FORMULATION AND EVALUATION OF FAST DISSOLVING FILM OF LISINOPRIL

SynopsisSubmitted to

H.N.B. Garhwal (Central) University, Srinagar (Uttarakhand)For The Award of Degree of

Master of Pharmacy(Pharmaceutics)

BySAURABH CHANDRA MISHRA

DEPARTMENT OF PHARMACEUTICAL SCIENCESH.N.B. Garhwal (Central) University

Srinagar (Uttarakhand)

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DEPARTMENT OF PHATRMACEUTICAL SCIENCES

H.N.B Garhwal University, Chauras Campus-249161Phone No: 01370-267395,FAX: 01346-252174,252247

Ref.no.pharm./14...... Date: SYNOPSIS

Title:FORMULATION AND EVALUATION OF FAST DISSOLVING FILMS OF LISINOPRIL

Name of Candidate : Saurabh Chandra Mishra

Enrollment Number: G1214506 Project Work: M.pharm (Pharmaceutics)2rd Year H.N.B Garhwal (central) University Srinagar(Uttarakhand)

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TITLE OF THE TOPIC:

“FORMULATION AND EVALUATION OF FAST DISSOLVING FILMS OF LISINOPRIL”

BRIEF RESUME OF THE INTENDED WORK

Introduction :

Recently, fast dissolving drug delivery systems have started gaining popularity and acceptance as new

drug delivery systems, because they are easy to administer and lead to better patient compliance. These

delivery systems either dissolve or disintegrate in the mouth rapidly, without requiring any water to aid

in swallowing.1They also impart unique product differentiation, thus enabling use as line extensions for

existing commercial products. This novel drug delivery system can also be beneficial for meeting the

current needs of the industry are improved solubility/stability, biological half-life and bioavailability

enhancement of drugs.2,3.Although oral disintegrating tablets have an advantage of administration

without choking and fast disintegration; the disintegrated materials contained in them are insoluble and

remain until swallowing. In such cases formulation of fast dissolving film will be advantageous.4,5

Hypertension, commonly known as “High Blood Pressure”. Hypertension or High Blood Pressure

is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated.Blood

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pressure is a measurement of the force against the walls of your arteries as the heart pumps blood

through the body. High blood pressure increases chances of having a stroke, heart attack, heart failure,

kidney disease & early death. Commonly used prescription drugs include ACE inhibitors, alpha-

blockers, angiotensin –ІІ receptor antagonists, beta-blockers, calcium channel blockers, diuretics

etc.6Hence in the present work, an attempt will be made to prepare and evaluate oral fast dissolving film

of Lisinopril for the effective management of hypertension and cardiac diseases.

Review of literature:

Literature survey was carried out on the proposed research work by referring various Scientific

Research Journals, Internet, Helinet facilities and Science Direct.

Pokharkar V et al (2007-08). Mouth dissolving tablets of Carvedilol were prepared with the

purpose of delivering the drug directly into the systemic circulation and by passing the hepatic first

pass metabolism with a concomitant increase in bioavailability, . The solubility of Carvedilol was

improved by forming inclusion complex with cyclodextrin which was then further used for the

formulation of mouth dissolving tablet. Differential scanning calorimetry and Infrared spectroscopy

results indicated no incompatibilities between drug-excipient mixtures. Effect of three different

superdisintegrants on disintegration was studied. The formulations were evaluated for drug

content,content uniformity, friability,disintegration time and in vitro dissolution. Tablets containing

Carvedilol-beta-cyclodextrin complex exhibited good tablet properties, with 90% drug dissolved

within 5 min. This demonstrated the effectiveness of using various superdisintegrants and

Carvedilol-beta-cyclodextrin complex in formulation of mouth dissolving tablet.8

Aditya Dinge and Mangal Nagarsenker (2008). Triclosan (TC) containing fast dissolving films

for local delivery to oral cavity was investigated by Various film forming agents, film modifiers and

polyhydric alcohols were evaluated for optimizing the composition of fast dissolving films. The

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potential of poloxamer 407 and hydroxypropyl-β- cyclodextrin (HPBCD) to improve solubility of

TC was investigated. Fast dissolving films containing hydroxypropyl methylcellulose (HPMC),

xanthan gum, and xylitol were formulated. Use of poloxamer 407 and HPBCD resulted in

significant improvement in the solubility of TC. Fast dissolving films containing TC-HPBCD

complex and TC-Poloxamer 407 were formulated and evaluated for the in vitro dissolution profile

and in vitro microbiological assay. Films containing TC-Poloxamer 407 exhibited better in vitro

dissolution profile and in vitro antimicrobial activity as compared to the films containing TC-

HPBCD complex. Effect of incorporation of eugenol on the in vivo performance of TC-Poloxamer

407 containing films was evaluated in human volunteers. Eugenol containing films improved the

acceptability of TC-Poloxamer 407 films with respect to taste masking and mouth freshening

without compromising the in vivo dissolution time.

KUNTE SAND TANDLE P (2010)Fast dissolving films containing Verapamil were prepared and

investigated. The fast dissolving strips were prepared by solvent casting technique with the help of

HPMC E6 and maltodextrin. The strips were evaluated for drug content uniformity, film thickness,

folding endurance, in vitro disintegration time, in vitro dissolution studies, surface pH study, and

palatability study. Disintegration time showed by formulations was found to be in range of 20.4–28.6

sec. Based on the evaluation parameters, the formulation containing 2% HPMC E6 and 3.5%

maltodextrin showed optimum performance against other formulations. It was concluded that the fast

dissolving strips of verapamil can be made by solvent casting technique with enhanced dissolution rate,

taste masking, and hence better patient compliance and effective therapy.10

Semalty Aet al (2010)..Formulate and evaluate mucoadhesive drug delivery system of enalapril

maleate . The buccal films were prepared by solvent casting technique. Sodium carboxy methyl

cellulose, hydroxyl propyl methyl cellulose, hydroxylethyl cellulose and polyvinyl pyrrolidone K-90

were used as mucoadhesive polymers. Prepared films were evaluated for their weight, thickness, surface

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pH, swelling index, drug content uniformity, in vitro residence time, folding endurance in vitro release

and permeation studies. It was found that the films containing 20 mg of enalapril maleate in sodium

carboxymethylcellulose 2% w/v and hydroxyl ethyl cellulose 2% w/v (formulation F5), showed good

swelling, a convenient residence time and promising controlled drug release as all the films exhibited

controlled release over more than 10 h in permeation studies. It was concluded that the drug can be

selected for the development of buccal film for effective therapeutic use.

. Fast dissolving films of levocetrizine were prepared by solvent casting method using different grades

of methocel K3, E3, E5, and E15 as film former and PG, PEG 400 and tween 80 as plasticizer.

Bitterness of levocetirizine was masked by forming inclusion complex with HP-ßCD. The complex was

evaluated by XRD, DSC and FT-IR. Optimized films were evaluated for mechanical properties, drug

content and dissolution characteristics. The combination of methocel E15 and PEG 400 exhibited

excellent mechanical properties, uniformity in drug content and in-vitro dissolution characteristics5

drug profile

Lisinopril dihydrate

Nomenclature:

INN: Lisinopril dihydrate

Chemical name: (2S) - 1- [(2S)-6-amino -2- [ [ (1S) – 1 – carboxy – 3 -

phenylpropyl] amino] hexanoyl] pyrrole – 2 - carboxylic acid

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Structure:

Molecular formula: C21H31N3O5,2H2O

Molecular weight: 441.5

Physical form: White to off white powder

Solubility: Lisinopril dihydrate is soluble in water, sparingly soluble in

methanol, and practically insoluble in acetone and in ethanol

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Need for the study:

Lisinopril is in a group of drugs called ACE inhibitors. ACE stands for angiotensin converting enzyme.

Lisinopril is used to treat high blood pressure (hypertension), congestive heart failure, and to improve

survival after a heart attack. Lisinopril may also be used for purposes other than those listed in this

medication guide.

Lisinopril is a drug of the angiotensin converting enzyme (ACE) inhibitor class that is primarily used in

treatment of hypertension, congestive heart failure, heart attacks and also in preventing renal and retinal

complications of diabetes. Onset of action is 1-2 hours. Duration of action is found to be 24 hours (once

daily dosing).Absorption of the drug is found to be absorbed slowly and incompletely from GI

tract(oral) and peak plasmaconcentration is achieved after 7 hours.The drug distribution i.e; protein

binding is not significantly bound i.e., is up to 25%.The excretion of the drug is via urine in unchanged

form of drug, and the elimination half-life of the drug is found to be 12 hours. The drug is given orally

in case of hypertension. Adult dose is initially 5-10 mg daily given at bedtime to avoid precipitous fall

in B.P. Patient with renovascular hypertension, volume depletion, severe hypertension; Initially 2.5-5

mg once daily. Diuretic patients are given 5 mg once daily. Maintenance of the dose i.e. 20 mg once

daily up to 80 mg daily may be used if required.In case of children ≥6 years: initially up to 0.07

mg/kg( up to 5 mg once daily) can be given and adjusted the dose until desired B.P. is achieved.

Bioavailability of the drug is approximately 25%, but wide range of 6-60% is also reported.7

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SALIENT FEATURES OF FAST DISSOLVING DRUG DELIVERY SYSTEM

1. Ease to administration for patients who are mentally ill, disabled and uncooperative.

2. Requires no water.

3. quick disintegration and dissolution of the dosage form.

4. Overcomes unacceptable taste of the drugs.

5. Can be designed to leave minimal or no residue in the mouth after administration and also to provide a pleasant mouth feel.

6. Allows high drug loading.

7. Ability to provide advantages of liquid medication in the form of solid preparation.

8. Adaptable and ameanable to existing processing and packaging machinery.

9. Cost- effective.

The formulation of poorly water soluble drug compounds for oral delivery now present one of the greatest challenges to formulation scientist in pharmaceutical industry.

The poor aqueous solubility of the drug result in variable dissolution profile hence poor bioavailability. The solubility behavior of a drug is the key determination of its oral bioavailability.

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Plan of work:

Fast dissolving films of Lisinopril will be prepared to provide fast action in hypertension with the

following objectives :-

1. To formulate Lisinopril fast dissolving films by using natural and synthetic polymers, following

solvent casting method.

2. To evaluate the oral film for surface pH, mechanical strength, thickness, folding endurance,

tensile strength.

3. To study the drug-excipient interaction through DSC and IR spectral studies.

4. To study the in vitro release profile.

5. The in vitro transmucosal permeation study can be done by using chicken pouches.

6. The in vitro bioavailability study is conducted in rabbits.

7. The in vivo residence time measurement study can be conducted in human volunteers.

MATERIALS & METHODS:

Source of Data :

Primary literature: Journal publications

Secondary literature: Abstracts (International Pharmaceutical Abstracts), online

material.

Tertiary literature: Text Books.

Prior unpublished research from our and other laboratories.

Data will be obtained from Science Direct, and other internet facilities, literature

search and related articles from library of Shree Devi College of Pharmacy,

Digital Library of RGUHS, Bangalore, etc.

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Journals

Asian Journal of Pharmaceutics

Journal of young Pharmacists

Indian Journal of Pharmaceutical Science

International Journal of Pharmacy and Pharmaceutical Science

Journal of Pharmacy Research

Digest Journal of Nano-materials & Bio-structures

Research Journal of Pharmaceutical, Biological & Chemical sciences

Journal of Liquid chromatography & related technologies

Text Books and Pharmacopoeia

Beckett AH, Stenlake JB, Practical Pharmaceutical Chemistry. 4th ed.

Delhi: CBS Publisher and Distributors, 1997

Sethi PD, Quantitative Analysis of Drugs in Pharmaceutical Formulation,

3rded. Delhi: CBS Publisher and Distributors

Higuchi T And Brochman E, Hanseen H, Pharmaceutical Analysis, Delhi: CBS Publisher and

Distributors, 2005

Mendham J, Denney RC, Barnes JD, K Thomas MJ, Vogel’s text Book of Quantitative

Chemical Analysis, 6thed. Pearson education Pvt. Ltd, 2002

The Indian Pharmacopoeia, Government of India, Ministry of Health and Family Welfare,

Published by The Indian Pharmacopoeia commission Gaziabad, Volume 2 & 3, 2007

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Internet Browsing

www.sciencedirect.com

www.google.com

www.rxlist.com

www.rjptonline.org

www.jyoungpharm.in

www.pharmainfo.net

www.scipharm.at

www.jocpr.com

Methods of collection of data (including sampling procedures if any) :

The data related to the physicochemical properties of the drug will be collected from the drug

information center, various standard books, journals and other sources like research literature data

bases such science direct etc. and laboratory equipments.

• Attempts will be made to design fast dissolving films of Lisinopril with different polymers.

• Prepared fast dissolving films will be evaluated for

1. Physical properties.

2. Drug content.

3. In vitro drug release and studying their release kinetics.

4. In vivo studies for Pharmacodynamics parameters in detail.

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REFERENCES :

1 Dixit R, Puthli S. Oral strip technology: Overview and future potential. J Control Release

2012;139: 94–107.

2 Arya A, Chandra A, Sharma V, PathakK. Fast dissolving oral films: An innovative drug delivery

system and dosage form. Int J ChemTech Res 2010;2: 576–83.

3 Mashru C, Sutariya V, Sankalia M, ParikhP. Development and evaluation of fast-dissolving

film of salbutamol sulphate. Drug Dev Ind Pharm 2005;31:25–34

4 Nishimura M, Matsuura K, Tsukioka T, Yamashita H, Inagaki N, Sugiyama T, et al. In vitro

and in vivo characteristics of prochlorperazine oral disintegrating film. Int J Pharm 2009;

368:98–102.

5 Shimoda H, Taniguchi K, Nishimura M, Matsuura K, Tsukioka T, Yamashita H, et al.

Preparation of a fast dissolving oral thin film containing dexamethasone: A possible application

to antiemesis during cancer chemotherapy. Eur J Pharm Biopharm 2009;73: 361–5.

6 Available from http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001502 [Last accessed on

2012 June 12].

7 The American Society of Health-System

Pharmacistshttp://www.drugs.com/monograph/lisinopril.html. Retrieved 3 April 2011.

8 Pokharkar V, Dhar S, Mandpe L. Studies on formulation development of mouth dissolving

tablets of Carvedilol. Hindustan Antibiot Bull 2007 -2008; 49-50(1-4):21-8.

9 Dinge A and Nagarsenker M. Formulation and Evaluation of Fast Dissolving Films for Delivery

of Triclosan to the Oral Cavity. AAPS Pharm SciTech 2008; 9(2): 349–56.

10 Kunte S and Tandale P. Formulation and Evaluation of fast dissolving films of verapamil J

PharmBioallied Sci2010; 2(4): 325–8.

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11 Semalty A, Semalty M, Nautiyal U. Formulation and evaluation of mucoadhesive buccal films

of enalapril maleate. Indian J Pharm Sci 2010; 72(5):571-5.

12 SA Tayel, Soliman, II and D Louis. Formulation of ketotifenfumarate fast melt granulation

sublingual tablet. AAPS Pharm Sci Tech 2010; 11(2): 679-85.

13 Magdy IM, Mohamed H, Muaadh A, Mohamed Ali. Buccal Mucoadhesive Films Containing

Antihypertensive Drug: In vitro/in vivo Evaluation. J Chem Pharm Res 2011; 3(6):665-86.

14 Yehia SA, El-Gazayerly ON, Basalious EB. Fluconazole mucoadhesive buccal films: In vitro/in

vivo performance. Curr Drug Deliv2009; 6(1): 17-27.

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