RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, BANGALORE, KARNATAKA.
M. PHARM SYNOPSIS
YEAR OF ADMISSION DECEMBER/JANUARY-2013
TITLE OF THE SYNOPSIS
FORMULATION AND EVALUATION OF SUSTAINED RELEASE MATRIX TABLETS OF RANOLAZINE USING SYNTHETIC AND NATURAL POLYMERS
BY
Mr. MAHADEVAPPA RUDRAXI
M. PHARM, PART-I
DEPARTMENT OF PHARMACEUTICS
UNDER THE GUIDANCE OF
Mr. B. SOMESWARA RAO. M. Pharm.
ASSOCIATE PROFESSOR
DEPARTMENT OF PHARMACEUTICS
INSTITUTION
SREE SIDDAGANGA COLLEGE OF PHARMACY
B. H.ROAD, TUMKUR-572 102.
KARNATAKA.
RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, BANGALORE, KARNATAKA.
ANNEXURE-II
PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION
1. / NAME OF THE CANDIDATEAND ADDRESS / Mr. MAHADEVAPPA.RUDRAXI
I M. PHARM, DEPT. OF PHARMACEUTICS
SREE SIDDAGANGA COLLEGE OF PHARMACY
B.H. ROAD, TUMKUR- 572 102.
KARNATAKA.
2. / NAME OF THE INSTITUTION / SREE SIDDAGANGA COLLEGE OF PHARMACY
B.H. ROAD, TUMKUR- 572 102
KARNATAKA.
3. / COURSE OF STUDY AND SUBJECT / MASTER OF PHARMACY IN PHARMACEUTICS
4. / DATE OF ADMISSION / DECEMBER/JANUARY 2013
5. TITLE OF THE TOPIC
“FORMULATION AND EVALUATION OF SUSTAINED RELEASE MATRIX TABLETS OF RANOLAZINE USING SYNTHETIC AND NATURAL POLYMERS”
6.
7. / BRIEF REVIEW OF THE INTENDED WORK
6.1 Need for the study;
The oral route of drug administration is the most important route of administering drugs for systemic effects. Nevertheless, it is probable that at least 80% of all drugs to produce systemic effect are administered by oral route. Among the solid dosage forms commonly employed, tablets have a number of potential advantages like they are unit dose form, they offer the greatest capabilities of all oral dosage forms for the greatest dose precision, the least content variability, having low cost, they are in general the easiest and cheapest to package and ship & they possess best-combined properties of chemical, mechanical and microbiologic stability.1
Sustained drug delivery system can achieve predictable and reproducible release rate, decreased toxicity, reduction in required dose, optimized therapy and better patient compliance. Matrix tablets are the type of sustained release drug delivery systems, which release the drug in slow and continuous manner. These systems release the drug by both dissolution controlled as well as diffusion sustained mechanisms. To control the release of the drugs, the drug is dispersed in swellable hydrophilic substances, an insoluble matrix of rigid non swellable hydrophobic materials or plastic materials. Matrix tablets can be classified on the basis of retardant material used which are divided into 5 subtypes as hydrophobic matrices, lipid matrices, hydrophilic matrices, biodegradable matrices and mineral matrices. Alternative approach to classify matrix tablets is based on the porosity of matrix which are subdivided into macroporous systems, micro porous systems and non-porous systems.2
The ultimate aim in the design of a sustained release dosage form includes maintaining relatively constant therapeutic blood levels of the drug for a desired period, reduce dosing frequency, improve patient compliance, decrease incidences of adverse drug reactions and increase safety margin of drugs.3 Development of controlled release drug delivery systems provide a uniform concentration or amount of drug at absorption site, maintained plasma concentration within a therapeutic range, minimizes the side effects and reduces the frequency of drug administration.4 Ranolazine is being used as a drug of choice for patient suffering from various cardiovascular diseases such as arrhythmias, chronic angina pectoris, myocardial ischemia. The mechanism of action of Ranolazine is by increasing oxygen supply to myocardium without compromising hemodynamic status, inhibit cardiac late sodium current and suppress fatty acid oxidation.5
Ranolazine is a racemic mixture, chemically described as N-(2,6-Dimethylphenyl)-2-[4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]piperazin-1-yl]acetamide.6 So an attempt is made to develop sustained release drug delivery system which will be characterized for its potential, cost effective and satisfactory in vitro release studies.
The aim of the present study is to develop sustained release matrix tablets of Ranolazine using synthetic and natural polymers and to investigate the factors influencing release kinetics.
6.2 - Review of Literature
Preparation of Ambroxol hydrochloride tablets by wet granulation technique employing different concentrations of HPMC to achieve sustained release of drug. They found drug is compatible with polymer with FT-IR studies. They obtained slow, controlled and complete release of Ambroxol hydrochloride over period of 12hours from the matrix tablets with the drug polymer ratio of 1:0.75. They found that drug release by diffusion coupled with erosion non-fickian anamolus transport mechanism. They concluded that drug release from the matrix tablets was found to be decrease with increase in drug-polymer ratio.7
Design and characterization of sustained release acelofenac matrix tablets containing tamarind seed polysaccharide by using microcrystalline cellulose, magnesium stearate, talc etc. The tamarind seed polysaccharide was extracted from tamarind kernel powder and this polysaccharide was utilized in the formulation of matrix tablets containing acelofenac by wet granulation technique and evaluated for its drug release characteristics. They concluded that stable formulation could be developed by incorporating hydrophilic polymer (Tamarind seed polysaccharide) in a definite proportion so that the controlled released profile is maintained for an extended period.8
Preparation and evaluation of sustained release matrix tablets of lornoxicam using tamarind seed polysaccharide, hydroxy propyl methyl cellulose (K4M) and sodium carboxy methyl cellulose. The tablets were formulated by wet granulation method by using 10%, 20% 30% and 40% tamarind seed polysaccharide as a natural binding agent and its optimized batch was compared with maximum ratio of various binders (HPMC K4M, sodium CMC, guar gum). Tablets with highest binder concentration showed maximum hardness (8.0 kg/cm2). They concluded that
matrix tablets of lornoxicam(LT-2) employing 20% tamarind seed polysaccharide were considered suitable for sustained release over 24 hour and were suitable for once a day (24 hours) administration.9
Formulation of sustained release diltiazem matrix tablets by using microcrystalline cellulose, hydroxy propyl methyl cellulose, locust bean gum and karaya gum. Matrix tablets of diltiazem were prepared at different ratios of drug: gum (1:1, 1:2 and 1:4) and of the gum blends (karaya gum, karaya gum/locust bean gum, karaya gum/hydroxy propyl methyl cellulose and karaya gum /locust bean gum/hydroxy propyl methyl cellulose) by direct compression. The matrix tablets were evaluated for hardness, friability, in vitro release and drug content. They concluded that, locust bean gum alone cannot efficiently control drug release, a suitable combination of the two natural gums (karaya and locust bean gum ) may be successfully employed for formulating sustain release matrix tablets of diltiazem.10
In vitro release characteristics of matrix tablets study of karaya gum and guar gum as release modulators. Tablets were evaluated for physical characteristics like hardness, weight variation, friability, swelling index and drug content. The effect of water soluble (lactose) and water insoluble (dicalcium phosphate) excipients on drug release was evaluated. Incorporation of lactose or dicalcium phosphate influenced drug release, but at lower levels only. A combination of karaya gum and guar gum exhibited more sustained release than individual gum.11
Matrix tablets of Ambroxol hydrochloride, using various viscosity grades of guar gum in three proportions by wet granulation method. They found that drug release pattern was very close to theoretical release profile as well as marketed sustained release Ambroxol hydrochloride tablets and found to be diffusion coupled with erosion mechanism of drug release and also found to be very stable after storing at 40 °C / relative humidity 75 % for 6 months.12
Ranolazine is indicated for the treatment of chronic angina in patients who have not achieved adequate response with other antianginal drugs. Its novel mechanism of action increases oxygen supply to the myocardium without compromising hemodynamic status.13
The release of the drug from the sustained release tablets was found to be influenced by various formulation factors, such as polymer viscosity, polymer particle size, drug-to polymer ratio, drug
solubility, drug particle size, compression force, tablet shape, formulation excipients, processing techniques, and dissolution medium.14
Sustained release matrix tablets of water soluble Tramadol hydrochloride are prepared using different polymers viz. Hydroxy propyl methyl cellulose (HPMC) and natural gums like Karaya gum and Carrageenan. Varying ratios of drug and polymer like 1:1 and 1:2 were selected for the study. It was observed that matrix tablets contained polymer blend of HPMC/CG were successfully sustained the release of drug up to 12 hours. The formulations prepared with drug: polymer ratio 1:1 show 100% drug release in 6 to 8 hours and formulations prepared with drug: polymer ratio 1:2 could retard the drug release up to desired time period.15
Formulation of oral controlled release Zidovudine matrix tablets by using Guar gum as rate controlling polymer and to evaluate drug release parameters as per various release kinetic models. The tablets were prepared by wet granulation method. All the formulations showed compliance with Pharmacopoeial standards. The in vitro dissolution study was carried out for 12 hours. Among all the formulations, F-2 showed 95.97% of drug release at the end of 12 hours. Selected formulation (F-2) was subjected to stability studies for 3 months, which showed stability with respect to release pattern. Fitting the in vitro drug release data to Korsmeyer equation indicated that diffusion along with erosion could be the mechanism of drug release.16
Preliminary trials were made to isolate pectin from dried orange fruit peel to assess its binding property in tablets using paracetamol as model drug. The tablets prepared with pectin were compared with a reference batch of starch as binding agent. On the basis of drug release behavior it was said that release of all four batches under study was less than that of reference batch. They concluded that orange peel was better binder over commercially used synthetic binders.17
6.9- Objective of the Study
Following are the objectives of the present study-
1. To formulate and develop sustained release matrix tablets of Ranolazine by using synthetic and natural polymers.
2. To carry out pre formulation studies for possible drug polymer interaction.
3. Stability studies of developed matrix tablets of Ranolazine as per ICH guidelines.
MATERIALS AND METHODS
Material:
Drug : Ranolazine.
Polymers: HPMC, Eudragit, Orange peel pectin, Locust bean gum etc.
Excipients: PVP, Micro crystalline cellulose, Lactose, Magnesium stearate and Talc.
Methods:
Development of sustained release matrix tablets by using suitable granulation method.
7.1 - Source of Data
Review of Literature from
a) Journals such as,
1) International Journal of Pharmaceutical Technology and Research
2) Indian Journal of Pharmaceutical Sciences
3) International Journal of Pharmaceutics
4) Asian journal of Pharmaceutical Technology
5) Journal of Global Pharmaceutical Technology
6) Tropical journal of Pharmaceutical Research
7) Research Journal of Pharmacy and Technology
b) AAPS Pharmaceutical Science and Technology
c) World Wide Web
d) J-gate@Helinet
7.2 - Method of collection of data
1) Pre-formulation studies for possible drug/polymer interaction by IR/DSC analysis.
2) Preparation of the sustained release matrix tablets by suitable granulation method.
3) Evaluation of the various properties of sustained release matrix tablets:
Physical properties:
1) Evaluation of granules:
a) Angle of repose
b) Bulk density
c) Compressibility index
d) Total porosity
2) Evaluation of tablets:
a) Thickness
b) Weight variation test
c) Drug content
d) Hardness & friability
4) in vitro release studies of the developed sustained release matrix tablets by using suitable in vitro model.
5) Stability studies as per ICH guidelines on the most satisfactory formulations
7.3 - Does the study require any investigation or investigation to be conducted on patients or other humans or animals?
“ NOT APPLICABLE”
7.4 - Has ethical clearance been obtained from your institution in case of 7.3?
“ NOT APPLICABLE ”
8.
/ REFERENCES:
1. Rehana Bibi, Baqir Shyum Naqvi, Muhammad Harris Shoaib, Najia Rahim. Design and evaluation of a new formulation of enalapril maleate tablet. Pak J Pharm Sci 2011; 24(2):211-5.
2. Sunil Kamboj, Gupta GD, Jagmohan Oberoy. Matrix tablets: An important tool for oral controlled release dosage forms. http://www.pharmainfo.net/reviews.
3. Khairuzzaman A, Ahmed SU, Savva M, Patel NK. Zero-order release of aspirin, theophylline and atenolol in water from novel methylcellulose glutarate matrix tablets. Int J Pharm 2006; 318:15-21.4. Rajesh N, Siddaramaiah. Design and evaluation of controlled release of piroxicam from the pellets of microcrystalline cellulose and hydroxypropylmethyl cellulose blend. Int J PharmTech Res 2010; 2(2):1465-73.
5. Kumari MV, Reddy PV, Sudhakar M. Formulation and evaluation of sustained release matrix tablets of Ranolazine. Int J Pharm 2012;2(1):224-9.
6. Krishnarajan D, Manivannan R, Nidhin C, Senthilkumar N. Design and characterization of floating tablets of ranolazine. Int Res J Pharm 2012;3(4):268-72.
7. Raparla Ramakrishna et al., Development and Evaluation of Ambroxol Hcl sustained release tablets using HPMC as polymer. Journal of Global pharm Tech,2009;1(1):88-93.
8. Basavaraj, Someswara Rao B, Kulkarni SV, Pramod P and Chetan S. Design and characterization of sustained release acelofenac matrix tablets containing tamarind seed polysaccharide.Asian J Pharm Tech 2011;1(1):17-21.
9. Phanikumar GK, Gangarao B, Lova Raju NS Kotha. Preparation and evaluation of sustained release matrix tablets of lornoxicam using tamarind seed polysaccharide. Int J Pharm Res Dev 2011;2(12):89-98.
10. Moin A and Shivkumar HG. Formulation of sustained release diltiazem matrix tablets using hydrophilic gum blends. Trop J Pharm Res 2010;9(3):283-91.
11. Senapati MK, Srinatha A, Pandit JK. In vitro release characteristics of matrix tablets study of karaya gum and guar gum as release modulators. Ind J Pharm Sci 2006;68(6):824-6.
12. GanesanV and Jayachandran DL. “Design and Evaluation of Matrix tablet of Ambroxol hydrochloride using Guar gum”. Res J Pharm Tech 2008;1(4):507-12.
13. Anderson JR, Nawarskas J, Ranolazine J. A Metabolic Modulator for the Treatment of Chronic Stable Angina Cardiology in Review. 2005;13:202-10.
14. Velasco MV, Ford JL, Rowe P, Rajabi-Siahboomi AR. Influence of drug: hydroxypropyl methylcellulose ratio, drug and polymer particle size and compression force on the release of diclofenac sodium from HPMC matrices. J control release 1999;57:75-85.
15. Raghavendra Rao NG, Gandhi Sagar, Patel Tarun, Formulation and evalution of sustained release matrix tablets of tramadol hydrochloride. Int J Pharm Pharm sci 2009; 1(1):60-70.
16. Amit S Yadav, Ashok Kumar P, Vinod R, Someshwara Rao B, Suresh V Kulkarni, Design and evaluation of guar gum based controlled release matrix tablets of zidovudine. J Pharm Sci Tech 2010; 2(3):156-62.
17. Rishaba M, Pranti S, Mayank B, Pramod KS. Mango peel pectin as a superdisintigrating agent. J Sci Ind Res 2010;69:688-90.
9. / SIGNATURE OF CANDIDATE
10. / REMARKS OF GUIDE / Recommended
11. / NAME AND DESIGNATION
OF
11.1 GUIDE /
Mr. B. SOMESWARA RAO, M. Pharm.
Associate professor
Department of pharmaceutics
11.2 SIGNATURE
11.3 CO-GUIDE (If any) / ------
11.4 SIGNATURE / ------
11.5 HEAD OF
DEPARTMENT / Dr. K. MANJUNATH M. Pharm., Ph.D.
Professor & Head
Department of Pharmaceutics
11.6 SIGNATURE
12. / 12.1 REMARKS OF THE
CHAIRMAN AND
PRINCIPAL / Forwarded to university for approval.
12.2 SIGNATURE /
Dr. SURESH V. KULKARNI, M. Pharm., Ph.D
Principal
Sree Siddaganga College of Pharmacy, Tumkur
10