FORMULATION AND EVALUATION OF

SUBLINGUAL TABLETS OF AN ANTIEMETIC DRUG

M. Pharm. Dissertation Protocol Submitted to

Rajiv Gandhi University of Health Sciences, Karnataka

Bangalore– 560041

By

MR. SOMNACHE SANDESH NARAYAN B pharm

Under the Guidance of

Prof. A.M.GODBOLE M.Pharm, PhD

Department of Pharmaceutics

S.E.T’s COLLEGE OF PHARMACY

S. R. Nagar, Dharwad–580002

2011-2012

RAJIV GANDHIUNIVERSITY OF HEALTH SCIENCES,

BANGALORE, KARNATAKA

ANNEXURE-II

PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION

1. / NAME OF THE CANDIDATE AND ADDRESS / MR. SOMNACHE SANDESH NARAYAN
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 COURSE / June 2011
5. / TITLE OF THE TOPIC
FORMULATION AND EVALUATION OF SUBLINGUAL TABLETS OF AN ANTIEMETIC DRUG
6.
7. / BRIEF RESUME OF THE INTENDED WORK
6.1 NEED FOR THE STUDY
Vomiting is the reflex action of ejecting contents of stomach through the mouth and sometimes through the nose, while nausea is the feeling that one is about to vomit. The act of emesis and sensation of nausea occurs due to a variety of reasons like ingestion of gastric irritant, certain drugs like ergot, digitalis, morphine etc, chemotherapy & radiotherapy, GI infection etc.1 It is a complexprocess consisting of Pre-ejection phase, Retching and Ejection. Vomiting occurs due to stimulation of the emetic center (CTZ) at medulla oblongata. Nausea is accompanied by reduced gastric tone.2
CTZ (ChemoreceptorTrigger Zone) & NTS(NucleusTractusSolitarius) are the most important relay areas for afferent arising in GIT, throat and other viscera. CTZ has high concentration of 5HT3, Dopamine D2 and opoid receptors while NTS is rich in eukephalin, histamine, Ach and 5HT3 receptors. These receptors relay the impulse of emesis which could be targets of antiemetic action.2 Based upon the prominent receptor on which the drug is acting, antiemetics are classified as 5HT3 antagonist, Dopamine antagonist (i.e. D2 antagonist), Antihistaminics etc.1
Ondansetron is a prototype of 5HT3 antagonist which blocks serotonin receptor and thus blocks emesis. It is mainly indicated for prevention of nausea & vomiting associated with chemotherapy, radiotherapy, post anesthetic nausea-vomiting andvomiting due to drug overdose. It has oral bioavailability of 60%(due to first pass metabolism) and half life of 3-4 hours. 1
Domperidone is D2 antagonist mainly used in treatment of nausea & vomiting associated with gastroparesis, pediatric gastroesophagal reflex. It absorbed orally but its bioavailability is only ~15% due to first pass metabolism. It has half life of 7.5 hrs.1
Administration of an Antiemetic Drug during emesis, dosage form (tablet,capsule,liquid oral etc.) may be expelled out leading to less effective therapy. To overcome this, one can select an alternative route such as
1)Injectables
2)Orodispersibleor Mouth dissolving tablet
3)Sublingual tablet.
Administration by injectable route is painful and requires skilled personnel.
Compared to orodispersible tablet, rate of absorption of drug through sublingual route is more.3
Sublingual delivery traditionally involves systemic administration of drug via mucosal membrane of floor of mouth or the ventral surface of tongue. The sublingual mucosa is relatively permeable due to the lipoidal nature of mucous membrane with a rich vasculature, which allows rapid absorption and has acceptable bioavailability. It is convenient, facilitates ease of administration and its ability to bypass hepatic first pass.4It is also helpful in case of Dysphagia (difficulty in swallowing) which is common problem for all age groups, especially elderly & children.3So the present study involves formulation & evaluation of a sublingual tablets with an antiemetic agent.
6.2 REVIEW OF LITERATURE:
Narang N, Sharma J.et al., in their review article on systemic drug delivery through sublingual mucosa are of the opinion that the sublingual route is capable of producing rapid onset of action as comparedto buccal, gingival and palatal route of drug administration because of high permeability and rich blood supply. They observed that absorption of drug through sublingual route is 3 to 10 times greater than oral route. Thus drug delivery via oral mucosal membrane is considered to be a promising alternative to the oral route. Sublingual route is useful when rapid onset of action is desired with better patient compliance than orally ingested tablets. The portion of drug absorbed through the sublingual capillary network of blood vessels bypasses the hepatic first‐pass metabolic processes giving acceptable bioavailability.3
Nystrom C.et al., concluded that new sublingual solid dosage form (i.e.finely divided potent drug mixed with a coarse water-soluble material) ought to result in both a high uniformity of drug content and rapid drug dissolution. They also suggested that addition of bioadhesive component to formulation, increase bioadhesive retention of drug in oral cavity, resulting in optimal exposure of active substance to the dissolving fluids in the mouth showing rapid sublingual absorption.5
Tas C. et al., concluded that, to ensure a more intimate contact of dosage form with the sublingual mucosa, there is a need of the adhesion of dosage form to the moist surface of mucosa and resistance to the flushing action of saliva. Bioadhesive polymer such as hydroxyl propyl methyl cellulose, chitosan and sodium carboxy methyl cellulose can be used in ratio of 0.5-5 in sublingual tablet formulation to provide necessary time for absorption of drug & also protect it from flushing action of saliva.6
Pinto J. in his review article suggested that sublingual administration of drug, avoid first pass metabolism & give fast entry into the systemic circulation.7
Bhardwaj V.et al., concluded that in formulation of sublingual tablet, as concentration of kollidon-CL & Ac-Di-Sol increases, the disintegration time decreases. For sodium starch glycolate, as concentration in tablet increases, disintegration time does not decrease significantly. Formulation containing 6% Ac-Di-Sol as superdisintegrant showed faster dissolution rate & disintegration rate compare to other superdisintegrant. The water absorption ratio & wetting time increases with increase in concentration of superdisintegrant. Increase in concentration of superdisintegrant, disintegration time decreases in the order of Ac‐Di‐Sol < Kollidon‐CL< Sodium starch glycolate.8
KolandM.concluded that, use of water soluble sweeteners like mannitol not only enhance taste of ondansetron containing film but also increase drug release & drug permeation through oral mucosa.The mannitol causes the disintegration of formulation faster compared to formulation without sweeteners and formulation containing sodium saccharin, which is also water-soluble salt but used in lesser concentrations as compared to mannitol.9
Kotagale NR.et al., concluded that in formulation of buccal drug delivery of ondansetron HCl, pH modifier such as sodium bicarbonate used to get controlled and desired release profile. Increase in sodium bicarbonate concentration increases the microenvironment pH water uptake and decreases the bioadhesive strength. Whereas increased carbopol-934 relative to sodium alginate and gelatin decreases the microenvironment pH and increase bioadhesive strength & water uptake. Increased gelatin leads to increased microenvironment pH to more satisfactory levels and decreased bioadhesive strength and water uptake.10
6.3 OBJECTIVE OF STUDY:
The objective of the proposed study are:-
  • To prepare standard calibration curve of an Antiemetic Drug.
  • To carry out compatibility studies between drug & polymers.
  • To develop sublingual formulations of ious sublingual formulution less111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111an Antiemetic Drug.
  • To evaluate the prepared formulations for various quality control parameters.
Materials and methods :
materials :
Drug: an Antiemetic Drug.
Polymers: Mucoadhesive Polymers.
Other tablet additives.
7.1 SOURCE OF DATA :
  • Standard reference text books
  • (RGUHS)
  • Pharmaceutical web sites
  • Scientific Journals (Indian journal of pharmaceutical sciences, AAPS Pharma Sci Tech, International journal of Pharmaceutics, European journal of pharmaceutics and biopharmaceutics) etc.
7.2 METHOD OF COLLECTION OF DATA :
  1. METHOD OF PREPRATION :
The active agent and excipients will be formulated into sublingual tablet by suitable technique such as direct compression, wet granulation etc. Different polymers will be screened to achieve desired physicochemical properties.
  1. CHARACTERIZATION OF SUBLINGUAL TABLET OF ONDANSETRON HCl
Following parameters will be evaluated,
Precompression studies
Bulk density
Tapped density
Carr’s index
Angle of repose
Post compression studies
Tablet size
Thickness
Hardness
Friability
Weight variation
Content uniformity
Wetting time
Disintegration time
In-vitro drug release: Using a USP dissolution apparatus type II(paddle method)
7.3 DOES THE STUDY REQUIRE ANY INVESTIGATION OR INVENTION 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.

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8. / REFERENCES:
  1. Tripathi KD. Essentials of medical pharmacology. 5thed. New Delhi: Jaypee Brothers Medical Publishers (p) Ltd; 2003.p.599-609.
  1. Brunton LL, Parkar KL.Goodman & Gillman's Manual of Pharmacology & therapeutics.NY: The McGraw-Hill; 2008.p.644-50.
  1. Narang N, Sharma J.Sublingual mucosa as a route for systemic drug delivery. Int J Pharm PharmSci2011;3(2):18-22.
  1. Webber W. Encyclopedia of controlled drug delivery. Vol.2 NY: A Wiley-Interscience publication; 2009.p.553-63.
  1. Nystrom C, Duberg M, Lennernas B, Lennernas H, Pettersson A, Westeberg M et al.,In vitro and in vivo evaluation of a new sublingual tablet system for rapid oromucosal absorption using fentanyl citrate as the active substance.Eur J PharmSci 2003;20:327-34.
  1. Bayrak Z, Tas C, Tasdemir U, Erol H, Ozkan CK, Savaser A et al., Formulation of zolmitriptan sublingual tablets prepared by direct compression with different polymers: In vitro and in vivo evaluation. Eur J Pharm Biopharm 2011;78:499-505.
  1. Pinto JF. Site-specific drug delivery systems within the gastro-intestinal tract: From the mouth to the colonInt J Pharm 2010;395:44-52.
  1. Bhardwaj V, Shukla V, Goyal N, Salim MD, Sharma PK. Formulation and evaluation of fast disintegrating sublingual tablets of Amlodipinebesylate using different superdisintegrants. Int J PharmPharmSci 2010;2(3).
  1. Koland M, Sandeep VP, Charyulu NR. Fast dissolving sublingual films of ondansetron hydrochloride: Effect of additives onin vitrodrug release and mucosal permeation. J Young Pharmacist2010;2(3):216-22.
  1. Kotagale NR, Patel CJ, Parkhe AP, Khandelwal HM, Taksande JB, Umekar MJ. Carbopol 934-sodium alginate-gelatin mucoadhesiveondansetron tablets for buccul delivery: effect of pH modifiers. Ind J pharmSci 2010 Jul;72(4):471-79.

9. / SIGNATURE OF CANDIDATE
10. / REMARK OF THE GUIDE
The above information and literature has been extensively investigated, 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 / Prof. A.M.GODBOLE M.Pharm, PhD
Professor,
DEPT.OF PHARMACEUTICS,
S E T’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. S. P. THAKKER M. Pharm.
PROFESSOR AND HEAD,
DEPT.OF PHARMACEUTICS,
S E T’s COLLEGE OF PHARMACY,
S. R. NAGAR, DHARWAD-580002.
12. / 12.1 REMARK OF THE
PRINCIPAL / The above mentioned information is correct and I recommend the same for approval.
12.2 SIGNATURE / Dr. V. H. KULKARNI M.Pharm, Ph.D.,
PROFESSOR AND PRINCIPAL,
S E T’s COLLEGE OF PHARMACY
S. R. NAGAR,
DHARWAD-580002.

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