RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES,

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES

KARNATAKA, BANGALORE

M. PHARM SYNOPSIS

YEAR OF ADMISSION 24/1/22011

TITLE OF THE SYNOPSIS

“FORMULATION AND EVALUATION OF BUCCAL PATCHES OF

VERAPAMIL”

BY

B.HEMALATHA

M. PHARM, PART- I

DEPARTMENT OF PHARMACEUTICS,

UNDER THE GUIDANCE OF

Dr. PRASANTH V.V, M. Pharm., PhD

PROFESSOR

DEPARTMENT OF PHARMACEUTICS

GAUTHAM COLLEGE OFPHARMACY

R. T. NAGAR, BANGALORE-32,

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES,

BANGALORE, KARNATAKA

ANNEXURE – II

PROFORMA FOR REGISTRATION OF SUBJECT FOR DISSERTATION

1.

NAME OF THE CANDIDATE AND ADDRESS

Ms. BODDU HEMALATHA

DEPARTMENT OF PHARMACEUTICS

GAUTHAM COLLEGE OF PHARMACY

SULTHAN PALAYA, R.T NAGAR (PO)

BENGALURU – 32, KARNATAKA.

2.

NAME OF THE INSTITUTION

GAUTHAM COLLEGE OF PHARMACY,

SULTHAN PALAYA, R.T NAGAR (PO)

BENGALURU – 32, KARNATAKA.

3.

COURSE OF STUDY AND SUBJECT

MASTER OF PHARMACY IN PHARMACEUTICS

4.

DATE OF ADMISSION TO COURSE

24/12/2011

5.

TITLE OF THE TOPIC

FORMULATION AND EVALUATION OF BUCCAL PATCHES OF VERAPAMIL

6.

BRIEF RESUME OF THE INTENDED WORK:

6.1 NEED FOR THE STUDY:

The buccal region offers an attractive route for systemic drug delivery for extended periods of time. Bioadhesive formulations have a wide scope of applications, for both systemic and local effects of drugs. Over the last two decades mucoadhesion becomes of interest for its potential to optimize localized drug delivery, by retaining a dosage form at the site of action (with in gastro intestinal tract) or systemic delivery, by retaining a formulation in intimate contact with absorption site (in the buccal cavity). Mucoadhesion may be defined as a state in which two materials, one of which mucus or a mucous membrane, is held together for extended period of time. The mucosa is relatively permeable with a rich blood supply. The oral transmucosal drug delivery bypasses liver and avoids presystemic elimination in the gastro intestinal tract and liver. These factors make the oral mucosa a very attractive and feasible site for systemic drug delivery. Buccal film may be preferred over adhesive tablet in terms of flexibility and comfort. In addition they can circumvent the relatively short residence time of oral gels on the mucosa, which are easily washed away and removed by saliva. Moreover, the buccal films are able to protect the wound surface, thus reducing pain and treating oral diseases more effectively1.

Buccal mucosa is well supplied with both vascular and lymphatic circulation and drug administered through buccal mucosa can circumvent first-pass hepatic metabolism and pre-systemic elimination in the gastrointestinal (GI) tract. The large absolute surface area of the oral cavity contributes to rapid and extensive drug absorption. Also, buccal drug delivery occurs in a tissue that is more permeable than skin and is less variable between patients, resulting in lower inter-subject variability. Moreover, buccal drug absorption can be promptly terminated in case of toxicity by removing the dosage form from the buccal cavity. It is also possible to administer drugs to patients who cannot be dosed orally2.

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. At the defining cutoff of 140/90 mmHg, 28-44% of the world population has hypertension, with ethnic variations3. It is estimated that the prevalence of hypertension in India is about 25% among urban adults and 10% in rural areas4. The life time risk of developing hypertension is estimated to be 90 %4.Even blood pressure not in the hypertensive range but above optimal increases the cardiovascular risk. Indeed, blood pressure in a continuum and any increase above optimal confers additional independent risk of coronary heart disease, stroke, congestive heart failure, end stage renal disease and peripheral vascular disease even in ranges previously considered nor mal5,6. It is estimated that almost one-third of BP related deaths from coronary heart disease occur in normotensive individuals with systolic BP of 120-139 mmHg or diastolic BP of 80-89 mmHg7.

Verapamil is in a class of medications called calcium-channel blockers. It works by relaxing the blood vessels so the heart does not have to pump as hard. It also increases the supply of blood and oxygen to the heart and slows electrical activity in the heart to control the heart rate. It undergoes hepatic metabolism and its half life is 2.8 to 7.4hrs. The oral bioavailability of Verapamil is less than 35.1%. The short half life and extensive first pass metabolism of Verapamil makes it a suitable candidate for administration via a buccal delivery system that provides sustained drug delivery without pre-systemic metabolism8.

Therefore, in this project we propose to overcome these lacunas by the way of

Formulating Verapamil into unidirectional buccal patches to avoid the first pass metabolism and their by improving the bioavailability.

6.2 REVIEW OF LITERATURE

Doijad et al., (2000) developed and characterized buccal delivery system for Isosorbidedinitrate in the form of unidirectional buccal film for improving bio availability. The films were formulated by solvent casting method using different bioadhesive polymers, Carbopol 934 p and polyvinylpyrrolidone by using two different plasticizers propylene glycol and diethyl phlthalate. Unidirectional release was achieved by preparing composite films with backing membrane. In Vitro studies revealed that release rate of iso sorbide di nitrate was higher from carbopol films containing ratio of eudragit RL 100 and polyvinyl pyrrolidone in proportion of 1:2 and 2:1 respectively by using both plasticizers. Results indicate that therapeutic level of isosorbidedinitrate can be achieved using this buccal adhesive formulation9.

Nafee et al., (2003) prepared the buccal mucoadhesive patches of miconazole nitrate using ionic polymers (SCMC, chitosan) non ionic polymers (PVA, HEC, HPMC). To Improve patch performance and release characteristics a water- soluble hydrophilic additive, PVP was added in two different concentrations 1% and 5 % W/V.Optimum release behavior was shown with patches containing 10% w/v PVA and 5% w/v PVP. Patches exhibited sustained release over more than 5hr.Study of the in vivo release from this formulation revealed uniform and effective salivary levels with adequate comfort and compliance during at least 6h.On the contrary, in vivo release of the commercial oral gel product resulted in a burst and transient release of miconazole, which diminished sharply after the first hour of application10.

Patel et al., (2007) chitosan was used as bioadhesive polymer and different ratio’s of chitosan to PVPK-30 were used. Patches exhibited Controlled release for period of 7 hr. Incorporation of PVP K-30 generally enhanced the release rate .Swelling index was proportional to the concenteration of PVP K-30.Good correlation was observed between the in vitro drug release and in vitro drug permeation with a correation coeffient of 0.9364. Stability study of optimized patches was done in human saliva and it was found that both drug and buccal patches were stable11.

Donnelly et al., (2000) designed and developed mucoadhesive patch containing toluidine blue of (TBO) as a potential delivery system for use in PACT of or pharyngeal candidiasis Patches prepared from aqueous blend of poly (methyl vinyl ether/maleic anhydride) and try propylene glycol methyl either possessed suitable properties for use as Muco adhesive drug delivery systems and were capable of resisting dissolution when immersed in artificial saliva. When releasing directly into can aqueous sink, patches containing 50 and 100 mg TBO cm-2 both generated receiver compartment concentrations exceeding the concenteration (2.0-5.0mgml-1) required to produce high levels of kill (>90%) of both planktonic and bio film-grown c.albicans upon illumination12.

Prasanth et al., (2011) developed salbutamol sulfate patches using Eudragit L-100, HPMC, PVA and Carbopol 934 in various proportions and combinations using PEG-400/PG as plasticizers. Patches were laminated on one side with a water impermeable backing layer for unidirectional drug release. The thickness of medicated patches were ranged between 0.23 ± 0.008 and 0.59 ± 0.007 mm and mass varied between 65.23± 3.3 and 117.92± 4.2 mg. Patches showed an increase in mass and swelling index with PEG-400 when compared with PG. The surface-pH of patches ranged between 6 and 7. Formulations E7, E12, F7, and F12 showed high folding endurance. Residence time of the tested patches ranged between 101 and 110 min. The maximum in vitro release was found to be 99.93% over a period of 120 min for formulation F12. Data of in vitro release from patches were fitted to different kinetic models such as Higuchi and Korsmeyer–Peppas models to explain the release profile. Formulations E7 and F7 were best fitted to the non-Fickian, where as formulations E12 and F12 showed Fickian/anomalous drug release. Stability studies indicated that there was no change in the chemical and physical characteristics during the test period13.

Mamatha et al., (2012) prepared mucoadhesive buccal patches of Aceclofenac using different polymers like hydroxypropyl methylcellulose, Carbopol 934-P, polyvinyl alcohol, polyvinyl pyrrolidone K-30, Eudragit L-100 in various proportion and combinations by solvent casting method. The prepared patches were smooth, elegant in appearance, uniform in thickness, mass and drug content. All the formulation showed folding endurance of _100. A 32 full factorial design was employed to study the effect of variable polymers like Carbopol 934-P and PVP K-30, hydroxypropyl methylcellulose, which significantly influenced characteristics like swelling index and ex vivoresidence time of Aceclofenac buccal patches14.

Surya et al., (2010) formulated and evaluated buccal patches for the delivery of atenolol using sodium alginate with various hydrophilic polymers like carbopol 934 P, sodium carboxymethyl cellulose, and hydroxypropyl methylcellulose in various proportions and combinations were fabricated by solvent casting technique. Various physicomechanical parameters like weight variation, thickness, folding endurance, drug content, moisture content, moisture absorption, and various ex vivo mucoadhesion parameters like mucoadhesive strength, force of adhesion, and bond strength were evaluated. An in vitro drug release study was designed, and it was carried out using commercial semipermeable membrane15.

Subhash et al., (2009) developed sustained release formulation to increase bioavailability and prevent first pass metabolism of drug, verapamil hydrochloride was embedded in sustained released buccal patch over period of 6 hour. The objective of present work was to characterize the effect of chitosan with PVP K-30 on water soluble drug by preparing mucoadhesive buccal patch. Each formulated batch was subjected to various evaluation parameters. The swelling percentage was found to be function of solubility of drug and PVP K-30. Themucoadhesive strength, vapour transmission and in-vitro released of water soluble drug through water insoluble chitosan base matrix were found satisfactorily. The physical appearance of buccal patch was examined by scanning electron microscopy. The released kinetic model best to fit for the optimized batch was Hixson Crowell, indicating that the drug release from systems in which there is a change in the surface area and the diameter of particles present in dosage form16.

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 in-vitro 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 interaction between drug and polymers. The results indicate that suitable mucoadhesive buccal tablets with desired properties could be prepared17.

Thimmasetty et al., (2008) designed buccal mucoadhesive patches of carvedilol. Carvedilol (dose,3.125-25 mg) is β-adrenergic antagonist. Its oral bioavailability is 25-35% because of first pass metabolism. Buccal absorption studies of a carvedilol solution in human volunteers showed 32.86% drug absorption. FTIR and UV spectroscopic methods revealed that there was no interaction between carvedilol and polymers. Carvedilol patches were prepared using HPMC, Carbopol 934, eudragit RS 100, and ethylcellulose. The patches were evaluated for their thickness uniformity, folding endurance, weight uniformity, content uniformity, swelling behaviour, tensile strength, and surface pH. In vitro release studies were conducted for carvedilol-loaded patches in phosphate buffer (pH, 6.6) solution. Patches exhibited drug release in the range of 86.26 to 98.32% in 90 min. Data of in vitro release from patches were fit to different equations and kinetic models to explain release profiles18.

Nelam et al., (2012) formulated and evaluated pantoprazole buccal patches. Buccal delivery of the desired drug using mucoadhesive polymers has been the subject of interest since the early 1980s. Advantages associated with buccal drug delivery have rendered this route of administration useful for a variety of drugs. The goal of the present investigation was to design and evaluate mucoadhesive buccal patches of pantoprazole which offers an attractive route of administration for systemic drug delivery. Pantoprazole (dose, 10-40mg) is proton pump inhibitor used in treatment of erosion and ulceration of the esophagus caused by gastro esophageal reflux disease. Its oral bioavailability is 77% metabolized in the liver by cyp-450 system. The patches were prepared and evaluated for their thickness uniformity, folding endurance, weight uniformity, content uniformity, and In vitro release studies were conducted for pantoprazole loaded patches in phosphate buffer (pH, 7.4)19.

Biswajit et al., (2010) formulated and evaluated pimozide buccal mucoadhesive buccal patches. Pimozide patches were prepared using HPMC (15 & 47 cPs), carbopol 934, poly vinyl alcohol, and poly vinyl pyrolidone. FTIR and UV spectroscopic methods revealed that there is no interaction between pimozide and polymers. The patches were evaluated for their thickness uniformity, folding endurance, weight uniformity, content uniformity, swelling behaviour, tensile strength, and surface pH. In vitro release studies of pimozide-loaded patches in phosphate buffer (pH, 6.6) exhibited drug release in the range of 55.32 % to 97.49 % in 60 min. Data of in vitro release from patches were fit in to different equations and kinetic models to explain release kineticslution20.

6.3 OBJECTIVES OF THE STUDY

The aim of the project was to formulate an alternative dosage form of verapamil (unidirectional mucoadhesive buccal patches), which bypass the hepatic metabolism and release the drug at predetermined rate. This formulation may present distinct advantages over conventional dosage forms by improving the bioavailability and reducing the frequency of administration. The main objective of the present work was to

· Formulate and evaluate the buccal patches of verapamil for unidirectional buccal drug delivery to

· Ensure satisfactory drug release

· Prevent the first-pass metabolism and thereby to enhance improved bioavailability.

· Reducing the frequency of administration

7.

MATERIALS AND METHODS

Drug : Selective anti hypertensive drug (Eg. Verapamil)

Polymer : Eudragit L or Eudragit S, HPMC, Chitosan water soluble, Chitosan acid soluble, Carbopol, PVP, PVA, NaCMC or any other suitable polymer.

Method : Preparation of drug loaded mucoadhesive patches using solvent-

 

casting technique.

7.1 EVALUATIONS

Pre formulation studies including

· Complete characterization of the drug and polymers, and its analytical method development

· Screening of excipients for suitability

· Drug –polymer compatibility study using FTIR/DSC21,22

Evaluation of drug loaded patches

 

A. Physio-chemical evaluation

a) Weight variation test23

b) Thickness uniformity test23

c) Folding endurance test23

d) Surface pH measurement24

e) Swelling study (moisture uptake)25

f) In vitro residence time26

On the basis of physio-chemical parameters best patches would be selected for further analysis

B. Drug content analysis of the selected patches

 

C. Drug –polymer compatibility study using FTIR/DSC21,22

 

D. In vitro release study by using dissolution apparatus27

E. Drug permeation study using chien cell27

  F. Determination of the mechanism of drug release from the buccal patches28

G. Application of ethyl cellulose as backing membrane ,to selected patches and further

Analysis29, 30.

7.2 METHOD OF COLLECTION OF DATA

· Literature review including pub med/med line and internet search.

· Lab experiment.

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.

NO

7.4 Has ethical clearance been obtained from your institution in

Case 7.3?

NO

8.

REFERENCES

1. Alagusundaram A, Chengaiah B, Ramkanth S, S Angala Parameswari, C Madhu, . Int. J. Pharm. Tech. Res. 2009:1(3);557-563.

2. Sudhana Chetty, D Dhachinamoorthi J, Hoogstraate, Verhoef JC, In-vivo buccal delivery of fluorescein isothiocyanate-dextran 4400 with glycodeoxycholate as an absorption enhancer in pigs, J. Pharm. Sci. 85(1996);457 – 60.

3. Gupta R. Trends in hypertension epidemiology in India. J. Hum Hypertens. 2004. 18(2): p 73-8.

4. Vasan RS, Ramachandran S, Vasan, Alexa Beiser, Sudha Seshadri, Martin GL, William BK, Ralph B, Agostino, Daniel Levy. Residual lifetime risk for developing hypertension in middle aged women and men: The Framingham Heart Study. Jama, 2002. 287(8):1003-10.

5. Mc Mahon, S MacMahon S, Peto R, Cutler J, Collins R, Sorlie P, Neaton J, Abbott R, Godwin J, Dyer A, Stamler J. Blood pressure, stroke, and coronary heart disease. Prolonged differences in blood pressure: prospective observational studies corrected for the regression dilution bias. Lancet, 1990.335(8692):765-74.

6. Klag MJ, Klag J, Paul KW, Bryan LR, James DN, Frederick LB, Charles EF, Neil B S, Jeremiah Stamler: Blood pressure and end-stage renal disease in men. N. Eng. J. Med. 1996;334(1):13-8.

7. Stamler J, Stamler R, and Neaton JD. Blood pressure, systolic and diastolic, and cardiovascular risks. US population data. Arch Intern. Med. 1993;153(5):598-615.

8. http://www.ncbi.nlm.nih.gov/pubmed?term=verapamil

9. Doijaid RC, Manvi FV, Malleswara Rao VSN, Patel PS. Buccoadhesive drug delivery system of isosorbide dinitrate: Formulation and evaluation Indian J. Pharma.Sci.2006:68(6);744-748.

10. Nafee NA, Boraie NA, Ismail FA Mortada LM. Mucoadhesive buccal patches of miconazole nitrate: In vitro and in vivo performance and effect of ageing. Int. J. Pharm. 264, 1- 14(2003).

11. Patel VM, Bhupendra GP, Madhabhai MP. Design and characterization of mucoadhesive buccal patches of propranol hydrochloride. (2007) 57, 61-72.

12. R.F.Donnely, P.A McCarron, M.M.Tunney a Woolfson. Topic, J.Photochem.Photobiol.B. (2000) .86, 59-69.

13. Prasanth VV, Ayarivan Puratchikody, Sam Thomarayil Mathew, Ashok Kumar Balaraman. Development and Characterization of Eudragit based Mucoadhesive Buccal Patches of Salbutamol sulphate. Saudi Pharmaceutical Journal, 2011, 19(4), 207-214.

14. Prasanth VV, Mamatha Y, Selvi Arunkumar, Sam TM, Abin Abraham. Formulation and Evaluation of Mucoadhesive Buccal Patches of Aceclofenac . Der. Pharmacia. Lettre. 2012; 4 (1):297-306 .

15. Surya N. Ratha A, Bhabani S. N, Amit K. Nayak, Bisw aranjan Mohanty. Formulation and Evaluation of Buccal Patches for Delivery of Atenolol. AAPS Pharm. Sci. Tech, Vol. 11, No. 3, September 2010.

16. Subhash v. Deshmane, Madhuri a. Channawar, Anil V. Chandewar, Unmesh M. Chitosan based sustained release mucoadhesive buccal patches containing verapamil hcl. Int. J. Pharm. Pharm. Sci. 1, Suppl 1, Nov.-Dec. 2009.

17. 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.

18. J Thimmasetty, GS Pandey and PR Sathesh babu. Design and in vivo evaluation of carvedilol buccal mucoadhesive patches. Pak. J. Pharm. Sci., vol.21, no.3, 2008, 241-248.

19. Neelam sandeep reddy, Deepak kumar B, Nitin kashyap u, Venkata sairam K, Ramya s. formulation and evaluation of pantoprazole Buccal patches. Int. J. Pharm & Ind. Res. 02(1).2012.

20. Biswajit basu kevin garala, Thimmasetty J. Formulation and Evaluation of pimozide Buccal mucoadhesive patches. Int. J. Pharm. Sci. nanotech. volume 2. issue 4 .2010.

21. James RL, Matroprolol Tartrate, Klaus Florey, Analytical profiles of drug J. Pharm. Pharmacol. substances. London: Academic press; 2005.325.

22. John GH, Wyka BE, Clotrimazole. In: Klaus Florey. Analytical profiles of drug substances. London: Academic press; 2005.11. 225.

23. Khanna R, Agarwal SP, Ahuja A. Preparation and evaluation of mucoadhesive buccal films of clotrimazole for oral Candida infections, Indian J. Pharm. Sci. 59 (1997) 299 – 305.

24. P. Bottenberg, C. D. Muynek, J. P. Remon, D. Coomans, D. Slop. Development and testing of bioadhesive, fluoride containing slow-release tablets for oral use,. 43 (1991) 457 – 464.

25. V. M.Patel, B. G. Prajapati. Design and characterization of chitosan-containing mucoadhesive buccal patches of propranolol hydrochloride, Acta Pharm 57 (2007) 61- 72.

26. F. Nakamura, R. O, Y. Machida. T. Nagai. In-vitro and in-vivo nasal mucoadhesion of some water-soluble polymers. Int. J. Pharm. 134(1996) 173 – 181.

27. N. A. Nafee, I. F. Boraie, N. A. and L. A. Mortada, Design and characterization of mucoadhesive buccal patches containing cetylpyridinium chloride, Acta Pharm. 53 (2003) 199-212.

28. S. T. Mathew, G. D, V. V. Prasanth and B. Vinod. Formulation and in vitro-in vivo evaluation of ketoprofen-loaded albumin microspheres for intramuscular administration. J. Microencapsul. 26 (2009) 456 -469.

29. B. Mukherjee , M. S, R. Gupta ,B. Patra ,A. Tiwari and P. Arora. A comparison between povidone-ethylcellulose and povidone-eudragit transdermal dexamethasone matrix patches based on in vitro skin permeation. European Journal of Pharmaceutics and Biopharmaceutics. 59 (2005) 475 – 483.

30. Rowe, Raymond C.; Sheskey, Paul J.; Owen, Sian C, Hand book of Pharmaceutical Excipients, 6th edition, Pharmaceutical Press (2009).

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., PhD

Professor and Head

Department of Pharmaceutics,

Gautham College of Pharmacy,

Sulthan palaya, R.T Nagar (p.o)

Bangalore – 32, Karnataka.

11.2 Signature

11.3 Co-Guide (IF ANY)

11.4 Signature

11.5 Head of the Department

Dr. PRASANTH V.V ,M. Pharm., PhD

Department of Pharmaceutics,

Gautham College of Pharmacy,

Sulthan palaya, R.T Nagar (P.O)

Bangalore – 32, Karnataka.

11.6 Signature

12.

12.1 Remarks of the Director and Principal

The above mentioned information is correct and I recommend the same for approval.

12.2 Signature

Mrs.ARCHANA SAMY,M. Pharm, (PhD)

Principal

Gautham College of Pharmacy,

Sulthan palaya, R.T Nagar (P.O)

Bangalore – 32, Karnataka.

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