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Current Research in Pharmaceutical Sciences 2015 05 04: 124-135 124 ISSN 2250 – 2688 Received: 03/12/2015 Revised: 18/12/2015 Accepted: 26/12/2015 Raghavendra Kumar Gunda J N Suresh Kumar V Satyanarayana G Swarupa Rani G Venkateswarlu Narasaraopeta Institute of Pharmaceutical Sciences Narasaraopet Guntur Dt Andhra Pradesh India- 522601 Correspondence Raghavendra Kumar Gunda Department of Pharmaceutics Narasaraopeta Institute of Pharmaceutical Sciences Narasaraopet Guntur Dt Andhra Pradesh India- 522601 E-mail: Formulation Design Optimization and Evaluation of Carvedilol Phosphate Gastro Retentive Floating Tablets Raghavendra Kumar Gunda J N Suresh Kumar V Satyanarayana G Swarupa Rani G Venkateswarlu e ABSTRACT The main objective of present research work is to formulate the floating tablets of Carvedilol Phosphate using 3 2 factorial design. Carvedilol Phosphate non-selective α 1- β 1 -blocking agent belongs to BCS Class-II and Indicated for treatment of Hypertension/moderate Heart Failure. The Floating tablets of Carvedilol Phosphate were prepared employing different concentrations of HPMCK100M and Sodium bicarbonate in different combinations by Direct Compression technique using 3 2 factorial design. The concentration of HPMCK100M and Sodium bicarbonate required to achieve desired drug release was selected as independent variables X 1 and X 2 respectively whereas time required for 10 of drug dissolution t 10 50 t 50 75 t 75 and 90 t 90 were selected as dependent variables. Totally nine formulations were designed and are evaluated for hardness friability thickness drug content Floating Lag time In-vitro drug release. From the Results concluded that all the formulation were found to be with in the Pharmacopoeial limits and the In-vitro dissolution profiles of all formulations were fitted in to different Kinetic models the statistical parameters like intercept a slope b regression coefficient r were calculated. Polynomial equations were developed for t 10 t 50 t 75 t 90. Validity of developed polynomial equations were verified by designing 2 check point formulations C 1 C 2 . According to SUPAC guidelines the formulation F 8 containing combination of 25 HPMCK100M and 3.75 Sodium bicarbonate is the most similar formulation similarity factor f 2 88.801 dissimilarity factor f 1 2.250 No significant difference t 0.095 to marketed product CARDIVAS. The selected formulation F 8 follows Higuchi’s kinetics and the mechanism of drug release was found to be Non-Fickian Diffusion n 1.035 Super Case-II transport. Keywords: Carvedilol Phosphate 3 2 Factorial Design Gastro retentive Floating Tablet HPMCK100M Floating Lag Time SUPAC. 1. INTRODUCTION Oral administration is the most convenient widely used route for both conventional and novel drug delivery systems and preferred route of drug delivery for systemic action. Tablets are the most popular oral solid formulations available in the market and are preferred by patients and physicians alike. There are many reasons for this not the least of which would include acceptance by the patient and ease of administration. patient compliance and flexibility in formulation etc. From immediate release to site specific delivery oral dosage forms have really progressed.

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Current Research in Pharmaceutical Sciences 2015 05 04: 124-135 125 In long-term therapy for the treatment of chronic disease conditions conventional formulations are required to be administered in multiple doses and therefore have several disadvantages 1 . However when administered orally many therapeutic agents are subjected to extensive presystemic elimination by gastrointestinal degradation and/or first pass hepatic metabolism as a result of which low systemic bioavailability and shorter duration of therapeutic activity and formation of inactive or toxic metabolites 2 . Rapid gastrointestinal transit can result in incomplete drug release from a device above the absorption zone leading to diminished efficacy of the administered dose. Therefore different approaches have been proposed to retain the dosage form in the stomach. These include bioadhesive systems swelling and expanding systems and floating systems. Large single-unit dosage forms undergo significant swelling after oral administration and the swollen matrix inhibits gastric emptying even when the pyloric sphincter is in an uncontracted state 3 . Gastric floating drug delivery system GFDDS can overcome at least some of these problems and is particularly useful for drugs that are primarily absorbed in the duodenum and upper jejunum segments. The GFDDS is able to prolong the retention time of a dosage form in the stomach thereby improving the oral bioavailability of the drug. Gastroretentive dosage forms significantly extend the period of time over which drug may be released and thus prolong dosing intervals and increase patient compliance. 45 Such retention systems are important for certain kind of drugs which are degraded in the intestine like antacids or certain antibiotics enzymes that act locally in the stomach 6-8 . This systems can be retained in the stomach and assist in improving the oral sustained delivery of drugs that have an absorption window in a particular region of the gastrointestinal tract thus ensuring optimal bioavailability. Over the past 30 years as the expense and complications involved in marketing new drug entities have increased with concomitant recognition of the therapeutic advantages of controlled drug delivery the goal in the designing sustained / controlled drug delivery system is to reduce the dosing frequency or to increase effectiveness of the drug by localization at the site of action reducing the dose required or providing uniform drug delivery 3 . Since the early 1950s the application of polymeric materials for medical purposes is growing very fast. Polymers have been used in the medical field for a large extent 4 . Natural polymers remain attractive primarily because they are inexpensive readily available be capable of chemical modifications non- carcinogenicity mucoadhesivity biodegradable biocompatible high drug holding capacity and high thermal stability and easy of compression 5 . This led to its application as excipient in hydrophilic drug delivery system. The various natural gums and mucilages have been examined as polymers for sustained drug release in the last few decades for example Sodium bicarbonate tragacanth gum xanthan gum pectin alginates etc. In the development of a Gastro retentive Floating tablet dosage form. Availability of wide variety of polymer and frequent dosing interval helps the scientist to develop sustained release product. cellulose derivatives such as carboxymethyl cellulose CMC sodium carboxymethyl cellulose hydroxyproyl cellulose HPC and hydroxypropyl methyl cellulose HPMC have been extensively studied as polymer in the Floating tablet formulations along with gas generating agent like NaHCO 3 9 . These polymers are most preferred because of its cost effectiveness broad regulatory acceptance non-toxic and easy of compression. These dosage forms are available in extended release targeted release delayed release prolonged action dosage form. Some factors like molecular size diffusivity pKa-ionization constant release rate dose and stability duration of action absorption window therapeutic index protein binding and metabolism affect the design of sustained release formulation. The future of sustained release products is promising in some area like chronopharmacokinetic system targeted drug delivery system mucoadhesive system particulate system that provide high promise and acceptability. Developing Floating formulations BCS Class-II drugs has become a challenge to the pharmaceutical technologists. Fast release drug generally causes toxicity if not formulated as extended release dosage form. Among various formulation approaches in controlling the release of water-soluble drugs the development of sustained release coated granules has a unique advantage of lessening the chance of dose dumping which is a major problem when highly water-soluble drug is formulated as matrix tablets. Oral sustained release dosage form by direct compression technique is a simple approach of drug delivery systems that proved to be rational in the pharmaceutical arena for its ease compliance faster production avoid hydrolytic or oxidative reactions occurred during processing of dosage forms 10 . The selection of the drug candidates for Floating drug delivery system needs consideration of several biopharmaceutical pharmacokinetic and pharmacodynamic properties of drug molecule 11 . In the present study a Gastro retentive floating dosage form of Carvedilol Phosphate has been developed that makes less frequent administering of drug also to improve Bioavailability. Carvedilol Phosphate is a a non-cardioselective alpha1- beta adrenergic blocking agent with no intrinsic sympathomimetic activity and weak membrane-stabilising activity. The alpha 1- adrenergic blocking activity of CV causes vasodilation and reduces peripheral vascular resistance. At higher doses calcium channel

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Current Research in Pharmaceutical Sciences 2015 05 04: 124-135 126 blocking activity also observed. It is most effective in management of hypertension angina pectoris moderate heart failure of ischemic or cardiomyopathic origin and left ventricular dysfunction with myocardial infarction. Chemical name of Carvedilol Phosphate is 2RS-1-9H-Carbazol-4-yloxy-3-2-2 methoxy phenoxy ethylaminopropan-2-ol phosphate salt 1:1 hemihydrate. has a terminal half-life of 7-10 hr but most of the drug is eliminated with a half-life of about 2 hr and the recommended oral dose for adult is two times a day. Carvedilol Phosphate has advantage over traditional β- blockers with respect to hemodynamic and metabolic effects. Such results indicate its safe and effective therapeutic application particularly in patients with complicated Cardiovascular Diseases CVDs even in paediatric and geriatric patients 12 . It has narrow absorption window i.e. upper part of gastrointestinal tract GIT.Therefore a good candidate for gastroretentive dosage form 1314 . The recommended adult oral dosage of Carvedilol Phosphate is 12.5 mg twice daily for the effective treatment of hypertension. However fluctuations of drug concentration in plasma may occur resulting in side effects or a reduction in drug concentration at receptor side. As the drug is effective when the plasma fluctuations are minimized therefore sustained release dosage form of Carvedilol Phosphate is desirable. The short biological half life of drug 7 h also favors development of sustained release formulations. The gastroretentive drug delivery systems can be retained in the stomach and assist in improving the oral sustained delivery of drugs that have an absorption window in a particular region of the gastrointestinal tract. These systems help in continuously releasing the drug before it reaches the absorption window thus ensuring optimal bioavailability. Thus there is a need to maintain Carvedilol Phosphate at its steady state plasma concentration. Hence the study was carried out to formulate and evaluate Floating dosage form of Carvedilol Phosphate as a model drug and had a aim that final batch formulation parameters should shows prolong drug release. Development of dosage form depends on chemical nature of the drug/polymers matrix structure swelling diffusion erosion release mechanism and the in vivo environment. It is an important issue is to design an optimized formulation with an appropriate dissolution rate in a short time period and minimum trials. Many statistical experimental designs have been recognized as useful techniques to optimize the process variables. For this purpose response surface methodology RSM utilizing a polynomial equation has been widely used. Different types of RSM designs include 3-level factorial design central composite design CCD Box-Behnken design and D-optimal design. Response surface methodology RSM is used when only a few significant factors are involved in experimental optimization. The technique requires less experimentation and time thus proving to be far more effective and cost-effective than the conventional methods of formulating sustained release dosage forms 15-18 . Hence an attempt is made in this research work to formulate Floating Tablets of Carvedilol Phosphate using HPMCK100M and Sodium bicarbonate . Instead of normal and trial method a standard statistical tool design of experiments is employed to study the effect of formulation variables on the release properties. Large scale production needs more simplicity in the formulation with economic and cheapest dosage form. The Floating tablets formulation by direct compression method is most acceptable in large scale production. A 3 2 full factorial design was employed to systematically study the drug release profile . A 3 2 full factorial design was employed to investigate the effect of two independent variables factors i.e the amounts of HPMCK100M and Sodium bicarbonate on the dependent variables i.e. t 10 t 50 t 75 t 90 Time taken to release 10507590 respectively. 2. MATERIALS AND METHODS 2.1 Materials Materials used in this study were obtained from the different sources. Carvedilol Phosphate was a gift sample from Cipla Ltd Mumbai India. HPMCK100M from colorcon Sodium bicarbonate Micro crystalline cellulose were procured from Loba Chemie Pvt.Ltd Mumbai. Other excipients such as Stearic acid citric acid Aerosil and talc were procured from S.D. Fine Chem. Ltd. Mumbai. 2.2 Formulation Development of Carvedilol Phosphate Sustained Release Tablets The factorial design is a technique that allows identification of factors involved in a process and assesses their relative importance. In addition any interaction between factors chosen can be identified. Construction of a factorial design involves the selection of parameters and the choice of responses 19 . A selected three level two factor experimental design 3 2 factorial design describe the proportion in which the independent variables HPMCK100M and Sodium bicarbonate were used in formulation of Carvedilol Phosphate Floating Tablets. The time required for 10 t 10 50 t 50 75 t 75 and 90 t 90 drug dissolution were selected as dependent variables. Significance terms were chosen at 95 confidence interval p0.05 for Final

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Current Research in Pharmaceutical Sciences 2015 05 04: 124-135 127 Equations. Polynomial equations were developed for t 10 t 50 t 75 t 90 step-wise backward Linear Regression Analysis. The three levels of factor X 1 HPMCK100M at a concentration of 25 31.25 37.25. three levels of factor X 2 Sodium bicarbonate at a concentration of 3.75 7.5 11.25 with respect to total Tablet weight was taken as the rationale for the design of the Carvedilol Phosphate floating tablet formulation. Totally nine Carvedilol Phosphate floating tablet formulations were prepared employing selected combinations of the two factors i.e X 1 X 2 as per 3 2 Factorial and evaluated to find out the significance of combined effects of X 1 X 2 to select the best combination and the concentration required to achieve the desired prolonged release of drug by providing gastro retentivity from the dosage form. 2.3 Preparation of Carvedilol Phosphate Floating Tablets All the ingredients were accurately weighed and passed through mesh 60. In order to mix the ingredients thoroughly drug and polymer were blended geometrically in a mortar and pestle for 15 minutes then sodium bicarbonate talc and aerosil were mixed one by one. After thoroughly mixing these ingredients the powder blend was passed through 44 mesh. Powder blend was compressed by using rotary tablet punching machine RIMEK Ahmedabad. Compressed tablets were examined as per official standards and unofficial tests. Tablets were packaged in well closed light resistance and moisture proof containers. 2.4 Experimental Design Experimental design utilized in present investigation for the optimization of Excipients concentration such as concentration of HPMCK100M was taken as X 1 and concentration of Sodium bicarbonate was taken as X 2 . Experimental design was given in the Table 1. Three levels for the Concentration of HPMCK100M were selected and coded as -1 25 031.25 +137.5. Three levels for the Concentration of Sodium bicarbonate were selected and coded as -1 3.75 07.5 +111.25. Formulae for all the experimental batches were given in Table 2 20 . 2.5 Evaluation of carvedilol phosphatesustained release tablets 2.5.1 Hardness 21 The hardness of the tablets was tested by diametric compression using a Monsanto Hardness Tester. A tablet hardness of about 2-4 kg/cm 2 is considered adequate for mechanical stability. 2.5.2 Friability 21 The friability of the tablets was measured in a Roche friabilator Camp-bell Electronics Mumbai. 20 Tablets were taken Weighed and Initial weight was noted W 0 are dedusted in a drum for a fixed time 100 revolutions in a Roche Friabilator and weighed W again. Percentage friability was calculated from the loss in weight as given in equation as below. The weight loss should not be more than 1 Friability Initial weight- Final weight/Initial weight x 100 2.5.3 Content Uniformity 21 In this test 20 tablets were randomly selected and the percent drug content was determined the tablets contained not less than 85 or not more than 115 100±15of the labelled drug content can be considered as the test was passed. 2.5.4 Assay 22 The drug content in each formulation was determined by triturating 20 tablets and powder equivalent to 100 mg was dissolved in 100ml of 0.1N Hydrochloric acid by sonication for 30 min. The solution was filtered through a 0.45μ membrane filter diluted suitably and the absorbance of resultant solution was measured spectrophotometrically at 240 nm using 0.1 N Hydrochloric acid as blank. 2.5.5 Thickness 21 Thickness of the all tablet formulations were measured using vernier calipers by placing tablet between two arms of the vernier calipers. 2.5.6 In Vitro Buoyancy Studies 2324 The tablets were placed in a 100-mL beaker containing 0.1N HCl. The time required for the tablet to rise to the surface and float was determined as floating lag time. 2.5.7 In vitro Dissolution Study 22 The In vitro dissolution study for the Carvedilol Phosphate Floating tablets were carried out in USP XXIII type-II dissolution test apparatus Paddle type using 900 ml of 0.1 N HCl as dissolution medium at 50 rpm and temperature 37±0.5°C. At predetermined time intervals 5 ml of the samples were withdrawn by means of a syringe fitted with a pre-filter the volume withdrawn at each interval was replaced with same quantity of fresh dissolution medium. The resultant samples were analyzed for the presence of the drug release by measuring the absorbance at 240 nm using UV Visible spectrophotometer after suitable dilutions. The determinations were performed in triplicate n3.

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Current Research in Pharmaceutical Sciences 2015 05 04: 124-135 128 2.5.8 Kinetic modeling of drug release 25-28 The dissolution profile of all the formulations was fitted in to zero-order first-order Higuchi and Korsmeyer-peppas models to ascertain the kinetic modeling of drug release. 3. RESULTS AND DISCUSSION Gastro Retentive Floating tablets of Carvedilol Phosphate were prepared and optimized by 3 2 factorial design in order to select the best combination of different release rate modifiers HPMCK100M Sodium bicarbonate and also to achieve the desired prolonged release of drug from the dosage formby retaining drug at gastric environment. The two factorial parameters involved in the development of formulations are quantity of HPMCK100M Sodium bicarbonate polymers as independent variables X 1 X 2 and In vitro dissolution parameters such as t 10 t 50 t 75 t 90 as dependent variables . Totally nine formulations were prepared using 3 levels of 2 factors and all the formulations containing 25 mg of Carvedilol Phosphate were prepared as a floating tablet dosage form by Direct Compression technique as per the formulae given in Table 2. All the prepared tablets were evaluated for different post compression parameters drug content mean hardness friability mean thickness mean diameter Floating lag time as per official methods and results are given in Table 3. The hardness of tablets was in the range of 4.49-4.69 Kg/cm 2 . Weight loss in the friability test was less than 0.68. Drug content of prepared tablets was within acceptance range only. Results for all Post-compression parameters were tabulated or shown in Table 3. In-vitro Dissolution studies were performed for prepared tablets using 0.1 N HCl as a dissolution media at 50 rpm and temperature 37±0.5°C. The In-vitro dissolution profiles of tablets are shown in Fig.1 and the dissolution parameters are given in Table 4. Cumulative Drug release of Factorial Design Formulations F 1 -F 9 at 10 Hr were found to be in the range of 72.93-100.78 . From the dissolution parameters of Formulations reveals that As the amount of polymer in the tablet formulation increases the drug release rate decreases and as the concentration of gas generating agent NaHCO 3 increases the drug release increases and at the same time floating lag time decreases. Therefore required release of drug can be obtained by manipulating the composition of HPMCK100M and Sodium bicarbonate. Much variation was observed in the t 10 t 50 t 75 and t 90 due to formulation variables. Formulation F 8 containing 100 mg of HPMCK100M 30 mg of Sodium bicarbonate showed promising dissolution parameter t 10 0.415 h t 50 2.750 h t 75 5.501 h t 90 9.130 h which meets the objective of work by providing more gastric retentivity and maximum drug release. The difference in burst effect of the initial time is a result of the difference in the viscosity of the polymeric mixtures. Dortunc and Gunal have reported that increased viscosity resulted in a corresponding decrease in the drug release which might be due to the result of thicker gel layer formulation 29 . The In vitro dissolution data of Carvedilol Phosphate Floating formulations was subjected to goodness of fit test by linear regression analysis according to zero order and first order kinetic equations Higuchi’s and Korsmeyer-Peppas models to assess the mechanism of drug release. The results of linear regression analysis including regression coefficients are summarized in Table 4 and plots shown in fig.1234. It was observed from the above that dissolution of all the tablets followed first order kinetics with co-efficient of determination R 2 values in the range of 0.872-0.998. The values of r of factorial formulations for Higuchi’s equation was found to be in the range of 0.931-0.997 which shows that the data fitted well to Higuchi’s square root of time equation confirming the release followed diffusion mechanism. Kinetic data also treated for Peppas equation the slope n values ranges from 0.809- 1.056 that shows Non-Fickian diffusion mechanism Super Case-II Transport. Polynomial equations were derived for t 10 t 50 t 75 and t 90 values by backward stepwise linear regression analysis. The dissolution data Kinetic parameters of factorial formulations F 1 to F 9 are shown in Table 5. Polynomial equation for 3² full factorial designs is given in Equation Y b 0 +b 1 X 1 +b 2 X 2 +b 12 X 1 X 2 +b 11 X 1 ²+b 22 X 2 ²… Where Y is dependent variable b 0 arithmetic mean response of nine batches and b 1 estimated co-efficient for factor X 1 . The main effects X 1 and X 2 represent the average result of changing one factor at a time from its low to high value. The interaction term X 1 X 2 shows how the response changes when two factors are simultaneously changed. The polynomial terms X 1 ² and X 2 ² are included to investigate non-linearity. Validity of derived equations was verified by preparing Two Check point Formulations of Intermediate concentration C 1 C 2 . The equations for t 10 t 50 t 75 and t 90 developed as follows Y 1 0.581+0.170X 1 -0.082X 2 +0.003X 1 X 2 -0.0910 X 1 2 -0.055X 2 2 for t 10 Y 2 3.820+1.110X 1 -0.550X 2 +0.015X 1 X 2 -0.600 X 1 2 -0.340X 2 2 for t 50 Y 3 7.630+2.225X 1 -1.10X 2 +0.025X 1 X 2 -1.200 X 1 2 -0.682X 2 2 for t 75 Y 4 12.680+3.700X 1 -1.820X 2 +0.04X 1 X 2 -1.980 X 1 2 -1.130X 2 2 for t 90

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Current Research in Pharmaceutical Sciences 2015 05 04: 124-135 129 The positive sign for co-efficient of X 1 in Y 1 Y 2 Y 3 and Y 4 equations indicates that as the concentration of HPMCK100M increases t 10 t 50 t 75 and t 90 value increases. In other words the data demonstrate that both X 1 amount of HPMCK100M and X 2 amount of Sodium bicarbonate affect the time required for drug release t 10 t 50 t 75 and t 90 . From the results it can be concluded that As the amount of polymer in the tablet formulation increases the drug release rate decreases and as the concentration of gas generating agent NaHCO 3 increases the drug release increases drug release pattern may be changed by appropriate selection of the X 1 and X 2 levels. The Dissolution parameters for predicted from the polynomial equations derived and those actual observed from experimental results are summarised in Table 6. The closeness of Predicted and Observed values for t 10 t 50 t 75 and t 90 indicates validity of derived equations for dependent variables. The Contour Plots were presented to show the effects of X 1 and X 2 on t 10 t 50 t 75 and t 90. The final best Optimised formulation F 8 is compared with marketed product CARDIVAS shows similarity factor f 2 88.801 difference factor f 1 2.25 There is no significant difference in drug release because t cal is0.05. Table 1: experimental design layout Formulation Code X 1 X 2 F 1 1 1 F 2 1 0 F 3 1 -1 F 4 0 1 F 5 0 0 F 6 0 -1 F 7 -1 1 F 8 -1 0 F 9 -1 -1 4. CONCLUSION The present research work envisages the applicability of rate retarding agent and Gas generating agent such as HPMCK100M and Sodium bicarbonate respectively in the design and development of Gastro Retentive Floating tablet formulations of Carvedilol Phosphate utilizing the 3 2 factorial design. From the results it was clearly understand that As the amount of polymer in the tablet formulation increases the drug release rate decreases and as the concentration of gas generating agent NaHCO 3 increases the drug release increases and both of these polymers can be used in combination since do not interact with the drug which may be more helpful in achieving the desired floating delivery of the drug for longer periods. The optimized formulation followed Higuchi’s kinetics while the drug release mechanism was found to be Non- Fickian Diffusion Super Case-II Transport First order release type controlled by diffusion through the swollen matrix. On the basis of evaluation parameters the optimized formulation F 8 may be used once a day administration in the management of Hypertension Angina Pectoris and moderate Heart Failure.. 5. ACKNOWLEDGEMENTS The author would like to thank Management Principal Teaching Non-teaching Staff of Narasaraopeta Institute of Pharmaceutical Sciences Narasaraopet Guntur D.t A.P. India for providing support for successful completion of research work. REFERENCES 1. Swati Jain Neelesh Kumar Mehra Akhlesh Kumar Singhai and Gaurav Kant Saraogi. Development and evaluation of sustained release matrix tablet of lamivudine. IJPSR 2011 Vol. 21: 454- 461 2. R. Ruben Singh. Design Formulation And In Vitro Evaluation Of Lamivudine Hcl Sustained Release Tablets. International Journal of Research in Pharmaceutical and Nano Sciences 2014 32: 113 – 121. 3. Dasharath M. PatelNatavarlal M. Patel Viral F. Patel and Darshini A. Bhatt. Floating Granules of Ranitidine Hydrochloride- Gelucire 43/01: Formulation Optimization Using Factorial Design. AAPS PharmSciTech 2007 8 2 Article 30. 4. Ravi PR Ganga S Saha RN. Design and study of lamivudine oral controlled release tablets. J American Association of Pharm Scientists Pharm Sci Tech 20078 4:1-9. 5. Prakash P Porwal M Saxena A. Role of natural polymers in sustained release drug delivery system:application and recent approaches. Int Res J of Pharmacy 201129:6-11. 6. Rouge N Buri P Deolkar E.Drug absorption sites in the gastrointestinal tract and dosageforms for site specific drug delivery system Int. J. Pharm 1996 136: 117 ‐139.

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Current Research in Pharmaceutical Sciences 2015 05 04: 124-135 130 7. Khatri S Girdhani D Pahwa R. Recent advances in floating drug delivery system. The Indian Pharmacist. 2007 17–20. 8. Alexander S Juergen S. Gastroretentive drug delivery systems. Expert Opin. Drug Deliv. 2006 3:217 233. 9. Nelson kenneth varadarajan parthasarathy chikkanna narendra prakasam kalyani. Development and evaluation of oral controlled release matrix tablets of lamivudine optimization and in vitro-in vivo studies . Int j pharm pharm sci 2015: 7 1:95-101 10. Amidon GL and R Löbenberg. Modern Bioavailability Bioequivalence and Biopharmaceutics Classification system. New Scientific Approaches to International Regulatory Standards. Eur. J. Pharm. Biopharm 2000 50: 3–12. 11. Rhodes C.T. Robinson J.R. Sustained and controlled drug delivery system In Banker GS editor Modern Pharmaceutics 4th ed. USA:Marcel Dekker.2003 pp 503-505. 12. Sweetman SC Martindale The complete drug reference Pharmaceutical Press London Chicago 34th edition 2005: 881. 13. Desai S Bolton S. Floating controlled-release drug delivery systems: in vitro–in vivo evaluation. Pharm Res. 1993 10: 1321– 1325. 14. Chaudhari ShilpaBawaskar Manish Shirsat Ajinath. Formulation and Evaluation of Bilayer Floating Tablet of Carvedilol Phosphate. Journal of Drug Delivery Therapeutics 2012 25 9-19. 15. M.A.Shende R.P.Marathe S.B. Khetmalas P. N. Dhabale. Studies on development of Sustained release Diltiazem hydrochloride matrices through jackfruit mucilage. International journal of pharmacy and pharmaceutical sciences 2014 6 7: 72- 78. 16. Swarbrick J Boylan JC. Optimization techniques in formulation and processing Encyclopedia of Pharmaceutical technology. New York:Marcel Dekker1994. p. 70. 17. Montgomery DC. Introduction to factorial deigns. Design and Analysis of Experiments. 5th ed. Wiley India Pvt. Ltd:New Delhi2004. p. 170-217. 18. Schwartz BJ Connor RE. Optimization technique in pharmaceutical formulations and processing. J Drugs and Pharm Sci in Modern Pharmaceutics 1996723:727-54. 19. A. Kharia s. N. Hiremath a. K. Singhai l. K. Omray and s. K. Jain. Design and Optimization of Floating Drug Delivery System of Acyclovir Indian J. Pharm. Sci. 2010 72 5: 599-606. 20. Raghavendra Kumar Gunda J. N. Suresh Kumar Ch Ajay Babu and M. V. Anjaneyulu. Formulation Development and Evaluation of Lamotrigine Sustained Release Tablets Using 3 2 Factorial Design International Journal of Pharamceutical Sciences and Research 2015 64: 1746-1752. 21. Raghavendra Kumar Gunda. Formulation Development and Evaluation of Rosiglitazone Maleate Sustained Release Tablets Using 3 2 Factorial Design International Journal of PharmTech Research 2015 84: 713-724. 22. Humera Anjum1 P. Sandhya1 Shama Sultana1 K. Someshwar.. Enhancement of Solubility of Poorly Soluble Drug Using Drug Solution Dropping Technique. International Journal of Scientific and Research Publications 2014 Vol.42: 1-6 23. Rosa M Zia H Rhodes T. Dosing and testing in-vitro of a bioadhesive and floating drug delivery system for oral application. Int J Pharm. 1994105:65-70. 24. Brijesh S. Dave1 Avani F. Amin1 and Madhabhai M. Patel. Gastroretentive Drug Delivery System of Ranitidine Hydrochloride: Formulation and In Vitro Evaluation. AAPS PharmSciTech 2004 5 2 Article 34.. 25. K.P.R.chowdary optimization of valsartan tablet formulation by 2 3 factorial design JGTPS 2014 Volume 5 Issue 11374-1379 . 26. Notari RE. Biopharmaceutics and clinical pharmacokinetics. 4th ed. New York: Marcel Dekker Inc 1987. p. 6-21. 27. Higuchi T. Mechanism of sustained-action medication. Theoretical analysis of rate of release of solid drugs dispersed in solid matrices. J Pharm Sci 1963 51:1145-9. 28. Peppas NA. Analysis of Fickian and non-Fickian drug release from polymers. Pharm Acta Helv 1985 60:110-1. 29. Dortunc B Gunal N. Release of acetazolamide from swellable HPMC matrix tablets. Drug Dev Ind Pharm 1997 23:1245-9.

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Current Research in Pharmaceutical Sciences 2015 05 04: 124-135 131 Table 2: Formulae for the preparation of carvedilol phosphate floating tablets as per experimental design Name of Ingredients Quantity of Ingredients per each Tablet mg F 1 F 2 F 3 F 4 F 5 F 6 F 7 F 8 F 9 Carvedilol Phosphate 25 25 25 25 25 25 25 25 25 HPMCK100M 150 150 150 125 125 125 100 100 100 Sodium bicarbonate 45 30 15 45 30 15 45 30 15 Micro crystalline cellulose 122 137 152 137 162 177 172 187 202 Stearic acid 40 40 40 40 40 40 40 40 40 Citric acid 10 10 10 10 10 10 10 10 10 Aerosil 4 4 4 4 4 4 4 4 4 Talc 4 4 4 4 4 4 4 4 4 Total Weight 400 400 400 400 400 400 400 400 400 Table 3: Post-compression parameters for the formulations S.No Formulation Code Hardness kg/cm 2 Floating lag time min Diameter mm Thickness mm Friability Weight Variation Drug Content 1 F 1 4.65 1.2 9.94 4.66 0.64 400.07 95.56 2 F 2 4.66 3.6 9.96 4.67 0.62 400.32 95.76 3 F 3 4.68 4.2 9.97 4.68 0.57 400.05 95.75 4 F 4 4.55 0.9 9.95 4.51 0.69 400.60 93.50 5 F 5 4.55 3.3 9.98 4.59 0.65 400.45 95.75 6 F 6 4.60 4.2 10.05 4.62 0.53 400.90 97.25 7 F 7 4.43 0.5 10.00 4.42 0.68 400.23 94.59 8 F 8 4.48 2.8 10.02 4.49 0.61 400.66 97.20 9 F 9 4.55 3.5 10.01 4.54 0.55 400.03 96.83

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Current Research in Pharmaceutical Sciences 2015 05 04: 124-135 132 Table 4: Regression analysis data of 3 2 factorial design formulations of carvedilol phosphate F 1 to F 9 are factorial formulations r-correlation coefficient a-Intercept b-Slope and MP-Marketed Product. Table 5: Dissolution parameters of carvedilol phosphate floating tablets 3² full factorial design batches S.NO Formulation Code KINETIC PARAMETERS ZERO ORDER FIRST ORDER HIGUCHI KORSMEYER-PEPPAS a b r a b r a b r a b r 1 F 1 12.34 7.72 0.970 1.993 0.072 0.998 5.285 27.410 0.991 0.960 1.055 0.938 2 F 2 10.578 7.330 0.975 1.991 0.063 0.998 5.716 25.920 0.992 0.934 1.050 0.941 3 F 3 9.403 7.168 0.978 1.991 0.058 0.998 6.300 25.234 0.991 0.909 1.059 0.949 4 F 4 14.531 8.269 0.961 2.004 0.090 0.994 4.639 29.625 0.991 0.998 1.062 0.919 5 F 5 12.925 7.403 0.959 1.978 0.066 0.994 4.295 26.553 0.990 0.965 1.043 0.914 6 F 6 10.515 7.484 0.965 1.989 0.064 0.994 6.388 26.596 0.986 0.901 1.104 0.924 7 F 7 42.205 6.711 0.808 1.926 0.159 0.872 20.915 26.853 0.931 1.300 0.809 0.822 8 F 8 18.632 8.402 0.952 2.018 0.110 0.984 1.682 30.512 0.995 1.056 1.035 0.890 9 F 9 16.335 8.466 0.964 2.026 0.105 0.986 3.459 30.413 0.997 1.031 1.044 0.910 10 MP 19.612 8.484 0.951 2.028 0.118 0.982 1.058 30.889 0.996 1.070 1.023 0.888 S. NO FORMULATION CODE KINETIC PARAMETERS t 10 h t 50 h t 75 h t 90 h 1 F 1 0.639 4.216 8.430 14.005 2 F 2 0.740 4.815 9.621 15.985 3 F 3 0.790 5.158 10.314 17.137 4 F 4 0.511 3.362 6.721 11.167 5 F 5 0.698 4.565 9.133 15.175 6 F 6 0.720 4.708 9.417 15.649 7 F 7 0.285 1.889 3.778 6.273 8 F 8 0.420 2.746 5.495 9.128 9 F 9 0.438 2.878 5.755 9.555 10 MP 0.387 2.545 5.092 8.462

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Current Research in Pharmaceutical Sciences 2015 05 04: 124-135 133 Table 6: Dissolution parameters for predicted and observed values for check point formulations FORMULATION CODE PREDICTED VALUE ACTUAL OBSERVED VALUE t 10 h t 50 h t 75 h t 90 h t 10 h t 50 h t 75 h t 90 h C 1 0.500 3.3075 6.603 10.973 0.502 3.302 6.602 10.971 C 2 0.588 3.868 7.728 12.852 0.587 3.870 7.730 12.849 Fig.1: Comparative Zero Order Plots for F 1 -F 9 COMPARITIVE HIGUCHI PLOTS FOR FORMULATIONS F 1 -F 9 0 20 40 60 80 100 120 0 1 2 3 4 √T CDR F1 F2 F3 F4 F5 F6 F7 F8 F9 Fig.3: Comparative Higuchi Plots for F 1 -F 9 Fig.2: Comparative First Order Plots for F 1 -F 9 COMPARITIVE KORSMEYER-PEPPAS PLOTS FOR FORMULATIONS F 1 -F 9 0 0.5 1 1.5 2 2.5 0 0.2 0.4 0.6 0.8 1 1.2 Log Time LogCDR F1 F2 F3 F4 F5 F6 F7 F8 F9 Fig.4: Comparative Korsmeyer-Peppas Plots for F 1 -F 9 COMPARITIVE ZERO ORDER PLOTS FOR FORMULATIONS F 1 -F 9 0 20 40 60 80 100 120 0 2 4 6 8 10 12 Timeh CDR F1 F2 F3 F4 F5 F6 F7 F8 F9 COMP ARITIVE FIRS T ORDER P LOTS FOR FORMULATIONS F 1 -F 9 -0.5 0 0.5 1 1.5 2 2.5 0 5 10 15 Timeh LogUR F1 F2 F3 F4 F5 F6 F7 F8 F9

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Current Research in Pharmaceutical Sciences 2015 05 04: 124-135 134 Fig.5:Response Surface plot for t 10 Fig.7: Response Surface plot for t 50 Fig.9: Response Surface plot for t 75 Fig.6: Contour plot for t 10 Fig.8: Contour plot for t 50 Fig.10: Contour plot for t 75

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Current Research in Pharmaceutical Sciences 2015 05 04: 124-135 135 Fig.11: Response Surface plot for t 90 Fig.12: Contour plot for t 90

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