Development and Appraisal of Mucoadhesive Tablets of Hydralazine using Isolated Mucilage of Annona Squamosa Seeds

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1 Sakhare and Mali: Design and Development of Microparticulate Drug Delivery System of Hydrochlorothiazide 3349 International Journal of Pharmaceutical Sciences and Nanotechnology Research Paper Development and Appraisal of Mucoadhesive Tablets of Hydralazine using Isolated Mucilage of Annona Squamosa Seeds Sudarshan Singh 1 * and R. Santoki 2 1 SMBT College of Pharmacy Nandi Hills, Nasik Maharashtra, India, and 2 Shree H. N. Shukla Institute of Pharmaceutical Education and Research, Rajkot, India. Received May 7, 2016; accepted June 1, 2016 Volume 9 Issue 4 July August 2016 MS ID: IJPSN SINGH ABSTRACT Bioadhesive materials are agents which adhere to the mucous membrane due to specific properties and release the drug at the site of action in a controlled fashion. Since the biodegradability of the synthetic polymer is at some instance hesitant. In this exploration, a bioadhesive polymer has been developed which was isolated from seeds of Annona squamosa (L.) Burm. fruit. The buccal bioadhesive tablet was prepared using Hydralazine and A. squamosa mucilage as bioadhesive polymer. The prepared tablets were evaluated against existing bioadhesive polymer like Carbopol 934 P and Polycarbophil. From the FTIR spectra it was found that mucilage contains functional group such as OH, NH confirmed that mucilage can probably form hydrogen bond with mucin which is required for the bioadhesion. Further FTIR Spectra reveled that there was no interaction between polymer and drug Hydralazine. Swelling index of A. squamosa mucilage was found to be 23 ± 1.4 (%) which was privileged than Polycarbophil but significantly lesser than Carbopol 934 P 22 ± 0.3 and 27 ± 1.6 (%) respectively. The outcome showed that force of adhesion of A. squamosa mucilage found to be 0.21 ± 0.08 N which was higher than Polycarbophil but lower than Carbopol 934 P having Force of adhesion 0.29 ± 0.02 N and 0.25 ± 0.06 respectively. The Ex-vivo Residence time and in-vitro drug release of optimize batch F 2 found to be 6.8 h and 97 ± 0.4%. Drug permeation through buccal mucosa found to be 89 ± 0.16 % at the end of 10 hr. Overall study concluded that the mucilage of A. squamosa can be used as a pharmaceutical excipient in oral bioadhesive drug delivery systems. KEYWORDS: Annona squamosa (L.) Burm. f., Mucoadhesive polymer; Mucilage, Carbopol 934. Introduction Today, the whole world is increasingly interested in natural drugs and excipients. Natural materials have advantages over synthetic materials because they are non-toxic, less expensive and freely available. Furthermore, they can be modified to obtain tailor made materials for drug delivery systems allowing them to compete with the synthetic products that are commercially available. Many kinds of natural gums are used in the food industry and are regarded as safe for human consumption. It should be noted that many old materials are still popular today after almost a century of efforts to replace them. It is usual to strike a balance between economics and performance in the face of commercial realities. A large number of plant-based pharmaceutical excipients are available today. Many researchers have explored the usefulness of plant-based materials as pharmaceutical excipients. The plant based polymers have been studied for their application in different pharmaceutical dosage forms like matrix controlled system, film coating agent, buccal film, microsphere, nanoparticles, viscous liquid formulations like ophthalmic solutions, suspensions, implants and their applicability and efficacy has been proven. They have also been utilized as viscosity enhancer, stabilizer, disintegrants, solubilizers, emulsifiers, suspending agent, gelling agent, bioadhesive agent and binder in the above mentioned dosage forms (Aungst and Rogers, 1988; Aungst et al., 1988; Lee, 1990). Natural product including plant, animal, and minerals have been the basic for medicinal system. There are some natural excipients which are reported from plant source (Guar gum, Xanthan gum, Acacia etc.) useful in developing bioadhesive drug delivery system. As this excipients are from natural sources are biocompatible and may be non-toxic. As, we know that plant mucilage are high molecular weight polysaccharide, contain functional group like O-H, N-H, C=O in their structure which may form the hydrogen bond with mucin, polyelectrolyte component in nature ABBREVIATIONS: FTIR: Fourier-Transformed Infrared Spectra; DSC: Differential Scanning Calorimeter. 3349

2 3350 Int J Pharm Sci Nanotech Vol 9; Issue 4 July August 2016 and have good swelling property. These all parameter make mucilage to use in bioadhesive system. In present study, the mucoadhesive tablets were developed using mucilage isolated from seeds of Annona squamosa (L.) Burm. f. Materials and Methods Materials Annona squamosa (L.) Burm. f. Seeds authenticated by New Delhi, India, Ref: No, NISCAIR / RHMD- 2189/195. Starch, Carbopol 934 P, PVK-30 and Aerosil were procured from Loba Chemie, Mumbai, India. Polycarbophil was obtained as gift sample from Lubrizol Advance Material, Mumbai. Hydralazine was obtained as gift sample from Medinex Lab, India. Isolation of mucilage from annona squamosa seeds : Fresh A. squamosa seeds were collected and washed with water. Then seeds were crushed and soaked in water for 5-6 h, boiled for 30 minutes and left to stand for 24 h to allow complete release of the mucilage into the water. The mucilage was extracted using a multi-layer muslin cloth bag to remove the marc from the solution. Acetone (three times the volume of filtrate) was added to precipitate the mucilage. A. squamosa seeds mucilage (AIM) was separated, dried in an oven at 40 C, collected, grounded, passed through a mesh # 80 and stored in desiccators at 30 C and 45% relative humidity (RH) for further use (Patidar et al., 2011). Drug-excipients compatibility study : Compatibility of the active ingredient (drug) with the inactive ingredient (other excipients) is one of the major factors amongst others, affecting the stability of the formulation which in turn may have a bearing on the bioavailability of drug. So, to study drug-excipients compatibility, DSC and FTIR study were performed. Fourier-transformed infrared spectra were obtained on FTIR spectrophotometer (Shimadzu 8300, Zapan) using the KBr disk method (2 mg physical mixture of drug and other excipients in 200 mg KBr). The scanning range was cm 1 and the resolution was 1 cm -1. (Singh and Singh, 2010) Differential Scanning Calorimetry curves were obtained by Differential scanning calorimeter (Shimadzu-60, Japan). Physical mixture of drug and other excipients was weighed into aluminum crucible and sample was analyzed by heating at a scanning rate of 10 o C/min over a temperature range 50 o C-300 o C under a nitrogen flow of 40 ml/min (Singh and Singh, 2010). Formulation and development of hydralazine mucoadhesive tablet : Buccal tablet of Hydralazine with A. squamosa seeds mucilage were prepared by using different mucilage concentration viz. 15, 25, 35 and 45 mg. A. squamosa seeds mucilage was used as mucoadhesive material, Starch used as a diluents, Aerosil as a lubricant and PVP K-30 as binder. All ingredients used were passed through a sieve no. 100, weighed and blended. Physicochemical characterizations of granules were determined such as Bulk density, Tapped density, Carr s index, Hausner s ratio and Angle of repose as they are official procedure. The formulations were compressed using 6 mm flat punches using various concentrations. Formulations of designed were presented in Table 1. These buccal tablets were evaluated for their physical properties like general appearance, thickness, hardness, friability, uniformity of weight and uniformity of drug content, as per official compendia Indian Pharmacopoeia, method and results were represented in Table 5. TABLE 1 Formulation of Hydralazine tablet with AIM, Carbopol 934 P and polycarbophil. Ingredient F1 F2 F3 F4 F5 F6 Hydralazine AIM Carbopol 934 P Polycarbophil Starch Aerosil PVP K-30 in IPA (3%) q.s. q.s. q.s. q.s. q.s. q.s. Total Wt. (mg) Swelling index : The swelling behavior of tablet described as the water absorbing capacity was determined by gravimetric methods. In this study, each sample was transferred into a stainless steel basket with 200 mesh of aperture and weighed. The modified basket was then placed in 10 ml distilled water, allowing the tablet to swell at 25 C. The basket was periodically weighed after removing the excess water on the surface with a filter paper (Yash et al., 2012). W 2 W 1 Swelling index (%) = 100 W1 Where, W 2 is the weight of the basket at time t and W 1 is the initial weight of the basket. Surface ph : The surface ph of the buccal tablets was determined in order to investigate the possibility of any side effects in-vivo while administered orally. As the acidic or alkaline ph may cause irritation to the buccal mucosa, the ph was maintained at neutral as closely as possible. A combined glass electrode was used for this purpose. The tablet was allowed to swell by keeping it in contact with 1 ml of distilled water for 2 h at room temperature. The ph was measured by bringing the electrode in contact with the surface of the tablet and allowing it to equilibrate for 1 min (Asha et al., 2010). Water uptake test: Water uptake test was performed on 1% agar gel plates. The tablets were placed with the core facing the gel surface and incubated for 6 h at 37 C. The tablets were weighed before and after standing on the agar plate, from that percentage water absorption was calculated and examined for any physical change (Marikanti, et al., 2010). Bioadhesive characterization of hydralazine buccal tablet : Bioadhesive strength: Goat buccal mucosa was collected from slaughter house and stored in Tyrode s solution. Buccal mucosa was placed on glass slide and tightly tied with thread. The glass slide with the buccal mucosa was affixed on one side of modified physical

3 Sudarshan Singh and Santoki: Development and Appraisal of Mucoadhesive Tablets of Hydralazine using Mucilage 3351 balance. Prepared tablet was stacked to plastic bottle closure with cyanoacrylate adhesive and attached the one arm of modified physical balance with nylon thread, below which glass slide was affixed. On the opposite side of balance, small plastic cup was attached. Now balance was calibrated. Glass slide with mucosa was raised to tablet surface. The mucosal and tablet surface was wetted with few drops of Phosphate buffer (ph 6.8) and tablet was slightly pressed on mucosa for 1 min. to allow mucoadhesion. In plastic cup small increments of water was added to detach the surfaces (Peh and Wong, 1999). The weight in gram required to detach the surfaces was noted. Bioadhesive strength Force of adhesion (N) = Force of adhesion (N) Bond strength (N/m 2 ) = 2 Surface area of tablet (m ) Recording of adherence : To characterize the mucoadhesive strength, recording of adherence method was used. The tablet (120 mg) prepared using test and standard mucoadhesive agent were placed on the slide with buccal segment and lightly pressed with forceps, the assembly kept in a fixed time that is for 5 min. Then water was added slowly, drop wise in to the beaker aside. The amount of water required to pull out the tablet from intestinal segment represent the force required to pull the tablet against the adhesion (Peh and Wong, 1999). The above same procedure is repeated for the comparative study. The force in Newton s is calculated by equation F = W 2 Ex-vivo drug permeation study : The ex-vivo permeation studies of mucoadhesive buccal tablets of drug through excised layer of Goat buccal mucosa were carried out using Franz diffusion cell having 3.14 cm 2 effective diffusion areas. It consists of two compartments one is donor compartment and the other is receptor compartment of 15 ml capacity. The cell contents were stirred with a magnetic stirrer and temperature was maintained at 36 C. The separated buccal epithelium was mounted between two chambers and in receptor chamber phosphate buffer of ph 6.8 was filled and epithelium was allowed to stabilize for the period of 1 h. After stabilization the tablet was placed into the donor compartment and was wetted with 1 ml of phosphate buffer. The amount of drug permeated through the membrane was determined by removing samples periodically and same volume of fresh medium was replaced. Then the samples were analyzed by using UV Visible spectrophotometer (Simadzu-1800) at λ max of 312 nm (Raval and Modi, 2011). In-vitro release studies : In-vitro release studies of Hydralazine bioadhesive tablets were determined using USP Dissolution Testing Apparatus II (Paddle type). The dissolution test was performed using 900 ml of 6.8 phosphate buffer, at (37 ± 0.5) C at 50 rpm. Aliquot (5 ml) of the solution was collected from the dissolution apparatus hourly for 7 h and were replaced with fresh dissolution medium. Aliquots were withdrawn at one hour interval from a zone midway between the surface of dissolution medium and the top of rotating paddle not less than 1 cm apart from the vessel wall. The aliquots were filtered, and the absorbance was measured at 312 nm UV spectrophotometrically (Simadzu-1800) (Marikanti, et al., 2010). Analysis of dissolution data for release kinetic and mechanism: The dissolution data was fitted to Zero order, First order, Higuchi and Korsmeyer-Peppas to ascertain the kinetic modeling of the drug release. The method was adopted for deciding the most appropriate model (Shoaib and Jaweria, 2006; Ameye et al., 2005). Accelerated stability study : The purpose of stability testing is to provide evidence on how the quality of a drug substance or drug product varies with time under the influence of a variety of environmental factors such as temperature, humidity, light, and to establish a retest for the drug substance or a shelf life for the drug product and recommended storage conditions. The storage conditions used for stability studies were accelerated condition (40 C ± 2 C/75% ± 5% RH) and Room temperature (30 C ± 2 C/65% RH ± 5%). Stability study was carried out for the optimized formulations. Tablets of optimized formulation were packed in glass bottle and kept in humidity chamber for 60 days at above mention temperature (Aulton and Taylor 2007; Martin and Swarbrick, 2008; Peh and Wong, 1999). Results and Discussion Plant was authenticated as Annona squamosa (L.) Burm.f and percentage yield for isolated mucilage was found in range of 3-6% w/w. Physico-chemical characterization of Isolated Mucilage: Bulk density of isolated mucilage was found to be ± g/ml and its tapped density was found to be ± g/ml. It was observed that tapped density was increased after tapping which indicate that mucilage has compressibility. Percentage Carr s (compressibility) index value was found to be ± Hausner s Ratio was found to be 1.17 ± and Angle of repose for the mucilage was found to be ± It indicated that isolated mucilage was poorly flowable. In general, compressibility index value up to 15% result in good to excellent flow properties. Drug-excipients compatibility analysis : FTIR spectrums of pure Hydralazine and physical mixture of Hydralazine with excipients are presented in Figure 1 and Figure 2. The FTIR spectral analysis showed that there was no appearance or disappearance of any characteristic peaks of pure drug in the optimized formulation of drug and polymer which confirms the absence of chemical interaction between drug and polymers. DSC curves obtained for pure Hydralazine and physical mixture of pure drug and polymers are shown in Figure 3. Pure powdered Hydralazine showed melting endotherm at C, while physical mixture of drug and excipients showed the melting peak of the drug at C.

4 3352 Int J Pharm Sci Nanotech Vol 9; Issue 4 July August 2016 Formulation and development of uncoated Hydralazine buccal tablet : The result of physicochemical characterization, formulation with different concentration of mucilage and evaluation of tablets are shown in Table 2. Physiochemical characterization showed that granules have good compressibility and good flow property. Hardness and Friability test suggest that tablets have good mechanical strength. Swelling index : Swelling property is important for the assessment of adhesion. Shortly after, swelling adhesion does occur, but a weak bond is formed. To develop maximum adhesion strength, optimum water was needed for polymer particle. It was found that as concentration of AIM increases (As in F1-F4) swelling index also increases (F4 > F3 > F2 > F1). All tablets were found to be stable throughout the period of swelling, without any disintegration being observed. Swelling index test gave idea of swelling behavior of the tablet which can be related to extent of drug release. Surface ph of all the formulation was found to be 6.6 to 6.8. These results revealed that all the formulation provide an acceptable ph in the range of salivary ph (5.5 to 7.0). This indicate that selected bioadhesive agent may not irritate the buccal mucus membrane and was found to be suitable for buccal dosage form. Fig. 1. FTIR spectra of hydralazine. Fig. 2. FTIR spectra of physical mixture of hydralazine with AIM.

5 Sudarshan Singh and Santoki: Development and Appraisal of Mucoadhesive Tablets of Hydralazine using Mucilage 3353 Fig. 3. DSC spectra of hydralazine. Fig. 4. DSC spectra of physical mixture of hydralazine with AIM. TABLE 2 Characterization of uncoated buccal tablet. Batch Code Diameter (mm) Thickness (mm) Hardness (kg/cm 2 ) Friability (%) Weight Variation Test Drug Content (%) Water uptake (%) Surface ph F ± ± ± ± ± ± ± 0.5 F ± ± ± ± ± ± ± 0.4 F ± ± ± ± ± ± ± 0.2 F ± ± ± ± ± ± ± 0.3 F ± ± ± ± ± ± ± 0.6 F ± ± ± ± ± ± ± 0.4 Note: Values are mean of 6 observation (N=6) and value in parenthesis are standard deviation TABLE 3 Swelling index. Batch Code Time (hrs) F ± ± ± ± F ± ± ± ± ± F ± ± ± ± ± F ± ± ± ± ± F ± ± ± ± ± F ± ± ± ± ± Note: Values are mean of 6 observation (N=6) and value in parenthesis are standard deviation (± SD)

6 3354 Int J Pharm Sci Nanotech Vol 9; Issue 4 July August 2016 Water uptake study : Among formulation F1-F4 water absorption order was found to be in following order F4 > F3 > F2 > F1. These revealed that as the concentration of AIM increases the water absorption also increases. Ex-vivo bioadhesive study of hydralazine buccal tablet : Adhesion force is considered to be depending on the formation of hydrogen bond between the functional group of polymer molecule and the mucus. In case of formulation F1-F4 as the concentration of AIM increases the bioadhesive strength and recording of adherence also were found to be increased. This was due to the increasing amount of functional group which formed the hydrogen bond with the mucus. The bioadhesion was found similar for F5 and F6 15. Dissolution profile The dissolution profile of F2 is described in the Table 4. The result of dissolution indicates that there was 7.37 % drug released in first 1 h and % drug released in 7 h. TABLE 4 Dissolution profile of Hydralazine buccal tablet. Time (hour) F1 F2 F3 F4 F5 F Note: Values are mean of 6 observation (N=6) Dissolution profile in simulated salivary medium The dissolution profile of F2 is described in the Table 5. The dissolution data was shown that there were 9.56 % drug released in first 1 h and % drug released in 7 h. TABLE 5 Dissolution profile of Hydralazine buccal tablet in simulated salivary medium. Time in hr Cumulative percentage release of optimized batch F Note: Values are mean of 6 observation (N=6) In vitro diffusion (permeation) study of Hydralazine buccal tablet To determine the diffusion study, formulation F2 was selected because it has promising drug release pattern, having convenient residence time, enough swelling property and having enough bioadhesive strength for the use of buccal tablet. Hydralazine was released from the formulation and permeated through the goat buccal membrane and could possibly permeate through the human buccal membrane. The drug permeation was found to be 89.02% of Hydralazine could permeate through the buccal membrane in 10 hours. TABLE 6 Diffusion profile of Hydralazine buccal tablet. Time in hr Cumulative Percentage Drug Diffuse F1 F2 F3 F4 F5 F Note: Values are mean of 6 observation (N=6) Analysis of dissolution data for release kinetic and mechanism The drug release profile of tablets formulations F1-F6 obtained by varying concentration of AIM is shown in Table 4. Release profile clearly indicates that with increasing the concentration of AIM, drug release rate increases (in case of zero order release rate decrease by h -1 to h -1 ) which may be due to formation of loose matrix and thus decreases the path length for drug to travel. The in-vitro drug release was found to be increased from 78.7 to 102% (F1 to F4) with increasing polymer concentration from 15 to 45% in duration of 7 h. Increase in drug release with increase in AIM concentration may be credited to increase in porosity of the matrices and decrease in drug diffusion path length of the polymeric matrices. These statistics clearly indicate towards and release retardant belonging of AIM tablets. Zero order, first order, Korsmeyer s Peppas and Higuchi model were tested for selected optimized batches. The highest correlation coefficient gives idea about model best fitted to the release data. In the zero order plot and first order plot, obtained r 2 value were and 0.804, indicating the dissolution rate of the drug was independent of the amount of drug available for dissolution and diffusion from the matrix. The mechanism of drug release was evaluated by drug release data into Korsmeyer Peppas model. The value of release exponent n ranges in between to (Table 7) amongst the formulated batches showing release follows non-fickian (anomalous) mechanism means both diffusion and erosion responsible for release of drug from matrix tablets. Table 7 Measurement of mucoadhesive strength and record of adherence. Batch Mucoadhesive Strength Recording of Code Force of adhesion (N) Bond strength (N/m 2 ) Adherence (N) F ± ± F ± ± F ± ± F ± ± F ± ± F ± ± 0.006

7 Sudarshan Singh and Santoki: Development and Appraisal of Mucoadhesive Tablets of Hydralazine using Mucilage 3355 Accelerated stability study Stability studies were carried out at 40 C ± 2 C/ 75% ± 5 RH for 60 days. The table of optimized batch was evaluated for percentage of friability, hardness, percentage drug release and percentage drug release after 60 days. There was no major change found in the drug content and the dissolution profile after 2 month of stability study. Conclusion The polymers are playing an important role in field of bioadhesive sustained release drug delivery system. The selected natural bioadhesive agent from seeds of Annona squamosa was successfully tested for DSC, IR, swelling index, water up tack, and surface ph. It was further tested against their adhesive characteristic like bioadhesive strength measurement and record of adherence along with some synthetic polymers such as Carbopol 934 P and Polycarbophil. The results were compared to that of synthetic polymer. From the FTIR spectra it was found that mucilage contains functional group like OH, NH from that it was conclude that mucilage forms hydrogen bond with mucin which is required for the bioadhesion. Also FTIR Spectra reveled that there was no interaction between polymer and drug Hydralazine. Mucilage was also evaluated for toxicity study and from that it was concluded that it was safe for human consumption. Based on mathematical data revealed from models, it was concluded that the release data was best fitted with zero order. Higuchi equation explains the diffusion controlled release mechanism. As per the release studies and release kinetic model studies, it was found that F2 formulation is considered to be the best formulation, the drug was retarding up to 7 hours with 97.4% drug release follows Non-Fickian mechanism of transport (all the n values are between 0.5 to 1) having dose of drug 25 mg of drug. As mucilage are high molecular weight polysaccharides, poly electrolyte in nature and are composed of various functional groups which are responsible for the hydrogen bond formation with mucin, good swelling index, it is concluded mucilage can be used as bioadhesive polymer. The mucilage obtained from Annona squamosa was having mucoadhesive character and if any modifications are done in chemical structure then it may possess an enhanced adhesiveness, which may replace the synthetic non-ideal mucoadhesive polymer. References Ameye D, Mus D and Foreman P (2005). Spray-Dried Amioca/Carbopol mixtures as buccal bioadhesive carriers. International Journal of Pharmaceutics 14: Asha S. John, Sathesh B. P. R, Goli Divakar, Manoj K. Jangid and Kapil K. Purohit (2010). Development and evaluation of buccoadhesive drug delivery system for Atorvastatin calcium. Journal of Current Pharmaceutical Research 1: Aulton, ME and Taylor MGK (2007). 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Physical pharmacy and pharmaceutical sciences, 5 th Edn; Wolters Kluwer publication, New Delhi pp.492. Patidar D, Jain A, Jatav RK and Sharma H (2011). Formulation and Evaluation of Pioglitazone Hydrochloride Matrix Tablet Containing Aloe Barbadensis Miller Mucilage Natural Antidiabetic Agent. International Journal of Drug Discovery and Herbal Research 1: Peh KK and Wong CF (1999). Polymeric Films as Vehicle for Buccal Drug Delivery: Swelling, Mechanical and Bioadhesive Properties. Journal of Pharmaceutics Science 2: Raval A and Modi V (2011). Formulation and process optimization of buccoadhesive tablet of Rabeprazole. International journal of pharmaceutical and chemical sciences 1: Shoaib HM and Jaweria RI (2006). Evaluation of Drug Release Kinetics from Ibuprofen Matrix Tablets Using HPMC. Journal of Pharmaceutical Science 19: Singh SK and Singh S (2010). Preliminary Investigation of Cassia Sophera Linn Seed Mucilage in Tablet Formulations. International Journal of Pharmaceutical and Applied Sciences. 2: Yash P, Sunil Kumar and Sehrawat R (2012). Design, Development and Characterization of Mucoadhesive tablets of Atenolol. International Journal of Pharma and Bio Sciences 3: Address correspondence to: Dr. Sudarshan Singh, SMBT College of Pharmacy Nandi Hills, Nasik Maharashtra India. Mob: ; sudarshansingh83@hotmail.com