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[pt] Microcáspulas são comumente utilizadas como veículos para a entrega de ativos em locais de interesse. As cápsulas protegem seu conteúdo interno, e são capazes de liberá-los de forma controlada. Além de ser muito utilizada na indústria farmacêutica, alimentícia e cosmética, elas também são uma solução viável na medicina e na indústria de petróleo para se replicarem como células no corpo ou otimizar a recuperação de óleo, respectivamente. No entanto, a utilização de microcápsulas implica em usar uma casca que, devido a urgência pela sustentabilidade, precisa mais do que nunca ser uma substância biodegradável. Neste trabalho, apresentamos um método de liberação controlada de ativos protegidos pelo bio-polímero de goma de gelana utilizando o gatilho de temperatura como ativador da destruição da cápsula. O estudo mostra a diferença que as propriedades físicas das cápsulas causam no tempo de entrega do seu conteúdo interno e como a liberação se comporta com o aumento da taxa de calor envolvida no processo. O controle das propriedades foi realizado através da produção de microcápsulas por microfluídica ao qual os diâmetros variaram entre 190 e 510 micrômetros enquanto as espessuras variaram entre 4 a 50 micrômetros. O estudo mostra que, além do tamanho, o material da casca (gelana), influencia o comportamento de liberação, a partir de certo limite de relação de espessura-diâmetro. Além disso, outro ponto importante é como a natureza da gelana afeta essa liberação visto que os resultados mostram que, quando a gelana está em sua forma desacilada (low-acyl) ela é mais resistente à mudanças, porém quando sua forma natural acilada (high-acyl) é adicionada à cadeia polimérica da mistura, a composição torna-se mais sensível ao gatilho até um certo limite de razão espessura-diâmetro, alterando o comportamento da degradação e a entrega é atrasada. Os resultados indicam que uma das possibilidades de aplicação de microcápsulas de gelana é o processo de recuperação de óleo, pois sua casca é resistente e estável até altas temperaturas, dessa forma servem como agente trasportador até entrar em contato com o óleo à temperatura de poço, liberando seu conteúdo. / [en] Microcapsules are commonly used as vehicles for on-demand delivery of active contents. The capsule protects the internal content from interference of the external environment and deliver it in a controlled manner. In addition to being widely used in the pharmaceutical, food and cosmetic industries, microcapsules can be also a viable solution in medicine and in the petroleum industry to replicate themselves as cells in the body or optimize oil recovery, respectively. However, the use of a microcapsule implies the use of a shell that, due to the urge for sustainability, needs more than ever to be a biodegradable substance.. In this work, we present a method of controlled release of actives protected by a biodegradable gellan-based microcapsule using temperature as the trigger for its destruction. The study shows the effect of physical properties of the capsules in the delivery time of their internal content and how the release behaves with the increase of the heat rate involved in the process. Microcapsules were produced with flow-focusing microfluidic devices with diameters variying between 190 and 510 micrometers while the shell thicknesses varied between 4 and 50 micrometers. The study shows that, in addition to the size, the shell material influences the release behavior. In addition, another important point is how the gellan gum nature affects the thermal trigger event, since the results show that when gellan is in its deacylated form (low-acyl) it is more resistant to changes, but when its natural form (high-acyl) is added to the chain, it becomes more sensitive to the trigger mechanism until a thickness-diameter ratio threshold, where the degradation behavior changes and the delivery is delayed. The results of this work indicate that one of the possibilities for the application of gellan microcapsules is in the oil recovery process, since its shell is resistant and stable until reaching high temperatures, thus acting as a transport agent until it comes into contact with the oil at well temperature, releasing its contents.

The objectives of this project encompass the design and development of a drug delivery system to continuously deliver therapeutic agents from the stomach to the proximal region of the intestine. The delivery system designed would have sufficient gastric residence time together with near zero-order release kinetics. The physicochemical properties pertaining to the formulation development of the model drug (alfuzosin HCl) were evaluated. Excipients were selected based on the studies of their physicochemical properties and compatibility with the active ingredient. Gastro-retentive dosage forms have been the topic of interest in recent years as a practical approach in drug deliveries to the upper GI tract or for release prolongation and absorption. These dosage forms are particularly suitable for drugs that have local effects on the gastric mucosa in the stomach. Other candidates include drugs that are likely to be absorbed in the upper small intestine, or drugs that are unstable in basic environment of distal intestine and colon or those with low solubility at elevated pH conditions (i.e. weak bases). To develop a gastro-retentive delivery system the following steps were taken. First, to investigate the possible incompatibility issues between the model drug and excipients to be used for the delivery system. Stability and physicochemical properties of the active agent and its mixture with excipients were studied using analytical techniques such as Raman spectroscopy and Differential scanning calorimetry (DSC). No incompatibility issues were detected. Second, Kollidon SR as a relatively new release-rate controlling polymer was incorporated in the final formulation. For solid dosage form the ability of the final powder mix to flow well during manufacturing and the intrinsic characteristics that make it compressible are critical. The in-depth compaction study of Kollidon SR was assessed with the help of a compaction simulator. The flowability, swelling and erosion behavior together with release-rate retarding properties of Kollidon SR were also assessed. The final oral delivery system was based on Kollidon SR and Polyethylene Oxide (PEO) 303 as a monolithic matrix system. The noneffervescent monolithic matrix was made by direct compression. In vitro evaluation of the designed system released the active content in a near zero manner. The dosage form was bouyant in pH 2.0 acidic buffer with no floatation lag time which minimizes the possibility of early gastric emptying. / Pharmaceutics

A unique dosage form which uses a hydrophilic polymer was developed to provide for a predicable release of several drugs. This drug release could be optimized for controlled release using erosion. It can also be designed to release drug utilizing electrochemical processes. The accuracy of drug delivery in terms of dose and timing is of utmost importance for the patient’s health status and compliance. A well-designed drug delivery technology offers many advantages to the patient. These advantages include: reduction in dose frequency, reduction of drug side effects, reduced unwanted fluctuations in circulating drug levels, and a more uniform effect of the drug over time. The practice of drug delivery has been dramatically developed in the last decade including electronic controlled release innovative dosage forms. In this study the iontophoretic flux of ibuprofen was investigated using side- by-side diffusion cells. Iontophoresis is the process where electric current is applied to enhance transportation of drugs across the skin. The pH change was found to be an important factor in increasing the diffusion of the drug. The principle of using electric current as a driving force to control the drug release was initially demonstrated on an initial setup. Subsequently, a calcium binding polymer was the hydrogel used as a matrix to develop a new electric oral dosage form. The calcium binding polymer is produced in different forms. The production process of these forms suffers several limitations. In order to apply electric current in a practical way to the calcium binding polymer matrix a novel method was developed. The novel method also allowed for addressing the limitations related to the production process of the conventional dosage form made with this polymer. More uniform gel tablets in shape and size were produced. Different formulations were developed. Ibuprofen was the model drug initially used to investigate the factors that affected the release profiles of these tablets. A two-level, three-factor statistical design of experiments (DOE) was performed to evaluate the effect of those factors on certain responses. These responses included the release rate, time needed to release 80% of the model drug, and lag-time. A new formulation with certain adjuvants was developed. This formulation had the ability to release different kinds of drugs in a uniform release rate. A fail-safe tablet that can only release less than 20% of the drug in 24 hours was developed. The drug release was initiated only when the electric current was applied. This new electric dosage form was aimed to overcome the disadvantages related to conventional dosage forms such as the inability to supply drugs on demand. / Pharmaceutical Sciences

Diabetes is a leading cause of death and disability in the United States. Diabetes requires a lifetime medical treatment. Some diabetes drugs could be taken orally, while others require daily injection or inhalation to maximize bioavailability and minimize toxicity. Parenteral delivery is a group of delivery routes which bypass human gastrointestinal track. Among all the parenteral methods, we chose subcutaneous implant based on its fast act and high patient compliance. When using subcutaneous implant, drug release needs to be strictly controlled. There are three major groups of controlled release methods. Solvent controlled system is already used as osmotic implant. Matrix controlled system is used in Zoladex® implant to treat cancer. Membrane controlled systems is widely used in coating tablets, but not that popular as an implant. Based on the research reported by previous scientists, we decided to build a hybrid system using both matrix and membrane control to delivery human insulin and other small molecule drugs. Subcutaneous environment is different from human GI track. It has less tolerance for external materials so many polymers cannot be used. From the FDA safe excipient database, we selected albumin as our primary polymer and gelatin as secondary choice. In our preliminary insulin diffusion study, we successfully found that insulin mixed with albumin provided a slower diffusion rate compared with control. In addition, we added zinc chloride, a metal salt that can precipitate albumin. The insulin diffusion rate is further reduced. The preliminary study proved that matrix control using albumin is definitely feasible and we might add zinc chloride as another factor. In order to fabricate an implant with appropriate size, we use lyophilisation technology to produce uniformly mixed matrix. Apart from albumin and human insulin, we added sucrose as protectant and plasticizer. The fine powder after freeze-dry was pressed as a form of tablet. The tablets were sealed in Falcon® cell culture insert. Cell culture insert provide a cylinder shape and 0.3 cm2 surface area for drug release. Insulin release study provided a zero order kinetics from prototypes with zinc chloride or 0.4 micron pore size membrane. Caffeine was used as a model drug to investigate the releasing mechanism. Three pore size membranes (0.4, 3 and 8 micron) were tested with same formulation. While 0.4 micron prototypes provided the slowest release, 3 micron ones surprisingly released caffeine faster than 8 micron implants. We calculated the porosity with pore size and concluded that the percentage of open area on a membrane is the key point to control caffeine release. 0.4 micron membranes were used for future research. We increased the percentage of albumin in our excipient, and achieved a slower caffeine release. However, the zero order release could only last for 3 days. After we replaced sucrose with gelatin, a 5 day zero order release of caffeine was achieved. With all the results, we proposed our “Three Phase” drug release mechanism controlled by both membrane and matrix. Seven other small molecule drugs were tested using our prototype. Cloudy suspension was observed with slightly soluble drugs. We updated our “Three Phase” drug release mechanism with the influence of drug solubility. Data shows that releasing rate with same formulation and membrane follows the solubility in pH 7.4. This result proves that our prototype might be used for different drugs based on their solubility. Finally, with all the information of our prototype, we decided to build a “smart insulin implant” with dose adjustment. We proposed an electrical controlled implant with different porosity membranes. Solenoid was used as the mechanical arm to control membrane porosity. 3-D printing technology was used to produce the first real prototype of our implant. Finally, insulin implant with clinically effective insulin release rate was achieved. / Pharmaceutical Sciences

Synthetic antioxidants have traditionally been added directly to food products in a single initial dose to protect against oxidation of lipids and generation of free radicals. Natural antioxidants have been shown to undergo loss of activity and become prooxidants at high concentrations; therefore, a need exists to develop active packaging which can gradually deliver antioxidants in a controlled manner. The objectives of this research were to (1) form and characterize cyclodextrin inclusion complexes with the natural antioxidants, alpha-tocopherol and quercetin, (2) incorporate cyclodextrin inclusion complexes of natural antioxidants into linear low density polyethylene (LLDPE), and (3) measure the release kinetics of inclusion complexes of natural antioxidants from LLDPE into a model food system. Cyclodextrin inclusion complexes of alpha-tocopherol and quercetin were formed by the coprecipitation method and characterized in the solid state by NMR, IR spectroscopy, and thermal analyses. Solid inclusion complex products of alpha-tocopherol:beta-cyclodextrin and quercetin:gamma-cyclodextrin had molar ratios of 1.7:1 as determined by UV spectrophotometry, which were equivalent to 18.1% (w/w) alpha-tocopherol and 13.0% (w/w) quercetin. Free and cyclodextrin complexed antioxidant additives were compounded with a twin-screw mixer into two LLDPE resin types followed by compression molding into films. Release of alpha-tocopherol and quercetin from LLDPE films into coconut oil at 30 °C was quantified by HPLC during 4 weeks of storage. The total release of alpha-tocopherol after 4 weeks was 70% from the free form and 8% from the complexed form averaged across both LLDPE resins. The mechanism by which alpha-tocopherol was released was modified due to its encapsulation inside the beta-cyclodextrin cavity within the LLDPE matrix as indicated by its diffusion coefficient decreasing by two orders of magnitude. Molecular encapsulation of natural antioxidants using cyclodextrins may be used as a controlled release mechanism within polymer food packaging to gradually deliver an effective antioxidant concentration to a food product, thereby, limiting oxidation, maintaining nutritional quality, and extending shelf life. / Ph. D.

Incorporation of chemicals into the internal matrix of cement or concrete, with later release occurring upon stimulation, alters the matrix parameters from those at the initial set. Permeability is reduced, for example, and therefore durability enhanced. The advantages of these designs would be the ability to reduce maintenance and repair costs in the initial building configuration and to delay the time of eventual repair. The components and the structure could take greater environmental abuse also. Permeability is significantly reduced by release of a polymer from wax-coated porous fibers upon heating to temperature of polymerization. Freeze/thaw damage is somewhat reduced by the timed release of linseed oil or antifreeze from porous aggregates due to the freezing action itself. These example designs using timed release mostly gave improved durability performance when compared to conventional treatments for durability or environmental distress. Concerns that significant strength reduction would occur due to heating or fiber loading were shown to be unfounded by our test results; indeed, heating and fiber inclusion increased strength. An adequate amount of wetting of the samples could be obtained with 2.75% volume of fibers; however, above a 2.75% volume of fibers, fibers do reduce the strength. Results were analyzed by the method of comparing results in the samples with factors varied to results in samples without variable factors, that is, by comparing to the controls. This research shows that timed internal release of chemicals into cement can be accomplished; it appears feasible and is potentially useful. Long-term tests need to be performed on such factors as chloride ion intrusion/ corrosion tests. Filled fiber, aggregate or prill manufacture, storage, and placement need to be researched and assessed for cost. Design of components using only targeted areas for release in the component and the use of time released fibers in reinforced cement laminates should be evaluated. / Ph. D.

The feasibility of the injection moulding (IM) was explored for the development of novel drug delivery systems. Controlled release formulations were developed using a substituted cellulose derivative, hydroxypropyl methyl cellulose acetate succinate (HPMCAS) and a graft co-polymer (Soluplus®). BCS class II drugs ibuprofen and the felodipine were selected based on their physicochemical properties. In the present work, a homogenous dispersion of drugs in the polymer matrices was achieved using Hot Melt Extrusion (HME) and extruded pellets obtained were used for the development of the injection moulded systems. Four systems were developed using the IM consisting of ibuprofen-HPMCAS, ibuprofen-Soluplus®, felodipine-PEO-HPMCAS and felodipine-Soluplus®. The ibuprofen acts as a good plasticiser compared to felodipine therefore, felodipine containing IM systems required a plasticiser (PEO) when processed with HPMCAS. The analysis of extruded pellets and injection moulded systems using modulated DSC (MDSC) and Raman spectroscopy confirmed the formation of an amorphous molecular dispersion (i.e solid solution) in the case of all four systems. The phase separation behaviour and the amorphous stability of the systems was studied at various stress conditions. This revealed the “surface crystallisation” behaviour of the ibuprofen-HPMCAS systems. Temperature-composition phase diagram constructed based on the melting point depression and the Flory-Huggins lattice solution theory provided the explanation for the phase separation and crystallisation behaviour of ibuprofen-HPMCAS systems. The advanced characterisation techniques like DMA, 2D XRD and 3D laser microscopy provided the detailed understanding of crystal habits, phase seperation and surface crystallisation. The significant effect of the stress conditions on the rate of shrinkage was observed where, higher shrinkage tendency of a HPMCAS IM system was observed compared to Soluplus® IM systems. The extruded pellets provided the faster drug release compared to the moulded tablets suggests the effect of particle size as well as the densification during IM on the dissolution rate of the dosage form. The nature of the polymer and processing history were the contributing factors for the dissolution of the dosage forms. / The thesis is hardbound in two volumes. Volume II starts at Chapter 5, page 135.