“FORMULATION AND EVALUATION OF TRIMETAZIDINE

HYDROCHLORIDE TRANSDERMAL PATCHES”

M.Pharm. Dissertation Protocol

Submitted to theRajiv Gandhi University of Health Sciences, Karnataka

Bangalore.

ByA.JAYENDRA REDDY

B.Pharm

Under the Guidance of Mr. SARFARAZ. Md

M.PharmAssistant professor

Department of pharmaceutics

DEPARTMENT OF PHARMACEUTICSN.E.T. PHARMACY COLLEGE

RAICHUR2011

Rajiv Gandhi University of Health Sciences, KarnatakaBangalore

ANNEXURE IIPROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION

1 Name of candidate and address (In Block Letters)

A.JAYENDRA REDDY, P NO:80, KRISHNA SAI ENCLAVE, HMT ROAD, MIYAPUR, HYDERABAD, AP-500050

2 Name of the Institute N.E.T. PHARMACY COLLEGE,RAICHUR.

3 Course of study and subject: M.PHARM. PHARMACEUTICS.

4 Date of admission of course: 20-09-2010

5 Title of the topic:

“FORMULATION AND EVALUATION OF TRIMETAZIDINE HYDROCHLORIDE TRANSDERMAL PATCHES”

6 Brief Resume of this intended work:6.1 Need for the study Enclosure-I6.2 Review of Literature Enclosure-II6.3 Objectives of study Enclosure-III

7 Materials and Methods:7.1 Source of data Enclosure-IV7.2 Method of collection of data (Including Sampling procedure, if any) Enclosure-V7.3 Does the study require any investigation or interventions to be conducted on

patients of humans or animals? If so, please describe briefly. YES Rat abdominal skin for permeation studies. 7.4 Has ethical clearance been obtained from your institution in case of 7.3? YES: IAEC NO: 576/2002/bc/IAEC/CPCSEA

8 List of References Enclosure-VI

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9 Signature of the candidate

10 Remarks of the Guide The proposed work can be carried out in the laboratory

11 Name and designation of (In block letters)

11.1 Guide

11.2 Signature

Mr. SARFARAZ. Md Assistant ProfessorDept. of PharmaceuticsN.E.T. Pharmacy CollegeRaichur-584103

11.3 Co-Guide (if any)

11.4 Signature

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11.5 Head of Department

11.6 Signature

Dr. H. DODDAYYAProfessorDept. of PharmaceuticsN.E.T. Pharmacy CollegeRaichur-584103

12 12.1 Remarks of the Chairman and Principal

12.2 Signature

Forwarded for scrutinyDr. H. DODDAYYAPrincipalN.E.T. Pharmacy CollegeRaichur-584103

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Enclosure-I

6) Brief resume of the intended work.

6.1) Need for the study:

Angina pectoris is severe chest pain due to ischemia of the heart muscle,

generally due to obstruction or spasm of the coronary arteries. There are two types

mainly, stable and unstable angina. Stable angina is chest pain or discomfort that

typically occurs with activity or stress. Unstable angina is a condition in which heart

doesn't get enough blood flow and oxygen. Major risk factors for angina include

cigarette smoking, diabetes, high cholesterol, high blood pressure, sedentary lifestyle

and family history of premature heart disease. Angina results when there is an

imbalance between the heart's oxygen demand and supply. This imbalance can result

from an increase in demand without a proportional increase in supply1. According to

recent estimates, cases of cardio vascular disease (CVD) in India may increase from

about 2.9 crore in 2000 to as many as 6.4 crore in 2015, and the number of deaths

from CVD will also be more than double. Most of this increase will occur on account

of coronary heart disease a mix of conditions that includes acute myocardial

infarction, angina pectoris, congestive heart failure and inflammatory heart disease2.

Trimetazidine hydrochloride chemically 1-[(2, 3, 4-Trimethoxybenzyl)

piperazine dihydrochloride is a 3-ketoacyl Co-A thiolase inhibitor (3-KAT) with a

cytoprotective effect in cells3.Trimetazidine, known for years to be an effective

antianginal agent, shifts cardiac energy metabolism from fatty acid oxidation to

glucose oxidation by inhibiting mitochondrial long-chain 3-ketoacyl coenzyme-A

thiolase. By decreasing fatty acid oxidation, trimetazidine stimulates glucose

utilization, restoring coupling between glycolysis and carbohydrate oxidation and

leading to adenosine triphosphate production with lesser oxygen consumption.

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The antianginal properties of this agent are devoid of haemodynamic changes, and

dramatically improve recovery of mechanical function after ischemia4.

Trimetazidine hydrochloride has oral dose of 20-60 mg daily in divided dose,

biological half life of 6 hrs, oral bioavailability 87%5. Chronic use of conventional

oral controlled release dosage forms of trimetazidine is inconvenient and may result

in unwanted side effects due to high fluctuation of drug concentration in blood6. The

most commonly encountered side effects are gastric discomfort, nausea, headache and

vertigo. Trimetazidine hydrochloride is safe & well tolerated. Trimetazidine is a

suitable choice for elderly coronary patients. The hemodynamic side effects and drug

interactions can be frequent and severe in elderly due to reduced creatinine clearance

or liver metabolism. The main side effect is gastric discomfort when it is taken in

conventional dosage for 2-3 times per day4.

The transdermal route of administration is recognized as one of the potential

route for local and systemic delivery of drugs. Transdermal delivery not only provides

controlled, constant administration of the drug, but also allows continuous input of

drugs with short biological half life, reduced frequency of administration, reduced

side effects, reduced load on digestive tract and liver that oral route places and

improved patient compliance7.

Thus in light of these observations the present study is planned to formulate

and evaluate transdermal patches of Trimetazidine HCl with an aim to overcome the

side effects, reduce the dosage, provide controlled release of drug and hence improve

the patient compliance.

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Enclosure-II

6.2) Review of literature:

Krishnaiah YSR et al. studied the transdermal permeation of trimetazidine

from hydroxypropylmethyl cellulose (HPMC) gel drug reservoir system using

nerodilol as a penetration enhancer. There was an increase in the amount of

trimetazidine permeated across the rat epidermis up to 24 hrs with an increase

in nerodilol concentration (5%w/v) in HPMC gel drug reservoir. There was no

significant difference observed in the amount of drug permeated with 5% w/v

of nerodilol when compared to that obtained with 4% w/v of nerodilol. The

HPMC gel drug reservoir containing 4% w/v of nerodilol showed optimal

transdermal permeation of trimetazidine8.

Krishnaiah YSR et al. designed and evaluated membrane-controlled

transdermal therapeutic system (TTS) for trimetazidine using limonene-based

membrane. The in -vitro permeation of trimetazidine from water, ethanol and

selected concentrations (25, 50 and 75% v/v) of ethanol-water co-solvent

systems showed that 50% v/v of ethanol-water solvent system provided an

optimal transdermal flux. The fabricated limonene-based TTS patch of

trimetazidine showed a mean steady state plasma concentration of 71.5 ng/mL

for about 14 hrs with minimal fluctuation when tested in rabbits. It was

concluded from the investigation that the limonene-based TTS patch of

trimetazidine provided constant drug delivery across the skin in rabbit model9.

Abdelbary A et al. formulated trimetazidine extended-release floating tablets

using different hydrophilic matrix forming polymers including HPMC 4000

cps, carbopol 971P, polycarbophil and guar gum. The tablets were fabricated

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by dry coating technique. The floating lag time and floating duration were also

evaluated. In-vivo bioavailability study was done on human volunteers for

selected formulations. Floating tablets showed an improvement in the drug

bioavailability compared to immediate-release tablets. The drug release in all

formulas followed zero-order kinetics10.

Prasad PT et al. formulated monolithic matrix tablets of Trimetazidine

Dihydrochloride employing hydroxy propyl methyl cellulose polymer.

Modified release matrix tablets contain 35.7 mg Trimetazidine

Dihydrochloride were developed using different drug polymer concentration

of HPMC. Formulation was optimized on the basis of acceptable tablet

properties and in vitro drug release. All tablets but one exhibited gradual

and near completion modified release for Trimetazidine Dihydrochloride, and

98.5 to 101.5% drug was released at the end of 8 hrs. The results of dissolution

studies indicated that formulation F-III was the most successful of the study.

An increase in release kinetics of the drug was observed on decreasing

polymer concentration11.

Ahmed M G et al. prepared transdermal patches of nifedipine with different

composition of PVP and PVA by moulding technique. Patches containing 3:2

ratio of PVA: PVP. In vitro release profiles of the drug from different patches

were studied using abdominal skin of albino rats and modified Keshary Chein

diffusion cell. In-vitro drug release studies were extended up to 24 hrs and it

was found that, as the concentration of PVP increased the drug release was

also increased. Effect of penetration enhancers on the in- vitro permeation of

nifedipine across rat abdominal skin was carried out for patches with three

different types of penetration enhancers showed all the patches with

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permeation enhancer increased the permeation of the drug from the

membrane12.

Patel HJ et al. prepared matrix type transdermal drug delivery system of

Amlodipine besilate, an antihypertensive using different polymers like

Carbopol 934, 940, Hydroxypropyl Methyl Cellulose and Eudragit L100 in

varied ratios for sustained release of Amlodipine .The Optimized

formulation containing Carbopol 934, Eudragit L100 (3:7), with enhancer

Hyaluronidase showed 84% drug release after 24 hrs. Higuchi and Peppa’s

models were used for optimizing the formulation13.

Sanap GS et al. developed transdermal monolithic system of indapamide by

solvent casting method and investigated the permeation enhancing capability

of various vegetable oils like sunflower oil, cotton seed oil, coconut oil, olive

oil and linseed oil. A significant improvement of flux was observed in the

following order: olive oil>linseed oil>sunflower oil>cotton seed oil>coconut

oil>castor oil. The in-vitro release studies revealed that the release was

sustained up to 24 hrs and it followed zero order kinetics14.

Barhate SD et al. developed bioadhesive transdermal patches containing

indapamide using Eudragit RS100, lauric acid, adipic acid, polyvinyl

alcohol, sorbitol. The in-vitro permeation experiments were performed in

Franz-diffusion cell using freshly excised rat skin for 12 hrs. The permeation

results of indapamide from 2 mg/ml and 5mg/ml solutions in phosphate buffer

(pH 7.4) showed significant permeation behavior. The Eudragit RS 100 and

polyvinyl acetate in 1:2 proportions proved to be better composition for

preparation of transdermal film which can be a promising and innovative

therapeutic system for indapamide15.

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Sanjay dey et al. formulated matrix type transdermal patches of carvedilol

by using solvent casting method using hydroxyl propyl methyl cellulose and 

eudragit RS100 polymers by incorporating  dibutyl  phthalate  and  propylene 

glycol  as  plasticizer  and  permeation  enhancer,  respectively.  Propylene 

glycol  was  incorporated  at  different  concentration  to enhance  the 

permeation  of  drug.  The  formulation  containing  30%  w/w  propylene 

glycol has  exhibited  better enhancement  for  the permeation of carvedilol16.  

Rathore RPS et al. designed transdermal matrix type patches of terbutaline

sulphate using ethyl cellulose and cellulose acetate polymer by solvent casting

technique employing a mercury substrate. Two types of polymeric patches

were prepared; cellulose acetate 5% in combination with PVP 5% and Ethyl

cellulose 5% in combination with PVP 5%. Higher drug permeability was

observed from cellulose acetate patches as compared to ethyl cellulose

patches17.

Sharan G et al. prepared drug loaded patches using various biocompatible

polymers like (EC + PVP) & (AC + HPMC) for propranolol. Drug loaded

patches were formulated by using solvent casting and evaporation technique.

The formulation containing oleic acid as permeation enhancer showed the

better permeation in comparison to the other enhancers18.

Enclosure-III

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6.3) Objectives of the study:

The present study is planned with the following objectives:

1. To carry out Preformulation studies on Trimetazidine hydrochloride for

identification, solubility, melting point, partition coefficient and permeability

coefficient.

2. To fabricate monolithic transdermal patches using various polymers like

celluloses, natural polymers and plasticizers.

3. To evaluate the patches for their physical appearance, weight and thickness

uniformity, water vapour transmission and drug content; scanning electron

microscopy and drug polymer interactions.

4. To study the in-vitro drug release through rat abdominal skin using Keshary-

Chein or franz diffusion cell.

5. To study the influence of concentration of polymer(s) and penetration

enhancers on release profiles.

6. To carry out the compatibility studies of drug and polymer interactions using

IR and DSC monographs.

7. To carry out the stability studies for selected formulations as per ICH

guidelines.

Enclosure-IV

1) Materials and Methods:

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7.1) Source of data:

Primary data: This data will be collected by conducting laboratory

experiments and recording the observation.

Secondary data: This will be collected from various journals and textbooks.

Enclosure-V

7.2) Method of collection of data:

1. Compatibility studies between the drug, polymers and penetration enhancers

will be carried out using IR and DSC instruments.

2. Patches will be designed using different polymers like cellulose acetate,

ethyl cellulose, Hydroxypropyl methyl cellulose, polyvinyl alcohol,

polyvinyl pyrrolidine, carbopol and plasticizers such as dibutylpthalate,

propylene glycol, glycerin) adopting suitable techniques.

3. Physical characterization like appearance, thickness, tensile strength, water

vapor transmission and absorption etc. will be carried out adopting suitable

method.

4. Drug release studies will be carried out through rat skin in simulated

physiological fluids using Keshary-chein or franz diffusion cell.

5. The prepared patches will be subjected to stability studies as per ICH

guidelines.

STATISTICAL ANALYSIS

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All values will be expressed as mean ± SEM for 10 animals in a group.

Results will be subjected to statistical analysis using one way ANOVA (analysis of

variance) followed by Dunnetëtí test p < 0.05 will be considered as statistically

significant.

7.3 Does the study require any investigations or interventions to be

conducted on

Patients other human or animals? If so, please describe briefly:

Study requires investigation on rat.

7.4 Has ethical clearance been obtained from your institute in case of 7.3:

Yes: IAEC NO: 576/2002/bc/IAEC/CPCSEA

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INSTITUTIONAL ANIMAL ETHICS COMMITTEEN.E.T PHARMACY COLLEGE, RAICHUR-584103, KARNATAKA, INDIA

The institutional animal ethics committee of N.E.T Pharmacy College, Raichur

Assembled on 30-5-2011 to discuss about the details of animal experiments required

to be carried out by PG students of different departments for their project works.

The following members were present.

1. Dr. H. DODDAYYA CHAIRMAN

2. Dr. BHEEMACHARI CONVENER

3. Dr. H. SRIDHARA MEMBER

4. Dr. R. H. UDUPI MEMBER

5. Mr. SHIVKUMAR MEMBER

Each PG student requirement and experiments were discussed in detail. After

through discussion, the experiments to be carried out by the students have been

approved.

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ENCLOSURE- VI

List of references:

1. Helms RA, Quan DJ, Herfindal ET and Gourley DR. Text book of

therapeutics: drugs and disease management. 8th ed. USA: Library of congress

cataloging-in-publication data; 2006.

2. http://www.whoindia.org/LinkFiles/

Commision_on_Macroeconomic_and_Health_Bg_P2_Burden_of_Disease_Es

timations_and_Casual_analysis.pdf

3. Sweetman SC. Martindale: The complete drug reference. 34th ed. London

(UK): Pharmaceutical press; 2005.

4. http://www.generalpharma.com/mag_vol_05/productprofile.html

5. McClellan KJ and Plosker GL. Trimetazidine: a review of its use in stable

angina pectoris and other coronary conditions. Drugs 1999; 58: 143–157.

6. Barry BW. Novel mechanisms and devices to enable successful transdermal

drug delivery. Eur J Pharm Sci 2001; 14: 101–114.

7. Patel DM and Kavitha K. Formulation and evaluation aspects of transdermal

drug delivery system: Review article. Intenational Journal of Pharmaceutical

Sciences Review and Research 2011; 6(2):83-90.

8. Krishnaiah YS and Al-Saidan MS. Transdermal Permeation of Trimetazidine

from Nerodilol- Based HPMC Gel Drug Reservoir System across Rat

Epidermis. Med Princ Pract 2008; 17:37–42.

9. Krishnaiah Y S and Al-Saidan M S. Limonene enhances the in-vitro and

in-vivo permeation of trimetazidine across a membrane-controlled

transdermal therapeutic system. Current drug delivery 2008; 5(1): 70-6.

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10. Abdelbary A, El-Gazayerly ON, El-Gendy NA and Ali AA. Floating tablet of

trimetazidine dihydrochloride: An approach for extended release with zero-

order kinetics. AAPS PharmSciTech 2010 Sep; 11(3):1058-67.

11. Tagalpallewar PP, Merekar AN, Parjane SK, Pratapwar AS and Dighe NS.

Formulation and Evaluation of Modified Release Trimetazidine

Dihydrochloride HPMC Matrix Tablet. Der Pharmacia Sinica 2010; 1 (2):

130-135.

12. Ahmed M G, Kiran Kumar GB and Satish Kumar BP. Formulation and

Evaluation of Nifedipine patches. Transdermal Journal of Pharmacy

Research 2010; 3(8):1785-1787.

13. Patel HJ, patel JS, desai BJ and patel KD. Design and evaluation of

amlodipine besilate transdermal patches containing film former. IJPRD

2009:1-12.

14. Sanap GS, Dama GY, Hande AS, Karpe SP, Nalawade SV, Kakade RS and

Jadhav UY. Preparation of transdermal monolithic systems of indapamide

by solvent casting method and the use of vegetable oils as permeation

enhancer. Int J Green Pharm 2008: 129-33.

15. Barhate SD, Gholap TN. In-vitro permeation studies of Indapamide from

transdermal patches. Der Pharmacia Lettre 2010; 2(4): 447-451.

16. Dey S and Malgope A. Preparation of carvedilol transdermal patch and the

effect of propylene glycol on permeation. International Journal of Pharmacy

and Pharmaceutical Sciences 2010; 2(1): 137-143.

17. Rathore RPS, Chauhan CS, Naruka PS, Tanwar YS and Chauhan LS.

Transdermal formulation of Terbutaline sulphate. www.priory.com.

18. Sharan G, Dey BK, Nagarajan K, Das S, Kumar SA, and Dinesh V. Effect of

various permeation enhancers on propranolol hydrochloride formulated

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patches. International Journal of Pharmacy and Pharmaceutical Sciences 2010;

2(2): 21-30.

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