FORMULATION AND EVALUATION OF BILAYERED BUCCAL TABLETS OF PROPRANOLOL HYDROCHLORDE

M. PHARM DISSERTATION PROTOCOL SUBMITTED TO

Rajiv Gandhi University of Health Sciences, Karnataka

Bangalore – 560 041

By

MR. CHABDA SURAJ B. Pharm

Under the Guidance of

Mrs. ASHWINI S. JOSHI M. Pharm

Department of Pharmaceutics

S.E.T’s COLLEGE OF PHARMACY

S. R. Nagar, Dharwad-560 002

2013-2014

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES

KARNATAKA, BANGALORE.

ANNEXURE –II

PROFORMA FOR REGISTRATION OF SUBJECT FOR DISSERTATION

1. / NAME OF THE CANDIDATE AND ADDRESS / MR. CHABDA SURAJ
DEPT. OF PHARMACEUTICS
SET’s COLLEGE OF PHARMACY
S.R.NAGAR,
DHARWAD-580002.
2. / NAME OF THE INSTITUTION / SET’s COLLEGE OF PHARMACY
S. R. NAGAR,
DHARWAD-580002.
3. / COURSE OF STUDY AND SUBJECT / MASTER OF PHARMACY IN PHARMACEUTICS
4. / DATE OF ADMISSION TO THE COURSE / JULY2013
5. / TITLE OF THE PROJECT:
“FORMULATION AND EVALUATION OF BILAYERED BUCCAL TABLETS OF PROPRANOLOL HYDROCHLORDE’’
6.0
7.
8.0 / BRIEF RESUME OF THE INTENDED WORK:
6.1 Need for study:
Propranolol hydrochloride is beta adrenergic blocker used in the treatment many ischemic heart diseases such as hypertension, cardiac antiarrhythmic, Angina pectoris etc and as a prophylactic for migraine. Though the absorption of the drug from oral dosage forms is about 90% but it is subjected to a very extensive hepatic first-pass metabolism. Its bioavailability is only about 20%1. Since this drug has a short elimination half-life of 4 - 5 hours and is eliminated rapidly repeated daily administration is required to maintain effective plasma levels. The short half life and extensive first pass metabolism of propranolol hydrochloride makes it a suitable candidate for administration via buccal delivery system that provides sustained drug delivery without pre-systemic metabolism. For the sustained action of propranolol hydrochloride through oral mucosal route2, several approaches such as trandermal patchs,3-5 nasal gels and microspheres6 have been tried to develop non-oral formulations in addition to injections.
Among the non-invasive routes buccal transmucosal administration has promising potential and a viable alternative for systemic medication of drugs. Buccal route of drug delivery provides direct access to the systemic circulation through the internal jugular vein bypassing the first pass metabolism leading to high bioavailability6.Other advantages such as excellent accessibility, low enzymatic activity, suitability for drugs or excipients that mildly and reversibly damage or irritate the mucosa, painless administration, easy drug withdrawal, facility to include permeation enhancer/enzyme inhibitor or pH modifier in the formulation, versatility in designing as multidirectional or unidirectional release systems for local or systemic actions make buccal adhesive drug delivery system as promising option for continued research 7. Buccal delivery offers a safer mode of drug utilization, since drug absorption can be promptly terminated in cases of toxicity 8 by removing the dosage form from the buccal cavity . A suitable buccal drug delivery system should possess good bioadhesive properties, so that it can be retained in the oral cavity for the desired duration. In addition, it should release the drug in the unidirectional way towards the mucosa (to avoid loss of drug due to wash out by saliva), in a controlled and predictable manner, to elicit the required therapeutic response. This unidirectional drug release can be achieved by using bilayer device9,in which one would be the mucoadhesive matrx containing active pharmaceutical ingredients and an impermeable backing layer which facilitates the unidirectional release of drug.
In the proposed study, mucoadhesive bilayered tablets of propranolol hydrochloride for buccal administration will be developed to study the various formulation variables and their effect on patch properties. Bilayered design of the tablet is selected to obtain unidirectional release of the drug, greater surface area of contact, and administer the bitter drug without taste masking 10.Gelatin and Chitosan are bioadhesive and biodegradable polymers which can be used for controlled drug delivery.11 The development of mucoadhesive, bilayered buccal tablets of Propranolol hydrochloride, will be prepared by using the blends of Chitosan and gelatin as base matrix polymer .Because of the properties such as hydrophobicity, low water permeability, drug impermeability, and moderate flexibility, ethyl cellulose or cellulose acetate will be used as a backing layer polymer12.
The concept of administration of propranolol hydrochloride via buccal route, by formulating the mucoadhesive bilayered buccal tablets has not been fully explored so far. Hence results of present investigation would help to establish the suitability of buccal route for administration of propranolol hydrochloride.
6.2 Review of literature:
Mucoadhesive tablets of Metoprolol tartrate have been formulated using different Mucoadhesive polymers such as Carbopol 934, Sodium alginate and HPMC K4M in combination. Formulations F1 to F5 were composed of Sodium alginate and HPMC K4M mixture in drug: polymer mixture ratios of 1:0.75 to 1:1.75 where as formulations F6 to F10 were composed of carbopol 934 and HPMC K4M mixture in same drug: polymer mixture ratios. In vitro bioadhesive strength and in vitro release studies showed that formulation F8 containing 1:1.25 ratio of drug and polymer combination showed optimum bioadhesive and exhibited optimum drug release.13
Mucoadhesive buccal tablets of terbutaline sulphate were developed. Different polymers and ingredients in different ratios were tried to select optimum formulation. They were selected on the basis of their effect on the retardation of release of drug from tablet matrix. The formulation consisted of terbutaline sulphate (5mg), carbopol 934P (40mg), HPMC K4M (40mg), mannitol (13mg), magnesium stearate (1mg) and talc (1mg) was selected was found to be the optimum formulation.14
Controlled release mucoadhesive buccal tablets of Lisinopril were prepared using Carbopol‐934, Hydroxy propyl methyl cellulose (HPMC), Hydroxy ethyl cellulose (HEC) as mucoadhesive polymers. Formulation (F4) containing Carbopol‐934 and HPMC K4M in the ratio of (2:4) showed good mucoadhesive strength (36.8) and maximum drug release of 97.1% in 10 hrs. The polymers Carbopol 934p and HPMC K4M in the ratio of 2:4 showed satisfactory mucoadhesive properties.15
Mucoadhesive buccal tablets of Metoclopramide Hydrochloride were formulated. The mucoadhesive polymers used in the formulations were Carbopol 934P, Chitosan, HPMC K4M and HPMC K15M. Tablets were prepared by direct compression method using polymers in different ratios. Formulation (F4) containing Carbopol 934P and HPMC K4M in the ratio of (1:1) showed good bioadhesive force and maximum drug release of 96.10% in 10 hours.16
Bioadhesive buccal tablet formulations for delivery of nicotine into the oral cavity were prepared. Carbomer (Carbopol®974P NF) (CP) and alginic acid sodium salt (NaAlg) were used as bioadhesive polymers in combination with hydroxypropyl methylcellulose (HPMC) at different ratios. Magnesium carbonate was incorporated into the formulations as a pH increasing agent. In-vitro release and bioadhesion studies were performed on the developed tablets. In the formulations containing CP:HPMC, the nicotine released increased with the increasing HPMC concentration whereas a decrease was observed with increasing HPMC concentration in formulations containing NaAlg:HPMC.17
The oral mucoadhesive tablets of Nitrendipine using some natural mucoadhesive material like Zizyphus maurtiana (Jujube), Tamarind seed polysaccharide (TSP), also synthetic polymers like sodium CMC and HPMCK15M were formulated and evaluated. It was found that mucoadhesive buccal tablets prepared from natural mucoadhesive material exhibited extended drug (85%) release up to 10 hrs. compared to tablets prepared from synthetic material like sodium CMC and HPMCK15M. Drug release from these tablets followed non-fickian diffusion controlled and zero order kinetics pattern up to 10 hrs.18
Timolol maleate mucoadhesive buccal tablets were prepared and evaluated. The best In-vitro drug release profile was achieved with the formulation F5 which contain the drug, Carbopol 934p and Sod. CMC in the ratio of 1:2.5:10.The surface pH, bioadhesive strength and swelling index of formulation F5 was found to be 6.38, 35.8 gm and 83.2 % respectively. The tablets (formulation F5) containing 10 mg of Timolol Maleate exhibited 7hrs sustained drug release i.e.99.10 % with desired therapeutic concentration. Drug was gradually released from all formulations over a period of 7 hr. The best in-vitro drug release profile was achieved with the formulation F5 i.e. (99.10%) which contained the drug, Carbopol 934p & Sod CMC polymers in the ratio of 1:2.5:10.19
Mucoadhesive buccal tablet of Domperidone were prepared. The mucoadhesive polymers used in the formulations were Carbopol 934P, Methocel K4M, MethocelE15LV and Chitosan. Tablets were prepared by direct compression method using polymer in different ratios. The formulations were characterized for swelling index, in-vitro bioadhesion strength and in-vitro release studies. The best mucoadhesive performance and in- vitro drug release profile were exhibited by the tablets containing chitosan and Methocel K4M in ratio of 1:1.20
In this study buccal tablets of Loratadine to increase the bioavailability by avoiding first pass metabolism have been prepared. Three different types of formulations were prepared carbopol 934P as a primary polymer and chitosan as secondary polymer, carbopol 934P as a primary polymer and sodium alginate as secondary polymer. The buccal tablets were prepared with varying the concentrations of polymers by direct compression method. The formulations CP1 ( with 30% Carbopol 934P) was found to be promising, which showed an in vitro drug release of 95.36% in 8 h along with satisfactory mucoadhesion strength of 5.1 gm.Stability studies (40±2 o C/75±5% RH for 3 months) showed no significant change in important evaluation parameters such as dissolution and drug content21.
Bilayer Nicotine mucoadhesive tablets were prepared and evaluated to determine the suitability of the formulation as a nicotine replacement product to aid in smoking cessation. A range of formulations containing 0–50% w/w Carbopol 934 and 0–50% w/w hydroxypropylcellulose (HPC) were prepared and tested for adhesive properties and drug release. Mucoadhesion was assessed using bovine buccal mucosa. Peak detachment force of the tablets was found to reach a maximum at 20% w/w Carbopol 934, whilst work of adhesion continued to increase with Carbopol 934 concentration. HPC concentrations of 20-30% w/w were found to provide nicotine hydrogen tartrate (NHT) release approaching zero order kinetics over a 4 h test period. A combination of 20% w/w Carbopol 934® and 20% w/w HPC was thus found to provide suitable adhesion and controlled drug release. The formulation of a bilayer tablet containing the adhesive controlled release layer (CRL) and a fast releasing layer provided an initial burst release of NHT followed by the controlled release for a period of up to 4 h.22
6.3Objectives of Study:
The objective of the present study is to prepare and evaluate bilayered mucoadhesive buccal tablets of propranolol hydrochloride:
a)Preformulation studies.
b)To carry out compatibility studies between the drug & polymers.
c)Formulation and preparation of bilayered mucoadhesive buccal tablets.
d)To characterize the obtained buccal tablets and in vitro release studies.
Materials and methods:
7. 1 Sources and collection of data:
Text-book.

Journals - Indian journal of pharmaceutical sciences,
International journal of Pharmaceutics,
International journal of PharmaTech Research,

J-Gate@ Helinet etc
7.2 Method of collection of Data:
The data will be collected from the prepared formulation; in-vitro evaluation will be carried out by referring various standard reference books, journals & other sources like research literature data bases such as science direct and laboratory experiments, etc.
Drugs : Verapamil hydrochlorde.
Polymers: By using the suitable polymers like carpool, chitosan, HPMC, sodium CMC for drug containing mucoadhesive layer and ethyl cellulose or cellulose acetate for backing layer.
Excipients: Diluents, lubricants and glidants.
Method :
a)Formulation of buccal mucoadhesive tablets by a suitable method.
b) Evaluation of the prepared buccal mucoadhesive tablet for :
Precompression studies:
Bulk density
Tapped density
Bulkiness
Angle of repose
Compressibility and Hausner’s ratio
Compatibility studies.
Post compression studies:
Drug Content
Hardness
Weight uniformity, Thickness and Friability
Swelling Study
Surface pH
In-Vitro bioadhesive strength
In-Vitro drug diffusion by Franz diffusion cell and sheep buccal mucosa.
 Short term stability
In-vitro dissolution studies will be carried out by USP XX111 dissolution apparatus at 50 rpm, using suitable dissolution media which is maintained at 37±0.50c. Samples are withdrawn at predetermined time and analysed by UV spectrophotometer
7.3 Does the study require any investigation or interventions to be conducted on patients or other humans or animals? If so please describe briefly.
-No-
7.4 Has ethical clearance been obtained from your institution in case of 7.3?
-Not applicable-
LIST OF REFERENCES:
  1. Martindale: The Complete Drug Reference. 34th ed. editor.S.C.Sweetman: Pharmaceutical press. New York; 2005.p. 32.5
  2. Dandagi PM , Mastiholimath VS , Gadad AP , Iliger SR . Mucoadhesive microspheres of propranolol hydrochloride for nasal delivery .Indian J Pharm S. 2007; 69(3): 402-7
  3. Amnuaikit C, Ikeuchi I, Ogawara K, Higaki K, Kimura T. Skin permeation of propranolol from polymeric film containing terpene enhancers for transdermal use Int J Pharm. 2005 Jan 31;289(1-2):167-78.
  4. Rao PR, Ramakrishna S, Diwan PV Drug release kinetics from polymeric films containing propranolol hydrochloride for transdermal use Pharm Dev Technol. 2000;5(4):465-72
  5. Rasool BK, Aziz US, Sarheed O, Rasool AA. Design and evaluation of a bioadhesive film for transdermal delivery of propranolol hydrochloride Acta Pharm. 2011 Sep 1;61(3):271-82.
  6. Shojaei AH. Buccal mucosa as a route for systemic drug delivery: A Review. J Pharm Pharma Sci. 1998; Jan-Apr:1(1):15-30.
  7. 7 JAJ Hoogstraate, Philip WW. Drug delivery via the buccal mucosa. PSTT. 1998;1(7):309–316
  8. Nakhat PD, Kondawar AA, Babla IV, Rathi LG, Yeole PG. Studies on buccoadhesive tablets of terbutaline sulphate. Ind J Pharm Sci 2007;69(4):505-10
  9. Patel VM, Prajapati BG, Patel HV, Patel KM. Mucoadhesive bilayer tablets of propranolol hydrochloride. AAPS PharmSciTech 2007;8(3):E1-E6.
  10. Guo JH, Cooklok KM. The effects of backing materials and multilayered systems on the characteristics of mucoadhesive buccal patches. J Pharm Pharmacol 1996;48:255.
  11. Thomas FH Shan K ,Karineh K,Molly S. S, Controlling cell adhesion and degradation of chitosan films by N-acetylation, Biomaterials26, 29, 2005, 5872–5878
  12. Vaidya VM, Manwar JV, Mahajan NM, Sakarkar DM. Design and In-Vitro Evaluation of mucoadhesive buccal tablets of Terbutaline sulphate. Int J PharmTech Res 2009 Jul-Sep;1(3):588-97.
  13. Velmurugan S, Raju KN, Deepika B, Vinushitha S. Formulation and in-vitro evaluation of buccal tablets of Metoprolol tartrate. Int J Pharm Pharm Sci 2011;3(2):239-46.
  14. Vaidya VM, Manwar JV, Mahajan NM, Sakarkar DM. Design and In-Vitro Evaluation of mucoadhesive buccal tablets of Terbutaline sulphate. Int J PharmTech Res 2009 Jul-Sep;1(3):588-97.
  15. Aditya G, Gudas GK, Bingi M, Debnath S, Rajesham VV. Design and evaluation of controlled release mucoadhesive buccal tablets of Lisinopril. Int J current Pharm Res 2010;2(4):24-7.
  16. Yadav DR, Ayyappan T, Shanmugam S, Sundaramoorthy K, Vetrichelvan T. Development and in-vitro evaluation of buccoadhesive Meoclopramide hydrochloride tablet formulations. Int J PharmTech Res 2011 Jan-Mar;3(1):516-25.
  17. 17Senel S, Ikinci G, Sumnu M, Wilson CG. Development of a buccal bioadhesive nicotine tablet formulation for smoking cessation. Int J Pharm 2004;277:173-8.
  18. Bangale GS, Shinde GV, Umalkar DG, Rajesh KS. Natural mucoadhesive material based buccal tablets of nitrendipine-formulation and in-vitro evaluation. J Pham Res 2011;4(1):33-8.
  19. Bhanja SB, Ellaiah P, Martha SK, Sahu PK, Tiwari SP, Panigrahi BB, et al. Design and Evaluation of Timolol Maleate mucoadhesive buccal tablets. Int J Pharm Health Sci 2010;1(2):100-8.
  20. Ganesh P, Balamurugan M, Saravanan VS, Senthil SP, Hemalatha PV, Pandya S.Development and In-vitro evaluation of mucoadhesive buccal tablets of Domperidone.Res J Pharm Tech 2008 Oct-Dec;1(4):377-80.
  21. Borgaonkar PA, Virsen TG, Hariprasanna RC, Najmuddin M. Development and Evaluation of mucoadhesive buccal tablet of Loratadine. J Pharm Res 2011;4(8):2699-702.
  22. Calum RP, Dale LM. Development and evaluation of a biphasic buccal adhesive tablet for nicotine replacement therapy. Int J Pharm 2002;237:215-26.

9. / SIGNATURE OF THE STUDENT
10. / REMARK OF THE GUIDE
The above mentioned information and literature has been , verified and was found to be correct. The present study will be carried out under my supervision and guidance.
11. / 11.1 NAME AND DESIGNATION OF THE GUIDE
11.2 SIGNATURE / Mrs. ASHWINI S. JOSHI, M. Pharm,
LECTURER
DEPT. OF PHARMACEUTICS,
SET’S COLLEGE OF PHARMACY, S.R.NAGAR, DHARWAD- 580002.
11.3 NAME AND DESIGNATION OF CO-GUIDE
11.4 SIGNATURE / ......
11.5 HEAD OF THE DEPARTMENT
11.6 SIGNATURE / Prof. A.M. GODBOLE, M. Pharm, Ph.D.,
PROFESSOR & HEAD
DEPT. OF PHARMACEUTICS
SET’s COLLEGE OF PHARMACY, S.R.NAGAR, DHARWAD- 580002.
12. / 12.1 REMARK OF THE PRINCIPAL
12.2 SIGNATURE / The above mentioned information is correct and I recommend the same for approval.
Dr. V. H. Kulkarni, M. Pharm. Ph.D.,
PROFESSOR & PRINCIPAL,
Set’s College of Pharmacy,
S.R.NAGAR, DHARWAD- 580002.