FORMULATION AND EVALUATION OF MUCOADHESIVE BUCCAL TABLETS OF LERCANIDIPINE HYDROCHLORIDE

M.PHARM DISSERTATION PROTOCOL

Submitted to

RajivGandhiUniversity of Health Sciences

Bangalore, Karnataka.

By

Mr. Khan Nadim Salim

B.Pharm.

Under the Guidance

Of

Dr. Upendra Kulkarni

M.Pharm. Ph.D

DEPARTMENT OF PHARMACEUTICS

R.M.E.S’sCOLLEGE OF PHARMACY,

GULBARGA-585102

2012-2013

Rajiv Gandhi University of Health Sciences, Bangalore, Karnataka.

ANNEXURE-II

PROFORMA FOR REGISTRATION OF SUBJECT FOR DISSERTATION

1. / Name and Address of the candidate / Mr. Khan Nadim Salim
Railway colony RB 2531B,Kurduwadi.
Tal-Madha Dist: Solapur
Maharastra-413208
2. / Name of the Institution / R.M.E.S’s College of Pharmacy, Gulbarga, Karnataka- 585102
3. / Course of study and subject / Master of Pharmacy in Pharmaceutics
4. / Date of admission to course / 08/01/2013
5. / Title of the topic / Formulation and evaluation of Mucoadhesive buccal tablets of LercanidipineHydrochloride
6. / Brief resume of the intended work:
6.1 Need of the study
Buccal delivery of drug provides an alternative to the oral route of drug administration; in recent years, delivery of therapeutic agent through various transmucosal routes gained significant attention owing to their pre-systemic metabolism or instability in the acidic environment associated with oral administration. Bioadhesive buccal delivery of drugs is one of the alternative to the oral route of drug administration, particularly to those drugs that undergo first-pass effect. The stratified squamous epithelium supported by a connective tissue lamina propria, which is present in buccal mucosa1, was targeted as a site for drug delivery several years ago. The term bioadhesive is used to define the attachment of synthetic or natural macromolecules to a biological substrate. When the substrate is mucosal epithelium, a bioadhesive system adheres; this phenomenon is referred as mucoadhesion2. Moreover, rapid absorption of drugs from the buccal mucosal route is observed because of thin mucosal membrane and rich blood supply, the oral cavity is easily accessible for self medication and can be promptly terminated in a case of toxicity just by removing the dosage form from buccal cavity. It is also possible to administer drugs to patients who cannot take orally3-4. Mucoadhesion is a aspect of bioadhesion that was derived from the need to localize drugs at a certain mucosal site in the body 5. In this method, the ability of certain water soluble polymers, which become adhesive on hydration, has been utilized. The most important goals in mucoadhesion consist of drug targeting, controlled and sustained releasing, increasing of residence time. Mucoadhesive polymers should be biocompatible, non-toxic, non-absorbable, strongly non-covalent adhesive and economic6-7. These polymers could be either natural such as Xanthan gum, Locust bean gum8 and Chitosan9. Mucoadhesive drug delivery has a high patient acceptability compared to other non-oral routes10.
Lercanidipine Hydrochloride is a calcium antagonist of the dihydropyridine group and selectively inhibits the transmembrane influx of calcium into cardiac and vascular smooth muscle. Lercanidipine is completely absorbed after oral administration. Peak plasma levels of 3.30 ng/ml ± 2.09 s.d and 7.66ng/ml ± 5.90 s.d occur 1.5-3 hours after dosing with 10mg and 20mg respectively. The absolute bioavailability of the drug is about 10% because of high first pass metabolism. Half life of Lercanidipine Hydrochloride is 2-4 hrs.11-12.
Hence, in the present research work, itis planned to develop new bioadhesive sustained-release tablets for buccal drug delivery of LercanidipineHydrchloride by using natural and synthetic polymers.
6.2 Review of Literature:
1)Noha Adel Nafee, et. al. (2004)13. Formulated buccal mucoadhesive tablets of Diltiazem Hydrochloride (DZ) and Metoclopramide Hydrochloride (MP) in two different doses (30 and 60 mg). The effect of drug and dose on the mucoadhesive properties and in-vitro drug release was evaluated. All formulae produced extended drug release over 8 to 12 hours. Polyacrylic acid based matrices (PAA) showed Fickian’s diffusion release pattern for both drugs. SCMC ensured zero order release for DZ which deviated to anomalous behavior in case of MP. Doubling the dose significantly reduced the bioadhesion strength (p < 0.05) with a slight improvement in drug release rate.
2)Shaila Lewis, et. al. (2006)14. Formulated mucoadhesive buccal tablets of Nicotine for smoking cessation. Three types of tablets were developed each containing two mucoadhesive components (HPMC K4M and Sodium alginate), (HPMC K4M and Carbopol), (Chitosan and Sodium alginate). For each of these types, batches were produced changing the quantity of polymers resulting in nine different formulations. The tablets were evaluated for release pattern and mucoadhesive performance. Pharmacokinetic studies were conducted in smokers. A peak plasma concentration of 16.78 ± 2.27 µg/ml was obtained in two hours, which suggests potential clinical utility in nicotine replacement therapy.
3)M. V. Raman, et. al. (2007)15. Formulated a mucoadhesive buccal drug delivery system by using Metoprolol Tartrate a model drug. The mucoadhesive polymers used in formulation were Carbopol-934, HPMC, Hydroxy ethyl cellulose and Sodium carboxy methyl cellulose. They have concludes that formulation containing Hydroxy ethyl cellulose and Carbopol-934 in the ratio of 1:2 showed the best result.
4)Libero Italo Giannola, et. al. (2007)16. Release of Naltrexone on buccal mucosa. Since a major limitation in buccal drug delivery could be the low permeability of the epithelium, the aptitude of NLX to penetrate the mucosal barrier was assessed. Ex vivo permeation across porcine buccal mucosa 800µm thick was investigated using Franz type diffusion cells and compared with in-vitro datapreviously obtained by reconstituted human oral epithelium 100 µm thick. Both fluxes (Js) and permeability coefficients (Kp) are in accordance, using either buffer solution simulating saliva or natural human saliva. Permeation was evaluated also in presence of chemical enhancers or iontophoresis. No significant differences in penetration rate were observed using chemical enhancers; in contrast, Js and Kp were extensively affected by application of electric fields. Tablets, designed for Naltrexone Hydrochloride (NLX) administration on buccal mucosa, were developed and prepared by direct compression of drug loaded (56%) poly-octylcyanocrylate (poly-OCA) matrices. NLX is slowly discharged from buccal tablets following Higuchian kinetic. Histologically, no signs of flogosis ascribable to NLX and/or poly-OCA were observed, while cytoarchitectural changes due to iontophoresis were detected.
5)David M. Simpson, et. al. (2007)17. Formulated buccal tablet of Fentanyl. Patient with chronic noncancerous pain, including neuropathic pain, may have transitory exacerbations of pain (BPT) that may reach peak intensity within minutes. Typical short-acting oral opioids may not provide sufficiently rapid relief (30 to 60 minutes onset of analgesia). The Fentanyl buccal tablet (FBT) provides a rapid onset of analgesia (10-15 minutes) by enhancing Fentanyl absorption across the buccal mucosa. The study evaluated the efficacy and tolerability of FBT in opioid-tolerant patients with BPT associated with chronic noncancerous neuropathic pain.
6)Vamshi Vishnu Yamsani, et. al. (2007)18. Designed buccal tablets of Carvedilol. The formulation was prepared using HPMC K4M, HPMC K15M and Carbopol-934 as mucoadhesive polymer. The result indicated that suitable bioadhesive buccal tablets with desired release and permeation could be prepared.
7)R Manivannan, et. al. (2008)19. Formulated mucoadhesive buccal tablet of Deltiazem Hydrochloride as a model drug. Carbopol-934, Sodium carboxy methyl cellulose, HPMC, Sodium Alginate, Gaur gum were selected as mucoadhesive polymer. They have reported a suitable mucoadhesive buccal tablet with desired property could be prepared.
8)Ashwini Madgulkar, et. al.(2009)20. Formulated trilayered mucoadhesive tablet of Itraconazole. Solid dispersion of Itraconazole with Eudragit E100 was prepared by spray-drying method to improve dissolution. Trilayered mucoadhesive tablet was prepared, with inner core containing solid dispersion of drug and with Carbopol and Hydroxypropyl methyl cellulose (HPMC) sandwiched between two layers of hydrophilic mucoadhesive polymer mixture of Carbopol and Hydroxypropyl methyl cellulose (HPMC). The drug-release pattern for all the formulation combinations was found to be nonfickian, approaching zero-order kinetics. Suitable combination of two polymers provided adequate bioadhesive strength and sustained-release profile with zero-order kinetics.
9)Margat Chandira, et. al. (2009)21. Formulated buccoadhesive tablet of Verapamil Hydrochloride using Cabopol-934P, HPMC K4M, Hydroxy ethyl cellulose and Sodium carboxy methyl cellulose. They concluded a formulation with Carbopol-934P and Hydroxy ethyl cellulose was optimized formulation with optimum bioadhesive strength, swelling index and desired in-vitro drug release.
10) Bhavain Patel, et. al. (2009)22. Formulated Nifedipine buccal adhesive tablet with objective of avoiding first-pass metabolism and prolonging duration of action. HPMC K4M and Carboxy methyl cellulose is used as polymer. They have reported a satisfactory drug release and good bioadhesion from prepared formulation.
11) R.S. Hirlekar, et. al. (2009)23. Designed buccal drug delivery system for poorly soluble drugs. Drug-methyl-β-cyclodextrin complex was prepared by kneading method. The buccal tablets were evaluated for drug release, mucoadhesive strength and ex-vivo permeability. Characterization of binary system revealed the formation of inclusion complex of drug with methyl-β-cyclodextrin. The complex showed complete release as compared to 32.8% and 42.7% from plane drug and physical mixture respectively in 60 minutes. Tablets containing complex showed complete release at the end of 180min compared to 40.23% from tablets containing plain drug. The buccal tablets containing complex had good mucoadhesive strength. The amount of drug permeated from the tablets occurs in the porcine buccal mucosa at the end of 5 hours was 6.2 mg as compared to 2.51mg from tablets containing plain drug. Thus it can be calculated that buccal tablet containing complexed CAR would have improvement in bioavailability.
7 /

Materials and Methods:

Drug: LercanidipineHydrochloride.
Excipients:
  1. Carbopol
  2. Guar gum
  3. Locust bean gum
  4. Xanthan gum
  5. Chitosan.
  6. Lactose.
  7. Ethyl cellulose.
  8. Magnesium stearate
  9. Talc
  10. Aerosil
Equipments:
  1. Dissolution test apparatus
  2. UV spectrophotometer
  3. Monsanto hardness tester
  4. Roche friabilator
  5. Electronic balance
  6. Single pan digital balance
  7. Tablet punching machine
  8. Sieves
  9. FTIR spectrophotometer & DSC.

Methods:
Direct compression technique: Lercanidipine HydrochlorideMucoadhesive tablets will be prepared by direct compression techniques using different natural and synthetic polymers with varying concentrations.The drug and the polymers will be mixed with other excipients and compression will be done.
Evaluation parameters: (pre and post compressional)
Bulk density and tap densities: Exactly 50 gm of powder blend will be weighed on chemical balance and transferred into a 100 ml measuring cylinder. The cylinder will be dropped on a wooden platform from a height of 2.5 cm three times at 2 seconds interval. The volume occupied by the granules will be recorded as the bulk volume. The cylinder will then tapped on the wooden platform until the volume occupied by the powder blend remained constant. This will be repeated three times for granules. The data generated will be used in calculating the Carr’s compressibility index and Hausner’s ratio.
Angle of repose: 50 gm of the powder blend will be placed in a plugged glass funnel which had a distance of 10 cm from the flat surface. The granules will then allowed to flow through the 8 mm funnel orifice by removing the cotton plug from the funnel orifice. The height of the heap (h) formed as well as the radius of the heap (r) will noted.
Tablet thickness: The thickness of 10 tablets each selected at random from the formulated tablets will be determined using a vernier caliper and the mean of these readings will taken as the mean tablets thickness
Tablet weight uniformity:Twenty tablets will be weighedindividually using a digital balance with the precision of 0.05 mg and readability of 0.1 mg, from which the mean will calculated and percentage deviations determined
Hardness (Crushing strength): The crushing strengths of tablets will determined individually with the Monsanto hardness tester, following 10 tablets will be used and the mean crushing strength will be calculated.
Friability : The friability of 10 tablets will be determined using Roche friabilator (Electrolab, Mumbai). This device subjects the tablets to the combined effect of abrasions and shock in a plastic chamber revolving at 25 rpm and dropping the tablets at a height of 6 inches in each revolution. Preweighed sample of tablets will be placed in the friabilator and will subjected to 100 revolutions. Tablets will be dedusted using a soft muslin cloth and reweighed.
Drug content uniformity: The drug content of the matrices will be determined in triplicate by equilibrating an accurately weighed quantity of theLercanidipineHydrochloride in appropriate dissolution medium. The samples will be filtered, suitably diluted and assayed spectrophotometrically.
Surface pH24 :
The surface pH of the tablets will be determined in order to predict the possible irritants effects of the formulation on the buccal mucosa. The Lercanidipine mucoadhesive tablets will allowed to swell at 37±10C for 2 hours in 50ml appropriate buffer.(pH 6.8). The surface pH of swollen Lercanidipinebuccal tablets will be measured using pH paper.
Swelling studies24: five buccal tablets will weighed individually (W1) and placed separately in 2% agar gel plates with core facing the gel surface and incubated at 37±10C. at regular one hour time intervals until 6hrs, the tablets will removed from the petridish and excess surface water will removed carefully with filter paper. The swollen tablet will then reweighed (W2) and the swelling index (SI) will be calculated using the following formula.
Swelling Index SI=[(W2-W1)/W1]×100
Ex Vivo Mucoadhesion Time24:
The ex vivo mucoadhesion time will be performed ( n=3) after application of the buccal tablet on freshly cut sheep buccal mucosa. The fresh sheep buccal mucosa will be tied on the glass slide, and a mucoadhesive core side of each tablet will wetted with 1 drop of phosphate buffer pH 6.8 and pasted to the sheep buccal mucosa by applying a light force with a fingertip for 30 seconds. The glass slide will bethen put in the beaker, which will filled with 200ml of phosphate buffer pH 6.8, and will kept at 37±10C. after 2 mins, a 50 rpm stirring rate will be applied to simulate the buccal cavity environment and tablet adhesion will be monitored for 12hours. Time for tablet to detach from the sheep buccal mucosa will be recorded as mucoadhesion time.
Bioadhesive strength25:
Bioadhesive strength of all the formulations will be tested; i.e., weight required to pull off the formulation from mucus tissue will be recorded as mucoadhesion/bioadhesion strength in g. This parameter for the tablets will be measured on a modified physical balance.
In-vitro dissolution studies: Release of drug, from the Lercanidipinetablets will be determined using USP Paddle method. The dissolution rate was studied using 900 ml appropriate dissolution medium.
Drug polymer interaction study: The drug and different polymers will be used in this research work. There will be a chance of interaction between drug and polymer. To know any interaction between drug and polymer we planned to check it by FTIR and DSC studies.
Fourier Transform Infrared ( FT-IR) Spectroscopy :
Compatibility studies will be carried out to know the possible interaction between Lercanidipine Hydrochloride and excipients used in formulations. Physical mixtures of drugs and excipients will be prepared to study the compatibility. The drug polymer compatibility studies will be carried out using FTIR spectroscopy.
Differntial Scanning Calorimetry (DSC) :
To study the compatibility pure drug, physical mixtures of drug and excipients the DSC studies will be carried out. The analysis will be performed under Nitrogen (nitrogen flow rate 50 ml per min) in order to eliminate oxidative and pyrolytic effects at standered heating rate of 100Cper min over the temperature range of 500C- 4000C.
Stability studies: On selected fabricated tablets will strip packaged and kept at 450 C with 75% RH. Samples will withdrawn at 0, 15, 30 and 45 days for evaluation of appearance, drug content and in- vitro drug release.
7.1Source of data:
a)Internet.
b)GulbargaUniversity Library, Gulbarga
c)RGUHS (Helinet).
d)International Pharmaceutical Abstracts
7.2 Method of collection of data:
The data for the study is planned to collect from the laboratories based on experiment which include the following:
  • Formulation and evaluation of mucoadhesive buccal tablets ofLercanidipineHydrochloride.
  • Evaluationmucoadhesive buccal tablets with respect to drug content determination and in-vitro release study.
  • Evaluation of mucoadhesive buccal tablets with respect to some physical parameters as given above.

7.3 Does the study require any investigation to be conducted on patients or other humans or animals? If so, please describe briefly
Not under the plan of work.
7.4 Has ethical clearance been obtained from your institution incase of 7.3
Not applicable
8. / List of References
1)Squier C.A, Wertz PW. Structure and function of the oral mucosa and implications for drug delivery. In: Rathbone MJ, editor. Oral mucosal drug delivery. New York: Marcel Dekker; 1996; 1-2.
2)Mortazavi S.A. An in-vitro assessment of mucus/mucoadhesive interactions. Int. J Pharm. 1995; 124; 173-182.
3)Junginger H. E, Hoogstrate JA and Verhoef JC. Recent advances in buccal drug delivery and absorption in-vitro and in-vivo studies. J. Control. Rel.1999; 62: 149-159.
4)Shojael H. Buccal mucosa as route for systemic drug delivery- A review. J. Pharm. Sci. 1998; 1:15-30.
5)Ahuja A, Khar R.K, J. Al. Mucoadhesive drug delivery systems, Drug Dev. Ind. Pharm.:1997;23 ;5: 489-515.
6)Gayot A. Bioadhesive polymers, J. Pharm. Belg. 1985;40: 332-338.
7)Ch’ng H.S, Park H, Kelly P, Robinson J.R. Bioadhesive polymers as platforms for oral controlled drug delivery, Synthesis and evaluation of some swelling, water insoluble bioadhesive polymers, J. Pharm. Sci. 1985;74: 399-405.
8)Deshmukh V.N., Harsulkar A.A., Sakarkar D.M.. Formulation and in-vitro evaluation of bioadhesive tablets using hydrophilic gum blends. Int. J. Pharm. Res. 2009; 1;1: 16-22.
9)Balamurugan M, Saravanan V.S, Ganesh P, Senthil S.P, Hemalatha P.V. and Sudhir Pandya. Development and in-vitro evaluation of mucoadhesive buccal tablets of Domperidone. Res. J. Pharm. and Tech. 1; 4;Oct.-Dec. 2008:377-380.
10) Viviana De Caro, Giulia Giandalia, Maria Gabriella Siragusa, Carlo Paderni, Giuseppina Campisi, Libero Italo Giannola. Evaluation of Galantamine transbuccal absorption by reconstituted human oral epithelium and porcine tissue as buccal mucosa model: PartI.Eur. J. Pharm., Biopharm.70 2008:869-873.
11)Doddayya H, Patil S.S, Suman M, Kumar P, Udupi R.H.Design and evaluation of Mucoadhesive buccal films of Lercanidipine HCL.Indian Drugs 2013; 50(7): 31-40.
12) Shrikant C, Madri M, Lajwinder K, Ranendra S. Development and evaluation of buccoadhesive controlled release tablets of Lercanidipine.Apps pharmsciTech.2007;9(1):182-190.