Chitosan has proven through the years as a versatile biomaterial to be used in pharmaceutical applications. Its mucoadhesive properties as well as its ability to manipulate the tight junctions in epithelium membranes have qualified it as an effective drug carrier in controlled drug delivery systems. Microparticles or beads as they are forward called in this study have advantages over conventional drug dosage forms because of a large surface to volume ratio and have the ability to target a specific site for drug release. Indomethacin is an anti-inflammatory drug that causes gastrointestinal side effects in conventional immediate-release dosage forms. The goal is to manipulate the drug delivery vehicle to target the intestines/colon as the site for drug delivery and to minimize this side effect. Thus chitosan beads have been chosen as a drug delivery system for indomethacin in this study. Chitosan beads have been prepared through the ionotropic gelation method using tripolyphophate (TPP) as a cross-linking agent. To prepare the most effective bead to encapsulate indomethacin different formulation and system variables (pH of the TPP solution, the concentration of the TPP solution as well as the indomethacin concentration) have been evaluated according to the following parameters: morphology, drug loading capacity and swelling capability. The ideal pH of the TPP solution was determined at 8.7 and the most effective TPP and indomethacin concentration were 5% w/v and 4% w/v respectively. The chitosan concentration was kept at 3% w/v throughout the study. These concentrations were used to examine the effect of pharmaceutical excipients on the indomethacin release from chitosan beads. The effect of the different excipients namely, ExplotabⒽ(0.25% w/v), Ac-Di-SolⓀ (0.5% w/v) and Vitamin C (0.25% w/v), on the morphology, drug loading capacity, swelling capability as well as the drug release of indomethacin chitosan beads (ICB's) were also studied. The excipients were used in the individually above mentioned concentrations and in combination with each other in the same concentrations. These formulations were used in dissolution studies over a period of 6 hours in PBS pH 7.4 solutions. The indomethacin release rate increased when an excipient was added to the formulation and it dramatically increased when the excipients were added in their various combinations, compared to the formulation that did not contain excipients. / Contents: Chitosan -- Controlled drug delivery -- Indomethacin -- Inotropic gelation -- Tripolyphosphate (TPP) -- Explotab® -- Ac-Di-Sol® -- Vitamin C / Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2007.

Orientador: Eliana Aparecida de Rezende Duek / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Engenharia Mecânica / Made available in DSpace on 2018-08-18T22:58:44Z (GMT). No. of bitstreams: 1 Santos_CintiaCristina_M.pdf: 1464458 bytes, checksum: 539c2342d9349f9bfd8f8d3807a840d7 (MD5) Previous issue date: 2011 / Resumo: Dispositivos de liberação controlada de fármacos têm sido indicados por profissionais da saúde como uma alternativa para aumentar a eficácia terapêutica de medicamentos assim como a adesão dos pacientes ao tratamento. Polímeros biorreabsorvíveis, seus copolímeros e blendas têm apresentado vantagens em relação a outros polímeros por serem: biocompatíveis, fáceis de processar, degradarem por hidrólise, apresentarem subprodutos não tóxicos, e determinarem a morfologia e distribuição de diâmetros de microesferas e consequentemente a taxa de degradação do dispositivo e a cinética de liberação do fármaco. O objetivo deste trabalho foi obter e caracterizar microesferas de PLDLA carregadas com sinvastatina. O poli L-co-D,L ácido láctico (PLDLA) é um copolímero do poli Ácido Láctico (PLA). A sinvastatina é um fármaco usado no tratamento de hiperlipidemias, que induz formação de tecido ósseo quando aplicado no local de fraturas e patologias ósseas. A técnica de simples emulsão permitiu a obtenção de microesferas com morfologia esférica, superfície lisa, tamanho em escala micrométrica, grande distribuição de diâmetros, manteve a integridade química do polímero e o fármaco encapsulado se encontra em estado amorfo disperso pela matriz polimérica. A eficiência de encapsulação do dispositivo foi de 96,2% e o estudo de liberação in vitro apresentou liberação inicial em explosão, característica de sistemas compostos por microesferas de diâmetros variados. A sinvastatina degradou em seu hidróxiácido e em produtos não identificados. As microesferas liberaram o fármaco até o 30º dia de estudo enquanto degradavam. Portanto, as microesferas de PLDLA obtidas são dispositivos promissores para a aplicação como carreadores na liberação local e controlada de fármacos / Abstract: Drug delivery systems have been indicated by health professional as an alternative to improve drug efficacy and acceptability of the treatment to the patient. Bioreabsorbable polymers, its copolymers and blends have presented advantages and importance in relation to others polymers due to characteristics like: biocompatibility, easily to process, hydrolytic degradation, byproducts are nontoxic, control to microspheres morphology size distribution and consequently degradation rate and drug release kinetics. The aim of this work was to obtain and characterize simvastatin loaded PLDLA microspheres. The Poly L-co-D,L lactic acid (PLDLA) is a Poly lactic acid (PLA) copolymer. Simvastatin is a drug used for hyperlipidemia, that locally applied induces bone formation and fracture healing. The oil/water single emulsion/solvent evaporation technique produced microspheres in a spherical and smooth surface, micrometric size, large diameter distribution, the microencapsulation process did not interfere in the polymer chemical structure and the drug is in a amorphous state in the polymeric matrix. Simvastatin encapsulation efficiency was 96,2% and in vitro drug release showed a burst release, which characterize large diameter distribution systems. Simvastatin had degradated in its hydroxiacid and non-identified products. Microspheres released the drug up to 30º day while the degradation process occured. Thus, the PLLA microspheres obtained are promising to apply as a carrier drug delivery system / Mestrado / Materiais e Processos de Fabricação / Mestre em Engenharia Mecânica

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The commonly used PLGA-based delivery systems are often limited by their inadequate drug loading and release properties. This study reports the integration of oil into PLGA to form the prototype of a hybrid drug carrier PONC. Our primary goal is to confer the key strength of lipid-based drug carriers, i.e. efficient encapsulation of lipophilic compounds, to a PLGA system without taking away its various useful qualities. The PONC were formulated by emulsification solvent evaporation technique, which were then characterized for particle size, encapsulation efficiency, drug release and anticancer efficacy. The ATRA loaded PONC showed excellent encapsulation efficiency and release kinetics. Even after surface functionalization with PEG , controlled drug release kinetics was maintained, with 88.5% of the encapsulated ATRA released from the PEG-PONC in a uniform manner over 120 hours. It also showed favorable physicochemical properties and serum stability. PEG-PONC has demonstrated substantially superior activity over the free ATRA in ovarian cancer cells that are non-responsive to the standard chemotherapy. The newly developed PEG-PONC significantly reduced the IC50 values (p<0.05) in the chemoresistant cells in both MTT and colony formation assays. Hence, this new ATRA-nanoformulation may offer promising means for the delivery of lipophilic compounds like all-trans retinoic acid to treat highly resistant ovarian cancer. / Pharmaceutical Sciences

Hydrogels are popular materials for biological applications since they exhibit properties like that of natural soft tissue and have tunable properties. Biodegradable hydrogels provide an added advantage in that they degrade in an aqueous environment thereby avoiding the need for removal after the useful lifetime. In this work, we investigated poly(β-amino ester) (PBAE) biodegradable hydrogel systems. To begin, the factors affecting the macromer synthesis procedure were studied to optimize the reproducibility of the resulting hydrogels made and create new methods of tuning the properties. Hydrogel behavior was then tuned by altering the hydrophilic/hydrophobic balance of the chemicals used in the synthesis to develop systems with linear and two-phase degradation profiles. The goal of the research was to better understand methods of controlling hydrogel properties to develop systems for several biomedical applications. Several systems with a range of properties were synthesized, and their in vitro behavior was characterized (degradation, mechanical properties, cellular response, etc.). From these studies, materials were chosen to serve as porogen materials and an outer matrix material to create a composite scaffold for tissue engineering. In most cases, a porous three dimensional scaffold is ideal for cellular growth and infiltration. In this work, a composite with a slow degrading outer matrix PBAE with fast degrading PBAE microparticles was created. First, a procedure for developing porogen particles of controlled size from a fast-degrading hydrogel material was developed. Porogen particles were then entrapped in the outer hydrogel matrix during polymerization. The resulting composite systems were degraded and the viability of these systems as tissue engineering scaffolds was studied. In a second area of work, two polymer systems, one PBAE hydrogel and one sol-gel material were altered through the addition of iron oxide nanoparticles to create materials with remote controlled properties. Iron oxide nanoparticles have the ability to heat in an alternating magnetic field due to the relaxation processes. The incorporation of these nanoscale heating sources into thermosensitive polymer systems allowed remote actuation of the physical properties. These materials would be ideal for use in applications where the system can be changed externally such as in remote controlled drug delivery.

Currently growth plate fractures account for nearly 18.5% of fractures in children and can lead to stunted bone growth or angular deformation. If the body is unable to heal itself a bony bar forms, preventing normal bone growth. Clinical treatment involves removing the bony bar and replacing it with a filler substance, which causes poor results 60% of the time. Using primarily poly(lactic-co-glycolic acid) (PLGA) as the scaffold material, the goal was to develop an implant that would support to the implant site, allow for cell ingrowth, and degrade away over time. Porous scaffolds were fabricated from PLGA microspheres using the salt leaching method. The first part of this work investigated the effect of sintering the microspheres by studying the mechanical properties, degradation and morphology and their potential applications for hard and soft tissue implants. Growth factor or drugs can be encapsulated into PLGA microspheres, which was the second part of this work. Encapsulated insulin-like growth factor I (IGF-I) was able to withstand the scaffold fabrication process without compromising it’s bioactivity and promoted cell proliferation. The next part of this work experimented with the addition of a hydrogel porogen. Porogen particles were made using a quick degrading poly(beta-amino ester) (PBAE) hydrogel and loaded with ketoprofen. The addition of the porogen creates a dual drug-releasing scaffold with a localized delivery system. The final step of this work involved animal studies to determine the effectiveness of the scaffolds in growth plate regeneration and how they compare to the current clinical treatment option. Gross observation, microCT analysis, angular measurement of bone growth and histological methods were employed to evaluate the scaffolds. The goal was to develop a versatile scaffold that could be used for a wide range of tissue engineering applications. The mechanical properties, degradation profiles and drug delivery capabilities can be all tailored to meet the specific needs of an implant site. One specific application was regenerating the native growth plate that can also encourage the endogenous mesenchymal stem cells to follow the desire linage. By regenerating the native growth plate, angular deformation and stunted limb growth were greatly reduced.

In situ forming implants (ISIs) are popular due to their ease of use and local drug delivery potential, but they suffer from high initial drug burst, and release behavior is tied closely to solvent exchange and polymer properties. Additionally, such systems are traditionally viewed purely as drug delivery devices rather than potential scaffold materials due to their poor mechanical properties and minimal porosity. The aim of this research was to develop an injectable ISI with drug release, mechanical, and microstructural properties controlled by micro- and nanoparticle additives. First, an injectable ISI was developed with appropriate drug release kinetics for orthopedic applications. Poly(β-amino ester) (PBAE) microparticles were loaded with simvastatin or clodronate, and their loading efficiency and drug retention after washing was quantified. Drug-loaded PBAE microparticles and hydroxyapatite (HA) microparticles were added to a poly(lactic-co-glycolic acid) (PLGA)–based ISI. By loading simvastatin into PBAE microparticles, release was extended from 10 days to 30 days, and burst was reduced from 81% to 39%. Clodronate burst was reduced after addition of HA, but was unaffected by PBAE loading. Scaffold mass and porosity fluctuated as the scaffolds swelled and then degraded over 40 days. Next, the mechanical properties of these composite ISIs were quantified. Both micro- and nanoparticulate HA as well as PBAE microparticle content were varied. Increasing HA content generally improved compressive strength and modulus, with a plateau occurring at 30% nano-HA. Injectability remained clinically acceptable for up to 10% w/w PBAE microparticles. Ex vivo injections into trabecular bone improved both strength and modulus. Lastly, HA-free ISIs were investigated for drug delivery into the gingiva to treat periodontitis. Doxycycline and simvastatin were co-delivered, with delivery of doxycycline over 1 week accompanied by simvastatin release over 30 days. PBAE-containing ISIs exhibited higher initial and progressive porosity and accessible volume than PBAE-free ISIs over the course of degradation. Additionally, PBAE-containing ISIs provided superior tissue retention within a simulated periodontal pocket. The ISIs investigated here have a wide range of potential applications due to their flexible material and drug release properties, which can be controlled by both the chemistry and concentration of various particulate additives.

Le procédé d’imprégnation en milieu supercritique est une alternative « propre » à l’imprégnation par voie liquide. Entre autres applications, les procédés d’imprégnation peuvent être utilisés pour l’élaboration de systèmes de délivrance de médicaments appliqués aux domaines pharmaceutique et médical. Cette étude porte sur l’élaboration de systèmes de délivrance de médicaments en utilisant l'imprégnation supercritique des principes actifs sur deux types de supports : des matrices polymériques (lentilles intraoculaires) et des matrices poreuses (silices mésoporeuses). Dans le premier cas, des lentilles polymériques intraoculaires (IOLs), utilisées pour la chirurgie de la cataracte, ont été imprégnées par des principes actifs : un anti-inflammatoire (Dexaméthasone 21-phosphate disodium: DXP) et un antibiotique (Ciprofloxacine: CIP). Plus particulièrement, deux types de lentilles ont été étudiés : des IOLs rigides à base de PMMA et des IOLs souples à base de P-HEMA. Les expériences d'imprégnation supercritique ont été effectuées en mode batch et les taux d'imprégnation ont été déterminés par des études de cinétique de relargage des principes actifs. L’influence des conditions opératoires sur l’efficacité de l’imprégnation a été étudiée en réalisant des expériences d’imprégnation préliminaires suivies par des plans d’expériences par la suite. Dans le second cas, une silice mésoporeuse a été utilisée comme support d’imprégnation pour un médicament faiblement hydrosoluble (Fénofibrate), afin d’augmenter sa cinétique de dissolution. L’imprégnation supercritique a été effectuée avec le CO2 pur en faisant varier la pression et le taux de dépressurisation (rapide et lent). / Supercritical impregnation is an attractive “clean” alternative to conventional impregnation processes using generally liquid organic solvents. Among other applications, the impregnation process can be used for the development of controlled drug delivery systems applied to the pharmaceutical and medical fields. This work focuses on the preparation of controlled drug delivery systems using supercritical impregnation of drugs in two kinds of impregnation supports: polymeric matrices (intraocular lenses) and porous supports (mesoporous silica). Firstly, the supercritical impregnation of polymeric intraocular lenses (IOLs), used in cataract surgery, by an anti-inflammatory drug (Dexamethasone 21-phosphate disodium: DXP) and an antibiotic (Ciprofloxacin: CIP), is studied. More particularly, two polymeric IOLs were tested: rigid intraocular lenses made from derivative of PMMA and foldable intraocular lenses made from derivative of P-HEMA. Supercritical impregnations were carried out in a batch mode and the impregnation yields were determined through drug release kinetics studies in a solution simulating the aqueous humor. The influence of operating conditions on impregnation was studied by performing preliminary impregnation experiments followed by experimental designs. The second part of this work deals with the loading of a poorly water-soluble drug (Fenofibrate) in a mesoporous silica for improving drug dissolution kinetics. Supercritical impregnations were carried out with pure CO2 at different pressures (100 to 200 bar) and depressurization rates (rapid and slow).

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