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Studies of submillimeter gels composed of covalently cross-linked poly(acrylic acid)-g-poly(ethylene oxide)-b-poly(propylene oxide)-b-poly(ethylene oxide) (Pluronic-PAA) networks are reviewed in light of potential applications of the microgels as drug carriers in oral delivery. The microgels are capable of volumetric transitions in response to environmental stimulae such as pH and temperature. It is shown that the type of Pluronic used in the microgel synthesis changes the structure of the resulting microgels, with the more hydrophobic Pluronic imparting porosity. Microgels based on Pluronic L92 (L92-PAA-EGDMA) possess higher ion-exchange capacity than microgels based on Pluronic F127 (F127-PAA-EGDMA), albeit the former are more hydrophobic. Analogously, more hydrophobic but heterogeneous L92-PAA-EGDMA exhibit superior capacity for equilibrium loading of hydrophobic drugs such as taxol, camptothecin and steroid hormones, as well as higher capacity for weakly basic drugs such as doxorubicin, mitomycin C, and mitoxantrone. / Singapore-MIT Alliance (SMA)

Hydrophobic drug paclitaxel nanoparticles (PAX NPs) and pH sensitive hydrogels were prepared in this study to build a colon targeting nanoparticle based drug delivery system for oral administration. Negative charged PAX NPs at the size of 110 +/- 10 nm were fabricated, characterized and then encapsulated in synthetic / biomacromolecule shell chitosan, dextran-sulfate using a layer by layer (LbL) self-assembly technique. Surface modifications were performed by covalently conjugating with poly (ethylene glycol) (H2N-PEG-carboxymethyl, Mw 3400) and fluorescence labeled wheat germ agglutinin (F-WGA), so as to build a biocompatible and targeted drug delivery system. Extended release of drug paclitaxel can be realized by adding more polyelectrolyte layers in the shell. High cell viability with PEG conjugated and high binding capacities of WGA modified nanoparticles with Caco-2 cells were observed. Preliminary study on stability of the nanoparticles in suspension at different pH was also performed. Two dextran based pH sensitive and enzyme degradable hydrogels: dextran maleic acid (Dex-MA), and glycidyl methacrylated dextran (Dex-GMA) were synthesized for oral delivery of nanoparticles. Hydrogels of both kinds were stable in simulated gastric fluid, but were prone to swelling and degradation in the presence or absence of enzyme dextranase in simulated intestinal fluid. The release profiles of nanoparticles could be tuned from 5 hr to 24 hr periods of time with more than 85% of the nanoparticle released in the simulated intestinal fluid. The release of PAX NPs was completed with longer time periods (45 hr-120 hr). Two possible release mechanisms were discussed for Dex-MA and Dex-GMA-co-AA hydrogels respectively: degradation controlled, and diffusion controlled. These biodegradable hydrogels, which can release nanoparticles depending on pH changes, together with the biocompatible and targeted nanoparticles, may be suitable as a potential colon targeting system for oral delivery of drug nanoparticles.

Currently, therapeutic proteins and peptides are delivered subcutaneously, as they are readily denatured in the acidic, protease rich environment of the stomach or gastrointestinal track and low bioavailability results from poor intestinal absorption through the paracellular route. Encapsulation of therapeutic peptides and proteins into polymeric micro- and nano- particle systems has been proposed as a possible strategy to overcome limitations to oral protein administration. Furthermore, it was shown that nanoparticles having diameters less than 5µm are able to be taken up by the M cells of Peyer’s patches found in intestinal mucosa . However, the current methodologies to produce particles within desired range involves organic solvents and several steps. In this study, spray drying was investigated as a microencapsulation alternative, as it offers the potential for single step operation, producing dry particles, with the potential for extending the microparticle size into the nano-range. The particles were produced by spray drying of alginate/protein solutions. The effect of spray drying operational parameters on particle properties such as recovery, residual activity and particle size was studied. Particle recovery depended on the inlet temperature of the drying air, whereas the particle size was affected by the feed rate and the alginate concentration of the feed solution. Increase in alginate:protein ratio increased protein stability during the process and shelf live experiments. Presence of 0.2 g trehalose/g particle increased the residual activity up to 90%. The resulting spherical micro and nanoparticles had smooth surfaces. Stable glycol-chitosan-ca-alginate particles were produced with single step operation. The resulting particles had mean diameter around 3.5μm and released 35% of the initial protein content to the simulated stomach environment within 2 hours. The protein distribution within the particle was studied by confocal laser scanning microscope with florescent labeled protein. The image showed protein deposition toward the surface of the particles. Total drying time and Peclet number was calculated for the particles and found to be 8.5 ms and 240, which indicates that particle formation was governed mainly by convection, which resulted in a hollow central region and protein distribution toward the particle surface. This study shows that stable alginate particles containing proteins can be produced in a single step by spray drying, where the particles had a mean size lower than the critical diameter necessary to be orally absorbed by M cell’s of the Peyer’s patches in the gastrointestinal tract and thus can be considered as a promising technology for oral peptide and protein delivery. / Thesis (Master, Chemical Engineering) -- Queen's University, 2007-10-30 12:20:47.728

Thesis (Ph.D.)--University of Wisconsin--Madison, 2006 / eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (p. 186-199).

Thesis (Ph.D.)--University of Wisconsin--Madison, 2006 / Includes bibliographical references (p. 186-199). Also available on the Internet.

The performance of regenerated cellulose (RC) films and capsules was investigated for their applications in oral controlled drug delivery. Regenerated cellulose films were prepared by non-solvent-mediated, phase inversion of native and depolymerized cotton linter solutions (methylolcellulose; cellulose dissolved in dimethyl sulfoxide/ paraformaldehyde solvent system) in water as well as by phase inversion of native cotton linter solutions in organic non-solvents followed by thermal annealing. These films were monolithic in dry state and formed porous structures when hydrated. Irrespective of the degree of polymerization of the starting cellulose source or the use of organic non-solvents, the cellulose chain length was not significantly altered and cellulose was in an amorphous state. Flux analysis in diffusion cells, using ethanol-water mixtures as the solvent medium, indicated that the films take up solvent to form porous routes for transport of solute. The amount of solvent uptake required to form these routes was greater for films prepared from depolymerized cotton linter. Ionic and hydrophobic solutes traverse the films using the porous pathways following hydration of the film. Blended RC films were prepared by combining native and depolymerized cotton linter solutions in varying ratios and phase-inverting in water, followed by thermal annealing. Porosity, pore size and water uptake of the hydrated films decreased, while the length of the transport pathway (tortuosity) increased, as the fraction of depolymerized cellulose increased in the blended films. Differences in methylene blue dye adsorption on phase-inverted vs. phase-inverted and thermally annealed RC films indicated that the type of non-solvent utilized for phase-inversion does not affect the internal RC film structure during the phase-inversion process. However, as the boiling point of the non-solvent increased, the amount of irreversible polymer consolidation and formation non-swelling domains (hornification) increased during the thermal annealing process. This, in turn, led to reduced porosity and solute flux through these RC films. Two-piece cellulose capsules were fabricated by phase-inversion of methylolcellulose solutions in water using a dip-coating approach. Zero-order release rates for a number of drugs increased as their water solubility increased. The release of water soluble drugs occurred by osmotically-driven convection and diffusion through the pores in the capsule wall, while the release of moderate to poorly soluble drugs predominantly occurred by diffusion. Moreover, as the drug solubility increased, the apparent permeability of the drugs through the capsule wall decreased, which indicated that the inward osmotic flux of water reduced the diffusivity of the drug through the pores. The hydraulic permeability of the cellulose capsules was determined to be higher than for conventional ethylcellulose and cellulose acetate coated osmotic drug delivery systems, indicating that the cellulose-based capsules may be better suited for osmotic drug delivery.

In this study, we demonstrated that the CSKSSDYQC-peptide ligand which was identified from a random phage-peptide library through an in vivo phage display technique with rats could prominently improve the transport efficiency of macromolecules, such as large filamentous phage particles (M13 bacteriophage), across the intestinal mucosal barrier. Synthetic CSKSSDYQC-peptide ligands significantly inhibited the binding of phage P1 encoding CSKSSDYQC-peptide ligands to the intestinal mucosal tissue and immunohistochemical analysis showed that the CSKSSDYQC-peptide ligands could be transported across the intestinal mucosal barrier via goblet cells as their specific gateway. Thus, we inferred that CSKSSDYQC-peptide ligand might have a specific receptor on the goblet cells and transported from intestinal lumen to systemic circulation by transcytosis mechanism. These results suggest that CSKSSDYQC-ligand could be a promising tool for development of an efficient oral delivery system for macromolecular therapeutics in the carrier-drug conjugate strategy.

Yes / Three-dimensional printing (3DP) has the potential to cause a paradigm shift in the manufacture of pharmaceuticals, enabling personalised medicines to be produced on-demand. To facilitate integration into healthcare, non-destructive characterisation techniques are required to ensure final product quality. Here, the use of process analytical technologies (PAT), including near infrared spectroscopy (NIR) and Raman confocal microscopy, were evaluated on paracetamol-loaded 3D printed cylindrical tablets composed of an acrylic polymer (Eudragit L100-55). Using a portable NIR spectrometer, a calibration model was developed, which predicted successfully drug concentration across the range of 4–40% w/w. The model demonstrated excellent linearity (R2 = 0.996) and accuracy (RMSEP = 0.63%) and results were confirmed with conventional HPLC analysis. The model maintained high accuracy for tablets of a different geometry (torus shapes), a different formulation type (oral films) and when the polymer was changed from acrylic to cellulosic (hypromellose, HPMC). Raman confocal microscopy showed a homogenous drug distribution, with paracetamol predominantly present in the amorphous form as a solid dispersion. Overall, this article is the first to report the use of a rapid ‘point-and-shoot’ approach as a non-destructive quality control method, supporting the integration of 3DP for medicine production into clinical practice. / Open Access funded by Engineering and Physical Sciences Research Council United Kingdom (EPSRC), UK for their financial support (EP/L01646X).