Formulation and Evaluation of Transdermal Films of Carvedilol

Dissertation Protocol Submitted to the Rajiv Gandhi University of Health Sciences, Karnataka Bangalore

By Dinesh Sachdeva M.Pharm Part-I Department of Pharmaceutics

Under the Guidance of Mr. B. APPA RAO M.Pharm Department of Pharmaceutics Dr. H.L.T. College of Pharmacy Kengal, Channapatna 571502 Bangalore (Rural) Karnataka.

Rajiv Gandhi University of Health Sciences, Karnataka BANGALORE Annexure-II Pro forma for Registration of Subjects for Dissertation

Name of the Candidate and Address (in Block Letters)

DINESH SACHDEVA M.Pharm Part-I Department of Pharmaceutics Dr. H.L.T. College of Pharmacy Kengal, Channapatna 571502 Bangalore (Rural), Karnataka

Name of the Institution

Dr. H.L.T. College of Pharmacy Kengal, Channapatna, Bangalore (Rural) 571502

Course of the Study and Subject

Master of Pharmacy in Pharmaceutics

Date of Admission to the course

19th May 2007

Title of the Topic

FORMULATION AND EVALUATION OF TRANSDERMAL FILMS OF CARVEDILOL

6. Brief Resume of the Intended work

6.1 Need for the study

Management of illness through medication has entered an era of rapid growth. Today, there are a host of drugs for combating virtually every disease or condition known to man and a variety of means by which these drugs are delivered to the human body for therapy such as tablets, capsules, injections, aerosols, creams, ointments, suppositories, liquids etc., often referred as to as conventional drug formulations. Drug administrations in these forms usually produce wide-ranging fluctuations in drug concentration in bloodstream and tissues and frequently lead to undesirable toxicity and poor efficiency. Conventional drug delivery systems are often not suitable for new protein based and other therapeutic compounds produced by modern technology. Also, the development of a new molecule is time-consuming procedure and requires approximately 125 million dollars. This is beyond the scope of pharmaceutical companies in developing countries like India. But, it is possible to give a new file to the existing molecules in the form of a novel drug delivery system like Transdermal Drug Delivery System (TDDS) which releases the drug at a predetermined rate over an extended period of time to provide therapeutic level of drug at the target site in the body to promptly achieve and maintain the desired drug concentration. Skin is the most extensive and readily accessible organ in the body. It is a complex phenomena of permeation of chemicals, toxicants and drugs lead to development of transdermal drug delivery systems, in which the skin serves as the site for drug administration for systemic action. Thus, Transdermal therapeutic system are defined as self contained, discrete dosage forms which, when applied to the intact skin, delivers the drug through the skin at a controlled rate to the systemic circulation. Following skin permeation, the drugs first reach the systemic circulation. The drug molecules are then transported to the target site, which could be relatively remote from the site of administration, to produce their therapeutic action. The following are the potential advantages and disadvantages of TDDS over other routes of drug delivery. Advantages of TDDS: Reduces dosing frequency; Increases, therapeutic value due to avoidance of hepatic first pass effect, gastrointestinal irritation and low absorption problem; Non-invasive drug delivery system; Improves patient compliance;

 Maintains constant blood levels for longer period of time; Utilizes short half-life of drugs; Terminates drug delivery in case of toxicity; Improves bioavailability; Improves physiological and pharmacological responses; Avoids fluctuation in drug levels, inter-& intra-patient variations; Suitable delivery system for macromolecules like proteins and peptides.

Disadvantages of TDDS: TDDS cannot delivery ionic drugs TDDS cannot achieve high drug levels in blood/plasma Development of formulations having does more than 10mg per day difficult TDDS cannot delivery drug in pulsatile fashion Cannot develop TDDS, if drug/formulation causes irritation to skin. But these limitations can be overcome to some extent by various means like permeation enhancers, iontophoresis, ultrasound etc. Principle involved in Transdermal Permeation: TDDS use intact skin as dependable route for systemic drug absorption. The Transdermal permeation of drug involves diffusion out of device to skin surface, partition into and transport through the cutaneous layers. Steps involved in Transdermal permeation are as follows: Sorption by stratum corneum, Penetration of drug through viable epidermis, Uptake of the drug by the capillary network in the dermal papillary layer. In vitro experiments have shown that stratum corneum is the principal barrier. Drug molecules may diffuse through the skin by three different routes, which are intact stratum corneum, hair follicle region and sweat gland ducts. In the initial transient diffusion stage, drug molecules may penetrate the skin along the hair follicles or sweat ducts and than absorbed through the follicular epithelium and the sebaceous glands.

When a steady state has been reached diffusion through the stratum corneum becomes the dominant pathway. Membrane limited flux (J) under steady condition is described by expression: J= Where, J = amount of drug passing through membrane system per unit area per unit time D = diffusion coefficient Ko/w = membrane / vehicle partition coefficient A = area of membrane H = thickness of membrane C = concentration gradient Carvedilol is both an alpha and a beta adrenoreceptor-blocking agent used in the treatment of various cardiovascular disorders such as angina pectoris, cardiac arrhythmia and hypertension. Its biological half-life (6 hours) is very short and therefore is an ideal drug candidate for rapid release drug delivery system. It is 90% absorbed from GIT, but its bioavailability is only 10-20% indicating extensive first pass metabolism in liver. In view of substantial first pass effect and its shorter plasma halflife; Carvedilol was selected for incorporating in transdermal films to bypass the hepatic first pass metabolism. This provide increased bioavailability, better patient compliance and advantages of transdermal drug delivery system DAKo/w - C -----------------H

6.2 Literature Review

Sagar Prasanna et al., 2006, developed membrane controlled transdermal therapeutic systems of ethyl cellulose and poly vinyl alcohol containing an antihypertensive drug, verapamil hydrochloride by casting on mercury surface. The enhancement of skin permeation of drug was done by using 3 terpenes. The formulation followed nearly zero order kinetics. Saraf Swarnlata et al., 2006, made possible delivery of Norfloxacin through transdermal patches. Two types of transdermal patches were prepared by mercury casting method. Patch one was a combination of HPMC and EC in the ratio of 10:90 to 50:50, while patch two was various concentrations PVA. Gupta P. Sadhna et al., 2005, formulated and evaluated metoprolol tartarate transdermal drug delivery system for controlled release of drug for extended period of

time. Eudragit RL and HPMC were used for fabrication of the matrix diffusion controlled system. These were characterized for their thickness, tensile strength, drug content, Invitro release kinetics and drug skin permeation studies. Bharkatiya Meenakshi et al., 2005, Prepared transdermal patches of propranolol hydrochloride by solution casting technique employing a glass substrate as monolithic matrices using various polymers to achieve a controlled release and improved bioavailability. Kulkarni V.R. et. al., 2002, prepared and controlling membrane for transdermal use surface employing chloroform as a solvent studied the effect of different concentrations and mechanical properties. evaluated Eudragit RS 100 films as rate by the casting method on the mercury and DBP & PEG400 as plasticizers and of various plasticizers on the permeability

Panigrahi L. et. al., 2005, designed a transdermal drug delivery system of diclofenac sodium based on polymeric dispersion system. Different combinations of hydrophilic and hydrophobic polymers were used for the preparation of pseudolatex system. The permeation kinetics of drug from system through hairless delipidizedand lipidized mouse skin was done. Kulkarni H.V. et al., 2005, chitosan was chemically modified by treating with two different aldehydes to form schiffs bases. Chemically modified chitosan and plain chitosan were compared for the film forming capacity, swelling property and water permeability rate. Further, the films were incorporat6ed with antihistaminic drug, salbutamol sulfate during casting. Drug loading & permeation characteristic were compared for plain and chemically modified chitosan. Ubaidulla U. et al.,. 2004, investigated effect of iontophoresis and permeation ehnancer on carvediolol from transdermal film. The films were made from HPMC as polymeric matrix PG as plasticizers. SLS, tween 20, DMSO and PEG 400 were used as permeation enhancers. Bhagyalakshmi J. et. al., 2004, studied the feasibility of transdermal delivery of amoxycillin from ethanol/pH 4.2 buffer solutions containing various penetration enhancers across rat skin. Experiments were performed to determine the permeation of drug across axcised rat skin from the ethanolic vehicle contaijning differentk penetration enhancers. Dr. Murthy T. et. al., 2004, the influence of three hydrophilic pllymers on the permeability of piroxicam through cellulose acetate films was studied with a view to develop matrix-disperson type transermal system by mercury substrate mewthod. The drug release followed first order kinetics and controlled by diffusion mechanism.

Kakkar P.A. et al., 29(7), matrices containing varying proportion of gelatin, glycerin and drug content were fabricated and were characterized by physiochemical evaluation and invitro drug permeation studies through mice skin. Willimann H. et al., 1992, organogels obtained were studied as matrices for the transdermal transport of drugs. Scopolamine and Broxaterol were drugs used. The transport rate of scopolamine obtained with obtained with lecithin gels was about one order of magnitude higher than that obtained with an aqueous solution of the drug at the same concentration. Hansen Bach Laila et al., 1992, the delivery of the opioid analgesic Ketobemidone was assessed in human skin penetration studies invitro using both Ketobemidone and three carbonate ester prodrugs formed at the phenolic hydroxyl group. It was seen that the ester prodrugs very readily penetrated through the skin from solutions in isopropyl myristate and from ethanol water solutions. Guyot M. et al., 2000, propranolol hydrochloride was incorporated in three transdermal systems using three polymers HPMC, ployisobutylene and ucecryl. The influence of different factors were investigated. Thysman Sophie et al., 1994, performed studies on electrical and physiochemical factors acting on the permeation kinetics of invitro iontophoresis of fentasnyl across hairless rat skin. Iontophoresis increased the transdermal permeation flux of fentanyl as compared to diffusion. Vlachou D.M. et al., 1992, prepared and evaluated several gel formulations of griseofulvin, in which the drug was dissolved for further clinical studies as an alternative topical dosage form.

6.3 Objective of the Study

Thus, objectives of the present study are: In the present work an attempt is made To prepare a transdermal films of antihypertensive agent like carvedilol To achieve a sustained release action. To by pass the hepatic first pass metabolism To overcome variable absorption profile and frequent dosing. To formulate transdermal films containing antihypertensive agent like Carvedilol etc. using different polymers such as Carbopol, gelatin, HPMC, Eudragit, Polyvinyl alcohol (PVA) etc. alone and in combination with plasticizers and permeation enhancers. To evaluate and to optimize the prepared transdermal films for their physicochemical properties like thickness, tensile strength, weight variation, uniformity of the weight, drug content analysis, percent moisture absorption and percent moisture loss.

 To carry out the in vitro and in vivo drug release studies. To carry out the skin irritation studies on the prepared transdermal films. To carry out stability studies on the selected formulation.

7. Materials and Methods:

7.1 Source of Data
The preliminary data required for the experimental study is obtained from 1. CD-Rom search available at National Center for Scientific Information (NSCI), Indian institute of Sciences, Bangalore, NIPER, Scientific abstracts, Journals, Internet sources and Relevant Books. Dr. H.L.T. College of Pharmacy, Library The data will be collected by Laboratory investigation and Recording the data.

2. 3.

7.2 Methods of Collection of Data

1. The selected drug shall be characterized and evaluated for its physicochemical and evaluated such as solubility in various solvents and compatibility of the drug with various polymers. 2. A suitable analytical method will be developed and validated for the estimation of the drug from its solution using UV spectrophotometer. 3. Transdermal films containing the selected drug and polymers will be prepared in the institute. 4. Prepared transdermal films will be evaluated for various parameters like thickness, tensile strength, weight variation, uniformity of the weight, drug content analysis, Percent moisture absorption and percent moisture loss. 5. The optimized films will be subjected for in vivo diffusion studies using suitable animal model. 6. Data will be tabulated and statistically analyzed. Results will be discussed in dissertation report. All the facilities would be provided by the college and if necessary help of industry, research center or other institute etc. may be taken.

7.3 Does the study require any investigation to be conducted on Patients / Humans /
Animals ? If so, please describe briefly.

-- No --

8. List of References
1. 2. 3. 4. 5. 6. 7. 8. 9. Kumar P., Sankar C., Mishra., Delivery of macromolecules through skin, The Indian Pharmacist, June 2004. Tanwar S.Y., Sisodia S.S., Sharma S., Iontophoretic drug delivery, The Indian Pharmacist, August 2005. Nanda Arun, Khar K. Roop, Iontophoretic delivery of drugs, Indian Drugs, 28(1). Nayak S.H., Nakhat P.D., Yeole P.G., Transdermal drug delivery, The Indian Pharmacist, September 2004. Misra A.N., Controlled and Novel Drug Delivery, (Jain, N.K. Eds), CBS Published and Distributors, New Delhi, 1997, p. 107-109. Chien, Y.W., Transdermal controlled systemic medications, Vol. 31 Marcel Dekker, Inc. Publication, New York, 1987, p. 6, 38. Chien, Y.W., Novel drug delivery system, Vol. 14, 50. Marcel Dekker, Inc. publication, New York, 1992, p. 55, 62, 191, 338-343. Vyas, S. and Khar, R.K., Controlled drug delivery, Concepts and Advances, Vallabh Parakashan, 2002, p. 412-429. Finnin C. Barrie and Morgan M. Timothy, Transdermal penetration enhancers: applications, limitations and potential, J.Pharm. Sci., 1999 88, 10.

10. Misra Ambikanadan, Transdermal drug delivery: present and future, The Pharma review, Jul-Aug 2004. 11. Panchagnula Ramesh, Transdermal delivery of drug, Ind. J. of Pharmaco., 1997, 29: 140-156. 12. Muthusamy K., Ravi T., Govindharanjan G., Gopalkrishnan S., The use of chitosan as drug carrier, 10th Edn., Mcgraw Hill medical publication division. 13. Gilman Goodman Alfred, Linbird E Lee, Hardman G. Joel, The pharmacological basis of therapeutics, 10th Edn., Mcgraw Hill medical publication division. 14. Satoskar S.R., Ainpure S.S., Pharmacology and Pharmacotherapeutic, 8 th Edn., Popular Prakashan, Mumbai. 15. Tripathi K.D., Essentials of Medical pharmacology, 5 th Edn, Jaypee brothers, New Delhi.

Signature of the candidate

10

Remarks of the Guide

Topic selected for Dissertation work is satisfactory. This can be carried out in our Laboratory. Mr. B. Appa Rao ,M.Pharm Assistant Professor Department of Pharmaceutics Dr. H.L.T. College of Pharmacy Kengal, Channapantna 571 502 Bangalore (Rural), Karanataka

11

Name and Designation of (In Block Letters) 11.1 Guide

11.2 Signature 11.3 Co-Guide (if any) 11.4 Signature 11.5 Head of the Department --

Mr. Ravada Ramesh , M.Pharm

Professor Department of Pharmaceutics Dr. H.L.T. College of Pharmacy Kengal, Channapantna 571 502 Bangalore (Rural), Karanataka

11.6 Signature 12 12.1 Remarks of the The above mentioned information is correct and I chairman and Principal recommend the same for the approval

12.2 Signature

From Dinesh Sachdeva M.Pharm Part-I Department of Pharmaceutics Dr. H.L.T. College of Pharmacy Kengal, Channapatna Bangalore (Rural) 571502 To The Registrar (Evaluation) Rajiv Gandhi University of Health Sciences Karnataka Bangalore 4th T Block, Jayanagar Bangalore 560041 Through Proper Channel Sub.: Submission of Synopsis of Dissertation. Respected Sir, Herewith, I am submitting synopsis of dissertation work Formulation and Evaluation of Transdermal films of Carvedilol for Registration in M. Pharm. (Pharmaceutics) of Rajiv Gandhi University of Health Sciences Karnataka Bangalore. Kindly accept the same and oblige. Thanking you Yours faithfully Place : Channapatna Date : 28.11.2007 (Dinesh Sachdeva) Guide: Mr. B. Appa Rao Assistant Professor Dept. of Pharmaceutics Dr. H.L.T. College of Pharmacy Channapatna. Principal Dr.H.L.T. College of Pharmacy Channapatna