Formulation and Evaluation of Buccal Tablets Containing

FORMULATION AND EVALUATION OF BUCCAL TABLETS CONTAINING

DOMPERIDONE

BY

RANJEET KISHOR TIWARI

DEPARTMENT OF PHARMACEUTICS

DISSERTATION PROTOCOL

SUBMITTED TO THE

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES

BANGALORE- 560041

KARNATAKA.

UNDER THE GUIDENCE OF

ABDUL WARIS KHAN

ASST. PROFESSOR

DEPARTMENT OF PHARMACEUTICS

M.M.U. COLLEGE OF PHARMACY

RAMANAGARAM-562159

KARNATAKA

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES,

BANGALORE- 560041, KARNATAKA.
ANNEXURE-II

PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION

1. / NAME OF THE CANDIDATEAND
ADDRESS (IN BLOCK LETTERS) / RANJEET KISHOR TIWARI
s/o- PREM CHANDRA TIWARI
V.D.C.- BINDASINI, WARD NO. 3,
DIST- PARSA, NEPAL.
2. / NAME OF THE INSTITUTION / M.M.U COLLEGE OF PHARMACY
K.K DODDI, RAMADEVARA BETTA ROAD, RAMANAGARAM - 562159.
KARNATAKA.
3. /

COURSE OF STUDY AND SUBJECT

/ M. PHARM
PHARMACEUTICS.
4. / DATE OF ADMISSION OF COURSE / 08.12.2011
5. /

TITLE OF TOPIC

/ FORMULATION AND EVALUATION OF BUCCAL TABLET CONTAINING
DOMPERIDONE.
6. / BRIEF RESUME OF THEINTENDED WORK
6.1 Need for the study
6.2 Review of the literature
6.3 Objectives of the study /
ENCLOSURE-I
ENCLOSURE-II
ENCLOSURE-III
7. /

MATERIALS AND METHODS

7.1 Source of data
7.2 Method of collection of data
7.3 Does study require any Investigations or interventions to be conducted on patients or Other human or animal? If so, Please describe briefly.
7.4 Has ethical clearance been obtained from your institution in case of 7.3 /
ENCLOSURE-IV
ENCLOSURE-V
ENCLOSURE-VI
ENCLOSURE-VI
8. / LIST OF REFERENCES / ENCLOSURE-VII
9. / SIGNATURE OF CANDIDATE
10. / REMARKS OF GUIDE / FORWARDED FOR APPROVAL
11. / NAME AND DESIGNATION OF
11.1 Guide
11.2 Signature
11.3 Co guide (if any)
11.4 Signature
11.5 Head of department
11.6 Signature / ABDUL WARIS KHAN
ASST. PROFESSOR,
M.M.U COLLEGE OF PHARMACY
K.K DODDI, RAMADEVARA BETTA ROAD, RAMANAGARAM - 562159.
KARNATAKA.
Not applicable
Not applicable
Mr.VAZIR ASHFAQ AHAMED
ASST.PROFESSOR
DEPARTMENT OF PHARMACEUTICS,
M.M.U COLLEGE OF PHARMACY
K.K DODDI, RAMADEVARA BETTA ROAD, RAMANAGARAM - 562159.
KARNATAKA
12. / 12.1 Remarks of the
Chairman and principal
12.2 Signature / SUBMITTED FOR APPROVAL
6. /
BRIEF RESUME OF THE INTENDED WORK
ENCLOSURE-I

6.1 Need for the study:

Despite tremendous advancement in drug delivery system, oral drug delivery remains the preferred route for administration of various drugs to produce systemic effects of drugs. Solid oral dosage form avoids errors in the dose as compared to other dosage forms which are self administered by the patients.
The concept of delivering drugs by buccal tablet through the buccal mucosa for systemic treatment of diseases is gaining increasingly great importance due to its numerous advantages like by passing hepatic first pass metabolism, enhancement of therapeutic efficiency, prolonged duration of action of drugs with short half life and maintenance of steady plasma levels of drug.
Emesis is the process of the sudden expulsion of gastric contents through the esophagus into the pharynx. The act is partly voluntary and partly involuntary. It is also known as vomiting and informally as throwing up.The act of vomiting is produced by a series of coordinated changes in G-I activity and in respiratory movements: salivation; sharp and deep inspiration; increase in intra-abdominal pressure; contraction of abdominal muscles; closure of the epiglottis and raising of the soft palate; forceful contractions of the stomach pylorus; and relaxation of the fundus, cardiac sphincter and esophagus. The feeling that one is about to vomit is called nausea, which usually precedes, but does not always lead to, vomiting. Antiemetics are sometimes necessary to suppress nausea and vomiting.
Domperidone is an antidopaminergicdrug used orally, rectally or intravenously, generally to suppress nausea and vomiting, as a prokinetic agent and for promoting lactation. Domperidone blocks the action of dopamine. It has strong affinities for the D2 and D3dopamine receptors, which are found in the chemoreceptor trigger zone, located just outside the blood brain barrier, which, among others, regulates nausea and vomiting (area postrema on the floor of the fourth ventricle and rhomboid fossa).
The main objective of present work is to formulate and evaluate mucoadhesive buccal tablets containing Domperidone for the treatment ofEmesis.
ENCLOSURE II
6.2Review of literature:

1. Shojaei AH: Studied that within the oral mucosal cavity, the buccal region offers an attractive route of administration for systemic drug delivery. The mucosa has a rich blood supply and it is relatively permeable. It is the objective of this article to review buccal drug delivery by discussing the structure and environment of the oral mucosa and the experimental methods used in assessing buccal drug permeation/absorption. Buccal dosage forms will also be reviewed with an emphasis on bioadhesive polymeric based delivery systems.1
2. Perioli L et al.: Prepared sustained-release mucoadhesive bilayered tablets, using mixtures of mucoadhesive polymers and an inorganic matrix (hydrotalcite), for the topical administration of flurbiprofen in the oral cavity. The first layer, responsible for the tablet retention on the mucosa, was prepared by compression of a cellulose derivative and polyacrylic derivative blend. The second layer, responsible for buccal drug delivery, was obtained by compression of a mixture of the same (first layer) mucoadhesive polymers and hydrotalcite containing flurbiprofen. Nonmedicated tablets were evaluated in terms of swelling, mucosal adhesion, and organoleptic characteristics; in vitroand in vivo release studies of flurbiprofen-loaded tablets were performed as well.2
3. Khanna R, Agarwal SP, Ahuja A: Prepared 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 vivoevaluation of placebo tablets in healthy human volunteers indicated a linear and positive correlation between the in vitro and in vivo adhesion time.3
4. Kashappa G, Desai H, Kumar P: Prepared and evaluate a novel buccal adhesive system (NBAS) containing propranolol hydrochloride (PH). A special punch was fabricated and used while preparing an NBAS. Solubility of PH in phosphate buffer solution (pH 6.6), partition coefficient between phosphate buffer (pH 6.6) and 1-octanol, and permeability coefficient through the porcine buccal mucosa were performed and found to be 74.66 mg/ml, 5.17, and 5.6, respectively. Stability of NBAS was determined in natural human saliva, and it was found that both PH and device are stable in human saliva. NBAS was evaluated by weight uniformity, thickness, hardness, friability, swelling, mucoadhesive strength, in vitro drug release, and in vivo human acceptability studies. Swelling index was higher (4.4) for formulations containing hydroxyl propyl methyl cellulose (HPMC) K4M alone, and it decreases with its decreasing concentration in the NBAS. Mucoadhesive strength (MS) was measured by using a modified apparatus. All NBASs showed higher MS with porcine buccal mucosa when compared with that of rabbit buccal mucosa.4

1. Darwish M, Elmeshad A: Prepared sustained-release mucoadhesive tablets of flurbiprofen. Mucoadhesive polymers used were chitosan as primary polymer and hydroxypropylmethyl celluose, hydroxypropyl cellulose, or sodium carboxymethyl cellulose as secondary polymer. Tablets were evaluated in terms of weight variation, thickness, hardness, friability, swelling, surface pH, in vitro mucoadhesive force, and in vitro release. Thecompatibility between flurbiprofen and the tablet excipients was confirmed by fourier transfer infrared studies. Both the primary and secondary polymers were found to have synergistic effects on tablet swelling, bioadhesion, and in vitro drug release. Formulations containing sodium carboxymethyl cellulose (F1) showed a maximum swelling index of 4.144 after 8 h, maximum mucoadhesive force (0.27 N), and convenient in vitro release over 8 h. D-optimal design was employed to evaluate the effect of the ratio of the primary polymer and the type of secondary polymer on the swelling index after 8 hrs., drug release after 8 h and time taken for 30% drug release.5

1. Balamurugan M et al.: Prepared mucoadhesive buccal tablet of Domperidone were fabricated with objective of avoiding first pass metabolism and to improve its bioavailability with reduction in dosing frequency. 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 tablet containing chitosan and Methocel K4M in ratio of 1:1. It was observed that the optimized formulation follows Hixson Crowel release kinetics.6
2. Miyazaki S et al.: Studied the potential of tablets containing 1:4, 1:1 and 4:1 weight ratios of pectin and hydroxypropyl methylcellulose (HPMC) for the sustained release of diltiazem by sublingual administration has been investigated. Measurements of maximum adhesive force to rat peritoneal membrane indicated satisfactory bioadhesive strength. An in vitro sustained release of diltiazem over 5 h was achieved with bilayer tablets composed of a drug-free ethylcellulose layer in addition to the pectin:HPMC layer containing drug. Plasma concentration-time curves obtained following sublingual administration to rabbits of single and bilayer tablets with 1:1 weight ratios of pectin and HPMC showed evidence of sustained release of diltiazem. Bioavailability of diltiazem was 2.5 times that achieved by oral administration for single layer tablets and 1.8 times for the bilayered tablets.7
3. Mumtaz AM et al.: Studied the behaviour of bioadhesive buccal tablets prepared from different ratios of poly(acrylic acid-2,5-dimethyl-l,5-hexadiene) (PADH) and hydroxypropylmethylcellulose (HPMC) with and without triamcinolonc acctonidc (TAA) has been investigated in the buccal cavities of healthy human volunteers. The results indicate that tablets with a higher ratio of PADH swell faster, causing the disintegration of the tablets and consequently give rise to more rapid release of drug. The inclusion of higher percentages of HPMC provides more prolonged release of drug lhrough 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.8

1. Manivannanl R et al.:Prepared mucoadhesive buccal tablets of Diltiazem hydrochloride were prepared using carbopol-934, Sodium carboxy methyl cellulose (SCMC), Hydroxy propyl 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 prepared.9
2. Yamsani V et al.: Prepared buccoadhesive tablets of carvedilol were prepared using HPMC K4M, HPMC K15M and Carbopol 934 as mucoadhesive polymers. Fifteen formulations were developed with varying concentrations of polymers. Formulations of the BC or BD series were composed of HPMC K4M or HPMC K15M in ratios of 1:1 to 1:5 whereas in the BE series Carbopol 934 was used (1:0.25 to 1:1.50). The formulations were tested for in vitro drug release, in vitro bioadhesion, moisture absorption and in vitro drug permeation through porcine buccal mucosa. Formulation BC3 showed maximum release of the drug (88.7 ± 0.4%) with the Higuchi model release profile and permeated 21.5 ± 2.9% of the drug (flux 8.35 ± 0.291 μg h–1cm–2) permeation coefficient 1.34 ± 0.05 cm h–1) through porcine buccal membrane. BC3 formulation showed 1.62 ± 0.15 N of peak detachment force and 0.24 ± 0.11 mJ of work of adhesion. FTIR results showed no evidence of interaction between the drug and polymers. XRD study revealed that the drug is in crystalline form in the polymer matrix. The results indicate that suitable bioadhesive buccal tablets with desired permeability could be prepared.10

ENCLOSURE-III

6.3Objectives of the study
The present work is an attempt,
To select suitable polymer for buccal drug delivery system.
To prepare and characterize buccaldrug delivery system for sustain release of an Domperidone.
To prepare and characterize the different formulation by using different polymer concentration.
For evaluation of prepared formulation consist of

• Content uniformity
• Thickness
• Weight variation
• Bioadhesive strength using modified physical balance
• Surface pH
• Swelling study
• Matrix erosion

To perform the In-vitro drug dissolution study.
Stability study of the most satisfactory formulation.
ENCLOSURE-IV
MATERIALS AND METHODS:
7. Materials:
Drug: Domperidone.
Polymers: carbopol 934p, hydroxy propyl methyl cellulose K4M, sodium carboxy methyl cellulose (Sod. CMC) and hydroxy ethyl cellulose (HEC).
Equipments:Analytical balance, Stability chamber, Dissolution test apparatus,
UV – Spectrophotometer, Magnetic Stirrer, Tablet PunchingMachine,
Pfizer Hardness Tester, Friability Testing Apparatus, Ovens, Bulk Density Test
Apparatus, Desiccator, pH Meter, Fourier transforminfra red(FTIR)
spectrometer.
Methods:
Preparation of buccal drug delivery system by Direct compression method.
ENCLOSURE-V
7.1. Source of Data
1) Review of literature from :
a. Journals : such as
- International journal of pharmacy and pharmaceutical sciences
- ActaPoloniaePharmaceutica – Drug Research
- ARS Pharmaceutica
- Indian drugs
- Indian journal of pharmaceutical sciences.
- Journal of pharmaceutical research
- Journal of basic and clinical pharmacy
b. Internet browsing.
2) Library: M.M.U. College of Pharmacy.
3) Laboratory based studies.
ENCLOSURE-VI
7.2. Method of Collection of Data
Data on drugs will be collected through literature survey and from physicochemical
database. The steps that will be followed are:
1. Buccal drug delivery system for an Domperidonewill be prepared using
different concentration of polymer.
2. Evaluation of the prepared tablets by different physicochemical characterization
studies.
ENCLOSURE-VII
7.3. Does the study require any investigation or intervention to be conducted on patients or other humans or animals? If so, please mention briefly.
-NO-
7.4. Has ethical clearance been obtained from your institution in case of 7.3?
-NOT APPLICABLE-
ENCLOSURE-VIII
LIST OF REFERENCES
1. Amir H, Shojaei. Buccal mucosa as a route for systemic drug delivery. J. Pharm Sci.
1998;1(1):15-30.
2. Mumtaz AM, Ching HS. Evaluation of bioadhesive buccal tablets containing
triamicinolone acetonide in healthy volunteers. Int. J. Pharm. 1995;121(6):249-54.
3. Khanna R, Agarwal SP, Auja A. Preparation and evaluation of bioerodible buccal
tablets. Int. J. Pharm. 1996;138(3):67-73.
4. Desai KH, Kumar TM, Prepartion and evaluation of a novel buccal adhesive system.
AAPS Pharm. Sci. Tech. 2004;5(1):1-9.
5. Darwish MK, Elmeshd AN. Buccal mucoadhesive tablets of flubriprofen:
charecterization and optimization. Drug Discov. Theory. 2009;3(4):181-9.
6. Chandira M, Venkateshwara SB, Debojit B, Jaykar B. Formulation and development
of controlled release mucoadhesive oral tablets of clarithromycine. Dev. Pharmacia.
Lettre. 2009;1(1):83-91.
7. Giunechedi P, Juliano C, Gavini E, Cossa M, Sorrentia M. Formulation and in vitro
evaluation of chlorhexidine buccal tablets. Eur J Pharm Biopharm 2002; 53(3):233-9.
8. Deshmane SV, Joshi UM, Channawar MA, Biyani KR, Chandewar AN. Design and
characterization of carbopol- HPMC- ethyal cellulose based buccal compact
containing propranolol hydrochloride. Ind. J. Pharm. Edu. Res. 2010;44(3):1-6.
9. Indian Pharmacopoeia. Ghaziabad: The Indian Pharmacopoeia Commission. 2010;
vol 1.
10. Yamsani VV, Gunna R, Kolli C, Bhanoji ME, Yamsuni MR. Development and in-
vitro evaluation of buccoadhesive carvedilol tablets.Acta Pharm.2007;57(2):185-
97.