By Charles J. White, Jr. a Thesis Submitted to the Graduate Faculty Of
Total Page：16
File Type：pdf, Size：1020Kb
SIMULTANEOUS CONTROLLED RELEASE OF MULTIPLE COMFORT MOLECULES AND THE PRODUCTION OF NOVEL HIGH COMFORT CONTACT LENS MATERIALS THROUGH BIPHASIC MOLECULAR IMPRINTING by Charles J. White, Jr. A thesis submitted to the Graduate Faculty of Auburn University in partial fulfillment of the requirements for the Degree of Doctorate Of Philosophy Auburn, Alabama December 13, 2014 Keywords - Molecular Imprinting, Silicone Hydrogel Contact Lens, Comfort Agents, Extended Drug Delivery, Physiological Flow, Controlled Release Rate Copyright 2014 by Charles J. White, Jr. Approved by Mark E. Byrne, Daniel F. & Josephine Breeden Associate Professor of Chemical Engineering Christopher B. Roberts, Dean of the Samuel Ginn College of Engineering Yoon Y. Lee, Uthlaut Family Professor of Chemical Engineering Sabit Adanur, Professor Of Polymer And Fiber Engineering ABSTRACT Contact lens induced dry eye (CLIDE) affects approximately 80% of contact lens wearers. Extrapolating to the world wide population of 300 million contact lens wearers, there are approximately 200 million wearers who express dissatisfaction with their current lenses. The design of contact lenses have evolved to promote high oxygen diffusion (Dk) to promote comfort and ocular health. Since the advent of silicone hydrogel lenses in the market in the later 1990’s, silicone hydrogel lenses have dominated the lens market in recent years, making up 60% of all lens fittings in the United States in 2009. Several brands are approved for 30 day continuous, extended wear, making these lenses very popular with consumers. The most popular modalities of wear in the current and near future for lens wearers within the US market are extended and daily disposable wear lenses. However, most lens wearers still express dissatisfaction with their lenses due to CLIDE-related symptoms. Controlled drug delivery methods applied to soft contact lenses deliver have been shown to deliver macromolecular comfort agents to the eye. Yet controlled drug delivery from silicone hydrogels has yet to be shown in silicone hydrogel contact lenses. This represents a large technology gap. To fill this unmet need, we have designed novel contact lenses materials capable of controlled delivery of diverse comfort molecules including 120 KDa hydroxypropyl methylcellulose (HPMC), trehalose, ibuprofen, prednisolone, aspirin, chloramphenicol, and other comfort molecules selected to provide comfort across a diverse range of propagators. The comfort molecules selected ii for use in this work were chosen as a group to address multiple propagators of discomfort and control over the mass release rate from the lens was demonstrated releasing both individually and simultaneously from the same imprinted lens. The release rate was controlled by engineering the lens formulation according to principles of biomimetic molecular imprinting. This is the first instance controlled and tailorable release of multiple simultaneous ocular therapeutics from contact lenses. Release of multiple diverse comfort molecules is the most promising method of ensuring true high comfort in contact lenses during the full duration of lens wear. Special care was taken to develop novel correlations between the mass release rate of comfort agents and in vivo levels of ocular comfort. Novel index values were developed from evaluation and analysis of comfort agent physical and solution properties. It was shown that the comfort contribution of comfort agent solutions depends strongly on both the comfort agent solution concentration, comfort agent molecular weight, and the precorneal contact time between the comfort agent and the ocular surface/tear fluid. The development of the index values was based on the rheological and physical behavior of static comfort agent solution concentrations and did not account for the gradual loss of concentration with time due to the natural flow of tears. Thus, the index values provided high value for the field by allowing comparison between diverse comfort agent eye drop solutions for the first time and resulted in a method to resolve many discrepancies in the clinical literature. In addition, a statistical meta-analysis of the clinical literature allowed us to accurately model the comfort agent concentration profile within the ocular tear film. It is hypothesized that the comfort contribution can be found and compared among any delivery vehicle with high degree of confidence by comparing the product of the specific v comfort index value for a specific comfort agent/solution in and the calculated area under the in vivo comfort agent concentration profile. Our Lab has pioneered the use of both large volume, static sink models and small volume, continuous flow sink devices, referred to as microfluidic devices, to accurately determine the release kinetics from drug-eluting contact lenses and to predict the mass release profile under physiological conditions. The most recent published device design has represented a major contribution to the field. However, there are several drawbacks of the design that could be improved upon with the design of a novel device. The conception, development, fabrication, programming, and evaluation of a novel heat exchanger-based automaton for the performance of in vitro dynamic mass release studies is described in this work. A novel automaton device was designed and fabricated to incorporate solutions to these drawbacks. The automaton was based upon a custom heat exchanger design and a servo-based mechanism to reproduce the blinking motion as well as a method to allow for controlled, variable flow rates of release media through the device. vi LIST OF FIGURES Figure 2.1. Propagators Of Ocular Discomfort In Contact Lens Wear ...........................47 Figure 2.2. Cross-Sectional Anatomy Of The Human Eye .............................................49 Figure 2.3. The Lacrimal System, Tear Flow, And The Tear Film .................................51 Figure 2.4. Repeating Unit Chemical Structure For Common Comfort Agents In Over- The-Counter Eye Drop Formulations ............................................................53 Figure 2.5. Number Of Dry Eye Drugs Undergoing Clinical Trials In The US During 2011................................................................................................................55 Figure 2.6. Chemical Structure Of Pharmagent Comfort Molecules Undergoing Clinical Trials For Use In The US To Treat Dry Eye Discomfort.................57 Figure 2.7. Annual Sales Revenue Of Restasis In The U.S. ............................................58 Figure 2.8. Annual Sales Revenue For Different Dry Eye Treatment Brands And Comfort Molecules ........................................................................................59 Figure 2.9. Annual Sales Of Different Classes Of Ocular Eye Drops .............................60 Figure 2.10. Worldwide Market For Dry Eye Relief Drops By Country/Region Presented As (A) Percent Of Total Market And (B) Millions Of Dollars ......61 Figure 3.1. Common Comfort Agents In Over-The-Counter Eye Drop Formulations ...98 Figure 3.2. Comfort Agent Water Retention ...................................................................100 Figure 3.3. Percent Change Of Comfort Agent Solution Surface Tension Relative From DI Water Surface Tension ....................................................................101 Figure 3.4. Comfort Agent Intrinsic Viscosity As A Function Of Molecular Weight ....102 Figure 3.5. Zero-Shear Viscosity Of Comfort Agent Solution Extrapolated To Zero Concentration .................................................................................................103 Figure 3.6. Apparent Flow Viscosity Of Aqueous Comfort Agent Solutions .................104 Figure 3.7. Comfort Property Contribution And Agent Index Values At Various Molecular Weights And Concentrations ........................................................109 ix Figure 3.8. Using The Comfort Agent Index Values To Compare Between Comfort Solutions ........................................................................................................115 Figure 4.1. Ocular Tear Film Comfort Agent Concentration Profiles For Different Vehicles..........................................................................................................180 Figure 4.2. Residence Time Studies Per Year .................................................................181 Figure 4.3. Residence Time Studies Per Comfort Agent Species....................................182 Figure 4.4. Fluorescent Hyaluronic Acid And Fluorescent Dextran ...............................183 Figure 4.5. Tracer Molecule Chemical Structures Of Tracer Molecules Used In The Clinical Literature To Evaluate Comfort Agent Residence Time .................185 Figure 4.6. Residence Time Studies Per Model ...............................................................186 Figure 4.7. Tracer Concentration Profile .........................................................................188 Figure 4.8. Tear Drainage Profiles At Various Orders ....................................................189 Figure 4.9. Polysaccharide 3D Plot With Percent Concentration ....................................198 Figure 4.10. Acrylic 3D Plot With Percent Concentration ..............................................202 Figure 4.11. Predicted In vivo Mass Profiles For Various Concentration And Molecular Weight Comfort Agent Solutions ..................................................................209 Figure 5.1. Trends In Oxygen Transport