The oral delivery of drugs has several disadvantages, particularly in pediatrics, geriatrics and other patients experiencing difficulty in swallowing tablets or capsules. A frequent approach to this problem is the use of liquid formulations or buccal drug delivery systems. However, with liquid formulations, many drugs have an undesirable solubility or stability in appropriate solvents and dosing accuracy is compromised due to the patient being required to measure doses. Current rapidly disintegrating buccal drug delivery systems, such as buccal tablets, are able to dissolve rapidly within the oral cavity; however the short residence time at the absorption surface is a limiting factor in the effectiveness of these delivery systems. Furthermore, buccal tablet and wafer systems tend to be brittle and fragile and hence require special protective packaging. A rapidly disintegrating, flexible, mucoadhesive fibrous matrix system (FMS) with drug-loaded electrospun fibers incorporated onto a polymeric backing film may be capable of overcoming some of the innate disadvantages of the non-invasive delivery of various drugs, especially those requiring a rapid onset of action. Various electrospinnable polymers were investigated for suitability in the development of the electrospun fibrous layer of the FMS, and it was determined that polyvinylalcohol (PVA) produced drug-loaded fibers with the most acceptable morphology and a desirable disintegration time. An ideal drug-loaded fiber formulation was obtained by design of experiments and employed in further investigations. The original model drug, zidovudine (AZT), exhibited less than 1% permeation after 90 minutes. Permeation was not adequately increased by penetration enhancers, and AZT was therefore tested against diphenhydramine (DPH), which exhibited 42-82% permeation after 5 minutes. The polymeric backing film layer was developed by investigating various film-forming polymers and methods of film or membrane preparation. Acceptable films were produced by film-casting of solutions containing combinations of PVA and hydroxypropylmethylcellulose (HPMC), and variables for an Experimental Design were obtained. The variables were fill volume (40-100mL), HPMC concentration (0-0.5%w/v) and concentration of glycerol (10-15%w/w of total polymer mass). The film layer was optimized according to a Box-Behnken experimental design, employing the responses disintegration time, work of adhesion, maximum detachment force, dissolution and ex vivo permeation. In vitro physicochemical and physicomechanical characterization, as well as ex vivo analysis, was performed on the optimized FMS in order to assess the suitability of the system for rapid oramucosal drug delivery. The FMS was deemed to be suitable for buccal drug delivery and able to overcome some of the inherent limitations of current drug delivery systems.

An oral proteomatrix drug delivery platform was formulated using pH responsive biostable polymers for slow release kinetics for the treatment of the neurodegenerative disease, multiple sclerosis (MS), which was the primary aim. After successful design and optimization for utilizing this system for MS, this system was further applied as a versatile platform for oral protein delivery. Interferon beta (INF- ) was selected as the oral treatment for MS. The fundamental effect of INF- in the treatment of MS is based on reducing the immune response that is directed against central nervous system myelin, i.e. the fatty sheath that surrounds and protects nerve fibers. Damage of nerve fibers, resulting in demyelination, consequently causes nerve impulses to be slowed or halted, thus producing symptoms of MS (Jongen et al., 2011). To date, INF- is effectively being used to treat MS subcutaneously or as intramuscular injections. These forms of administration have commonly been associated with multiple problems of pain, allergic reactions, poor patient compliance and chances of infection (Chiu et al., 2007). It was thus concluded to design an oral platform for the delivery of multiple protein therapeutic formulations. To prove the versatility of the proteomatrix system, two other demanding protein therapeutics for oral delivery, insulin and erythropoietin, were selected for further in vitro Box-Behnken series of formulations and in vivo analysis. By administration of these oral protein systems, a greater patient compliance can be achieved, thus enhancing the therapeutic profiles of patients with conditions of MS, diabetes and chronic renal failure resulting in chronic anemia. All studies consisted of in vitro drug release studies, characterization using specific analytical techniques for testing the mechanical properties, as well as the physicochemical characteristics of the copolymeric system. All proteins, INF- , insulin and erythropoietin, were analyzed in vivo using New Zealand White rabbits (NZW) with determination of the protein from serum obtained during regular blood sampling intervals.

Oral delivery of drugs is inundated by formulation challenges predominantly due to poor physicochemical properties of chemical entities resulting in anomalies in serum levels and inconsistent pharmacokinetics and pharmacodynamics. Similar challenges exist for nutraceutical products however, there has been a recent shift in research paradigms towards novel formulation strategies to render these agents invaluable complementary treatments. In this view, vitamin D has gained interest, however it’s effective therapeutic use is limited by low aqueous solubility, erratic inter-patient response, and inadequate formulation design. Cholecalciferol (D3), being a potent form of the vitamin, is widely supplemented and prescribed and was selected as the model agent for proof of concept in the design of a novel oral Drug Delivery System (DDS) in the current research. An ideal physiological milieu is often essential for intended performance of even advanced DDS’s. GIT topology may have an even greater impact on modified dosage forms compared to conventional dosage forms. The use of absorption and solubility enhancers is a tried and tested formulation strategy to improve bioavailability and efficacy of drugs with unfavourable physicochemical characteristics. Despite being an integral part of modern formulation design, these bioenhancers may prove only marginally effective in oral delivery unless the physiological state is considered during formulation. It was therefore imperative that the DDS designed in this investigation included measures to mitigate this effect and achieve robust efficacy regardless of the dynamic GIT condition. In addition, most nutraceuticals typically occur as multicomponent products, yet different combined BCS class vitamins may encounter erratic absorption due to differences in solubility and flocculation effects that impede dispersion in aqueous media. It is therefore imperative to formulate and evaluate a DDS containing more than one nutraceutical agent for greater “real-world” relevance instead of a single vitamin DDS formulation that has been pursued in past studies. The current work therefore set out to develop a DDS capable of orally delivering multiple nutraceutical actives and biological constituents from a single formulation framework with modifiable release kinetics and a unified release of synergistic vitamins, with D3 as the focus agent for enhanced oral bioavailability. Few researchers have investigated the use of multiple biological enhancers combined with synthetic carriers in a dosage form to aid nutraceutical delivery

Zeolites and mesoporous silica were used as drug delivery systems for the loading and release of small drug molecules, aspirin and 5-fluorouracil. Different parameters were varied such as aluminum content in the zeolite, effect of distribution of functional groups and the method of surface modification in case of mesoporous silica. The effect of the aforementioned variables was studied on drug loading and release from these microporous and mesoporous systems. The drug loaded materials were extensively characterized using various physical techniques such as powder X-ray diffraction, nitrogen isotherms, infrared spectroscopy, solid state NMR and thermogravimetric analysis. Quantum calculations and molecular dynamics simulations were performed in order to validate the experimental data and also to obtain a molecular level insight of the drugs inside the pores of the host materials. Drug templated synthesis of mesoporous silica was also carried out in the presence of aspirin as the template. The aspirin templated material was characterized by aforementioned techniques and showed a sustained drug release profile.

Thesis (Ph. D.)--Virginia Commonwealth University, 2006. / Prepared for: Dept. of Pharmaceutics. Bibliography: leaves 163-178. Also available online.

A variety of dendrimers based on melamine are designed, synthesized, and evaluated for drug delivery systems. The synthesis of a dendrimer, including multiple copies of four orthogonally reactive groups, is described. The three groups on the surface are nucleophilic and include four free hydroxyl groups, four tert-butyldiphenylsilyl (TBDPS) ether groups, and sixteen amines masked as tert-butoxycarbonyl (BOC) groups. The core of the dendrimer displays two electrophilic monochlorotriazines. The dendrimer above is further manipulated for in vivo biodistribution: incorporation of the reporting groups Bolton-Hunter and DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid); PEGylation for biocompatibility and size tuning. In preliminary biodistribution studies, dendrimers circulate in the blood for a longer time as the molecular weight increases, which is important to passively target tumor tissues via the EPR effect. Also, high uptake by the tumor tissues was observed in mice bearing prostate cancer xenografts. A drug delivery vehicle for the anticancer agent paclitaxel is described. This drug delivery vehicle contains sixteen molecules of paclitaxel via acid-labile ester linkage, two Bolton-Hunter groups, and sixteen monochlorotriazine groups for PEGylation. The in vitro drug release studies shows faster release of paclitaxel at lower pH in PBS.

The convergent strategy towards dendrimer synthesis is well-suited to generate macromolecules with a diverse periphery, at the expense of time and effort, while the divergent strategy has historically been effective at yielding higher generation dendrimers, although they are often plagued by impurities. Both the convergent and divergent routes were applied to the synthesis of melamine-based dendrimers, offering a comparison of the routes within a system. Generation-1 dendrons heterogeneously functionalized with Boc-protected amines and hydrazones were synthesized convergently and coupled to a generation-1 tris(piperazine) core to yield a generation-2 dendrimer bearing 18 Boc-amines and three hydrazones. Although the yield for the final coupling step was rather low (56%), the yields for all intermediate steps were quite high. Attempts toward obtaining a generation-3 dendrimer through this route were unsuccessful due presumably to steric hindrance. The materials obtained showed no impurities in their 1H and 13C NMR and mass spectra, although several chromatographic purifications were necessary throughout the synthesis. A divergent strategy based on addition of a dichlorotriazine monomer to polyamine cores was used to synthesize dendrimers of generations 1-5. All intermediates and dendrimers were either purified by precipitation, or did not need purification. 1H NMR spectroscopy indicated that reactions were complete up to G4-NH2 by integration, and mass spectroscopy confirmed that assignment. HPLC and GPC of Gn-Cl dendrimers showed sharp peaks for G1-G3, but G4-Cl appeared to have a small amount of impurities that are similar in size and polarity to the fully-substituted dendrimer. The G1-G3 dendrimers were confidently assigned as pure by conventional organic chemistry standards, but the assignment of purity to higher generations remained tentative. A G1-Cl dendrimer was functionalized with imidazole, and then deprotected and PEGylated with PEG5000 to yield a water soluble dendrimer. The imidazole-capped, Boc-protected dendrimer and the deprotected dendrimer were characterized by 1H and 13C NMR spectroscopy and mass spectrometry. The degree of PEGylation on the PEGylated material could not be definitively ascertained; however, the material is capable of solubilizing very hydrophobic Zn-phthalocyanines in water.

The convergent strategy towards dendrimer synthesis is well-suited to generate macromolecules with a diverse periphery, at the expense of time and effort, while the divergent strategy has historically been effective at yielding higher generation dendrimers, although they are often plagued by impurities. Both the convergent and divergent routes were applied to the synthesis of melamine-based dendrimers, offering a comparison of the routes within a system. Generation-1 dendrons heterogeneously functionalized with Boc-protected amines and hydrazones were synthesized convergently and coupled to a generation-1 tris(piperazine) core to yield a generation-2 dendrimer bearing 18 Boc-amines and three hydrazones. Although the yield for the final coupling step was rather low (56%), the yields for all intermediate steps were quite high. Attempts toward obtaining a generation-3 dendrimer through this route were unsuccessful due presumably to steric hindrance. The materials obtained showed no impurities in their 1H and 13C NMR and mass spectra, although several chromatographic purifications were necessary throughout the synthesis. A divergent strategy based on addition of a dichlorotriazine monomer to polyamine cores was used to synthesize dendrimers of generations 1-5. All intermediates and dendrimers were either purified by precipitation, or did not need purification. 1H NMR spectroscopy indicated that reactions were complete up to G4-NH2 by integration, and mass spectroscopy confirmed that assignment. HPLC and GPC of Gn-Cl dendrimers showed sharp peaks for G1-G3, but G4-Cl appeared to have a small amount of impurities that are similar in size and polarity to the fully-substituted dendrimer. The G1-G3 dendrimers were confidently assigned as pure by conventional organic chemistry standards, but the assignment of purity to higher generations remained tentative. A G1-Cl dendrimer was functionalized with imidazole, and then deprotected and PEGylated with PEG5000 to yield a water soluble dendrimer. The imidazole-capped, Boc-protected dendrimer and the deprotected dendrimer were characterized by 1H and 13C NMR spectroscopy and mass spectrometry. The degree of PEGylation on the PEGylated material could not be definitively ascertained; however, the material is capable of solubilizing very hydrophobic Zn-phthalocyanines in water.

A variety of dendrimers based on melamine are designed, synthesized, and evaluated for drug delivery systems. The synthesis of a dendrimer, including multiple copies of four orthogonally reactive groups, is described. The three groups on the surface are nucleophilic and include four free hydroxyl groups, four tert-butyldiphenylsilyl (TBDPS) ether groups, and sixteen amines masked as tert-butoxycarbonyl (BOC) groups. The core of the dendrimer displays two electrophilic monochlorotriazines. The dendrimer above is further manipulated for in vivo biodistribution: incorporation of the reporting groups Bolton-Hunter and DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid); PEGylation for biocompatibility and size tuning. In preliminary biodistribution studies, dendrimers circulate in the blood for a longer time as the molecular weight increases, which is important to passively target tumor tissues via the EPR effect. Also, high uptake by the tumor tissues was observed in mice bearing prostate cancer xenografts. A drug delivery vehicle for the anticancer agent paclitaxel is described. This drug delivery vehicle contains sixteen molecules of paclitaxel via acid-labile ester linkage, two Bolton-Hunter groups, and sixteen monochlorotriazine groups for PEGylation. The in vitro drug release studies shows faster release of paclitaxel at lower pH in PBS.

Thesis (Ph. D.)--University of Texas at Austin, 2002. / Supervisor: JAmes W. McGinity. Vita. Includes bibliographical references.