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Submitted by Johnny Rodrigues (johnnyrodrigues@ufcg.edu.br) on 2018-04-05T19:05:37Z No. of bitstreams: 1 IMARALLY VITOR DE SOUZA RIBEIRO NASCIMENTO - DISSERTAÇÃO PPG-CEMat 2014..pdf: 2760797 bytes, checksum: 7ecba4dc55afbb264d93e04510c69d66 (MD5) / Made available in DSpace on 2018-04-05T19:05:37Z (GMT). No. of bitstreams: 1 IMARALLY VITOR DE SOUZA RIBEIRO NASCIMENTO - DISSERTAÇÃO PPG-CEMat 2014..pdf: 2760797 bytes, checksum: 7ecba4dc55afbb264d93e04510c69d66 (MD5) Previous issue date: 2014-08-29 / Capes / Os sistemas de liberação controlada de fármacos oferecem inúmeras vantagens quando comparados a outros de dosagem convencional tendo os polissacarídeos biodegradáveis ganhando bastante aceitação no desenvolvimento desses sistemas. A quitosana é um exemplo de polissacarídeo biodegradáveis, cuja taxa de liberação pode ser modulada a partir da reticulação iônica com o Tripolifosfato de sódio (TPP). A piperina é um dos principais constituintes da pimenta negra, possuindo diversas ações farmacológicas que podem causar a morte de células cancerígenas e quando conjugada com a quitosana apresenta melhor biodisponibilidade e ação mais rápida. Sendo assim, esse trabalho objetivou desenvolver e avaliar comparativamente membranas poliméricas de quitosana e quitosana reticulada pelo TPP para uso em sistema de liberação controlada de piperina, com a finalidade de obter uma via alternativa para a administração desse fármaco. A piperina foi adicionada sob agitação constante à solução de quitosana e as membranas foram obtidas pelo método de evaporação do solvente. As membranas desenvolvidas foram caracterizadas pelas técnicas de Espectroscopia na Região do Infravermelho com Transformada de Fourier (FTIR), Difração de Raios X (DRX), Microscopia Ótica (MO), Microscopia Eletrônica de Varredura (MEV), Espectroscopia por Energia Dispersiva de Raios X (EDS), Análise Termogravimétrica (TG), Análise de Calorimetria Exploratória Diferencia (DSC), Eficiência de Carregamento (EC) através da Cromatografia Liquida de Ultra Eficiência (CLUE), Avaliação da Viabilidade Celular dos Macrófagos (MTT). Observou-se na análise por FTIR bandas características da quitosana, do agente reticulante e da piperina, como também bandas que caracterizam uma interação entre a quitosana e a piperina. A técnica de DRX demonstrou alteração no caráter semicristalino da quitosana com a presença da piperina e do tripolifosfato. Foi possível perceber, através das técnicas de MO e MEV, alteração na morfologia da membrana contendo piperina quando comparada a de quitosana pura, com a presença de partículas fibrilares. As análises de TG e DSC evidenciaram que quando a piperina foi adicionada à quitosana esta proporcionou uma maior estabilidade térmica ao sistema. O ensaio eficiência de carregamento evidenciou que a extração do o fármaco foi eficaz e que a reticulação influenciou na extração deste. As membranas desenvolvidas apresentaram potencial citotóxico para as células de câncer mamário humano MCF 7. Nas condições desenvolvidas nesta pesquisa o sistema indicado como referência para ensaios de liberação e novos ensaios biológicos é o sistema MQPR. Diante do exposto o sistema desenvolvido apresenta-se como promissor para a obtenção de um sistema para liberação controlada de fármacos. / Controlled drug delivery systems offer many advantages when compared to other conventional dosage methods with biodegradable polysaccharides gaining enough acceptance in the development of these systems. Chitosan is an example of a biodegradable polysaccharide, whose rate of release can be modulated from the ionic crosslinking with sodium tripolyphosphate (TPP). Piperine is one of the major constituent of black pepper, having many pharmacological actions that can cause the death of cancer cells and when combined with chitosan has better bioavailability and faster action. Therefore, this study aimed to develop and comparatively evaluate polymer membranes of chitosan and crosslinked chitosan by TPP to be used in a controlled release system of piperine, in order to obtain an alternative route for the administration of this drug system. Piperine was added under constant stirring to the solution of chitosan and membranes were obtained by the solvent evaporation method. The developed membranes were characterized by the techniques of Infrared Spectroscopy in the Region Fourier Transform (FTIR), X-ray Diffraction (XRD), Optical Microscopy (OM), scanning electron microscopy (SEM), Energy Dispersive Spectroscopy X-Ray (EDS), Thermogravimetric Analysis (TGA), Scanning Calorimetry Analysis of Difference (DSC), Efficiency Charge (EC) by liquid Chromatography Ultra Efficiency (HPLC), Assessment of Cell Viability of Macrophages (MTT). It was observed by FTIR analysis, bands characteristic of chitosan, the crosslinking agent and piperine, as well as bands characterizing an interaction between chitosan and piperine. The XRD technique showed change in semi-crystalline nature of chitosan in the presence of piperine and tripolyphosphate. It was possible to see, through the techniques of OM and SEM, changes in the morphology of the membrane containing piperine compared to pure chitosan, with the presence of fibrillar particles. TG analysis showed that, when piperine was added to the chitosan it provided a smaller weight loss of the system, showing the interaction between chitosan and piperine. DSC analysis showed that addition of piperine into chitosan provided greater stability to the system. The charging efficiency test showed that the drug can be entrapped by 57% in the uncrosslinked membranes and crosslinking influenced the extraction of drug. The developed membranes showed cytotoxic potential for human breast cancer cells MCF 7. Under the developed conditions in this research, MQPR system was shown as a reference for drug delivery testing and new biological tests. Given the above, the developed system is presented as promising for obtaining a system for controlled release of drugs.

The influence of plasticization and other formulation factors on the properties of hot-melt extruded dosage forms for the controlled release of water-soluble active compounds was investigated. Citric acid monohydrate was demonstrated to function as a solid-state plasticizer in hot-melt extruded Eudragit® RS PO tablets and in cast films when concentrations below the compatibility limit were employed. Melting of the organic acid and solubilization in the polymer during extrusion were necessary to observe the plasticizing effect. The release rate of diltiazem hydrochloride, used as a high-melting, water-soluble model drug, from melt extruded Eudragit® RS PO matrix tablets increased and became independent of the original drug particle size in the presence of citric acid monohydrate. Thermal analysis of physical mixtures demonstrated that citric acid promoted drug melting during extrusion by interaction and melting point depression. Diltiazem hydrochloride remained amorphous in the final dosage form, and leaching of citric acid monohydrate enhanced drug diffusion by increasing the matrix porosity. Delayed-release matrix pellets with particle sizes below one mm were prepared by hot-melt extrusion, and the influence of the matrix forming polymer and the type and level of plasticizer on the processibility and release properties was investigated. Pellets complied with the USP requirement for delayed release articles to release less than 10% drug at pH 1.2 after 2 hours when plasticized Eudragit® S100 was used as the release-controlling material. High levels of efficient plasticizers had to be employed to decrease the polymeric melt viscosity, increase the process yield and enable extrusion at moderate temperatures to avoid instabilities during processing and storage. The aqueous solubility of the plasticizer further impacted the drug release rate in acid. A novel application of hot-melt extrusion for the preparation of monolithic matrices comprising enteric coated particles was studied. The influence of the mechanical strength of the multiparticulates, pellet loading and nature of the hydrophilic carrier material on the preservation of the delayed-release properties after extrusion was investigated. Soft particles coated with brittle films remained intact when low-melting carriers that did not solubilize the enteric film during extrusion were used, and the dissolution profile was stable over one year. / text

Chronic diseases can often be managed by constantly delivering therapeutic amounts of drug for prolonged periods. A controlled release for extended duration would replace the need for multiple and frequent dosing. Local drug release would provide added benefit as a lower dose of drug at the target site will be needed as opposed to higher doses required by whole body administration. This would provide maximum efficacy with minimum side effects. Nonetheless, a problem with the known implantable drug delivery devices is that the delivery rate cannot be controlled, which leads to drug being released in an unpredictable pattern resulting in poor therapeutic management of patients. This dissertation is the result of development of an implantable drug delivery system that is capable of long-term zero order local release of drugs. The device can be optimized to deliver any pharmaceutical agent for any time period up to several years maintaining a controlled and desired rate. Initially significant efforts were dedicated to the characterization, biocompatibility, and loading capacity of nanoporous metal surfaces for controlled release of drugs. The physical characterization of the nanoporous wafers using Scanning electron microscropy (SEM) and atomic force microscopy techniques (AFM) yielded 3.55 x 10⁴ nm³ of pore volume / μm² of wafer surface. In vitro drug release study using 2 - octyl cyanoacrylate and methyl orange as the polymer-drug matrix was conducted and after 7 days, 88.1 ± 5.0 % drug was released. However, the initial goal to achieve zero order drug release rates for long periods of time was not achieved. The search for a better delivery system led to the design of a perforated microtube. The delivery system was designed and appropriate dimensions for the device size and hole size were estimated. Polyimide microtubes in different sizes (125-1000 μm) were used. Micro holes with dimensions ranging from 20-600 μm were fabricated on these tubes using photolithography, laser drilling, or manual drilling procedures. Small molecules such as crystal violet, prednisolone, and ethinyl estradiol were successfully loaded inside the tubes in powder or solution using manual filling or capillary filling methods. A drug loading of 0.05 – 5.40 mg was achieved depending on the tube size and the drug filling method used. The delivery system in different dimensions was characterized by performing in vitro release studies in phosphate buffered saline (pH 7.1-7.4) and in vitreous humor from the rabbit’s eye at 37.0 ± 1.0°C for up to four weeks. The number of holes was varied between 1 and 3. The tubes were loaded with crystal violet (CV) and ethinyl estradiol (EE). Linear release rates with R²>0.9900 were obtained for all groups with CV and EE. Release rates of 7.8±2.5, 16.2±5.5, and 22.5±6.0 ng/day for CV and 30.1±5.8 ng/day for EE were obtained for small tubes (30 μm hole diameter; 125 μm tube diameter). For large tubes (362-542 μm hole diameter; 1000 μm tube diameter), a release rate of 10.8±4.1, 15.8±4.8 and 22.1±6.7 μg/day was observed in vitro in PBS and a release rate of 5.8±1.8 μg/day was observed ex vivo in vitreous humor. The delivery system was also evaluated for its ability to produce a biologically significant amounts in cells stably transfected with an estrogen receptor/luciferase construct (T47D-KBluc cells). These cells are engineered to produce a constant luminescent signal in proportion to drug exposure. The average luminescence of 1144.8±153.8 and 1219.9±127.7 RLU/day, (RLU = Relative Luminescence Units), yet again indicating the capability of the device for long-term zero order release. The polyimide device was characterized for biocompatibility. An automated goniometer was used to determine the contact angle for the device, which was found to be 63.7±3.7degreees indicating that it is hydrophilic and favors cell attachment. In addition, after 72 h incubation with mammalian cells (RAW 267.4), a high cell distribution was observed on the device’s surface. The polyimide tubes were also investigated for any signs of inflammation using inflammatory markers, TNF-α and IL-1β. No significant levels of either TNF-α or IL-1β were detected in polyimide device. The results indicated that polyimide tubes were biocompatible and did not produce an inflammatory response. / text

Even though the role of oxidative stress in a variety of disease states is known, strategies to alleviate this oxidative stress by antioxidants have not been able to achieve clinical success. Particularly, treatment of oxidative stress by small molecule antioxidants has not received due attention because of the challenges associated with its delivery. Antioxidant polymers, where small molecule antioxidants are incorporated into the polymer backbone, are an emerging class of materials that can address some of these challenges. In this work, biodegradable polymers incorporating phenolic antioxidants in the polymer backbone were synthesized. Antioxidant polymers were then characterized for their in vitro degradation, antioxidant release and their effect on oxidative stress levels (redox state) in the cells. Trolox, a water-soluble analogue of vitamin E, was polymerized to synthesize poly(trolox ester) with 100% antioxidant content which undergoes biodegradation to release trolox. Nanoparticles of poly(trolox ester) were able to suppress oxidative stress injury induced by metal nanoparticles in an in vitro cell injury model. In another study, we polymerized polyphenolic antioxidants (e.g. curcumin, quercetin) using a modified non-free-radical polymerization poly(β-amino ester) chemistry. This synthesis scheme can be extended to all polyphenolic antioxidants and allows tuning of polymer degradation rate by choosing appropriate co-monomers from a large library of monomers available for β-amino ester chemistry. Poly(antioxidant β-amino esters) (PABAE) were synthesized and characterized for their degradation, cytotoxicity and antioxidant activity. PABAE degradation products suppressed oxidative stress levels in the cells confirming antioxidant activity of degradation products.

Growth plate injuries account for 15-30% of long bone fractures in children. About 10% of these result in significant growth disturbances due to formation of a boney bar. If not treated correctly, this can lead to life-lasting consequences of limb length inequalities and angular deformities. Current treatments for growth plate injuries include removal of boney bar and insertion of fat, silicone, bone cement, etc.. This treatment y is inadequate, leaving almost half of these patients with continued deformities. This dissertation reports characterization of a DNA–containing porous poly(lactic-co-glycolic acid) (PLGA) scaffold system, chondrogenesis using insulin-like growth factor I (IGF-I) plasmid-releasing scaffolds in vitro, and in vivo testing of IGF-I plasmid-releasing scaffolds to regenerate growth plate . Controlled release of naked and DNA complexed with polyethylenimine (PEI) was achieved from porous PLGA scaffolds. PEI affected release of complexes from PLGA scaffolds, as PEI:DNA complexes were released at a lower rate compared to naked DNA encapsulated in low molecular weight (LMW) and high molecular weight PLGA scaffolds, as well as hydrophilic and hydrophobic PLGA scaffolds. Hydrophilicity and molecular weight of PLGA affected the release profiles of both naked DNA and PEI:DNA complexes from the scaffolds, as evidenced by later peak DNA and PEI:DNA release with increasing hydrophilicity and molecular weight. LMW hydrophilic PLGA scaffolds supported growth and chondrogenic differentiation of mesenchymal multipotent D1 cells, chondrocytes, and bone marrow cells (BMCs) in vitro. Culturing BMCs on IGF-I plasmid-encapsulated scaffolds resulted in elevated expression of IGF-I compared to blank scaffolds. Removal of boney bar and implantation of IGF-I plasmid-releasing LMW PLGA scaffolds in a rabbit model of growth plate injury resulted in some improvement of leg angular deformity compared to no scaffold implantation. Histological analysis of the newly developed cartilage showed growth plate-like columnar arrangement of chondrocytes in a defect that received IGF-I plasmid encapsulated scaffold, although the level of organization of newly formed cartilage was inferior to that of native growth plate. This appears to be the first report of the regeneration of growth plate-like structure without the use of stem cells in an animal model of physeal injury.

Technological limitations have prevented interrogation and manipulation of many signaling pathways in model and living systems required for the development of diagnostic and therapeutic modalities in diseases, such as cancer. Liposome-supported plasmon resonant gold nanoshells are biologically inspired composite structures, in which the liposome allows for the encapsulation of substances, and the plasmon resonant structure facilitates rapid release of encapsulated contents upon laser light illumination. As shown in this work, we overcome current limitations in cellular manipulation using plasmon resonant gold-coated liposomes in conjunction with light-activated release to achieve accurate probing of complex cellular responses. Development toward this goal was demonstrated with four specific aims. The first specific aim was to develop a computational model of heat diffusion to investigate the light-induced heating of gold-coated liposomes. This model was used to optimize the photothermal process for release of an encapsulated payload. The second aim was to demonstrate encapsulation and on-demand release of molecules in a spectrally-controlled manner, where plasmon resonant nanoparticles only release content upon illumination with a wavelength of light matching their plasmon resonance band. The third specific aim was to demonstrate that this release mechanism can be used in a biological setting to deliver a peptide and extracellularly activate surface membrane receptors with single-cell spatial and high temporal resolution. The fourth specific aim further refined the level of spatial and temporal control of payload release using gold-coated liposomes with optical trapping to demonstrate mirco-manipulation of liposome movement and rapid content release to enable accurate perturbation of cellular functions in response to released compounds. Through this work, we have developed an experimental system with the potential for the delivery and localized release of an encapsulated agent with high spatial and temporal resolution. This on-demand release system is compatible with a broad range of molecules and uses biologically safe near-infrared light. In combination with the spectral tunability of these plasmon resonant nanoshells and spectrally-selective release, this technology may allow for interrogation of complex and diverse signaling pathways in living tissues or their models with unprecedented spatial and temporal control.

Controlled release systems aim at achieving a predictable and reproducible drug release profile over a desired time period. These controlled release formulations offer many advantages over conventional dosage forms. These advantages include: reduced dosing intervals, constant drug levels in the blood, increased patient compliance and decreased adverse effects. Complex controlled release formulations such as those with sustained release properties, often require additional steps during the production phase. The cost and economic impact associated with these complex controlled release dosage formulations often outweigh the short term benefits. Thus the development of an economic method to produce controlled release particles is of great importance especially in third world countries. In controlled release formulations the drug is often equally dispersed throughout a polymer matrix. In the presence of a thermodynamically compatible solvent, swelling occurs and the polymer releases its content to the surrounding medium. The rate of drug release can be controlled by interfering with the amount of swelling and rate of diffusion by manipulating the viscosity of the polymer matrix. Chitosan is an ideal candidate for controlled drug delivery through matrix release systems. It is a biodegradable polymer with absorption-enhancing properties. Cross-linking chitosan with different cross-linking agents allow the preparation of beads. Beads are frequently used in controlled release dosage forms as they are very flexible in dosage form development and show various advantages over single unit dosage forms. Because beads disperse freely in the gastrointestinal tract they maximize drug absorption, reduce fluctuation in peak plasma, and minimize potential side effects without lowering drug bio-availability. Chitosan beads and excipient containing chitosan beads were prepared and investigated as possible controlled release formulations. Pyrazinamide was chosen as the model drug. Chitosan beads and excipient containing chitosan beads were prepared by ionotropic gelation in tripolyphosphate. In this study chitosan/pyrazinamide beads containing pharmaceutical excipients (Ascorbic acid, Explotab and Ac-Di-Sol) were produced. The excipients were added individually and in combinations to the chitosadpyrazinamide dispersion and the beads were characterized on the basis of their morphology, solubility, fiability, drug loading capacity and swelling behaviour, as well as drug release (dissolution properties). The drug loading of the pyrazinarnide loaded chitosan beads, was 52.26 % 0.57%. It was noted that the inclusion of excipients in the beads resulted in an increase in drug loading with the combination of Ascorbic acid and Ac-Di-Sol giving the highest drug loading of 67.09 ± 0.22%. It was expected that the addition of the pharmaceutical excipients would lead to a sustained release of pyrazinamide. Dissolutions studies, however, revealed a burst release in both phosphate buffer solution (PBS) pH 5.60 and 7.40 over the first 15 minutes and the curve reached a plateau after 30 minutes. Thus, apparently the inclusion of the pharmaceutical excipients did not contribute to a sustained release of pyrazinamide over the tested period of six hours. In future studies the dissolution time can possibly be extended to a period of 24 hours. It might be possible for the remaining drug (approximately 40%) in the beads to be released over the extended period. Other polymers can also be investigated to control the release of pyrazinamide. Further studies are, however, necessary to investigate this possibility in the future. / Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2007.

In today’s drug discovery, the number of candidate drugs based on new molecular entities with poor aqueous solubility is increasing. Since poor aqueous solubility of an active pharmaceutical ingredients (APIs) is associated with low bioavailability and thus limite their therapeutic effect, this is often a great challenge in the development of new drugs when oral administration is the preferred route of administration. A number of different strategies have been developed to circumvent this problem where salt formulations of an API is the most widely employed method. However, new strategies are needed since there is no one solution that solves this issue for all substances. In recent time, the concept of stabilizing poorly soluble APIs in their amorphous form has gained a lot of attention since amorphous compounds exhibit a higher apparent solubility compared to their crystalline counterparts. Amorphous substances are prone to crystallize if left in a non-constricted environment and thus need to be stabilized if the amorphous state is to be conserved until administration. Inorganic mesoporous materials have been proposed as an interesting type of excipients that can conserve the amorphous state of APIs. In this work, the focus was to investigate the possibilities of using a mesoporous type of magnesium carbonate to stabilize the amorphous state of different APIs. Due to the nanometer sized pores in the material, complete conservation of amorphous APIs was obtained. This resulted in both an increase in in vitro release rate and a higher solubility of the substances which may translate to both a faster onset of action and an improved therapeutic effect of the APIs in a clinical situation. The long term stability of formulations was also investigated showing promising results. The results presented in this work show that mesoporous magnesium carbonate represents an interesting type of excipient for oral formulations of APIs with poor aqueous solubility. / <p>Felaktigt ISBN 978-91-554-9702-6 i tryck version.</p>