration of Carbopol 934P and HPMC K4M polymers. From dissolution study it was found that D1, D2 and D3 formulations having 10% concentration of polymers but in ratio of 1:2, 1:1 and 2:1 respectively, it shows 92.28%, 89.65% and 87.30% release after 8 hours it shows in same concentration of polymers release decreased because of ratio of polymers, D1 to D3 Carbopol 934P increase and release was decrease so, it shows in formulation which having higher rate of Carbopol 934P shows lowering the release. In D4, D5 and D6 batches 15% of polymer concentration so, lower release rate and as concentration of Carbopol 934P increase release rate was decreased it shows 87.80%, 84.74% and 82.60% release respectively. In D7, D8 and D9 formulations retardation of release was higher than other because higher concentration of polymers. www.pharmasm.com IC Value 4.01 2547
Figure 6 In-vitro release of factorial batches D1-D3 Figure 7 In-vitro release of factorial batches D4-D6 www.pharmasm.com IC Value 4.01 2548
Figure 8 In-vitro release of factorial batches D7-D9 Swelling Study of Prepared Tablets: The swelling index of the tablets was increased with increasing concentration of polymer absorbed large volumes of water rapidly and swells to its maximum hydrated size without dissolving in aqueous media, TABLE 9: SWELLING INDEX OF FACTORIAL BATCHES D1-D9 Batch code Swelling index (%) D1 40.21 D2 33.40 D3 30.11 D4 53.58 D5 45.14 D6 40.35 D7 58.45 D8 50.12 D9 48.30 Mucoadhesive strength of Prepared Tablets: Mucoadhesive strength was determined by using self developed force detachment method and observed within the range of 15.26 to 35.68gm. From study it was observed that as www.pharmasm.com IC Value 4.01 2549
ratio of Carbopol 934P increase the mucoadhesion was increase. Decreasing the content of the Carbopol 934P resulted in decreased adhesion force. TABLE 10: MUCOADHESIVE STRENGTH OF FACTORIAL BATCHES D1-D9 Formulation code Mucoadhesive strength (gm) D1 15.26 D2 20.93 D3 30.34 D4 18.24 D5 25.03 D6 32.77 D7 27.09 D8 29.22 D9 35.68 Kinetic of Domperidone Buccal Tablets:- In 3 2 full factorial design study, the effect of combination of independent variables i.e. ratio of polymer (Carbopol: HPMC K4M) (X 1 ), concentration of polymers (Carbopol and HPMC K4M) (X 2 ), on dependent variables Q 8 (Cumulative percentage drug release after 8 hr), swelling index and mucoadhesive strength. A statistical model incorporating interactive and polynomial terms was used to evaluate responses. To know the mechanism of drug release from these formulations the data were treated according to first-order (log cumulative percentage of drug remaining vs. time), Higuchi s (Cumulative percentage drug released vs. squared root of time & Korsmeyer and peppas (log cumulative percentage drug released vs. time) pattern. The results of kinetic treatment applied to dissolution profiles of tablet of each batch were shown in table 5.16. All the formulation follows the zero order patterns as compare to first order. Zero order Correlation co-efficient value is nearest to 0.999 as compare to first-order correlation co-efficient value. Here zero order values are between 0.993 0.999 and first order values are between 0.983 0.990. www.pharmasm.com IC Value 4.01 2550
TABLE 11: RESULTS OF DEPENDENT VARIABLES FOR 3 2 FULL FACTORIAL DESIGNS The kinetic of the dissolution data were well fitted to zero order, Higuchi model and Krossmayer-Peppas model as evident from regression coefficients (Table 11). In case of the controlled release formulations, diffusion, swelling and erosion are the three most important rate controlling mechanisms. Formulation containing swelling polymers show swelling as well as diffusion mechanism because the kinetic of swelling include relaxation of polymer chains and imbibitions of water, causing the polymer to swell and changing it from a glassy to rubbery state. The value of diffusion exponent n for most factorial formulations is between 0.425-0.512 (Table 11) indicating Fickian drug release from the formulations. Batch code Q 8 Swelling index Mucoadhesive strength D1 92.28 40.21 15.26 D2 89.52 33.4 20.93 D3 87.32 30.11 30.34 D4 87.74 53.58 18.24 D5 84.64 45.14 25.03 D6 82.41 40.35 32.77 D7 85.32 58.45 27.09 D8 80.93 50.12 29.22 D9 76.09 48.3 35.68 TABLE 12: KINETIC TREATMENT OF DISSOLUTION PROFILE OF BATCH D1-D9 D1 D2 D3 D4 D5 D6 D7 D8 D9 Zero Order Model B 7.584 7.862 7.742 7.373 7.417 7.122 7.547 7.341 7.069 A 34.261 28.502 26.008 27.344 26.359 24.986 25.306 21.638 19.466 R 2 0.993 0.998 0.999 0.997 0.997 0.997 0.998 0.998 0.999 First Order Model B 0.052 0.057 0.059 0.056 0.057 0.058 0.058 0.062 0.064 A 1.586 1.531 1.501 1.513 1.501 1.477 1.490 1.438 1.398 www.pharmasm.com IC Value 4.01 2551
R 2 0.971 0.987 0.988 0.988 0.988 0.983 0.990 0.990 0.988 Higuchi Model B 29.709 30.460 29.936 28.471 28.670 27.599 29.120 28.283 27.299 A 7.834 1.796-0.170 2.490 1.299 0.780-0.085-2.974-4.363 R 2 0.998 0.992 0.991 0.988 0.989 0.991 0.988 0.987 0.990 Korsmeyer and Peppas Model n 0.425 0.454 0.470 0.445 0.456 0.466 0.464 0.492 0.512 k 0.375 0.335 0.311 0.322 0.312 0.294 0.306 0.271 0.246 R 2 0.997 0.987 0.990 0.987 0.986 0.990 0.982 0.984 0.988 B = Slope, A = Intercept, R 2 = Square of Correlation co-efficient, n = diffusion exponent Full and Reduce Model for Q 8 : Surface response plot to depict the polymer ratio (x1) and polymer concentration (x2) on Q8, swelling index and mucoadhesive strength. Full Model of Q 8 = 84.8-3.25 X 1-4.46 X 2 + 0.163 X 11 + 0.313 X 22-1.07 X 12 (Eq. 3.1) Reduce Model of Q 8 = 85.1-3.25 X 1-4.46 X 2-1.07 X 12 (Eq. 3.2) From the reduced model generated based on study of magnitude of co-efficient and the mathematical sign it carries, the above polynomial equations can be used to draw the conclusion regarding the influence of independent variable on the given dependent variables. The positive and negative coefficient value of independent variables indicates the change in response of dependable variable. The results of reduced model depicts that dependable variable Q 8 has negative signs of coefficients of factor X 1 and X 2 which indicates as there was increase in concentration and ratio of polymers from 1:2, 1:1 to 2:1 was decrease in release of drug at 8 hr. Full and Reduce Model for Swelling Index Full Model of swelling index = 44.4-5.58 X 1 + 8.86 X 2 + 2.28 X 11-2.93 X 22-0.013 X 12 Reduce Model of swelling index = 42.9-5.58 X 1 + 8.86 X 2 + 2.28 X 11 (Eq. 3.4) The results of reduced model depicts that dependable variable swelling index has negative signs of coefficients of factor X 1 which indicates as there was increase in ratio www.pharmasm.com IC Value 4.01 2552
of polymers, means increase in concentration of matrix forming polymer HPMC K4M from 1:2 to 1:1 and 2:1 was decrease in swelling index of tablet. Full and Reduce Model for Mucoadhesive Strength Full Model of mucoadhesive strength = 24.3 + 6.37 X 1 + 4.24 X 2 + 1.50 X 11 + 1.07 X 22-1.62 X 12 (Eq. 3.5) Reduce Model of mucoadhesive strength = 26.1 + 6.37 X 1 + 4.24 X 2 (Eq. 3.6) The results of reduced model depicts that dependable variable mucoadhesive strength has positive signs of coefficients of factor X 1 and X2 which indicates as there was increase in concentrations and ratio of polymers from 1:2 to 1:1 and 2:1 was increase in mucoadhesive strength of tablet because of mucoadhesive polymer Carbopol 934P. www.pharmasm.com IC Value 4.01 2553
Figure 9 Response surface plot of Q 8, Swelling Index and Mucoadhesive Strength TABLE 13: CALCULATIONS OF TESTING MODEL IN PORTIONS Regression FM RM Error FM RM Regression FM RM Error FM RM Regression FM RM Error FM RM For Q 8 DF SS MS F R 2 F Cal. F Crit. DF = (1,5) 5.00 187.84 37.57 94.14 0.994 3.00 187.59 62.53 216.08 0.992 3.00 1.20 0.40 - - 0.31 9.55 5.00 1.45 0.29 - - For swelling index DF SS MS F R 2 F Cal. F Crit. DF = (1,5) 5.00 685.15 137.03 98.68 0.994 3.00 674.75 224.92 77.22 0.979 3 4.17 1.29 - - 3.74 9.55 5.00 14.56 2.91 - - For Mucoadhesive strength DF SS MS F R 2 F Cal. F Crit. DF = (3,3) 5.00 368.60 73.72 63.05 0.991 2.00 351.24 175.62 50.51 0.944 3.00 3.51 1.17 - - 4.95 9.27 6.00 20.86 3.48 - - www.pharmasm.com IC Value 4.01 2554
SELECTION OF OPTIMUM BATCH The values of similarity factor (f 2 ) for the batch D1 showed maximum f 2 value 72.43 as shown in Table 5.10. Hence, formulation batch D1 was considered as optimum batch. TABLE 14: SIMILARITY FACTOR (F 2 ) FOR BATCHES D1-D9 Batch Similarity factor (f 2 ) Dis-similarity factor (f 1 ) D1 72.43 1.24 D2 61.51 7.75 D3 52.82 12.13 D4 51.38 12.60 D5 49.82 13.74 D6 44.57 17.64 D7 49.08 14.41 D8 41.23 21.05 D9 36.76 15.95 Figure 10 Comparisons of ex-vivo permeation study www.pharmasm.com IC Value 4.01 2555
TABLE 15: EX-VIVO PERMEATION STUDY OF OPTIMIZE BATCH Time(hr.) Ex-vivo Release of D1 batch In-vitro Release of D1 batch 0 0.00 0.00 1 33.75 38.02 2 45.84 51.22 3 53.59 58.13 4 61.23 64.75 5 67.35 74.46 6 76.01 81.59 7 84.04 86.65 8 89.12 92.28 RESULTS OF ACCELERATED STABILITY STUDY In order to determine the change in in-vitro release profile on storage, stability study of formulation D1 was carried out at 40 C in a humidity jar having 75 % RH. Samples evaluated after one month showed no change in-vitro drug release pattern as shown in Table 16. The value of similarity factor (f 2 ) was 81.53 (Table 16) indicating good similarity of dissolution profiles before and after stability studies. The similarity factor must be above 50. If the similarity factor value is near to 100, similarity factor is very good. The comparative dissolution profile of before and after accelerated stability study showed in figure 11. TABLE 16: ACCELERATED STABILITY STUDY Time (hr) CPR (Initial) CPR (After storage at 40 o C for 1month) 0 0 0 1 38.02 37.49 2 51.22 49.61 3 58.13 56.69 4 64.75 63.12 5 74.46 71.56 6 81.59 78.8le4 7 86.65 85.30 8 92.28 90.03 Similarity factor (f 2 ) 67.49 Dissimilarity factor (f 1 ) 3.86 www.pharmasm.com IC Value 4.01 2556
Figure 11 Accelerated Stability Study CONCLUSION Mucoadhesive bilayer buccal tablets contains Domperidone drug, Carbopol 934P and HPMC K4M as polymers. Mucoadhesive bilayer buccal tablets of Domperidone composed of a drug containing core layer of Carbopol 934P: HPMC K4M and backing layer ethyl cellulose. Magnesium stearate, lactose and sweetening agents. Tablets of all formulations showed good physical appearance, both layers of the tablet were easily distinguishable. Weight variation tests showed that tablets of all formulations passes USP specifications. Hardness and friability test indicates that, tablets of all formulations were having good compactness and mechanical strength. The content uniformity of tablets revealed that the drug was uniformly mixed in the polymers. The surface ph of tablets was almost within the range of salivary ph. Swelling study showed that, HPMC exhibited high swelling capacity and concentration of polymers increase the swelling index. Mucoadhesive strength studies of all formulations showed that mucoadhesion was increased with increasing concentration of Carbopol 934P. Highest mucoadhesion was found in (2:1) combination of Carbopol and HPMC K4M. In-vitro dissolution studies revealed that the drug release increased with decrease in concentration of Carbopol www.pharmasm.com IC Value 4.01 2557
934p.the high cumulative release was obtained in the formulation of (1:2 ratio of Carbopol 934P and HPMC K4M) and 10% concentration of total polymer. The kinetic data showed that the optimized formulations were followed diffusion and erosion supported by regression coefficient(r) and followed non fickian behavior with nearly zero order release pattern. Stability study for the three months at 40 C in a humidity jar having 75 % RH as specified by ICH guideline, revealed that the selected batch D1 was stable(f1 value<50%<f2 value). REFERANCES 1. Gandhi PA A review article on mucoadhesive buccal drug delivery system Int. J. Pharma Research and Dev., 2011, 3, 11. 2. European pharmacopoeia. 3 rd ed. Strasbourg: Council of European, Strasbourg; 1997. pp. 779-80. 3. British Pharmacopoeia. Vol. 1. London: HMSO; 2001. pp. 215. 4. Rowe RC, Shesky PJ and Owen SC. Hand book of pharmaceutical excipients; 3rd Edn; American pharmaceutical association, Washington publisher, 2000, pp 398, 1446, 1617. 5. Indian Pharmacopoeia, 6th Edn, the Indian Pharmacopoeia Commission, Ghaziabad, Sept. 2010, Volume-I, pp 111-117. 6. ICH guideline Q1A- Q1F, www.ich.org/cache/compo/363-272-1.html. 7. Flese EF, Hugen TA. Preformulation, Lachman L., The theory and practice of industrial pharmacy, 4th Edn, Varghese publishing house, Mumbai, 1987, pp 171-293. 8. Indian Pharmacopoeia, volume I, Year 2010, 192-193. 9. Higuchi T. Mechanism of sustained action mediation, theoretical analysis of rate of release of solid drugs dispersed in solid matrices. J. Pharm. Sci. 1963, 52, 1145-1149. 10. Korsmeyer RW, Gurny R, Doelker E, Buri P and Peppas NA. Mechanism of solute release from porous hydrophillic polymers. Int. J. Pharma. 1983, 15, 25-35. For Correspondence: Rahul B. Patel Email: rahul1389patel@gmail.com www.pharmasm.com IC Value 4.01 2558