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1 Available online at International Journal of Trends in Pharmacy and Life Sciences Vol. 1, Issue: 4, 215: FORMULATION AND IN-VITRO EVALUATION OF IVABRADINE BUCCAL TABLETS Garika Swapna*, Sharadha Srikanth, Uma Maheswar Rao CMR College of Pharmacy, Kandlakoya (V), Medchal Road, Hyderabad 5141 E.Mail: ABSTRACT The main objective of the present study was to formulate and evaluate Ivabradine mucoadhesive buccal tablets by direct compression technique. Ivabradine is a novel medication used for the symptomatic management of stable angina pectoris and it has short half -life (2 hrs) with a bioavailability of 4% orally. The drug identity was confirmed by UV spectroscopy. The polymers used to sustain the drug release are Guar gum, Xanthum gum, HPMC K4M and Carbopol934. The compatibility studies between the drug and the polymer were studied using the FTIR spectroscopy and were found to be compatible. Preformulation parameters like tapped density, bulk density, Carr s index, Hausner s ratio, compressibility index, angle of repose are studied and the results were found to be within the limits. Using the above polymers formulations f1 to f12 were manufactured by direct compression technique and the tablets were evaluated for their thickness, hardness, friability, weight variation and content uniformity test. The in vitro drug release studies were performed in Phosphate buffer of ph6.8 using USP type-ii dissolution apparatus. From the dissolution studies it was found that f2 formulation containing HPMC K4M was best since it release minimum amount of drug (9.8%) initially and maximum drug (99.6%) at the end of 8hrs.The f2 formulation was subjected to stability studies for about 3months as per ICH guidelines and found to be stable. Key words: Ivabradine, mucoadhesive buccal tablets, direct compression, angina pectoris *Corresponding Author: Garika Swapna CMR College of Pharmacy, Kandlakoya (V), Medchal Road, Hyderabad 5141 E.Mail: swapnagarika199@gmail.com Received: 25/9/215 Revised: 28/1/215 Accepted: 31/1/215 INTRODUCTION Buccal delivery refers to drug release which can occur when a dosage form is placed in the outer vestibule between the buccal mucosa and gingival. Advantages of mucoadhesive buccal drug delivery: Drug administration via the oral mucosa offers several advantages. a. Flexibility in physical state, shape, size and surface. b. Ease of administration and termination of therapy in emergency. c. Permits localization of the drug for a prolonged period of time. d. Administered to unconscious and trauma patients. e. Offers an excellent route for the systemic delivery of drugs which bypasses first pass metabolism, there Swapna G* et al. Int J Trends in Pharm & Life Sci. 215: 1(4);

2 by offering a greater bioavailability. f. Significant reduction in dose can be achieved, thereby reducing dose dependent side effects. Disadvantages of buccal drug delivery system: Drug administration via buccal mucosa has certain limitations, a) Drugs which irritate the oral mucosa have a bitter or unpleasant taste or odor cannot be administered by this route. b) Drugs, which are unstable at buccal ph, cannot be administered by this route. c) Only drugs with small dose requirements can be administered [1]. Ivabradine is a novel medication used for the symptomatic management of stable angina pectoris. Ivabradine acts by reducing the heart rate via specific inhibition of the If funny channel, a mechanism different from beta-blockers and calcium channel blockers, two commonly prescribed anti-angina drugs. Ivabradine is a cardio tonic agent [2]. MATERIALS AND METHODOLOGY Materials: Ivabradine was obtained as a gift sample from Chandra labs, HYD, HPMC K4M, Carbapol Xanthan gum were obtained from Merck specialties private limited, Guar gum, Mg.sterate, Mannitol, Aspartame, are purchased from SD Fine Chem [3]. Methodology: Calibration curve of Ivabradine in ph 6.8 Phosphate buffer: Ivabradine (1mg) was dissolved in small quantity of phosphate buffer and volume was made up to 1 ml in volumetric flask using Phosphate buffer ph 6.8. From this stock solution 1 ml was withdrawn and is diluted to 1ml in volumetric flask which gives the concentration of 1µg/ml. From this stock solution aliquots were withdrawn in volumetric flask to give concentrations 2µg/ml, 4µg/ml, 6µg/ml, 8µg/ml and 1µg/ml. Absorbance of each solution was measured at 286 nm using Shimadzu UV- 17 UV- Vis double beam spectrophotometer with Phosphate buffer ph 6.8 as a reference standard [4]. Compatibility Studies: To investigate any possible interactions between the drug and excipients used, the FT-IR spectra of pure Ivabradine and its physical mixture with different excipients were carried out using thermo Electron Corporation (Nicolet IR 2 FTIR) spectrophotometer. The samples were prepared as KBr (potassium bromide) disks compressed under a pressure of 15 lbs. The wave number range is selected in between 5-35cm -1. Method: 1 mg of drug is mixed with the 1 mg of Spectroscopic grade of KBr and triturated for uniform mixing. The thin and transparent pellet is prepared by applying 15 lbs pressure. The prepared pellet is exposed to IR beam and spectra are recorded by using FT-IR [5]. Swapna G* et al. Int J Trends in Pharm & Life Sci. 215: 1(4);

3 Formulation of Mucoadhesive Tablets of Ivabradine: Direct compression method was employed to prepare buccal tablets of Ivabradine using HPMC K4M, Carbapol, Xanthan gum and Guar gum as polymers. All the ingredients including drug, polymer and excipients were weighed accurately according to the batch formula and were passed through #6 to get uniform particle size. The drug and all the ingredients except lubricants were taken on a butter paper with the help of a stainless steel spatula and the ingredients were mixed in the order of ascending weights and blended for 1 min in a porcelain mortar. After uniform mixing of ingredients, lubricant was added and again mixed for 2 min. The prepared blend (15mg) of each formulation was compressed by using 8mm punch on a single stroke, multi-station tablet punching machine. The buccal tablets containing 7.5 mg Ivabradine were prepared using different polymers in varying ratios [6]. Table 1: formulation Of Mucoadhesive Tablets of Ivabradine Ingredients F-1 F-2 F-3 F-4 F-5 F-6 F-7 F-8 F-9 F-1 F-11 F-12 Ivabradine HPMC 5% 1% 15% K4M Carbopol % 1% 15% Xanthum % 1% 15% gum Guar gum % 1% 15% Aspartame Mannitol q.s q.s q.s q.s q.s q.s q.s q.s q.s q.s q.s q.s Magnesium Stearate Characterization of Tablets: Thickness: The thickness of the tablets was measured by Vernier calipers. It is expressed in mm [7]. Hardness: Tablets require a certain amount of strength or hardness and resistance to friability, to withstand mechanical shocks of handling in manufacture, packing and shipping. The hardness of tablet was measured by Monsanto hardness tester. The tablets from each batch were used for hardness studies and results are expressed in Kg/cm 2 [7]. Weight variation test: Ten tablets were selected at randomly from the lot and weighed individually to check for weight variation [7]. Friability: It was performed in Roche friabilator where the tablets were subjected to the combined effect of abrasion and shock by utilizing a plastic chamber that revolves at 25 rpm dropping the tablets at a distance of six inches with each revolution. Pre weighted samples of 2 tablets were placed in the Friabilator, which Swapna G* et al. Int J Trends in Pharm & Life Sci. 215: 1(4);

4 is then operated for 1 revolutions. The tablets are then dusted and reweighed. Conventional compressed tablets that loose less than.5 to 1 % of their weight are generally considered acceptable [7]. % Friability= (initial weight-final weight/initial weight) x1 Twenty tablets were taken and triturated well. The quantity equivalent to 5mg of Ivabradine was dissolved in 1ml of phosphate buffer ph 6.8 solutions on rotary shaker overnight. The solution was centrifuged and supernatant was collected. The absorbance was measured using UV-Visible spectrophotometer at 286nm. Microenvironment ph study: The microenvironment ph of the tablets were determined by the method proposed by Battenberg, et al, 1991.The tablets were allowed to swell for 2hours in 2ml of ph 6.8 phosphate buffer (ph ) in specially fabricated glass tubes and microenvironment ph was measured by placing the ph electrode in contact with the surface of the tablet and allowing it to equilibrate for 1 minute [8]. Swelling Study: The swelling properties of the tablets were evaluated by determination of percent of swelling. Each tablet was weighed (W1) and placed in Petri dish with 5ml of PB P H 6.8 and incubated at 37 c for predetermined times. After placing the formulation for specified time, the tablets were wiped off to remove excess of surface water by using filter paper and weighed (W2). %swelling index = (W2) (W1) W1 1 Where, W 1=Initial weight of the tablet. W2= Weight of tablet after swelling time interval [8]. Determination of the Ex-Vivo Residence Time: The ex vivo residence time was found using a locally modified USP disintegration apparatus. The disintegration medium was composed of 8 ml ph 6.8 phosphate buffer maintained at 37 C. The sheep buccal tissue was tied with thread to the central stand. The buccal tablet was hydrated with.5ml of ph 6.8 phosphate buffer and then the hydrated surface was brought in contact with the mucosal membrane. The tissue was allowed to run in such way that the tablet completely immersed in the buffer solution at the lowest point and was out at the highest point. The time taken for complete erosion or dislodgment of the tablet from the mucosal surface was noted [9]. In Vitro Drug Release Study: In vitro drug release study of mucoadhesive tablets were performed using standard USP dissolution apparatus type II. The bowls of the dissolution apparatus was filled with 9ml of phosphate buffer ph 6.8 and maintained at a temperature of 37±.5 C. The protocol of the dissolution apparatus was settled for automatic 5ml sample withdrawal and replacement of fresh media at predetermined time interval the dissolution apparatus was covered with the black colour polythene cover to protect the solution from light. The collected samples were filtered through the.45μm 59millipore filter. The samples were analyzed for drug release using double beam UV spectrophotometer at 286nm [9]. Swapna G* et al. Int J Trends in Pharm & Life Sci. 215: 1(4);

5 Drug Release Kinetics: To examine the release mechanism of Ivabradine from the prepared buccoadhesive tablets, the results were analyzed according to the following equation: Mt M =k.tn Where M t /M is the fractional drug released at time t, k is a kinetic constant incorporating structural and geometrical characteristics of drug / polymer system [device], and n is the diffusion exponent that characterizes the mechanism of drug release. It is known that for non-swelling tablets, drug release can be generally expressed by the Fickian diffusion mechanism, for which n=.5, whereas for most erodible matrices, a zero order release rate kinetics is followed, for which n = 1. For non-fickian release, the n value falls between.5 and 1. (.5< n<.89) whereas in the case super case II transport n >.89. Data of the in-vitro release was fit in to different equations and kinetic models to explain the release kinetics of Ivabradine from buccal tablets. The kinetic models used were zero-order equation (eq.1), first order equation (eq.2), Higuchi equation (eq.3), and Korsmeyer-peppas equation (eq.4). Zero Order Kinetics: A zero-order release would be predicted by the equation. A t = A -k t (1) First Order Kinetics: A first-order release would be predicted by equation Log C = log C Kt/ (2) Higuchi s Model: Drug released from the matrix devices by diffusion has been described by following Higuchi s classical diffusion equation. Q = [Dε / τ (2 A - εcs) Cst] (3) Korsmeyer and Peppas Model: The release rates from the controlled release polymeric matrices can be described by the equation proposed by the Korsemeyer et al [1]. Q = K 1 t n Stability studies: Stability studies were performed data temperature of 4 Cat 75% RH, over a period of three months (9days) for the optimized buccal tablet. Sufficient number of tablets (15) were packed in amber colored screw capped bottles and kept in stability chamber maintained at 4 ±1 C & 75% RH. Samples were taken at monthly intervals for drug content estimation. At the end of three months period, dissolution test and drug content studies were performed to determine the drug release profiles and drug content [1]. Swapna G* et al. Int J Trends in Pharm & Life Sci. 215: 1(4);

6 RESULTS AND DISCUSSION Preformulation Studies: These tests were performed as per the procedure and the results are illustrated in the following table no.9 Table 2: Table showing the description of Ivabradine (API) Test Description Colour Odour A white to off white colour crystalline powder Odourless The results were found as per specifications. Solubility: It is soluble in water (1 mg/ml), methanol, and ethanol and slightly soluble in hexane. Melting Point: This test is performed as per procedure and the result was illustrated in the following table.no1. Table 3: showing the melting point of API s Material Melting Point Melting Point Range Ivabradine 137 c c The Result was found to be within limit. Calibration Curve of Ivabradine: Table 4: calibration curve data S.No Concentration (μg/ml) Absorbance(nm) Swapna G* et al. Int J Trends in Pharm & Life Sci. 215: 1(4);

7 absorbance RESEARCH ARTICLE e-issn: y =.1565x +.5 R² = concentration μg/ml Compatibility Studies: Fig.1: Calibration curve plot of Ivabradine in 6.8 phosphate buffer Fig.2: Ft-Ir Spectra of Ivabradine Pure Drug Fig.3: FT-IR Spectra of Ivabradine optimized Drug-excipient compatibility study indicates that the all used excipients in the optimized formulation are compatible with the drug based on FT-IR spectra. Swapna G* et al. Int J Trends in Pharm & Life Sci. 215: 1(4);

8 Characterization of Blend: Formulations Angle of repose ( ) Table 5: Physical Properties of Pre-compression Blend Bulk Density (g/ml) Tapped Density (g/ml) Carr s Index (%) Hausner s ratio Flow property F Good F Good F Excellent F Excellent F Excellent F Good F Excellent F Good F Excellent F Excellent F Excellent F Good Physical Evaluation of Buccoadhesive Tablets: Table 6: Physical Evaluations of Buccoadhesive Tablets F.Code Hardness (kg/cm 2 ) Thickness (mm) Weight (mg) Friability (%) Drug content (%) F1 6.5 ± ± ± ±1.37 F2 6.6± ± ± ±.8 F3 6.72± ± ± ±2.47 F4 6.86± ± ± ±.88 F5 6.34± ± ± ±1.25 F6 6.49± ± ± ±1.87 F7 6.51± ± ± ±.6 F8 6.53± ± ± ±.87 F9 6.52± ± ± ±.6 F1 6.76± ± ± ±.88 F ± ± ± ±1. F ± ± ± ±1. Microenvironment ph study: Table 7: Results of Microenvironment ph study F.Code Surface ph F1 6.4 F2 6.6 F3 6.2 F4 6.6 Swapna G* et al. Int J Trends in Pharm & Life Sci. 215: 1(4);

9 F5 6.5 F6 6.3 F7 6.5 F8 6.4 F9 6.6 F1 6.3 F F Swelling Index: Table 8: Results of Percent swelling Index Time (min) Formulation code % F1 F2 F3 F4 F5 F6 F7 F8 F9 F1 F11 F Mucoadhesion time: Table 9: Effects of polymers on Mucoadhesion time Formulation Code Mucoadhesion time (hr) F1 6 F2 8 F3 9 F4 5 F5 7 F6 >9 F7 6 F8 7 F9 9 F1 5 F11 6 F12 6 Swapna G* et al. Int J Trends in Pharm & Life Sci. 215: 1(4);

10 CUMULATIVE % DRUG RELEASE CUMULATIVE % DRUG RELEASE RESEARCH ARTICLE e-issn: In-Vitro drug Release Study: Table 1: Cumulative drug release of formulation F1-F12 %CDR Tim F1 F2 F3 F4 F5 F6 F7 F8 F9 F1 F11 F12 e (hrs) TIME IN HRS F1 F2 F3 Fig.4: In-Vitro Drug Release for Formulation F1, F2, F F4 F5 F6 5 1 TIME IN HRS Fig.5: In-Vitro Drug Release for Formulation F4, F5, F6 Swapna G* et al. Int J Trends in Pharm & Life Sci. 215: 1(4);

11 %CDR CUMULATIVE % DRUG RELEASE RESEARCH ARTICLE e-issn: F7 F8 F9 5 1 TIME IN HRS Fig.6: In-Vitro Drug Release for Formulation F7, F8, F F1 F11 F12 5 Time in hrs 1 Fig.7: In-Vitro Drug Release for Formulation F1, F11, F12 Drug Release Kinetics: % C D R ZERO ORDER y = x R² = TIME IN HRS Fig.8: Zero order kinetic graph for formula F2 % C D R HIGUCHI PLOT y = x R² = SQUARE ROOT OF TIME Fig.9: Higuchi kinetic graph for formula F2 Swapna G* et al. Int J Trends in Pharm & Life Sci. 215: 1(4);

12 L O G PEPPAS % C D R 1.5 y = x R² = LOG TIME Fig.1: Peppas kinetic graph for formula for F2. L O G % D R U G 2.5 R2 E 1.5 M A I1 N.5 I N G FIRST ORDER y = x R² = TIME IN HRS Fig.11: First Orders Kinetic Graph for Formula F2 Discussion: In-vitro drug release data of all the buccal tablet formulations was subjected to goodness of fittest by linear regression analysis according to zero order, first order, Higuchi s and Korsmeyer-Peppas models to ascertain the mechanism of drug release. From the above data, it can be seen the formulation, F2have displayed zero order release kinetics ( r 2 value of.9842).from Peppas data; It is evident that the drug is released by non-fickian diffusion mechanism. This is because as the proportion of polymers in the matrix increased the rewash an increase in the amount of water uptake and proportionally greater swelling leading to a thicker gel layer. Zero-order release from swellable hydrophilic matrices occurs as a result of constant diffusion path lengths. Ex-Vivo Drug Permeation Studies for F2: Table 11: Ex-vivo drug permeation studies for F2 Time (hr) F Swapna G* et al. Int J Trends in Pharm & Life Sci. 215: 1(4);

13 % DRUG PERMEATED RESEARCH ARTICLE e-issn: TIME IN HRS F2 Fig.12: Graph showing permeation studies of formulation F2 Discussion: The drug permeation was slow and steady, 84.1% of drug could permeate through the buccal membrane in 8 hours. Stability Studies: Table 12: Stability studies of Ivabradine buccoadhesive tablet (F2) at room temperature Time Colour Assay Cumulative % drug release Surface PH 25±2 c and 65±5%R H 4±2 c and 75±5%R H 25±2 c and 65±5%R H 4±2 c and 75±5%R H 25±2 c and 65±5%R H 4±2 c and 75±5%R H First day White days White days White days White Results from stability studies indicate that the formulated Ivabradine Bucco adhesive tablets are stable for a period of 3 months under 2 different conditions at 25±2 c and65±5%rh and 4±2 c and 75±5%RH. There were no remarkable changes were observed during the period of storage. Swapna G* et al. Int J Trends in Pharm & Life Sci. 215: 1(4);

14 CONCLUSION It can be concluded that Ivabradine can certainly be administered through the oral mucosa. The designed Bucco adhesive tablets can overcome the disadvantage of extensive first pass effect and low oral bioavailability of Ivabradine. This increased and predictable availability of Ivabradine from designed formulation may result in substantial dose reduction of the dosage form when the drug is administered through oral mucosa so that it will be economical to the patient. Further work is recommended to support its efficacy claims by pharmacokinetic and Pharmacodynamics studies in human beings. REFERENCES 1. Ahuja A, Dogra M, Agrawal SP. Development of buccal tablets of diltiazem hydrochloride. Ind J Pharm Sci. 1995: 57; Anay R, Patel. Muco-adhesive Buccal Drug Delivery system. International Journal of Pharmacy and Life sciences. 211: 2(6); Amit, Sharad S, Ajazuddin, Mohammed K, Swarna. Theories and Factors Affecting Mucoadhesive Drug Delivery Systems: A Review. IJRAP. 211: 2 (4); Asha S, John, Sathesh BPR, Divakar G, Manoj K, Jangid and Kapil, K Purohit. Development and Evaluation of Buccoadhesive Drug Delivery System for Atorvastatin Calcium. Journal of Current Pharmaceutical Research. 21: 1; Bhaskara J. Recent Advances in mucoadhesive Drug delivery system. Business Briefing Pharma tech. 24: 2(3); Basanta B, Ranjit M, Sunit S, Vikram M, Santosh A. Mucoadhesivebuccal drug delivery systems containing rosiglitazone maleate for treatment of type ii diabetes: formulation design and in vitro evaluation. World Journal of Pharmaceutical research. 213: 1(3); Borgaonkar PA, Virsen TG, Hariprasanna RC and Najmuddin M. Formulation and In Vitro Evaluation of Buccal Tablets of Loratadine for Effective Treatment of Allergy. International Journal of Research in Pharmacy and Chemistry. 211: 1(3); Basawaraj S, Patil, Sandeep S, Tate, Upendra K, Srinivas R, Soodam, Prasad A, Vedpathak. Development And In Vitro Evaluation Of Mucoadhesive Buccal Tablets Of Tizanidine Hydrochloride Using Natural Polymer Guar Gum. Pharma nest. 211: 2 (2-3); Satyabrata B, Ellaiah P, Sujit M, Pravind S, Bibhuti P, Debajyoti D. Design and In-Vitro Evaluation of Mucoadhesive Buccal Tablets of Repaglinide. Int J Pharma Sci Tech. 21: 4(1); Chatterjee CC. Human physiology. 1th ed., Calcutta, Medical Allied Agency, 1985; Swapna G* et al. Int J Trends in Pharm & Life Sci. 215: 1(4);