“FORMULATION AND EVALUATION OF IMMEDIATE RELESE OF ANTI – HYPERTENSIVE DRUG VALSARTAN TABLETS”
DISSERTATION PROTOCOL
SUBMITTED TO
RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES
BANGALORE, KARNATAKA.
BY
PEMMAKA GANGADHARA REDDY
M.PHARM, PART-1,
DEPARTMENT OF PHARMACEUTICS
OXBRIDGE COLLEGE OF PHARMACY
MADESHWARA NAGAR
VISHWANEEDAM POST
MAGADI MAIN ROAD
BANGALORE-560 091.
UNDER THE GUIDANCE OF
Prof.MANJUNATH U.MACHALE
DEPARTMENT OF PHARMACEUTICS
OXBRIDGE COLLEGE OF PHARMACY
MADESHWARA NAGAR
VISHWANEEDAM POST
MAGADI MAIN ROAD
BANGALORE-560 091.
RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES,
KARNATAKA, BANGALORE
ANNEXURE- II
PROFORMA OF REGISTRATION OF SUBJECT FOR DISSERTATION
1) / NAME OF THE CANDIDATE AND ADDRESS / PEMMAKA GANGADHARA REDDY2) / NAME OF THE INSTITUTION / OXBRIDGE COLLEGE OF PHARMACY
3) / COURSE OF THE STUDY AND
SUBJECT / M.PHARM (PHARMACEUTICS)
4) / DATE OF ADMISSION TO THE COURSE / 21 -06- 2012
5) / TITLE OF THE TOPIC / FORMULATION AND EVALUATION OF IMMEDIATE RELESE OF ANTI – HYPERTENSIVE DRUG VALSARTAN TABLETS
6) / BRIEF RESUME OF THE INTENDED WORK:
6.1) NEED FOR THE STUDY:
Immediate release drug delivery system is a conventional type of drug delivery. It is designed to disintegrate and release their medicaments with no special rate controlling features. These are the dosage forms in which ≥ 85% of labeled amount dissolves with in 30 min (Patel HP et al., 2011)17. However for immediate release tablets, tablet disintegrants play an important role in ensuring that the tablet matrix break up on contact with fluid in the stomach to allow the release the active drug which then become available in whole or in part, for absorption from gastrointestinal tract.1
Mechanism of drug release: On exposure to aqueous fluids, hydrophilic matrices take up water and the polymer starts hydrating to form a gel layer. Drug release is controlled by diffusion barriers/by surface erosions. An initial burst of soluble drug may occur due to surface leaching.2
Systemic hypertension represents a significant risk factor for the development of atherosclerotic coronary artery disease, myocardial Infarction, cerebro vascular accidents & congestive heart failure. A major barrier to the management of hypertension is the extent to which patient comply with the treatment regimen.3
In view to the above mentioned factors, we aim to developed the immediate drug delivery of angiotensin II receptor blocker like Valsartan ( Valsartan is characterized by low bioavailability by oral route of 23% & half life of about 6hrs) hence valsartan is chosen for delivery via immediate drug release. Various formulations of valsartan will be prepared in different rate controlling polymer matrices. These formulations will be subjected to physicochemical evaluation & invitro studies.4
Polymers such as L-HPC LH 21 ,Corn starch, Aerosil, Povidone, are used as main polymers and super disintegrating agents and opadry as coating material for the preparation of immediate drug delivery tablets.5
Immediate release drug delivery system is a conventional type of drug delivery systems for such drugs so with these we can have better management of the Hypertension & improve patient compliance.
6.2) REVIEW OF LITERATURE:
Holwerda NJ et al (1996)19 aimed to compare the antihypertensive efficacy and systemic tolerability of valsartan, a new angiotensin II receptor antagonist, with placebo and with an angiotensin converting enzyme (ACE) inhibitor, enalapril.
Jay N. Cohn et al (2001)20 Actions of angiotensin II may contribute to the progression of heart failure despite treatment with currently recommended drugs. Therefore Cohn et al evaluated the long-term effects of the addition of the angiotensin-receptor blocker valsartan to standard therapy for heart failure.
Giancarlo Viberti et al (2002)21 Elevated urine albumin excretion (UAER) is a modifiable risk factor for renal and cardiovascular disease in type 2 diabetes. Blockade of the renin-angiotensin system lowers UAER, but whether this effect is independent of blood pressure (BP) reduction remains controversial.
Suzanne Oparil et al (2007)22 aimed assess dual renin system intervention with the maximum recommended doses of aliskiren and valsartan, compared with each drug alone in patients with hypertension.
Roberto Latini et al (2002)23 Brain natriuretic peptide (BNP) and norepinephrine (NE) are strongly related to severity of and are independent predictors of outcome in heart failure. The long-term effects of angiotensin receptor blockers on BNP and NE in heart failure patients are not known.
Paresh Dandona et al (2003)24 In view of the pro-oxidant and proinflammatory effects of angiotensin II, they have tested the hypothesis that valsartan, an angiotensin receptor blocker, may exert a suppressive action on reactive oxygen species (ROS) generation, nuclear factor κB (NF-κB) in mononuclear cells.
McMurray, J.J et al (2010)24 It is not known whether drugs that block the renin–angiotensin system reduce the risk of diabetes and cardiovascular events in patients with impaired glucose tolerance. In this double-blind, randomized clinical trial with a 2-by-2 factorial design.
6.3) OBJECTIVES OF THE STUDY:
Following are the objectives of present study :
1) The aim and objective of the present study is to develop a pharmaceutically stable, cost effective and quality improved robust formulation of Valsartan Immediate Release tablets.
2) To achieve this goal various prototype formulation trials shall be taken and evaluated with respect to the various quality control parameters such as Dissolution, Assay.
3) The formula will be finalized by comparing the invitro dissolution profile with that of the marketed tablets.
4) The objective includes providing a robust formulation for the production of the dosage form for which the influence of various factors on disintegration time and dissolution parameters are to be studied and also analyzed using software called Design Expert.
5) To formulate and achieve formulation with similarity factor > 50 when compared to the innovator valsartan (DIOVAN) .
7) / MATERIALS AND METHODS: -
7.1) Source of data: Preliminary data required for the experimental study would be obtained from PUBMED, Science Direct, Google search, Library of Oxbridge College of Pharmacy, Bangalore, other industrial/academic resources, etc.
7.2) Methodology
· The process in consideration is the wet granulation technique as the flow property is found to be poor
· Dispense all the excipients and the API in required quantities and label them. Pass the Valsartan + L-HPC together through sieve, 16Pass corn starch and aerosil together through the same, Add the binder (Povidone 30) to the specified amount of water and stir continuously till complete mixing.
· After dry mixing for 10 min, add the granulating fluid to the dry mix with slow impellar and chopper off with in 2.30 min. Keading is done with slow impellar and slow chopper for 1 min. After kneading the granules are allowed to dry till the specific LOD has been reached. Pass the dried granules through sieve 24 and mill the retains using 1575 micron mesh using co-mill and pass through the same. Dispense the extra granular ingredients compensating the yield
· Pass the avicel and aerosil through sieve 30 and add to the granules, blend for 10min. Pass Mg.stearate through sieve 60 and add, carry out lubrication for 5 min. This final blend is compressed and the tablets are checked for the characteristic parameters. Finally coating is done for the elegance with opadry white ( generally 2.5% weight build up)
B.3 Method of collection of data(including sampling procedure )
1. From available literature
2. Laboratory investigation such as
i. By carrying out the physical characterization of immediate drug release tablets like content uniformity, thickness, weight variation, angle of repose, bulk density, hardness, friability.
ii. By carry out the disintegration time and in – vitro drug release profile of immediate drug release tablets.
iii. Out of this the best formulation of the medicated tablets give the immediate drug release to show the good therapeutic action.
7.4) Does the study require any investigation or intervention to be conducted on patient or other humans or animals if so, please describe briefly.
-- NO --
7.5) Has ethical clearance been obtained from your institution?
-Not applicable-
8) / List of reference:
1. Solid Dosage Forms, Barbara R.Conway, Pharmaceutical Manufacturing Handbook Production & Process. Vol-1,236-242.
2. Zhao, C., Jain, A., Hailemariam, L., Suresh, P., Akkisetty, P., Joglekar, G., Venkatasubramanian, V., Reklaitis, G.V., Morris, K., and Basu, P. (2006), Toward intelligent decision support for pharmaceutical product development, J. Pharm. Innovation, 1, 23–35.
3. Banker, G. S., and Rhodes, C. T. (2002), Modern Pharmaceutics, 4th ed., Drugs and the Pharmaceutical Sciences 121, Marcel Dekker, New York.
4. Chowhanzi, palagyil (1978) J Pharm Sci, 67:1335.
5. R.Shangraw, J.Wallace, and F.Bowers, “Morphology and Functionality in Tablet Excipients For Direct Compression”, Pharm.Techol.5 (10), 44-60(1981).
6. Handbook of Pharmaceutical Granulation Technology, Dilip M parikh 7-25(1997)
7. Handbook of Pharmaceutical excipients , Ainley Wade and Paul J. Weddereds, 2nd Ed, 1994
8. Rowe, R. C., Sheskey, P. J., and Weller, P. J. (2001), Handbook of Pharmaceutical Excipi- ents, 4th ed., Pharmaceutical Press, London.
9. Lachman, L., Lieberman, H. A., and Kanig, J. L. (1986), The Theory and Practice of Indus- trial Pharmacy, 3rd ed., Lea Febiger, Philadelphia.
10. Augsburger, L. L., Hahm, H. A., Brzeczko, A. W., and Shah, U. (2002), Superdisintegrants: Characterization and function, in Swarbrick, J., and Boylan, J. V., Eds., Encyclopedia of Pharmaceutical Technology, Vol. 3, 2nd ed., Marcel Dekker, New York.
11. Ladak, N.; Thompson, J. Drugs acting on the heart: antihypertensive drugs. Anaesth. Intensive Care Med. 2009, 10, 392–395.
12. Mahmud, A.; Feely, J. Low-dose quadruples antihypertensive combination more efficacious than individual agents–a preliminary report. Hypertension 2007, 49, 272–275.
13. M.M. RAS inhibition in hypertension. J. Human Hypert. 2006, 20, 101–108.
14. Li, H.A liquid chromatography/tandem mass spectrometry method for the simultaneous quantification of valsartan and hydrochlorothiazide in human plasma. J. Chromatogram. B 2007, 852, 436–442.
15. Therapeutic systems research laboratories, Biopharmaceutivs classification system. http://www.tsrlinc.com/services/bcs/results.cfm (2010) (accessed 6 March 2010).
16. Loftsson, T.; Duchêne, D. Cyclodextrins and their pharmaceutical applications. Int. J. Pharm. 2007, 329, 1–11. Formulation and In-vitro Evaluation of Immediate release tablets of Drotaverine HCl, patel HP 2011, J. Chem. Pharm. Res., 2011, 3(4):333-341
17. Design of Experiments for Formulation Development, Ruey-ching (Richard) Hwang, PhD,Kowalski, Pharmaceutical Technology, dec 20112005. pharmatech.com
18. Valsartan, a new angiotensin II antagonist for the treatment of essential hypertension: efficacy and safety compared with placebo and enalapril, Holwerda NJ, Fogari R (1996) (PMID: 8986917) pubmed.
19. Jay N. Cohn et al (2001) A Randomized Trial of the Angiotensin-Receptor Blocker Valsartan in Chronic Heart Failure N Engl J Med 2001; 345:1667-1675 December 6, 2001
20.Giancarlo Viberti et al (2002) Microalbuminuria Reduction With Valsartan in Patients With Type 2 Diabetes Mellitus A Blood Pressure–Independent Effect, ahajounals.org, July 15, 2002, doi: 10.1161.
22.Suzanne Oparil et al (2007) Efficacy and safety of combined use of aliskiren and valsartan in patients with hypertension: a randomised, double-blind trial, the lancet volume 330 issue 9583 21–27 July 2007, Pages 221–229.
23. Suzanne Oparil et al (2007) Efficacy and safety of combined use of aliskiren and valsartan in patients with hypertension: a randomised, double-blind trial, the lancet volume 330 issue 9583 21–27 July 2007, Pages 221–229.
24. Paresh Dandona et al (2003) Angiotensin II Receptor Blocker Valsartan Suppresses Reactive Oxygen Species Generation in Leukocytes, Nuclear Factor-κB, in Mononuclear Cells of Normal Subjects: Evidence of an Anti-inflammatory Action. The Journal of Clinical Endocrinology & Metabolism September 1, 2003 vol. 88 no. 9 pages 4496-4501.
25. McMurray, J.J et al Effect of valsartan on the incidence of diabetes and cardiovascular events New England Journal of Medicine, Volume: 362, Issue: 16 (2010), pages. 1477-1490.
6. / Signature of the candidate / PEMMAKA GANGADHARA REDDY
7. / REMARKS OF THE GUIDE / RECOMMENDED FOR
DISSERTATION WORK.
8. / Name & Designation of
(in block letters)
/ 8.1 GUIDE
8.2 SIGNATURE
Name & Designation of
(in block letters)
8.3 HEAD OF THE DEPARTMENT
8.4 SIGNATURE / Prof.MANJUNATH U.MACHALE
H.O.D ,DEPARTMENT OF PHARMACEUTICS
OXBRIDGE COLLEGE OF PHARMACY.
Prof.MANJUNATH U.MACHALE
H.O.D ,DEPARTMENT OF PHARMACEUTICS
OXBRIDGE COLLEGE OF PHARMACY.
9. / 9.1 REMARKS OF THE PRINCIPAL
9.2 SIGNATURE / FORWARDED AND RECOMMENDED FOR FAVOURABLE COSIDERATION
(Prof.R.K.MOHAMED MUTAHAR)
9