formulation and evaluation of anti emetic patch comprising on dan set ron hydro chloride

i

““FFOORRMMUULLAATTIIOONN AANNDD EEVVAALLUUAATTIIOONN OOFF AANNTTIIEEMMEETTIICC

PPAATTCCHH CCOOMMPPRRIISSIINNGG OONNDDAANNSSEETTRROONN

HHYYDDRROOCCHHLLOORRIIDDEE””

Dissertation

Submitted to KLE University, Belgaum, KarnatakaSubmitted to KLE University, Belgaum, KarnatakaSubmitted to KLE University, Belgaum, KarnatakaSubmitted to KLE University, Belgaum, Karnataka In partial fulfillment of the requirement for the award of In partial fulfillment of the requirement for the award of In partial fulfillment of the requirement for the award of In partial fulfillment of the requirement for the award of

the degree ofthe degree ofthe degree ofthe degree of

MMMaaasssttteeerrr ooofff PPPhhhaaarrrmmmaaacccyyy IIInnn

PPPhhhaaarrrmmmaaaccceeeuuutttiiicccsss

By

Miss. PRAMEELA KIRAN SURYADEVARA B.Pharm

Under the guidance of

DR. BASAVARAJ K. NANJWADE PPhhDD

DEPARTMENT OF PHARMACEUTICS, JN MEDICAL COLLEGE, BELGAUM-590010, KARNATAKA, INDIA

MAY-2010

ii

KKLLEE UUNNIIVVEERRSSIITTYY,, BBEELLGGAAUUMM,, KKAARRNNAATTAAKKAA

DeclaratioDeclaratioDeclaratioDeclaration by the Candidaten by the Candidaten by the Candidaten by the Candidate

II hheerreebbyy ddeeccllaarree tthhaatt tthhiiss ddiisssseerrttaattiioonn eennttiittlleedd

““FFOORRMMUULLAATTIIOONN AND EVALUATION OF ANTIEMETIC PATCH

COMPRISING OF ONDANSETRON HYDROCHLORIDE”” iiss aa

bboonnaaffiiddee aanndd ggeennuuiinnee rreesseeaarrcchh wwoorrkk ccaarrrriieedd oouutt bbyy mmee uunnddeerr

tthhee gguuiiddaannccee ooff Dr. B.K. NANJWADE,, AAssssoocciiaattee PPrrooffeessssoorr,,

DDeeppaarrttmmeenntt ooff PPhhaarrmmaacceeuuttiiccss,, JJNN MMeeddiiccaall CCoolllleeggee,,

BBeellggaauumm.

DDaattee::

PPllaaccee:: BBeellggaauumm..

MMiissss.. PPRRAAMMEEEELLAA KKIIRRAANN SSUURRYYAADDEEVVAARRAA BB..PPhhaarrmm DDeepptt.. ooff PPhhaarrmmaacceeuuttiiccss,, JJNN MMeeddiiccaall CCoolllleeggee,, BBeellggaauumm �� 559900 001100,, KKaarrnnaattaakkaa..

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iii


Certificate by the GuideCertificate by the GuideCertificate by the GuideCertificate by the Guide

II hheerreebbyy ddeeccllaarree tthhaatt tthhiiss ddiisssseerrttaattiioonn eennttiittlleedd

““FFOORRMMUULLAATTIIOONN AND EVALUATION OF ANTIEMETIC PATCH

COMPRISING OF ONDANSETRON HYDROCHLORIDE”” iiss aa

bboonnaaffiiddee rreesseeaarrcchh wwoorrkk ddoonnee bbyy MMIISSSS.. KKIIRRAANN SSUURRYYAADDEEVVAARRAA

iinn ppaarrttiiaall ffuullffiillllmmeenntt ooff tthhee rreeqquuiirreemmeenntt ffoorr tthhee ddeeggrreeee ooff

MMaasstteerr ooff PPhhaarrmmaaccyy iinn PPhhaarrmmaacceeuuttiiccss..

DDaattee:: PPllaaccee:: BBeellggaauumm..

DDrr.. BB.. KK.. NNAANNJJWWAADDEE PPhhDD PPrrooffeessssoorr,, DDeepptt.. ooff PPhhaarrmmaacceeuuttiiccss,, JJNN MMeeddiiccaall CCoolllleeggee,, BBeellggaauumm �� 559900 001100,, KKaarrnnaattaakkaa..

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Endorsement Endorsement Endorsement Endorsement By By By By The HOD, Principal/ Head The HOD, Principal/ Head The HOD, Principal/ Head The HOD, Principal/ Head oooof The Institutionf The Institutionf The Institutionf The Institution

This is to certify that the dissertation entitled

“FFOORRMMUULLAATTIIOONN AND EVALUATION OF ANTIEMETIC PATCH

COMPRISING OF ONDANSETRON HYDROCHLORIDE” is a

bonafide research work done by Miss. KIRAN SURYADEVARA in

partial fulfillment of the requirement for the degree of Master of

Pharmacy in Pharmaceutics, under the guidance of DDrr.. BB.. KK..

NNAANNJJWWAADDEE,, Professor, Department of Pharmaceutics, JN

Medical College, Belgaum.


DDRR.. VV.. DD.. PPAATTIILL MMDD,, DDCCHH

PPrriinncciippaall,, JJNN MMeeddiiccaall CCoolllleeggee,, BBeellggaauumm �� 559900 001100,, KKaarrnnaattaakkaa..

MMRRSS.. RR.. SS.. MMAASSAARREEDDDDYY MM..PPHHAARRMM AAssssoocciiaattee PPrrooffeessssoorr && HHeeaadd,, DDeepptt.. ooff PPhhaarrmmaacceeuuttiiccss,, JJNN MMeeddiiccaall CCoolllleeggee,, BBeellggaauumm �� 559900 001100.. KKaarrnnaattaakkaa

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Copyright Declaration by Copyright Declaration by Copyright Declaration by Copyright Declaration by thethethethe CandidateCandidateCandidateCandidate

II hheerreebbyy ddeeccllaarree tthhaatt tthhee KKLLEE UUnniivveerrssiittyy,, BBeellggaauumm,,

KKaarrnnaattaakkaa sshhaallll hhaavvee tthhee rriigghhttss ttoo pprreesseerrvvee,, uussee aanndd

ddiisssseemmiinnaattee tthhiiss ddiisssseerrttaattiioonn//tthheessiiss iinn pprriinntt oorr eelleeccttrroonniicc

ffoorrmmaatt ffoorr aaccaaddeemmiicc//rreesseeaarrcchh ppuurrppoossee..

DDaattee::

PPllaaccee:: BBeellggaauumm..

© J.N. Medical College, KLE University, Belgaum, Karnataka

MMiissss.. PPRRAAMMEEEELLAA KKIIRRAANN SS BB..PPhhaarrmm DDeepptt.. ooff PPhhaarrmmaacceeuuttiiccss,, JJNN MMeeddiiccaall CCoolllleeggee,, BBeellggaauumm �� 559900 001100,, KKaarrnnaattaakkaa..

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vi

Affectionately D edicatedAffectionately D edicatedAffectionately D edicatedAffectionately D edicated totototo

MyMyMyMy

FamilyFamilyFamilyFamily

The family is a haven in this world

vii

AcknowledgementAcknowledgementAcknowledgementAcknowledgement

The Almighty, has been bestowing us with his blessings throughout our life. I

thank thou force for all that he has done for me and my friends. We all are his

disciples.

Words are few to express the feeling of thanks and gratitude to the following

persons.

I would like to grab the opportunity to thank my guide

Dr. B.K. Nanjwade (prof) KLE University, Belgaum, for his immense support

for the project. Sir you been a great support for me, enlightening my path of

education and knowledge. Thanks for your unparalleled and excellent

guidance, continuous encouragement for my project.

It is a great pleasure and honour to thank Chancellor, Vice-Chancellor, Dr.

V.D. Patil(principal) , Dr. F.V. Manvi, Dr. P.V. Patil (Cont of Examination) , Prof A.D.

Taranalli and Dr. Pramod HJ (Pharmacognosy) of KLE University, for such a

temple of education that they provided.

I would like to thank all the teaching and non-teahing staff of the KLE’s

Women’s College of Pharmacy, Belgaum, for their support. I would like to

thank Yellapa and Gajanan for their support during the project.

I owe my thanks to the whole staff of Library.

viii

I would like to cast a vote of thanks to my friends and batchmates Sushmitha,

Venkatlaxmi, Anu, Sank ,Mohite, Vishwas, Eshwar, Amol, Bhushan, Rajesh,

Ritesh, Ayaz, Jatin, Ketan, Dhaval, Suhas, Chirag, Kemy, Rucha and Vishal

for their kind support throughout my project.

My gratitude goes to my seniors Chakridhar and Kotishwar for their guidance

during the project.

A very special thanks to all my juniors Bhavya Shanthi, Swathi, Hima,

Nirmala Devi, Haritha, Kishori, Alok, Navik and Vedprakash for making my

stay a pleasant one in Belgaum.

Thanks to my friends who always care for me Raghu Ram, Rahul, Raghu

Kumar, Guru Prasad, Chandna, Srinivas, Prem and Anurupa.

A heartily and warm thanks to Mac R. Kella for supporting me throughout my

project and studies.

This dissertation is dedicated to my family, for without their blessings nothing

would have been possible. My sisters and jijus have been a driving force behind

me for my accomplishments and achievements. Thanks a lot for everything that

you have been doing for me.

A special thanks to my Maternal Uncles V. Ashok Vardhan and Mr. V. S.

Prasad.

KKKKKKKKIIIIIIIIRRRRRRRRAAAAAAAANNNNNNNN SSSSSSSSUUUUUUUURRRRRRRRYYYYYYYYAAAAAAAADDDDDDDDEEEEEEEEVVVVVVVVAAAAAAAARRRRRRRRAAAAAAAA

ix

LIST OF ABBREVIATIONS

EC - Ethyl Cellulose

FT-IR - Fourier transform Infrared spectroscopy

gm - Grams

HPMC - Hydroxy Propyl Methyl Cellulose

ml - Milli-litres

PBS - Phosphate buffer solution

pKa - Dissociation constant

PVA - Polyvinyl alcohol

PVP - Poly Vinyl Pyrrolidone

RH - Relative Humidity

t ½ - Elimination half-life

t max - Time to attain peak concentration

µg - Micrograms

x

ABSTRACT

The skin can be used as the site for drug administration for continuous transdermal

drug infusion into the systemic circulation. For the continuous diffusion/penetration

of the drugs through the intact skin surface membrane-moderated systems, matrix

dispersion type systems, adhesive diffusion controlled systems and micro reservoir

systems have been developed. Various penetration enhancers are used for the drug

diffusion through skin. In matrix dispersion type systems, the drug is dispersed in the

solvent along with the polymers and solvent allowed to evaporate forming a

homogeneous drug-polymer matrix.

Matrix type systems were developed in the present study. In the present work, an

attempt has been made to develop a matrix-type transdermal therapeutic system

comprising of Ondansetron-HCl with different ratios of hydrophilic and hydrophobic

polymeric combinations using solvent evaporation technique. The physicochemical

compatibility of the drug and the polymers was studied by infrared spectroscopy. The

results obtained showed no physical-chemical incompatibility between the drug and

the polymers. The patches were further subjected to various physical evaluations

along with the in-vitro permeation studies using rat skin. On the basis of results

obtained form the in-vitro study and physical evaluation the patches containing

hydrophilic polymers i.e. polyvinyl alcohol and poly vinyl pyrrolidone, with oleic

acid as the penetration enhancer(5%) were considered as suitable for large scale

manufacturing with a backing layer and a suitable adhesive membrane.

Keywords: Transdermal drug delivery, penetration enhancers, hydrophilic and

hydrophobic polymers, Ondansetron HCl.

xi

CONTENTS

SL. NO. TITLE PAGE

NO.

1. INTRODUCTION 1

2. RESEARCH OBJECTIVES 28

3. REVIEW OF LITERATURE 31

4. METHODOLOGY 53

5. RESULTS AND DISCUSSION 64

6. CONCLUSION 86

7. SUMMARY 87

8. BIBLIOGRAPHY 89

xii

LIST OF TABLES

Sr. No. Title of Table Page No.

1. Regional variation in water permeability of stratum corneum 9

2. Examples of marketed transdermal drug delivery system 27

3. List of chemicals used with grade and supplier 53

4. List of Instruments used 54

5. Formulation table of Ondansetron HCl Patches 57

6. Standard calibration curve of Ondansetron HCl 67

7. Solubility data for Ondansetron HCl 67

8. Physicochemical evaluation data of Ondansetron HCl Transdermal patches

68

9. Ex-vivo diffusion study of OND 1 69






15. Data for regression 75

xiii

LIST OF FIGURESLIST OF FIGURESLIST OF FIGURESLIST OF FIGURES

Sl. No. Title of Figure Page

No.

1 Comparative graphs of conventional, sustained- and controlled release delivery systems.

1

2 SSttrruuccttuurree ooff sskkiinn 6

3 A multilayer skin model showing sequence of Transdermal permeation of drug for systemic delivery

9

4 The microstructure of stratum corneum 10

5 Routes for drug permeation 11

6. Epidermal routes for drug permeation 11

7. Action of penetration enhancers 15

8. Cross-sectional view of polymer membrane permeation-controlled TDD systems

20

9. Cross-sectional view of polymer matrix diffusion-controlled TDD Systems

22

10. Cross-sectional view of a drug reservoir gradient-controlled TDD system

23

11. Cross-sectional view of a drug microreservoir dissolution-controlled TDD system

24

12. Assembly for % elongation 60

13. kesary Chein diffusion cell 62

14. UV spectrum for Ondanstron HCl 76

15. Calibration curve of Ondansetron HCl 76

16. Ex vivo diffusion study of OND F1 77

17. Ex vivo diffusion study of OND F2 77

18. Ex-vivo diffusion study of OND F3 78



xiv


22. Higuchi’s plot for OND F1 80






28. Formulated patches 83

29 IR spectra of OND F1 84

30 IR spectra of OND pure drug 85

Chapter 1 Introduction

Dept of Pharmaceutics, KLE University, Belgaum 1

INTRODUCTION

Controlled drug delivery

Treatments of acute and chronic diseases have been accomplished by delivery

of drugs to patients using various pharmaceutical dosage forms. These dosage forms

are known to provide a prompt release of drug. But recently several technical

advancements have been done and resulted in new techniques for drug delivery.

These techniques are capable of controlling the rate of drug release.

The term-controlled release has a meaning that goes beyond scope of

sustained release. The release of drug ingredients from a controlled release drug

delivery advances at a rate profile that is not only predictable kinetically, but also

reproducible from one unit to another1. The difference between sustained release and

controlled release is shown by fig.1.

Figure. 1: Comparative graphs of conventional, sustained- and controlled release

delivery systems.

The classification of controlled drug delivery can be given as follows.



1. Rate-preprogrammed drug delivery systems

2. Activation-modulated drug delivery systems

3. Feedback-regulated drug delivery systems

4. Site-targeting drug delivery systems

Out of these classes first class contains new drug delivery systems as transdermal

delivery, intra uterine delivery, ocular inserts, and sub dermal implants. The

transdermal drug delivery has advantage to deliver medicines via skin to systemic

circulation at a predetermined rate and maintain therapeutic concentration for prolong

period of time.

Transdermal drug delivery: An Introduction

The idea of delivering drugs through skin is old, as the use is reported back in

16th century B.C. The husk of castor oil plant in water was placed on an aching head2.

Today the transdermal drug delivery is well accepted for delivering drug to systemic

circulation.

Until recently, the use of transdermal patches for pharmaceuticals has been

limited because only a few drugs have proven effective delivered through the skin —

typically cardiac drugs such as nitroglycerin and hormones such as estrogen.

A skin patch uses a special membrane to control the rate at which the liquid

drug contained in the reservoir within the patch can pass through the skin and into the

bloodstream. The basic components of any transdermal delivery system include the

drug(s) dissolved or dispersed in a reservoir or inert polymer matrix; an outer backing

film of paper, plastic, or foil; and a pressure-sensitive adhesive that anchors the patch

to the skin. The adhesive is covered by a release liner, which needs to be peeled off

before applying the patch to the skin. Drugs administered via skin patches include

scopolamine, nicotine, estrogen, nitroglycerin, and lidocaine (Table 2).



Non-medicated patch markets include thermal and cold patches, nutrient

patches, skin care patches (a category that consists of two major sub-categories —

therapeutic and cosmetic), aroma patches, weight loss patches, and patches that

measure sunlight exposure.

Transdermal drug delivery has many advantages over conventional drug

delivery and can be discussed as follows.

Advantages2, 3, 4, 5

1. They can avoid gastrointestinal drug absorption difficulties caused by

gastrointestinal pH, enzymatic activity, and drug interactions with food, drink, and

other orally administered drugs.

2. They can substitute for oral administration of medication when that route is

unsuitable, as with vomiting and diarrhea.

3. They avoid the first-pass effect, that is, the initial pass of s drug substance through

the systemic and portal circulation following gastrointestinal absorption, possibly

avoiding the deactivation by digestive and liver enzymes.

4. They are noninvasive, avoiding the inconvenience of parenteral therapy.

5. They provide extended therapy with a single application, improving compliance

over other dosage forms requiring more frequent dose administration.

6. The activity of a drugs having s short half-life is extended through the reservoir of

drug in the therapeutic delivery system and its controlled release.

7. Drug therapy may be terminated rapidly by removal of the application from the

surface of the skin.

8. They are easily and rapidly identified in emergencies (e.g., unresponsive,

unconscious, or comatose patient) because of their physical presence, features, and

identifying markings.



9. They are used for drugs with narrow therapeutic window.

At the same time transdermal drug delivery has few disadvantages that are limiting

the use of transdermal delivery.

Disadvantages 3, 4, 6

1. Only relatively potent drugs are suitable candidates for transdermal delivery

because of the natural limits of drug entry imposed by the skin’s impermeability.

2. Some patients develop contact dermatitis at the site of application from one or more

of the system components, necessitating discontinuation.

3. The delivery system cannot be used for drugs requiring high blood levels.

4. The use of transdermal delivery may be uneconomic.

For better understanding of transdermal drug delivery, the structure of skin should be

briefly discussed along with penetration through skin and permeation pathways.

Structure of skin 1, 4, 7, 8

The skin, the heaviest single organ of the body, combines with the mucosal

lining of the respiratory, digestive, and urogenital tracts to form a capsule which

separates the internal body structures from external environment. For an average 70

kg human with skin surface area of 1.8 m2, a typical square centimeter covers 10 hair

follicles, 12 nerves, 15 sebaceous glands, 100 sweat glands, and 3 blood vessels with

92 cm total length. The skin has several functions, which can be summarized as

follows.

Functions of skin4, 9

1. Protection – from invasion by microbes, chemicals, physical agents (e.g. mild

trauma, UV light), and dehydration.

2. Reflex action – due to sensory nerves to stimuli

3. Regulation of body temperature – regulate body temperature about 36.8°C (98.4°F)



with variation of 0.5°C to 0.75°C.

4. Formation of vitamin D – fatty substance present in skin, 7- dehydrocholesterol, in

presence of UV light from sun is converted to vitamin D.

5. Absorption – absorbs some drug with low molecular weight as well as toxic

chemicals like mercury.

6. Excretion – excretes sodium chloride in sweat, urea when kidney function is

impaired, and aromatic substances (e.g. garlic and other spices)

Now, it’s important to understand the detailed structure of skin so as to understand the

concept related to permeation of drug.

Anatomy and Physiology7, 8

Human skin comprises of three distinct but mutually dependent tissues.

A) The stratified, a vascular, cellular epidermis,

B) Underlying dermis of connective tissues, and

C) Hypodermis.

1. Epidermis

The multilayered envelop of the epidermis varies in thickness, depending on

cell size and number of cell layers, ranging from 0.8 mm on palms and soles down to

0.06 mm on the eyelids. Stratum corneum and the remainder of the epidermis so

called viable epidermis cover a major area of skin.



Figure . 2: Structure of skin

i) Stratum corneum

This is the outermost layer of skin also called as horney layer. It is

approximately 10mm thick when dry but swells to several times this thickness when

fully hydrated. It contains 10 to 25 layers of parallel to the skin surface lying dead,

keratinized cells, called corneocytes. It is flexible but relatively impermeable. The

stratum corneum is the principal barrier for penetration. The barrier nature of the

horney layer depends critically on its constituents: 75-80%proteins, 5-15%lipids,

and5-10%ondansetron material on a dry weight basis. Protein fraction predominantly

contains alpha-keratin (70%) with some beta keratin (10%) and cell envelope (5%).

Lipid constituents vary with body site (neutral lipids, sphingolipids, polar lipids,

cholesterol). Phospholipids are largely absent, a unique feature of mammalian

membrane. The architecture of horney layer may be modeled as a wall-like structure.



In this model, the keratinized cells function as a protein “bricks” embedded in lipid

“mortar.” The lipids are arranged in a multiple bi layers, and it has been suggested

that there is sufficient amphipilic material in the lipid fraction, such as polar free fatty

acids and cholesterol, to maintain a bi layer form.

ii) Viable epidermis

This is situated beneath the stratum corneum and varies in thickness from

0.06mm on the eyelids to 0.8mm on the palms. Going inwards, it consists of various

layers as stratum lucidum, stratum granulosum, stratum spinosum, and the stratum

basale. In the basale layer, mitosis of the cells constantly renews the epidermis and

this proliferation compensates the loss of dead horney cells from the skin surface. As

the cells produced by the basale layer move outward, they alter morphologically and

histochemically, undergoing keratinization to form the outermost layer of stratum

corneum.

1. Dermis

Dermis is 3 to 5mm thick layer and is composed of a matrix of connective

tissue, which contains blood vessels, lymph vessels, and nerves. The cutaneous blood

supply has essential function in regulation of body temperature. It also provides

nutrients and oxygen to the skin, while removing toxins and waste products.

Capillaries reach to within 0.2 mm of skin surface and provide sink conditions for

most molecules penetrating the skin barrier. The blood supply thus keeps the dermal

concentration of a permeate very low, and the resulting concentration difference

across the epidermis provides the essential driving force for transdermal permeation.



2. Hypodermis

The hypodermis or subcutaneous fat tissue supports the dermis and epidermis.

It serves as a fat storage area. This layer helps to regulate temperature, provides

nutritional support and mechanic protection. It carries principal blood vessels and

nerves to skin and may contain sensory pressure organs. For transdermal drug

delivery drug has to penetrate through all these three layers and reach into systemic

circulation while in case of topical drug delivery only penetration through stratum

corneum is essential and then retention of drug in skin layers is desired.

Fundamentals of skin permeation9

Until the last century the skin was supposed to be impermeable with exception

to gases. However, in the current century the study indicated the permeability to lipid

soluble drugs like electrolytes. Also it was recognized that various layers of skin are

not equally permeable i.e. epidermis is less permeable than dermis. After a large

controversy, all doubts about stratum corneum permeability was removed and using

isotopic tracers, it was suggested that stratum corneum greatly hamper permeation.

A. Stratum corneum as skin permeation barrier

The average human skin contains 40-70 hair follicles and 200-250 sweat ducts

per square centimeter. Especially water-soluble substances pass faster through these

ducts; still these ducts don’t contribute much for skin permeation. Therefore, most

neutral molecules pass through stratum corneum by passive diffusion. Thus, the

stratum corneum acts as a passive, but not inert, diffusion medium.

Series of steps in sequence:

1. Sorption of a penetrant molecule on surface layer of stratum corneum.

2. Diffusion through it and viable epidermis, and finally

3. The molecule is taken up into the microcirculation for systemic distribution.



Table 1: Regional variation in water permeability of stratum corneum

Sr.

No.

Skin Region Thicknes (µm) Permeation

(mg/cm2/hr)

Diffusivity

(cm2/sec x 1010)

1 Abdomen 15 0.34 6.0

2 Volar forearm 16 0.31 5.9

3 Back 10.5 0.29 3.5

4 Forehead 13 0.85 12.9

5 Scrotum 5 1.70 7.4

6 Back of hand 49 0.56 32.3

7 Palm 400 1.14 535

8 Plantar 600 3.90 930

Figure. 3: A multilayer skin model showing sequence of Transdermal

permeation of drug for systemic delivery



B. Intracellular verses transcellular diffusion

Figure. 4: The microstructure of stratum corneum

Intracellular regions in stratum corneum are filled with lipid rich amorphous

material. In dry stratum corneum intracellular volume may be 5% to 1% in fully

hydrated stratum corneum.

C. Permeation pathways1.4

Percutaenous absorption involves passive diffusion of the substances through

the skin. A molecule may use two diffusional routes to penetrate normal intact skin,

the appendageal route and the epidermal route (Fig.5).

1. Appendageal route

Appendageal route comprises transport via sweat glands and hair follicles with

their associated sebaceous glands (shown as no.1&3 in fig.5). These routes

circumvent penetration through the stratum corneum and are therefore known as

“shunt” routes. This route is considered to be of minor importance because of its

relatively small area, approximately 0.1 % of the total skin area.



Figure. 5: Routes for drug permeation

2. Epidermal route (shown as no.2 in fig.5)

For drugs, which mainly cross-intact horney layer, two potential micro routes

of entry exists, the transcellular (intracellular) and intercellular pathways. (Fig.6)

Fig. 6: Epidermal routes for drug permeation

i) Transcellular-



Transcellular pathway means transport of molecules across epithelial cellular

membrane. These include passive transport of small molecules, active transport of

ionic and polar compounds, and endocytosis and transcytosis of macromolecules.

ii) Paracellular-

Paracellular pathway means transport of molecules around or between the

cells. Tight junctions or similar situations exist between the cells.

The principal pathway taken by a permeant is decided mainly by the partition

coefficient (log k). Hydrophilic drugs partition preferentially into the intracellular

domains, whereas lipophilic permeants (o/w log k >2) traverse the stratum corneum

via the intercellular route. Most permeants permeate the stratum corneum by both

routes. However, the tortuous intercellular pathway is widely considered to provide

the principal route and major barrier to the permeation of most drugs.

Factors influencing transdermal drug delivery4

The effective transdermal drug delivery can be formulated by considering

three factors as Drug, Skin, and the vehicles. So the factors affecting can be divided in

to classes as biological factors and physicochemical factors.

A. Biological factors

Skin condition – Acids and alkalis; many solvents like chloroform, methanol

damage the skin cells and promote penetration. Diseased state of patient alters the

skin conditions. The intact skin is better barrier but the above mentioned conditions

affect penetration.

Skin age – The young skin is more permeable than older. Children are more

sensitive for skin absorption of toxins. Thus, skin age is one of the factors affecting

penetration of drug in TDDSs.



Blood supply – Changes in peripheral circulation can affect transdermal

absorption.

Regional skin site – Thickness of skin, nature of stratum corneum, and density

of appendages vary site to site. These factors affect significantly penetration.

Skin metabolism –Skin metabolizes steroids, hormones, chemical carcinogens

and some drugs. So skin metabolism determines efficacy of drug permeated through

the skin.

Species differences – The skin thickness, density of appendages, and

keratinization of skin vary species to species, so affects the penetration.

B. Physicochemical factors

Skin hydration – In contact with water the permeability of skin increases

significantly. Hydration is most important factor increasing the permeation of skin. So

use of humectants is done in transdermal delivery.

Temperature and pH – The permeation of drug increase ten folds with

temperature variation. The diffusion coefficient decreases as temperature falls. Weak

acids and weak bases dissociate depending on the pH and pKa or pKb values. The

proportion of unionized drug determines the drug concentration in skin. Thus,

temperature and pH are important factors affecting drug penetration.

Diffusion coefficient – Penetration of drug depends on diffusion coefficient of

drug. At a constant temperature the diffusion coefficient of drug depends on

properties of drug, diffusion medium and interaction between them.

Drug concentration – the flux is proportional to the concentration gradient

across the barrier and concentration gradient will be higher if the concentration of

drug will be more across the barrier.



Partition coefficient – The optimal K, partition coefficient is required for good

action. Drugs with high K are not ready to leave the lipid portion of skin. Also, drugs

with low K will not be permeated.

Molecular size and shape – Drug absorption is inversely related to molecular

weight; small molecules penetrate faster than large ones. Because of partition

coefficient domination, the effect of molecular size is not known.

Ideal molecular properties for transdermal delivery4, 6

From the above considerations we can conclude with some observations that

can be termed as ideal molecular properties for drug penetration. They are as follows.

Ø The partition coefficient will be high if the molecular weight is less than 600

daltons.

Ø An adequate solubility in lipid and water is necessary for better penetration of

drug.

Ø (1mg/ml)

Ø Optimum partition coefficient is required for good therapeutic action

Ø Low melting point of drug is desired. (<200°C)

Ø The pH of the saturated solution should be in between 5 to 9.

Ø The potent drug with dose of 10-15 mg/day is desired.



Penetration Enhancers3, 4

Figure. 7: Action of penetration enhancers

If the skin absorbs high concentrations of organic solvents such as DMSO,

ethanol, or propylene glycol, the resulting medium (skin/solvent) may have an

increased partition coefficient for the therapeutic agent of interest.

Chemical enhancers

By definition, a chemical skin permeation enhancer increases skin

permeability by reversibly damaging or altering the physicochemical nature of the

stratum corneum to reduce its diffusional resistance. Among the alterations are

increase in hydration of stratum corneum, a change in the structure of the lipids and

lipoproteins in the intracellular channels through the solvent action or denaturation, or

both.

Some drugs have inherent capacity to permeate the skin without chemical

enhancers. However when this is not case, chemical permeation enhancers are useful

in transdermal drug delivery. More than 275 chemical compounds have been cited in

the literature as skin penetration enhancers; they include acetone, dimethyl acetamide,

dimethyl formamide, dimethyl sulfoxide (DMSO), ethanol, oleic acid, propylene

glycol, and polyethylene glycol and sodium lauryl sulphate.



The selection of a permeation enhancer should be based not only on its

efficacy in enhancing skin permeation but also on its physicochemical and biologic

compatibility with the system’s other components.

Methods are provided for enhancing the permeability of skin or mucosal tissue

to topical or transdermal application of local anesthetic agents minimizing the skin

damage, irritation or sensitization. The permeation enhancer can be an inorganic or

organic base10.

The possibility of applying a highly lipophilic drug, the anti estrogen AE (log

P=5.82), transdermally by polyacrylate-based matrix TDS was checked and in-vitro

release as well as in-vitro permeation of AE through excised skin of hairless mice was

found to be independent of concentrations of both drug and enhancers. Therefore, the

permeation of this highly lipophilic drug seems to be limited by the stratum corneum

barrier function. In contrast, the transdermal permeation of the enhancers was

dependent on the TDS composition. Increase in enhancer content resulted in a higher

permeation of enhancers, whereas skin pretreatment did not11.

The synthesis of alkyldisiloxanes containing sugar moiety with various alkyl

chain lengths was developed a penetration enhancer, which was expected to show a

low irritation to the skin12.

Iontophoresis and Sonophoresis

In addition to chemical means, some physical methods are being used to

enhance transdermal drug delivery and penetration, as, iontophoresis and

sonophoresis.

Iontophoresis is delivery of charged chemical compound across the skin

membrane using electrical field. A number of drugs have been the subjects of

iontophoretic studies; they include Lidocaine, Dexamethasone, amino acids, peptides



and insulin, verapamil and propranolol. There is particular interest to develop

alternative routes for biologically active peptides. At present peptides are delivered by

injection because of their rapid metabolism and poor absorption after oral delivery.

They are poorly absorbed by transdermal route because of large molecular size an

ionic character and general impermeability of the skin. However, iontophoresis-

enhanced transdermal drug delivery has shown some promise as a mean of peptide

and protein administration.

Sonophoresis, or high frequency ultrasound, is also being studied as a means

to enhance transdermal drug delivery. Among the agents examined are

hydrocortisone, Lidocaine, and salicylic acid in formulations such as gels, creams,

and lotions. It is thought that high frequency ultrasound can influence the integrity of

the stratum corneum and thus affects its permeability.

The transfer of sotalol and salicylate was measured varying the salt (NaCl)

concentration in the donor and receiver compartments. It appears that osmotic

pressure and ion exchange make a significant contribution to the flux enhancement by

the diffusion potential13.

Iontophoresis and enhancers were performed to enhance percutaneous

absorption of enoxacin so as to compare the enhancement between these two

enhancing methods. The cationic surfactant of benzalkonium chloride showed the

highest enhancing activity for enoxacin for all pH values of buffer vehicles. The

enhancement factor of sodium lauryl sulfate showed a dose-dependent property

between the ranges of 0.1% to 3.0% concentration. Nonionic surfactant of Polysorbate

80 did not exhibit any enhancing effect on the percutaneous absorption of enoxacin.

The highest enhancement factor of iontophoretic delivery was observed at pH 5.0

solutions of anodal iontophoresis for cationic enoxacin. The cathodal iontophoresis of



negative molecules and anodal iontophoresis of neutral molecules showed lower

enhancing effect for enoxacin. The skin residuals of enoxacin after iontophoresis

showed both tremendous and current density-dependent amounts for cationic

enoxacin. This suggested local skin and soft tissue infections might be treated by this

physical enhancement method. Combination of benzalkonium chloride and

iontophoresis exerted a synergistic effect for anionic enoxacin in pH 10.0, which was

possibly due to the shielding of negative charge in skin and the water molecules

carried by chloride14.

The effect of current, its magnitude and penetration enhancers (propylene

glycol/oleic acid) on the transdermal flux of AZT (Zidovudine) across hairless mouse

skin was studied and the results were compared. The in vitro iontophoretic flux from

AZT solution increased to about 5-40 fold that obtained by passive diffusion,

depending on the magnitude of current density. When the donor side was karaya gum

matrix, instead of solution, the flux enhancement effect by iontophoresis was much

smaller. Incorporation of penetration enhancers into the matrix increased the passive

flux 2-50 fold, depending on the amount of penetration enhancers in the matrix. These

enhancers worked synergistically with iontophoresis in the transdermal transport: a

much larger flux than that expected from a simple additive effect was observed.

Electrical resistance data from our previous work is utilized to further discuss this

synergistic effect15.

The effect of various liposome formulations on the iontophoretic transport of

enoxacin through excised rat skin was studied16. The effect of terpenes/Ethyl alcohol

combination in comparison to Ethyl alcohol and neat terpene on transdermal

iontophoretic permeation of insulin was done and found higher than the individual

effect17.



Electroporation

Skin electroporation has recently been shown to increase transdermal transport

of small-size drugs as well as considerably larger molecules by up to 4 orders of

magnitude in vitro. Nevertheless, no in vivo studies have proven that high-voltage

pulses can induce therapeutic plasma levels of drug. Thus, the study of the potential of

skin electroporation in transdermal delivery of fentanyl was done in vivo18.

The transdermal transport of timolol through human stratum corneum was studied in

three compartment diffusion cells. The electrodes, buffer composition and pulse

conditions were optimized to study the effect of skin electroporation to achieve

therapeutic fluxes of timolol. Electroporation enhanced the transdermal transport of

timolol by 1-2 orders of magnitude as compared to passive diffusion. Therapeutic

fluxes of timolol (>50 microg/cm2/h) through human stratum corneum were achieved

by electroporation19.

Oral delivery of buprenorphine, a synthetic opiate analgesic, is less efficient

due to low absorption and large first-pass metabolism. While transdermal delivery of

buprenorphine is expected to avoid the first-pass effect and thereby be more

bioavailable, use of electrical enhancement i.e. the electrically assisted transdermal

delivery of buprenorphine could provide better programmability20.

Technologies for developing transdermal drug delivery systems1, 9

The technologies can be classified in four basic approaches.

A Polymer membrane partition-controlled TDD systems:

In this type of systems, the drug reservoir is sandwiched between a drug-

impermeable backing laminate and a rate controlling polymeric membrane. (Fig.8)



Figure. 8: Cross-sectional view of polymer membrane permeation-controlled

TDD systems

The drug is allowed to permeate only through the rate controlling membrane.

The drug solids are homogeneously dispersed in a solid polymer matrix, suspended in

an unleachable, viscous liquid medium e.g. silicone fluid, to form a paste like

suspension, or dissolved in a releasable solvent e.g. alkyl alcohol, to form a clear drug

solution. The rate controlling membrane can be either a microporous or a nonporous

polymeric membrane e.g. ethylene-vinyl acetate copolymer, with specific drug

permeability. On the external surface of the polymeric membrane a thin layer of drug-

compatible, hypoallergenic pressure sensitive adhesive polymer e.g. silicone adhesive,

may be applied to provide intimate contact of TDD system with the skin surface.

Varying the composition of drug reservoir formulation and the permeability

coefficient and thickness of rate controlling membrane can alter the drug release rate.

E.g. Some FDA approved systems – Transderm-Nitro for angina pectoris, Transderm-

Scop for motion sickness, Catapres-TTS system for hypertension.

The intrinsic rate of drug release from this type of TDD system is defined by



where, CR is drug concentration in reservoir compartment;

Km / r the partition coefficient for the interfacial partitioning of drug from the

reservoir to the membrane

Ka / m the partition coefficient for the interfacial partitioning of drug from membrane

to adhesive

Da diffusion coefficient in rate controlling membrane

Dm diffusion coefficient in adhesive layer

ha thickness of rate controlling membrane

hm thickness of adhesive layer

B Polymer matrix diffusion-controlled TDD systems

In this system, the drug reservoir is formed by homogeneously dispersing the

drug solids in a hydrophilic or lipophilic polymer matrix, and then the medicated

polymer formed is molded into medicated disks with defined surface area and

thickness. This drug reservoir containing polymer disk is then mounted on occlusive

base plate in a compartment fabricated from a drug-impermeable plastic backing.

Instead of coating adhesive polymer directly on the surface of medicated disk,

it is applied along the circumference of the patch to form a strip of adhesive rim

surrounding the medicated disk.

E.g. Nitro-Dur system and NTS system for angina pectoris.



Figure. 9: Cross-sectional view of polymer matrix diffusion-controlled TDD

systems.

The rate of release from polymer matrix drug dispersion-type is

Where, Ld is drug loading dose initially dispersed in polymer matrix

CP is solubility of drug in polymer matrix

DP is diffusivity of drug in polymer matrix

Only drug is dissolved in polymer matrix can release, CP is practically equal

to CR.

Alternately, the polymer matrix drug dispersion-type TDD system can be

fabricated by directly dispersing drug in a pressure-sensitive adhesive polymer, e.g.

polyacrylate, and then coating the drug-dispersed adhesive polymer by solvent casting

or hot melt onto a flat sheet of a drug-impermeable backing laminate to form a single

layer of drug reservoir.this yields a thinner patch.

E.g. Minitran system, Nitro-Dur II system for angina pectoris.

C. Drug reservoir gradient-controlled TDD systems:

Polymer matrix drug dispersion-type TDD systems can be modified to have

the drug loading level varied in an incremental manner, forming a gradient of drug

reservoir along the diffusional path across the multi laminate adhesive layers. The

drug release from this type of drug reservoir gradient- controlled TDD systems can be

expressed by



In this system the thickness of diffusional path through which drug molecules diffuse

increases with time, i.e. ha (t). The drug loading level in the multi laminate adhesive

layer is designed to increase proportionally i.e. Ld (ha) so as to compensate time

dependent increase n diffusional path as a result of drug depletion due to release.

Thus, theoretically this should increase a more constant drug release profile.

E.g. Deponit system containing nitroglycerine for angina pectoris.

Figure. 10: Cross-sectional view of a drug reservoir gradient-controlled TDD

system.

D. Microreservoir dissolution-controlled TDD systems:

A hybrid of reservoir- and matrix dispersion-type drug delivery systems,

which contains dug reservoir formed by first suspending the drug solids in an aqueous

solution of water-miscible drug solubilizer e.g. propylene glycol, then homogeneously

dispersing the drug suspension, with controlled aqueous solubility, in a lipophilic



polymer, by high shear mechanical force, to form thousands of unleachable

microscopic drug reservoirs.

Figure. 11 : Cross-sectional view of a drug microreservoir dissolution-controlled

TDD system.

E.g. Nitrodisk system for angina pectoris.

The rate of drug release from this system is defined by

Components of a Transdermal Patch3

The main components to a transdermal patch are:

1. Release Liner

Protects the patch during storage. The liner is removed prior to use.

2. Drug reservoir

The most important part of TDDS is drug reservoir. It consists of drug

particles dissolved or dispersed in the matrix.



To make the drug soluble, use of solvents and co solvents is done. The effect

of solvent and co solvent should be considered while doing selection. The effect of

various vehicles on the in vitro permeation of melatonin across porcine skin. Flux

values of melatonin with Labrasol, propylene glycol and mineral oil were

significantly lower than that of water (P<0.001). In general, vehicles with high

melatonin solubility showed low permeability coefficient values. The flux had no

correlation to the solubility data, suggesting that high solubility values do not translate

to high drug permeation21.

3. Adhesive

Serves to adhere the components of the patch together along with adhering the

patch to the skin. The adhesive must posses sufficient adhesion property so that the

TDDS should remain in place for a long time. Pressure sensitive adhesives are

commonly used for transdermal patch to hold the skin. Commonly used adhesives are

silicone adhesives, poly iso butylenes adhesives, and poly acrylate based adhesives.

4. Membrane

Membrane controls the release of the drug from the reservoir and multi-layer patches.

It may or may not contain rate-controlling membrane. It should be flexible enough not

to split or crack on bending or stretching. Some of rate-controlling membranes are

polyethylene sheets, ethylene vinyl acetate co-polymer, and cellulose acetate.

5. Backing

Protects the patch from the outer environment. The backing layer should be

impermeable to drug and penetration enhancers. It serves a function of holding the

entire system and protects drug reservoir from atmosphere. The commonly used

backing materials are polyesters, aluminized polyethylene terepthalate, and

siliconized polyethylene terepthhalate.



General clinical considerations in the use of TDDS3

The patient should be advised of the following general guidelines. The patient should

be advised of the importance of using the recommended site and rotating locations

within the site. Rotating locations is important to allow the skin to regain its normal

permeability and to prevent skin irritation.

1. TDDSs should be applied to clean, dry skin relatively free of hair and not oily,

inflamed, irritated, broken, or callused. Wet or moist skin can accelerate drug

permeation beyond ondansetron time. Oily skin can impair the adhesion of patch. If

hair is present at the site, it should be carefully cut, not wet shaved, nor should a

depilatory agent be used, since later can remove stratum corneum and affect the rate

and extent of drug permeation.

2. Use of skin lotion should be avoided at the application site, because lotions affect

the hydration of skin and can alter partition coefficient of drug.

3. Cutting should not physically alter TDDSs, since this destroys integrity of the

system.

4. The protecting backing should be removed with care not to touch fingertips. The

TDDS should be pressed firmly against skin site with the heel of hand for about 10

seconds.



Table. 2: Examples of marketed transdermal drug delivery system3

Sr.

No.

Therapeutic agent Marketed name (company)

1. Clonidine Catapres-TTS (Boehringer Ingelheim)

2. Estradiol Vivelle (Novartis)

3. Fentanyl Duragesic (Janssen)

4. Nicotine Prosstep (Lederie)

5. Testosterone Testoderm (Alza)

6. Nicotine Habitrol (Novartis Consumer)

7. Nicotine Nicoderm CQ (Smithkline Beecham

Consumer)

8. Nitroglycerine Transderm-Nitro (Novartis)

9. Scopolamine Transderm-Scop

(Novartis Consumer)

Chapter 2 Objective of Study


OBJECTIVE OF STUDY

At present, the most common form of delivery of drugs is the oral route. While

this has the notable advantage of easy administration, it also has significant

drawbacks – namely poor bioavailability due to hepatic metabolism (first pass) and

the tendency to produce rapid blood level spikes (both high and low), leading to a

need for high and/or frequent dosing, which can be both cost prohibitive and

inconvenient.

To overcome these difficulties there is a need for the development of new drug

delivery system; which will improve the therapeutic efficacy and safety of drugs by

more precise (i.e. site specific), spatial and temporal placement within the body

thereby reducing both the size and number of doses.

One of the methods most often utilized has been transdermal drug delivery –

meaning transport of therapeutic substances through the skin for systemic effect.

Closely related is percutaneous delivery, which is transport into target tissues, with an

attempt to avoid systemic effects.

Ondansetron Hcl is an anti nauseant and antiemetic agent indicated for the prevention

of nausea and vomiting associated with moderately-emetogenic cancer chemotherapy

and for the prevention of postoperative nausea and vomiting.

The chemotherapeutic agents produce nausea and vomiting by releasing

serotonin from the enterochromaffin cells of the small intestine, and that the released

serotonin then activates 5-HT3 receptors located on vagal efferents to initiate the

vomiting reflex. Therefore Ondansetron HCl works by blocking the reception of

serotonin at these 5-HT3 receptors.



Ondansetron HCl has the half-life of 5-6 hours. It’s total bioavailability

in the body is 60% due to first pass metabolism. The total dose of Ondansetron

HCl is 24mg daily.

Transdermal administration of drugs that undergo first pass metabolism can

improve the bioavailability and reduce the dosing frequency compared with the oral

route.

A number of drug molecules have been developed in the transdermal drug

delivery system. Some of the potential advantages of transdermal drug delivery

system include:

• Avoidance of the first pass metabolism

• Elimination of gastrointestinal irritation

• Reduce dosing frequency

• Rapid termination of the drug action

Hence in present work, an attempt is been made to provide a transdermal drug

delivery system using water soluble and water insoluble polymers with model

drug as Ondansetron HCl.

Objective of the Study:

• Preparation of matrix transdermal patches by using combination of appropriate

polymers.

• To study the effect of varying concentration of polymers on in vitro drug

release.



• To study the effect of permeation enhancers on in vitro drug release.

Ø Characterization of prepared matrix transdermal patches for the following

parameters.

A. Thickness

Using screw gauge.

B. Weight variation

By using digital weighing balance

C. Drug content uniformity

By using ultraviolet spectrophotometer

D. Tensile strength

Using pulley system

E. % Elongation

Using pulley system

F. Folding endurance

Using appropriate method suggested in the article

G. Moisture content

Using dessicator and digital weighing balance

H. In-vitro drug permeation study

Using Keshary-chein diffusion cell

Chapter 3 Review of Literature

Dept. Of Pharmaceutics, KLE University, Belgaum 31

DRUG PROFILE

Ondansetron Hydrochloride Dihydrate22

Proprietary name: Zofran; Zophren.

IUPAC Name: 1,2,3,9-Tetrahydro–9–methyl–3-[(2–methyl–1H-imidazol–1–

yl)methyl] 4Hcarbazol– 4–one hydrochloride dehydrate

Molecular formula: C18H19N3O,HCl,2H2O

Molecular weight: 365.9

CAS No 99614–01–4

Structure:

Description

A white crystalline solid from water/isopropanol with m.p. 178.5° to 179.5°. It is

soluble in aqueous solutions but solubility decreases with pH >5.7.

Dissociation Constant.

Hydrochloride dihydrate; pKa7.4.

Ultraviolet Spectrum.

Aqueous acid (pH 2.8)—210, 248, 266, 310 nm.



Standard UV visible Spectrum of Ondansetron HCl

Mass Spectrum

Principal ions at m/z: 96, 293, 198, 211, 143, 183, 55, 115.

Standard mass spectrum of Ondansteron HCl

Bioavailability

60% (young healthy subjects), 65% (elderly); 85% (patients with cancer) and 100%

(severe hepatic impairment).

Half–life

3 h (young healthy subjects), 5 h (elderly) and 15 to 32 h (severe hepatic impairment).

Volume of distribution

Approx. 140 to 160 L; also reported as 1.3 to 2.9 L/kg. 3.05 L/kg (mild liver disease);

3.36 L/kg (moderate); 3.86 L/kg (severe); 2.5 L/kg (healthy individuals).



Clearance

16.6 L/h (patients with mild liver disease); 15.9 L/h (moderate liver disease); 11.6 L/h

(severe); 28.3 L/h (healthy volunteers).

Distribution in blood

Blood:plasma ratio is 0.83. It distributes into erythrocytes and circulates bound

within.

Protein binding

70 to 75%.

Dose

Adult: 8 mg (orally) before treatment followed by 8 mg every 12 h. 16 mg daily (by

rectum administration) or 32 mg (intravenously). Children: 5 mg/m2 (intravenously)

immediately before treatment and then 4 mg orally every 12 h. Alternatively, 100

g/kg (maximum 4 mg) (over 2 years old).

Uses and Administration

Ondansetron is a 5-HT3 antagonist (5-HT3-receptor antagonist) with antiemetic

activity. It is used in the management of nausea and vomiting induced by cytotoxic

chemotherapy and radiotherapy. It is also used for the prevention and treatment of

postoperative nausea and vomiting. For the management of nausea and vomiting, and

the important role of 5-HT3 antagonists.

Ondansetron is given by intramuscular or slow intravenous injection as the

hydrochloride, by

mouth as the hydrochloride or base, or rectally as the base. Doses are expressed in

terms of the base. Ondansetron hydrochloride 4.99 mg is approximately equivalent to

4 mg of ondansetron base.



For highly emetogenic chemotherapy the following dose schedules appear to be

equally effective in preventing acute emesis: a single dose of 8 mg by slow

intravenous or intramuscular injection immediately before treatment

or

8 mg by slow intravenous or intramuscular injection immediately before treatment,

either followed by a continuous intravenous infusion of 1 mg/hour for up to 24 hours,

or by a further two doses of 8 mg two to four hours apart

or

a single dose of 32 mg given by intravenous infusion over at least 15 minutes

immediately before treatment

or

a 16-mg suppository rectally, given 1 to 2 hours before treatment

The efficacy of ondansetron in highly emetogenic chemotherapy may be enhanced by

intravenous administration of dexamethasone sodium phosphate 20 mg before

chemotherapy.

For preventing acute emesis with less emetogenic chemotherapy and radiotherapy:

8 mg may be given as a slow intravenous or intramuscular injection immediately

before treatment

or

16 mg rectally can be given 1 to 2 hours before treatment

or

8 mg can be given by mouth 1 to 2 hours before treatment followed by 8 mg 12 hours

later.

Drug class

Antiemetic



Polymer Profile23

Ethyl Cellulose:

Nonproprietary Names

BP: Ethylcellulose

PhEur: Ethylcellulosum

USPNF: Ethylcellulose

Synonyms

Aquacoat ECD; Aqualon; Ethocel; Surelease.

Structure

Molecular formula (C12H23O5)n

CAS Registry Number: 9004-57-3

Functional Category:

Coating agent; flavoring fixatives; tablet binder; tablet filler; viscosity-increasing

agent.

Applications in Pharmaceutical Formulation or Technology

Ethyl cellulose is widely used in oral and topical pharmaceutical formulations. Ethyl

cellulose coatings are used to modify the release of a drug, to mask an unpleasant



taste, or to improve the stability of a formulation. Ethyl cellulose, dissolved in an

organic solvent or solvent mixture, can be used on its own to produce water-insoluble

films. Higher-viscosity ethyl cellulose grades tend to produce stronger and more

durable films.

Ethyl cellulose films may be modified to alter their solubility, by the addition of

hypromellose or a plasticizer.

Ethyl cellulose has also been used as an agent for delivering therapeutics agents from

oral appliances.

In topical formulations, ethyl cellulose is used as a thickening agent in creams,

lotions, or gels, provided an appropriate solvent is used.

Description

Ethyl cellulose is a tasteless, free-flowing, white to light tan-coloured powder.

Typical Properties

Density (Bulk): 0.4 g/cm3

Moisture content: ethyl cellulose absorbs very little water from humid air or during

immersion, and that small amount evaporates readily.

Solubility: ethyl cellulose is practically insoluble in water, propylene glycol, and

glycerin.

Ethyl cellulose that contains less than 46.5% of ethoxyl groups is freely soluble in

chloroform, methyl acetate, and tetrahydrofuran, and in mixtures of aromatic

hydrocarbons with ethanol (95%).

Specific Gravity: 1.12-1.15 g/cm3

Viscosity: the viscosity of ethyl cellulose is measured typically at 25°C using 5%v/v

ethyl cellulose dissolved in a solvent blend of 80% toluene: 20% ethanol. The

Viscosity of an ethyl



cellulose solution increases with an increase in ethyl cellulose concentration; e.g., the

viscosity of a 5% w/v solution of Ethocel standard 10 premiums is 9 – 11 mPa s. In

addition, no pharmaceutical grades of ethyl cellulose that differ in their ethoxyl

content and degree of polymerization are available.

Stability and Storage Conditions

Ethyl cellulose is a stable, slightly hygroscopic material. It is chemically resistant to

alkalis, both dilute and concentrated, and to salt solutions, although it is more

sensitive to acidic materials than are cellulose esters.

Ethyl cellulose should be stored at a temperature not exceeding 32°C in a dry area

from all sources of heat. It should not be stored next to peroxides or other oxidizing

agents.



Poly Vinyl Pyrrolidone

Nonproprietary Names:

BP: povidone

JP: povidone

PhEur: polyvidonum

USP: povidone

Synonyms:

E1201:kollidon; plasdone; poly[1-(2-oxo-1-poyrrolidinyl)ethylene];

Polyvidone; polyvinyl pyrrolidone;PVP; 1-vinyl 2-pyrrolidinone polymers.

Chemical Name: 1-ethenyl-2-pyrrolidinone homopolymer

Empirical Formula: (c6H9NO)n

Molecular Weight: 2500-3000000

Functional Category:

Disintegrant; dissolution aid; suspending agent; tablet binder.

Description:

Povidone occurs as a fine, white to creamy-white colored, and almost odorless,

hygroscopic powder. Povidone with K – values equal to (or) lower than 30 are

manufactured by spray-drying and exist as spheres. Povidone with K-90 and higher

K-values povidones are manufactured by drum drying and exist as plates.

Typical properties:

Acidity/alkalinity : pH=3.0-7.0(s%w/v aqueous solution)

Denstiy(bulk) : 0.409g/cm3

Density(tapped) : 0.508g/cm3

Density(true) : 1.180g/cm3



Flow ability: 20g/s for povidone k-15,

16g/s for povidone k-29/32,

Melting point: softens at 150 ºc

Moisture content: povidone is very hygroscopic, significant amounts of moisture

being absorbed at low relative humilities.

Particle size distribution:

Kollidon 25/30:90% >50um, 50% >100um,

5% > 200um; kollidon 90: 90 % >200um, 95% >250um.

Solubility:

Freely soluble in acids, chloroform, ethanol(95%), ketones, methanol and water;

practically insoluble in ether, hydrocarbons and mineral oil. In water, the

concentration of solution is limited Only by the viscosity of the resulting solution,

which is a function of the K value.

Viscosity (dynamic):The viscosity of aqueous povidone solution depends on both the

concentration and the molecular weight of the polymer employed.

Stability and storage conditions:

Povidone darkens to some extend on heating at 150 c, with a reduction in aqueous

solubility. It is stable to a short cycle of heat exposure around 110-130 c; steam

sterilization of an aqueous solution does not alter its properties. Aqueous solution are

susceptible to mold growth and consequently require the addition of suitable

preservatives.

Povidone may be stored under ordinary conditions without undergoing

decomposition or degradation. However, since the powder is hygroscopic, it should be

stored in an airtight container in a cool and dry place.



Incompatibilities:

Povidone is compatible in solution with a wide range of inorganic salts, natural and

synthetic resins and other chemicals. It forms molecular adduct in solution with

sulfathiazole, sodium salicylate, salicylic acid, Phenobarbital, tannin and other

compounds.

Safety: Povidone is widely used as a excipient, particularly in oral tablets and

solutions. When consumed orally, povidone may be regarded as essentially nontoxic

since it is not absorbed from the gastrointestinal tract or mucous membranes.

Povidone additionally has no irritant effect on the skin and cause no sensitization.

Comments: the molecular adduct formation properties of povidone may be used

advantageously in solution, slow – release solid-dosage forms, and parenteral

formulation. Perhaps the best-known example of povidone complex formation is

povidone-iodine, which is used as topical disinfectant.

Application in pharmaceutical formulation or technology:

• In tableting, pvp solutions are used as binder in wet-granulation processes.

• It is used as a solubilizer in oral and parenteral formulation and has been

shown to enhance dissolution of poorly soluble drugs from solid-dosage

forms.

• It may also be used as coating agent.

• It is usedas suspending, stabilizing or viscocity-increasing agent in a number

of topical and oral suspension and solution.

Used as: carrier for drug (10-25%)

Dispersing agent (5%)

Eye drops (2-10%)

Suspending agent (5%)



Polymethacrylates:

Synonyms: Eudragit

Functional category:

Film former, binder

Chemical names:

Copolymers synthesized from dimethylaminoethyl methacrylate and other neutral

methacrylate esters.

CAS registry number: none

Molecular weight: ≥ 100,000

Description:

Eudragit RL is a co-polymer of acrylic and methacrylic acid esters containing

ammonium groups, available as 12.5% ready to use solution in isopropanol and

acetone (60:40). Colorless, clear to cloudy granules with a faint amine like odour.

Density:

12.5;0.825 g/cm3

Solubility:

Soluble in isopropanol and ethanol in combination with acetone or

methacrylate chloride, also in methanol, chloroform and glycerol monethyl ether.

Insoluble in petroleum ether or light petroleum.

Viscosity:

5 to 15 cps.

Stability and storage conditions:

Dry powder forms appear to be stable at room temperature. Dispersions are

stable for about 1 year after manufacturing and stored at room temperature in tight

containers.



Incompatibilities:

Incompatibilities occur with acid and/or alkaline conditions depending upon

which polymer is being used.

Applications:

Binder –Eudragit E (concentration between 5 and 20%)

Film former: Eudragit forms water insoluble film coats for delayed release products.



Polyvinyl alcohol


PhEur: Poly(vinylis acetas)

USP: Polyvinyl alcohol

Synonyms

Airvol; Alcotex; Elvanol; Gelvatol; Gohsenol; Lemol; Mowiol; Polyvinol; PVA;

vinyl alcohol polymer.

Chemical Name and CAS Registry Number

Ethenol, homopolymer [9002-89-5]

Empirical Formula and Molecular Weight

(C2H4O)n, 20 000–200 000.

Structural Formula

Functional Category

Coating agent; lubricant; stabilizing agent; viscosity-increasing agent.


Polyvinyl alcohol is used primarily in topical pharmaceutical and ophthalmic

formulations.

Use Concentration (%)

Emulsions 0.5

Ophthalmic formulations 0.25–3.00

Topical lotions 2.5



Description

Polyvinyl alcohol occurs as an odorless, white to cream-colored granular powder.

Typical Properties

Melting point:

228°C for fully hydrolyzed grades;

180–190°C for partially hydrolyzed grades.

Solubility:

Soluble in water; slightly soluble in ethanol (95%); insoluble in organic solvents.

Dissolution requires dispersion (wetting) of the solid in water at room temperature

followed by heating the mixture to about 90°C for approximately 5 minutes. Mixing

should be continued while the heated solution is cooled to room temperature.

Stability and Storage Conditions

Polyvinyl alcohol is stable when stored in a tightly sealed container in a cool, dry

place. Aqueous solutions are stable in corrosion-resistant sealed containers.

Preservatives may be added to the solution if extended storage is required. Polyvinyl

alcohol undergoes slow degradation at 100°C and rapid degradation at 200°C; it is

stable on exposure to light.

Incompatibilities

Polyvinyl alcohol undergoes reactions typical of a compound with secondary hydroxy

groups, such as esterification. It decomposes in strong acids, and softens or dissolves

in weak acids and alkalis. It is incompatible at high concentration with inorganic salts,

especially sulfates and phosphates; precipitation of polyvinyl alcohol 5% w/v can be

caused by phosphates. Gelling of polyvinyl alcohol solution may occur if borax is

present.



Plasticizer review

Di butyl phthalate24

Synonyms: butyl phthalate; DBP

Structure:

Chemical name:

Dibutyl benzene 1,2-dicarboxylate

Empirical formulation: C16H22O4

Molecular weight: 278.3

Description: A clear, colorless some what viscous

Density: 1.045 g/cm3 at 20c

Boiling point: 3300

Refractive index: 1.492-1.495

Solubility: very soluble in ethanol, ether acetone, benzene, miscible with ethanol

ether and most other organic solvents.



Propylene Glycol


BP: Propylene Glycol

JP: Propylene Glycol

PhEur: PropylenGlycolum

USP: Propylene Glycol

Synonyms

1,2 –Dihydroxypropane; E1520; 2-hydroxypropranol; methyl ethylene glycol;

propane-1, 2-diol.

Chemical Name and CAS Registry Number

1,2- propanediol [57-55-6]

(-)-1,2- propanediol [4254-14-2]

(+)-1,2- propanediol [4254-15-3]

Empirical Formula:C3 H8 O2

Molecular Weight: 76.08

Structure:

Functional Category

Antimicrobial preservatives; disinfectant; humectant; plactisizer; solvent; stabilizer

for vitamins; water-miscible co-solvent.




Propylene Glycol has become widely used as solvent, extractant, and preservative in a

variety of parenteral pharmaceutical formulations. It is a better solvent than glycerin

and dissolves a wide variety of materials, such as corticosteroids, phenols, sulfa drugs,

barbiturates, vitamins (A and D), mostly alkaloids, and many local anesthetics. As an

antiseptic it is similar to ethanol, and against molds it is similar to glycerin and only

slightly less effective than ethanol. Propylene Glycol is commonly used as a

plasticizer in aqueous film-coating formulations. Propylene Glycol is also used in

cosmetics and in the food industry as a carrier for emulsifiers and as a vehicle for

flavors in preference to ethanol, since its lack of volatility provides a more uniform

flavor.

Description

Propylene glycol is a clear, colorless, viscous, practically odorless liquid with a sweet,

slightly acrid taste resembling that of glycerin.

Typical Properties:

Boiling point: 188°C

Density: 1.038 g/cm3 at 20°C

Melting point: -59°C

Osmolarity: a 2.0%v/v aqueous solution is iso-osmotic with serum.

Refractive index: 1.4324

Solubility: miscible with acetone, chloroform, ethanol (95%), glycerin, and water;

soluble at 1 in 6 parts of ether; not miscible with light mineral oil or fixed oils, but

will dissolve some essential oils.

Viscosity (dynamic): 58.1-mPa s (58.1 CP) at 20°C.



Stability and Storage Conditions:

At cool temperatures, propylene glycol is stable in a well-closed container, but at high

temperatures, in the open, it tends to oxidize, giving rise to products such as

propionaldehyde, lactic acid, pyruvic acid, and acetic acid. Propylene glycol is

chemically stable when mixed with ethanol (95%), glycerin, or water; aqueous

solutions may be protected from light, in a cool, dry place. Sterilized by autoclaving.

Propylene glycol is hygroscopic and should be stored in a well-closed container.



Permeation enhancers Oleic acid25 Synonyms: (9Z)-octadecenoic acid Structure:

CAS number: 112-80-1 Empirical formula: C18H34O2 Appearance formulation: pale yellow or oily liquid with lard-like odor Density: 0.895 g/ mL Boling point: 3600c Solubility: soluble in methanol, chloroform, insoluble in water. Uses:

Oleic acid may hinder the progression of ALD, or adrenoleukodystrophy, a fatal

disease that affects the brain and adrenal glands.

Oleic acid is also the most abundant fatty acid in human adipose tissue.



Review of work done on Drug

Gattani SG et al. formulated transdermal films of ondansetron HCl by using

different hydrophilic and lipophilic polymers. In vitro results obtained showed that

hydrophilic polymers had higher release than the lipophilic and hydrophilic-lipophilic

combinations. Permeation enhancers like oleic acid, limonene were found to give

favorable permeation enhancement26.

H.S. Gwak, I.S. Oh and I.K. Chun found feasibility of developing an

Ondansetron transdermal system using Duro-Tak 87-2100 and Duro-Tak 87-2196 as

pressure sensitive adhesives (PSA). Effect of vehicles, propylene glycol

monocaprylate (PGMC)-diethylene glycol monoethyl ether (DGME)-propylene

glycol (PG) cosolvents with 3% oleic acid, was studied & found that DGME in

PGMC-DGME cosolvent system decreased release rate as its concentration was

increased. Also as amount of PSAs increased, the permeation flux was decreased.

Overall fluxes from PSAs were significantly lower compared to those obtained

from solution formulations. Lag time decreased significantly from 5.14 ± 3.31 hr to

0.31 ± 0.12 hr as PG increased from 40% to 60%27.

H.S. Gwak, I.S. Oh and I.K. Chun studied effect of vehicles and penetration

enhancers on transdermal delivery of Ondansetron across dorsal hairless mouse skin.

Among vehicles used, water and ethanol showed high permeation fluxes as 48.2 ±

23.7 & 41.9 ± 17.9 µg/cm2/hr. respectively. The highest flux was achieved at 40% of

DGME combinations with PGMC & ethanol (80:20) and PGMC & PG (60:40)

increased permeation by six- & two-fold respectively, compared to PGMC alone28.



Review of work done on Polymers

Calpena A C, Blanes C, Moreno J, Obach R, Domenech J studied comparative

in vitro study of transdermal absorption of antiemetics that was used in treatment of

nauseas and their use in patients receiving oncogenic treatment with chemotherapy.

They studied permeation parameters of antiemetics in order to predict their potential

therapeutic formulation in TDD29.

Agrawal SS et al. developed matrix type transdermal patches of atenolol and

metoprolol using polymers like polyvinyl pyrrolidone, cellulose acetate phthalate,

hydroxyl propyl methyl cellulose. The results obtained showed drug release from the

formulation containing PVP and HPMC was for 48 hour and it caused no irritation on

the skin30.

Sankar V et al. investigated ethyl cellulose films for the permeation of the

nifedipine drug through the film by using castor oil and glycerol as the plasticizers. It

was found that the drug release from the patches containing the glycerol as the

plasticizer was more than that from the one containing castor oil31.

Gattani SG et al. investigated transdermal films of chlorpheniramine maleate

using different polymer combinations and concluded that hydrophilic polymer

showed higher release than the lipophilic and hydrophilic-lipophilic combination32.

Manvi FV et al. Formulated transdermal films of ketotifen fumarate using

combination of eudragit L100: hydroxypropylmethylcellulose and ethyl cellulose:

hydroxypropylmethylcellulose as polymers along with permeation enhancers such as

ethyl sulfoxide and propylene glycol. Polyethylene glycol was used as a plasticizer. It

was found that there was decrease in drug release rate from EL100:HPMC films in

comparison to EC:HPMC was found, due to the hydrophobic nature of the polymer33.



Saxena M et al. prepared transdermal patches of metoclopramide

hydrochloride using polyvinyl alcohol and polyvinylpyrrolidone. The combination of

PVA:PVP in the ratio 1:4 containing 20 mg of drug showed the required sustained

release effect34.

Ubaidulla U et al. developed a matrix-type transdermal therapeutic system

containing carvedilol with different ratios of hydrophilic and hydrophobic polymeric

combinations by the solvent evaporation technique and reported that the developed

transdermal patches increased the efficacy of carvedilol for the therapy of

hypertension by using different polymer ratios35.

Chapter 4 Methodology


METHODOLOGY

Materials:

The following materials of Pharma grade or the best possible Laboratory

Reagent were used as supplied by the manufacturer.

Table 3: List of chemicals used with grade and supplier

Sr.

No.

Materials Used Grade Manufacturer

1. Ondansetron Hcl Pharma Grade Sun rise Pharma

2. Polyvinyl Pyrrolidone LR Hi-media pharma

3. Ethyl Cellulose Pharma Grade Colorcon Goa

4. Eudragit LR Evonik Pharma

Germany

5. Chloroform LR Merck Ltd., Mumbai

6. Oleic acid LR Ranbaxy fine chemicals

Ltd., New Delhi.

7. Dibutyl Phthalate LR

Ranbaxy Fine

Chemicals Ltd., New

Delhi.

8. Methanol LR Rankem, fine chemicals

Limited, Mumbai

9. Poly Vinyl Alcohol LR Hi-media pharma



Table 4: List of Instruments used

Sr.

No.

Instrument Manufacturer

1. Double beam UV Visible Spectrometer Shimadzu Corporation,

Japan.

2. FTIR 200 Spectrometer Spectrum one, Perkin

Elmer, USA.

3. Magnetic Stirrer 2MLH Remi Equipments,

Mumbai, India.

4. Keshry diffusion cell

Bhanu Scientific

Instruments Co.,

Bangalore.

5. Electronic Balance Petit

6. Distillation Assembly Bhanu scientific

Instruments Co., Bangalore



METHODS:

Preformulation studies:

Preformulation testing is the first step in the rationale development of dosage

forms of a drug. It can be defined as an investigation of physical and chemical

properties of drug substance, alone and when in combined with excipients. The

overall objective of the preformulation testing is to generate information useful to the

formulator in developing stable and bio availability dosage forms which can be mass

produced.

The goals of preformulation studies are:

• To establish the necessary physicochemical characteristics of a new drug

substance.

• To determine it’s kinetic release rate profile.

• To establish it’s compatibility with different excipients.

Hence, preformulation studies on the obtained sample of drug include colour,

taste, solubility analysis, melting point determination and compatibility studies.

Characterization of Ondansetron Hydrochloride:

A. Melting point determination:

The melting point of Ondansetron hydrochloride was determined by using melting

point apparatus.

B. Spectroscopic studies:

a. IR spectrum interpretation:

The infrared spectrum of the pure Ondansetron Hydrochloride sample was recorded

and the spectral analysis was done. The dry sample of drug was directly placed after

mixing and triturating with dry potassium bromide.



b. UV spectroscopy36:

I. Determination of λmax

A 10mg of Ondansetron Hydrochloride was accurately weighed and was first

dissolved in 35ml methanol solution. The solution was then diluted using phosphate

buffer (pH- 7.4) to 100 ml. UV spectrum was recorded in the wavelength range 200-

600 nm.

II. Preparation of calibration curve for Ondansetron hydrochloride

A standard curve was prepared by dissolving 10 mg of Ondansetron hydrochloride in

50ml of methanol. It was further diluted with phosphate buffer pH – 7.4 to

get solutions in concentration range of 4 to 16 µg /ml. The absorbances of these

solutions were determined spectrophotometrically at 305 nm.

C. Determination of solubility of ondansetron hydrochloride37

The ondansetron hydrochloride has very low aqueous solubility. Its solubility is not

reported in any official book, so determination of solubility is important. The

solubility was determined in distilled water and phosphate buffer pH 7.4. The

procedure can be detailed as follows.

Saturated solution of o

Ondansetron hydrochloride prepared using 10 ml. of distilled water/ phosphate buffer

pH 7.4 in 25 ml volumetric flasks in triplicate. Precaution was taken so that the drug

remains in medium in excess. Then by using mechanical shaker, the flasks were

shaken for 48 hours. The sampling was done on 24th & 48th hour. The sample

withdrawn (1 ml after filtration) was diluted with appropriate medium and analyzed

by using UV spectrophotometer at 305 nm and 303.5 nm for phosphate buffer and

distilled water respectively.



FORMULATION OF TRANSDERMAL PATCHES34, 35

Preparation of blank patches:

Polymers of single or in combination were accurately weighed and dissolved in

respective solvent and then casted in a Petri-dish with mercury as the plain surface.

The films were allowed to dry overnight at room temperature.

Formulation of Drug Incorporated Transdermal Patches:

The matrix-type transdermal patches containing Ondansetron Hcl were prepared using

different ratios of ethyl cellulose, Polyvinyl pryrrolidone, Eudragit and polyvinyl

alcohol. The polymers in different ratios were dissolved in the respective solvents.

Then the drug was added slowly in the polymeric solution and stirred on the magnetic

stirrer to obtain a uniform solution. Di-n-butyl phthalate and propylene glycol were

used as plasticizers. Oleic acid was used as the penetration enhancer. Then the

solution was poured on the Petri dish having surface area of 78.5 cm2 and dried at the

room temperature. Then the patches were cut into 2x2 cm2 patches. Drug incorporated

for each 2x2 cm2 patch was 14.5 mg. the formulation table is given in table no. 5.

Table 5: Formulation table of Ondansetron Hcl Patches

Formulation Polymer

PVA:PVP

Polymer

RLPM:RSPM

Polymer

EC:PVP

Plasticizer Oleic

acid

Solvent

OND-1 5:5 - - PG (10%) 10% Water

OND-2 3:7 - - PG (10%) 10% Water

OND-3 - 5:5 - DBP

(5%)

10% Acetone

OND-4 - 7:3 - DBP

(5%)

10% Acetone

OND-5 - - 8:2 DBP

(5%)

10% Chloroform

OND-6 - - 5:5 DBP

(5%)

10% Chloroform



D. Evaluations of films

a. Physical evaluations

1. Thickness39

The thickness of films was measured by digital Vernier calipers with least count

0.001mm. The thickness uniformity was measured at five different sites and average

of five readings was taken with standard deviation.

2. Moisture uptake35

The percent moisture absorption test was carried out to check the physical

stability and integrity of the films at high humid conditions. In the present study the

moisture absorption capacities of the films were determined in the following manner.

The films were placed in the dessicator containing saturated solution of

aluminium chloride, keeping the humidity inside the dessicator at 79.5 % R.H. After 3

days the films were taken and weighed the percentage moisture absorption of the

films was found.

3. Tensile Strength40

The tensile strength was determined by the apparatus designed as shown in fig 13 .

The instrument was designed such that it had horizontal wooden platform with fixed

scale and attachments for two clips that holds transdermal patch under test. Out of the

two clips one was fixed and other was movable. Weights were hanged to one end of

pulley and the other end of pulley was attached with movable clip. The wooden

platform was such fitted that it would not dislocate while the test is running. Three

strips of patch were cut having 2cm length and 2cm breadth. The thickness and

breadth of strips were noted at three sites and average value was taken for calculation.

The rate of change of stress was kept constant with the increment of 0.5g per 2



minutes. The elongation was observed and the total weights taken were used for

calculation. The tensile strength was calculated by using following formula.

where, S = tensile stress in 980 dynes/cm2

m = mass in grams

g = acceleration due to gravity (980 dynes/cm2)

b = breadth of strip in centimeters

t = thickness of strip in centimeters

The strain is change resulting in size of strip after the force was applied to its original

size. Therefore, the strain can be given as,

Where, L = length after force was applied

L0 = original length



Figure 12: Assembly for % elongation

4. Percent elongation

The percent elongation at break was measured by formula given below.

where, L = length after force was applied

L0 = original length

5. Folding endurance41

Using an apparatus designed in laboratory, folding endurance test for films was

performed. The disintegration apparatus was modified as a folding endurance

apparatus. The apparatus consists of two clamps for holding the film. Out of two

clamps, one clamp was fixed while other was moving. The clamps were able to move

5cm distance from each other at speed of 30 rpm. The film was attached in such a way



that when clamps were at maximum distance the film will be slightly stretched. The

apparatus was put on and allowed to run until film broke into two pieces. The foldings

were counted by rpm.

6. Drug content42

The patch of area 2x2 cm2 was cut and dissolved in distilled water. Then solvent

ethanol and dichloromethane, to make polymer soluble, were added to the mixture

and the remaining volume was made up with distilled water to 100ml in 100ml

volumetric flask. Then 1 ml was withdrawn from the solution and diluted to 10ml.

The absorbance of the solution was taken at 303.5nm and concentration was

calculated. By correcting dilution factor, the drug content was calculated.

7. Weight variation34

The three disks of 2*2 cm2was cut and weighed on electronic balance for weight

variation test. The test was done to check the uniformity of weight and thus check the

batch- to- batch variation.

D. Diffusion studies43

Preparation of skin

A full thickness of skin was excised from dorsal site of dead rat and skin was washed

with water. The fatty tissue layer was removed by using nails of fingers. The outer

portion with hairs was applied with depilatory and allowed to dry. With the help of

wet cotton the hairs were scrubbed and washed with normal saline solution. The skin

was kept in normal saline solution in refrigerator until skin was used for diffusion

study. Prior to use, the skin was allowed to equilibrate with room temperature. Then

skin was mounted between donor and receptor compartment of cell. The skin was

clamped in such a way that the dermal side will be in contact with receptor medium.



Diffusion cell

The diffusion studies were done to get an idea of permeation of drug through barrier

from the transdermal system. In vitro studies are also done for TDDS development.

Usually, two types of diffusion cells are used as horizontal and vertical. The Franz

and Keshary Chien (K-C) type of diffusion cells are of horizontal type of cells. In this

work, K-C type of diffusion cell was used.

Diffusion cells generally comprise two compartments, one containing the active

Compartment (donor compartment) and the other containing receptor solution

(receptor compartment), separated by barrier i.e. rat abdominal skin. The cell

consisted of sampling port and temperature maintaining jacket. The outlet and inlet

was connected with latex tube so the jacket had stagnant water inside and heat was

provided by hot plate. The stainless steel pin was used to stir the receptor solution

using magnetic stirrer. The rat abdominal skin was placed on receptor compartment

and both compartments held tight by clamps.

Figure 13: Kesary Chein diffusion cell



Method

Phosphate buffer pH 7.4 was used as receptor solution. The volume of diffusion cell

was 10 ml and stirred with bent stainless steel pin. The temperature was maintained at

37 ± 1°C with the help of hot plate. The diffusion was carried out for 10 hours and 1

ml sample was withdrawn at an interval of 1 hour. The same volume of phosphate

buffer pH 7.4 was added to receptor compartment to maintain sink conditions and the

samples were analyzed at 305.5nm. Other designs of diffusion cells that are in

existence include Valia-Chien (V-C) cell, Ghannam-Chien (G-C) cell, Jhawer-Lord

(J-L) Rotating disc system, etc.

Chapter 5 Results and Discussion


RESULTS AND DISCUSSION

Six formulations of Ondansetron HCl transdermal patches were formulated

using different polymer ratios, the composition of which is shown in table 5. The

prepared formulations are shown in figure. the formulations are subjected to

evaluation parameters like thickness, drug content, folding endurance, tensile

strength, % elongation, % moisture absorption, IR studies, ex-vivo permeation

studies.

A. Preformulation studies

a. Melting point determination:

The melting points were found to be in the range of 178° to 179°C.

The reported melting point is 178.5° to 179.5°C.

b. Spectroscopic Studies:

1. The spectra showed no incompatibility between the polymer and

Ondansetron HCl drug. The spectra of the formulation F1 and the pure

drug is given in the spectra 1 and 2 respectively.

2. Determination of λmax

The spectrum obtained is shown in the figure 14. The peak showed in the

figure is much similar to the reported peak.

3. Calibration curve of Ondansetron HCl

The absorbance values obtained, are shown in table 6. Using concentration

and absorbance data, a beer and lambert’s plot was obtained. The plot is

given the figure 15.



c. Solubility determination

The solubility of ondansetron hydrochloride was determined and found very less as

78.94 µg/ml in phosphate buffer. The solubility in distilled water was found more

than that in phosphate buffer. The solubility data was shown in table 7.

B. Physical evaluation:

1. Thickness:

The thickness of the films varied from 0.025 to 0.048 mm. The values obtained for

all the formulations is given in the table 8.

2. Moisture uptake:

The formulation OND 5 (EC:PVP 8:2) showed lowest percent moisture absorption

than other formulations. This might be because of the low water permeability of

ethyl cellulose polymer. The values for the moisture uptake has been given in the

table 8.

3. Tensile strength:

The tensile strength was found to be in the range of 0.75 to 0.58. The formulation

OND 1 showed the best tensile strength. The values for all the patches is

tabulated in the table 8.

4. % Elongation:

The % elongation was found to be in the range of. The formulation OND 1

showed minimum % elongation among all the other patches 15.25 to 30.5 %. The

results obtained for all the formulations is tabulated in the table 8.

5. Folding Endurance:

The folding endurance was found to be in the range of 72 ± 1 to 79 ± 2. The

values for all six formulations is given in the table. This data revealed that the

patches had good mechanical strength along with flexibility 8.



6. Weight variation:

The weight variation was to be in the range of 65.24 ± 1.2 to 67.05 ± 1.8. The

values for all the formulations is tabulated in the table 8.

7. Drug content:

The drug content was in the range of 92.41 to 95.9 %. The values are given in the

table 8.

C. Diffusion study:

The rat skin was used to carry out the study. The formulation OND 1 (PVA:PVP

; 5:5) showed drug diffusion for 10 hours upto 76.69 %. The % drug diffusion

for six formulations is given in the table 9, 10, 11, 12, 13 and14 along with the

Higuchi’s plot. The regression for Higuhi’s plot for all the formulations is given

in table 15. The plot for the diffusion study for all the formulations is given in the

figures 16, 17, 18, 19, 20 and 21 respectively.

The Higuchi’s plot for all the formulations is given in the figures 22, 23, 24, 25,

26 and 27 respectively.



Table 6: Standard calibration curve of Ondansetron HCl

Sr. No. Concentration (µg/ml) Absorbance

1 0 0

2 4 0.277

3 6 0.361

4 8 0.482

5 10 0.58

6 12 0.6

7 14 0.823

8 16 0.928

Table 7: Solubility data for Ondansetron HCl

Solubility medium Time duration Solubility (µg/ml)

Distilled water

24 hours 55.03 ± 4.25

48 hours 76.94 ± 0.93

Buffer pH 7.4

24 hours 78.5 ± 1.48

48 hours 93.13 ± 1.89


Dep

t of P

harm

aceu

tics

, KLE

Uni

vers

ity,

Bel

gaum

6

8

Tab

le 8

: Phy

sico

chem

ical

eva

luat

ion

data

of O

ndan

setr

on H

Cl T

rans

derm

al p

atch

es

For

mul

atio

n

code

Thi

ckne

ss

(mm

)

± SD

Wei

ght

vari

atio

n

(mg)

± SD

% d

rug

cont

ent

± SD

Fol

ding

endu

ranc

e

± SD

Ten

sile

stre

ngth

% e

long

atio

n

% m

oist

ure

abso

rpti

on

OND 1

0.036 ± 1.2

65.24 ± 1.2

92.41 ± 0.1

78 ± 2

0.75

15.25 %

4.5 %

OND 2

0.032 ± 1.5

62.50 ± 1.8

94.28 ± 0.5

76 ±1

0.73

20.54 %

4.8 %

OND 3

0.045 ± 1.8

67.05 ± 1.8

95.03 ± 0.2

79 ± 2

0.68

22.89 %

5.07 %

OND 4

0.048 ± 1.3

66.55 ±1.8

95.9 ± 0.4

77 ± 1

0.70

23.86 %

5.18 %

OND 5

0.025 ± 1.4

66.89 ±1.9

93.66 ± 0.5

72 ± 1

0.61

30.5 %

3.5 %

OND 6

0.029 ± 1.6

65.05 ±1.6

94.16 ± 0.6

71 ± 0.9

0.58

29.56 %

3.9 %



Table 9: Ex-vivo diffusion study of OND 1

Ex-vivo drug diffusion Higuchi’s plot

Time (h) % CDR Square root of

time

% CDR

1 15.46 1 15.46

2 21.10 1.41 21.10

3 28.10 1.73 28.10

4 34.02 2 34.02

5 39.85 2.23 39.85

6 47.21 2.44 47.21

7 57.23 2.64 57.23

8 64.04 2.82 64.04

9 69.71 3 69.71

10 76.69 3.16 76.69






time

% CDR

1 12.70 1 12.70

2 17.74 1.41 17.74

3 22.88 1.73 22.88

4 29.18 2 29.18

5 33.99 2.23 33.99

6 41.40 2.44 41.40

7 47.78 2.64 47.78

8 54.20 2.82 54.20

9 60.21 3 60.21

10 65.52 3.16 65.52






time

% CDR

1 8.74 1 8.74

2 12.11 1.41 12.11

3 15.07 1.73 15.07

4 19.88 2 19.88

5 23.96 2.23 23.96

6 27.24 2.44 27.24

7 32.74 2.64 32.74

8 36.90 2.82 36.90

9 40.57 3 40.57

10 47.40 3.16 47.40






time

% CDR

1 8.40 1 8.40

2 11.76 1.41 11.76

3 14.55 1.73 14.55

4 18.92 2 18.92

5 23.17 2.23 23.17

6 26.78 2.44 26.78

7 30.95 2.64 30.95

8 36.13 2.82 36.13

9 40.65 3 40.65

10 46.46 3.16 46.46






time

% CDR

1 10.53 1 10.53

2 13.24 1.41 13.24

3 16.46 1.73 16.46

4 19.88 2 19.88

5 23.89 2.23 23.89

6 28.67 2.44 28.67

7 34.35 2.64 34.35

8 40.24 2.82 40.24

9 46.34 3 46.34

10 52.69 3.16 52.69






time

% CDR

1 11.20 1 11.20

2 13.91 1.41 13.91

3 16.71 1.73 16.71

4 20.34 2 20.34

5 24.50 2.23 24.50

6 28.17 2.44 28.17

7 33.37 2.64 33.37

8 39.46 2.82 39.46

9 45.85 3 45.85

10 51.13 3.16 51.13



Table 15: Data for regression

Formulation code Regression for Higuchi’s plot

OND 1 0.983

OND 2 0.984

OND 3 0.977

OND 4 0.975

OND 5 0.960

OND 6 0.960



Figure 14: UV spectrum for Ondanstron HCl

Figure 15: Calibration curve of Ondansetron HCl



Figure 16: Ex vivo diffusion study of OND F1




Figure 22: Higuchi’s plot for OND 1




Plate 1: Formulated Ondansetron HCl patches

F1 F2

F3 F4

F5 F6

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Chapter 6 Conclusion


CONCLUSION

• Ondansetron HCl, an anti-emetic drug has been selected which has half-life of 5-6

hrs, the drug undergoes first pass metabolism. Hence in the present work, an

attempt has been made to provide transdermal drug delivery using water soluble

and water insoluble polymers with Ondansetron HCl as the model drug.

• IR study shows that there is no incompatibility between drug and polymers.

• The transdermal patches were prepared using solvent casting method using

combination of EC, PVP, PVA and Eudragit in various ratios using Dibutyl

phthalate and propylene glycol as plasticizers and oleic acid as a permeation

enhancer.

• The formulation OND 1 (PVA:PVP ; 5:5) shows optimum difusion in

concentration independent manner. The above formulation gave a maximum drug

diffusion of 76.69% over a period of 10 hours.

• Higuchi’s plot for the formulation revealed that the predominant mechanism of

drug release is diffusion. However; from Peppa’s plot the n value for OND F1

was found to be 0.721, thus indicating non-fickian diffusion.

As an extension of this work pharmacokinetic studies, in-vivo studies on higher

animals and controlled clinical studies on human beings can be carried out in

future.

Chapter 7 Summary

Dept Of Pharmaceutics, KLE University, Belgaum 87

SUMMARY

Ø In this work an attempt was made to formulate and evaluate TDDS for sustained

release Ondansetron HCl by solvent casting method. Low molecular weight, good

permeability and shorter half-life of Ondansetron HCl made it a suitable drug

candidate for the development of transdermal patches.

Ø The main objective of formulating the transdermal system was to prolong the drug

release time, reduce the frequency of administration and to improve patient

compliance. The compatibility parameters characterization was done by IR

method.

Ø Six formulations were prepared using different polymers in different ratios and

combinations, along with plasticizers and penetration enhancer.

Ø Mercury was used as a substrate for pouring the polymeric solution.

Ø The films were evaluated for uniformity of thickness, weight variation, drug

content, folding endurance, tensile strength, % elongation, % moisture absorption

and ex-vivo diffusion studies using kesary chein diffusion cell.

Ø The weight variation was found in the range of 65.24 to 67.05.

Ø Thickness variation was found to be between 0.025 to 0.048 mm.

Ø Tensile strength was found to be between 0.58 to 0.75 for 2 x 2 cm2 patches.

Ø The % moisture absorption for all the formulations was in the range of 3.9 to

5.18%.

Ø The formulation OND F1 showed the % moisture absorption of 4.5 %.

Ø The ex-vivo diffusion study was carried out in phosphate buffer pH 7.4 for 10

hours.

Chapter 7 Summary

Dept Of Pharmaceutics, KLE University, Belgaum 88

Ø Rat skin was used for the diffusion study.

Ø The formulation OND 1 showed the best diffusion through the skin.

Ø It showed the diffusion of 76.69%.

Ø The formulations followed the Higuchi’s model for the drug diffusion study.

Ø Since the formulations follow Higuchi’s model, thus they indicate diffusion

mechanism.

Ø The peppa’s plot showed the n value of 0.721 for formulation OND F1, thus

indicating non-fickian diffusion.

Ø There is scope for the further study and development of the Ondansetron HCl

transdermal patches.

Chapter 8 Bibliography


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formulation and evaluation of anti emetic patch comprising on dan set ron hydro chloride

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