Liposomes for the controlled delivery of multiple drugs.

摘要

Various pathological conditions, such as cancer, osteoporosis, AIDS, tuberculosis, and other pathologies, require the concurrent use of multiple drugs, known as combination therapy or polytherapy, for effective treatment. The concurrent delivery of multiple drugs in a single dosage form, such as a tablet, capsule or parenteral, has been demonstrated in a number of products, but current technologies for multiple drug delivery remain limited for broad application. Physicochemical incompatibility, limited aqueous and lipid solubility, and chemical instability of the individual drugs, as well as detrimental drug-drug and drug-excipient interactions within the multiple-component dosage form, may all compromise the development of stable, multiple drug delivery systems.;Liposomes have been employed for the delivery of pharmaceuticals, nutraceuticals, and cosmetics for a number of years. Liposomes are now emerging as potential tools for the delivery of multiple therapeutic and diagnostic agents in a single dosage form. While useful for some pharmaceutical applications, liposomes may have certain limitations, such as low drug encapsulation efficiency, poor mechanical and physical stability, and fragile structures that can lead to premature release of encapsulated drug before reaching the target site. Empirical attempts have been made to assemble liposomal structures and divide the space controllably and spontaneously at a nanometer scale into hydrophobic and hydrophilic regions. By understanding the nature of the different microenvironments located within liposomes, multiple drugs with a wide range of physiochemical properties may be incorporated into appropriately designed liposomal structures. Various modifications can be made to the composition and surface modification of liposomes in order to control their size, enhance their stability, and incorporate a combination of multiple therapeutic and diagnostic agents, thereby producing a polyfunctional `theranostic' liposome for improved therapeutic compliance and clinical effectiveness.;We hypothesize that in order make these liposomes and optimize the drug delivery it is necessary to understand the liposome formation procedure with emphasis on the nature of both aqueous and lipid microenvironments so that suitable combinations of therapeutics and diagnostics can be identified and incorporated into the liposome system. Optimization of these nanostructures is necessary in order to enhance their stability while emphasizing the use of GRAS (generally regarded as safe) materials and conforming to compendial standards for injectables. This is followed by characterization of these delivery devices in terms of their structure, drug loading, size, morphology, thermal characteristics, reproducibility of formulation, and stability using microscopic, light, electric, magnetic, chromatographic, and thermal analysis, as well as an appreciation of the interaction of encapsulated small molecules with lipid components. Finally, an evaluation of the performance of these vesicles as controlled delivery devices using an externally applied magnetic field in order to trigger bolus or pulsatile drug release is summarized.;This study has provided important predictive information regarding the formation, formulation, stability, and performance characteristics of theranostic liposomal delivery systems in the context of the specific physicochemical properties of selected combinations of chemically diverse drugs and other small molecules that are nevertheless clinically relevant. It is hypothesized that these data will be useful in the design and optimization of analogous systems containing drugs with similar properties. The use of a magnetic field-induced release mechanism will afford data regarding the utility of this controlled release mechanism in multiple drug-containing systems. The successful design and characterization of these systems may lead to improved therapeutic efficacy of combination drug therapy, increased patient compliance, ease of use, and targeted drug delivery for reducing both dosing frequency and toxicity.;The work has been prepared for publication and included in the thesis as follows: 1) Manuscript 1: Design and development of liposomes for concurrent, controlled delivery of therapeutic agents for bone osteoporosis (in preparation Pharmaceutical Research). 2) Manuscript 2: The interactions and effects of di- and polyphenolic compounds on lipid vesicles (in preparation Lipid Research). 3) Manuscript 3: The design and development of liposomes for the concurrent, controlled delivery of multiple therapeutic agents for improving the efficacy of pancreatic cancer treatment (in preparation Journal of Controlled Release). (Abstract shortened by UMI.).