The buccal tablets of Famotidine were prepared by direct. compression technique by using various proportions of mucoadhesive

Transcription

1 FORMULATION AND EVALUATION OF BUCCOADHESIVE TABLETS OF FAMOTIDINE 7.1 Formulation of buccoadhesive tablets The buccal tablets of Famotidine were prepared by direct compression technique by using various proportions of mucoadhesive polymers such as Sodium alginate, HPMC K1, SCMC, Eudragit RL1 and PVP K3. Ethyl cellulose was used as an impermeable backing membrane. Method The mucoadhesive buccal tablets were prepared by using different polymers with varying ratios summarized in the table 7.1 (a&b). The Buccal tablets were prepared by the method of direct compression procedure involving two consecutive steps 16. First, weighed accurately all the ingredients including drug and mucoadhesive polymers thoroughly mixed in a glass mortar for 15 min. Then magnesium stearate was added as a lubricant in the blended material and mixed. After uniform mixing of all ingredients, lubricant was added and again mixed for min. The prepared blend (1 mg) of each formulation was lightly compressed by using 9 mm, flat punch in a single stroke using 9 station rotary machine to form a single layered tablet. Then, 5 mg of ethyl cellulose polymer added and final compression was done to get a bilayer mucoadhesive tablets. Each tablet weighed 15 mg with a thickness of. to.5 mm.

2 134 Table 7.1(a): Composition of buccal tablets of Famotidine Ingredients (mg) T1 T T3 T4 T5 T6 T7 T Famotidine C o r e Sodium alginate SCMC Eudragit RL l a y e r HPMC K PVP K3 Mg Stearate Ethyl cellulose (Backing layer) Total weight Table 7.1(b): Composition of buccal tablets of Famotidine Ingredients (mg) T9 T1 T11 T1 T13 T14 T15 T16 Famotidine C Sodium alginate o r SCMC e Eudragit RL 1 l a HPMC K1 y e PVP K3 r Mg Stearate Ethyl cellulose (Backing layer) Total weight

3 Powder characteristics Before formulation of drug substances into a dosage form, it is essential that drug and polymer should be characterized for their micromeritic properties169. This study gives the information needed to define the nature of the drug substance and provide a framework for the drug combination manufacture of a with dosage pharmaceutical form. The limits excipients of in powder the flow characteristics were present in the table Bulk density and tapped density Bulk density is defined as the mass of the powder divided by the bulk volume. An accurately weight quantity of a powder (W) which was previously passed through sieve number was carefully poured into a graduated cylinder and the volume (Vo) occupied was measured. Then the graduated cylinder was closed with lid, set into density determination apparatus. After that, the volume (Vf) was measured and the operation was continued till the difference between the two readings were less than %. The bulk and tapped density was calculated by using the formula, Bulk density (Db) = W/Vo Tapped density (Dt) =W/Vf 7.. Hausner s ratio The Hausner s indicates the flow property of the powder material. It is the ratio of tapped density to bulk density of the powder and calculated by using the formula,

4 136 Hausner ratio = Dt / Db 7..3 Angle of repose Weighed quantity of the drug was passed through a funnel kept at a height of cm from the surface. The powder was passed, till it formed a heap that touches the tip of the funnel. The radius was measured and it was calculated by the formula. = tan1(h/r) Where, Angle of repose, h Height of the heap formed from the surface r Radius of the heap in cm 7..4 Compressibility index or Carr s index Compressibility is an important measure that can be obtained from bulk and tapped densities. It is calculated by using the following formula and expressed in terms of %. I = 1 (Dt Db)/ Dt Where, I Compressibility index, Dt Tapped density, Db Bulk density Limits for powder flow characteristics was given in table 7. and the obtained results of the powder characteristics such as bulk density, tapped density, angle of repose, Carr s index and Hausner s ratio were present in the table 7.3.

5 137 Table 7.: Limits for powder flow characteristics Flow character Excellent Hausner s ratio Angle of repose (o) 53 Carr s index (%) 1 Good Fair Passable Poor Very poor >1.6 >66 >3 Very, very poor Table 7.3: Data of powder characteristics Derived properties Formulation Code Mean± SD (n=3) Flow properties Mean± SD (n=3) Bulk Tapped Angle of Carr s Hausner s density density repose (o) index (%) ratio T1.437±.1.493± ± ± ±. T.447±.15.53±. 7.1± ± ±.3 T3.493±.15.56± ± ± ±.5 T4.476±.15.56± ± ± ±. T5.433±..496± ± ±1.1 T6.4±.1.463±.6 4.5± ± ±.4 T7.453±.5.536±.5.1± ± ±. T.45±.1.51± ± ± ±.5 T9.41±.1.457± ± ± ±.4 T1.443± ±.3 6.7± ± ±.1 T11.46±..47± ± ± ±.3 T1.413±..477±.15.1± ± ±. T13.453± ±..7± ± ±. T14.4±.17.43±. 6.9± ± ±. T15.453±.15.5±. 5.1±. 9.5±.71 T16.43±.17.47± ± ± ± ±.3 1.1±.3

6 Physicochemical evaluation of buccoadhesive tablets Drug release from the buccoadhesive tablets of Famotidine influenced by the physicochemical parameters such as thickness, weight variation, hardness, friability, drug content, surface ph. Hence evaluation of these parameters is very important to bring out the successful formulation. The physicochemical characteristics obtained for the formulation were presented in the table Thickness The thickness of randomly selected three tablets was measured by using a digital vernier caliper (Absolute digimate) at different positions of the tablet and the average thickness was calculated Weight variation Twenty tablets were randomly selected from each formulation and were weighed individually. The mean weight was calculated and by comparing the individual weight of each tablet deviation from mean weight was calculated. The weight variation was calculated in terms of % by using the formula. % Weight var iation Average weight Individual weight X 1 Average weight Hardness Tablets require a certain amount of strength or hardness and resistance to friability, to withstand mechanical shocks of handling in manufacture, packaging and shipping. The hardness of the tablets was determined using Monsanto hardness tester and expressed in Kg/cm. The hardness of three randomly selected tablets from each

7 139 formulation was determined by placing each tablet diagonally between the two plungers and applying pressure until the tablet broken down into two parts completely and the reading on the scale was noted Friability The Roche friability test apparatus was used to determine the friability of the tablets. Twenty preweighed tablets were placed in the apparatus and operated for 1 revolutions (5 rpm) in four minutes and the tablets are reweighed. The percentage friability was calculated according to the following formula. % Friability Initial Weight Final Weight Initial Weight X Drug content randomly selected tablets from each formulation were finely powdered and powder equivalent to mg of Famotidine was exactly weighed and transferred to 1 ml standard flask containing 5 ml of phosphate buffer ph 6.. The contents were shaken thoroughly. The volume was made up to 1 ml with ph 6. buffer and filtered. 1 ml of the filtrate with suitable dilution was estimated for Famotidine content at 7 nm using a double beam UVvisible spectrophotometer Surface ph As an acidic or alkaline ph may cause irritation to the buccal mucosa, were necessary to keep the surface ph as close to neutral as possible. The tablet was allowed to swell by keeping it in contact with 5 ml of phosphate buffer containing %w/v agar medium for h at

8 14 room temperature. The ph was measured by using ph meter17. The mean of three reading was recorded. Table 7.4: Physicochemical evaluation of buccoadhesive tablets Formu lation code T1 Thickness (mm).3±.3.9± T..19± T3.3.± T4.5.31± T5.3.9± T6.4.3± T7.7.6± T..3± T9..5± T1..6± T11.3.7± T1.3.5± T13..± T14.1.6± T15..4± T16.3 Mean±SD (n=3) Weight variation (%) 1.1± ±.3 1.1± ±.5 1.1± ±.5 1.±.14 1.± ±.7 1.± ±.4 1.±.9 1.4± ±.7 1.±.3 1.5±.53 Friability (%) Hardness (Kg/cm) Surface ph.43±.5.54±.3.6±.4.4±.36.4±.1.51±..61±.3.54±.5.44±.1.44±.6.4±.3.69±.5.47±.15.44±.36.5±.41.5±.3 4.± ±.5 4.3± ±.1 4.3±. 4.±.6 4.± ±.5 4.3±.45 4.± ±.1 4.1±.15 4.±.31 4.± ± ± ± ±.3 6.6± ± ± ± ± ± ± ± ± ± ± ± ±. 6.7±.41 Drug content (mg) 19.77± ±.1 19.± ± ± ± ± ± ± ± ± ± ± ± ± ±.5

9 Measurement of buccoadhesive strength The exvivo buccoadhesive strength171 were determined by modified balance method. Fresh sheep buccal mucosa was obtained and used within h of slaughter. The mucosal membrane was separated by removing underlying fat and loose tissues. The membrane was washed with distilled water and then with phosphate buffer ph 6.. The both sides of the balance were made equal prior to the experiment, by keeping a 5 g weight. The Sheep buccal mucosa was cut into pieces and washed with phosphate buffer ph 6.. A piece of buccal mucosa was tied to the glass vial, which was filled with phosphate buffer. The glass vial was firmly attached into a glass beaker containing phosphate buffer so that it just touched the mucosal surface. The buccal tablet was attached to the lower side of a rubber stopper with cyanoacrylate adhesive and adds weight on the righthand pan. A weight of 5 g was removed from the right hand pan, which lowered the pan along with the tablet over the mucosa. The balance was kept in this position for 5 minutes contact time. The water was added slowly with an infusion set at a rate of 1 drops/min until equivalent weight. The weight was required to detachment from the mucosal surface was noted and this were referred as buccoadhesive strength in grams. Force of adhesion (N) = (Bioadhesive strength (g) 9.)/1 Bond strength (N m ) = Force of adhesion / surface area

10 14 Table 7.5: Buccoadhesive strength of Famotidine buccal tablets Formulation code Buccoadhesive Strength in g T1 3.4 T 5.6 T3 1.5 T4 6.4 T T6 6. T7 9.5 T 33. T9 3.4 T1 3.7 T T1 1.3 T T14 7. T T16.6 Fig: 7.1. Buccoadhesive strength of Famotidine buccal tablets

11 Invitro swelling studies The swelling index of tablets was determined by gravimetry 17. The swelling rate of the bioadhesive tablet was evaluated by using 1% agar gel plate. The average weight of the tablet was calculated (W1).The tablets were placed on gel surface in a petridish placed in an incubator at 37.1C. Tablets was removed at different time intervals (1,, 3, 4, 5 and 6 h), wiped with filter paper and reweighed (W). The swelling index was calculated by the formula. Swelling Index (S.I) = [(WW1)/W1] x 1 Where, W1 initial weight of tablet, W weight of tablet at time Fig: 7.. Swelling of Famotidine buccal tablets at different time intervals

12 144 Table 7.6: Swelling index of Famotidine buccal tablets Formul ation code 1 T1 6.9± ±1. T.3±.7 T3 Swelling index (Mean±S.D) Time in h ± ± ± ± ± ± ± ± ± ± ± ± ±.6 51.± ±.51 T4 3.73± ± ± ± ±. 6.91±.93 T5 7.39± ± ± ± ± ±1.4 T6 19.1± ± ± ± ± ±.43 T7 16.1± ± ± ± ± ±.64 T 6.65±.7 4.9± ± ± ± ±.6 T9 3.35± ± ± ± ± ±.64 T ± ± ± ± ± ±.65 T11 4.7± ± ± ± ± ±.51 T ± ± ± ±. 4.7± ±.75 T13 1.4± ±. 4.1± ±. 57.± ±.7 T14.3± ± ± ± ± ±.3 T15.47± ± ±.6 4.1±.6 57.±.4 64.±.63 T16 5.±.37 3.± ±.5 5.7± ± ±.43 Fig: 7.3. Swelling index of Famotidine buccal tablets

13 Invitro drug release and kinetic studies Invitro drug release studies The release of drug was calculated using USP type II rotating paddle type. The medium used is ph 6. phosphate buffer of 9 ml at 37±.5 c with 5 rpm speed. Backing layer placed towards the glass slide with help of cyanoacrylate adhesive. Aliquots of 5 ml were withdrawn at regular intervals of time and fresh medium is replaced to maintain a sink condition. The samples were filtered and after dilution were analyzed spectrophotometrically at 7 nm.

14 146 Table 7.7: Invitro drug release and Higuchi s data for T1T5 Time in h Sqrt of time Cumulative % release T1 T T3 T4 T Table 7.: Peppa s data for T1T5 Log time Log cumulative % release T1 T T3 T4 T

15 147 Fig: 7.4. Invitro drug release data of T1T5 Fig: 7.5. Higuchi s plot of T1T5 Fig: 7.6. Peppa s plot of T1T5

16 14 Table 7.9: Invitro drug release and Higuchi s data for T6T1 Time in h Sqrt of time Cumulative % release T6 T7 T T9 T Table 7.1: Peppa s data for T6T1 Log time Log cumulative % release T6 T7 T T9 T

17 149 Fig: 7.7. Invitro drug release data of T6T1 Fig: 7.. Higuchi s plot of T6T1 Fig: 7.9. Peppa s plot of T6T1

18 15 Table 7.11: Invitro drug release and Higuchi s data for T11T16 Time in h Sqrt of time Cumulative % release T11 T1 T13 T14 T15 T Table 7.1: Peppa s data for T11T16 Log time Log cumulative % release T11 T1 T13 T14 T15 T

19 151 Fig: 7.1. Invitro drug release data of T11T16 Fig: Higuchi s plot of T11T16 Fig: 7.1. Peppa s plot of T11T16

20 Invitro kinetics studies Data of invitro release were fit into different equations and kinetic models to explain the release kinetics of Famotidine from the buccal tablets. The kinetic models used were a zeroorder equation, higuchi s model and peppa s models i.e. cumulative percentage release of drug Vs square root of time (Higuchi s) and log cumulative percentage release Vs log time (Peppas). To find out the mechanism of drug release from hydrophilic matrices, the invitro dissolution data of each formulation with different kinetic drug release equations. Namely Zero order: Q=K t; Higuchi s square rate at time: Q=K Ht1/ and Peppas: F=Kmtn, where Q is amount of drug release at time t, F is Fraction of drug release at time t, K is zero order kinetic drug release constant, KH is Higuchi s square root of time kinetic drug release constant, Km is constant incorporating geometric and structural characteristic of the tablets and n is the diffusion exponent indicative of the release mechanism. The correlation coefficient values (r) from Higuchi s model indicate the kinetic of drug release and diffusion exponent values (n) from Peppas model indicate the mechanism of drug release.

21 153 Fig: 7.13.Comparative invitro drug release data of T1T16 Fig: Comparative Higuchi s data of T1T16

22 154 Fig: Comparative Peppa s data of T1T16 Table 7.13: Diffusion characteristics of Formulations T1T16 Formulation Correlation coefficient values (r) Diffusion exponent code Zero Order Higuchi s Model value (n) T1 T T3 T4 T5 T6 T7 T T9 T1 T11 T1 T13 T14 T15 T

23 155 Table 7.14: Diffusion exponent drug release mechanism S. No. Diffusion exponent value (n) Drug release mechanism 1 <.45 Fickian release.45 to.9 Non fickian release 3.9 Case II transport 4 >.9 Super case II transport 7.6 Exvivo studies Exvivo permeation study through sheep buccal mucosa An exvivo permeation173 study of Famotidine was carried out using a fresh sheep buccal mucosa using modified diffusion cell at 37±1 C. Fresh sheep buccal mucosa was placed between the donor and receptor compartments. Sheep Buccal mucosa was tied to one end of an open ended compartment. The cylinder, which acts buccal tablet should be as placed a in donor such a way that it should be stuck on the mucous membrane. The receptor compartment was filled with isotonic phosphate buffer ph 6.. The assembly was maintained at 37 ºC and stirred magnetically. Samples were withdrawn at predetermined time intervals and analyzed using UV Spectrophotometer at 7 nm.

24 156 Table 7.15: Exvivo permeation studies of best formulation T5 Time in h Cumulative% Drug Release Fig: Exvivo permeation plot of T5

25 Exvivo muco irritation by histological examination Exvivo muco irritation of Famotidine buccal tablets (T5) were performed by using a fresh sheep buccal mucosa was purchased from local slaughter house immediately after slaughter (sheep buccal mucosa was used for the histological examination within h). Histological examination174 was performed to evaluate the pathological changes in cell morphology and tissue structure during administration of buccoadhesive tablets. The epithelial tissues of mucosa were fixed in 1% neutral buffered formalin for h, washed with distilled water upto 1 h and dehydrated with graded ethanol (6%, %, 9%, 95% and 1%). Then it is treated with xylene for permeation and embedded with liquid paraffin. After h the samples were cut in 4 µm thick sections on a microtome with a surgical blade and suitably stained with eosin. The photograph of both controlled untreated and Famotidine buccal tablet subjected to simple diffusion in sheep buccal mucosa were shown in figure 7.17 and 7.1.

26 15 Fig: Controlled untreated sheep buccal mucosa Fig: 7.1. Famotidine buccal tablet (T5) subjected to simple diffusion in sheep buccal mucosa

27 Invivo drug absorption studies on rabbits175,176 Six male New Zealand white rabbits (.5 kg) were selected for the invivo study, which was already free from disease condition.take iron rod and the hind limbs were tied and kept rabbit in dorsal portion. The optimized formulation T5 kept in the buccal region by the use of clip.a solution of dextrose is used for whole period of study. The blood samples of 1 ml are withdrawn with help of syringe in periodic intervals of time and add in to the test tube containing 1 ml of heparin to prevent blood clotting. subjected 1 ml of for centrifuging supernatant was analyzed at 7 nm The study was at These blood samples were,5 rpm for about 3 minutes. taken, and after suitable dilution, using UV spectrophotometer. approved by the Ethical committee of Annamacharya College of pharmacy, Rajampet, Andhra Pradesh, India, (Reg. No.1/a//CPCSEA/ANCP/IAEC/14/1). Table 7.16: Invivo drug release data for formulation T5 Time (h) Cumulative % drug release 1.15± ± ± ± ±.67

28 16 Fig: Invivo drug release plot of T5 7. Invivo drug absorption kinetics The pharmacokinetic parameters177 such as Cmax, Tmax and AUCt were anticipated from the plasma concentration time profiles of absorption data followed by buccal administration of Famotidine buccal tablet formulation Analysis of Famotidine in plasma The pharmacokinetic parameters of Famotidine were determined after the administration of buccal tablet formulation T5. The buccal tablet of Famotidine was attached on buccal mucosa of rabbit; during the experiment attachment of the tablet was confirmed. Then.5 ml of blood was collected from the ear marginal vein at predetermined interval. The plasma samples were analyzed using a reversed phase high performance liquid chromatographic (HPLC) method. The HPLC system composed of an Agilent compact LC 11 pump and a

29 161 Rheodyne sample injector fitted with a µl sample loop. The detector was operated using a wavelength of 7 nm. A ODS (Octadecyl silane) C1 column (1 µm, 5x4.6 mm) fitted with a guard column was used for separation. The mobile phase consisted of acetonitrile and methanol at the ratio of 7.5:.5. The ph was adjusted to 1. by using triethyl amine. The mobile phase filtered through a.45 µm membrane filter (Sartorius USA) and was then degassed by ultrasonication. Analysis was run at a flow rate of 1. ml/min and quantification was by peak height. The invivo parameters were calculated from the measured concentration of Famotidine in plasma at various time intervals, C max, Tmax, AUCt, and Bioavailability by using WagnerNelson method and the data s are run through the MBV6 software. The WagnerNelson method is one method of calculating absorption kinetics, from plasma concentrationtime data (Cp vs t) following on buccal administration of buccoadhesive tablets of Famotidine in rabbit. C max (4. µg/ml) and Tmax (4 min) were directly obtained from plasma concentrationtime data. The area under the curve is calculated using the trapezoidal rule and the value of kel is estimated from the terminal loglinear portion of the curve, using a least squares linear regression analysis on the last 4 points. By using kel=.19 the bioavailability (Fa) was calculated as a function of time. The semilog graphs were plotted by using Jagfit software Cp vs t and Fa vs t and shown in the figure 7. and 7.1.

30 16 Table 7.17: Invivo kinetic parameters of T5 Time (min) Cp in µg/ml Log Cp AUC(t) Fa Calculated kel, using last 4 points:.19 AUC( z)= 5.63 AUC( )=

31 163 Fig: 7.. Semi log plot of Plasma concentration vs Time Fig: 7.1. Semi log plot of Bioavailability vs Time

32 Stability studies Stability study in human saliva The stability study of buccoadhesive tablets was performed in natural human saliva. Samples of human saliva were collected from 1 humans (ages 14 years) and filtered. The tablets were placed in separate petridishes containing 5 ml of human saliva and put in a temperature controlled oven at 37 C ±. C for 6 h. At regular time intervals tablets were examined for morphology and physical stability Stability studies as per ICH The formulation T5 was selected and the stability studies were carried out at accelerated condition of 4± C, 75±5% RH conditions, stored in desiccators, the tablets were packed in aluminium foil and kept in above said condition for period of three months. The tablets were analyzed periodically for their physical appearance, swelling index, drug content, buccoadhesive strength and invitro drug release. Results were analyzed by Oneway ANOVA followed by Tukey s test. Differences were considered statistically significant at p<.5 and the data were presented in table 7.1.

33 165 Table 7.1: Stability studies of best formulation (T5) Parameters 1st month nd month 3rd month p value Physical appearance No Change No Change No Change Swelling index 7.66±.53ns 7.43±.53ns 7.4±.3ns.739 Drug content 19.5±.1ns 19.7±.116ns 19.73±.11ns.46 Buccoadhesive strength Invitro drug release 34.36±.5ns 33.6±.351ns 33.46±.53ns ±.53ns 97.73±.55ns 9.13±.79ns.6931 All values are expressed as Mean±SD ns = non significant 7.1 Correlation studies The correlation of drug release was carried out for the therapeutic efficacy of a pharmaceutical formulation and is governed by the factors related to invitro and exvivo, invitro and invivo characteristics of the drug. The cumulative percentage of drug release both in invitro and exvivo or invivo was plotted Invitro Exvivo Correlation The data obtained from the invitro drug release of formulation T5 is correlated with exvivo permeation though sheep buccal mucosa followed by diffusion of drug from T5. The correlation of data was carried out by plotting graph in excel. The graph was plotted by taking invitro cumulative percentage of drug release on xaxis and exvivo permeation of cumulative percentage of drug followed by diffusion on yaxis for the same period of time.

34 166 Table 7.19: Invitro and exvivo correlation data of T5 Time (h) Invitro cumulative percentage drug release Exvivo permeation of cumulative percentage drug release Fig: 7.. Invitro and exvivo correlation plot

35 Invitro Invivo Correlation The data obtained from the invitro drug release of formulation T5 is correlated with invivo drug release in rabbit followed by diffusion of drug from T5. The correlation of data was carried out by plotting graph in excel. The graph was plotted by taking invitro cumulative percentage of drug release on xaxis and invivo cumulative percentage of drug release on yaxis for the same period of time. Table 7.: Invitro and invivo correlation data of T5 Time (h) Cumulative% drug release (invitro) Cumulative% drug release (invivo) Fig: 7.3. Invitro and Invivo correlation plot

36 Results and discussion The Novel mucoadhesive buccal tablets of Famotidine were prepared by the method of direct compression by using rotary tablet punching machine. The prepared tablets having two layers, first layer contains pure drug with the mucoadhesive polymers such as Sodium Alginate, Hydroxy Propyl Methyl Cellulose (HPMC), Sodium Carboxy Methyl Cellulose (SCMC), Eudragit RL1 and Poly Vinyl Pyrrolidone (PVP). Second layer contains Ethyl cellulose; it acts as a backing layer to prevent release of drug into saliva of buccal cavity. Powder characteristics It is essential that drug and polymer should be characterized for their micromeritic properties. The powder material is characterized for derived and flow properties. The obtained results were presented in the table 7.3. Physicochemical evaluation of buccoadhesive tablets Drug release from the buccoadhesive tablets of Famotidine influenced by the physicochemical parameters such as thickness, weight variation, hardness, friability, drug content, surface ph. Hence evaluation of these parameters is very important to bring out the successful formulation. The physicochemical characteristics obtained for the formulation were presented in the table 7.4. Measurement of Buccoadhesive strength The buccoadhesive properties of the formulated tablets were shown in table 7.5 and figure 7.1. The bioadhesive strength exhibited

37 169 by Famotidine buccal tablets was satisfactory for maintaining them in oral cavity. The combination of SCMC and sodium alginate shows good adhesion. The SCMC content increases the bioadhesive strength will increase. Upon addition of PVP the bioadhesive strength increases which may be due to hydrogen bond formation and vanderwaals forces and the reaction between sodium ion and alginic acid. Hence the formulation T5 shows maximum buccoadhesive strength when compared to all other formulation. Invitro swelling studies The swelling behavior of the polymer was reported to be crucial for its bioadhesive character. The adhesion occurs shortly after swelling but the bond formed is not very strong. The adhesion increases with the degree of hydration till the point of disentanglement at the polymer tissue surface, which leads to abrupt drop in adhesive strength due to over hydration. The formulation T5 shows maximum swelling index at the end of 6 h (7.6±1.4) due to the highest percentage of SCMC with Sodium alginate. The swelling photos of Famotidine tablet at different time intervals were shown in the figure 7.. The results were shown in the table 7.6 and graphically represented in figure 7.3. Invitro drug release and kinetic studies Significant difference was observed in the release of Famotidine in all formulations. The invitro drug release and Higuchi s plot have shown that the drug release followed zero order kinetics, which was

38 17 known from the regression value (r). Sodium alginate is present in an ionized state, and as a result, the polymeric network gets loosened comparatively, attributing for the higher drug release. The addition of PVP decreases the Famotidine release which may be due to enhancement in swelling of the polymer, which in turn increases the barrier effect and decreases the drug release, thereby controlling the drug release. The data of zero order release; Higuchi s and peppas of all formulations were presented in the tables 7.7 to 7.1 and represented in figures 7.4 to 7.1. Data of invitro release were fit into different equations and kinetic models to explain the release kinetics of Famotidine from the buccal tablets. The kinetic models used were a zero order equation, Higuchi s model and Peppas models. The obtained results in these formulations were plotted in various model treatments as cumulative percentage release of drug versus square root of time (Higuchi s) and log cumulative percentage release versus log time (Peppas). To find out the mechanism of drug release from hydrophilic matrices, the invitro dissolution data of each formulation were calculated with different kinetic drug release equations. The correlation coefficient values (r) indicate that the kinetic of drug release was of zero order. The mechanism of drug release by Peppas model indicates the nonfickian evidenced with diffusion exponent values (n). The diffusion characteristics data of all formulation were presented in the table 7.13.

39 171 Exvivo studies The buccal mucosa represents a barrier to drug permeation and it is intermediate between skin epidermis and the gut in its permeability characteristics. The effectiveness of the buccal absorption could provide means for Famotidine administration can be determined through permeation sheep buccal mucosa. The exvivo permeation study of optimized formulation (T5) through sheep buccal mucosa was shown in the figure 7.16 and the data were present in the table Histomorphological analyses were confirmed that there is no change cell morphology and tissue organization of sheep buccal mucosa. The histolopathological photograph of Famotidine treated sheep buccal mucosa resembles to the control untreated mucosa. The photographs were shown in the figure 7.17 and 7.1 respectively. Invivo drug absorption studies on rabbits Based on the invitro evaluation study the fabricated Famotidine buccal tablet (T5) were selected for invivo evaluation by applying the tablets to rabbits one of its control untreated. The invivo studies of optimized formulation shows zero order release pattern. The study also shows more suitability of the buccal mucosa during administration of buccal tablet. Hence, in rabbits did not show any inflammation or any other sensitization reactions at the administration site. The invivo drug release data of T5 were given in table 7.16 and shown in the figure 7.19.

40 17 Invivo drug absorption kinetics The basic pharmacokinetic parameters such as C max= 4. µg/ml, Tmax= 4 min and AUCt were measured by using plasma concentrationtime profiles. The results were presented in the table Stability study in human saliva The prepared formulation was placed in natural human saliva containing petridish and these were checked regularly for the appearance, color, shape and physical stability. The results were indicating there is no change in the tablet physical properties. Stability studies as per ICH The stability of the formulation at accelerated conditions shows satisfactory results in physical appearance, swelling index, drug content, buccoadhesive strength and invitro drug release. Differences were considered statistically significant at p<.5 and the data were presented in table 7.1. Correlation studies The correlation of drug release was carried out for the therapeutic efficacy of a pharmaceutical formulation and is governed by the factors related to invitro and exvivo, invitro and invivo characteristics of the drug. The drug release follows zero order, showing the correlation coefficient value.99 &.996, the data were presented in the table 7.19 & 7. and shown in figure 7. & 7.3 respectively.

41 Conclusion The Famotidine buccal tablets were prepared by direct compression technique using HPMC K1, Soium alginate, Eudragit RL1, SCMC and PVP as a mucoadhesive polymers and ethyl cellulose as a backing layer. Drug polymer interaction studies by FTIR shows there is no significant interaction between drug and polymers. The prepared Famotidine buccal tablets were characterized based upon their physicochemical characteristics like weight variation, thickness, hardness, friability, surface ph and drug content. The invitro swelling exvivo studies, buccoadhesive strength, exvivo permeation studies, invitro release studies and invivo release studies in rabbits were performed. The satisfactory results were obtained in all prepared formulation and based on the results T5 [SCMC (35 mg) + Sodium alginate (35 mg) + PVP ( mg)] was the best one when compared to other. Good correlation was observed between invitro and in vivo profile, revealed the ability of the formulation to reproduce the invitro release pattern through the biological membrane. Hence Famotidine oral mucoadhesive buccal tablets which are used mainly in minimizing dose and mainly help to improve the patient compliance and Famotidine is a drug of choice for delivery through the control release via buccal tablets.