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Design and development of an implantable drug delivery polymeric scaffold for the treatment of Parkinson's diseasePillay, Samantha 11 November 2009 (has links)
M. Pharm., Faculty of Health Sciences, University of the Witwatersrand, 2009 / Parkinson's disease, primarily defined as the depletion of dopaminergic neurons in the subtantia nigra of the brain, gives rise to
severely debilitating motor symptoms. The pharmacological gold standard treatment for the disease, Levodopa , holds great
limitations yet still remains the most effective treatment for the disease for the last 40 years. There has been research into novel drug
delivery systems for the treatment of the disease that include the development of implantable devices however none have been
introduced onto the market. As the neurodegenerative disorder ravages the younger-aged population so the urgency for the effective
chronic treatment of the disease escalates. The field of nanotechnology brings promise for the targeted delivery of drugs which is
highly sought after in the treatment of central nervous system disorders. A nano-enabled scaffold device (NESD) incorporating
dopamine nanoparticles into a polymeric scaffold for implantation into the brain parenchyma may be able to address and overcome
the limitations of the current treatment for Parkinson's disease.
Investigations performed cellulose acetate phthalate dopamine-loaded nanoparticles, employing an adopted emulsification-diffusion
approach, produced particles with a notably high drug entrapment efficiency (63.05±0.354%) and desirable controlled drug release
profiles (16.23% in 24hr). The employment of an experimental design, namely the Box-Behnken design, allowed for the attainment of
optimized nanoparticles with high zeta potentials (.34.00mV), minimal particle size (197.20nm) and extended mean dissolution times
(40.96).
Barium chloride was employed to crosslink calcium-alginate scaffolds formulated in an adopted freeze-drying approach. Highly
resilient (63.58±5.13) and porous structures (pore sizes of 100-400μm) were developed. A statistical approach employing the Box-
Behnken design resulted in the formulation of a candidate barium-alginate scaffold displaying maximum matrix resilience (82.46%)
and minimal matrix erosion (18.23%) over in 30 days. In addition, dopamine-loaded nanoparticles were dispersed within the scaffold
that formed the NESD with the desired drug release profiles (5.12% in 168hr).
Nanosystems of levodopa, nicotine and dopamine nanofibers were preliminary investigated. Drug release profiles for levodopa
(4.21%: in 75hr), nicotine (0.42% in 24hrs) and drug entrapment efficiency for the polymeric nanofibers (75-85%) as well as data
from scanning electron microscopy, zetasize analysis and drug release studies proved that these systems hold potential for the
treatment of the disease and therefore require further investigation.
Ex vivo cytotoxic studies carried out on the NESD and it's separate entities proved that the NESD was biocompatible with the white
blood (70-80% cell viability in 24hr) and carcinomic brain cells (25% cell viability in 48hr) despite literature reports of dopamine being
highly toxic in vivo.
Extensive in vivo studies resulted in the development of a protocol for the surgical implantation of the NESD in the parenchyma of
the frontal lobe of the rat brain. Scanning electron microscope images showed the gradual bioerosion (26% in 30 days) of the NESD
while histological findings of the brain tissue proved clinically insignificant (absence of ischemia or chronic inflammation). Ultra Liquid
Performance Chromatography revealed higher concentrations of dopamine in the CSF of rats which received brain implants of the
NESD (28%) than in those administered the oral preparation, Sinemet (0.000012%) in 3 days.
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Additives to Control Mechanical Properties and Drug Delivery of Injectable Polymeric ScaffoldsFisher, Paul 01 January 2014 (has links)
In situ forming implants (ISIs) are popular due to their ease of use and local drug delivery potential, but they suffer from high initial drug burst, and release behavior is tied closely to solvent exchange and polymer properties. Additionally, such systems are traditionally viewed purely as drug delivery devices rather than potential scaffold materials due to their poor mechanical properties and minimal porosity. The aim of this research was to develop an injectable ISI with drug release, mechanical, and microstructural properties controlled by micro- and nanoparticle additives.
First, an injectable ISI was developed with appropriate drug release kinetics for orthopedic applications. Poly(β-amino ester) (PBAE) microparticles were loaded with simvastatin or clodronate, and their loading efficiency and drug retention after washing was quantified. Drug-loaded PBAE microparticles and hydroxyapatite (HA) microparticles were added to a poly(lactic-co-glycolic acid) (PLGA)–based ISI. By loading simvastatin into PBAE microparticles, release was extended from 10 days to 30 days, and burst was reduced from 81% to 39%. Clodronate burst was reduced after addition of HA, but was unaffected by PBAE loading. Scaffold mass and porosity fluctuated as the scaffolds swelled and then degraded over 40 days.
Next, the mechanical properties of these composite ISIs were quantified. Both micro- and nanoparticulate HA as well as PBAE microparticle content were varied. Increasing HA content generally improved compressive strength and modulus, with a plateau occurring at 30% nano-HA. Injectability remained clinically acceptable for up to 10% w/w PBAE microparticles. Ex vivo injections into trabecular bone improved both strength and modulus.
Lastly, HA-free ISIs were investigated for drug delivery into the gingiva to treat periodontitis. Doxycycline and simvastatin were co-delivered, with delivery of doxycycline over 1 week accompanied by simvastatin release over 30 days. PBAE-containing ISIs exhibited higher initial and progressive porosity and accessible volume than PBAE-free ISIs over the course of degradation. Additionally, PBAE-containing ISIs provided superior tissue retention within a simulated periodontal pocket. The ISIs investigated here have a wide range of potential applications due to their flexible material and drug release properties, which can be controlled by both the chemistry and concentration of various particulate additives.
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