Purpose: The purpose of this study was to investigate possible effects of different microemulsion structure-types and types of monomer used on the formation of poly(alkylcyanoacrylate) nanoparticles, the entrapment into and release of insulin from these formulations as well as the bioactivity of the insulin upon intragastric delivery of the insulin-loaded nanoparticles dispersed in the microemulsion template.
Methods: For two different microemulsion systems consisting of water, isopropyl myristate and either sugar-based surfactants or a macrogol glyceride-based surfactant-mixture, pseudo-ternary phase diagrams were established. Microemulsion samples therein were identified and characterised with polarising light microscopy, viscosity and conductivity measurements, differential scanning calorimetry, cryo-field emission scanning electron microscopy and self-diffusion nuclear magnetic resonance to determine the microemulsion structure-type. Nanoparticles were prepared from various microemulsion templates by interfacial polymerisation using ethyl (2) cyanoacrylate and butyl (2) cyanoacrylate. Particle size distribution and surface charge were measured using photon correlation spectroscopy and electrophoretic mobility. The morphology of the particles was characterised by scanning and transmission electron microscopy. Insulin was used as a model protein and the amount entrapped into and released from the particles was determined using a reverse phase HPLC assay. A diabetic rat model was employed to examine the bioactivity of different nanoparticle-microemulsion formulations with blood glucose and serum insulin as parameters measured by a proprietary glucometer and enzyme-linked immunosorbent assays, respectively.
Results: The microemulsion system based on sugar-surfactants only formed solution-type microemulsions which could not all satisfactorily be used as a polymerisation template in the presence of insulin. The system however also showed an environmentally responsive gelling behaviour which may be suitable for depot delivery. The macrogol glyceride-based microemulsion system resulted in microemulsions with a continuous transition from water-in-oil to oil-in-water droplet-types via the bicontinuous structure-type. Microemulsion samples of each structure-type could serve as nanoparticle templates and resulted in particles with similar properties. Entrapment efficiency of insulin into the nanoparticles was template and monomer dependent. However, insulin was found to interfere with the polymerisation leading to a high variability in entrapment and release kinetics of these drug delivery systems. The degree of interference depended on the type of monomer and the size of the aqueous pseudo-phase of the microemulsion template. The interpretation of the results was further complicated by a possible competitive polymerisation initiation of insulin with the surfactant-mixture. Upon intragastric administration of the insulin-loaded nanoparticles dispersed in the oil-in-water microemulsion template a significant reduction in blood glucose could be achieved for up to 30 hours. However, no significant serum insulin concentration was detectable.
Conclusions: Structurally different microemulsion templates resulting in nanoparticles with similar properties may offer increased formulation flexibility, in that a microemulsion template can be chosen which best solubilises the drug. Thus the microemulsions investigated in this thesis may serve as nanoparticle templates for designing entrapment processes for peptides and proteins with a simple one-step preparation by interfacial polymerisation. However, only if one was able to optimise and control the factors leading to the high entrapment and release variability these nanoparticles on the basis of microemulsions might be promising carriers for the oral delivery of peptide and protein bioactives.
| Identifer | oai:union.ndltd.org:ADTP/197585 |
| Date | January 2008 |
| Creators | Graf, Anja, n/a |
| Publisher | University of Otago. School of Pharmacy |
| Source Sets | Australiasian Digital Theses Program |
| Language | English |
| Detected Language | English |
| Rights | http://policy01.otago.ac.nz/policies/FMPro?-db=policies.fm&-format=viewpolicy.html&-lay=viewpolicy&-sortfield=Title&Type=Academic&-recid=33025&-find), Copyright Anja Graf |
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