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«SURFACTANT SYSTEMS FOR DRUG DELIVERY AND WATER EVAPORATION REDUCTION By DUSHYANT SHEKHAWAT A DISSERTATION PRESENTED TO THE GRADUATE SCHOOL OF THE ...»

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SURFACTANT SYSTEMS FOR DRUG DELIVERY AND WATER EVAPORATION

REDUCTION

By

DUSHYANT SHEKHAWAT

A DISSERTATION PRESENTED TO THE GRADUATE SCHOOL

OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT

OF THE REQUIREMENTS FOR THE DEGREE OF

DOCTOR OF PHILOSOPHY

UNIVERSITY OF FLORIDA

© 2007 Dushyant Shekhawat To my parents and sisters who have been my #1 supporters.

ACKNOWLEDGMENTS

I would like to express my sincere appreciation to Professor Dinesh O. Shah, chairman of my supervisory committee, for allowing me to be a part of the Center for Surface Science and Engineering (CSSE), and for his kind guidance, motivation and encouragement during my Ph.D.

program. I would also like to thank other supervisory committee members, Professors Anuj Chauhan, Brij Moudgil and Richard B. Dickinson, for their valuable time and suggestions.

Thanks go also to Dr. Timothy E. Morey for his numerous inputs in my research and Dr. Jerome H. Modell and Dr. Donn M. Dennis for their help in Animal Experiments.

CSSE, a wonderful place with a number of fulltime and visiting scholars in different areas of expertise, is the ideal place for a perfect brain massage. I thoroughly enjoyed my learning experience here. I wish to thank all my colleagues for their help and mentorship: Dr. Rahul Bagwe, Dr. Samir Pandey, Dr. Tapan Jain, Dr. Manoj Varshney, Dr. Monica James and Dr.

Daniel Carter. PERC is acknowledged for allowing me to use its research facilities and acknowledgements are due to Gary Scheiffele and Gill Brubaker for teaching me how to use them. Dr. Amar Shah is gratefully acknowledged for several informal brainstorming sessions, and for proofreading of the dissertation. Special mention goes to Dr. Monica James for her critique of my chapters.

My heartfelt appreciation goes to my parents and my sisters. Without their consistent emotional support, I simply could not have come this far. Finally, I want to thank my friends Kamalesh Somani, Saurav Chandra, Vijay Krishna, Uday Tipnis, Siddharth Gaitonde, Naveen Margankune, Gunjan Mohan, Toral Zaveri, Yash Kapoor, Suresh Yeruva and Madhavan Esayanur, for making my stay in Gainesville enjoyable.

TABLE OF CONTENTS

page ACKNOWLEDGMENTS

TABLE OF CONTENTS

LIST OF TABLES

LIST OF FIGURES

ABSTRACT

CHAPTER 1 INTRODUCTION AND LITERATURE REVIEW

1.1 Colloidal Drug Delivery

1.1.1 Micelles

1.1.2 Macroemulsions

1.1.2.1 Emulsion droplet size

1.1.2.2 Viscosity of emulsions

1.1.2.3 Emulsion stability

1.1.2.4 Coalescence and phase inversion

1.1.2.5 Demulsification

1.1.2.6 Surfactant selection for emulsification

1.1.2.7 Applications of emulsions

1.1.3 Microemulsions

1.1.3.1 Formation of microemulsions

1.1.3.2 Applications of microemulsions

1.1.4 Nano-emulsions

1.2 Non-Toxic Biomedical and Pharmaceutical Microemulsions

1.2.1 Applications

1.2.2 Introduction to Pharmaceutical Microemulsions

1.2.2.1 Biocompatibility

1.2.2.2 Solubility and stability

1.2.2.3 Bioavailability

1.2.3 Method of Drug Delivery

1.2.3.1 Parenteral delivery

1.2.3.2 Oral delivery

1.2.3.3 Topical delivery

1.2.4 Pharmaceutical Microemulsions Using Nonionic Surfactants

1.2.5 Pharmaceutical Microemulsions Using Anionic Surfactants

1.2.6 Pharmaceutical Microemulsions Using Phospholipids and Cholesterol................45 1.2.7 Pharmaceutical Microemulsions Using Sugar based Surfactants

1.2.8 Pharmaceutical Microemulsions for Drug Detoxification

1.3 Retardation of Water Evaporation

1.3.1 Duplex Films

1.3.2 Spreading of Oil on Water Surface

2 PREPARATION OF PROPOFOL MICROEMULSIONS

2.1 Introduction

2.2 Methods and Materials

2.2.1 Materials

2.2.2 Synthesis of Propofol Microemulsions

2.2.3 Viscosity Measurements

2.2.4 Stability Evaluation of Microemulsions

2.2.5 Stability on Dilution of Microemulsions

2.2.6 Oxidation Studies

2.3 Results

2.3.1 Microemulsion Synthesis and Characterization

2.4 Discussion

2.4.1 Microemulsion Technology for Drug Delivery

2.4.2 Selection of Surfactants

2.4.3 Nonionic Surfactants

2.4.4 Ionic Surfactants

2.4.5 Propofol Anesthetic Action

2.5 Conclusions

3 ANESTHETIC PROPERTIES OF PROPOFOL MICROEMULSIONS

3.1 Introduction

3.2 Methods and Materials

3.2.1 Materials

3.2.2 Synthesis of Propofol Microemulsions

3.2.3 Rat Experiments

3.2.3.1 Animal experimental protocol

3.2.3.2 Statistical analysis

3.2.4 Dog Experiments

3.2.4.1 Animal experimental protocol

3.2.4.2 Blood sample acquisition and processing

3.2.4.3 Measurement of plasma propofol concentration





3.2.4.4 Statistical and pharmacokinetic analysis

3.3 Results

3.3.2 Anesthetic Properties in the Rat

3.3.2.1 Modification of nonionic surfactant concentration

3.3.2.2 Modification of ionic surfactant concentration

3.3.3 Anesthetic Properties in the Dogs

3.3.3.1 Effects on erythrocytes and leukocytes

3.3.3.2 Effects on platelets and thrombosis

3.3.3.3 Propofol pharmacokinetics

3.4 Discussion

3.4.1 Microemulsion Fate Upon Injection

3.4.2 Propofol Anesthetic Properties

3.4.3 Propofol Concentration

3.4.4 Coagulation

3.5 Conclusions

4 RETARDATION OF WATER EVAPORATION THROUGH DUPLEX FILMS OF SURFACTANT IN OIL

4.1 Introduction

4.2 Methods and Materials

4.2.1 Materials

4.2.2 Spreading of Duplex Film

4.2.3 Evaporation Studies

4.2.4 Brewster Angle Microscopy Studies

4.3 Results and Discussion

4.4 Conclusion

5 SUMMARY AND RECOMMENDATIONS FOR FUTURE WORK

5.1 Propofol Microemulsions for Anesthesia

5.1.1 Summary

5.1.2 Future Work

5.2 Reduction of Water Evaporation

5.2.1 Summary

5.2.2 Future Work

LIST OF REFERENCES

BIOGRAPHICAL SKETCH

–  –  –

1-1 Physical characteristics of various drug delivery systems

1-2 Types of breakdown processes occurring in emulsions

1-3 Factors influencing the stability of emulsions

1-4 Parameters that affect phase inversion in emulsion and the effect they have

1-5 A summary of HLB ranges and their application

1-6 Microemulsions vs. Nano-emulsions

2-1 List of propofol microemulsion

2-2 Size of propofol microemulsions

Viscosity of propofol microemulsions at 25 °C

2-3 3-1 Dose and latency intervals for anesthetic induction and emergence in rat following intravenous infusion of a propofol macroemulsion formulation and several propofol microemulsion formulations with C8 fatty acid salt and differing purified poloxamer 188 (Pluronic F68) concentrations

3-2 Dose and latency intervals for anesthetic induction and emergence in rat following intravenous infusion of a propofol macroemulsion formulation and several propofol microemulsion formulations containing with C8, C10, or C12 fatty acid salts and 5% purified poloxamer 188 (Pluronic F68)

3-3 Effects of propofol microemulsions (Micro) and macroemulsions (Macro) on parameters of the Red Blood Cell population in Dogs

3-4 Effects of propofol microemulsions (Micro) and macroemulsions (Macro) on the White Blood Cell count and population differential in Dogs

3-5 Effects of propofol microemulsions (Micro) and macroemulsions (Macro) on Platelet population and indices of Thrombosis in Dogs

3-6 Plasma propofol concentration after induction of anesthesia in Dogs

–  –  –

1-1 Various types of colloidal drug delivery systems.

1-2 Schematic diagram of a surfactant molecule, micelle, and reverse micelle.

1-3 Properties of surfactant solutions showing abrupt change at the solution critical micelle concentration (cmc)

1-4 Schematic diagram of the adsorption of surfactant monomers from the bulk to the oil/water interface during emulsion formation.

1-5 Schematic diagram of an oil-in-water (O/W) microemulsion.

1-6 Thermodynamic explanation for behavior of macroemulsions and microemulsions........54 1-7 Difference between monolayer and duplex film

1-8 Problems in forming uniform duplex film.

2-1 Propofol

2-2 Schematic diagram of an oil-in-water (O/W) microemulsion.

2-3 Binary diagram noting the concentrations of purified pluronic 68 and the cosurfactant fatty acids necessary to form propofol microemulsions in a bulk media of normal saline

2-4 Binary diagram noting the concentrations of purified pluronic 127 and the cosurfactant fatty acids necessary to form propofol microemulsions in a bulk media of normal saline

2-5 Effects of purified pluronic 68 concentration and fatty acid chain length on nanodroplet diameter for propofol microemulsions.

2-6 Effect of dilution on propofol microemulsions formulated using various concentrations of purified pluronic 68 and several fatty acid salts with variable carbon chain length

2-7 Gas chromatography of propofol microemulsion.

2-8 Mass spectroscopy of propofol.

2-9 The pH of F68 microemulsion

2-10 Conductivity of F68 microemulsion.

2-11 Formation of propofol dimer and propofol dimer quinone in propofol emulsions............85 2-12 Dynamic behavior of microemulsions

3-1 Anesthetic induction parameters in Rats

3-2 Anesthetic emergence in Rats

3-3 Time-dependent effects of a propofol microemulsion or macroemulsion on Dogs........111 3-4 Time-dependent effects of a propofol microemulsion or macroemulsion on respiratory rate in Dogs

4-1 Langmuir film balance

4-2 Evaporation experiment setup

4-3 Comparison of water evaporation reduction by duplex film and monolayers.................123 4-4 Effect of film thickness on evaporation.

4-5 Effect of concentration of Brij 93 in hexadecane on evaporation.

4-6 Brewster Angle Microscopy images of duplex film of hexadecane and Brij-93.............124 4-7 Effect of various polymers on evaporation

4-8 Effect of aging and compression/expansion of film on evaporation.

4-9 Effect of films of various commercial products on water evaporation

–  –  –

Chair: Dinesh O. Shah Cochair: Anuj Chauhan Major: Chemical Engineering Surfactant systems are used to enhance the quality of products used in every aspect of life;

from food to cosmetics, from pharmaceutics to detergency, and even from oil recovery to chemical mechanical polishing of silicon wafers. In this dissertation, we investigate these systems for drug delivery as well as water evaporation reduction applications.

Microemulsions are excellent candidates as potential drug delivery systems because of their improved drug solubilization, long shelf-life, and ease of preparation and administration. In the present study, Propofol (2,6-diisopropylphenol) was selected as a test drug to form water external microemulsion. Propofol is intravenous general anesthetic drug, having several favorable anesthetic characteristics, including rapid emergence from unconsciousness without drowsiness. Several oil-in-water microemulsions constituting Propofol (oil), biodegradable nonionic polymers, surfactants and fatty acid salts were formulated. Various properties of these microemulsions, like particle size, stability on dilution, and pH etc. were measured as a function of time, which shows that these systems are thermodynamically stable. Anesthetic studies of these microemulsion systems were done using randomized crossover design in rats and dogs.

Rats randomly received propofol either as a microemulsion or conventional macroemulsion (Diprivan®) to determine endpoints of anesthetic induction and recovery. Pharmacodynamic and Pharmacokinetic properties of Propofol microemulsion were measured by experiments in dogs.

In conclusion, Propofol microemulsions caused general anesthesia in rat/dogs similar to that resulting from macroemulsions. The surfactant concentration and type markedly affects the spontaneous destabilization and anesthetic properties of microemulsions.

Retardation of water evaporation is important from number of viewpoints. In this work, we proposed a new approach to reduce the evaporation of water, i.e. multimolecular (duplex) films of micron or sub-micron thickness of oil and surfactants that spontaneously spreads on the water surface and reduce the water evaporation rate. Investigation of the duplex film of Brij93 and hexadecane has shown some promising results that it can decrease the evaporation rate of water as much as 80%. Addition of polymer (Polyvinyl alcohol) in the water beneath this duplex film helps in further reduction of the evaporation rate. Effects of various parameters like concentration of surfactant, different surfactants in hexadecane, and thickness of the film deposited and various polymeric additives on water evaporation through these films have been studied.

–  –  –

Surfactant systems are used to enhance the quality of products used in every aspect of life;

from food to cosmetics, from oil recovery to detergency, and even from pharmaceutics to chemical mechanical polishing of silicon wafers. Here in this thesis, we present studies on two of such system, namely drug delivery by microemulsions and reduction of water evaporation by duplex films of surfactant in oil.

Microemulsions are excellent candidates as potential drug delivery systems because of their improved drug solubilization, long shelf-life, and ease of preparation and administration.



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