“FORMULATION AND EVALUATION OF TRIMETAZIDINE HYDROCHLORIDE TRANSDERMAL PATCHES”
M.Pharm. Dissertation Protocol
Submitted to the
Rajiv Gandhi University of Health Sciences, Karnataka
Bangalore.
By
A.JAYENDRA REDDY
B.Pharm
Under the Guidance of
Mr. SARFARAZ. Md
M.Pharm
Assistant professor
Department of pharmaceutics
DEPARTMENT OF PHARMACEUTICS
N.E.T. PHARMACY COLLEGE
RAICHUR
2011
Rajiv Gandhi University of Health Sciences, Karnataka
Bangalore
ANNEXURE II
PROFORMA 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-I
6.2 Review of Literature Enclosure-II
6.3 Objectives of study Enclosure-III
7 / Materials and Methods:
7.1 Source of data Enclosure-IV
7.2 Method of collection of data (Including Sampling procedure, if any)
Enclosure-V
7.3 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
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 Professor
Dept. of Pharmaceutics
N.E.T. Pharmacy College
Raichur-584103
11.3 Co-Guide (if any)
11.4 Signature / ------
------
11.5 Head of Department
11.6 Signature / Dr. H. DODDAYYA
Professor
Dept. of Pharmaceutics
N.E.T. Pharmacy College
Raichur-584103
12 / 12.1 Remarks of the Chairman and Principal
12.2 Signature / Forwarded for scrutiny
Dr. H. DODDAYYA
Principal
N.E.T. Pharmacy College
Raichur-584103
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.
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.
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 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 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.
· Sanjaydey et al. formulated matrix type transdermal patches of carvedilol byusingsolventcastingmethodusinghydroxylpropylmethylcelluloseand eudragitRS100polymersbyincorporating dibutyl phthalate and propylene glycol as plasticizer and permeation enhancer, respectively. Propylene glycol was incorporated at different concentration toenhance the permeation of drug. The formulation containing 30% w/w propylene glycolhas exhibited betterenhancement for thepermeationofcarvedilol16.
· 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
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:
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
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
INSTITUTIONAL ANIMAL ETHICS COMMITTEE
N.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.