Controlled release formulations deliver an active ingredient over an extended period of time. It is an ideal dosage form for an active ingredient with a short elimination half-life. An active ingredient with a short elimination half-life would be released in small portions over an extended period of time and thus less frequent administration is necessary and this improve patient compliance. Other advantages of these formulations include: decreased side effects, constant drug levels in the blood, improvement in treatment efficiency and reduction in cost of administration. Controlled release beads are formulated in such a way that the active ingredient is embedded in a matrix of insoluble substance like chitosan; the dissolving drug then has to find its way through the pores of the matrix into the surrounding medium. The chitosan matrix swells to form a gel, the drug then has to first dissolve in the matrix and diffuse through the outer surface into the surrounding medium. Chitosan is a biocompatible, biodegradable polymer of natural origin. It has mucoadhesive properties as well as the ability to manipulate the tight junctions in the epithelium membrane and these properties have qualified chitosan as an effective drug carrier in controlled release dosage forms. The effect of a modern controlled release polymer namely Kollidon® SR in combination with chitosan on drug release was investigated. Ketoprofen was chosen as model drug. Ketoprofen is an anti-inflammatory drug that causes gastrointestinal side effects in conventional dosage forms. Ketoprofen has a short elimination half-life of 2.05 ± 0.58 h and this characteristic makes it an ideal candidate for use in a controlled release formulation. The aim of this study was to achieve controlled release and minimize gastrointestinal effects of ketoprofen with chitosan particles. Kollidon® SR was used as polymer because it exhibits pH independent release characteristics and previous studies have shown potential for this combination. Chitosan beads and chitosan-Kollidon® SR beads, as well as chitosan granules and chitosan-Kollidon® SR granules, were prepared and investigated as potential controlled release formulations. Chitosan beads were prepared through the inotropic gelation method using tripolyphosphate as a cross linking agent. Granules were prepared through wet granulation using 2% v/v acetic acid as the granulating fluid or by dissolving ketoprofen in ethanol and Kollidon® SR in 2-pyrrolidinone and using the solution as granulating fluid. Kollidon® SR was added in concentrations of 0.25, 0.5 and 1% (w/v) in the bead formulations and concentrations of 1, 5 and 10% (w/w) in the granule formulations. The beads and granules were characterised by evaluating the following properties: morphology, drug loading and drug release. Additionally swelling and friability tests were also conducted on the bead formulations. The cross linking times of the bead formulations were varied to investigate the effect of cross linking time on the characteristics of the beads. Chitosan-Kollidon® SR beads showed promising results for controlled release formulations and ketoprofen were released over an extended period of time. Drug loading of the plain chitosan beads was 74.65 ± 0.71% and it was noted that the inclusion of Kollidon® SR in the beads resulted in an increase in drug loading and the formulation containing 1% (w/v) Kollidon® SR, cross linked for 30 minutes had a drug loading of 77.38 ± 0.01%. Drug loading of the beads that were cross linked for a longer time were slightly lower which is an indication that some of the drug might have leached out during cross linking. The degree of swelling was promising with some beads swelling to a degree of 2.5 in phosphate buffer solution pH 5.6. Granules had a drug loading between 81.73 ± 1.53% and 93.30 ± 0.50%. Ketoprofen release from the beads and the granules in PBS pH 7.40 at 37 °C over a period of 6 hours were investigated. The bead formulations were more effective in achieving controlled release and it was noted that the bead formulations that was cross linked for a longer period was more efficient in achieving controlled release. The granules did not form a matrix and were not effective in achieving controlled release. Controlled release of ketoprofen were achieved and the results show potential for chitosan-Kollidon® SR formulations in the future. / Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2008.

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.

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.

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.

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.

Thesis (M.S.)--University of Akron, Dept. of Biomedical Engineering, 2006. / "December, 2006." Title from electronic thesis title page (viewed 12/31/2008) Advisor, Yang Yun; Committee members, Stephanie Lopina, Steven Schmidt; Department Chair, Daniel Sheffer; Dean of the College, George K. Haritos; Dean of the Graduate School, George R. Newkome. Includes bibliographical references.

Thesis (Master)--İzmir Institute of Technology, İzmir, 2004. / Includes bibliographical references (leaves. 55-58).

Thesis (Ph. D.)--Virginia Polytechnic Institute and State University, 1991. / Vita. Abstract. Includes bibliographical references (leaves 179-181). Also available via the Internet

This paper presents the fabrication of controlled release devices for anticancer drug paclitaxel using supercritical antisolvent method. The thermodynamic and hydrodynamic effects during supercritical antisolvent process on the particle properties obtained were investigated. Scanning electron microscopy was employed to study particle sizes and morphologies achieved. It was observed that increasing supercritical pressure improves the surface morphology of particles obtained, and increasing the flow rate of the organic solution jet reduces the particle sizes obtained. A modified Supercritical Antisolvent with Enhanced Mass transfer setup was developed to produce monodispersed nanoparticles with high recovery yield. High performance liquid chromatography was used to determine the encapsulation efficiency and in vitro release profiles of paclitaxel loaded particles obtained. The encapsulation efficiencies of particles obtained using the modified SASEM process were high and up to 83.5%, and sustained release of paclitaxel from the polymer matrix was observed over 36 days release. The thermogram properties of the particles were also analyzed using differential scanning calorimetry to determine the crystalline state of polymer and drug. / Singapore-MIT Alliance (SMA)

abstract: Mesoporous materials that possess large surface area, tunable pore size, and ordered structures are attractive features for many applications such as adsorption, protein separation, enzyme encapsulation and drug delivery as these materials can be tailored to host different guest molecules. Films provide a model system to understand how the pore orientation impacts the potential for loading and release of selectively sized molecules. This research work aims to develop structure-property relationships to understand how pore size, geometry, and surface hydrophobicity influence the loading and release of drug molecules. In this study, the pore size is systematically varied by incorporating pore-swelling agent of polystyrene oligomers (hPS) to soft templated mesoporous carbon films fabricated by cooperative assembly of poly(styrene-block-ethylene oxide) (SEO) with phenolic resin. To examine the impact of morphology, different compositions of amphiphilic triblock copolymer templates, poly(ethylene oxide)-block-poly(propylene oxide)-block-poly(ethylene oxide) (PEO-PPO-PEO), are used to form two-dimensional hexagonal and cubic mesostructures. Lastly, the carbonization temperature provides a handle to tune the hydrophobicity of the film. These mesoporous films are then utilized to understand the uptake and release of a model drug Mitoxantrone dihydrochloride from nanostructured materials. The largest pore size (6nm) mesoporous carbon based on SEO exhibits the largest uptake (3.5μg/cm2); this is attributed to presence of larger internal volume compared to the other two films. In terms of release, a controlled response is observed for all films with the highest release for the 2nm cubic film (1.45 μg/cm2) after 15 days, but this is only 56 % of the drug loaded. Additionally, the surface hydrophobicity impacts the fraction of drug release with a decrease from 78% to 43%, as the films become more hydrophobic when carbonized at higher temperatures. This work provides a model system to understand how pore morphology, size and chemistry influence the drug loading and release for potential implant applications. / Dissertation/Thesis / M.S. Chemical Engineering 2011