A multidisciplinary literature survey revealed that copolymeric nanoparticles could be applied in various technologies such as the production of paint, adhesives, packaging material and lately especially drug delivery systems. The specialized application and investigation of copolymers in drug delivery resulted in the synthesis of two series of copolymeric materials, i.e. poly(styrene-co-methyl methacrylate) (P(St-co-MMA)) and poly(styrene-co-ethyl methacrylate) (P(St-co-EMA)) were synthesized via the technique of o/w microemulsion copolymerization. These copolymers have not as yet been utilized to their full potential in the development of new drug delivery systems. However the corresponding hydrophobic homopolymer poly(styrene) (PS) and the hydrophilic homopolymer poly(methyl methacrylate) (PMMA) are known to be biocompatible. Blending of homopolymers could result in novel applications, however is virtually impossible due to their unfavorable mixing entropies. The immiscibility challenge was overcome by the synthesis of copolymers that combined the properties of the immiscible homopolymers. The synthesized particles were analyzed by gel permeation chromatography combined with multi-angle laser light scattering (GPC-MALLS) and attenuated total reflectance Fourier infrared spectroscopy (ATR-FTIR). These characterizations revealed crucial information to better understand the synthesis process and particle properties i.e. molecular weight, nanoparticle size and chemical composition of the materials. Additionally, GPC-MALLS revealed the copolymer chain conformation. These characterizations ultimately guided the selection of appropriate copolymer nanoparticles to develop a controlled-release drug delivery system. The selected copolymers were dissolved in a pharmaceutically acceptable solvent, tetrahydrofuran (THF) together with a drug, rifampin. Solvent casting of this dispersion resulted in the evaporation of the solvent and assembly of numerous microscale copolymer capsules. The rifampin molecules were captured in these microcapsules through a process of phase separation and coacervation. These microcapsules finally sintered to produce a multi-layer film with an unusual honeycomb structure, bridging yet another size scale hierarchy. Characterization of these delivery systems revealed that both series of copolymer materials produced films capable of controlling drug release and that could also potentially prevent biofilm adhesion. / Thesis (Ph.D. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2008.

Fibroin is a biopolymer obtained from the cocoons of the Bombyx mori silkworm that offers many unique advantages. In this thesis work, fibroin was processed into a regenerated film and examined for potential biomaterial applications. The adsorption of bovine serum albumin onto the fibroin film was investigated to examine the biocompatibility of the film, and it was found that BSA adsorption capacity increased with an increase in BSA concentration. At 10 mg/mL of BSA, the BSA sorption reached 0.045 mg/cm2. This level of BSA is indicative of good blood compatibility and biocompatibility of the fibroin. The gas permeabilities of oxygen, nitrogen, and carbon dioxide were tested for potential applications in contact lenses and wound dressings. Over a pressure range of 70 – 350 psig, the permeability of oxygen and nitrogen was 5 Barrer, while that of carbon dioxide ranged from 26 to 37 Barrer. The oxygen transmissibility of the fibroin films prepared in this study was on the low end required for use in daily wear contact lenses, but sufficient to aid the healing process for use in wound dressings. The permeability and diffusivity of four model drugs in the fibroin film was investigated for potential applications in controlled drug release. The permeability at higher source concentrations leveled out to 0.8 – 4.3 x 10-7 cm2/s depending on the drug tested. The diffusion coefficient determined from sorption experiments was approximately 1.8 x 10-9 cm2/s, while the diffusion coefficients from desorption experiments were determined to be 0.8 – 2.7 x 10-9 cm2/s. The magnitude of the drug permeability and diffusivity are consistent with many other controlled release materials, and the fibroin film showed good potential for use in controlled release.

Hydrogels have successfully proved themselves useful for drug delivery applications and several delivery routes have been developed over the years. The particular interest in this work was to design, synthesise and evaluate in situ forming drug eluting hydrogels, which have the potential to ameliorate the healing of cardiovascular diseases. With this aim the anti-inflammatory and immunosuppressant drugs rapamycin (Ra) and dexamethasone (Dex) were made water soluble by conjugation with polyethylene glycol (PEG). Ra was attached pendant from the terminal of PEGs while Dex was incorporated into dendritic structures grown from PEGs. These conjugates were further crosslinked into hydrogels by either conjugate or thiol-ene addition. The gel degradation was tuned to take between 5 and 27 days by using gel building block combinations that induced either 2 or 4 hydrolytically labile bonds per crosslink or by varying the number of crosslinking sites of the building blocks. The use of thiol-ene addition prolonged the degradation time nearly seven folded compared to conjugate addition as a more stable crosslink was formed. Two different formulations for gelling via conjugate addition were used (acrylate-thiol or vinyl sulphone-thiol) to deliver Ra, which was carried by either a 4- or 2-armed PEG. The elution kinetic for the respective gel formulation was of zero order during 15 and 19 days of gel degradation. In addition, Ra was PEGylated via esters, with a distance of either one or two carbons to a nearby thio-ether functionality. The difference in ester conjugation resulted in a slight but significant change in drug-PEG conjugate stability, which was mirrored by the increased time to reach the half amount of total drug elution; from 9.3 to 10.2 days and from 5.1 to 9.7 days for the two gel formulations, respectively. Dexamethasone was incorporated via an ester into dendrons of first and second generation pending from 2- and 4-armed PEGs at loadings of 2, 4 or 6 Dex molecules per carrier molecule. The resulting elution kinetic was of zero order during degradation periods of 5-27 days. Released Dex still possessed biological activity as determined by an in vitro cell assay. The novelties in this thesis are: (A) slow release of rapamycin obtained by covalent incorporation into hydrogels, (B) the use of unique PEG-based dendrimers to incorporate dexamethasone into a hydrogel and (C) zero order sustained release of dexamethasone at physiological pH. / Hydrogeler har framgångsrikt visat sig användbara för att leverera läkemedel och ett flertal metoder har utvecklats de senaste 20 åren. Fokuset i den här avhandlingen ligger på att designa, framställa och utvärdera läkemedelsutsöndrande hydrogeler som spontanhärdar in situ, vilka har potential att förbättra läkningen efter kardiovaskulär sjukdom. Med det syftet gjordes de anti-inflammatoriska och immunsänkande läkemedlen rapamycin (Ra) och dexametason (Dex) vattenlösliga genom att konjugeras med polyetylenglygol (PEG). Ra fästes kovalent längst ut på PEGar medans Dex inkluderades i dendritiska strukturer vilka byggdes från ändpunkten av PEGar. De här konjugaten tvärbands till hydrogeler via antingen konjugerad addition eller radikal polymerisation. Nedbrytningen av gelerna trimmades till att ta mellan 5 och 27 dagar genom att använda kombinationer av gelbyggstenar som bildar antingen 2 eller 4 hydrolyserbara estrar per tvärbindning eller genom att variera antalet tvärbindningspunkter hos byggstenarna. Användandet av radikal polymerisation i sig ledde till att nedbrytningen av geler tog nära sju gånger längre tid jämfört med geler gjorda via konjugerad addition eftersom stabilare tvärbindningar då formas. Två olika kombinationer för härdning via konjugerad addition (akryl-tiol eller vinylsulfon-tiol) användes för att leverera Ra som bars av antingen en 4- eller 2-armad PEG. Utsöndringskinetiken av Ra för de två kombinationerna var av nollte ordningen under de 15 och 19 dagar som gelerna degraderade. Dessutom, Ra PEGylerades via estrar med ett avstånd på antingen ett eller två kol till en närliggande tioeter. Skillnaden i avstånd ledde till en liten men signifikant skillnad i stabiliteten hos Ra-PEG konjugaten, vilket speglades i den förlängda tiden att nå halva mängden av den totala läkemedelsutsöndringen; från 9.3 till 10.2 dagar och från 5.1 till 9.7 dagar för de två respektive gelkombinationerna. Dex kopplades in via en esterbindning till dendroner av första och andra generationen byggda från PEGar med 2 eller 4 armar, vilket resulterade i att 2, 4 eller 6 Dex levererades per bärarmolekyl. Dex eluerade med nollte ordningens kinetik under degraderingsperioder på mellan 5 och 27 dagar. Vidbehålllen biologisk aktivitet av eluerad Dex bekräftades genom cellexperiment in vitro. Nyheterna i den här avhandlingen består av: (A) kontrollerad utsöndring av rapamycin uppnådd genom kovalent inbindning till hydrogeler, (B) användandet av unika PEGbaserade dendrimerer för kovalent inbindning av dexametason till hydrogeler och (C) nollte ordningens utsöndring av dexametason vid fysiologiskt pH. / <p>QC 20130204</p>

Chronic total occlusions are a common problem in patients with coronary artery disease. The primary barrier to successful percutaneous coronary intervention is inability to cross the lesion with a guidewire. We seek to characterize polymer microspheres as a controlled delivery mechanism for collagenase and VEGF, novel intralesional therapies being investigated to alter CTO structural properties. Release profiles for protein-loaded PLGA [poly(lactic-co-glycolic acid)] microspheres showed sustained BSA and VEGF release over eight and 48 hours respectively. Polymer degradation products had no impact on endothelial cell growth and protein bioactivity was maintained post-release. In vivo localization of microsphere-released collagenase was not possible due to low concentrations remaining at the site. Histology confirmed microspheres remained in the collagen-dense, proximal 15 mm of the lesion, likely altering the structural integrity of the plaque.

Chronic total occlusions are a common problem in patients with coronary artery disease. The primary barrier to successful percutaneous coronary intervention is inability to cross the lesion with a guidewire. We seek to characterize polymer microspheres as a controlled delivery mechanism for collagenase and VEGF, novel intralesional therapies being investigated to alter CTO structural properties. Release profiles for protein-loaded PLGA [poly(lactic-co-glycolic acid)] microspheres showed sustained BSA and VEGF release over eight and 48 hours respectively. Polymer degradation products had no impact on endothelial cell growth and protein bioactivity was maintained post-release. In vivo localization of microsphere-released collagenase was not possible due to low concentrations remaining at the site. Histology confirmed microspheres remained in the collagen-dense, proximal 15 mm of the lesion, likely altering the structural integrity of the plaque.

Graduation date: 1993

The peak and valley problems caused by oral administration, injection or other conventional methods, call for developing systems that can deliver therapeutics more effectively. As one of the techniques, diffusion-controlled drug release membranes have significant interest due to great ease with which they can be designed to achieve near-zeroth-order release kinetics. Since diffusion is the rate-limiting step in these systems, determining the permeability and diffusivity of drug molecules in the membrane is therefore important in evaluating drug release performance. This study focuses on the Membrane Permeation Controlled Release (MPC) system, which involves a non-porous (dense) membrane, comprising of two biopolymers, sericin and chitosan. Ciprofloxacin hydrochloride and (+)-cis-diltiazem hydrochloride were used as hydrophilic model drugs, and nitro-2-furaldehyde semicarbazone (Nitrofurazon) was used as a hydrophobic model drug. Permeation experiments were carried out in a semi-infinite reservoir/receptor system to simulate in-vitro drug release. The intrinsic permeability and diffusivity (P, D) of the drugs through the membranes were determined using a modified time-lag method based on short time permeation and mass balance method based on long time permeation. The partition coefficients Kd of the drugs in the membranes and the swelling degree of the membranes were determined by sorption/desorption experiments. The diffusivities of the drugs were also determined from the sorption/desorption kinetics. Over the experimental ranges tested, the drug concentration and membrane cross-linking did not have significant effects on these parameters presumably due to the relatively low drug concentrations and mild crosslinkings of the membranes. The diffusivity coefficients of ciprofloxacin hydrochloride, (+)-cis-diltiazem hydrochloride and nitrofurazon in the membranes were found to be in the range of (2.0-2.6)×〖10〗^(-9)±2.6×〖10〗^(-10) cm2/s, (2.5-2.6) ×〖10〗^(-9)±1.1×〖10〗^(-10) and (38-134) ×〖10〗^(-9)±33.1×〖10〗^(-9) (cm2/s), respectively, and their permeability coefficients were in the range of (24-29)×〖10〗^(-8),(51-52) ×〖10〗^(-8) and (131-169) ×〖10〗^(-8) (cm2/s), respectively. The partition coefficients were determined to be around 0.91±0.21, 25±0.12 and 26±0.31, respectively. The diffusivity coefficients determined from sorption experiments for ciprofloxacin hydrochloride, diltiazem hydrochloride and nitrofurazon were found to be in the range of (3.2-7.6) ×〖10〗^(-9)±6.3×〖10〗^(-8), (6-10) ×〖10〗^(-9)±2.6×〖10〗^(-8) and (15-18) ×〖10〗^(-9)±2.7×〖10〗^(-7) (cm2/s), respectively. Also the diffusivity coefficients determined from sorption experiments for ciprofloxacin hydrochloride, diltiazem hydrochloride and nitrofurazon were in the range of (20-47) ×〖10〗^(-9), (12-24) ×〖10〗^(-9) and (11-20) ×〖10〗^(-9) (cm2/s), respectively. Nonetheless the differences in the diffusivities calculated from permeation and sorption/desorption experiments are considered to be acceptable, in view of the different experimental techniques used in this work, for the purpose of comparison of the membrane diffusivity and permeability.

The purpose of this study was to use controlled release technology combining with in situ chemical oxidation (ISCO) and permeable reactive barrier (PRB) to remediate TCE-contaminated groundwater. In this study, potassium permanganate (KMnO4) releasing material was designed for potassium permanganate release in groundwater. The components of potassium permanganate releasing material included poly (£`-caprolactone) (PCL), potassium permanganate, and starch with a weight ratio of 2:1:0.5. Approximately 63.8% (w/w) of potassium permanganate was released from the material after 76 days of operation. The released was able to oxidize contaminant in groundwater. Results from the solid oxidation demand (SOD) experiment show that the consumption rate increased with increased contaminant concentration. TCE removal efficiency increased with the increased TCE concentration. The second-order rate law can be used to simulate the TCE degradation trend. In the column experiment, results show that the released MnO4- could oxidize TCE and TCE degradation byproducts when 95.6 pore volume (PV) of contaminated groundwater was treated. More than 95% of TCE removal can be observed in the column study. Although the concentration of manganese dioxide (MnO2) began to rise after 8.8 PV of operation, TCE removal was not affected. Results also show that low level of hexavalent chromium was detected (< 0.05 mg/L). Results from the scanning electron microscope (SEM) and energy-dispersive spectroscope (EDX) analyses show that the amounts of manganese and potassium in the materials decreased after the releasing experiment. Results indicate that the concentration of TCE and SOD need to be analyzed before the releasing materials are applied in situ. In the practical application, the releasing materials will not become solid wastes because they are decomposed after use. If this slow-releasing technology can be combined with a permeable reactive barrier system, this technology will become a more economic and environmentally-friendly green remedial system.

Controlled drug delivery systems deliver drugs at predetermined rates for extended periods. Although there are various types such as capsules, tablets etc, micro and nano spheres are the most commonly used systems. In this study, a set of chitosan-polyvinylpyrrolidone (CH-PVP) microspheres containing different amounts of polyvinylpyrrolidone as semi inter penetrating networks (semi-IPN) were prepared as controlled release systems. Emulsification method was applied for the preparation of microspheres and some of them were conjugated with a monoclonal antibody which is immunoglobulin G (IgG). CH-PVP films were also prepared by solvent casting method with the same composition as in the microspheres and, mechanical and surface properties of the films were examined. Prepared microspheres were characterized by SEM, stereo and confocal microscopes. Some microspheres were loaded with a model chemotherapeutic drug, 5-Fluorouracil (5-FU), and in-vitro release of 5-FU were examined in phosphate buffer solutions (pH 7.4, 0.01 M.) It was shown that for semi-IPN samples release was faster compared to pure CH samples and the total release was achived 30 days for CH:PVP-2:1, CH:PVP-3:1 semi-IPNs and CH microspheres and 27 days for CH:PVP-1:1 semi-IPN microspheres. The antibody conjugated microspheres were targeted to MDA-MB (human causasian breast carcinoma cancer cells and coculture cells in culture medium. For the CH-PVP films, it was obtained that as the amount of PVP increased, hydrophobicity as well as mechanical strength of the system was decreased.

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