DEVELOPMENT AND IN-VITRO EVALUATION OF MUCOADHESIVE BUCCAL TABLETS OF CINNARIZINE
M.PHARM DISSERTATION PROTOCOL
Submitted to
Rajiv Gandhi University of Health Sciences,
Bangalore, Karnataka.
By
Mr. Balu Maruti Metkari.
B. Pharm.
Under the Guidance
of
Prof. Hariprasanna R. C.
M. Pharm. (Ph. D).
DEPARTMENT OF PHARMACEUTICS
R.M.E.S’s COLLEGE OF PHARMACY,
GULBARGA-585102
2010-2011
Rajiv Gandhi University of Health Sciences, Bangalore, Karnataka.
Curriculum Development Cell
Conformation for Registration of Subject
for Dissertation
Registration No. :
Name of the Candidate : Mr. Balu Maruti Metkari.
Name of the Institution : R.M.E.S’s College of Pharmacy
Gulbarga, Karnataka.
Course of Study and Subject : M. Pharm. in Pharmaceutics
Date of Admission to the Course : 27/06/2010
Title of the Topic : Development and in-vitro evaluation of
mucoadhesive buccal tablets of cinnarizine
Brief resume of the intended work : Enclosed
Signature of the student :
Guide Name : Prof. Hariprasanna R.C. M.Pharm. (Ph.D)
Remarks of the Guide : Recommended for approval
Signature of the Guide :
Co-Guide Name : Mr. Upendra Kulkarni. M.Pharm. (Ph.D)
Signature of the Co-Guide :
HOD Name : Prof. Hariprasanna R.C. M.Pharm. (Ph.D)
Signature of the HOD :
Director/Principal Name : Prof. Kishoresingh K. C. M.Pharm. Ph.D
Mobile : +919880200905
Director/Principal E-mail ID :
Remarks of Director/Principal : Recommended for approval
Director/Principal Signature :
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. Balu maruti MetkariMangalmurti complex, B.No.10,D, shop no. 7 PMGP Colony road, mankhurd . Mumbai-43
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 / 27th June 2010
5. / Title of the topic / Development and in-vitro evaluation of mucoadhesive buccal tablets of Cinnarizine
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 trans - mucosal routes gained significant attention owing to their pre- systemic metabolism or in stability in the acidic environment associated with oral administration1. Buccal delivery provides direct entry of drug into the systemic circulation, this avoiding the hepatic first pass affect, ensuring ease of administration, and making it possible to terminate delivery when required2.
The term bioadhesive describes material that bind to biological substrate such as mucosal membrane adhesion of bioadhesive drug delivery devices to mucosal membrane lead to an increased drug concentration gradient at the absorption site and therefore improved bioavailability of systemically delivered drug. In addition, bioadhesive dosage forms have been use to target local disorder at the mucosal surface. (eg. Mouth ulcers) to reduce the overall dosage and minimize aide effect that may be used by systemic administration of drug. Drug absorption in to the oral mucosal is mainly via passive diffusion into the lipoidal membrane.
Compounds with partition coefficient in the range 40 –2000 and PKa 2-10 are considered optimal to be absorbed through buccal mucosa. Drug can be absorbed from the oral cavity through the oral mucosa either by sublingual or buccal route, Absorption of therapeutic agents from their routes over come premature drug degradation within the gastrointestinal tract as well as a active drug loss due to first – pass hepatic metabolism that may be associated with oral route of administration. In general rapid absorption from these routes is observed because of the mucus membrane and rich blood supply. After absorption, drug is transported through the deep lingual vein or facial vein which then drains in to the general circulation via the jugular vein bypassing the liver and through sparing the drug from first pass metabolism3.
Cinnarizine is chemically I – benzhydry 1-4 – cinnamyl piperazine. With antihistamine, sedative, and calcium – channel blocking activity, with PKa value 7 and is used for the symptomatic treatment of nausea and vertigo caused by menierre’s disease and other vestibulr disorders and for the prevention and treatment of motion sickness. It is also used in the management of various peripheral and cerebral vascular disorders. Cinnarizine is absorbed from the gastrointestinal tract, peak plasma concentrations occurring 2 to 4 hours after oral doses. It undergoes extensive first- pass metabolism and has a half life of 3 to 6 hour 4 - 7.
Hence, in the present research work an attempt will be made to formulate mucoadheshive tablets of Cinnarizine by using Natural and synthetic polymers.
6.2 Review of Literature:
1) Shaila Lewis,et.al.(2006)8 Formulated mucosdesive buccal tablet 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.
2) Vishnu M. Patel et al (2007)9 established mucoadhesive buccal device of propranolol hydrochloride in the forms bilayed and multilayer tablets. The tablets were prepaid using HCMC and crobopol 934 as bioodhesive polymers to import mucoadhesion and ethycellulose to act as an impermeable backing layer buccal device were evaluated by different parameter such as weight infirmity, content informity, thickness hardnsse surface PH swelling index, ex vivo mucoadhesive strength, ex vivo mucoadhesive time, in vitro drug release and in vitro drug permeation as compared with bilayered tables, multilayed tablet showed slow release rate of drug with improved ex vivo bioadhesive strength and enhanced ex vivo mucoadhesion time.
3) Libero Italo Giannola, et. al. (2007)10. 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 data previously 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.
4) David M. Simpson, et. al. (2007)11. 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.
5) Vamshi Vishnu Yamsani, et. al. (2007)12. 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.
6) R Manivannan, et. al. (2008)13. Formulated mucoadhesive buccal tablet of Deltiazem Hydrochloride as a model drug. Carbopol-934, Sodium carboxy methylcelluloses, HPMC, Sodium Alginate, Gaur gum were selected as mucoadhesive polymer. They have reported a suitable mucoadhesive buccal tablet with desired property could be prepared.
7) Ashwini Madgulkar, et. al.(2009)14 . 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 nonfictions, approaching zero-order kinetics. Suitable combination of two polymers provided adequate bioadhesive strength and sustained-release profile with zero-order kinetics.
8) Margat Chandira, et. al. (2009)15. 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.
9) Bhavain Patel, et. al. (2009)16. 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.
10) R.S. Hirlekar, et. al. (2009)17. 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.
11) Sonia panday, et. al. (2010)18 were formulated bilyred buccal tablets in ordered to avoid the first – pass effect and decreased the drug loss using different polymer and excipients by using different ratio of carbopol 934p and HPMC K4M formulation were tested for in vitro drug released, in vitro bioadhesion, moisture absorption and in- vitro drug permeation through pores in buccal mucosa. Dissolution studies of tablet of optimized batch containing 5% corbopol 934p /65% HPMC 4K4M/30% Lactose showed 82.7% drug released in 6 hours.
12) Arya RK, et. al, (2010)19 Formulated mucodhesive tablets of salbutamol sulfate by non- aques granulation of polymer HPMC K4M and ethylcelluloce in different ration. The tablet were evaluated far weight variation Hardness, Thickness, drug content, mucadhesion and swelling index. Swelling index of batches containing more HPMC, K 4 M was greater than that of contain less HPMC K 4M Invitro boiadhesive strength studies showed that tablets containing more HPMC K4M use great bioachhesive in nature. The maximum in vitro release observed in formulation HE.1 (1: 1 ratio) and the kinetics studies shows that release follows peppers model.
6.3 Objectives of the study
The present research investigation is planed with the following objectives.
1) To develop mucoadesive Buccal Tablet of Cinnarizine.
2) To Investigate the parformanse of.selected of Natural and Synthetic polymer.
3) To evaluate the Formulation with respect to various physical parameter.
4) To evaluate the Formulation with respect to Content uniformity , In vitro release study,Drug excipients include studies .
7. / Materials and Methods:
Materials :
Drug : Cinnarizine.
Excipients :
1. Agle marmelos gum
2. Corbopol
3. Hydroxy propyl methyl Cellulose
4. Lactose.
5. Magnesium stearate
6. Talc
7. Aerosil
Equipments:
1. Dissolution test apparatus
2. Disintegration test apparatus
3. UV spectrophotometer
4. Monsanto hardness tester
5. Roche friabilator
6. Electronic balance
7. Single pan digital balance
8. Tablet punching machine
9. Sieves
10. FTIR spectrophotometer & DSC.
11. Stability chamber
Methods:
1. Direct compression technique: Mucoadhesive 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). 20
1. Bulk density and tap densities: Exactly 50 gm of powder blend will weigh on chemical balance and transferred into a 100 ml measuring cylinder. The cylinder was 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 record as the bulk volume. The cylinder will then tap on the wooden platform until the volume occupied by the powder blend remained constant. This will repeat three times for granules. The data generated will use in calculating the Carr’s compressibility index and Hausner’s ratio.
2. Angle of repose: 50 gm of the powder blend will placed in a plugged glass funnel which had a distance of 10 cm from the flat surface. The granules will then allow flowing 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.
3. Tablet thickness: The thickness of 10 tablets each selected at random from the formulated tablets will determine using a vernier caliper and the mean of these readings will taken as the mean tablets thickness.
4. Tablet weight uniformity: Twenty tablets will weigh individually using a digital balance with the precision of 0.05 mg and readability of 0.1 mg, from which the mean will calculate and percentage deviations determine.
5. Hardness (Crushing strength): The crushing strengths of tablets will determine individually with the Monsanto hardness tester, following 10 tablets will use and the mean crushing strength will calculate.
6. Friability: The friability of 10 tablets will determine 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 place in the friabilator and will subject to 100 revolutions. Tablets will dedust using a soft muslin cloth and reweigh.