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Design of diffusion controlled drug delivery systems

Dissertation
Author: Kandarp Patel
Abstract:
Pharmaceutical controlled release systems, generally constructed from polymers, are defined as the systems which delivers a drug at a predetermined and constant rate for a specified period of time. Such systems exist in many forms, including injectable microspheres, specially designed tablets, implants and transdermal patches. Diffusion, degradation and dissolution are the most important mechanisms that control the drug release from these controlled release systems. However, diffusion controlled drug delivery system is the most widely used drug delivery systems. Diffusion control is particularly important to transdermal drug delivery where degradation and dissolution are nonviable mechanisms to control the release rates. Generally, in diffusion controlled release systems where a drug to be released is uniformly dissolved through a polymer, the release shows initially high rate followed by a rapidly declining rate. Various approaches have been employed over the last two decades to overcome this undesired burst effect and to obtain the desired dose of a drug. The present optimization study, however, concerns the optimal initial concentration distribution of a drug in the delivery device to eliminate the burst effect and obtain a zero-order release. A commonly used objective function for the optimization is the standard of deviation between the instantaneous dose and the desired dose. The numerical value of the objective function provides a little insight from a therapeutic viewpoint. This work describes a novel and systematic approach to the design of transdermal or implanted delivery systems based on medically relevant specifications of maximum allowable dose rate, minimum effective dose rate, time to achieve the effective dose rate, and the design life of the patch. The delivery system is a three layer patch consisting of two drug containing layers of equal thickness and one barrier layer laminated together to form a matrix with a non-uniform initial concentration distribution. This device allows drug release behavior conforming to the medically relevant specifications while maximizing utilization of the drug, i.e. the depletion of the drug from the patch. The thickness of the barrier layer and the relative concentrations in the two drug containing layers are the key design parameters. Optimization studies show little advantage from using variable thicknesses of the two drug containing zones or of using more than two drug containing zones. The application of the design approach is further extended to design a patch considering the skin as a barrier. The last part of the thesis addresses the issue of the particle size distribution of a dispersed drug. It is known that the particle size of a dispersed drug plays a significant role in the release behavior. Compositional quenching, previously used in the manufacture of impact modified conventional polymer blends and biocatalytic composites is applied to disperse a model protein in the natural biopolymer. The green fluorescent protein and chitosan are used as a model protein and polymer, respectively. The manufacture of chitosan composites by solvent evaporation and compositional quenching process is investigated. The chitosan-protein composite manufactured by compositional quenching showed particle size distribution of dispersed protein of the superior quality compared to the solvent evaporation technique.

CONTENTS

DESIGN OF DIFFUSION CONTROLLED DRUG DELIVERY SYSTEMS…………… i CONTENTS……………………………………………………………………………….. ii LIST OF TABLES…………………………………………………………………………. v LIST OF FIGURES………………………………………………………………………... vi ACKNOWLEDGEMENT………………………………………………………………… x ABSTRACT……………………………………………………………………………….. xi 1. INTRODUCTION……………………………………………………………………… 1 1.1 Organization of thesis……………………………………………………………….. 3 2. TRANSDERMAL DRUG DELIVERY………………………………………………... 5 2.1 The reservoir system………………………………………………………………… 6 2.2 Single-layer drug-in-adhesive……………………………………………………….. 7 2.3 Multi-layer drug-in-adhesive…………………………………………………………8 2.4 Drug dispersed in matrix systems…………………………………………………… 9 2.5 Micro-reservoir dissolution-controlled systems…………………………………….. 10 2.6 The burst effect ……………………………………………………………………... 10 3. THE DESIGN PHILOSOPHY…………………………………………………………. 20 3.1 Packaging techniques……………………………………………………………….. 20 3.2 Theoretical formulation…………………………………………………………….. 23 3.3 Design philosophy………………………………………………………………….. 26 3.3.1 Operational characteristics……………………………………………………. 26 3.3.2 Design parameters…………………………………………………………….. 28 3.3.3 Optimization………………………………………………………………….. 29 3.3.4 Optimization technique……………………………………………………….. 31

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4. OPTIMIZATION RESULTS AND DISCUSSIONS………………………………….. 33 4.1 Introduction…………………………………………………………………………. 33 4.2 Effect of equal thickness of drug containing zones…………………………………. 35 4.3 Effect of variable thickness of drug containing zones……………………………… 41 4.4 Effect of non-uniform diffusivity………………………………………………….. 42 4.5 Comparison of analytical and numerical design……………………………………. 46 4.6 Effect of number of drug containing zones on optimization………………………... 53 4.7 Design of two zones patch without a barrier…………………………………………58 4.7.1 The design…………………………………………………………………….. 60 5. SKIN: THE BARRIER…………………………………………………………………. 65 5.1 Skin physiology…………………………………………………………………….. 65 5.2 Drug permeation routes…………………………………………………………….. 66 5.3 Theoretical considerations………………………………………………………….. 67 5.4 Design philosophy…………………………………………………………………... 70 5.5 Optimization results………………………………………………………………… 70 5.5.1 Higher skin diffusivity………………………………………………………… 71 5.5.2 Lower skin diffusivity………………………………………………………… 75 6. COMPOSITIONAL QUENCHING…………………………………………………… 79 6.1 Influence of particle size distribution………………………………………………. 79 6.2 Thermodynamics of mixing and phase separation………………………………….. 82 6.3 The Cahn-Hilliard equation…………………………………………………………. 86 6.4 Compositional quenching…………………………………………………………… 89 6.5 Materials and method………………………………………………………………. 91 6.5.1 Green fluorescent protein…………………………………………………….. 92 6.5.2 The process description……………………………………………………….. 94

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6.5.3 Solvent casting………………………………………………………………… 95 7. CONCLUSION AND FUTURE WORK………………………………………………. 103 REFERENCES……………………………………………………………………………. 107 NOMENCLATURE……………………………………………………………………… 112 APPENDICES…………………………………………………………………………….. 114

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LIST OF TABLES

Table 1 Optimal value of concentrations and barrier thickness as a function of f min

for two zones patch…………………………………………………………………… 35 Table 2 Optimal values of concentrations and barrier thickness as a function of f min for three zones patch……………………………………………………………… 56 Table 3 Optimal values of concentrations and barrier thickness as a function of f min for five zones patch………………………………………………………………. 57

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LIST OF FIGURES

Figure 2-1 Schematic of reservoir type system……………………………………………. 7 Figure 2-2 Schematic of single-layer drug-in-adhesive type system……………………… 8 Figure 2-3 Schematic of multi-layer drug-in-adhesive type system………………………. 9 Figure 2-4 Schematic of drug dispersed in matrix system…..…………………………….. 9 Figure 2-5 Schematic of micro-reservoir dissolution-controlled system…………………. 10 Figure 2-6a Drug release profiles from a single layered drug delivery device under burst conditions……………………………………………………………………………. 13 Figure 2-6b Release rate of a drug from a single layered drug delivery device………….. 13 Figure 2-7 Drug release………………………………………………………………….. 15 Figure 2-8 Optimized initial concentration profiles………………………………………. 17 Figure 2-9 Ideal and optimized release profiles…………………………………………… 17 Figure 2-10 Drug release from multilaminated matrix device……………………………. 18 Figure 3-1a Before application of patch to skin. Release liners are intact………………… 22 Figure 3-1b Release liner are removed and the patch is applied to the skin……………… 22 Figure 3-2 Drug release from a multilayered device……………………………………… 23 Figure 3-3 Graphical explanation of medically relevant operational characteristics……… 27 Figure 4-1 Normalized dose versus depletion for various designs……….……………..… 34 Figure 4-2 Optimized and approximated depletion profiles as a function of f min …………. 36 Figure 4-3 Optimized and approximated values of f max corresponding to f min …………..…

37 Figure 4-4 Rise times obtained by using approximated values of c 2 and b….……………. 38 Figure 4-5 Optimized flux profiles versus depletion for different values of f min …….……. 40 Figure 4-6 Effect of variable thickness of drug containing zones on depletion profile….… 41

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Figure 4-7 Non-uniform diffusivity profiles……………………………………………… 42 Figure 4-8 Depletion as a function of f min for non-uniform diffusivity profiles…………… 43 Figure 4-9 Effect of non-uniform diffusivity profiles on barrier thickness……………….. 44 Figure 4-10 Effect of non-uniform diffusivity profiles on initial concentration…………... 45 Figure 4-11 Comparison of analytical approximation and numerical approximation of depletion as a function of f min ………………………………………………………….

47 Figure 4-12 Comparison of analytical approximation and numerical approximation of rise time as a function of f min ………………………………………………………….

48 Figure 4-13 Comparison of numerical and analytical values of optimized depletion as a function of f min ………………………………………………………………………….

49 Figure 4-14 Comparison of numerical and analytical values of optimized concentration profiles as a function of f min …………………………………………………………….

50 Figure 4-15 Comparison of numerical and analytical values of optimized barrier thickness profiles as a function of f min ……………………………………………………………..51 Figure 4-16 Schematic of a three layer device…………….……………………………….. 53 Figure 4-17 Schematic of a three layer device ………………..…………………………… 53 Figure 4-18 Comparison of optimized depletion for 2, 3 and 5 zones……………………. 55 Figure 4-19 Flux profile for the patch without barrier as a function of depletion………… 59 Figure 4-20 Minimized ratios versus its components i.e. f min and f max …………………….

61 Figure 4-21 Optimized ratios versus depletion profile……………………………………. 62 Figure 4-22 Optimal concentration profiles………………………………………………. 63 Figure 4-23 Minimized ratios versus excess depletion…………………………………… 64 Figure 5-1 Schematic representation of the drug diffusion considering the stratum corneum………………………………………………………………………………. 68

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Figure 5-2 Optimized and approximated depletion profiles as a function of f min (Higher Skin Diffusivity)……………………………………………………………………….

72 Figure 5-3 Optimized and approximated values of f max corresponding to f min (Higher Skin Diffusivity) ………………………………………………………………….…... 73 Figure 5-4 Rise times obtained by using approximated values of c 2 (Higher Skin Diffusivity)……………………………………………………………………………..

74 Figure 5-5 Optimized and approximated depletion profiles as a function of f min (Lower Skin Diffusivity)……………………………………………………………………….

76 Figure 5-6 Optimized and approximated values of f max corresponding to f min (Lower Skin Diffusivity) ………………………………………………………………….…... 77 Figure 5-7 Rise times obtained by using approximated values of c 2 (Lower Skin Diffusivity)……………………………………………………………………………..

78 Figure 6-1 Illustration of the effect of particle size on drug delivery device performance…81 Figure 6-2 Phase diagram depicting the Homogeneous, Metastable and Spinodal regions………………………………………………………………………………… 85 Figure 6-3 Schematic diagram of compositional quenching process……………………... 90 Figure 6-4 Beta-barrel structure of GFP………………………………………………….. 93 Figure 6-5 Structure of chromophore. R groups are first 64 and last 170 residues of amino acids………………………………………………………………………………….. 93 Figure 6-6 Experimental setup for compositional quenching……………………………. 97 Figure 6-7 20X photograph of chitosan film……………………………………………… 98 Figure 6-8 20X photograph of protein polymer composite prepared by compositional Quenching…………………………………………………………………………….. 99 Figure 6-9 20X photograph of protein/polymer composite prepared by solvent casting…. 100

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Figure 6-10 Particle size distribution for compositionally quenched composites………… 101 Figure 6-11 Particle size distribution of composites prepared by solvent casting………… 102 Figure 7-1a The patch applied to the skin at time t = 0. Skin contacting layer is intact….. 105 Figure 7-1b The patch after some time t = t 1 . The skin contacting layer has degraded….. 105

x

ACKNOWLEDGEMENT

A graduate degree completion requires time, effort, commitment, patience especially encouragement and a lot of support from friends, colleagues and family. I would like to express my sincere gratitude to Professor Nauman, my thesis adviser, for his instructions, guidance and undaunting support especially through the later part of my research. He has been a source of inspiration to me and taught me to think critically. Special thanks are also due to the members of my doctoral thesis committee, Professor P. Karande, Professor R. Linhardt and Professor J. Plawsky. The discussions I had with Prof. Karande gave me insights to the problems and that were valuable for me to understand fundamentals of this study. Many thanks to Rose Primett, Jean Mulson, Angela Bocketti and Sharon Sorell, not just for their help, but for making the everyday problems of the Chemical Engineering Department go away. My group members deserve a special mention. They have been a source of great support to me. I enjoyed my discussions with Abdul, Ashish, Mike, Harshit, Tim, Jon, Matt, Becky, Jakub and Kevin. I would also express my thanks to Sashi, Manas and Arya for making Ricketts enjoyable. Special thanks to my friends Sunil and Samir. I would also like to thank my all friends in the department who made the graduate school fun. I dedicate this thesis to my family. None of this would be possible without the undying support of my parents, my grandfather, my brother and sister. They believed in me and when things looked gloomy they were always there to cheer me up and keep me motivated. Finally, my wife who joined me a year ago has made my journey all the more enjoyable. Without her patience, support, endless love and understanding this task would have been very difficult.

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ABSTRACT

Pharmaceutical controlled release systems, generally constructed from polymers, are defined as the systems which delivers a drug at a predetermined and constant rate for a specified period of time. Such systems exist in many forms, including injectable microspheres, specially designed tablets, implants and transdermal patches. Diffusion, degradation and dissolution are the most important mechanisms that control the drug release from these controlled release systems. However, diffusion controlled drug delivery system is the most widely used drug delivery systems. Diffusion control is particularly important to transdermal drug delivery where degradation and dissolution are nonviable mechanisms to control the release rates. Generally, in diffusion controlled release systems where a drug to be released is uniformly dissolved through a polymer, the release shows initially high rate followed by a rapidly declining rate. Various approaches have been employed over the last two decades to overcome this undesired burst effect and to obtain the desired dose of a drug. The present optimization study, however, concerns the optimal initial concentration distribution of a drug in the delivery device to eliminate the burst effect and obtain a zero-order release. A commonly used objective function for the optimization is the standard of deviation between the instantaneous dose and the desired dose. The numerical value of the objective function provides a little insight from a therapeutic viewpoint. This work describes a novel and systematic approach to the design of transdermal or implanted delivery systems based on medically relevant specifications of maximum allowable dose rate, minimum effective dose rate, time to achieve the effective dose rate, and the design life of the patch. The delivery system is a three layer patch consisting of two drug containing layers of equal thickness and one barrier layer laminated together to form a matrix with a non-uniform initial concentration distribution.

xii

This device allows drug release behavior conforming to the medically relevant specifications while maximizing utilization of the drug, i.e. the depletion of the drug from the patch. The thickness of the barrier layer and the relative concentrations in the two drug containing layers are the key design parameters. Optimization studies show little advantage from using variable thicknesses of the two drug containing zones or of using more than two drug containing zones. The application of the design approach is further extended to design a patch considering the skin as a barrier. The last part of the thesis addresses the issue of the particle size distribution of a dispersed drug. It is known that the particle size of a dispersed drug plays a significant role in the release behavior. Compositional quenching, previously used in the manufacture of impact modified conventional polymer blends and biocatalytic composites is applied to disperse a model protein in the natural biopolymer. The green fluorescent protein and chitosan are used as a model protein and polymer, respectively. The manufacture of chitosan composites by solvent evaporation and compositional quenching process is investigated. The chitosan-protein composite manufactured by compositional quenching showed particle size distribution of dispersed protein of the superior quality compared to the solvent evaporation technique.

1

Chapter 1 INTRODUCTION

Optimum therapeutic outcomes require not only proper drug selection but also an effective drug delivery system to maintain constant plasma drug concentration for drugs possessing a narrow range of therapeutic index, avoiding the peaks and valleys. A therapeutic index, which is also known as the therapeutic ratio, is a comparison of the amount of a therapeutic agent that causes a toxic effect to the amount that causes therapeutic effects. Quantitatively, it is the ratio of the toxic dose to the therapeutic dose. Research in the area of controlled drug delivery systems has become increasingly important due to their advantages in safety and efficacy (Langer, 1993). The purpose of these systems is to maintain desired drug concentration in the blood or in the tissue as long as possible. Controlled release systems exist in many forms, including specially-designed tablets that can be taken orally, injectable microspheres and implants. These systems are generally constructed from polymers due to the manufacturing advantages and cost effectiveness. Diffusion, solvent activation and degradation are the main fundamental mechanisms by which the polymer-controlled drug delivery systems release drugs. Among these mechanisms, diffusion is the most important mechanism used to control the drug release from drug delivery systems (Siepmann, et. al., 1999). Release rates from these systems are determined by Fick’s law of diffusion which is given by,

dc J D dx = − (1.1)

2

Here J is the drug flux, D is the drug diffusion coefficient and dc/dx is the drug concentration gradient in the polymer. Apart from the controlled release methods listed in the beginning, diffusion controlled drug delivery systems are particularly important for transdermal drug delivery. However, in conventional diffusion controlled matrix systems, where a drug to be released is distributed uniformly through a polymer, the release shows an initially high release rate or burst followed by a rapidly declining rate (Georgiadis, et al., 2001). The most common disadvantage cited for these systems is their inability to achieve zero order release kinetics. Over the years, various methods have been designed to eliminate the initially high burst and to approach zero-order release. The present study to design diffusion-controlled drug delivery systems concerns the initial concentration distribution of a drug in the delivery device. Practically, an initial concentration distribution of a drug is achievable by constructing a multilayered drug delivery patch. Recent market interest is not only to achieve a constant release rate but also to decrease the size of the device. The dispersion of a drug rather than dissolution in the matrix not only improves the size (Marty, 1996) but also improves the release behavior (Charalambopoulou, et al., 2001). The common technique to disperse a drug in the polymer matrix is by slow solvent evaporation. However, slow evaporation gives large particle sizes for the dispersed drug. As explained in chapter six, the particle size of a dispersed drug plays an important role in the release behavior. The compositional quenching, a technique developed by Nauman, et al., (1987) for blending commercial polymers can be used to produce dispersions with a micron scale particle sizes, which is a dispersion quality suitable for a controlled drug delivery. This technique is based on the principle of flash devolatilization, which rapidly quenches a homogeneous

3

polymer-polymer-solvent system from the single phase region into the two-phase region by spinodal decomposition. Kosto (2003) extended the application of this process to systems of biological importance, for e.g. biocatalysis, by incorporating a model enzyme, α-chymotrypsin, into low-density polyethylene, polystyrene and PLGA (poly(lactic-co-glycolic acid)) and confirmed that enzyme-polymer composites made by compositional quenching process exhibited considerable activity retention over time. The current work extends the application of the process further by incorporating a model protein into a natural biopolymer to produce a unique particle size distribution of the protein for application in diffusion controlled drug delivery systems. Chitosan, a natural, swellable, biodegradable, biocompatible and a waste product from seafood industry was used as matrix system while green fluorescent protein, a protein which is stable in the pH of wide ranges and temperatures up to 70 °C was used as a model protein.

1.1 Organization of thesis: The thesis is divided into seven chapters. The major objective of the present work is to develop a design approach suitable for diffusion controlled transdermal drug delivery systems based on medically relevant specifications. But before this intricacy can be addressed, it is prudent to understand transdermal drug delivery patch systems. In Chapter 2, we review and explain various types of transdermal drug delivery patches available in the market. We also review recent contributions made to design the transdermal patches pertaining to non-uniform initial concentration distribution of a drug. Chapter 3 describes a novel systematic design approach based on medically relevant specifications. Fick’s law of diffusion is assumed and delivery rates are determined using both classical analytical solutions and numerical methods. Chapter 3 also discusses the issue of

4

packaging, details of theoretical framework, design parameters, the optimization problem and the optimization technique to solve the problem. In chapter 4, the results for two layered patch are discussed. The key design parameters include the initial concentration distribution and layer thicknesses. We also compare two layered patches to three and five layered patches. In chapter 5, we extend the application of our design approach while considering the skin as a barrier. Chapter 6 addresses the issue of particle size distribution in diffusion and degradation controlled drug delivery systems. It discusses the details of spinodal decomposition, which is the governing mechanism in compositional quenching process. Finally, it deals with the details of the compositional quenching process for the dispersion of a model polymeric drug in a natural biopolymer and gives details of experimental procedures, materials and results. Chapter 7 summarizes conclusions and the potential for future work.

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Chapter 2 TRANSDERMAL DRUG DELIVERY

The main goal of controlled-release pharmaceutical dosage forms is to establish relatively constant plasma drug concentrations, avoiding the peaks and valleys associated with the intermittent dosage forms. Various approaches to achieve constant release rates are preparing polymer erosion controlled devices (Rosen, et al., 1983; Gopferich, et al., 1993; Gopferich, et al., 1996) and polymer dissolution controlled devices (Narasimhan, et al., 1995; Narasimhan, et al., 1997) One more method of achieving a constant release rate is to have the drug delivery controlled by a membrane and to maintain an excess of drug inside the delivery device. The drug from this type of system is released into an infinite sink (Brown, et al., 1988). Infinite sink condition means the concentration of a drug in the release medium does not exceed 10-20% of its solubility (Banakar, 1991). Delivering drugs by a transdermal route provides the opportunity to take advantage of the skin to help maintain constant plasma levels of the drug, resulting in reduced systemic adverse effects and the possibility of improved efficacy over other dosage forms (Brown, et al., 1988; Hadgraft, et al., 2006). Importantly, a drug administered by this route is not subject to the first- pass metabolism in the liver, which is a phenomenon of drug metabolism whereby the concentration of a drug is greatly reduced, for e.g., by degradation in the liver before it reaches the systemic circulation. Improved patient compliance is a further advantage that arises from convenience of application and dose flexibility (Hadgraft, et al., 2006). Because of these advantages, the worldwide transdermal drug market was approximately $US 13 billion in 2005 and is expected to increase to $US 21.5 billion by 2010 (Hadgraft, et al., 2006).

6

Absorption of drugs by a transdermal route occurs through a slow diffusion process driven by the concentration gradient of a drug between the delivery device and the skin. Thus, the delivery system must be kept in constant contact with the skin for considerable time. The major drug products currently marketed for transdermal drug delivery are in the form of ointments, gels and transdermal therapeutic systems popularly known as patches. Gels and ointments are disadvantageous due to the varying skin contact area and messiness after application as compared to the neat and precise patch (Scheindlin, et al., 2004). The functional parts of a patch, proceeding from the visible surface inward to the surface opposed to the skin are an impermeable backing membrane, the drug dispersed or dissolved in a polymer matrix or a drug reservoir with a membrane, an adhesive to hold the patch in place on the skin and a release liner that is peeled away before applying the patch (Scheindlin, et al., 2004). Based on the design, five types of patches are available in the market that effectively deliver drug across the skin. They are a) Reservoir systems b) Single-layer drug-in-adhesive c) Multi-layer drug-in-adhesive d) Drug dispersed in matrix systems e) Micro-reservoir dissolution-controlled systems

2.1 The reservoir system: The reservoir system is a first generation approach to transdermal drug delivery. It is characterized by a reservoir containing a solution or suspension of a drug. This reservoir is separated from the release liner by a semi-permeable membrane and an adhesive. The membrane

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controls the rate at which the drug is transferred from the reservoir to the skin surface. The adhesive component of the system can either be incorporated as a continuous layer between the membrane and the release liner or in a concentric configuration around the membrane (3M web site). This adhesive layer may or may not contain a drug. This type of patch design can provide a zero order release pattern to achieve a constant plasma drug level (Hadgraft, et al., 2006). Figure 2-1 shows the schematic for this type of system. Transderm Nitro is a common example of reservoir type system, which contains nitroglycerin and other excipients in the drug reservoir, EVA copolymer as a rate controlling membrane and silicone as an adhesive.

Figure 2-1: Schematic of reservoir type system.

2.2 Single-layer drug-in-adhesive: The simplest devices use the same material as an adhesive and as the drug-containing layer, but conceptually, the adhesive layer can be thin and have no effect on the diffusion behavior beyond sticking the patch to the skin. This design gives the burst effect. Thus, in this design, the adhesive not only serves to affix the system to the skin, but also serves as the drug reservoir containing a drug and all the excipients under a single backing membrane (3M website). Figure 2-2 shows schematic for this type of the system (Hadgraft, et al., 2006). Nitro- Dur II is an example of this type of system, in which the drug, niroglycerin is directly blended with an acrylic based adhesive. These types of patches usually avoid the need for the inclusion of Impermeable backing membrane

Drug reservoir

Rate controlling

membrane

Adhesive layer

Release liner

8

solvents and are thinner and smaller than their reservoir predecessors due to advances in the design and, therefore, they have the benefit of improved patient acceptability and compliance.

Figure 2-2: Schematic of single-layer drug-in-adhesive type system.

2.3 Multi-layer drug-in-adhesive: The goal of this research is to develop a design approach for devices that fits this general scheme, although it differs in details from commercial devices. Specifically, there is no requirement that the drug-containing layers be adhesives. Commercially available systems are similar to the single-layer drug-in-adhesive in that the drug is incorporated directly into the adhesive. These systems help to control the drug release behavior in better way than the single-layer type devices. The multi-layer encompasses either an addition of a membrane between two distinct drug-in-adhesive layers or addition of the multiple drug-in-adhesive layers under a single backing membrane (3M website). The adhesive layers in this system may or may not be composed of same material. Schematic of this type of system is shown in Figure 2-3. Estradiol patch developed by Mylan technologies Inc is an example for this type of system. In this patch, estradiol and other excipients are incorporated in two distinct layers of acrylic based and silicone based adhesive without any addition of membrane in between them (Jackson, et al., 2005).

Impermeable backing membrane

Drug/Adhesive layer

Release liner

9

Figure 2-3: Schematic of multi-layer drug-in-adhesive type system. 2.4 Drug dispersed in matrix systems: In such systems, the drug reservoir is formed by dispersing the drug solids in a hydrophilic or lipophilic polymer matrix and the medicated polymer formed is then molded into medicated discs with a defined surface area and controlled thickness (Chien, et al., 1987). This disc is then mounted onto an occlusive base plate in a compartment formed from a drug impermeable backing membrane. Instead of applying the adhesive polymer directly on the surface of the medicated polymer disc, it is spread along the circumference of the patch to form a strip of adhesive rim around the medicated disc as shown in the following Figure 2-4. This type of system is exemplified by the development of nicotine transdermal system.

Figure 2-4: Schematic of drug dispersed in matrix system.

Impermeable backing membrane

Drug/Adhesive layer 1 Rate controlling membrane Drug/Adhesive layer 2 Release liner

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2.5 Micro-reservoir dissolution-controlled systems: These systems can be considered as a hybrid of the reservoir and matrix type drug delivery systems. In this design, the drug reservoir is formed by first suspending the drug solids in an aqueous solution of a water soluble polymer like polyethylene glycol, and then dispersing homogeneously the drug suspension in a lipophilic polymer, by a high-shear mechanical force to form thousands of unleachable microscopic drug reservoirs as shown in Figure 2-5 (Chien, et al., 1987). This unstable dispersion is stabilized by in situ cross-linking of the polymer chains. The transdermal delivery system can be manufactured by forming the medicated disc at the center of an adhesive pad. This technology has been successfully utilized in the development and marketing of Nitrodisc system (Sanvordeker, et al., 1982).

Figure 2-5: Schematic of micro-reservoir dissolution-controlled system.

2.6 The burst effect: As mentioned earlier, transdermal drug delivery systems are diffusion controlled. Generally, diffusion controlled drug delivery systems, where a drug to be released is uniformly dissolved throughout the polymer, show an initially high release rate or burst effect followed by a rapidly declining rate (Georgiadis, et al., 2001). There are several methods available to overcome this burst effect. Before reviewing these methods, it is necessary to understand the drug release kinetics from a single layered device having uniform initial drug concentration.

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Hadgraft (1979) developed a mathematical model that describes drug release from a single layered release device applied to the skin as a patch. He assumed Fick’s second law of diffusion:

2 2 c c D t x ∂ ∂ = ∂ ∂ (Fick’s law) (2.1)

With an initial condition,

0 0,,0 t c c x L = = < < (2.2)

Subject to the boundary conditions,

,0,0 x L c t = = ≥ (2.3)

0 0,0,0 c x t x ∂   = = ≥   ∂   (2.4)

Where D is diffusivity, L is the thickness, and c is the concentration of a drug in the device.

The first condition (Equation 2.2) states that at 0 t = , there is a uniform concentration ( 0 c ) of the drug in the layer; the second condition (Equation 2.3) shows that the skin is acting as a perfect sink since the concentration at the interface between skin and the patch is zero. Specifically, this assumes that diffusion through the skin and absorption into the body is fast compared to the rate of diffusion out of the patch. The third condition (Equation 2.4) states that there is an impermeable layer on the outside of the patch. Solution of the diffusion equation with the above boundary conditions is well known (Hadgraft, 1979) and gives the following expression.

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2 2 2 2 2 1 8 1 (2 1) 1 exp (2 1) 4 t n M n Dt M n L π π ∞ = ∞     − = − −     −     ∑ (2.5)

Here, M t is the cumulative amount of drug released at time t. M ∞ is the cumulative amount of drug released at time ∞. As shown in Figure 2-6a, the release profile calculated by Hadgraft (1979) using the Equation 2.5 shows rapid initial depletion that corresponds to the burst effect. Although trivially obtained from the analytical solution, Hadgraft (1979) did not calculate the instantaneous drug delivery rate, with representative units of milligrams per day or the flux with representative units of milligrams per day per square centimeter of patch area that more clearly shows the burst effect. Differentiating Equation 2.5 with respect to time and evaluate the result at the skin surface gives Equation 2.6 as,

2 2 2 (2 1) 4 2 1 (/) 2 n Dt L t n d M M D Exp dt L π   − − ∞     ∞   = = ∑ (2.6)

See Figure 2-6b that shows unbounded rates of delivery when a one-layer patch is first applied to the skin.

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To overcome the undesired burst effect, various methods such as modification of the geometries of the device (Conte, et al., 1993; Narsimhan, et al., 1997) and the use of the rate controlling barriers (Lee, et al., 1980; Bodmeier, et al., 1990) have been employed. One additional method is the manipulation of the spatial variation of the initial drug concentration by formation of multilaminates based on the same matrix material containing different initial drug concentration (Lu, et al., 1998; Georgiadis, et al., 2001). Experimentally, the non-uniform initial concentration profiles can be achieved by preparing multilaminates by solvent casting (Bodmeier, et. al., 1990) and photpolymerization techniques (Lu, et al., 1998, 1999). Also, theoretically, it has been proven that this approach can efficiently control the burst effect. Extensive advances have been made in modeling diffusion controlled systems containing a dispersed drug in the single layered drug delivery systems (Paul, et al., 1976, Lee et al., 1980). More contributions involve employment of the finite element method to study the effect of several factors on the kinetics of diffusional drug release from complex geometries (Wu, et al., 1998) and numerical investigation of the diffusional release of a dispersed solute from polymeric multilaminate matrices (Paul, et al., 1985; Charlambopoulu, et al., 2001). However, considerably less effort has been spent on simulating diffusion of a drug when its concentration is non- uniform and below the solubility limits in multi-layered polymer devices. Lee (1986) has examined the effect of non-uniform drug concentration distribution on the release kinetics from diffusion controlled and surface erosion controlled matrix systems containing a dissolved drug. Lu tried to contribute further not only by developing the optimization method to determine the initial drug concentration in layers to attain a system that exhibits a constant drug flux profile as close to the desired required profile as possible (Lu, et al., 1998) but also by developing a photopolymerization technique to create layered matrix devices

Full document contains 142 pages
Abstract: Pharmaceutical controlled release systems, generally constructed from polymers, are defined as the systems which delivers a drug at a predetermined and constant rate for a specified period of time. Such systems exist in many forms, including injectable microspheres, specially designed tablets, implants and transdermal patches. Diffusion, degradation and dissolution are the most important mechanisms that control the drug release from these controlled release systems. However, diffusion controlled drug delivery system is the most widely used drug delivery systems. Diffusion control is particularly important to transdermal drug delivery where degradation and dissolution are nonviable mechanisms to control the release rates. Generally, in diffusion controlled release systems where a drug to be released is uniformly dissolved through a polymer, the release shows initially high rate followed by a rapidly declining rate. Various approaches have been employed over the last two decades to overcome this undesired burst effect and to obtain the desired dose of a drug. The present optimization study, however, concerns the optimal initial concentration distribution of a drug in the delivery device to eliminate the burst effect and obtain a zero-order release. A commonly used objective function for the optimization is the standard of deviation between the instantaneous dose and the desired dose. The numerical value of the objective function provides a little insight from a therapeutic viewpoint. This work describes a novel and systematic approach to the design of transdermal or implanted delivery systems based on medically relevant specifications of maximum allowable dose rate, minimum effective dose rate, time to achieve the effective dose rate, and the design life of the patch. The delivery system is a three layer patch consisting of two drug containing layers of equal thickness and one barrier layer laminated together to form a matrix with a non-uniform initial concentration distribution. This device allows drug release behavior conforming to the medically relevant specifications while maximizing utilization of the drug, i.e. the depletion of the drug from the patch. The thickness of the barrier layer and the relative concentrations in the two drug containing layers are the key design parameters. Optimization studies show little advantage from using variable thicknesses of the two drug containing zones or of using more than two drug containing zones. The application of the design approach is further extended to design a patch considering the skin as a barrier. The last part of the thesis addresses the issue of the particle size distribution of a dispersed drug. It is known that the particle size of a dispersed drug plays a significant role in the release behavior. Compositional quenching, previously used in the manufacture of impact modified conventional polymer blends and biocatalytic composites is applied to disperse a model protein in the natural biopolymer. The green fluorescent protein and chitosan are used as a model protein and polymer, respectively. The manufacture of chitosan composites by solvent evaporation and compositional quenching process is investigated. The chitosan-protein composite manufactured by compositional quenching showed particle size distribution of dispersed protein of the superior quality compared to the solvent evaporation technique.