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|Title:||Bioactivty and controlled release studies of ranibizumab from polymeric carriers||Authors:||Chua, Hui Yee||Keywords:||DRNTU::Engineering::Materials::Biomaterials||Issue Date:||2018||Source:||Chua, H. Y. (2018). Bioactivty and controlled release studies of ranibizumab from polymeric carriers. Doctoral thesis, Nanyang Technological University, Singapore.||Abstract:||Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in developed societies. Ranibizumab is an anti-angiogenic agent commonly prescribed to treat AMD. However several issues associated with its frequent intravitreal injections have intensified the need for a sustained delivery system. This thesis aims to explore the feasibility of using synthetic polymer- poly(lactic-co-glycolic) acid (PLGA), as the carrier for sustained ranibizumab delivery, at the same time addressing the common issues encountered while incorporating delicate hydrophilic drug such as ranibizumab inside polymeric carriers using emulsions techniques. Protein instabilities that aroused due to carrier release condition or fabrication process have been evaluated using in-house enzyme linked immunoassay for quantification of bioactive ranibizumab. Significant proteins loss was observed due to adsorption only when the protein content was low (in nanograms range), which could be prevented with the use of appropriate buffers, leveraging on excipients and pH of the buffer. In addition, ranibizumab stability as a result of fabrication stresses was simulated and it was demonstrated that ranibizumab bioactivity was indeed affected during emulsion, where ranibizimab might have denatured at the organic-water interface. This denaturation can be salvaged through the use of polyvinyl alcohol as the emulsifying agent at an optimal concentration of 1% in the first aqueous phase during the water-in-oil-in-water (WOW) emulsion process. Notably, in the solid-in-oil-in-water (SOW) emulsions, the use of solid ranibizumab proteins was found to be stable without the need of emulsification agent. In vitro release study demonstrated that particles formulated from SOW possessed relatively lower burst release and ranibizumab released was sustained for 15 days while particles formulated from WOW suffered from burst release with no further release. The sustained release observed from SOW particles was deemed to be diffusion controlled. It is worth to note that the released ranibizumab from SOW particles retained the highest bioactivity, which could be attributed to the reduced interaction between the encapsulated protein and polymer, where the proteins in the interior of the solid protein particle is shielded with less homogenous drug distribution. The applicability of SOW technique in preserving ranibizumab activity and achieving sustained release was further demonstrated through varying the particle size and the hydrophobicity of the polymer used. Despite suffering from burst release, WOW particles possessed higher encapsulation efficiency an important factor for its translational potential. Porous surface morphology, identified as the main cause for the burst release in WOW particles needs to be addressed. For the first time, non-porous ranibizumab-loaded WOW particles were fabricated through manipulating the osmotic pressure between different phases via varying sodium chloride (NaCl) concentration in the external aqueous phase. These WOW particles fabricated with NaCl in the second aqueous phase (W2) maintained their typical high drug encapsulation efficiency. Notably, these particles displayed minimal burst release and biphasic profiles for the subsequent release: the initial slow release could be attributed to the diffusional release, while the faster release after 2 weeks was due to bulk degradation that corroborated with mass loss of the particles. The release was improved and continued for 40 days. In conclusion, the use of a biodegradable polymer to incorporate and release bioactive ranibizumab over a period of 40 days was highlighted in this work. This is a significant achievement, and points the way to particulate or implantable systems that can deliver ranibizumab against various conditions, for example AMD and diabetic retinopathy.||URI:||http://hdl.handle.net/10356/73341||DOI:||10.32657/10356/73341||Fulltext Permission:||open||Fulltext Availability:||With Fulltext|
|Appears in Collections:||IGS Theses|
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Updated on May 6, 2021
Updated on May 6, 2021
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