O perfil de liberação e o efeito de um sistema de liberação prolongada contendo metronidazol, antimicrobiano prescrevido para o tratamento da periodontite, foram avaliados na presença de biofilmes supra e subgengivais, representados respectivamente pelas bactérias Streptococcus mutans e Porphyromonas gingivalis. Os biofilmes foram crescidos e expostos ao sistema de liberação prolongada contendo metronidazol (MDZ) ou ao controle de veículo da formulação (CV), composto de monoglicerídeos e monoesterato de sorbitano. Biofilmes não tratados foram utilizados como controle negativo (CN). Os biofilmes e os meios de cultura de S. mutans foram coletados após a primeira exposição aos tratamentos nos tempos 24, 48, 72 e 96 horas enquanto para biofilmes de P. gingivalis os tempos foram 24, 48 e 72 horas. Após coleta, os biofilmes foram analisados em relação à quantificação de fármaco e viabilidade bacteriana (biofilmes de S. mutans: n=3; biofilmes de P. gingivalis: n=6). Biofilmes de S. mutans também foram avaliados em relação à acidogenicidade. Nos biofilmes supragengivais, a quantificação de MDZ nas primeiras 24 horas foi de 7% em relação à concentração inicial de fármaco na formulação, permanecendo em torno de 1% para os demais tempos. O teor de MDZ liberado da formulação reduziu a viabilidade bacteriana no tempo 24 horas e diminuiu a acidogenicidade dos biofilmes por 48 horas em relação aos grupos CV e NC (p<0,05). Já para os biofilmes subgengivais, 19% de MDZ foram liberados da formulação nas primeiras 24 horas e 5% do fármaco foram quantificados nas análises dos demais tempos. O antimicrobiano liberado reduziu a viabilidade bacteriana em todos os tempos em relação à CV e NC (p<0,05), não sendo diferente estatisticamente entre si (p>0,05). O grupo CV apresentou menor viabilidade bacteriana se comparado ao grupo CN (p<0,05), mas maior viabilidade em comparação ao grupo MDZ em todos os tempos (p<0,05). De uma forma geral, o sistema de liberação prolongada proposto neste estudo foi capaz de inviabilizar a proliferação de biofilmes de P. gingivalis e de desestabilizar biofilmes de S. mutans. Além disso, os microambientes originados pelos biofilmes interferiram na cinética de liberação do metronidazol, diminuindo sua disponibilidade biológica. Assim, considerando a continuidade do biofilme sub e supragengival, torna-se interessante aprofundar os estudos sobre formulações que possam inibir biofilmes subgengivais ao mesmo tempo em que desestabilizam biofilmes supragengivais, evitando a rápida recolonização dos nichos periodontais tratados. Em acréscimo, a possibilidade de estudar parâmetros operacionais de desenvolvimento da formulação farmacêutica utilizando-se modelos de biofilmes patogênicos pode ser considerada em futuros estudos / The drug release profile and the effect of a controlled release system containing metronidazole, an antibiotic prescribed for the treatment of periodontitis, were evaluated in the presence of supra and subgingival biofilms, represented respectively by the bacteria - Streptococcus mutans and Porphyromonas gingivalis. The biofilms were grown and exposed to the controlled release system containing metronidazole (MDZ) as well as vehicle control (VC) of the formulation containing monoglycerides and sorbitan monostearate. Untreated biofilms were used as negative control (NC). The biofilms and culture media of S. mutans were collected after the first exposure to the treatments at times 24, 48, 72 and 96 hours while for P. gingivalis biofilms, the times were 24, 48 and 72 hours. After collection, biofilms were analyzed for drug quantification and bacterial viability (S. mutans biofilms: n=3; P. gingivalis biofilms: n=6). Biofilms of S. mutans were also evaluated for acidogenicity. In the supragingival biofilms, the MDZ quantification in the first 24 hours was 7% in relation to the initial concentration of drug in the formulation, remaining around 1% for the remaining times. The amount of MDZ released from the formulation reduced the bacterial viability in the 24 hour and decreased the acidogenicity of the biofilms by 48 hours in relation to the VC and NC groups (p <0.05). As for subgingival biofilms, 19% of MDZ was released from the formulation in the first 24 hours and 5% of the drug was quantified in the other analyses. The MDZ released reduced bacterial viability in relation to VC and NC (p <0.05), and was not statistically different at all sampling times studied (p> 0.05). The VC group presented lower number of viable bacteria than NC (p <0.05), however, it was higher when compared to the MDZ-treated group at all sampling times studied (p <0.05). In general, the controlled release system proposed in this study was able to prevent the proliferation of P. gingivalis biofilms and to destabilize S. mutans biofilms. In addition, microenvironments caused by biofilms interfered with the release kinetics of metronidazole, reducing its bioavailability. Thus, considering the continuity of the sub and supragingival biofilms, it is imperative to deepen the studies on formulations that can inhibit the formation of subgingival biofilms while destabilizing supragingival biofilms, thereby avoiding the rapid recolonization of the treated periodontal niches. In addition, the possibility of studying operational parameters for the development of pharmaceutical formulations using models of pathogenic biofilms can be considered in future studies

With recent development of nanoscience and nanotechnology, a great amount of efforts have been devoted to nanomedicine development. Among various nanomaterials, silica nanoparticle (NP) is generally accepted as non-toxic, and can provide a versatile platform for drug loading. In addition, the surface of the silica NP is hydrophilic, being favorable for cellular uptake. Therefore, it is considered as one of the most promising candidates to serve as carriers for drugs. / The present thesis mainly focuses on the design of silica based nanocarrier-drug systems, aiming at achieving safe nanocarrier excretion from the biological system and enhanced drug efficacy, which two are considered as most important issues in nanomedicine development. / To address the safe carrier excretion issue, we have developed a special type of self-decomposable SiO₂-drug composite NPs. By creating a radial concentration gradient of drug in the NP, the drug release occurred simultaneously with the silica carrier decomposition. Such unique characteristic was different from the conventional dense SiO₂-drug NP, in which drug was uniformly distributed and can hardly escape the carrier. We found that the controllable release of the drug was primarily determined by diffusion, which was caused by the radial drug concentration gradient in the NP. Escape of the drug molecules then triggered the silica carrier decomposition, which started from the center of the NP and eventually led to its complete fragmentation. The small size of the final carrier fragments enabled their easy excretion via renal systems. / Apart from the feature of safe carrier excretion, we also found the controlled release of drugs contribute significantly to the drug efficacy enhancement. By loading an anticancer drug doxorubicin (Dox) to the decomposable SiO₂-methylene blue (MB) NPs, we achieved a self-decomposable SiO₂(MB)-Dox nanomedicine. The gradual escape of drug molecules from NPs and their enabled cytosolic release by optical switch, led to not only high but also stable drug concentration in cytosol within a sustained period. This resulted in enhanced drug efficacy, which is especially manifested in multidrug resistant (MDR) cancer cells, due to the fact that the NP-carrier drug can efficiently bypass the efflux mechanisms and increase drug availability. Together with its feature of spontaneous carrier decomposition and safe excretion, this type of nanomedicine’s high drug efficacy highlights its potential for low dose anticancer drug treatment and reduced adverse effect to biological system, holding great promise for clinical translation. / The enhanced drug efficacy by employing the self-decomposable silica nanocarrier is also demonstrated in photodynamic therapy (PDT). The loose and fragmentable features of the self-decomposable SiO₂-photosensitizer (PS) NPs promoted the out-diffusion of the generated ROS, which resulted in a higher efficacy than that of dense SiO₂-PS NPs. On the other hand, we also explored another nanocarrier configuration of Au nanorods decorated SiO₂ NP, with PS drug embedded into dense SiO₂ matrix. A different mechanism of drug efficacy enhancement was presented as the Au’s surface plasmon resonance enhanced the ROS production. Although the drug efficacy of such SiO₂(PS)-Au NPs was similar to that of self-decomposable SiO₂-PS NPs, their potential for clinical applications was limited without the feature of safe carrier excretion. / In summary, the self-decomposable SiO₂ based NP developed is a most promising system to serve as safe and effective carriers for drugs. Together with the known biocompatibility of silica, the feature of controllable drug release and simultaneous carrier decomposition achieved in the self-decomposable SiO₂-drug NPs make it ideal for a wide range of therapeutic applications. / 隨著近年來納米科學技術的快速發展，致力於納米藥物的研发也越來越多。在眾多納米材料體系中，二氧化硅納米顆粒因其無毒、易載藥、且易於細胞攝入等特性，被認為是最具前景的藥物載體之一。 / 本文主要致力於設計以二氧化硅納米顆粒為載體的納米藥物體系，使之同時具備能夠被生物體安全排泄以降低潛在不良影響，并且能夠加強藥效的特性，而這兩方面被認為正是納米藥物發展中最重要的議題。 / 爲了實現藥物載體安全排泄，我們設計了一種特殊類型可自降解的二氧化硅-藥物複合納米顆粒。通過在納米顆粒中控制形成徑向藥物濃度梯度分佈，我們達到了藥物釋放的同時伴隨二氧化硅載體解體的效果。這一特徵不同於傳統二氧化硅-藥物複合納米顆粒中藥物均勻分佈而難以擴散出載體的情況。我們發現在這種可自降解的二氧化硅-藥物複合納米顆粒中，首先徑向藥物濃度梯度分佈所引起的擴散控制著藥物釋放，而後藥物分子的流失促發二氧化硅載體由內而外的逐步分解，最終全面解體分裂成碎片。這些碎片的小尺度使得它們易於經泌尿系統安全排泄出體外。 / 除此之外，我們發現這種納米載體的可控藥物釋放特性可以大大提高藥效。通過將抗癌藥阿黴素載入自降解二氧化硅-亞甲藍納米顆粒中，我們得到一種可自降解二氧化硅/亞甲藍-阿黴素(SiO₂(MB)-Dox)複合納米顆粒。藥物分子可以逐漸擴散出納米顆粒，並且在光控開關作用下釋放到細胞胞漿中，使之在胞漿中持續保持穩定高濃度。這樣使得藥效得以加強，尤其是在多藥抗藥性腫瘤細胞中作用尤為明顯，這得益於納米載體藥物可以有效避開藥泵機制并提高藥物利用率。除了它的自發載體分解和安全排泄特性，這種納米藥物的高藥效使得它在低藥量治療和減少不良副作用方面的潛力突出，臨床應用前景廣大。 / 可自降解二氧化硅納米載體所帶來的的藥效增強亦顯示在光動力學治療法中。可自降解二氧化硅-光敏劑藥物(SiO₂-PS)複合納米顆粒鬆散易分解的結構特性促使其內部產生的活性氧物質易於擴散出藥物載體，這使得它的藥效高於傳統二氧化硅-光敏劑複合納米顆粒。另一方便，我們設計了一種金修飾的二氧化硅納米顆粒載體。它具有另一種不同的藥效增強機制，即利用金納米顆粒表面等離子體共振效應來增強活性氧物質的產生。雖然藥效與可自降解二氧化硅-光敏劑複合納米顆粒相似，但是它無法安全排泄，限制了其在臨床上的應用。 / 綜上所述，我們發展的可自降解二氧化硅納米顆粒作為一種安全高效的藥物載體顯示出其非常大的應用前景。二氧化硅以其衆所周知的生物相容性，和我們發展的可控藥物釋放及同步載體分解特性，已成為理想的藥物載體并有希望廣泛適用於治療應用。 / Zhang, Silu = 基於無定二氧化硅納米顆粒的安全高效納米藥物的研究 / 張思鷺. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2014. / Includes bibliographical references. / Abstracts also in Chinese. / Title from PDF title page (viewed on 12, October, 2016). / Zhang, Silu = Ji yu wu ding er yang hua gui na mi ke li de an quan gao xiao na mi yao wu de yan jiu / Zhang Silu. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only.

Recent advances in the area of nanotechnology have led to interesting applications of nanomaterials in medicine, especially in the areas of imaging and treatment. This thesis presents the development of two molecularly imprinted polymers (MIPs) based on the same fluorescent functional monomer. One MIP, prepared in the bulk format, is investigated for its ability to detect tamoxifen and its metabolites. The other MIP synthesised in the nanogel format, holds the potential to be used as pH-responsive drug delivery system. Four objectives were identified within this project. The first was the design and synthesis of fluorescent functional monomer. Two coumarin derivatives carrying a polymerisable unit, for covalent bonding within the polymer, and a carboxylic moiety, for interaction site with the template, were synthesised and characterised. However, only one of them (the VCC: 6-vynilcoumarin-4-carboxylic acid) showed high fluorescent yield and was selected as functional monomer. The second objective involved the development of a detection system based on bulk MIP containing the VCC fluorescent monomer. This system proved effective in generating a detectable signal upon binding the analytes. The signal was observed as a quenching of the polymer fluorescence and it was proportional to the amount of target molecules detected. The third objective was the preparation of tamoxifen-imprinted nanogels for potential application in the drug delivery field. The optimisation of the procedure gave a set of NIP/MIP with the desired solubility, particle size and fluorescence emission. These nanogels were then employed in the last objective, which involved the toxicity study and evaluation of the drug loading on of transgenic line of zebrafish. The nanogels were non-toxic at the tested concentrations and the presence of tamoxifen was confirmed.

Polymer brushes generated via "grafting-from" approach emerged as an attractive surface modification tool offering chemical stability, synthetic flexibility and unprecedented control over the polymer grafting density, thickness, chemical composition and functionality. They display interesting features to many applications in regenerative medicine including cell culture, tissue engineering and as delivery systems due to exquisite control of physicochemical and biological properties. Cationic polymer brushes are particularly attractive in the field of designing effective vectors for gene delivery as polymer brush allows the design and coating of a variety of particles with well-defined core-shell architecture and chemistry to efficiently condense and deliver nucleic acids. This thesis concentrates on designing safe and efficient gene delivery vectors based on 'graft from' cationic polymer brush and understanding the interaction of nucleic acids with polymer brush. Chapter one presented fundamental knowledge of polymer brush and its biomedical application. The first part of this chapter describes the definition of polymer brush, the preparation strategies, mechanism of atom transfer radical polymerisation and the responsiveness of polymer brush including solvent, pH and ionic strength. The second part discusses the state-of-art applications of polymer brush in regenerative medicine including protein resistant polymer brush for tissue engineering and as drug/gene delivery systems.

This thesis details our early efforts towards the discovery of polymeric and macromolecular platforms for the targeted delivery of sensors and actuators to specific cell types in the living brain tissue. Chapter 1 of this thesis discusses the small molecule tropane tag chosen as a homing ligand and the dopamine transporter (DAT) chosen as a cellular target, as well as the synthesis of new tropane-based molecular tags for evaluation in cultured human DAT (hDAT)-expressing cells and targeting in brain tissue. Chapter 2 discusses the results obtained from evaluation of the new tropane tags in hDAT-expressing and hNET-exressing cells, including early results from the first example of a DAT-specific voltage sensing dye. In Chapter 3, we discuss the principles governing molecular targeting of probes in the living brain tissue. Part I of Chapter 3 gives important background necessary for understanding some of the complexities involved in targeting chemical probes to specific sites in living brain tissue. Part II of Chapter 3 discusses early results obtained from targeting of our tropane tags in living brain tissue. We provide, perhaps, the first example of a binding-site barrier effect in healthy tissue and demonstrate successful delivery of a moderate-sized protein, neutravidin, to dopaminergic axons. Chapter 3 also discusses preliminary results demonstrating the behavior of our small molecule tag and tagged quantum dot construct in the living mouse brain. Studies of our tagged polymers in cultured cells and our work thus far in the brain suggest which polymers may be most effective as delivery platforms for chemical targeting to specific cell types in living brain tissue.

by Tai Fai Fok. / Thesis (Ph.D.)--Chinese University of Hong Kong, 1997. / Includes bibliographical references (p. 211-215). / Microfiche. Ann Arbor, Mich. UMI, 1998. 3 microfiches ; 11 x 15 cm.

Aim: Subunit vaccines have received increasing attention due to their good safety profile. However, subunit vaccines feature low immunogenicity, and soluble antigen is largely ignored by the immune system due to its lack of danger signals. To stimulate an appropriate immune response, subunit antigen vaccines require the addition of an adjuvant and multiple administrations. This study aimed to formulate biodegradable lipid implants, containing a suitable adjuvant, which delivers antigen in a sustained manner. The physico-chemical characteristics of the implants and their ability to stimulate immune responses towards a model antigen in vivo were investigated. Methods: Lipid implants were prepared from phospholipid and cholesterol. Different adjuvants were added, and their potential to induce an immune response to the model antigen ovalbumin (OVA) was investigated. The adjuvants and immunomodulators assessed were Quil-A (QA), imiquimod, and an α-Galactosylceramide (α-GalCer) analogue. Liposomal dispersions were prepared using the lipid film hydration method. These were freeze-dried, and the powder compressed into matrices (diameter of 2 mm). Physico-chemical characterisation was undertaken by transmission electron microscopy (TEM) to investigate the release of colloidal structures (liposomes, immunostimulating complexes [ISCOMs]) upon hydration with release media. Surface changes of the implant matrices were analysed using scanning electron microscopy (SEM). The release of the fluorescently-labelled antigen ovalbumin (FITC-OVA) and its entrapment into the colloidal particles was investigated using spectrofluorophotometry. Additionally, incorporation of the cationic cholesterol derivative DC-cholesterol (DCCHOL) into implants to allow for charge-charge interactions with the negatively-charged OVA, and replacement of the phospholipid with a phospholipid having a higher transition temperature to facilitate the manufacturing process, were attempted and assessed. The immune response stimulated towards OVA released from the implants was analysed in vivo using a C57Bl/6 mouse model. Expansion of CD8⁺ T cells and CD8 T cells specific for the CD8 epitope of OVA (SIINFEKL), as well as expansion of CD4⁺ T cells, were assessed. The ability of implants to stimulate T cell proliferation and interferon-γ production after in vitro restimulation with OVA was analysed. Serum samples were analysed for OVA-specific IgG antibodies. Results: Lipid implants containing Quil-A released colloidal structures upon hydration with buffer. The type of colloids observed by TEM depended on the ratio of QA:cholesterol:phospholipid. Release of OVA was sustained over ten days in implants prepared with egg yolk PC. However, the release kinetics depended strongly on the choice of phospholipid. In vivo, lipid implants containing Quil-A evoked expansion of CD8⁺ T cells. The immune response to one implant was comparable to that obtained by two equivalent injection immunisations. Therefore, the implants obviated the need for multiple immunisations in the vaccination regime tested here. Expansion of CD8⁺ T cells towards the Quil-A-containing implant was greater than that achieved by the immunomodulators imiquimod and the α-GalCer analogue. Quil-A-containing implants produced OVA-specific IgG antibodies to a greater extent than the implants containing imiquimod or α-GalCer. Incorporation of the cationic DCCHOL did not increase the entrapment efficiency of OVA into liposomes. However, the in vivo investigation of DCCHOL-containirig implants showed an adjuvant effect of DCCHOL on antibody responses, but not on cell-mediated immunity. Conclusion: Lipid implants offer great potential as sustained release vaccine delivery systems. The lipid components in the implant formulation were well-tolerated and biodegradable. Lipid implants combine the advantages of sustained release of antigen and particulate delivery by the formation of colloidal particles.

Since its discovery 15 years ago there has been an explosion of research in the field of DNA immunisation. Unfortunately despite early promises that DNA immunisation had the potential to cure almost any infectious disease, autoimmune disease or even cancer, progress towards clinical trials has been slow. This has been due in part to the huge range of permutations possible in delivering the DNA. One approach is to deliver the DNA by gene gun. Gene gun delivery is a very efficient way of transfecting cells however also has a number of possible disadvantages. These drawbacks include a weak immunogenicity in larger animals as well as the tendency to bias towards the development of a strong type 2 response. In an effort to enhance antigen-specific immune responses and counter the type 2 polarisation of gene gun delivery, a series of DNA vaccines were created where the extracellular portion of the hemagglutinin (HA) gene from influenza A/PR8/34 virus was genetically fused the type 1 cytokines IFNγ, IL-12 and IL-23. Interleukin-23 has been recently discovered and even though both IL-12 and IL-23 contain the p40 subunit they seem to have dissimilar functions. The vaccine constructs were first tested in cellular assays in vitro to ensure correct production and biological activity of the attached cytokines. They were then delivered in various combinations to groups of BALB/c mice to test development of immune responses and the effect of different delivery regimes. Finally mice were immunised then challenged with live influenza virus to determine the different DNA vaccines� protective efficacy. DNA vaccines containing the HA gene alone (pHA) or fused to IFNγ (pIFNγHA), IL-12 (pIL-12HA) or IL-23 (pIL-23HA) were successfully constructed. The fusion of the HA gene to the genes for IFNγ, IL-12 or IL-23 did not significantly disturb the structure of the antigen or prevent the biological actions of the cytokines. Mice immunised three times with pHA had high titres of serum IgG1 antibody and their splenocytes produced approximately equal amounts of IFNγ and IL-5. Co-delivery of IFNγ was unable to alter immune responses regardless of whether it was delivered at the first, last or during all immunisations. Surprisingly co-delivery of IL-12 acted to suppress both antibody and cellular immune responses, possibly through an IFNγ/nitric oxide feedback loop. On the other hand co-delivery of IL-23 tended to enhanced immune responses and, while it did not significantly alter the type 1 to type 2 balance, it was able to increase the ability of mice to clear live influenza virus from their lungs when they were challenged 26 weeks after immunisation. This protection was associated with increased levels of neutralising antibody in the serum of pIL-23HA immunised mice. This research has illuminated several of the pitfalls in the development of DNA vaccines and the use of cytokine as adjuvants. However it has also broadened our understanding of IL-23 and implies that IL-23 could be effectively used to increase the development of longterm immunity after immunisation.

Purpose: The aim of this thesis was to investigate a suitable formulation for the topical delivery of growth factors to chronic wounds, and then to determine the concentrations reached within an animal wound model. A secondary aim was to determine if the chosen growth factor was present at levels able to stimulate the production of other cytokines, specifically IL-1β and MCP-1. Methods: An in vitro testing apparatus was designed and made and the release of model actives [bromophenol blue (BPB) and horseradish peroxidase (HRP)] from gels and films of hydroxylpropylmethylcellulose (HPMC) (E4M CR, K4M CR and E10M CR) was determined. In this study, Fibroblast Growth Factor -2 (FGF-2) (0.3 [mu]g) was incorporated into three formulations (solution, gel and dried gel film on Melolin[TM] backing) and together with a control formulation were administered to punch biopsy wounds in rats. The in vivo release was followed over three time periods (two, five and eight hours) and the amount of FGF-2 at various wound depths was quantified by ELISA. Two biological markers IL-1β and MCP-1 were quantified using ELISA. The FGF-2 was additionally tagged with a fluorescent dye so that visualisation of the penetration could be obtained via confocal microsopy. Results: For the HPMC gels, the more viscous gel (E10M) provided a greater diffusional barrier and slowed the release of BPB (12 � 3.5 [mu]g/min compared with 16 � 1.7 [mu]g/min and 18 � 1.4 [mu]g/min for K4M and E4M respectively). However, when HPMC was formulated as a dried film a burst release was seen and release of BPB was slowest from the more rapidly hydrating K4M. With the larger model active HRP, there was a slower diffusion through the gel barrier formed upon film hydration, such that time of 100% release was up to 300 minutes compared to approximately 60 minutes for BPB. When the film was dried onto a supportive backing, the initial burst release was minimised as the film did not break apart on contact with the wound, and hence film integrity was maintained and release prolonged. The in vivo studies showed that, two hours after application, the highest concentration of FGF-2 was seen in the surface granulation tissue of rats that received the solution formulation (2280 � 790 pg/g). The concentration decreased with increasing tissue depth but was significantly greater than the saline control in the surface granulation and subcutaneous fat layers (p<0.05). Tissue concentrations following application of the gel and film formulations were only marginally greater than control in the surface granulation layer. After eight hours, rats that received the solution retained elevated surface tissue concentrations (surface granulation and subcutaneous fat) of FGF-2. Repeated measures ANOVA using a general linear model showed statistically significant differences in the mean FGF-2 level with respect to formulation and length of time of application of the formulation (p<0.05). In terms of other cytokines, there was a release of both IL-1β and MCP-1 in all groups, immediately post-wounding, probably in response to cellular damage. After eight hours, the film formulation appeared to elevate IL-1β levels which may be useful to drive wound healing. Confocal microscopy images showed diffuse distribution of FGF-2 eight hours after application of the solution formulation after eight hours and that with the gel formulation FGF-2 initially aggregated at the wound surface. Conclusion: In vitro experiments investigating the effect of hydration rate and viscosity of HPLC polymers allowed a formulation to be chosen for further in vivo study. Elevated FGF-2 could be measured in superficial wound tissues up to eight hours after application of a solution. However, application of a comparable amount of FGF-2 in HPMC gels or films did not produce appreciable elevations in FGF-2 in wound tissues, although confocal microscopy indicated the penetration of FGF-2 into the wound for up to eight hours.

This thesis describes evaluation of a gastric retention device (GRD) developed at Oregon State University. The device was originally fabricated from Xanthan gum and Locust bean gum. A modified gastric retention device containing other additives was developed and investigated in this work. The modified device was evaluated in vitro for swelling and dissolution properties using riboflavin as a model drug. Different shapes and sizes of GRDs were tested in dogs to study the gastric retention potential of these devices. The effect of the device on food emptying from the stomach in dogs was also investigated. Endoscopic studies in dogs also showed that the device swells rapidly and considerably in gastric fluid. The bioavailability of riboflavin from three different size GRDs was determined in six fasted human volunteers and compared to an immediate release formulation. The biostudy indicated that the bioavailability of riboflavin from a large size GRD was more than triple that measured after administration of the immediate release formulation. Deconvolution was used to determine gastric residence time of the different size GRDs. A new colonic delivery system made of acetaminophen loaded beads produced by extrusion and spheronization and coated with different ratios of pectin and ethylcellulose coating solutions in a spray coating apparatus was also developed in this work. Such beads release their drug content in the colon due to susceptibility of pectin in the outer coat to enzymatic action of colonic bacteria. The new delivery system was evaluated in vitro by conducting release studies in different dissolution media to mimic transit times, pH and enzyme conditions in the gastrointestinal tract. The gastrointestinal transit behavior of drug beads was also assessed by conducting gamma-scintigraphic studies in dogs. The bioavailability and pharmacokinetic parameters of acetaminophen from several colonic delivery system formulations were determined in human volunteers and compared to the immediate release commercial product Tylenol®. A selected pectin-ethylcellulose coat formulation in the ratio 1:3 was further evaluated in six volunteers under both fed and fasting conditions and was found to be effective and to provide sustained drug release in the colon over a period of 12 hours. / Graduation date: 2003