RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, KARNATAKA, BANGALORE.
M. PHARM SYNOPSIS
YEAR OF ADMISSION-JUNE 2011
TITLE OF THE SYNOPSIS
“AN APPROCH TO IMPROVE AVAILABILITY OF DILTIAZEM HCL BY DESIGNING SUBLINGUAL TABLET”
BY
Mr.Surendra S. Sankapal
M. Pharm. Part-I
Department of Pharmaceutics
UNDER THE GUIDANCE OF
Prof. Jagdish K. Saboji. M. Pharm.,
Professor &Head
Dept. Of Pharmaceutics.
KLES’s COLLEGE OF PHARMACY
NIPANI,
KARNATAKA.
RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES KARNATAKA, BANGALORE.
ANNEXURE-II
PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION
1. / NAME OF THE CANDIDATEAND ADDRESS /
Mr. Surendra sankapal
S/o.- Shripati Sankapal
A/P. – Vhannur,
DIST. – Kolhapur,
PIN CODE - 416216
STATE - MAHARASTRA
2. / NAME OF THE INSTITUTION /
KLES’s COLLEGE OF PHARMACY
Akkol Road,NIPANI
DIST:- BELGAUM
KARNATAKA.
3. / COURSE OF STUDY
AND SUBJECT /
MASTER OF PHARMACY IN PHARMACEUTICS
4. / DATE OF ADMISSION / June 2011
5. TITLE OF THE TOPIC
“AN APPROCH TO IMPROVE AVAILABILITY OF DILTIAZEM HCL BY DESIGNING SUBLINGUAL TABLET ”
6.0 /BRIEF REVIEW OF THE INTENDED WORK
6.1 - Need for the study
Angina is a chest pain due to ischemia (a lack of blood or lack of oxygen supply) of the heart muscle. Generally due to obstruction or spasm of the coronary arteries. The main cause of angina is due to atherosclerosis of the cardiac arteries. There are two types of angina, stable angina and unstable angina. Stable angina attacks are predictably provoked by exercise, emotion eating when increased energy demand is withdraw. In unstable angina, attack occur at rest or during sleep, Coronary vasospasm and platelet deposition is occur. The risk factors for coronary heart disease include diabetes, family history of coronary heart disease before age 50, high blood pressure, male gender, enough exercise, obesity and smoking.1
Treating angina include life style changes, medication and procedure such as coronary angioplasty and coronary artery bypass surgery. Medication include 1) Nitroglycerin pills or spray may be used to stop chest pain. 2) ACE inhibitors to lower blood pressure and protect the heart.3) Beta-Blockers to lower heart rate, blood pressure and oxygen use by the heart. 4) Calcium channel blockers to release arteries, lower blood pressure and reduce strain on the heart. Surgical treatment include angioplasty and blockages that can not be treated with angioplasty may need a heart bypass.2
Pharmacokinetic properties of diltiazem, bioavailability- 40%, plasma half life- 3-5 hour, dose in angina- 120-360 mg per day , protein binding- 70-80%. Diltiazem inhibits the influx of extracellular calcium across both the myocardial and vascular smooth muscle cell membrane. The resultant inhibition of the contractile processes of the myocardial smooth muscle cell leads to dilation of coronary and systemic arteries and improved oxygen delivery to the myocardial tissue.2
Diltiazem Undergoes first pass metabolism in liver and gut wall which has oral bioavailability is 40-60%. Absorption of diltiazem is approximately 80% on oral dose from GI tract. Only 40% of an oral dose reaches the systemic circulation since diltiazem undergoes extensive metabolism on first pass through the metabolism. Deltiazem has large volume of distribution because of its lipophilicity the main apparent volume of distribution of diltiazem at steady state range from 360-390 L in healthy adults receiving an IV infusion of 4.8-13.2 mg per hr for 24 hours. Approximately 2-4% of the dose of drug eliminated from urine . The remaining drug is eliminated in to urine and via bile mainly as metabolites.3
First pass metabolism is a phenomenon of drug metabolism where the concentration of drug is greatly reduced before it reaches the systemic circulation. The liver metabolizes many drug. The first pass through the liver thus greatly reduced before it reaches the systemic circulation. The liver metabolizes many drug , the first pass through the liver thus greatly reduces the bioavailability of drug. Alternative routes of administration like intravenous, intramuscular, suppository and sublingual avoid the first pass effect because they allow drug to be absorbed directly in the systemic circulation.4
The sublingual route usually produces a faster onset of action than orally ingested tablet and the portion absorbed through the sublingual blood vessels bypass the hepatic first pass metabolism process. The sublingual dosage form offers fast release of drug from the formulation and it reaches the systemic circulation directly, which bypass the metabolism of drug in the liver and offers fast relive from the angina pain or hypertension. The sublingual dosage form offers 1) Rapid absorption 2) Reduce first pass metabolism. 3) Enhance bioavailability. 4) Fast onset of action.5
Sublingual administration of the drug means placement of the drug under the tongue and drug reaches directly in to the blood stream through the ventral surface of the tongue and floor of the mouth. The drug solutes are rapidly absorbed into the reticulated vein which lies under the oral mucosa, and transported through the facial veins, internal jugular vein, and braciocephalic vein and then drained in to systemic circulation.6
Taking above findings in consideration the present study is focusing on formulation of sublingual tablets of diltiazem HCL to circumvent the first pass metabolism which will lead to increased availability of drug in angina.
6.2 - Review of Literature
1. Hess O. M. et al (1989), prepared Diltiazem alone and combined with nitroglycerin: effect on normal and diseased human coronary arteries. The vasodilator effect of diltiazem and nitroglycerin on the large epicardial luminal arteries . it is concluded that diltiazem prevents exercise-induced coronary vasoconstriction of stenotic vessel. Diltiazem combine with nitroglycerine elicits an additive effect on coronary vasodilation of the stenotic vessel segments but not on the normal coronary arteries.7
2. Vineet Bhardwaj. et al (2010), prepared Formulation and evaluation of fast disintegrating sublingual tablets of amlodipine besylate using different superdisintegrants . By using different disintergrants and to evaluate the effect of increasing amlodipin besylate load on the characteristics of fast disintegrating sublingual tablets for the potential emergency treatment of angina. Superdisintegrant used in this study were Kollidon CL and sodium starch glycolate in varying concentration (2%, 4%, 6% ).8
3. Bujold E. et al (2003), Formulated sublingual nitroglycerin as a tocolytic in external cephalic version : a comparative study. To study the effect of sublingual nitroglycerine as a tocolytic on the success rate of external cephalic version in nulliparous and parous women.9
4. Ducharme A. et al (1999), prepared comparison of nitroglycerin lingual spray and sublingual tablet on time of onset and duration of brachial artery vasodilation in normal subjects. This study compared the rapidity of onset, the magnitude and the duration of action of 2- short acting nitroglycerin preparation using high resolution brachial ultrasound. Both sublingual tablet and lingual spray formulation caused maximal vasodilation at 3 minutes. However, the spray provided faster ( at 2 min ) greater and more prolonged (15 min ) vasodilation than the tablet.10
5. Sheeba F. R. et al (2009), prepared formulation and evaluation of nifedipin sublingual tablet. Three different groups of formulations (A, R, and V) with variation in tablet excipients were prepared by direct compression method. Tablet weight variation, hardness, friability, drug content, disintegration time and dissolution time were evaluated for each formulation and found satisfactory. The studied sublingual tablet group V shows a lesser T50% compared to commercial oral tablet. The Group V also indicates the fast dissolution and disintegration rate of the optimized nifedipine sublingual tablet, which is prerequisite for rapid management of angina.11
6. Shinde Anilkumar, et al (2010), prepared development and characterization of oral fast dissolving tablet of nifedipin using camphor as a subliming material. The aim of these study was to evaluate the effect of increasing nifedipin load on the characteristic of fast disintegrating sublingual tablets for the potential emergency treatment of angina pain. Sublingual dosage form bypass the metabolism of the nifedipin in the liver and offers a fast relieve from angina pain. These fast dissolving tablet prepared by wet granulation technique using camphor as subliming agent and sodium starch glycolate together with crosscarmellose sodium as super disintegrants , flavour and sweeteners impart the test to the formulation . the porous granules were compressed in to tablets by single punch tablet machine . all the formulation were evaluated for weight variation , hardness, friability , content uniformity ,wetting time and dissolution rate.12
7. Ziya Bayrak . et al (2010), prepared formulation of zolmitriptan sublingual tablets prepared by direct compression with different polymers : In vivo and in vitro evaluation. Zolmitriptan sublingual tablet were prepared by direct compression method using different mucoadhesive polymers to reduce flushing action of saliva and provide enough time for drug to be absorbed . In vivo studies indicated that formulation containing 5% chitosan has the maximum Cmax and AUC and minimum Tmax values ( P 0.05) . As a result sublingual tablet administration zolmitriptan appeared to be promising alternative to traditional drug administration route.13
8. Ho-Leung. et al (1976), Development of a stable sublingual nitroglycerin tablet : formulation and evaluation of tablet containing povidone. Stable and pharmaceutically elegant sublingual nitroglycerin tablets were formulated using povidone to retard volatilization of the drug. The blend of two grade of povidone of different degree of cross – linkage and water solubility , provided stable tablets which exhibited rapid disintegration directly compressed sublingual tablets made in this study retained over 80% of the initial nitroglycerin when exposed to the atmosphere at room temperature for 2 months. The direct compression tablets are of good appearance and low friability, the formulation is readily compressed without problem.14
6.3 - Objective of the Study
Following are the objectives of the present study
1) To carry out preformulation study.
2) To develop and formulate the sublingual tablets of antianginal drug Diltiazem HCL.
3) To evaluate the formulated dosage form by official in vitro studies .
4) To carry out stability studies as per ICH guidelines .
7.0 / MATERIALS AND METHODS
Materials
Drug : Diltiazem,
Binding agent : Avicel pH 101 etc
Diluents : Mannitol , Lactose DCL, etc
Sweetening agent : Sacchrine sodium etc
Antioxident : Citric acid etc
Disintegrants : Cros carrmellose sodium , sodium starch glycolate etc.
Method :
Development of Diltiazem sublingual tablet by direct compression or any suitable /Developed method.
7.1 - Source of Data
a) Journals such as,
1) Indian Drug.
2) Indian Journal of Pharmaceutical Sciences.
3) Indian Journal of Pharmaceutical Education and research.
4) European Journal of Pharmaceutical Sciences.
5) International Journal of Pharmaceuticals.
6) Drug Development & Industrial Pharmacy.
7) Journal of Controlled Release.
b) Review articles
c) World Wide Web.
d) Science Direct, Pub med.
e) Library: KLES’s College of Pharmacy.
f) E-library: KLES’s College of Pharmacy.
7.2 - Method of collection of data
1) Preformulation studies for possible drug or other excipient.
2) Preparation of sublingual tablet of Diltiazem Drug by Direct compression method or any suitable /developed method.
3) Evaluation of the various properties of sublingual Diltiazem tablet .
· Angle of repose.
· Bulk density and tap density.
· Tablet thickness.
· Weight uniformity.
· Hardness .
· Friability.
· Disintegration.
· Drug content uniformity.
· Dissolution.
· Swelling studies.
· Surface pH
4) Carry out stability studies as per ICH guidelines.
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”
(The study do not requires animal to evaluate antianginal activity)
7.3-Has ethical clearance been obtained from your institution in case of 7.3 ?
“ NOT APPLICABLE “
8.0 /
REFERENCES
1. Barar F.S.K , “Essential of Pharmacotherapeutics”. S. Chand. 2007 ; 3rd : 268-277.
2. Tripathi K.D, “Essential of medical pharmacology”. Jaypee . 2008; 6th : 521-536.
3. Satoskar R.S, Bhandarkar S.D, Ainapure S.S, “Pharmacology and pharmacotherapeutics”. S. Chand. 2003 ; 8th: 392-404.
4. Golan D. E , Tashjian H. A. Jr , Ehrin J. Armstrong, April W. Armstrong, “principal of pharmacology”. Wolters Kluwer . 2008 ; 2nd : 34-36.
5. Puttalingaiah Lokesha , Kunchu K , Tamizh Mani T, “Fast disintegration tablet : an overview of formation , technology and evalution”. Research Journal of Pharmaceutical , Biological and Chemical Science. 2011; 2 (2) : 589-601.
6. Narang Neha , Sharma Jyoti, “Sublingual mucosa as a route for systemic drug delivery.” International Journal of Pharmacy and Pharmaceutical science.
2011 ; 3 : 18-22.
7. Hess O.M, Honogi H.N, Bortone Z, Gage J. E, “Diltiazem alone and combined with nitroglycerin: effect on normal and diseased human coronary arteries”, European Heart Journal.1989 : 142-146.
8. Bhardwaj Vineet, Shukla Vikesh, Goval Narendra, Sharma P.K , “Formulation and evaluation of fast disintegrating sublingual tablets of amlodipin besylate using different superdisintigrants”. International Journal of Pharmacy. 2010 ; 2 : 89-92.
9. Bujold E, Sergerin M, Masse A, Bedard M.J, Dube J, “Sublingual nitroglycerine as a tocolytic in external cephalic version of a comparative study”. J Obstet Gynaecol Can. 2003 ; 25 (3) : 203-207.
10. Ducharme A, Dupuis J, Mcnicoll F, Tardif J. C. “Comparison of nitroglycerin lingual spray and sublingual tablet on time of onset and duration of brachial artery vasodilation in normal subjects”. American Journal of Cardiology. 1999; 84: 952-954. .
11. Sheeba F.R. Rameshwaris S. Jeya Anandi J, “Formulation and evaluation of nifedipin sublingual tablet”. Asian Journal of Pharmaceutical and Clinical Research. s
2009 ; 2 : 44-48.
12. Shinde Anilkumar J. Waghule Arun N. Paithane Amol, “Development and characterization of oral fast dissolving tablet of nifedipin using camphor as a
subliming material.” Research Journal of Pharmaceutical and Clinical Reseach .
2010 ; 1 : 46-50.
13. Bayrak Ziya, Tas Cetin, Tasdemir Umut , Halil Erol, “Formulation and evaluation of zolmitriptan sublingual tablet prepared by direct compression with different polymers: In vitro evaluation”. European Journal of Pharmaceutics. 2010 ; 78 : 499-505.
14. Ho – Leung Fung, Yap S. K , Rhodes C. T , “Development of a sublingual Nitroglycerin tablet : Formulation and evaluation of tablet containing povidone”, Journal of Pharmaceutical Science. 1976 ; 2 : 558-560.
9. /
SIGNATURE OF THE CANDIDATE
10. / REMARKS OF THE GUIDE / Recommended
11. / NAME AND DESIGNATION OF
11.1 Guide / Prof. Jagdish K.Saboji, M. Pharm.
Professor of Pharmaceutics
11.2 Signature
11.3 Co-Guide ( If any)
11.4 Signature
11.5 Head of the Department / Prof. J. K. Saboji, M.Pharm
Professor & Head
Department of Pharmaceutics
11.6 Signature
12. / 12.1 Remarks of the Chairman
Principal / Forwarded to the University for approval
12.2 Signature
/ Principal
Prof. J. K.SABOJI
KLES’s College of Pharmacy
Akkol Road,
NIPANI-591237.
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