cdpceut00038

8/12/2019 CDPCEUT00038

1/156

i

STUDIES ON LECITHIN-MICROEMULSION BASEDORGANOGELS AS CARRIERS FOR TOPICAL

DELIVERY OF MICONAZOLE NITRATE

By

MD.MUQTADAR AHMEDReg. No. 04PU254

Dissertation Submitted to theRajiv Gandhi University of Health Sciences, Karnataka, Bangalore

In partial fulfillmentof the requirements for the degree of

MASTER OF PHARMACYin

PHARMACEUTICS

Under the Guidance of

Dr.MOHAMED HASSAN DEHGHANM.Pharm., Ph.D.

DEPARTMENT OF PHARMACEUTICSLUQMAN COLLEGE OF PHARMACY,

GULBARGA-585 102APRIL 2006

Create PDFfiles without this message by purchasing novaPDF printer (http://www.novapdf.com)
http://www.novapdf.com/http://www.novapdf.com/http://www.novapdf.com/http://www.novapdf.com/

8/12/2019 CDPCEUT00038

2/156

ii

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES,

KARNATAKA, BANGALORE

Declaration By The Candidate

I hereby declare that this dissertation/ thesis

entit led STUDIES ON LECITHIN-MICROEMULSION

BASED ORGANOGELS AS CARRIERS FOR TOPICAL

DELIVERY OF MICONAZOLE NITRATE i s a bonafi de

and genui ne research w ork carri ed out by me under t he

guidance of Dr.Mohamed Hassan Dehghan.

Date:

Place: GULBARGA MD.MUQTADAR AHMED


8/12/2019 CDPCEUT00038

3/156

iii

Certificate By The Guide

This is to cert i fy t hat t he dissert ati on ent it l ed

STUDIES ON LECITHIN-MICROEMULSION BASED

ORGANOGELS AS CARRIERS FOR TOPICAL

DELIVERY OF MICONAZOLE NITRATE i s a bonafi de

research w ork done by Mr.MD.MUQTADAR AHMED

i n part i al ful fi l lment of t he requirement for t he degree of

MASTER OF PHARMACY i n PHARMACEUTICS.

Date:

Place: GULBARGA Dr.M ohamed Hassan DehghanM.Pharm. Ph.D.

Hon. Research Guide


8/12/2019 CDPCEUT00038

4/156

iv

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES,

KARNATAKA, BANGALORE

ENDORSEMENT BY THE HOD, PRINCIPAL/HEAD OF THE INSTITUTION

This is to cert i fy t hat t he dissert ati on enti t l ed

STUDIES ON LECITHIN-MICROEMULSION BASED

ORGANOGELS AS CARRIERS FOR TOPICAL

DELIVERY OF MICONAZOLE NITRATE is a bonafide

research w ork done by Mr.MD.MUQTADAR AHMED under

t he guidance of DR.MOHAMED HASSAN DEHGHAN.

Date:

Place: GULBARGA Prof.Syed Sanaull ah

Principal,Luqman College of Pharmacy,

Gulbarga-585102


8/12/2019 CDPCEUT00038

5/156

v

COPYRIGHT

Declaration By The Candidate

I here by decl are t hat t he Raj i v Gandhi Uni versit y of

Health Sciences, Karnataka shall have the rights to

preserv e, use and di ssemi nat e t hi s dissert at i on/ t hesis i n

pri nt or el ect roni c format for academi c/ research purpose.

Date:

Place: GULBARGA Mr.MD.MUQTADAR AHMED

Raj i v Gandhi Uni versit y of H ealt h Sciences, Karnat aka


8/12/2019 CDPCEUT00038

6/156

vi

ACKNOWLEDGEMENT

I am especially deeply indebted to my honourable research guide

Dr.Mohammed Hassan Dehghan for the constant guidance,encouragement and support, which I have received from him whole-

heartedly. I substituted for the feeling of gratitude, indebtedness and

appreciation for him who brought me from darkness to lightness in my

life, which I would never forge Thank You Sir.

It is my privilege to express my heartfelt thanks to Prof.Syed Sanaullah,Principal, Luqman College of Pharmacy for allowing me to use all the

facilities of the college and support me like a pillar for constant

inspiration and guidance as environment required.

I am most thankful to Dr.Syed Rahmatullah, General Secretary,Vocational Education Society, Gulbarga for his silent encouragement.

My sincere thanks to Dr.Mujeeb and Mr.Abdul Majeed, President,Vocational Education Society, Gulbarga for providing me all the facilities.

I honestly acknowledge Prof.M.A.Saleem, Prof.S.S.Bushetti, Prof.Syeda

Humera, Prof.Divakar, Mr.M.H.Hugar, Mr.Jafar, Mr.Najmuddin,Prof.Satyanandam and Mr.Omar Khan and other teaching staff of

Luqman College of Pharmacy, Gulbarga for their timely encouragement

during my entire P.G. course.

A very special thanks to Mr.Zahid, Lecturer, Y.B.Chauhan College of

Pharmacy, Aurangabad.

My heartfelt gratitude and sincere thanks to my teachers Mr.RajeshPatwari, Mr.Shaikh Bahadur, Dr.Mazhar Farooqui and Mr.Sadat Ali

for their timely suggestions and perspective guidance in enriching my

knowledge.

I place on record a respectful thanks to Dr.M.G.Purohit, Department of

Pharmaceutical Chemistry, Gulbarga University, Gulbarga for his

guidance in my analytical work.

A special thanks to M/s.Adelphi A/c Sigma Labs, Goa for providing drug

sample of Miconazole Nitrate.

I also thanks Mr.Sridhar, Sipra Labs, Hyderabad for IR analytis of allformulations, the Librarians of NIN, O.U., IICT, Hyderabad for their kind

help during literature survey.


8/12/2019 CDPCEUT00038

7/156

vii

I could never forget (Mrs).Ayesha, (Mrs).Florence for the inspiration,

encouragement and moral support during the course of my studies.

It gives me immense pleasure to record my sincere thanks to my

colleagues and friends Abdul Muqtadir, Asif, Aleem, Vinod Singh,Taher, Imran, Anant Kulkarni, Nagashesha R, Mohan VK, Masood,Rizwan, Saleem, Mir Imran, Sajid, Ilyaz, Vijay, Imtiyaz, Manish KumarMital, Fazil, Shad, Noor, Shahid, Sarim, Abhisek, Wali, Areefulla H.forhelping me in carrying out this work.

It gives me immense pleasure to record my thanks to my seniors Faisal,

Azim, Riyaz, Ismail Mauzamfor their guidance during work.

I express my thnaks to non-teaching staffAsad, Pasha, Naveed, Narender,Hassan and Librarian Rubina Anjum and Pratibha for their help and

cooperation.

I am thankful to Micro Computers, Gulbarga for their cooperation during

the time of typing of this research work.

In closing I have reserved my special and most grateful thanks to one who

has not only initiated my interest in this work but has also led me through

the dark alley and abyssess to the brighten path. I am referring to none

other than my seniors Mr.Abdullah KhanandMr.Md.Jafarwho workedfor my success thank you.

The presence of the Almighty God was felt by me during my research

work. I am thankful to the Supreme energy for manifesting Himself

through the various helpful people, I came across in my life. I bow my

head to Him and ask for His blessings to be with me forever.

And above all words fails to express my feelings to my Parents and myFamily whose initiation, constant source of inspiration and

encouragement throughout my life.

Date:

Place: Gulbarga Md.Muqtadar Ahmed


8/12/2019 CDPCEUT00038

8/156

viii

LIST OF ABBREVIATIONS USED

..................... micro% .................... Percentage

BP................... British Pharmacopoeia

cm................... centimeter

CPs ................. centipoise

F127 ................. Pluronic

fig ................... figure

gm .................. gramhrs................... hour

ICH................. International Conference for Hormonization

IP.................... Indian Pharmacopoeia

IPM................. Isopropyl myristate

IR.................... infrared

Km.................. weight ratios

LOs................. Lecithin organogelsMBGs............ Microemulsion based organogels

mcg/g............ microgram(s)

mg .................. milligram(s)

min ................. minute(s)

ml ................... milliliter

mol-wt ............ Molecular weight

nm .................. nanometerNTU ............... Nephaloturbidity unit

PLO................ Pluronic lecithin organogels

rpm ................. Revolution per minute

sec .................. Second(s)


8/12/2019 CDPCEUT00038

9/156

ix

Sq-cm ............. Square centimeter

Std .................. Standard(s)

USP ................ United States Pharmacopoeia

UV.................. Ultraviolet

w/w................. Weight per weight

Wt................... Weight

P ..................... Penicillin chrysogenum

C..................... Candida albicans

A..................... Aspergillus niger

T ..................... AM1Formulation

F ..................... FM1Formulation

I ...................... SR1Formulation

P ..................... MN1Formulation

Mkd................ Marketed


8/12/2019 CDPCEUT00038

10/156

x

LIST OF FORMULATION CODE

AM1 .................... Lecithin 7.54%, tween-80 3.77%, isopropyl myristate 30.16%,

water 56.56%, miconazole nitrate 2%

AM2 .................... Lecithin 20.63%, tween-80 10.31%, isopropyl myristate 30.95%,water 36.11%, miconazole nitrate 2%



FM1 ..................... Lecithin 7.54%, isopropyl myristate 30.16%, pluronic 30% in

water 60.32, miconazole nitrate 2%

FM2 ..................... Lecithin 20.63%, isopropyl myristate 26.73%, pluronic 30% inwater 53.47%, miconazole nitrate 2%



SR1 ...................... Lecithin 8.9%, IPM 35.1%, water 53.5%, miconazole 2%




MN1 .................... Lecithin 13.43%, paraffin 53.78%, water 30.88%, miconazole 2%





8/12/2019 CDPCEUT00038

11/156

xi

ABSTRACT

In the present study lecithin-microemulsion based organogels were formulated as

topical carrier for miconazole nitrate, an antifungal drug practically insoluble in

water. The organogels were prepared by two different methods employing

lecithin, lecithin in combination with Tween-80 and lecithin with pluronic,

isopropyl myristate(IPM) was used as organic solvent, whereas gelation was

achieved on addition of aqeuous phase. Organogels using lecithin in liquid

paraffin and water were also prepared by hot-melt method. Increase in the

amount of lecithin resulted in organogels with higher viscosity and lower

spreadability. MN4formulation showed maximum viscosity 22868 CPs, whereasAM1 formulation containing Tween-80 (3.77%) was least viscous 15726 CPs.

Organogels with higher viscosity were found to be more stable. Organogels

containing lecithin and Tween-80 were the most stable. AM4showed highest gel

life of 220 hours at 25C. 28.5 gm% of water was required to produce maximum

gelation in SR1organogels containing lecithin and IPM. Organogels produced by

hot melt method required least amount of water for maximum gelation 9.09 gm%.

In vitro release of miconazole nitrate from organogels showed that organogels

containing lecithin and Tween-80 in IPM (AM1) gave highest release. The order

of release for the best releasing formulation prepared by different methods was

AM1>FM1>SR1>MN1. In vitro antifungal activity of miconazole nitrate

organogels against Candida albicans, P.chrysogenum, A.niger was in the order

AM1>FM1Mkd>SR1>MN1. In vitro antifungal activity significantly correlated

with in vitro release of miconazole nitrate. Lecithin microemulsion based

organogels have good potential as carrier for topical delivery of antifungal agent

such as miconazole nitrate.

Keywords: Lecithin organogels; Miconazole nitrate;In vitrorelease,In vitroanti-fungalactivity.


8/12/2019 CDPCEUT00038

12/156

xii

TABLE OF CONTENTS

LIST OF TABLES........................................................... xiv-xv

LIST OF FIGURES.............................................................. xvi

CHAPTER-1 INTRODUCTION ............................................................ 01-29

1.1 Conventional Technologies.......................................... 01

1.2 Newer Technologies .................................................... 02

1.3 Topical Dosage Forms ................................................. 04

1.4 Historical Overview ..................................................... 06

1.5 Skin as a Route of Topical and Transdermal Drug

Delivery System........................................................... 07

1.6 Fungal Infection........................................................... 11

1.7 Rational Approach to Drug Delivery to and ViaSkin ............................................................................. 14

1.8 Utilization of Different Gels as Topical Vehicles ......... 15

1.9 Emulsion Gels as Topical Formulations ....................... 15

1.10 Organogels................................................................... 16

1.11 Lecithin Organogels An Overview ............................ 19

1.12 Method of Preparation ................................................. 23

1.13 Characterization of Organogels .................................... 24

1.14 In VitroDrug Release .................................................. 25

1.15 Topical Drug Delivery Applications of LecithinOrganogel Based System........................................... 26

1.16 Safety and Skin Compatibility...................................... 28

1.17 Future Prospects........................................................... 28

CHAPTER-2 OBJECTIVES .................................................................. 30-32

2.1 Need for the Study....................................................... 30

2.2 Objective of the Study.................................................. 31

2.3 Scheme of the Work..................................................... 31


8/12/2019 CDPCEUT00038

13/156

xiii

CHAPTER-3 REVIEW OF LITERATURE .......................................... 33-58

3.1 Review of Literature .................................................... 33

3.2 Drug Profile ................................................................. 42

3.3 Polymer Profile............................................................ 50

CHAPTER-4 METHODOLOGY........................................................... 59-69

4.1 Raw Material Characterization..................................... 61

4.2 Preparation of Miconazole Nitrate Loaded LecithinMicroemulsion based Organogels ................................ 61

4.3 Construction of Calibration Curve of MiconazoleNitrate.......................................................................... 64

4.4 Evaluation of Lecithin-Microemulsion basedOrganogels................................................................... 65

CHAPTER-5 RESULTS ....................................................................... 70-115

5.1 Standardization of Raw Materials............................ 70-79

5.2 Preparation of Lecithin based Organogels .................... 80

5.3 Construction of Curve of Miconazole Nitrate ............... 80

5.4 Evaluation of Lecithin-Microemulsion basedOrganogels............................................................ 82-115

CHAPTER-6 DISCUSSION ............................................................... 116-119

CHAPTER-7 CONCLUSION............................................................. 120-121

CHAPTER-8 SUMMARY .................................................................. 122-124

BIBLIOGRAPHY......................................................... 125-134

ANNEXURE


8/12/2019 CDPCEUT00038

14/156

xiv

LIST OF TABLES

Sl.

No.

Table

No.Title

Page

No.

1. 1.1 Major Lipids of the Stratum Corneum 10

2. 4.2.1 Preparation of Organogels Loaded with Miconazole Nitrate 62

3. 4.2.2 Preparation of Pluronic Lecithin Organogels 63

4. 4.2.3 Preparation of Miconazole Nitrate Loaded Organogels 63

5. 4.2.4 Preparation of Hot Melt Type Organogels 64

6. 5.1.1 Standardization of Miconazole Nitrate 70

7. 5.1.2a Standardization of Lecithin 72

8. 5.1.2b Standardization of tween 80 72

9. 5.1.2c Standardization of pluronic (poloxames) 75

10. 5.1.2d Standardization of Isopropyl myristate 75

11. 5.1.2e Standardization of Lipid Paraffin 78

12. 5.3 Calibration curve of Miconazole Nitrate 80

13. 5.4 Physical Evaluation of Formulations 82

14. 5.4.1a Gelation Kinetics AM1 83

15. 5.4.1b Gelation Kinetics AM2 84

16. 5.4.1c Gelation Kinetics AM3 85

17. 5.4.1d Gelation Kinetics AM4 86

18. 5.4.2a Gelation Kinetics FM1 88

19. 5.4.2b Gelation Kinetics FM2 89

20. 5.4.2c Gelation Kinetics FM3 90

21. 5.4.2d Gelation Kinetics FM4 91

22. 5.4.3a Gelation Kinetics SR1 93

23. 5.4.3b Gelation Kinetics SR2 94


8/12/2019 CDPCEUT00038

15/156

xv

Sl.

No.

Table

No.Title

Page

No.

24. 5.4.3c Gelation Kinetics SR3 95

25. 5.4.3d Gelation Kinetics SR4 96

26. 5.4.4a Gelation Kinetics MN1 98

27. 5.4.4b Gelation Kinetics MN2 98

28. 5.4.4c Gelation Kinetics MN3 99

29. 5.4.4d Gelation Kinetics MN4 99

30. 5.4.5 Gelatin Kinetics Data 101

31. 5.4.6 Percentage drug contents of Organogels 102

32. 5.4.7a Invitro percentage drug release of formulations AM1, AM2,AM3and AM4

103

33. 5.4.7b Invitro percentage drug release of formulations FM1, FM2, FM3and FM4

105

34. 5.4.7c Invitro percentage drug release of formulations SR1, SR2, SR3

and SR4

107

35. 5.4.7d Invitro percentage drug release of formulations MN1, MN2,MN3and MN4

109

36. 5.4.8 In Vitro Antifungal Activity of Miconazole Nitrate Organogels 111


8/12/2019 CDPCEUT00038

16/156

xvi

LIST OF FIGURES

Sl.

No.

Figure

No.Title

Page

No.

1. 1.1 Structure of Skin 8

2. 5.1.1 IR Spectra of Miconazole Nitrate 71

3. 5.1.2a IR Spectra of Lecithin 73

4. 5.1.2b IR Spectra of Tween-80 74

5. 5.1.2c IR Spectra of Pluronic 76

6. 5.1.2d IR Spectra of Isopropyl Myristate 77

7. 5.1.2e IR Spectra of Liquid Paraffin 79

8. 5.3 Calibration curve of miconazole nitrate 81

9. 5.4.1 Effect of addition of water on turbidity of microemulsion basedorganogel of formulations AM1, AM2, AM3& AM487

10. 5.4.2 Effect of addition of water on turbidity of microemulsion based

organogel of formulations FM1, FM2, FM3& FM492


organogel of formulations SR1, SR2, SR3& SR497


organogel of formulations MN1, MN2, MN3& MN4100

13. 5.4.7a Invitro percentage drug release of formulations AM1, AM2,

AM3and AM4104

14. 5.4.7b Invitro percentage drug release of formulations FM1, FM2, FM3

and FM4106

15. 5.4.7c Invitro percentage drug release of formulations SR1, SR2, SR3

and SR4108

16. 5.4.7d Invitro percentage drug release of formulations MN1, MN2,

MN3and MN4110

17. 5.4.8 Comparative Antifungal Activity of Selected Miconazole

Nitrate Organogel Formulations with Control111

18. 5.4.9a IR Spectra of AM1Organogel 112

19. 5.4.9b IR Spectra of FM1Organogel 113

20. 5.4.9c IR Spectra of SR1Organogel 114

21. 5.4.9d IR Spectra of MN1Organogel 115


8/12/2019 CDPCEUT00038

17/156

xvii


8/12/2019 CDPCEUT00038

18/156

1

CHAPTER1

INTRODUCTION

With the advent of high throughput screening techniques the discovery of

biologically active molecules is taking place at a pace never seen before. Most of the

chemical entities that are being discovered are lipophilic in nature and have poor

aqueous solubility, there by posing problems in their formulation into delivery

systems. Because of their low aqueous solubility and high permeability, dissolution

and/or release rate from the delivery system forms the rate-limiting step in their

absorption and systemic availability. More than 60% of potential drug products

suffer from poor water solubility. This frequently results in potentially important

products not reaching the market or not achieving their full potential. Pharmaceutical

industry is quick in realizing the importance of solubility and dissolution rate in

bioavailability and good deal of research has been done in this area. Currently a

number of technologies are available to address the poor solubility, dissolution rate

and bioavailability of insoluble drugs1.

1.1 CONVENTIONAL TECHNOLOGIES

Conventionally used techniques2 based on Noyes-Whitney equation

3 for

enhancing solubility, dissolution rate and thereby bioavailability of insoluble drugs

include buffered tablets, use of salts, solvates and hydrates, polymorphic forms,

complexation, prodrugs, micronisation, solid dispersions and solvent deposited

systems.


8/12/2019 CDPCEUT00038

19/156

2

1.2 NEWER TECHNOLOGIES

Newer and novel drug delivery technologies developed in recent years for

bioavailability enhancement of insoluble drugs are described below.

1.2.1 LIPID BASED DELIVERY SYSTEMS

1. Lipid emulsion technology4.

2. Self-emulsifying drug delivery system5.

3. Micro emulsion media as novel drug delivery system6.

1.2.1.1 MICRO EMULSION SYSTEM6, 7

:

Microemulsions are four component mixtures composing of an oil phase, a

water phase surfactant/s and a co-surfactant. The tendency towards formation of w/o

or o/w microemulsions is dependent on the properties of the oil and the surfactant, the

water-to-oil-ratio and the temperature. When a mixture of surfactant and co-

surfactant is added to a biphasic oil-water system, a thermodynamically stable,

optically transparent or translucent, low viscosity and isotropic mixture spontaneously

forms. The transparency of these systems arises from their small droplets

diameter(10-100 nm). Such small droplets produce only weak scattering of visible

light when compared with that from the coarse droplets (0.5-100 m) of traditional or

standard macroemulsions such as emollient liquids, cream, lotions, etc., Structurally,

microemulsions have normal micellar solutions, reverse micelles, cores or droplets of

water or oil, and, for some systems, even bicontinuous structures could solubilize

large amounts of both oil and water soluble drugs within microemulsions.


8/12/2019 CDPCEUT00038

20/156

3

There is rather confusing situation in the medical literatures, where the term

microemulsion is indifferently used to indicate systems of presumably unlike

structure (true microemulsions and miniemulsions). Some studies have compared

the performance of different emulsified systems (macroemulsions, microemulsion,

multiple emulsion and gel-emulsions) prepared with similar oils and surfactants for

applications such as controlled drug release or drug protection.

The surfactants used to stabilized such systems may be (i) Non-ionic (ii)

Zwitterionic (iii) Cationic (iv) Anionic surfactants. Combinations of these,

particularly ionic and non-ionic, can be very effective at increasing the extent of the

microemulsion region.

Advantages:

Advantages associated with microemulsions include their thermodynamic

stability, optical clarity and ease of preparation.

Applications6:

a. Oral delivery

b. Parentral delivery

c. Pulmonary delivery

d. Ocular delivery

e. Topical delivery


8/12/2019 CDPCEUT00038

21/156

4

1.3 TOPICAL DOSAGE FORM:

Topical dosage forms are those which are applied to the skin. These

preparation are applied to the skin either for their physical effects, that is for their

ability to act as skin protectants, lubricants, emollients, drying agents, etc. or for their

specific effect of medicinal agents present. Preparations sold over the country

frequently contain mixtures of medicinal substance used in the treatment of such

condition as minor skin infection, itching, bruise, acne, psoriasis and eczema. Skin

application, which require a prescription generally contain a single medicinal agent

intended to counter a specific diagnosed condition8.

Topical dosage forms have been used since very ancient times. The

application of medicinal substance to skin or to various body orifices is a concept as

old as humanity. Various ointments, creams, gels, lotions, pastes, powders and

plasters have been used for many years9.

The primary topical drug delivery systems (TDDS) is that they could provide

controlled constant administration of a medicament by simple application to the skin

surface.

1.3.1 Advantages of Topical Systems10

:

1. They are of least therapeutic interest but of practical relevance is good patient

compliance. The systems are easy to apply and remove. It avoids risks and

inconveniences associated with intravenous therapy.


8/12/2019 CDPCEUT00038

22/156

5

2. They eliminate the variables, which influences gastrointestinal absorption

such as food intake, stomach emptying, intestinal motility and transit time.

3. Produces sustained and controlled level of drug in plasma thus reduces the

chance of over or under-dosing.

4. Reduces frequency of drug dosing.

5. Topical systems are easily retractable thereby termination of drug input, if

toxic effects are observed.

6. Offers an alternative route when oral therapy is not possible as in case of

nausea and vomiting.

7. Helps in achievement of more constant blood levels with lower dosage of drug

by continuous drug input and by by-passing hepatic first-pass metabolism and

consequent degradation.

8. In certain circumstances, enzymatic transformation within epidermis may be

used to improve permeability of certain hydrophilic drugs when applied to the

skin in the form of prodrug.

1.3.2 Limitations of Topical Systems11

:

1. Drugs with reasonable partition coefficient and possessing solubility both in

oil and water are most ideal, as drug must diffuse through lipophilic stratum

corneum and hydrophilic viable epidermis to reach the systemic circulation.

Only drugs, which are effectively absorbed by the percutaneous routes as such

or by using penetration promoters, can be considered.

2. The route is not suitable for drugs that irritate or sensitize the skin.


8/12/2019 CDPCEUT00038

23/156

6

3. The route is restricted by the surface area of delivery system and the dose that

needs to be administered in the chronic state of disease.

4. Topical drug delivery systems are relatively expensive compared to

conventional dosage forms. They may contain a large amount of drug, of

which only a small percentage may be used during the application period.

Apart from these limitations other problems include pharmacokinetics and

pharmacodynamic restrictions. Thus clinical need has to be examined carefully

before developing a TDDS.

1.4 HISTORICAL OVERVIEW:

With the advent of scientific medicine in the last half of the 19th

century, this

route of administration fell out of favour. In 1877, Fliescher declared that the skin

was totally impermeable. This extreme view could not hold for long. By the turn of

the century, Schwenkenbecker perceived that the skin would admit some substances

much better than others. In 1957, Monash proved a superficially located barrier in

skin as an obstacle to penetration. Later Stoughton used simple methods to explore

the permeability behaviour of human skin. He brought to light many important facts

by applying substances, which cause some rapid physiologic display such as

blanching, reddening or sweating.

The most important efforts in establishing a theoretical foundation were from

works by Ireger, Blank and Scheuplein.


8/12/2019 CDPCEUT00038

24/156

7

These pioneering works were followed by extensive research ultimately

proving that the stratum corneum was the main barrier to percutaneous absorption and

that although it allows no substance to penetrate easily, it does allow all substances to

enter slightly12

.

1.5 SKIN AS ROUTE OF TOPICAL AND TRANSDERMAL DRUG

DELIVERY:

The transdermal permeation of a chemical involves partitioning into and

transport through the cutaneous layers, namely the stratum corneum, the viable

epidermis (stratum basale) and the upper dermis10

. A topical product is designed to

deliver the drug into the skin to treat dermal disorders and therefore skin is the target

organ. Non steady state transport generally characterizes a topical product. The skin

is a barrier to topically administered drugs13,14

. Topical formulations usually contain

several excipients, which also partition into the skin according to their

physicochemical properties. Certain excipients change the integrity of stratum

corneum. Stratum corneum can exhibit swelling by water. Thus, the permeability of

drugs depends on the degree of hydration. Cosolvents may later the barrier properties

of the skin3,15

. Some substances having considerable polarities also enhance the

permeability of the horney layer. It is known that use of oleaginous vehicles

enhances the skin permeation

10

.

Topical preparation applied to the skin may be designed for surface, local or

systemic offers. In order to understand these effects, a brief review of the skin

structure is provided16,17

.


8/12/2019 CDPCEUT00038

25/156

8

Figure-1.1: Structure of Skin


8/12/2019 CDPCEUT00038

26/156

9

1.5.1 Relevant Anatomy and Microstructure:

The skin is one of the most extensive and readily accessible organs of the

human body. The skin of average adult covers over 20,000 cm of surface area and

receives overall of all blood circulation through the body. It is a multilayered organ18

.

The skin is composed of three layers: the outer most is the epidermis, next is the

dermis and the innermost layer is the subcutaneous. The epidermis itself is composed

of the stratum corneum, horny layer (about 10 m thick), which is a layer of

compressed, overlapping keratinized cells that form a flexible, tough, coherent

membrane. This layer contain dead cells with keratin filaments in a matrix of

proteins with lipids and water-soluble substances. The epidermis is more resistant to

the diffusion of chemicals than other layers of the skin, infact, it forms the protective

barrier for the layer.

Below the epidermis is the dermis, a matrix of connective tissue,

approximately 4 mm thick, woven from fibrous proteins, which are embedded in an

amorphous ground substance of mucopolysaccharide. Nerves, blood vessel and

lymphatics are contained in the dermis. The innermost layer of skin is the

subcutaneous tissue, which contains adipose cells and collagen fibers. The eccrine

sweat glands produce sweat, empty on the skin surface and function to control heat

exchange16

.


8/12/2019 CDPCEUT00038

27/156

10

1.5.2 Biochemical Makeup of the Stratum Corneum:

Along with cellular maturation of the keratonocytes, there is also a remarkable

shaft of the lipid composition of the epidermal layers. In humans, the extracellular

motor consists of a structural complex containing several groups of lipids.

Table-1.1: Major lipids of the stratum corneum17

Lipid typeAmount (weight

percent)

Polar lipids (phosphotidyl serine, choline, ethanol,

sphigmyelin)

4.9

Neutral lipids 64.6

Free sterols 14.0

Sterol esters 6.1

Free fatty acids 19.3

Triglycerides 25.2

Sphigolipids 18.1

Glycosphingolipids 2.6

Ceramides 15.5

*Abdominal region

1.5.3 Immunological Functions of Cells found in the Skin:

As the skin is increasingly understood as an immunological organ, the

immunologic functions of the skin has recently become an issue of considerable

concern. Termination of drug through the skin may be associated with immunologic

side effect19

.


8/12/2019 CDPCEUT00038

28/156

8/12/2019 CDPCEUT00038

29/156

12

Yeast like Fungi:

They grow partly as yeast and partly as elongated cells resembling hyphae.

The latter form as pseudomycelium, candida albicans in a pathogenic yeast like

fungus. On solid media most creamy coloured colonies are produced23

.

Moulds (Filamentous mycelial fungi):

They grow as long as filamentus or hyphae, which branch and interlace to

form a meshwork or mycelium, the vegetative mycelium grows on and penetrate into

substrate absorbing nutrient for growth. This may become powdery on its surface due

to the abundant formation of spores e.g. ring worm fungi.

The Dimorphic Fungi:

They either as filamentus or as yeast, according to the culture condition.

Growth usually take place in the mycelial form on culture media at 22C and in the

soil but in the yeast form on media at 37C and in the animal body, Histoplasma

capsulatumis the most important of them.

Fungal Infection23

:

Fungal infections are termed mycoses and is general can be divided into

superficial infections (affecting skin, nails, scalp or mucous membranes) and systemic

infections (affecting deeper tissue and organ).

Superficial fungal infections can be classified into the dermatomycoses and

candidiasis. Dermatomycoses are infection of the skin, hair and nails caused by

dermatophytes. The commonest are due to the tinea organism, which cause various


8/12/2019 CDPCEUT00038

30/156

13

types of ring worm, tenia capitis affect the scalp. Tinea pedis causes atheletes foot.

In superficial candiasis, yeast like organism infect the mucous membrane of the

mouth, vagina or skin.

Some of the fungal infections are as follows:

Pityriasis versicolor:

Pityriasis versicolor (Tenia versicolor) is a chronic usually asymptomatic

involvement of stratum corneum characterized by multiple scalum in children discrete

or confluent macular areas of discoloration or depigmentation of the skin. The areas

involved are mainly the chest, abdomen, upper limb and back. Facial involvement is

common. The causative agent is a lipophilic yeast like fungus pityrosporum

orbiculare(Malassezia furfur).

Tinea Nigra:

Tinea nigra is localized infection of stratum corneum, particularly of palm,

producing black or brown macular lesion. It is found mainly in the tropics and is

caused by cladosporium wernickii (now designated as exophiala wernickii).

Piedra:

Piedra is a fungus infection of the hair, characterized by the appearance of

firm, irregular nodules along the hair shaft. Nodules are composed of fungus

filaments, cemented together on the hair. Two varieties of piedra are recognized

black piedra caused by piedra kortai and white piedra caused by trichosporon

beigelli.


8/12/2019 CDPCEUT00038

31/156

14

Candidiasis:

Candidiasis is an infection of the skin, mucosa and rarely of the internal organ

caused by a yeast like fungus candida albicans normally present in the mouth,

intestine and vagina21

.

Vulvovaginal candidiasis is the infection with Candida albicans.

Approximately 75% of women have a vaginal infection with Candida strains during

their life and about 40-50% of them suffer a second one, and a small percentage

shows chronic cause24

.

Sporotrichosis:

Sporotrichosis is caused by fungus sporothrix schenckii and is characterized

by the development of the skin in subcutaneous tissue and lymph node, of nodules

which soften and breakdown to form indolent ulcers.

Rhinosporidiosis:

Rhinosporidiosis is a chronic granulomatus disease characterized by the

development of friable polyps usually confined to nose, mouth and eye but rarely

seen in the genitalia or other mucous membrane. The causative fungus is

Rhinosporidium seebri.

1.7 RATIONAL APPROACH TO DRUG DELIVERY TO & VIA SKIN20

:

There are three main ways to solve the problem of formulating a successful

topical dosage formulation:


8/12/2019 CDPCEUT00038

32/156

15

1. We can manipulate the barrier function of the skin e.g., topical antibiotics and

antibacterials help a damaged barrier to ward-off infection, sunscreen agents and

the horny layer protect the viable tissue from ultraviolet radiation and emollient

preparations restore palatability to a desiccated horny layer.

2. We can direct drug to the viable skin tissue without using oral, systemic or other

route of therapy.

3. The third approach uses skin delivery for systemic treatment. For example,

topical drug delivery systems provide systemic therapy for conditions such as

motion sickness, angina and pain.

Dermatologists aim at five main target regionskin surface, horny layers,

viable epidermis and upper dermis, skin glands and systemic circulation.

1.8 UTILISATION OF DIFFERENT GELS AT TOPICAL VEHICLES17

:

Gels have a variety of applications in the administration of medications orally,

topically, intranasally, vaginally and rectally.

1.9 EMULSION-GELS AS TOPICAL FORMULATIONS17

:

Transdermal and topical formulations are becoming increasingly important

and their use in therapy is becoming more widespread. But the skin acts as a barrier

to topically administered drugs. Attempts have been made to circumvent the skin

barrier by several means, emulsion-gels being one such promising technique.


8/12/2019 CDPCEUT00038

33/156

16

1.10 ORGANOGELS:

The topical administration of drugs in order to achieve optimal cutaneous and

percutaneous drug delivery has recently gained an importance because of various

advantages such as ease of administration, non-invasive, better tolerated and

compliance, local enhanced transdermal delivery, avoidance of local gastrointestinal

toxicity, avoidance of first pass metabolism.

In search of a vehicle to deliver the medicament into the skin layer (cutaneous

delivery) or through the skin and into systemic circulation (percutaneous absorption)

and to target the skin, varied kind of formulation systems and strategies have been

evolved.

Amongst the many, the lipid-based formulations have been in use since

decades. Pharmaceutically, lipid emulsions may allow the sustained release of drugs

by sink mechanism7

.

The importance of lipids has especially increased after realizing the utility of

phospholipids. The natural bio-friendly molecules which in collaboration with water

can form diverse type of polymolecular/ super molecular structure with retardant

release in sustained release formulation25.

The topical delivery has been attempted and made successful using a number

of lipid based systems viz., vesicular systems26

, lipid microsphere, lipid

nanoparticles1, lipid emulsion

4, polymeric gels

27. In a recent development,

phospholipids in conjunction with some other additives have been shown to provide a


8/12/2019 CDPCEUT00038

34/156

17

very promising topical drug delivery vehicle i.e., lecithin organogel. Lecithin

organogels (LOs) are thermodynamically stable, clear, viscoelastic, biocompatible

and isotropic gels composed of phospholipids (lecithin), appropriate organic solvent

and a polar solvent28

. Lecithin organogel, the jelly like phase consists of three

dimensional network of entangled reverse cylindrical (polymer like) micelle, which

immobilize the continuous or macroscopic external organic phase, thus turning liquid

into a gel25

. The formation of three-dimensional network in the organogel is the

result of transition at the micellar level in a low viscous network liquid consisting of

lecithin cause micelles in non-polar organic liquid29

. This spherical reverse micellar

state of lipid aggregates, twins on to form elongated tubular micelles with the addition

of water, and subsequently entangle to form a temporal three dimensional network in

the solution bulk. The latter serves to immobilize the external organic phase, thus

producing a gel form or the jelly like state of the initial non-viscous solution.

However, the transparency and optical isotropy of the organogel remain as before.

For this reason, these systems are often called as polymer like micelles and are also

termed as living or equilibrium polymer, worm like or thread like micelles25

.

1.10.1 Advantages of Organogels28,30,31

:

Template vehicle: Lecithin organogels provide opportunities for incorporation of

wide range of substances with diverse physicochemical characters viz., chemical

nature, solubility, molecular weight, and size etc.


8/12/2019 CDPCEUT00038

35/156

18

Process Benefits: Spontaneity of organogel formation by virtue of self-assembled

supramolecular arrangement of surfactant molecules, makes the process very simple

and easy to handle.

Structural/ Physical Stability: Being thermodynamically stable, the structural

integrity of lecithin oranogels is maintained for longer time periods.

Chemical Stability:Lecithin organogels are moisture insensitive and being organic

in character also resist microbial contamination.

Topical Delivery Potential:

Being well balanced in hydrophilic and lipophilic character, they can efficiently

partition with the skin and therefore enhance the skin penetration and transport of

the molecules.

Lecithin organogels also provide the desired hydration of skin in a lipid-enriched

environment so as to maintain the bioactive state of skin.

Lecithin might influence the structure of the skin by disorganizing the lipid layer

in the stratum.

Safety:Use of biocompatible, biodegradable and non-immunogenic materials makes

them safe for long-term applications.

1.10.2 Limitations of Organogels:

In the lecithin organogels, the lecithin should be pure otherwise no gelling will

occur.


8/12/2019 CDPCEUT00038

36/156

19

Lecithin is most costly.

Lecithin is not available on large scale.

Should be stored in a proper condition.

The organogel has greasy property.

Less stable to temperature.

1.11 LECITHIN ORGANOGEL AN OVERVIEW:

The first description of lecithin organogels was given in an article published

by Scartazzini and Luisi in the year 198828. In this study, water was added to various

organic solutions of purified soyabean lecithin. It was observed that addition of soy-

lecithin caused an abrupt rise in the viscosity (10104times)

30, producing a transition

of the initial non-viscous solution into gel of jelly like state. The amount of water

required to produce the gel was found to be critical. The phenomenon was observed

with various non-polar media and the list includes more than fifty solvents28

.

By now, lecithin organogels have been studied extensively in many

laboratories worldwide with regard to their varied aspects such as formulation

component, formation and gelling mechanism, physicochemical properties, etc. and

have also been proposed as a matrix for topical drug delivery.

1.11.1 Organogelling Composition:

The organogel matrix chiefly consists of surfactant (lecithin) as gelation

molecules, a non-polar organic solvent as external or continuous phase and polar

agent, usually water. Lecithin is a trivial name for 1,2-diacyl-Sn-3-phosphocholine.


8/12/2019 CDPCEUT00038

37/156

20

It belongs to a biological essential class of substance termed phosphoglycerides or

phospholipids. The latter form the lipid matrix of biological membrane and also play

a key role in the cellular metabolism.

As a biocompatible surfactant, it is widely used in every day life including

human and animal food, medicine, cosmetics and manifold industrial applications 32.

Synthetic lecithin containing residues of saturated fatty acids failed to form

organogel28,30,33

. However, it has been established that unsaturation in phospholipid

molecules is a desired property for the formation of lecithin organogels.

Besides lecithin as gelation molecules, the role of organic solvent in providing

the desired solvent action into the gelatin molecules is much emphasized. A large

variety of organic solvent are able to form gel in the presence of lecithin. Among

them are linear, branched and cyclic alkenes, ethers and esters, fatty acids and

amines. Specific examples includes ethyl laurates, ethyl myristate, isopropyl

myristate (IPM), isopropyl palmitate (IPP), cyclopentane, cycloclane, trans-decalin,

trans-pinane, n-pentane, n-hexane, n-hexadecane nd tripropylamine28

.

Amongst the above, the fatty acid esters i.e., application of lecithin

organogels. This has been attributed to their skin penetration enhancing property

besides their biocompatible and biodegradable nature

32,34

.

The third component of polar agent acts as a structure forming and stabilizing

agent and has a very crucial role to play in the process of gelling. Water is the most

commonly employed polar agent although some other polar solvents such as glycerol,


8/12/2019 CDPCEUT00038

38/156

21

ethylene glycol and formamide have also been found to possess the capability of

transferring an initial non-viscous lecithin solution into jelly like state on organogel25.

As described earlier, the major limitation in formation of lecithin organogels

is the requirement of high purity lecithin, the high purity grade lecithin is not only

expensive but also difficult to obtain in large quantities. However, recent reports

indicates the incorporation of synthetic polymers i.e., pluoronic in lecithin

organogels, for their usefulness as cosurfactant and stabilizer35

. It has been shown

that the inclusion of pluronic as cosurfactant makes the organogelling feasible with

lecithin of relatively lesser purity36

. The term pluronic refers to series of non-ionic

closely related block copolymers of ethylene oxide and propylene oxide32

. Also

known as poloxamers, poloxamer polyols or Lutrol. These are primarily used in

pharmaceutical formulations as co-surfactants, emulsifier, solubilizers, suspending

agents and stabilizers. These pluronic containing lecithin organogels have been

termed as pluronic lecithin organogels, poloxamer organogels, pluronic organogels,

PLO gel or simply PLOs.

1.11.2 Phase-behavior of organogels:

Sameles containing different weight ratios (km) of lecithin/IPM (20:80)

(40:60) (60:40) (80:20) were prepared, phase studies were carried out by adding

water while stirring. After each addition of 1liter of aqueous phase of pure water to

the lecithin solutions, the resulting systems were examined for clarity and viscosity.

The course of each addition was monitored through cross polaroids in order to

determine the boundaries of any organogel and briefringent liquid crystalline


8/12/2019 CDPCEUT00038

39/156

22

domains. The endpoint of the organogel domain at a given kmwas determined when

the system became turbid after the addition of a specific amount of water. The phase

behavior of the systems was mapped on phase diagrams with the top apex

representing the lecithin and the other apices representing IPM and water solution.

The transparent, homogeneous, nonbirefringent area enclosed by the line connecting

the endpoints was considered as microemulsion based organogel37

.

1.11.3 Organogel structure and mechanism of organogelling37

:

The initially spherical reverse micelles that are formed by lecithin molecules

in a nonpolar organic solvent transform into cylindrical micelles, once water is added.

This was established with the help of light scattering and small angle neutron

scattering techniques. This one dimensional growth of micelles is caused by the

formation of hydrogen bonds between water molecules and phosphate groups of

lecithin molecules so that two adjacent lecithin molecules are bridged together by one

water molecule IR and NMR spectroscopic methods have revealed that water

molecules could interact simultaneously with phosphate groups of neighboring lipid

molecules via hydrogen bonding, acting as a bridge between them. In this case

solvent molecules and lecithin phosphate groups can arrange in such a way that a

hydrogen-bonded network will be formed. The increase in the amount of water

results in the formation of long tubular and flexible micelles. These micelles can be

entangled and therefore build up a transient three-dimensional network, that is

responsible for the viscoelastic properties of the lecithin organogels. At a critical

concentration of water, network shrinks and phase separation occurs. At still higher


8/12/2019 CDPCEUT00038

40/156

23

contents of water a transformation to a solid, nontransparent precipitate can be

observed. This diluted solution is composed of rod-like micelles, which their length

is not enough to overlap and form a three-dimensional network. The existence of

microdomains of different polarity within the same single-phase solution enables

water-soluble and oil-soluble drugs to be incorporated. Results have shown that for a

given system, as km increases, the incorporation capacity increases. This could be

attributed either to the increase in the number of cylindrical micelles or to the further

growth of the cylindrical micelles or both, leading to the increase in the solubilizing

capacity.

1.12 METHOD OF PREPARATION:

The oil-surfactant mixture was heated at 60C to obtain a clear solution which

on cooling forms organogels38

. Based on the phase diagrams constructed, lecithin

solutions were prepared by first dissolving lecithins in an organic solvents with the

aid of magnetic stirrer. Formation of organogels takes place on addition of water

with the help of micropiopette syringe. Sometime heat is applied for complete

solubilization of drug29

.

The oil phase is prepared by mixing lecithin and organic solvent, the mixture

is allowed to stand overnight to ensure complete dissolution. The aqueous (polar)

phase is prepared by adding pluronic to ice cold water, the mixture is agitated to

ensure complete dissolution. The prepare PLO, the oil phase is mixed with aqueous

phase of pluronic using a high shear mixing method by magnetic stirrer35

.


8/12/2019 CDPCEUT00038

41/156

24

1.13 CHARACTERIZATION OF ORGANOGELS:

In contrast to the ease of preparation, characterization of LOs is relatively

complicated on account of their interior structural design build up on the self-

associated supramolecules. These microstructures, the resultant of varied polar non-

polar interactions, are highly sensitive and pose difficulties in the investigative

studies. However, different characterization studies are extremely useful while

investigating the potential applications of organogel systems as a topical vehicle. For

instance, it has been reported that many of the physicochemical properties of Los viz.

Rheological behavior, physical and mechanical stability, and drug release behavior

are dependent upon how do molecules arrange themselves to provide the specific

structural network within the organogel system25,38

.

1.13.1 Rheological behavior

For any vehicle to be used for topical drug delivery applications, it is essential

to study its rheological behavior. The latter is important for it efficacy in delivering

the molecules onto or across the skin site. The critical parameters like spreadibility,

adhesiveness (property related to bioadhesion on skin site), cohesiveness (which

indicates structural reformation following application of shear stress, and consistency

need to be modified in a favorable manner. Lecithin organogels (LOs) have been

studied extensively for their rheological attributes and determined to be viscoelastic

in nature25

.

At higher lecithin concentrations, there is more extensive entanglement of

long cylindrical micelles with each other, forming a network-like structure with a


8/12/2019 CDPCEUT00038

42/156

25

very high viscosity. The entrapment of the drug within this network lowers the

amount of free drug available for release, causing a decrease in the release across the

membrane29

.

1.13.2 Determination of gelation temperature39

:

Formulations were enclosed in glass tubes (2 mm inside diameter) and

observed over a temperature range of 4-5C. The change from solution to gel ov

vice-versa was determined by inverting the tube. The temperature was changed at a

rate of 5C h and the temperature at which the physical state of the formulation was

changed was regarded as the gelation temperature. In all cases the gelation

temperature was reproducible to within 0.1C. The gel melted completely within a

0.2 0.3 C range.

1.13.3 Gelation Kinetics40

:

The gelation properties of organogels were investigated in the presence of

various solvents. Gel-sol and sol-gel transitions were evaluated by the inverse

method and gelation kinetics were determined by turbidimetry.

1.14 IN VITRODRUG RELEASE29,41

:

The permeation apparatus designed as described by Chowdary et al was

employed to study the release profile of drugs from the semisolid formulations.

Phosphate buffer 6.4 used as receptor fluid.

The release/ permeation of drugs from lecithin gels through various membrnes

was determined using Franz diffusion cell.


8/12/2019 CDPCEUT00038

43/156

26

1.15 TOPICAL DRUG DELIVERY APPLICATIONS OF LECITHIN

ORGANOGEL-BASED SYSTEMS:

Organogel formulation Major findings

Lecithin (200mM) IPP gel of broxateroland scopolamine42.

Transdermal delivery of compounds

Phosphatidylcholine (PC) gel in

isopropyl palmitate (IPP) orcyclooctane

30.

Investigated for transdermal transport of

various drugs along with aminoacids andpeptides

IPP-lecithin gel of diclofenac and

indomethacin43

Enhanced efficacy of NSAIDs

administered through topical route

Phytosphingosine or sphingosine lecithinorganogel comprising soy PC, IPP,

ethanol and water44

Treatment of scars

Soya lecithin-isopropyl myristate (IPM)

organogel containing ketaminehydrochloride and amitryptiline

hydrochloride45

Enhance skin penetration and partitioning

of the drugs into the skin layers

Nicardipine lecithin-IPM organogel46

Enhanced skin permeation across guineapig and human skin

Methimazole in LO gel31

Significant percutaneous absorption ofmethimazole

LO gel of cardiac glycoside digoxin47

Topial administration of the compound in

LO gel was found to be effective for thetreatment of muscle spasm

Cyclobenzaprin in lecithin organogel48

(lecithin 10-30%, IPM 10-30%, water 30-60%)

Topical formulation for bauxism.


8/12/2019 CDPCEUT00038

44/156

27

1.15.2 Topical delivery of therapeutic substances in pluronic lecithin organogels:

PLO gel formulation Applications

Ketoprofen PLO gel30

Administration of ketoprofen in PLO gel offered

convenience, produced less side effects andalleviated pain in a specific location

PLO gel of Diclofenac,

Ibuprofen, Ketamine48

Randomized, placebo controlled study on

lateral epicondylites employing diclofenac in PLOgel reduced pain and increased functional status

Preparation also found to be effective treatmentfor osteoarthritis

Lecithin organogjel in

combination of Pluronic F-127

(poloxamer 407) solution/Cyclobenzaprin

36

Effective formulation for topical treatment of

carpal tunnel syndrome

Lecithin (20-40% v/v) in

isopropyl palmitate or isopropylmyristate containing suitable

amount of pluronic and waterwith or without short chain

alcohol44.

The components of PLO gel provide desired

hydration state to the skin, thus effective in thetreatement of eczema or psoriasis

1.15.3 Commercially available pluronic lecithin organogels49

:

Therapeutic category Therapeutic agents

Antiemetics Dexamethasone, Dimenhydrate, Scopolamine

Muscle relaxants Cyclobenzaprine, Baclofen, Buspirone

Neuropathy drugs Clonidine, Capsaicin, Amitryptilne, Gabapentin, Phenytoin,

NSAIDs Diclofenac, Ibuprofen, Ketoprofen, Indomethacin,

Systemic analgesics Acetaminophen, Hydromorphone, Morphine sulphate

Systemic hormones Progestrone, Testosterone


8/12/2019 CDPCEUT00038

45/156

28

1.16 SAFETY AND SKIN COMPATABILITY STUDIES:

Lecithin-based organogel system i.e., LO or PLO gels are composed of

pharmaceutically approved (non-immunogenic and biocompatible) excipient.

However, the level of surfactant and organic solvents in lecithin organogels is faily

high. Therefore, it is important to consider the safety and irritancy of the formulation

on prolong use. In this context, skin (human skin) compatibility of the gels have been

evaluated employing various techniques before and after applications with either IPP

alone or with 200 mM-IPP gel. No significant alteration in the skin were apparent

after three days and stratum corneum was still intact. The irritation potential of LOs

has been assessed by Dreher et al by carrying out human skin irritation study50.

Result indicated a very low cumulative skin irritation potential of LOs. That supports

the stability of LO based gels as topical vehicle for long-term application.

1.17 FUTURE PROSPECTS:

In the field of topical drug delivery, LOs have emerged as one of the most

potential carrier systems. In contrast to other lipid-based system such as vesicular

system (liposomes and niosomes) lecithin-organogel systems may prove to have an

edge in term of efficacy, stability and most importantly, the technological feasibility.

Morevoer, the topical drug delivery of new biotech generated proteinaceous

molecules in the protective non-polar microenvironment of these systems may help

protect these sensitive macromolecules from and degradation, while their transport to

the desired site48

.


8/12/2019 CDPCEUT00038

46/156

29

Thus, amidst the increasing opportunities and challenges, the LOs may prove

to be highly promising system in realizing the drug delivery objectives while

scientists are desperately trying for more viable alternative viz-a-viz existing carrier

system.

PLO is probably due to financial constrains as well as the industry focusing on

area such as biotechnology and genomics. However, the great interest in PLO in the

US has led to formulation of a second generation lecithin organogel premium, lecithin

organogel base by Xenex Labs and Max Pharmaceuticals, USA35

.


8/12/2019 CDPCEUT00038

47/156

30

CHAPTER2

OBJECTIVES

2.1 NEED FOR THE STUDY:

A gel can be described as the cross-linked material that retains a large amount

of solvent inside its medium and if the solvent retained in organic one, such material

is known as organogel. Traditionally organogel type systems are applied topically

when the active agent is oil soluble one or if we need the sustained release of the drug

into the deep skin layers51

. A polar organic solvents, soya bean lecithin can form

thermo-reversible, isotropic, non-birefrigerant gel like system so called micro-

emulsion based organogels, characterized by high viscosity and optical

transparency13

.

In the present study, various polymers such as soya bean lecithin, isopropyl

myristate, poly sorbate 80, mineral oil (liquid paraffin), pluronic F-127, have been

employed for organogels29,52,53

.

Miconazole nitrate is a synthetic imidazole derivative with molecular formula

C18H14C14N2CHNO3and practically insoluble in water has the antifungal activity with

a broad spectrum activity against pathogenic fungi (including yeast and

dermatophytes and gram positive Candida albicans, Staphylococcus and

Streptococcus)54

. It may act by interfering with permeability by inhibiting the fungal

cytochrome P-450 enzyme responsible for the synthesis of ergosterol the main sterol

in the fungal cell membrane55. Miconazole is topically active drug and only rarely


8/12/2019 CDPCEUT00038

48/156

31

administered parenterally due to its extensive first pass metabolism and severe

toxicity56. Miconazole on oral administration causes nausea, vomiting and diarrhea57.

Miconazole readily penetrate the stratium corneum of the skin58

, but less than 1% in

blood. Irritation and burning are rare after cutaneous application. It is also used in

the treatment of several systemic fungal infections including Candidiasis.

Organogels may be formulated to enhance the release and to provide more

sustained topical antifungal effect of miconazole nitrate.

2.2 OBJECTIVES OF THE STUDY:

1. Formulation of lecithin based organogels of miconazole nitrate.

2. Evaluation of in vitro antifungal activity of optimized miconazole

nitrate organogels.

3. To evaluate the influence of formulation variables on the release rate

of miconazole nitrate.

2.3 SCHEME OF WORK:

Phase-I:

1. Extensive literature survey.

2. Procurement of materials.

Phase-II:

Standardization of Materials:

a) Standardization of miconazole nitrate

b) Standardization of polymers


8/12/2019 CDPCEUT00038

49/156

32

1. Lecithin

2. Tween-80

3. Isopropyl myristate

4. Pluoronic F-127

5. Liquid paraffin.

Phase-III:

1. Formulation of lecithin based organogels

2. Preliminary evaluation of organogels.

3. Selection of best composite based on preliminary evaluation.

Phase-IV:

1. Incorporation of drug

2. Preparation of standard calibration curve of miconazole nitrate

3. Evaluation of Organogels.

a) pH

b) Spreadibilityc) Viscosity

d) Gelation kinetics

e) Gel life (stability)

Phase-V:

1. Drug content uniformity

2. In vitro drug diffusion

3. In vitro antifungal activity


8/12/2019 CDPCEUT00038

50/156

33

CHAPTER3

REVIEW OF LITERATURE

3.1 REVIEW OF LITERATURE

Rajani V and Verma PRP (1993) determine the diffusion studies of ibuprofen

from ointment bases using cellophase membrane. Data reveals that percent drug

release were concentration dependent. Similar observations have been made with

respect to the release of benzocaine, sorbic acid, salicyclic acid and benzocaine acid.

The diffusion rate was higher in the first hour and therefore decline. The general rank

of order of the drug release was found to be water soluble > water miscible >

hydrophilic > oleaginous. The slowest release was found with a water-oil emulsion.

Release was generally dependent on the drug concentration59

.

Shoba Rani R Hiremath, et al60

had carried out the permeation studies of

marketed clotrimazole creams. The drug release was less than 20% with all the

formulations tested at the end of 8 hours and hence isopropyl myristate was chosen

next as a medium because of its bipolar properties.

Gondaliya DP and Pundarika Kshudu K61

had carried the investigation-

examined preparation and evaluation of nimesulide clear aqueous gels and emulgel

using acrypol 940p. A 3 factorial design was adopted for the optimization of aqeous

gel formulation. Propylene glycol and polyethylene glycol 400 were chosen as

independent variable to study their effects as cosolvents. The clear aqueous gel

formulation containing 15% w/w ethanol, 20% w/w propylene glycol and 30% w/w


8/12/2019 CDPCEUT00038

51/156

34

PEG-400 showed maximum drug penetration (18.68%) in 5 hours in in-vitro

diffusion study. Drug diffusion was increased by addition of chromophore EL, a

lipophilic penetration enhancer.

Ilango R et al62

developed transdermal preparation of nimesulide gel. The

effect of polymer-concentration on in vitro nimesulide release from carbpol 940

HPMC gel and effect of permeation enhancer like Tween-80 and SLS at different

concentration on drug release were studied.

Magdy C Mohammed63

have studied optimization of chlorphenesin emulgel

formulation. He prepared emulgel using different polymers and evaluate emulgel for

various parameter like rheological study, in vitrostudy release, antifungal activity and

stability studies.

Miconazole nitrate used in the treatment of severe systemic fungal infection,

chronic muco cutaneous candidasis, fungal meningitis, vulvo vaginal candidiasis,

tinea infection, otomicosis, cutaneous candidiasis and rarely given as i.v for system

mycosis58.

Mucoadhesive buccal patches of miconazole nitrate was prepared and its in

vitro / in vivoperformance were evaluated by Wafee and Ismail64

. The patches were

prepared with ionic polymers sodium corboxy methylcellulose and chitosan and non

ionic like hydroxy ethyl cellulose and hydroxy propyl methyl cellulose. Convenient

bio adhesion, acceptable elasticity, swelling and surface pH were obtained patches

exhibited sustained release over more than 5 generally enhanced the release rate.


8/12/2019 CDPCEUT00038

52/156

35

Dibiase MD and Rhodes CT65

had carried out the work on pluronic F-27 gel

and evaluated as a potential topical vehicle for epidermal growth factor delivery. The

chemical stability of the polypeptide within the gel matrix was investigated using

HPLC. Thermal stability studies was performed on the base gel formulation.

Modifications to the formulation was made to improve physical characteristics and

chemical stability. Humectants and antioxidants was investigated as potential

formulation additives and the microbial status of the product was also evaluated.

Minghetti Patel66

reported dermal patches of miconazole were evaluated for

their technological characters by Minghetti et al for the treatment of tinea argium

infection. Artificial silk used as backing layer. Eudragit and plastoid were used

which provided release of at least 24 hours.

Khurana and Ahuja67 prepared and evaluated mucoadhesive tablets of

miconazole nitrate for the treatment of oral candidiasis. It produced satisfactory drug

release.

David H et al68

investigation of two hundred eighty (280) patients with

symptomatic vulvovaginal candidiasis were randomly assigned to treatment with

either miconazole nitrate 4% vaginal cream for 3 days, followed by placebo for 4

days, or Monistat-7 (miconazole nitrate 2%) vaginal cream for 7 days in this double-

blind, parallel-group, outpatient study. Sixteen US centers participated. Patients

were seen on admission and then at 8 to 10 days and 30 to 35 days after completion

of treatment. Clinical, microbiologic, and therapeutic efficacy was assessed. This


8/12/2019 CDPCEUT00038

53/156

36

study compared the safety and efficacy of a new cream formulation of 5g of

miconazole nitrate 4% administered once daily for 3 days with that of 5g of

miconazole nitrate 2% vaginal cream, the currently marketed product, administered

for 7 days. Although not significantly clinically different, cure rates were slightly

higher with the 3-day treatment. Relapse rates were low in both treatment groups and

symptom relief was also comparable. The most frequent adverse experiences were

genital (itching, burning, irritation, and discharge), as well as headache and

respiratory congestion; reports of adverse experiences were similar in the two

treatment groups. Miconazole nitrate 4% vaginal cream administered for 3 days was

found to be promising new candidate for over-the-counter treatment of vulvovaginal

candidiasis.

Chandia Valenta et al34

studied the soya-lecithin aggregates prepared by a

technique using compressed gas to formulate new dermal preparations. Ketoprofen

(KP) a Non-steroidal anti-inflammatory drug (NSAID) is included as a model drug.

The novel soya-lecithin aggregates are promising candidates for new drug delivery

system in dermatology and cosmotology. Lecithin aggregates loaded with drugs are

multifunctional causes that also act as penetration enhancers. The improvement in

skin permeation is related to both the solubilizing effect of lecithin matrix and

penetration enhancing effect of lecithin itself.

Murda S35

reported the great interest in pluronic lecithin organogel in the US

has led to the formulation of a second generation lecithin organogel, premium lecithin


8/12/2019 CDPCEUT00038

54/156

37

organogel base by Xenex laboratories and has non-greasy, non-tacky and improved

stability to temperature as compared with original pluronic lecithin organogels.

Reza Aboofazeli et al69

stated that the partial phase diagrams were constructed

with soybean lecithin water, sodium salicylate, alcohol and isopropyl myristate.

Phase diagrams showed the area of existence of a stable isotropic region along the

surfactant / oil axis (i.e., reverse microemulsion area).

Shilpa K et al75

showed that the microemulsion based organogel are useful in

iontophoretic drug delivery vehicles include their potential to increase the maximum

loading of a water soluble agent and the drug ability may be improved especially in

comparison to the use of hydrogels where the presence of an aqueous continuous

phase may allow degrative processes to occurs.

Singh R et al70 investigation reveals that the antifungal activity measured as

zone of inhibition of lecithin organogel ketoconazole as a model drug was better as

compared to the activity recorded for hydrogel base.

William N et al30

concludes that lecithin gels may be efficient vehicles for the

transdermal transport of various drugs. The presence of lecithin in organic solvent

result with increase in drug solubility as compared with heat solvent the transport rate

is 10 times higher that with the aqueous solution of drug. Lecithin organogel can be

prepared easily and rapidly and can be obtained with biocompatible components.

They are stable for a long time, can incorporate sizeable amount of different chemical

as guest molecules and fulfill the cosmetics and pharmacological application.


8/12/2019 CDPCEUT00038

55/156

38

Shelke VB et al38

research result shows that the organogels can be used for all

type of drug molecule, controlled release increased resistance to microbial

contamination and reduced risk of toxicity.

Meiying Ning et al24

reveals vulvovaginal candidiasis is the infection with

Candida albicans. Approximately 75% of women have a vaginal infection with

candida strain during their life and about 40 to 50% of them suffer a second one and

small percentage shows a chronic cause. The entrapment of drug in vesicles may

help in the localized delivery of the drug and an improved solubility and availability

of the drug at the site may reduce the dose and systemic side effects.

Hoffmann G et al31

showed that lecithin organogels were developed for

transdermal transport of drugs and consists of a spaghetti like network of lecithin

micelles, which can host various guest molecules by solubilization in their

transdermal methimazole treatment research work to treat cat hyperthyroidism.

Marco Antonio M et al71

evaluate the system containing water lecithin/

polysorbate 80/ isopropyl myristate the results showed high stability, very low

toxicity for the parentral use.

Vitonial M, Bentley M et al

39

studies showed that in vitro permeation of a

model drug triamcinolone acetonide was decreased when the lecithin concentration

was increased. The presence of lecithin in the poloxamer (pluronic) gel improved the

characteristics for topical drug delivery.


8/12/2019 CDPCEUT00038

56/156

39

Gelatin containing microemulsion based organogels (MBGs) have been

formulated using pharmaceutical acceptable surfactant and oils such as tween-85 and

isopropyl myristate. MBGs are clinically conducting employed for ionotphoretic

delivery of a model drug. MGBs also appear to offer improved microbial resistance

in comparison to aqueous solution or hydrogels. This work is done by Kantaria S et

al72

.

Scartazzini R, Luisi R28

showed that the interest in lecithins as basic

components for gel materials lies in biomimetic chemistry. This is vague term and

one that should be used sparingly. The point can be made that lecithin gels may be

related more closely than others to gel like lipidic aggregates that exist in vivo.

Luisi PL et al30

suggested organogels can be used to solubilize a variety of

drug candidates therefore it is widely applied in chemical, pharmaceutical, cosmetic

applications.

Dreher F et al43

in investigation to estimate the function of the gel as a

potential transdermal penetration enhancer system performed the interaction of

lecithin, isopropyl palmitate with the human stratum corneum using DSC and FTIR

and found more significant irritancy. Lecithins and isopropyl palmitate affects the

stratium corneum lipid organization.

Murdan S et al77

determined the sorbitan monostearate organogels can be used

as delivery vehicles for hydrophilic and hydrophobic drug and vaccines. The gels


8/12/2019 CDPCEUT00038

57/156

40

may also provide sustained release of appropriate active entity after intramuscular and

subcutaneous administration.

In short communication, Murdan S et al26

showed that sorbitan monostearate

organogels are opaque, thermo reversible, semisolid whose microstructure consists of

surfactant tubules dispersed in organic continuous phase. Inverse toroidal vesicles are

the precursors of the surfactant tubules. The toroids are thought to be analogues to

other well known vesicles, liposomes and niosomes except for their toroidal (rather

than spherical) shape and their inverse nature.

Murdan S et al76 suggested in their studies that the sorbitan stearate and

isopropyl pulmitate organogels may have potential

cdpceut00038

Documents