FORMULATION AND EVALUATION OF MUCOADHESIVE

BUCCAL TABLETS OF ONDANSETRON HCL

M. Pharm. Dissertation Protocol

Submitted to the

Rajiv Gandhi University of Health Sciences, Karnataka

Bangalore.

By

Mr. VIJAY V PAWAR B. Pharm.

Under the Guidance of

Dr. C.C. PATIL M.Pharm, ph.D

Professor & Head

DEPARTMENT OF PHARMACEUTICS

B L D E A’S COLLEGE OF PHARMACY

BIJAPUR-586103

2013-2014

Rajiv Gandhi University of Health Sciences, Karnataka

Bangalore.

ANNEXURE II

PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION

1)

Name of candidate and address

(In Block Letters)

Mr. VIJAY.V.PAWAR

AT-MAGARWADI

POST-CHANDAPURI

TAL- MALSHIRAS

DIST- SOLAPUR-413 310

2)

Name of the Institute

B.L.D.E.A’S COLLEGE OF

PHARMACY, BIJAPUR-586 103

3) Course of study and subject: M. PHARM IN PHARMACEUTICS.

4) Date of admission of course: 27-12-2012

5) Title of the topic: -

“FORMULATION AND EVALUATION OF MUCOADHESIVE BUCCAL

TABLETS OF ONDANSETRON HCL”.

6) Brief Resume of this intended work :-

6.1 Need for the study Enclosure-I

6.2 Review of Literature Enclosure-II

6.3 Objectives of study Enclosure-III

2

7) Materials and Methods :-

7.1 Source of data Enclosure-IV

7.2 Method of collection of data (Including sampling procedure, if any)

Enclosure-IV

7.3 Does the study require any investigation or interventions to be conducted on

patients of 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----

8) List of References Enclosure-V

9)

Signature of the candidate

10)

Remarks of the Guide

Enclosure-VI

11) Name and designation of

(in block letters)

11.1 Guide

11.2 Signature

Dr. CHANDRASHEKAR.C. PATIL

Professor & Head,

Dept. of Pharmaceutics

B.L.D.E.A’S COLLEGE OF PHARMACY,

BIJAPUR-586103.

11.3 Co-Guide (if any) ------------

3

11.4 Signature ------------

11.5 Head of Department

11.6 Signature

-------------

12)

12.1 Remarks of the

Chairman and Principal

12.2 Signature

This study Can be carried out in our laboratory

Enclosure-I

4

6) Brief resume of the intended work.

6.1) Need for the study: -

Buccal delivery of drugs provides an attractive alternative to the oral route of drug

administration, particularly in overcoming the disadvantages associated with the later

mode of dosing. Moreover, the oral cavity is easily accessible for self medication and can

be promptly terminated in case of toxicity just by removing the dosage form from buccal

cavity. It is also possible to administer drug to patients who cannot be dosed orally via

this route.1

Among the various transmucosal routes, buccal mucosa has excellent accessibility, an

expanse of smooth muscle and relatively immobile mucosa, hence suitable for

administration of retentive dosage form. Technically, an ideal buccal adhesive system

must have the following properties: (1) maintains its position in the mouth for a few

hours, (2) releases the drug in a controlled fashion, and (3) provides drug release in a

unidirectional way toward the mucosa.2

Three different categories of drug delivery fall within the oral cavity: sublingual, buccal,

and local. The sublingual mucosa is relatively permeable, giving rapid absorption and

acceptable bioavailabilities of many drugs, and is convenient, accessible, and generally

well accepted.3

The drug directly reaches to the systemic circulation through the internal jugular vein and

bypasses the drugs from the hepatic first pass metabolism, which leads to high

bioavailability. The other advantages of buccal drug delivery include: low enzymatic

activity, suitable for drugs or excipients that mildly and reversibly damage or irritate the

mucosa, painless drug administration, easy drug withdrawal, possible to include the

permeation.4

Therefore, the oral mucosa may be potential site for controlled or sustained drug delivery.

The permeability of the oral mucosa is low; hence, the oral mucosa could be utilized to

potent drugs which are required in small doses.5

In this study, ondansetron HCl (ODN) was selected as a model drug; it is a selective

serotonin 5-HT3 receptor blocking agent.6 It is a potent antiemetic drug used in the

treatment of chemotherapy or radiotherapy induced emesis and also used in the early

5

onset of alcoholism. Although, it is well absorbed in the gastrointestinal tract; ODN

undergoes first pass-metabolism resulting in low bioavailability. The low dose (4mg) and

maximum like (8mg) and low molecular weight (365.86 Da) make it as a suitable

candidate for buccal delivery. It has been classified as BCS Class III drug owing to its

low permeability and high solubility. Therefore, it was excogitated to use permeation

enhancer in delivering ODN through buccal mucosa.7

It is effective in the treatment of nausea and vomiting, It has a half-life 3-5 h and oral

bioavailability is < 60 %. ODH shows promising pharmacokinetics and physicochemical

properties hence this drug was selected as model drugs for this investigation.8

6

Enclosure-II6.2) Review of literature: -

1) Guda aditya et al., have developed and evaluate controlled release mucoadhesive

buccal tablets of Lisinopril. a drug widely used in the treatment of hypertension.

However, its extensive first pass metabolism results in poor bioavailability. The

objective of present research work is to design and evaluate the controlled release

of mucoadhesive buccal tablets of Lisinopril with a goal to increase the

bioavailability, reduce dosing frequency and improve patient compliance. The

tablets were prepared using Carbopol‐934, Hydroxy propyl methyl cellulose

(HPMC), hydroxy ethyl cellulose (HEC) as mucoadhesive polymers. Analysis of

Lisinoprile is done by UV visible spectrophometer using wavelength 210nm.

Results of in-vitro swelling study indicate that the Total six different formulations

(F1 to F6) of Lisinopril buccal tablets were prepared by direct compression

techniques using various proportions of polymers and excipients. In order to

select the best formulations, various evaluation parameters were checked and

subjected to in-vitro dissolution studies and their release profiles.9

2) Satyabrata Bhanja et al., have prepared and evaluate of mucoadhesive buccal

tablets of Timolol maleate. The best in-vitro drug release profile was achieved

with the formulation F5 which contains the drug, Carbopol 934p and HPMC K4M

in the ratio of 1:2.5:10. The in vitro release of Timolol maleate was performed

under sink conditions (Phosphate buffer PH(6.8, 37±0.5ºC, rpm 50) using USP-

XXIV dissolution apparatus type II. The formulation F5, containing 10 mg of

Timolol maleate exhibited 7 h sustained drug release i.e. 98.18 % with desired

therapeutic concentration. The samples were filtered through Whitman filter paper

No.40 and analyzed for Timolol after appropriate dilution by UV

spectrophotometer at 296 nm. The in-vitro release kinetics studies reveal that all

formulations fits well with zero order kinetics followed by Korsmeyer-Peppas,

first order and then Higuchi’s model and the mechanism of drug release is non-

Fickian diffusion. FTIR studies showed no evidence on interactions between drug,

polymers, and excipients..In conclusion, the results indicated that the prepared

7

sustained-release tablets of TM could perform therapeutically better than

conventional tablets with improved efficacy and better patient compliance.10

3) G Ìkinci et al., have developed a buccal bioadhesive nicotine tablet formulation

for smoking cessation. 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. A decrease in pH

of the dissolution medium to acidic values was avoided by incorporation of

magnesium hydroxide into the formulations. The developed formulations released

NHT for 8 h period, and remained intact except for the formulation containing

CP: HPMC at 20:80 ratios. Tablets were prepared by direct compression of the

mixture of HPMC either with CP or NaAlg at different ratios. The release of

NHT from tablets was studied using modified Franz diffusion cells. The samples

were filtered and assayed for NHT at 259 nm using a UV 160A Shimadzu

spectrophotometer. It was shown that with the developed formulations, the NHT

release and bioadhesion properties of buccal tablets can be controlled by changing

the polymer type and concentration. 11

4) Calum R et al., have formulated oral controlled release matrix tablets of Losartan

potassium. 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 effluent from the cells was collected over a 4 h period and

assayed for nicotine at certain time intervals using U.V. detection at 259 nm. In-

8

vitro nicotine release Dissolution testing was initially carried out to investigate the

effect of HPC on NHT release. The rate of NHT release from the CRL’s and

bilayer tablets was investigated using USP (XXI) apparatus IV. It has been

proposed that mucoadhesion occurs in three stages (Duchene et al., 1988). The

first stage involves the formation of an intimate contact between the

mucoadhesive and the mucus. Secondly, the mucoadhesive macromolecules swell

and interpenetrate with the mucus macromolecules, becoming physically

entangled. Thirdly, these molecules interact with each other via secondary, non-

covalent bonds such as hydrogen bonds.12

5) Paolo Giunchedia et al., have prepared buccal tablets of chlorhexidine using

drug-loaded chitosan microspheres. This investigation deals with the development

of buccal formulations (tablets) based on chitosan microspheres containing

chlorhexidine diacetate. The microparticles were prepared by a spray-drying

technique, their morphological characteristics were studied by scanning electron

microscopy and the in vitro release behaviour was investigated in pH 7.0 USP

buffer. Chlorhexidine in the chitosan microspheres dissolves more quickly in vitro

than does chlorhexidine powder. The anti-microbial activity of the microparticles

was investigated as minimum inhibitory concentration, minimum bacterial

concentration and killing time. The loading of chlorhexidine into chitosan is able

to maintain or improve the anti-microbial activity of the drug. The improvement

is particularly high against Candida albicans. This is important for a

formulation whose potential use is against buccal infections. Drug-empty

microparticles have an anti-microbial activity due to the polymer itself. Buccal

tablets were prepared by direct compression of the microparticles with mannitol

alone or with sodium alginate. After their in-vivo administration the determination

of chlorhexidine in saliva showed the capacity of these formulations to give a

prolonged release of the drug in the buccal cavity.13

6) Ahmad Mahmood Mumtaz et al., have developed bioadhesive buccal tablets

containing triamcinolone acetonide in healthy volunteers. Bioadhesive buccal

tablets prepared from different ratios of poly (acrylic acid-2,5-dimethyl-l,5-

hexadiene) (PADH) and hydroxypropylmethylcellulose (HPMC) with and

9

without triamcinolonc acctonidc (TAA) has been investigated in the buccal

cavities of healthy human volunteers. The inclusion of higher percentages of

HPMC provides more prolonged release of drug through its properties of gelling

and slow dissolution. However, adhesion of the tablet is reduced in the excessive

flow of saliva and there is also a tendency for the tablet to be dislodged from the

mucosa. The tablet with a PADH/HPMC ratio of 50:50 seems to provide a

suitable compromise for good bioadhesion and prolonged release of drug. The

triamcinolone acetonide concentration was determined by a UV

spectrophotometer (Hitachi, Model 2000U, and Japan) at 240.8 nm. Shows that

tablet III hydrates and swells immediately and disintegration occurs within 30 min

which reaches the maximum at 1.0 h. The relatively large fall in wet weight after

1.5 h is probably due to difficulty in removing all the swelled PADH particles

from the mucosa.14

7) Rajesh Khanna MA et al., have prepared Preparation bioerodible buccal tablets

containing clotrimazole. Buccoadhesive erodible tablets for local delivery of

clotrimazole (CLT) to the oral cavity were developed using different bio-adhesive

polymers along with soluble excipients like mannitol and polyethylene glycol-

6000. An apparatus simulating the in-vivo conditions of the mouth was designed

in order to assess in-vitro, the bio-adhesive performance and release

characteristics of these tablets. The in-vitro adhesion time and release

characteristics were found to be a function of the type of polymer and also the

total composition of the tablets. In vivo evaluation of placebo tablets in healthy

human volunteers indicated a linear and positive correlation between the in-vitro

and in-vivo adhesion time.15

Enclosure-III

10

6.3) Objectives of the study: -

The present study is planned with the following objectives: -

1) To prepare standard calibration curve of Ondansetron Hcl.

2) To prepare mucoadhesive buccal tablets by wet granulation method using

polymer likes- 1) Natural polymer- chitosan, Sodi.Alginate etc. and Semi-

Synthetic polymers- HPMC, EC etc

3) Drug- excipients compatibility study by FTIR Spectroscopy.

4) To perform evaluation parameter likes

1. Appearance, thickness, hardness, weight variation, friability test.

2. Determination of swelling.

3. Surface pH study.

4. Bioadhesion.

5. Resistance time

6. In-vitro dissolution study using USP XXIII (Electro lap, TDT

06p) analysed them by using UV-Spectrometer (pharmaspec

1700, Shimadzu, Japan).

7. Stability testing.

8. In-vitro permeation studies of the optimized formulations.

Enclosure-IV

11

7) Materials and Methods: -

7.1) Source of data: -

Primary data: - This data will be collected by conducting laboratory

experiments and recording the observation.

Secondary data: - This will be collected from various journals and textbooks.

7.2) Method of collection of data: -

The study is planned to collect the data from the laboratory-based experiments,

which include the following:

1) Preparation of Ondansetron hcl tablets by using different polymers by wet

granulation method.

2) Compatibility study of drug with various polymers will be carried out by using

FT-IR-8400 S Shimadzu, Japan.

3) Evaluation parameter such as, appearance, thickness, hardness, weight variation

test, friability test, drug content uniformity, bioadhesion, in-vitro dissolution

studies, swelling index, in-vitro resistance time.

4) In-vitro permeation studies will be carried out for the optimized formulation.

5) The stability studies of the formulation will be carried out as per ICH guidelines

and data will be collected.

ENCLOSURE-V

12

List of references: -

1. Yadav Deepak RT, Ayyappan S, hanmugam K, Sundaramoorthy and T.

Vetrichelvan. Development and in-vitro Evaluation of Buccoadhesive

Metoclopramide Hydrochloride Tablet Formulations. International journal of

pharmatech Research coden , 2011; 3:516-525.

2. Prasanth Vasantha Viswanadhan, Anand Padole, Abin Abraham and Sam

Thomarayil Mathew. Buccal Tablets of Lisinopril by Direct Compression Method

for Buccal Drug Delivery. International research Journal of Pharmaceuticals,

2012; 2:30-38.

3. Patel KV, Patel ND, Dodiya HD, Shelat PK. Buccal Bioadhesive Drug Delivery

System. An Overview. International Journal of Pharmaceutical and Biological

Archives, 2011; 2(2): 600-609.

4. K Naga Raju, S Velmurugan, B Deepika , Sundar Vinushitha . Formulation and

invitro evalution of buccal tablet of Metoprolol tartrate. International Journal of

pharmacy and Pharmaceutical science, 2011; 3: 239-246.

5. Swamy PV, Kinagi MB, Biradar SS, Gada SN and Shilpa H. Formulation Design

and Evaluation of Bilayer Buccal Tablets of Granisetron Hydrochloride. Indian

Journal of Pharmaceutical Education and Research, 2011; 242-247.

6. Upendra nagaich , Vandana chaudhary , Roopa karki , Akash yadav , Praveen

Sharma . Formulation of medicated chewing gum of ondansetron hydrochloride

and its pharmacokinetic evaluations. International Journal of Pharmaceutical

science and research, 2010; 1(2): 32-40.

7. M Praveen Kumar, M Rajendra Prasad, M Pramod and V Prabhakar Reddy.

Effect of permeation enhancer on ex-vivo permeation of Ondansetron hcl buccal

tablets. International Journal of Pharmaceutical science and research, 2011; 2

(11): 2841-2845.

8. Syed Amezuddin Azhar, Putta Rajesh Kumar, Vivek Sood and Somashekar

Shyale. Studies on directly compressed ondansetron hydrochloride mucoadhesive

buccal tablets. Journal of applied pharmaceutical science, 2012; 2 (5): 100-105.

9. Guda Aditya, Ganesh Kumar Gudas , Manasa Bingi , Subal Debnath , VV

Rajesham . Design and Evaluation of Controlled Release Mucoadhesive Buccal

13

Tablets of Lisinopril. International Journal of current Pharmaceutical research,

2010 ; 2 (4) : 24-27.

10. Satyabrata Bhanja , P Ellaiah , Sujit Kumar Martha , Pratit Kanchan Sahu , Sandip

Prasad Tiwari , Bibhuti Bhusan Panigrahi , Debajyoti Das . Formulation and in

vitro evaluation of mucoadhesive buccal tablets of Timolol maleate. International

Journal of Pharmaceutics and Medical Research, 2010; 1(4): 129-134.

11. G Ìkinci, S Senel, C G Wilson , M Sumnua. Development of a buccal

bioadhesive nicotine tablet formulation for smoking cessation. International

Journal of Pharmaceutics, 2004; 173-178.

12. Calum R Park, Dale L Munday. Development and evaluation of a biphasic buccal

adhesive tablet for nicotine replacement therapy. International Journal of

Pharmaceutics, 2002; 215-226.

13. Paolo Giunchedi, Claudia Juliano, Elisabetta Gavini , Massimo Cossu , Milena

Sorrenti . Europen Journal of Pharmaceutics and Biopharmaceutics, 2002; 233-

239.

14. Ahmad Mahmood Mumtaz, Hung-Seng Ch'ng . Evaluation of bioadhesive buccal

tablets containing triamcinolone acetonide in healthy volunteers. International

Journal of Pharmaceutical Science, 1995; 249-254.

15. Rajesh Khanna, SP Agarwal, Alka Ahuja. Preparation and evaluation of

bioerodible buccal tablets containing clotrimazole. International Journal of

Pharmaceutics, 1996; 67-73.

ENCLOSURE-VI

14

10) Remarks of the Guide

The present work is aimed to develop and evaluate the Buccal tablet of

Ondansetron HCl. Ondansetron HCl is a widely used as anti emetic drug. The drug has a

shorter biological half-life of about 3-5 hrs and its bioavailability is only 60%. Sustained

released tablet possibly improve oral bioavailability of Ondansetron HCl. The proposed

study can be carried out in the laboratory.

Dr. C. C. Patil.

Professor & Head

Research Guide

15