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RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES KARNATAKA, BANGALORE M. PHARM SYNOPSIS YEAR OF ADMISSION 17/9/2013 TITLE OF THE SYNOPSIS “FORMULATION AND EVALUATION OF BUCCAL TABLETS OF VERAPAMIL HYDROCHLORIDE” BY AJAY CHAUHAN M. PHARM, PART- I DEPARTMENT OF PHARMACEUTICS UNDER THE GUIDANCE OF Dr. PRASHANTH V.V., M. Pharm., PhD. Professor and HOD DEPARTMENT OF PHARMACEUTICS INSTITUTION GAUTHAM COLLEGE OF PHARMACY SULTAN PALYA, R. T. NAGAR Post, BANGALORE-560 032 1 RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, BANGALORE, KARNATAKA ANNEXURE – II PROFORMA FOR REGISTRATION OF SUBJECT FOR DISSERTATION 1. NAME OF THE CANDIDATE AND Mr. AJAY CHAUHAN ADDRESS DEPARTMENT OF PHARMACEUTICS GAUTHAM COLLEGE OF PHARMACY SULTAN PALYA, R.T. NAGAR Post, BANGALORE – 560 032 2. NAME OF THE INSTITUTION GAUTHAM COLLEGE OF PHARMACY, SULTAN PALYA, R.T NAGAR Post, BANGALORE – 560 032 3. COURSE OF STUDY AND SUBJECT MASTER OF PHARMACY IN PHARMACEUTICS 4. DATE OF ADMISSION TO COURSE 5. TITLE OF THE TOPIC 17/9/2013 “FORMULATION AND EVALUATION OF BUCCAL TABLETS OF VERAPAMIL HYDROCHLORIDE” 2 6. BRIEF RESUME OF THE INTENDED WORK 6.1 NEED FOR THE STUDY Amongst the various routes of drug delivery, the oral route is most preferred to the patient and the clinician alike. However, oral administration of drugs has disadvantages such as hepatic first pass metabolism and enzymatic degradation within the gastro intestinal (GIT), that prohibit oral administration of certain classes of drugs especially peptides and proteins. Trans mucosal routes of drug delivery (mucosal linings of nasal, rectal, Vaginal, ocular and oral cavity) offers distinct advantages over oral administration for systemic drug delivery1. Buccal delivery of drugs provides an attractive alternative to the oral route of drug administration, particularly in overcoming drawbacks associated with the oral mode of dosing2. Other than the common advantages of novel drug delivery systems, buccal mucosa has several specific advantages like, faster and richer blood flow than other parts of oral region. The thickness of the buccal mucosa is 500 - 800 μm and is rough textured. Moreover, the permeability of the buccal mucosa is 4 - 400 times greater than that of the skin. The mucus network of buccal mucosa carries a negative charge, which may play role in mucoadhesion. Buccal drug delivery offers direct access to the systemic circulation through the external jugular vein, which bypass the drugs from the hepatic first-pass metabolism, leading to higher bioavailability3. Cardiovascular disease is responsible for one third of the global deaths and is increasing contributor to the global disease burden. According to WHO globally, an estimated 17.5 million people died from cardiovascular disease in only 2005, representing 30% of global deaths. In United States itself there are 73.6 million people who are diagnosed for hypertension and in Indian subcontinent, it accounts to more than 25% of deaths. High blood pressure is an independent risk factor for cardiovascular disease.4 Hypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. Means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and diastolic. Normal blood pressure is at or below 120/80 mmHg5. High blood pressure is anything above 140/90 mmHg. Hypertension is the opposite of hypotension. Hypertension is classified as either primary (essential) hypertension or 3 secondary hypertension; about 90–95% of cases are categorized as "primary hypertension," which means high blood pressure with no obvious medical cause6.The remaining 5-10% of cases (Secondary hypertension) are caused by other conditions that affect the kidneys, arteries, heart or endocrine system6. The antihypertensive are a class of drugs that are used to treat hypertension (high blood pressure). Evidence suggests that reduction of the blood pressure by 5 mmHg can decrease the risk of stroke by 34%, of heart disease by 21%, and reduce the likelihood of dementia, heart failure, and mortality from cardiovascular disease7. There are many classes of antihypertensive, which lower blood pressure by different means; among the most important and most widely used are the thiazide diuretics, the ACE inhibitors, the calcium channel blockers, the beta blockers, and the angiotensin II receptor antagonists. This type of medication to use initially for hypertension has been the subject of several large studies and resulting national guidelines. The fundamental goal of treatment should be the prevention of the important endpoints of hypertension, such as heart attack, stroke and heart failure. Patient age, associated clinical conditions and end-organ damage also play a part in determining dosage and type of medication administered8. Verapamil is a calcium channel blocker (Class 4) and has the most prominent cardiac electrophysiological action. It blocks L type calcium channels and delays their recovery. The basic action of verapamil is to depress calcium mediated depolarization. This is to suppress automaticity or reentry dependent on slow response. Verapamil has negative inotropic action due to interference with Ca+ + mediated excitation – contraction coupling in myocardium9. Verapamil inhibits voltage-dependent calcium channels. Specifically, its effect on Ltype calcium channels in the heart causes a reduction in ionotropy and chronotropy, thus reducing heart rate and blood pressure. Verapamil's mechanism of effect in cluster headache is thought to be linked to its calcium-channel blocker effect, but which channel subtypes are involved is presently not known. Approximately 70% of an administered dose is excreted as metabolites in the urine and 16% or more in the faeces within 5 days. About 3% to 4% is excreted in the urine as unchanged drug. It has a biological half life of 2.8 – 7.4 hrs10. The oral absorption of the drug from oral dosage forms is about 90% but it is subjected to a very extensive first-pass metabolism in the liver and its bioavailability is only 4 about 20%. Since this drug has a short elimination half-life of 2-4 hours and is eliminated rapidly, repeated daily administration are required to maintain effective plasma levels. It has been suggested that drugs with biological half-life in the range of 2-8 hours are good candidates for sustained release formulations. Verapamil Hydrochloride slow release tablets in doses of 120 to 240 mg and controlled-onset extended release tablets in doses of 180 and 240 mg are available11. Verapamil hydrochloride is water soluble drug and has site specific absorption from GIT and on other hand, the drug is unstable in the alkaline pH of the intestine, but it is widely absorbed from the buccal region12. Based on the above reasons there is a clear need to localize the developed formulation at the target area of the mucosa by preparing a buccal tablets. Previously, studies have been carried out to formulate various mucoadhesive buccal drug delivery devices, including tablets13-16, films17-19, patches20-22, disks23, ointments24 and gels25. Among these formulations, buccal tablets are preferred owing to their accurate dosing, ease of preparation and stability. This is a main concern in the delivery of this category of drugs. Therefore, in this project we propose to overcome these lacunas by the way of formulating them into buccal tablets. 6.2 REVIEW OF LITERATURE Perioli et al (2004), prepared mucoadhesive tablets using different mixtures of cellulose and polyacrylic derivatives to obtain new formulations containing metronidazole for periodontal disease treatment. All tablets were characterized by swelling studies, ex vivo and in vivo mucoadhesive time, ex vivo mucoadhesion force, in vitro and in vivo release. The best mucoadhesive performance and the best in vitro drug release profile were achieved by using hydroxyethyl cellulose (HEC) and carbomer 940 in 2:2 ratios. The chosen tablet, containing 20 mg of metronidazole, performed 12 hrs drug sustained release in healthy human volunteers with buccal concentrations always higher than its MIC. Statistical analysis of in vitro release data showed that the formulation followed non-Fickian release26. Takahashi et al (2007), developed bioadhesive tablets of bovine lactoferrin (B-LF) for the treatment of chronic inflammation in the oral cavity, which has antibacterial properties and 5 immune regulatory functions. B-LF tablets containing pectin, tamarind gum or carboxymethylcellulose (CMC) were prepared by direct compression. Tablets consisting of BLF, pectin and xylitol passed through 60- or 100-mesh sieves were also prepared. The tablets containing CMC had insufficient bioadhesive force. Although the tablets containing tamarind gum showed the longest residence time in the oral cavity, an unpleasant taste gradually developed. The tablets containing pectin showed the highest value of bioadhesive force and the taste was acceptable. The characteristics of the B-LF tablets were improved by adding an appropriate amount of xylitol and using the ingredients sieved by a 100-mesh sieve. The therapeutic effect was evaluated by using rats with an ulcer on the oral mucosa. In the present study, swelling on the periphery of the ulcer was observed after administration of the B-LF tablets, and then the ulcer has reduced overall27. Borgaonkar et al (2011), Formulated mucoadhesive buccal tablets of Loratadine with an objective of enhancing the bioavailability by minimizing first pass metabolism. The buccal tablet were prepared by using HPMC K4M as primary polymer alone and in combination with secondary polymers like chitosan and sodium alginate in varying concentrations by direct compression method28. Ankarao et al (2010), developed mucoadhesive buccal tablets of carvedilol in the form of bilayered tablets. The tablets were prepared using HPMC K4M, sodium CMC and carbopol 934 (CP) to impart mucoadhesion, and ethyl cellulose (EC) was used an impermeable backing layer. Buccal tablets were evaluated for different parameters such as weight uniformity, content uniformity, thickness, hardness, surface pH, swelling index, ex vivo mucoadhesive strength, in vitro drug release, and in vitro drug permeation. The mechanism of drug release was found to be non-Fickian diffusion for all the formulations. Thus, this study has concluded that mucoadhesive buccal tablets of carvedilol may be a better choice to overcome the extensive hepatic first-pass metabolism and to improve the bioavailability of carvedilol29. Velmurugan et al (2010), developed buccoadhesive tablets of piroxicam by using HPMC K4M and carbopol 934 as mucoadhesive polymers. Ten formulations were developed with varying concentrations of polymers. H1 to H5 formulations were composed of HPMC K4M in ratios of 6 1:1 to 1:5 whereas in C1 to C5 formulations Carbopol 934 were used in ratios of 1:0.25 to 1:1.5. The formulations were tested for in-vitro drug release, bioadhesive strength, moisture absorption, residence time and drug permeation through porcine buccal mucosa. Optimized formulation H3 showed maximum release of the drug (97.67±0.41) with the peppas model release profile and permeated 26.52±0.19 of the drug through porcine buccal membrane. H3 formulation showed 12.5gm of mucoadhesive strength, the FTIR results showed no evidence of interaction between the drug and polymers. The results indicated that suitable bioadhesive buccal tablets with desired permeability could be prepared. Stability of piroxicam buccal tablets was determined in natural human saliva; it was found that both piroxicam and buccal tablets were stable in human saliva30. Ashwini et al (2008), developed and evaluated sustained release mucoadhesive tablets of itraconazole. A solid dispersion of itraconazole with eudragit E100 was prepared by spray drying. This was formulated in matrix of hydrophilic mucoadhesive polymers carbopol 934P (CP) and methocel K4M (HPMC). Amounts of CP and HPMC were taken as formulation variables for optimizing response variables i.e. mucoadhesion and dissolution parameters. The optimized mucoadhesive formulation was orally administered to albino rabbits, and blood samples collected were used to determine pharmacokinetic parameters. The solid dispersion markedly enhanced the dissolution rate of itraconazole. The bioadhesive strength of formulation was found to vary linearly with increasing amount of both polymers31. Manivannan et al., (2008) prepared mucoadhesive buccal tablets of diltiazem hydrochloride using Carbopol-934, Sodiumcarboxy methylcellulose (SCMC), Hydroxypropyl methyl cellulose (HPMC), sodium alginate and guar-gum as mucoadhesive polymers. Eight formulations were developed with varying concentrations of polymers. The carbopol-934 is used as a primary polymer because of its excellent mucoadhesive property and secondary polymers like HPMC, SCMC, sodium alginate and guar-gum were used. The effect of secondary polymer loading on drug release was studied. The formulations were tested for invitro drug release and in-vitro swelling studies. Formulation FA2 showed maximum release of 76.98% in 8hours. Formulation FC2 showed maximum swelling index of 3.7 after 8hours. Formulation FA2 follows zero order drug release. FTIR studies show no evidence on 7 interaction between drug and polymers. The results indicate that suitable mucoadhesive buccal tablets with desired properties could be prepared32. Rajkumar et al (2010), designed a mucoadhesive bi-layered tablet containing glibenclamide. Carbopol-940, polyvinylpyrrolidone (PVP), and sodium carboxy methyl cellulose (sodium CMC) were used as polymers. Tablets were obtained through direct compression. The core layer constituents were glibenclamide (5 mg), carbopol, SCMC and PVP in 3 different ratios. The mixture CP: SCMC (2:3) showed good water absorption. The CP: PVP (1:4) formulation showed the best drug release pattern and bioadhesion property. The in vitro release data showed zero order release kinetics based on Higuchi diffusion which was the possible drug release mechanism33. Saikat et al (2010), formulated buccal tablets of losartan potassium with an objective to increase the bioavailability of the drug. Carbopol 934P was used as a primary mucoadhesive polymer and either sodium CMC, HPMC K4M or sodium alginate as secondary polymer, in different ratios. The results of weight variation, thickness, content uniformity, surface pH and bioadhesive strength of all batches were satisfactory and complied with theoretically expected values. In vitro release studies demonstrated a highest percentage of drug release for the formulations with sodium alginate as a secondary polymer. However formulation of this group showed fast fragmentation and higher matrix erosion. Formulations containing SCMC and HPMC K4M, respectively, as secondary polymers showed an adequate release and better mucoadhesion. In vitro drug release showed that the formulations followed zero order kinetics34. 8 6.3 OBJECTIVES OF THE STUDY From literature it has been noted that, the physicochemical and pharmacokinetic profiles of Verapamil Hydrochloride make it a suitable candidate for the preparation of a buccal adhesive drug delivery system. The main objectives of the present work is To formulate and characterize the buccal tablets of Verapamil Hydrochloride with different polymer composition for buccal drug delivery To ensure satisfactory drug release To avoid the first-pass metabolism and thereby to enhance improved bioavailability. 7. MATERIALS AND METHODS Drug : Verapamil Hydrochloride Polymer : Chitosan, HPMC, PVA, Carbopol, PVP, NaCMC, Ethyl Cellulose etc Method : Preparation of buccal tablet by direct compression Method 7.1 EVALUATIONS Pre formulation studies includes Complete characterization of the drug and polymers, and its analytical method development Screening of excipients for suitability Formulation studies includes Preparation of buccal tablets35 Weight variation test36 Thickness uniformity test36 9 Measurement of bioadhesion strength37 In vitro mucoadhesion time38 Swelling studies39,40 Surface pH Study41 In vitro drug release of buccal tablets35 Ex vivo permeation of buccal tablets42 Determination of the mechanism of drug release from the buccal tablet43,44 Stability of buccal tablets Drug –polymer compatibility study & surface morphology study using FTIR45, 46 7.2 METHOD OF COLLECTION OF DATA Literature review including pub med/med line and internet search. Gautham College of Pharmacy Library. Scientific journals and Articles:o International Journal of Pharmaceutical Sciences o International Journal of Pharmaceutics o Topical Pharmaceutical Journals o Advanced DD Reviews Laboratory based studies. Internet Browsing. 7.3 Does the study require any investigations or invention to be conducted on patients or other human or animals? If so, please mention briefly. Buccal mucosal membrane of pig from the slaughter house. 7.4 Has ethical clearance been obtained from your institution in case of 7.3? NO 10 8. REFERENCES 1. Singh J, Saini K. Design and development of mucoadhesive buccal tablets of labetalol hydrochloride. Int J Pharm Bio Med Res. 2013; 4(1):27-33. 2. Velmurgan S, Srinivas P. Formulation and evaluation of losartan potassium mucoadhesive buccal tablets. Asian J Pharm Clin Res. 2013; 6(3)125-130. 3. Hoogsraate AJ, Vehloef JC. In-vivo buccal delivery of fluorescein isothiocyanatedextran 4400 with glycodeoxycholate as an absorption enhancer in pigs. J. Pharm. 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No author reported, Fentanyl effervescent buccal tablets: new formulation for cancer patients with breakthrough pain: a second buccal formulation with minimal evaluation. Prescrire Int. 2009; 18:205. 17. Cui Z, Mumper RJ. Bilayer films for mucosal (genetic) immunization via the buccal route in rabbits. Pharm. Res. 2002; 19:947–53. 18. Averineni RK, Sunderajan SJ. Development of mucoadhesive buccal films for the treatment of oral sub-mucous fibrosis: a preliminary study. Pharm. Dev. Technol. 2009; 14:199–207. 19. Pongjanyakul T, Suksri H. Alginate-magnesium aluminum silicate films for buccal delivery of nicotine. Colloids Surf B Biointerfaces. 2009; 74: 103–113. 20. Wong CF, Yuen KH. Formulation and evaluation of controlled release Eudragit buccal patches. Int. J. Pharm. 1999; 178:11–2. 21. Thimmasetty J, Pandey GS. Design and in vivo evaluation of carvedilol buccal mucoadhesive patches. Pak. J. Pharm. Sci. 2008; 21:241–248. 22. Chinwala MG, Lin S. Application of hydrogel polymers for development of thyrotrophic releasing hormone-loaded adhesive buccal patches. Pharm. Dev. Technol. 2009; 1-17. 23. Han RY, Fang JY. Mucoadhesive buccal disks for novel nalbuphine prod rug controlled delivery effect of formulation variables on drug release and mucoadhesive performance. Int .J. Pharm. 1999; 177:201–9. 24. Bremecker KD, Strempel H. Novel concept for a mucosal adhesive ointment. J. Pharm. 12 Sci. 1984; 73:548–552. 25. Karavana SY, Guneri P. Benzydamine hydrochloride buccal bioadhesive gels designed for oral ulcers: preparation, rheological, textural, mucoadhesive and release properties. Pharm. Dev. Technol. 2009; 14:623-631. 26. Perioli L, Ambrogi V, Rubini D, Giovagnoli S, Ricci M, Blasi P. Novel mucoadhesive buccal formulation containing metronidazole for the treatment of periodontal disease. J Cont Rel. 2004; 95:521–33. 27. Takahashi Y, Takeda C, Seto I, Kawano G, Machida Y. Formulation and evaluation of lactoferrin bioadhesive tablets. Int. J. Pharm. 2007; 343:220-227. 28. Borgaonkar PA, Virsen TG, Hariprasanna RC, Najmuddin M. Formulation and in vitro evaluation of buccal tablets of loratadine for effective treatment of allergy. Int J Res Pharm Chem. 2011;1(3):2231-2781. 29. Ankarao A, Ch.babu rao, Devanna K. Formulation and evaluation of buccoadhesive bilayered tablets of carvedilol. Int J Adv Pharm Sci. 2010;1(1):71-76. 30. Velmurugan S, Deepika B, Nagaraju K, Sundar V. Formulation and in-vitro evaluation of buccal tablets of piroxicam. Int. J. Pharm. Tech. Res. 2010;2(3):1958-1968. 31. Ashwini M, Shivajirao K, Varsha P. Studies on formulation development of mucoadhesive sustained release itraconazole tablet using response surface methodology. AAPS Pharm Sci Tech. 2008;9(3):998-1005. 32. R Manivannan, A Balasubramaniam, DC Prem Anand,G Sandeep and N Rajkumar. Formulation and in-vitro evaluation of mucoadhesive buccal tablets of diltiazem hydrochloride. Res. J. Pharm. Tech. 1(4):2008. 33. Rajkumar MA, Kumar KI, Nagaraju T, Laxmi BS, Srikanth G, Sandeep P. Design and in vitro evaluation of drug release and bioadhesive properties from bucoadhesive tablets of glibenclamide for systemic delivery. J Chem Pharm Res. 2010;2(4):291-03. 34. Saikat P, Marina K, Jolly RP, Ajay BS, Gaurav N, Rahul T. Buccoadhesive tablets of losartan potassium: design and characterization. Int J Pharm Bio Arch. 2010;1(2):150– 54. 35. Patel VM, Prajapti BG, Patel MM. Design and characterization of chitosan containing mucoadhesive buccal patches of propranolol hydrochloride. Acta Pharm. 2007;57(1):61-72. 36. Khanna R, Agarwal SP, Ahuja A. Preparation and evaluation of mucoadhesive buccal films of clotrimazole for oral Candida infections. Indian J. Pharm. Sci. 1997; 59:299– 305. 37. Gupta A, Garg S, Khar RK. Interpolymer complexation and its effect on bioadhesion 13 strength and dissolution characteristics of buccal drug delivery systems, Drug Dev. Ind. J. Pharm. 1994; 20:315-325. 38. Nakamura F, Machida ROY, Nagai T. In-vitro and in-vivo nasal mucoadhesion of some water-soluble polymers. Int. J. Pharm. 1996; 134:173–181. 39. Ritthidej GC, Phaechamud T, Koizumi T. Moist heat treatment on physicochemical change of chitosan. Int. J. Pharm. 2002; 232(1-2):11-22. 40. Agarwal V, Mishra B. Design, development, and biopharmaceutical properties of buccoadhesive compacts of pentazocine. Drug Dev Ind. Pharm. 1999; 25:701–709. 41. Bottenberg P, Cleymaet R, Muynek CD, Remon JP, Coomans D, Slop D. Development and testing of bioadhesive, fluoride-containing slow-release tablets for oral use. J. Pharm. Pharmacol. 1991; 43:457-464. 42. Mira Becirevic-Lacan, Mario Jug. Influence of hydroxypropyl - cyclodextrin complexation on piroxicam release from buccoadhesive tablets. Eur. J. Pharm. Sci. 2004; 21:251–260. 43. Mathew ST, Gayathri DS, Prasanth VV, Vinod B. Formulation and in vitro- in vivo evaluation of ketoprofen – loaded albumin microsphere for intramuscular administration. J. microcapsule. 2009; 26:456-469. 44. Puratchikody A, Prasanth VV, Mathew ST, Kumar BA. Development and characterization of mucoadhesive patches of salbutamol sulfate for unidirectional buccal drug delivery. Acta pharm. 2011; 61:157-170. 45. James RL, Matroprolol Tartrate. In: Klaus Florey, editor- Analytical profiles of Drug substances London: Academic press.2005; 12:325. 46. John GH, Wyka BE, Clotrimazole. In: Klaus Florey, editor- Analytical profiles of Drug substances London: Academic press. 2005; 11:225. 14 9. Signature of Candidate 10. Remarks of the guide The above information is true to the best of my knowledge and the work will be done under my guidance. 11. 11.1 Name and Designation of Guide Dr. Prasanth V.V, M. Pharm., Ph. D. Professor & Head Department of Pharmaceutics Gautham college of Pharmacy Sultan palya, R.T. Nagar Post, Bangalore – 560 032 11.2 Signature 11.3 Co-Guide (IF ANY) 11.4 Signature 11.5 Head of the Department Dr. Prasanth V.V., M. Pharm., Ph. D. Professor & Head Department of Pharmaceutics Gautham college of Pharmacy Sultan palya, R.T Nagar Post, Bangalore – 560 032 11.6 Signature 12. 12.1 Remarks of the Chairman and Principal The above mentioned information is correct and I recommend the same for approval. 12.2 Signature Dr. ARCHANA SWAMY P., M. Pharm., Ph.D. Principal Gautham college of pharmacy Sultan playa, R.T. Nagar Post, Bangalore-560 032 15