DEVELOPMENT OF CONTROLLED DRUG DELIVERY SYSTEMS USING UNIFORM NANOPOROUS MATERIALS AS MATRICES SONG SHIWEI (M. Eng, ICC, CAS) A THESIS SUBMITTED FOR THE DEGREE OF DOCTOR OF PHILOSOPHY DEPARTMENT OF CHEMICAL & BIOMOLECULAR ENGINEERING NATIONAL UNIVERSITY OF SINGAPORE 2007 Acknowledgements Acknowledgements My debts outweigh my achievements. First and foremost, I would like to warmly thank my supervisors, A/Prof. Sibudjing Kawi and A/Prof. Kus Hidajat, who have been offering continuous support and guidance throughout my PhD candidate period. I greatly appreciate their ways to direct me how to think critically and write logically. Their strong knowledge and broad vision infused into me made this research a creative experience. I would like to take this opportunity to express my sincere gratitude to my PhD thesis committee members: A/Prof. Feng Si-Shen and Dr. Lanry Yung, who dedicated their precious time to discuss my project, raising good points and giving insightful comments. Special thanks would be given to Prof. Tai-Shung Chung, who has been generously offering me help during my PhD candidature. I also wish to take this opportunity to thank all our group members, past and present: Dr. Shen Shoucang, Dr. Manickam Selvaraj, Yong Siek Ting, Zeng Houxu, Li Peng, Luan Deyan, Yang Jun, Sun Gebiao, Malik Jamal J and Wu Xusheng, who have been sharing the important time in my life, giving me kindly assistance and listening to my complaints and frustrations, about research and life. I’m grateful for the excellent assistance from Mdm Siew Woon Chee, Mdm Chew Pek, Ms Chew Su Mei, Ms Li Feng Mei, Mdm Li Xiang, Ms Tay Choon Yen, Ms Goh Siew Ping and Ms Lee Chai Keng who helped me during the course of this research. Thanks to those who took so much of drudgery on TEM, FESEM and XPS characterizations: Mr. Chia Phai Ann, Dr. Yuan Zeliang, Mr. Shang Zhenhua, Mdm Fam Hwee Koong and Mr. Mao Ning. Thanks also to Mr. Zhong Shaoping who did MTT cytotoxicity studies of the materials. i Acknowledgements I had the pleasure to instruct and work with several undergraduate students: Ramya Priyadarsini Selvaraj, Regina Karmacharya, Zhang Shouyin and Ng Chuk Yung who did their final year projects with me and somehow have done beneficial work for this thesis. I also wish to thank National University of Singapore for providing me abundant resources and financial assistance to make accomplishment of my PhD research become possible. Last, but not least, I’m greatly indebted to my family: my mother and father, especially my husband, Chang Jie, who have given me endless love and infinite patience during the long journey of inspiration, gestation and perspiration required for this PhD thesis research. ii Table of Contents Table of Contents Acknowledgements i Table of Contents iii Summary vii Nomenclature x List of Figures xii List of Tables and Schemes xvi CHAPTER - INTRODUCTION 1.1 Background 1.2 Research Objectives 1.3 Thesis Organization CHAPTER - LITERATURE REVIEW 2.1 Polymers 2.1.1 Reservoir devices 2.1.1.1 General Considerations 9 2.1.1.2 Release Mechanisms 11 2.1.1.3 Fabrication of Reservoir Devices 14 2.1.1.4 Limitations 15 2.1.2 Matrix devices 15 2.1.2.1 General Considerations 15 2.1.2.2 Release Mechanisms 16 2.1.2.3 Fabrication of Matrix Devices 19 2.1.2.4 Limitations 21 2.1.3 Biodegradable polymeric devices 21 2.1.3.1 General Considerations 21 2.1.3.2 Polymer Erosion Mechanisms 24 2.1.3.3 Biodegradable Polymeric Materials 26 2.1.3.4 Limitations 28 2.2 Liposomes 28 2.2.1 General Considerations 28 2.2.2 Classification of Liposomes 30 iii Table of Contents 2.2.3 Methods of Preparation 33 2.2.4 Limitations of Liposomes 34 2.3 Activation-Controlled Devices 35 2.4 Ordered Mesoporous Materials 37 2.4.1 Synthesis of Ordered Mesoporous Silica 38 2.4.2 Applications of Ordered Mesoporous Silica 45 2.4.2.1 Catalytic Applications 45 2.4.2.2 Nanocasting 48 2.4.2.3 Sorption and Separate Applications 50 2.4.2.4 Biomedical Applications 53 CHAPTER - MATERIALS AND METHODS 57 3.1 Materials 57 3.1.1 Ibuprofen 57 3.1.2 Bovine Serum Albumin 57 3.2 Methods 58 CHAPTER - AMINE-FUNCTIONALIZED SBA-15 MATERIALS AS CARRIERS FOR CONTROLLED DELIVERY OF IBUPROFEN 62 4.1 Introduction 62 4.2 Experimental 64 4.2.1 Materials and Synthesis 64 4.2.2 Drug Loading Procedures 65 4.2.3 In vitro Drug Release Studies 65 4.2.4 Characterization Methods 66 4.3 Results and Discussion 67 4.3.1 Characterization of Functionalized SBA-15 67 4.3.2 Loading SBA-15 with IBU 76 4.3.3 In vitro Release Studies 78 4.3.4 Surface Interaction between SBA-15 and IBU 79 4.4 Conclusions 83 CHAPTER - ADSORPTION AND SUSTAINED RELEASE OF BOVINE SERUM ALBUMIN ON FUNCTIONALIZED SBA-15 84 5.1 Introduction 84 5.2 Experimental 87 5.2.1 Materials and Synthesis 87 iv Table of Contents 5.2.2 Adsorption Isotherms 87 5.2.3 In vitro Drug Release Studies 88 5.2.4 Characterization Methods 88 5.3 Results and Discussion 5.3.1 Characterization of Materials 89 89 5.3.2 Effects of Different Functional Groups on BSA Adsorption and Release 96 5.3.3 Effects of pH Values and Amine Group Contents on BSA Adsorption 97 5.3.4 Effect of Pore Size on BSA Adsorption 103 5.3.5 In vitro Release Studies 107 5.4 Conclusions 111 CHAPTER - FACTORS AFFECTING THE STABILITY OF BOVINE SERUM ALBUMIN IN FABRICATION OF DRUG DELIVERY SYSTEMS 113 6.1 Introduction 113 6.2 Experimental 115 6.2.1 Materials and Synthesis 115 6.2.2 Adsorption Isotherms 116 6.2.3 Determination of Conformational Changes of BSA by CD 116 6.2.4 Characterization Methods 117 6.3 Results and Discussion 117 6.3.1 Effect of Functionalization Methods 117 6.3.2 Effect of Pore Size 125 6.3.3 Effects of Temperature 129 6.3.4 Effects of pH Value 133 6.4 Conclusions 137 CHAPTER - SMART PH-CONTROLLABLE DRUG DELIVERY SYSTEM BASED ON REMOVABLE POLY(ACYLIC ACID) ENCAPSULATED SBA-15 138 7.1 Introduction 138 7.2 Experimental 140 7.2.1 Materials 140 7.2.2 BSA Loading 140 7.2.3 PAA Encapsulation 140 7.2.4 In vitro Release Studies 141 7.2.5 Characterization Methods 141 7.3 Results and Discussion 142 v Table of Contents 7.3.1 Surface Properties of Materials on PAA Encapsulation 142 7.3.2 Characterization of Materials 146 7.3.3 In vitro Release Studies 150 7.3.4 Cytotoxicity Studies 153 7.4 Conclusions 156 CHAPTER - CONCLUSIONS AND FUTURE RECOMMENDATIONS 158 8.1 Conclusions 158 8.2 Future Recommendations 160 References 163 Publications 186 vi Summary Summary This thesis reports the study of fine-tuning the properties of ordered mesoporous silicas and their potential application in controlled drug delivery. The recent application of mesoporous silicas extended to controlled drug delivery has raised much interest due to their non-toxic nature, high surface area, large pore volume, tunable pore size and chemically modifiable surfaces, allowing them to be potential hosts for various drugs. In this research, ordered mesoporous silica SBA-15 materials have been functionally modified and investigated as controlled drug delivery matrices for both small molecule model drug of ibuprofen (IBU) and large protein drug of bovine serum albumin (BSA). In the preparation of controlled drug delivery system for IBU, mesoporous SBA15 materials were functionalized with amine groups through post synthesis and one-pot synthesis. It is revealed that the adsorption capacities and release behaviors of IBU are highly dependent on the different surface properties of SBA-15 materials. The release rate of IBU from SBA-15 functionalized by post synthesis is found to be effectively controlled as compared with that from pure SBA-15 and SBA-15 functionalized by one-pot synthesis due to the stronger ionic interaction between carboxyl groups in IBU and amine groups on the surface of SBA-15 functionalized by post synthesis. In contrast to small molecular drug IBU, the fabrication of controlled drug delivery system for large protein model drug BSA is more complicated, as it involves not only the properties of drug matrix itself but also the stability of protein drug. In the first part of the work, the adsorption isotherms of BSA on SBA-15 were determined at various conditions in order to find the favorable conditions for large adsorption capacities. Based on their plateau adsorptions values, it is observed that higher BSA vii Summary adsorption capacities are obtained on SBA-15 with higher amine group content, larger pore size and near the isoelectric region of BSA. Electrostatic interaction is suggested to be the driving force that prompts mild BSA adsorption on hydrophilic surface of amine-functionalized SBA-15 and slower release rate on SBA-15 with higher amine group contents. Due to relatively larger amount of BSA adsorbed on the external surface of SBA-15 of smaller size, the overall release rate of BSA from SBA-15 with smaller pore size is faster than that with larger pore size. In the second part of the work, the conformational changes of BSA under various processing conditions were investigated. It is found that BSA displays reduced α-helix content when released from amine-functionalized SBA-15 prepared by post-synthesis, due to the hydrophobic interaction between BSA and the material which tends to induce conformational changes. In addition, BSA adsorption on SBA-15 of smaller pore size, adsorption process occurring at high temperatures and high pH values are found to induce more loss of α-helix, and the possible explanations for the results are proposed. Finally, a smart pH-controllable drug delivery system was prepared through encapsulation of amine-functionalized SBA-15 with poly(acrylic acid) by electrostatic assembly. Surface charge and hydrophilicity are found to be two important surface properties of SBA-15 determining the encapsulation process. It is shown the entrapped protein from the resulting system can be released at neutral medium (pH 7.4) rather than at acidic medium (pH 1.2). Cytotoxicity studies show that such pH-sensitive system has little toxicity effect even at a high particle concentration of 0.5 mg/ml. 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(Poster Presentation). 186 [...]... need to develop new controlled release strategies has been intensified by development of solid-phase peptide synthesis and emergence of gene therapy The revival of established drugs and clinical success of innovative drugs may be dependent on the design of controlled release systems that ensure that the drugs reach their desired sits precisely at the optimal dosage for optimal length of time Therefore,... variety of visco-elastic properties special characteristics associated with phase transitions ablility to contract when heated variety of dissolution times specialized chemical reactivities tolerance of a variety of manufacturing methods Polymeric drug delivery systems under wide investigations are classified according to the mechanism controlling the release of the drug Some of the basic systems are... Therefore, there have been a lot of attempts to design various types of controlled drug delivery system During the past three decades these systems have experienced massive advancement in terms of scope and sophistication Broadly categorized based on the properties of materials and release mechanisms, different delivery systems including polymers, liposomes, activation -controlled devices, and mesoporous... Therefore, it can give benefits to drug companies by creating new forms of established drugs and offering improved versions of drugs It has been shown that companies developing new drug delivery systems seem to enjoy a good return on their investment in the form of increased revenue and market share (Tyle, 1988) In its therapeutic aspect, the rationale for controlled drug delivery is to alter the pharmacokinetics... melting of a polymer /drug mixture, and the drug release rate can be mathematically expressed as 1 J =− dM t 1 = f (kt 2 ) dt A 15 2 / Literature Review Drug Drug is dispersed uniformly in non-degradable matix Matrix Increasing time Drug Drug Drug Drug Drug Figure 2.3 A schematic representation of the matrix devices Matrix devices include the following formulations (Langer and Wise, 1983): 1 Dissolved systems. .. displacement of drug by solvent 2.1.2.2 Release Mechanisms The release of drugs from matrix devices is governed by the diffusion of solution within the matrix phase The development of the appropriate form of the release rate 16 2 / Literature Review equation is generated via solutions of Fick’s first and second laws of diffusion In general, three limiting cases exist First, when the initial drug load... within the zone of depletion As a consequence, release-rate equations are dependent upon the geometry of the device 2.1.2.3 Fabrication of Matrix Devices As the composition of different polymers used as matrices can permit very different rates of diffusion, thus manipulating drug release rates extensively, there is a need to choose suitable polymer matrices based on the properties of the drug and the... resulting materials have good stability against water The discovery of SBA-15 has opened up new application of mesoporous materials as its large pores can be hosts for large proteins or biomacromolecules (Washmon et al., 2000; Vinu et al., 2004; Hudson et al., 2005; Balas et al., 2006) One of the main purposes of this research is to explore the potential application of SBA-15 as drug delivery systems. .. activation -controlled devices are summarized Further emphasis has been placed upon synthesis and application of ordered mesoporous materials, which is proposed as a novel drug delivery system in this research Chapter 3 introduces the materials and experimental menthods employed in this thesis work Chapter 4 describes the application of SBA-15 in the delivery of the small molecule model drug of ibuprofen... current controlled- release systems can respond to changing biological environments such as temperature (Dong and Hoffman, 1990), pH (Peppas and Peppas, 1989), or glucose concentration (Ishihara and Matsui, 1986), and the delivery or cease -delivery of the particular drug can be triggered by external environment changes Therefore, materials that have been developed could lead to targeted delivery systems, . DEVELOPMENT OF CONTROLLED DRUG DELIVERY SYSTEMS USING UNIFORM NANOPOROUS MATERIALS AS MATRICES SONG SHIWEI (M. Eng, ICC, CAS) A THESIS. give benefits to drug companies by creating new forms of established drugs and offering improved versions of drugs. It has been shown that companies developing new drug delivery systems seem. molecule model drug of ibuprofen (IBU) and large protein drug of bovine serum albumin (BSA). In the preparation of controlled drug delivery system for IBU, mesoporous SBA- 15 materials were functionalized