Please use this identifier to cite or link to this item:
Title: Development of gelation emulsion based method for fabrication of composite nanoparticles
Authors: Huang, Wenfei
Degree: Ph.D.
Issue Date: 2017
Abstract: The demands for developing effective drug delivery systems will continue to expand significantly in the foreseeable future, due to increasing patients and medical treatments. Nanoparticulated controlled drug delivery system has become increasingly attractive, because of their capabilities to deliver the active ingredients to the target disease sites and then release in a controlled manner, which contributes to improve the therapeutic efficiency and minimize the potential side effects. Biodegradable polymer nanoparticle is one of the promising controlled drug delivery systems, owing to its superior biocompatibility and controllable biodegradability. Various water soluble active ingredients have been successfully encapsulated in the polymer nanoparticles of a core-shell structure. Drug release kinetics of these polymer nanoparticles can only be adjusted by changing the composition of the polymeric shell. The relatively fast release rates of these polymer nanoparticles have been found, due to the poor long-term physical and chemical stability. Both the fast release rate and narrow drug release adjustment window have limited the application of polymer nanoparticles in prolonged controlled drug delivery. Double emulsion/solvent evaporation technique is usually adopted for preparation of core-shell polymer nanoparticles. However, it was discovered that hydrophilic active ingredients as the cores tended to leak to the external aqueous phase during emulsification leading to undesirable waste of these ingredients and thus low encapsulation efficiency. To solve all the aforementioned problems, a drug loaded silica xerogel core-polymer shell composite nanostructure was proposed. Drug leakage was designed to be minimized by stabilizing the ingredients with the help of the gelation of silica xerogel during the emulsification process. Different from conventional polymer nanoparticles, the proposed composite nanoparticles with the core-shell structure were assumed to exhibit two-stage drug release kinetic. The first release stage is characterized by the dissolution behavior of drugs attached or embedded on the surfaces of the polymeric shells; the second release stage is primarily influenced by the degradation behaviors of the polymeric shell and drug dissolution behaviors from silica xerogel core. With this proposed structure, the drug release kinetics would be well manipulated by changing the composition of polymeric shell and silica xerogel core. It was found that the current fabrication techniques of polymer nanoparticles were not applicable to prepare the proposed composite nanoparticles. A facile gelation emulsion based method is therefore proposed by the integration of sol gel and double emulsion technologies. Besides controllable drug release kinetics, prolonged drug release duration, enhanced encapsulation efficiency, controllable size is a fundamental property for nanoparticles as effective controlled drug delivery systems. There were several challenges before all these desired properties of composite nanoparticles could be addressed, such as investigating effects and optimization strategy of fabrication parameters (comprised of process and compositional parameters).
To study the effects of process parameters and develop the corresponding optimization strategy, the dominant process factors and corresponding effects on the size and encapsulation efficiency were firstly determined by a theoretical study. A 4-factor central composite face-centered experimental design was performed to confirm and quantify these effects. To investigate the effects of the compositional parameters on the size of composite nanoparticles, theoretical analysis was firstly performed to assess changing tendencies of the compositional factors (in terms of polymer concentration and drug loading capacity). A semi-empirical equation was well established in the first attempt with the combination of theoretical studies and experimental results to interpret the effects of polymer concentration and drug loading capacity on the size of the composite nanoparticles. The gelation emulsion based technique has been successfully developed for the fabrication of composite nanoparticles with desired properties, which has filled the research gap of nanofabrication by providing a simple and effective way to prepare the composite nanoparticles. Spherical polymer/silica xerogel composite nanoparticles were prepared with an adjustable size range of 190 to 1000 nm and optimal encapsulation efficiency up to 92%. The drug release profiles were well interpreted by the Baker and Lonsdale model on a predicted two-stage basis. The drug release of the first stage (1 day) was well controlled from 18.6% to 45.9%; while drug release of the second release stage (14 days) were tailored in a range of 28.7- 58.2% by changing the composition of silica xerogel cores and polymeric shells. Significant achievement was also achieved in reducing the drug release rate of the composite nanoparticles up to over 40 times lower than conventional polymer nanoparticles by virtue of the silica xerogel cores. The optimization strategy has been established to explore the optimal combination of primary process variables for target size and encapsulation efficiency. With the help of the silica xerogel core as well as the developed optimization strategy, encapsulation efficiency of the prepared composite nanoparticles has enhanced 1-3 times over the conventional polymer nanoparticles. The application of the developed gelation emulsion method is not limited to processing of silica xerogel/polymer materials, which has been confirmed after successfully achieved all the targeted properties of the proposed composite nanoparticles. Surface charge switchable and pH responsive vancomycin loaded chitosan/polymer composite nanoparticles have been successfully fabricated based on the modified gelation emulsion technique. An adjustable size range of 316-573 nm and optimal drug encapsulation efficiency of 70.8% were observed. Surface charges of the particles could be controlled from -27.6 to 31.75 mV by adjusting the concentrations of the chitosan and NH3 solutions. A modified first order release kinetic has been made to well interpret the first release stage (1 day). The release rates of the second release stage (14 days) of the prepared composite nanoparticles were accelerated by two orders of magnitude in a PBS solution with a pH value reduced from 7.4 to 1.2, which has confirmed the pH responsive property of the composite nanoparticles. All these results have confirmed he feasibility of applying the gelation emulsion based method for the other formulations. After evaluation of the applicability for other formulations, preliminary modification of the proposed technique for scalable production has also been conducted. An ultrasonic atomization assisted gelation nano-precipitation method was proposed by replacing the second emulsion process with the ultrasonic assisted nano-precipitation. This modified method has shown reduced particle agglomeration as compared with the emulsion based method for a large batch of nanoparticle fabrication. All these results confirmed the composite nanoparticles to be promising controlled drug delivery systems. The effectiveness and broad applicability of the developed gelation emulsion based method in preparing the composite nanoparticles has also been confirmed, which opens a new window for nanofabrication research.
Subjects: Hong Kong Polytechnic University -- Dissertations
Nanostructured materials -- Design and construction
Pages: xxiv, 218 pages : illustrations
Appears in Collections:Thesis

Show full item record

Page views

Last Week
Last month
Citations as of Jun 4, 2023

Google ScholarTM


Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.