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1
Jones, Stephen Joseph. "Investigating nonlinear enzyme kinetics as an internal control system for nanoreactor drug release." Thesis, University of Leeds, 2018. http://etheses.whiterose.ac.uk/22207/.
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The improper administration of therapeutic compounds is not only financially inefficient, but, there exists a very real risk of harmful, or potentially life-threatening effects. To gain control, nano-drug delivery systems provide a discernible option for temporal and spatial regulation of drug bioavailability within the body. In current regimes, temporal control is realised through gradual release over an extended period of time, or triggered release in response to a change in the physiochemical environment. Of course, when considering the design of an ideal drug delivery system, we think of adaptivity – adaptivity to dynamically modulate drug release in response to a changing biological macroenvironment. In nature, this ability to sense, communicate, and respond is fundamental to the existence of any living organism, irrespective of complexity. In most instances, this responsiveness is achieved through feedback-controlled biochemical processes that work to regulate a functional process, and so, any “smart” delivery system would be smart to do the same. Of course, where conventional chemical feedback is concerned, potential toxicity and lack of biocompatibility, caused by inappropriate catalysts, is problematic, however, the emergence and enhanced understanding of enzymatic feedback provides an interesting and more compatible alternative. As such, this doctoral thesis focuses on drawing together two distinct entities of intense scientific focus, nonlinear enzyme kinetics and nanoreactor technology, and works towards the idealism of a feedback-controlled secondary response. To achieve this, through the utilisation of bottom-up synthetic chemistry, we have successfully built, investigated, and optimised a platform that has allowed up to systematically and extensively investigate the effect of confinement on an enzymatic feedback reaction. Through this process, we have uncovered a system more complicated than first anticipated. This complexity, driven firstly by the fragility of constituents in relatively harsh conditions, but more importantly by the dynamism of the system in terms of membrane transport, and associated pH-linked permeability coefficients. However, by building this platform, we have not only learned how to control the kinetic output of the reaction, but have gained an overview of how the system behaves as a whole. It is this organic discovery, and ultimate understanding, that has allowed us to extend our reach, pushing the functionality of our novel system, to achieve both temporally-controlled drug delivery and nano-motor-based vesicular propulsion.
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Fugit, Kyle Daniel. "QUANTIFICATION OF FACTORS GOVERNING DRUG RELEASE KINETICS FROM NANOPARTICLES: A COMBINED EXPERIMENTAL AND MECHANISTIC MODELING APPROACH." UKnowledge, 2014. http://uknowledge.uky.edu/pharmacy_etds/37.
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Advancements in nanoparticle drug delivery of anticancer agents require mathematical models capable of predicting in vivo formulation performance from in vitro characterization studies. Such models must identify and incorporate the physicochemical properties of the therapeutic agent and nanoparticle driving in vivo drug release. This work identifies these factors for two nanoparticle formulations of anticancer agents using an approach which develops mechanistic mathematical models in conjunction with experimental studies.
A non-sink ultrafiltration method was developed to monitor liposomal release kinetics of the anticancer agent topotecan. Mathematical modeling allowed simultaneous determination of drug permeability and interfacial binding to the bilayer from release data. This method also quantified the effects of topotecan dimerization and surface potential on total amount of drug released from these liposomal formulations. The pH-sensitive release of topotecan from unilamellar vesicles was subsequently evaluated with this method. A mechanistic model identified three permeable species in which the zwitterionic lactone form of topotecan was the most permeable. Ring-closing kinetics of topotecan from its carboxylate to lactone form were found to be rate-limiting for topotecan drug release in the neutral pH region.
Models were also developed to non-invasively analyze release kinetics of actively-loaded liposomal formulations of topotecan in vivo. The fluorescence excitation spectra of released topotecan were used to observe release kinetics in aqueous solution and human plasma. Simulations of the intravesicular pH in the various release media indicated accelerated release in plasma was a consequence of increased intravesicular pH due to ammonia levels in the plasma instead of alterations in bilayer integrity. Further studies were performed to understand the roles of dimerization, ion-pairing, and precipitation on loading and release kinetics obtained from actively-loaded topotecan.
Extension of this type of modeling for other types of nanoparticles was illustrated with doxorubicin-conjugated polymeric micelles. Mathematical modeling of experimental studies monitoring doxorubicin release identified conjugation stability during storage, hydrazone hydrolysis kinetics, and unconjugated doxorubicin partitioning affected micellar doxorubicin release. This work identifies several of the key parameters governing drug release from these liposomal and micellar nanoparticles and lays the framework for future development of in vivo release models for these formulations.
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He, Xingyu. "Long-term Light-activated Drug Delivery Systems." University of Cincinnati / OhioLINK, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1613752062550859.
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Liu, Quan. "Development of a novel gastro-retentive delivery system using alfuzosin HCl as a model drug." Diss., Temple University Libraries, 2010. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/80170.
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Pharmaceutics;Ph.D.
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.
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Modi, Sweta. "The Critical Role of Mechanism-Based Models for Understanding and Predicting Liposomal Drug Loading, Binding and Release Kinetics." UKnowledge, 2013. http://uknowledge.uky.edu/pharmacy_etds/19.
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Liposomal delivery systems hold considerable promise for improvement of cancer therapy provided that critical formulation design criteria can be met. The main objective of the current project was to enable quality by design in the formulation of liposomal delivery systems by developing comprehensive, mechanism-based mathematical models of drug loading, binding and release kinetics that take into account not only the therapeutic requirement but the physicochemical properties of the drug, the bilayer membrane, and the intraliposomal microenvironment.
Membrane binding of the drug affects both drug loading and release from liposomes. The influence of bilayer composition and phase structure on the partitioning behavior of a model non-polar drug, dexamethasone, and its water soluble prodrug, dexamethasone phosphate, was evaluated. Consequently, a quantitative dependence of the partition coefficient on the free surface area of the bilayer, a property related to acyl chain ordering, was noted.
The efficacy of liposomal formulations is critically dependent on the drug release rates from liposomes. However, various formulation efforts to design optimal release rates are futile without a validated characterization method. The pitfalls of the commonly used dynamic dialysis method for determination of apparent release kinetics from nanoparticles were highlighted along with the experimental and mathematical approaches to overcome them. The value of using mechanism-based models to obtain the actual rate constant for nanoparticle release was demonstrated.
A novel method to improve liposomal loading of poorly soluble ionizable drugs using supersaturated drug solutions was developed using the model drug AR-67 (7-t-butyldimethylsilyl-10-hydroxycamptothecin), a poorly soluble camptothecin analogue. Enhanced loading with a drug to lipid ratio of 0.17 was achieved and the rate and extent of loading was explained by a mathematical model that took into account the chemical equilibria inside and outside the vesicles and the transport kinetics of various permeable species across the lipid bilayer and the dialysis membrane.
Tunable liposomal release kinetics would be highly desirable to meet the varying therapeutic requirements. A large range of liposome release half-lives from 1 hr to 892 hr were obtained by modulation of intraliposomal pH and lipid composition using dexamethasone phosphate as a model ionizable drug. The mathematical models developed were successful in accounting for the change in apparent permeability with change in intraliposomal pH and bilayer free surface area. This work demonstrates the critical role of mechanism-based models in design of liposomal formulations.
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Cui, Yong. "Enhanced Release of Lidocaine From Supersaturated Solutions of Lidocaine In A Pressure Sensitive Adhesive." The Ohio State University, 2003. http://rave.ohiolink.edu/etdc/view?acc_num=osu1054210962.
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Pavurala, Naresh. "Oral Drug Delivery -- Molecular Design and Transport Modeling." Diss., Virginia Tech, 2013. http://hdl.handle.net/10919/53505.
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One of the major challenges faced by the pharmaceutical industry is to accelerate the product innovation process and reduce the time-to-market for new drug developments. This involves billions of dollars of investment due to the large amount of experimentation and validation processes involved. A computational modeling approach, which could explore the design space rapidly, reduce uncertainty and make better, faster and safer decisions, fits into the overall goal and complements the product development process. Our research focuses on the early preclinical stage of the drug development process involving lead selection, optimization and candidate identification steps. Our work helps in screening the most favorable candidates based on the biopharmaceutical and pharmacokinetic properties. This helps in precipitating early development failures in the early drug discovery and candidate selection processes and reduces the rate of late-stage failures, which is more expensive.
In our research, we successfully integrated two well-known models, namely the drug release model (dissolution model) with a drug transport model (compartmental absorption and transit (CAT) model) to predict the release, distribution, absorption and elimination of an oral drug through the gastrointestinal (GI) tract of the human body. In the CAT model, the GI tract is envisioned as a series of compartments, where each compartment is assumed to be a continuous stirred tank reactor (CSTR). We coupled the drug release model in the form of partial differential equations (PDE's) with the CAT model in the form of ordinary differential equations (ODE's). The developed model can also be used to design the drug tablet for target pharmacokinetic characteristics. The advantage of the suggested approach is that it includes the mechanism of drug release and also the properties of the polymer carrier into the model. The model is flexible and can be adapted based on the requirements of the clients. Through this model, we were also able to avoid depending on commercially available software which are very expensive.
In the drug discovery and development process, the tablet formulation (oral drug delivery) is an important step. The tablet consists of active pharmaceutical ingredient (API), excipients and polymer. A controlled release of drug from this tablet usually involves swelling of the polymer, forming a gel layer and diffusion of drug through the gel layer into the body. The polymer is mainly responsible for controlling the release rate (of the drug from the tablet), which would lead to a desired therapeutic effect on the body.
In our research, we also developed a molecular design strategy for generating molecular structures of polymer candidates with desired properties. Structure-property relationships and group contributions are used to estimate the polymer properties based on the polymer molecular structure, along with a computer aided technique to generate molecular structures of polymers having desired properties. In greater detail, we utilized group contribution models to estimate several desired polymer properties such as grass transition temperature (Tg), density (ρ) and linear expansion coefficient (α). We subsequently solved an optimization model, which generated molecular structures of polymers with desired property values. Some examples of new polymer repeat units are - [CONHCH₂ - CH₂NHCO]n -, - [CHOH - COO]n -. These repeat-units could potentially lead to novel polymers with interesting characteristics; a polymer chemist could further investigate these. We recognize the need to develop group contribution models for other polymer properties such as porosity of the polymer and diffusion coefficients of water and drug in the polymer, which are not currently available in literature.
The geometric characteristics and the make-up of the drug tablet have a large impact on the drug release profile in the GI tract. We are exploring the concept of tablet customization, namely designing the dosage form of the tablet based on a desired release profile. We proposed tablet configurations which could lead to desired release profiles such as constant or zero-order release, Gaussian release and pulsatile release. We expect our work to aid in the product innovation process.Ph. D.
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Lee, Tak-yee. "Part 1: Computer aided dosage form design: theory and applications. Part 2: Kinetics and mechanism of captopril oxidation in aqueous solutions under controlled oxygen partial pressure /." The Ohio State University, 1986. http://rave.ohiolink.edu/etdc/view?acc_num=osu1487266011224445.
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Knaack, Sven. "Entwicklung und Charakterisierung von Scaffolds auf Basis von mineralisiertem Kollagen zur gezielten Wirkstofffreisetzung für die Knochengewebe-Regeneration." Doctoral thesis, Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2016. http://nbn-resolving.de/urn:nbn:de:bsz:14-qucosa-188547.
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Beim Tissue Engineering ist die Vaskularisierung von größeren Zell-Matrix-Konstrukten nach Implantation bis heute ein großes Problem. Durch das initiale Fehlen eines mikrovaskulären Netzwerkes kommt es zu einem raschen Zellsterben im Scaffold.
Aufgrund dessen war das Ziel dieser Arbeit, im Sinne des in situ-Tissue Engineering ein Scaffold auf Basis von mineralisiertem Kollagen zu entwickeln, welches mit dem angiogenen Wachstumsfaktor VEGF funktionalisiert wird, um den Prozess der Vaskularisierung – die Einsprossung von Blutgefäßen – zu fördern und gleichzeitig durch Chemoattraktion in vivo Zellen aus dem umliegenden Knochengewebe in das Innere des Scaffolds migrieren zu lassen, so dass eine beschleunigte Defektheilung erzielt wird.
Poröse Scaffolds aus mineralisiertem Kollagen wurden durch zwei unterschiedliche Strategien funktionalisiert und durch in vitro-Testungen charakterisiert. Die erste Strategie umfasste die Heparin-Modifizierung der gesamten Scaffolds, während die zweite Strategie die Injizierung eines zentralen VEGF-haltiges Depots in das Scaffoldinnere darstellte.
Neben der Charakterisierung der Scaffolds wurde die Freisetzungskinetik des Modellwachstumsfaktors VEGF aus den modifizierten Scaffolds untersucht und die biologische Aktivität des freigesetzten Faktors auf Endothelzellen getestet. Zusätzlich wurde bei der 2. Strategie, der Injizierung eines Wirkstoffdepots, die Ausbildung eines Wirkstoffgradienten und die zielgerichtete Migration von Endothelzellen in Richtung des Wirkstoffdepots analysiert.
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Lee, Wang Wang. "Factors affecting drug release and absorption from a novel oral delayed release drug delivery system." Thesis, Durham University, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.269886.
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Thapa, Pariksha. "Kinetics of Microvesicle Particle Release in Keratinocytes." Wright State University / OhioLINK, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=wright1566504910360327.
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Pygall, Samuel R. "Critical processes in drug release from HPMC controlled release matrices." Thesis, University of Nottingham, 2009. http://eprints.nottingham.ac.uk/14128/.
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This study has investigated the drug release mechanisms from hydroxypropyl methylcellulose (HPMC) hydrophilic matrices. A hypothesis was developed from interpretation of a previous study that drug surface activity has an influence on drug liberation. The validity of the hypothesis was tested by studying the interactions between HPMC and the two non-steroidal anti-inflammatory drugs diclofenac Na and meclofenamate Na, using tensiometry, rheology, NMR, neutron scattering and turbimetry. Meclofenamate Na was found to interact with HPMC, resulting in detectable changes in drug diffusion coefficients and polymer structure in solution. There were increases in HPMC solution solubility and changes in viscoelasticity, which suggested drug solubilisation of the methoxyl-rich regions of the polymer chains. Diclofenac Na did not show evidence of an interaction and exhibited changes consistent with a 'salting out' of the polymer. A confocal microscopy technique was used to image the drug effects on early gel layer development. The presence of drugs affected gel layer development, depending on the level of drug in the matrix and the concentration of sodium chloride in the hydration medium. Diclofenac Na matrices became increasingly susceptible to disintegration, while meclofenamate Na matrices exhibited resistance to the effects of sodium chloride. The influence of incorporated diluents on the gel layer was also investigated and it was found that lactose had a disruptive effect, whereas microcrystalline cellulose was relatively benign. When co-formulating drugs and diluents in the matrix, lactose acted to antagonise the effect of meclofenamate, but acted synergistically with diclofenac to reduce gel layer integrity and accelerate matrix disintegration. In contrast, MCC was found to have a relatively neutral effect on drug-mediated effects. HPMC particle swelling and coalescence are critical processes in gel layer formation extending drug release. Drug surface activity and capability of interacting with HPMC appears to influence particle swelling processes, affecting gel layer formation and provides a mechanistic explanation for the differing release profiles of diclofenac and meclofenamate Na.
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Steiner, Katrin [Verfasser]. "The influence of drug core properties on drug release from extended release reservoir pellets / Katrin Steiner." Berlin : Freie Universität Berlin, 2011. http://d-nb.info/1025239733/34.
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Fitzpatrick, John J. "Drug release from methotrexate polumer conjugates." Thesis, University of Nottingham, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.259695.
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Stenton, Benjamin James. "Metal mediated mechanisms of drug release." Thesis, University of Cambridge, 2018. https://www.repository.cam.ac.uk/handle/1810/284402.
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In this thesis will be described research towards the development of bioorthogonal bond-cleavage reactions, and their applications in targeted drug delivery (Figure 1). The first project relates to the development of a palladium mediated bond-cleavage or "decaging" reaction which can cause a propargyl carbamate to decompose and release an amine. This was further developed by the incorporation of a protein modification handle which allowed an amine-bearing drug to be covalently ligated to a protein by a palladium-cleavable linker. This chemistry was demonstrated by the conjugation of the anticancer drug doxorubicin to a tumour targeted anti-HER2 nanobody. The drug could then be delivered to cancer cells upon addition of a palladium complex. The second project relates to the development of a platinum mediated bond-cleavage reaction. This was developed with the aim of using platinum-containing anticancer drugs - such as cisplatin - as a catalyst to cause drug release reactions in tumours. In this reaction an alkyne-containing amide can decompose to release an amine upon addition of platinum complexes, and was applied to the release of prodrugs of the cytotoxins monomethylauristatin E and 5-fluorouracil in cancer cells. A cisplatin-cleavable antibody-drug conjugate was designed and synthesised, and progress towards its biological evaluation will be discussed.
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Sheldon, Jonathon. "Light Controlled Drug Activation and Release." VCU Scholars Compass, 2015. http://scholarscompass.vcu.edu/etd/4055.
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Cancer constitutes a terrible burden on modern society. In the United States there are an estimated 1,658,370 new cancer diagnoses resulting in 589,430 deaths in 2015 alone.[1] An estimated 41,170 of these cases will be diagnosed right here in Virginia. With new cancer patients comes the expanding demand for new treatments. As we all know, many modern chemotherapeutics cause adverse reactions to patients. This is because the toxic nature of these therapies often affects normal tissue alongside the tumors that are infesting the body. Therefore, researching novel ways to make chemotherapeutics selective for cancer, while leaving healthy tissue unscathed, is of paramount importance. There are a few ways in which we have approached cancer-specific chemotherapeutics. Through the use of light controlled toxicity and drug release and the targeting of tumor phenotypes such as overexpressed proteins and the Warburg effect, we begin to tackle the problem of non-specificity of current chemotherapeutics.
Combretastatin A-4 (CA4) is highly potent anticancer drug that acts as an inhibitor of tubulin polymerization.[2, 3] The core of the CA4 structure contains a cis-stilbene, and it is known that the trans isomer is significantly less potent. We prepared an azobenzene analog of CA4 (Azo-CA4) that shows 13-35 fold enhancement in potency upon external irradiation. GI50 values in the light were in the mid nM range. Due to its ability to thermally revert to the less toxic trans form, Azo-CA4 also has the ability to automatically turn its activity off with time. Therefore, this work establishes a novel strategy for switchable potency for cancer treatment.
Doxorubicin (Adriamycin) is an anthracycline type of chemotherapeutic that intercalates double-stranded DNA.[4] Although this drug has played a huge role in the treatment of cancer, its usefulness declines in cases of cancer recurrence because of the impact this drug has on the cardiovascular system. Therefore, we prepared this drug as a cell impermeable conjugate that gains penetrability through the use of external radiation.[5]
Folate receptor alpha (FRα) is overexpressed in a variety of cancer cells and accepts folic acid as a natural ligand.[6] Therefore, conjugation of drugs to folic acid introduces a promising way to bring these drugs to cancer cells with greater specificity. We took this concept one step further with the introduction of a photo-labile linker, connecting doxorubicin to folic acid, which offers dual-specificity through ligand targeting and light activation.
Finally, many cancer cells produce adenosine triphosphate, the energy currency of a cell, through an abnormal upregulation of glycolysis.[7] This pathway results in a larger-than-normal production of lactic acid and lowers the pH of cancer cells through a phenomenon known as the Warburg Effect. We hypothesized that through the use of L-canavanine, an L-arginine analog, we could construct short peptides that would gain cell permeability in a low pH environment. Attaching a cargo to these peptides, such as doxorubicin will ultimately allow for targeting the low pH extracellular environment of cancer cells. Through the use of these strategies we have furthered the fight against cancer. Targeting cancer by taking advantage of its phenotypes or through the use of light is vital in reducing negative side-effects of current chemotherapeutics. The novel technologies offered above bring us a step closer to side-effect free treatment of cancer patients.
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Gao, Xiang. "Kinetics of drug disposition and effects /." The Ohio State University, 1997. http://rave.ohiolink.edu/etdc/view?acc_num=osu1487942739808919.
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Ali, Mohamed A. "Preparation, kinetics and mechanism of release of carbofuran lignin-based controlled release formulations." Thesis, University of Newcastle Upon Tyne, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.289103.
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Sinha, Piyush M. "Nanoengineered implantable devices for controlled drug delivery." The Ohio State University, 2005. http://rave.ohiolink.edu/etdc/view?acc_num=osu1115138930.
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Milroy, Georgina Emily. "Degradation and drug release behaviour of polyglycolide." Thesis, University of Cambridge, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.415273.
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Shehab, M. A. "Drug release from liquid filled capsule formulations." Thesis, De Montfort University, 1986. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.373432.
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Ambardekar, Rohan. "Controlled drug release from oriented biodegradable polymers." Thesis, University of Bradford, 2015. http://hdl.handle.net/10454/14867.
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This research is the first systematic investigation of solid-state orientation as a novel method for controlling drug release from biodegradable polymers. The effect of various degrees of polymer orientation was studied in oriented Poly (L-lactic acid) (PLA) films containing curcumin and theophylline as model drugs. Additionally, direction specific drug release was studied from oriented PLA rods containing paracetamol. The films oriented to 2X uniaxial constant width (UCW) or 2X2Y biaxial draw ratio showed retardation of drug release, when their nematic structure was stabilised by the presence of crystalline theophylline. Contrarily, the same films when contained solid solution of curcumin, shrunk in the release medium and exhibited a release profile similar to the un-oriented films. All films oriented to the UCW draw ratio ≥ 3X contained α crystalline form of PLA and showed acceleration of drug release proportionate to the draw ratio. According to the proposed mechanism augmented formation of water filled channels in these films was responsible for faster drug release. Similarly, the paracetamol loaded PLA rods die-drawn to uniaxial draw ratios ≥ 3X exhibited enhancement of drug release. Importantly, the amount of drug released along the oriented chain axis was significantly larger than that in the perpendicular direction. Drug release from the die-drawn rods was accelerated by a greater degree than that observed from the oriented films. This can be correlated to the differences in their size, geometry and the crystalline form of PLA. In conclusion, the current study provided substantial evidence that solid-state orientation can offer a control over drug release from PLA.
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Sevim, Kevser. "Modelling of drug release from biodegradable polymers." Thesis, University of Leicester, 2017. http://hdl.handle.net/2381/40864.
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Biodegradable polymers have highly desirable applications in the field of biomedical engineering, such as coronary stents, tissue engineering scaffolds and controlled release formulations. All these applications are primarily rely on the fact that the polymers ultimately disappear after providing a desired function. In this respect, the mechanism of their degradation and erosion in aqueous media has attracted great attention. There are several factors affecting the rate of degradation such as composition, molecular weight, crystallinity and sample size. Experimental investigations showed that the type of drug also plays a major role in determining the degradation rate of polymers. However, so far there is no theoretical understanding for the changes in degradation rate during the degradation in the presence of acidic and basic drugs. Moreover, there exists no model to couple the hydrolysis reaction equations with the erosion phenomena for a total understanding of drug release from biodegradable polymers. A solid mathematical framework describing the degradation of bioresorbable polymers has been established through several Ph.D. projects at Leicester. This Ph.D. thesis consists of three parts: the first part reviews the existing literature of biodegradable polymers and drug delivery systems. In the second part, the previous models are refined by considering the presence of acidic and basic drugs. Full interactions between the drug and polyesters are taken into account as well as the further catalyst effect of the species on polymer degradation and the release rates. The third part of this thesis develops a mathematical model combining hydrolytic degradation and erosion in order to fully understand the mechanical behaviour of the biodegradable polymers. The combined model is then applied to several case studies for blank polymers and a drug eluting stent. The study facilitates understanding the various mass loss and drug release trends from the literature and the underlying mechanisms of each study.
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McMillan, Hannah Louise. "Sustained release biodegradable ocular drug delivery systems." Thesis, Queen's University Belfast, 2015. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.678216.
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Delivery of drugs to the posterior segment of the eye is notoriously difficult and unfortunately many chronic conditions of the posterior segment often lead to sight-loss if not treated effectively. Current methods of delivery such as topical drops result in poor bioavailability at the back of the eye, while the blood brain retina imposes restrictions on the entry on drugs into the eye delivered by the systemic system. The gold-standard method for delivery of therapeutic concentrations of drugs is intravitreal delivery, which involves an injection into the vitreous cavity. Although this provides therapeutic levels of drugs, numerous injections are required to maintain these concentrations, and the frequency of injection can cause various adverse effects such as retinal detachment, vitreous haemorrhage and endophthalmitis. The present study investigates the potential use of solvent-induced in situ forming implants (ISFI) as a method of delivering drugs in a prolonged manner to the posterior segment of the eye. These systems are composed of a water-insoluble polymer dissolved in an organic solvent. Their low viscosity allows for easy administration through small-bore needles (e.g. 27 gauge) and on contact with an aqueous environment, such as the vitreous humour, phase inversion through solvent exchange takes place resulting in a biodegradable polymeric implant that can release drugs for an extended period. . As another method to improve posterior drug delivery in a minimally-invasive manner, microneedles (MN) were used to inject small amounts of ISFI formulation into sclera. Drug release and permeation stUdies across sclera indicated that the use of MN did indeed improve scleral permeation, with potential to allow posterior drug delivery from an intrascleral depot. From investigations carried out in the present study, ISFI show promise in transforming drug delivery to the eye and therefore possibly preventing the loss of sight in numerous individuals.
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Robinson, Susan. "Poly(α-hydroxyacids) : degradation and drug release." Thesis, University of Cambridge, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.624353.
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Chia, Leonard Sze Onn. "Investigating controlled release pulmonary drug delivery systems." Thesis, University of Cambridge, 2018. https://www.repository.cam.ac.uk/handle/1810/273209.
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The therapeutic effect of pulmonary drug delivery systems is limited by its rapid clearance from the lungs by robust clearance mechanisms. By controlling the release of drugs, the therapeutic effect of pulmonary drug delivery systems, as well as patient convenience and compliance could be improved by reducing the number of times drugs need to be administered. In this study, two controlled pulmonary drug delivery systems for drugs of different solubilities were investigated and they were characterised for their viability as effective controlled release pulmonary drug delivery systems, particularly in areas of aerosol performance and dissolution profile. A hybrid protein-polymer controlled release pulmonary drug delivery system was developed to sustain the release of a water-soluble anti-asthma drug, cromolyn sodium (CS). Two excipients with complementary characteristics – a protein, bovine serum albumin, and a polymer, polyvinyl alcohol – were formulated together with CS via co-spray drying, with varying protein-polymer ratios and drug loadings. The hybrid particles showed promise in combining the positive attributes of each excipient, with respirable particles shown to sustain the release of CS with a fine particle fraction of 30%. Combining the two excipients was complex, with further optimisation of the hybrid formulations possible. A commercially available polymer, Soluplus® was spray-dried with a poorly-water soluble corticosteroid, beclomethasone dipropionate (BDP). The resultant respirable powders were shown to have potential for use as a controlled release pulmonary drug delivery system with up to 7-fold improvement in the amount of BDP released compared to spray-dried BDP. The spray-dried BDP-Soluplus® powders were found to be amorphous, and physically stable against re-crystallisation for up to 9 months at accelerated stress test conditions with drug loadings of up to 15 % (w/w). Although it provided a platform to compare between formulations, the USP 4 flow-through cell dissolution apparatus was found to be inadequate to accurately study the dissolution profiles of the pulmonary drug delivery systems due to the formation of a gel in the apparatus. Preliminary work on the use of a novel technique to predict the crystallisation of amorphous formulations with terahertz time-domain spectroscopy was also conducted. The system confirmed the re-crystallisation tendencies of several hybrid CS/BSA/PVA formulations. Modification to the experimental setup to probe the formulations at different relative humidities instead of temperatures could yield improved results.
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Podaru, George. "Exploring controlled drug release from magneto liposomes." Diss., Kansas State University, 2017. http://hdl.handle.net/2097/35544.
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Doctor of PhilosophyDepartment of Chemistry
Viktor Chikan
This thesis focuses on exploring fast and controlled drug release from several liposomal drug delivery systems including its underlying mechanics. In addition, the construction of a pulsed high-voltage rotating electromagnet is demonstrated based on a nested Helmholtz coil design. Although lots of different drug delivery mechanisms can be used, fast drug delivery is very important to utilize drug molecules that are short-lived under physiological conditions. Techniques that can release model molecules under physiological conditions could play an important role to discover the pharmacokinetics of short-lived substances in the body. In this thesis, an experimental method is developed for the fast release of the liposomes’ payload without a significant increase in (local) temperatures. This goal is achieved by using short magnetic pulses to disrupt the lipid bilayer of liposomes loaded with magnetic nanoparticles. This thesis also demonstrates that pulsed magnetic fields can generate ultrasound from colloidal superparamagnetic nanoparticles. Generating ultrasound remotely by means of magnetic fields is an important technological development to circumvent some of the drawbacks of the traditional means of ultrasound generation techniques. In this thesis, it is demonstrated that ultrasound is generated from colloidal superparamagnetic nanoparticles when exposed to pulsed and alternating magnetic fields. Furthermore, a comparison between inhomogeneous and homogeneous magnetic fields indicates that both homogeneous and inhomogeneous magnetic fields could be important for efficient ultrasound generation; however, the latter is more important for dilute colloidal dispersion of magnetic nanoparticles. In strong magnetic fields, the ultrasound generated from the colloidal magnetic nanoparticles shows reasonable agreement with the magnetostriction effect commonly observed for bulk ferromagnetic materials. At low magnetic fields, the colloidal magnetic nanoparticle dispersion produces considerable amount of ultrasound when exposed to a.c. magnetic fields in the 20−5000 kHz frequency range. It is expected that the ultrasound generated from magnetic nanoparticles will have applications toward the acoustic induction of bioeffects in cells and manipulating the permeability of biological membranes
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Talbert, Ann Marie. "Drug protein binding kinetics from chromatographic profiles." Thesis, Imperial College London, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.406921.
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Awosanya, Ibikunle. "The kinetics of ion release by glass-ionomer cements." Thesis, University of Greenwich, 2008. http://gala.gre.ac.uk/6103/.
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Ten brands of GIC were used in this study: four commercial conventional GICs, one in-house conventional GIC made from G338 glass powder, one commercial glass-ionomer bone cement and four in-house novel aluminium free Fe2O3 based GICs. Cylindrical specimens of GICs were prepared in stainless steel moulds to form 6 mm height x 4 mm diameter cylinders which were then placed in a 37°C oven for one hour to cure and harden. These were then immersed in 5 ml aliquots of de-ionised water and 20mM lactic acid for storage periods of 14, 28 and 84 days, 8 weeks and 21 months. The leachate was collected daily, weekly and monthly respectively to determine the concentration of ions eluted using an optimised and validated method employing ICP-OES. The kinetic study showed that ion release in GICs generally follows a two or three phase process. Initially, there is a short-term rapid burst of ion release, non-linear with respect to time (t). Thereafter under neutral conditions, release is a diffusion process as given by [F]c = a + bt1/2 + ct or [F]c = [F]l.t / (t1/2 + t) + ßt1/2. The latter equation best described the ion release profile of GICs when immersed in water. Under acid conditions, by contrast, long term release was found to be proportional to t, indicating that dissolution is the controlling force, as given by [F]c = [F]l.t / (t1/2 + t) + at. HPLC was used to study ion release under dynamic conditions using crushed cement as the column packing material. This showed that these GICs are depleted of traceable amounts of Na, Ca, Al, Is and P within 2 days under these conditions. A speciation study by ion chromatography showed conclusively that phosphorus released from GICs into de-ionised water was present as simple monomeric phosphate. Unfortunately, results from 31PNMR were not as conclusive. However, the speciation result is consistent with previous studies, which have shown by MAS-NMR that phosphorus is also present within the set cement in simple monomeric form.
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Leo, Tiffany. "Uptake and Release Kinetics of Sulfolane by Cattail Plants." DigitalCommons@USU, 2008. https://digitalcommons.usu.edu/etd/47.
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Sulfolane (tetrahydrothiophene 1,1-dioxide, C4H8O2S) is a highly water-soluble, non-ionizable, organic compound used along with diisopropanolamine in the SulfinolTM process to remove hydrogen sulfide from natural gas. Sulfolane has been identified in wetland vegetation near a sour gas processing facility in Alberta, Canada, and extensive uptake of sulfolane by cattails has also been demonstrated in a laboratory environment. Consequently, it has been suggested that plants could play an important role in the natural attenuation of sulfolane in contaminated wetlands. This assumes that the sulfolane is metabolized and/or sequestered in the plant and not released back into the environment during winter dieback. To address the potential release issue, individual cattails (Typha latifolia) were grown hydroponically in 500-mL glass containers containing one of three initial sulfolane concentrations (8, 40, or 200 mg/L) for a specified duration (7 to 28 days). Half the cattails were used to quantify uptake as a function of time and exposure concentration and the other half were used to evaluate the potential release of sulfolane into the hydroponic solution. Non-exposed cattails and non-planted systems containing sulfolane served as controls. The cattails used to evaluate the potential release of sulfolane were frozen directly in their individual containers at the end of the appropriate exposure period. After being frozen for a minimum of 72 hours, the containers were thawed and the amount of sulfolane released was monitored. At the end of the 28-day uptake period, sulfolane leaf tip tissue concentrations as high as 3600, 1050, and 165 mg/kg dry weight were found for the cattails initially exposed to 200, 40, and 8 mg/L sulfolane, respectively. The percentage of sulfolane subsequently released by the cattails after the freeze-thaw treatment declined as a function of the duration exposed. The percentages of sulfolane released measured in the water after 72 hours in addition to the plant tissue extractions were 71%, 54%, 27%, and 12% for the 40 mg/L concentration at 7-, 14-, 21-, and 28-day exposure periods, respectively. Other concentrations showed the same decreasing trend for increasing exposure periods. The declining release as a function of time suggests metabolism and/or sequestration of the sulfolane within the plant. The significant uptake and limited release of sulfolane from mature plants indicate that wetland plants could play an important role in its natural attenuation.
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Ghori, Muhammad U. "Release kinetics, compaction and electrostatic properties of hydrophilic matrices." Thesis, University of Huddersfield, 2014. http://eprints.hud.ac.uk/id/eprint/24269/.
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This thesis illustrates the behaviour of cellulose ethers during powder processing, compaction and drug release, as these are frequently employed in the fabrication of compressed hydrophilic matrices. The handling operations can give rise to the electrification of powder particles, which can affect the end product‘s quality. Controlling the parameters which can dictate the quality of compressed matrices is an ambition inherent in the development of pharmaceutical formulations. Thus, the aims and objectives of this thesis were to firstly study the electrostatic, surface adhesion, dissolution and compaction properties of plain polymers and model drugs. Secondly, binary mixtures of fixed drug to polymer ratios were made in order to investigate the effect of polymer concentration and physico-chemical attributes (particle size, chemistry and viscosity) on the tribo-electric charging, surface adhesion (SA), swelling, erosion, drug release kinetics and compaction properties of model drugs. It can be discerned that the both drugs charged negatively, whereas the methylcellulose (MC) and hydroxypropyl methylcellulose (HPMC) particles charged positively. The physico-chemical properties associated with MC and HPMC, such as particle size, chemical heterogeneity and molecular size of cellulose ethers all have a significant effect on charging and adhesion behaviour of plain MC and HPMC particles. Moreover, the concentration, particle size, chemical heterogeneity and molecular size of MC/HPMC all significantly affect the charging and SA propensity of the model drugs studied. The swelling and dissolution results confirm that the extent and rate of swelling, swelling exponent, dissolution rate and drug release kinetic parameters were affected by physico-chemical attributes (concentration, particle size, substitution and viscosity) of MC/HPMC and drug solubility. The mechanism of swelling and drug release was found to be anomalous. However, it inclined towards more diffusion-oriented swelling/drug release with higher MC/HPMC levels, viscosity, Hpo/Meo substitution ratios, drug solubility but smaller MC/MC particle size. The matrix erosion results obtained from newly developed phenol-sulphuric acid assay (PSA) method confirmed that the solubility of the drug, and levels of HPMC in a particular matrix tablet, significantly affect the matrix erosion rate and the results were similar to those determined using the much more labour-intensive gravimetric method. Moreover, the combination of conventional UV drug analysis technique and PSA assay can be used to simultaneously quantify the matrix erosion, polymer dissolution and drug release kinetics in a single set of experiments avoiding the need for separate studies. The compaction results confirmed that the FBP has poor compaction as compare to THP. The particle size, substitution ratios and molecular size of MC/HPMC affect the compaction and consolidation behaviour of plain MC/HPMC compacts. Furthermore, it can be noticed that the concentration and physico-chemical attributes (particle size, chemistry and molecular size) of MC/HPMC have a significant influence on the densification and consolidation process of hydrophilic matrices. In summary, the information obtained can be used in the future to develop and adopt strategies for development and further optimization of compressed hydrophilic matrices.
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Chaerunisaa, Anis Yohana [Verfasser]. "Release adjustment of drug combinations with different drug solubility / Anis Yohana Chaerunisaa." Berlin : Freie Universität Berlin, 2014. http://d-nb.info/1048327388/34.
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Pavlakis, Evangelos K. "Novel drug coatings of pharmaceutical suspensions to control drug release of ibuprofen." Thesis, University of Huddersfield, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.417301.
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Wang, Juan. "Characterization of microsphere drug delivery systems during encapsulation and initial drug release /." The Ohio State University, 2000. http://rave.ohiolink.edu/etdc/view?acc_num=osu1488202678776876.
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Feely, L. C. "Controlled release hydroxypropylmethylcellulose mini-matrices." Thesis, University of Nottingham, 1986. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.373348.
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Bramer, Tobias. "Prolonged Drug Release from Gels, using Catanionic Mixtures." Doctoral thesis, Uppsala University, Department of Pharmacy, 2007. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-8303.
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The use of catanionic drug-surfactant mixtures was proven to be an efficient novel method of obtaining prolonged drug release from gels. It was shown that various commonly used drug compounds are able to form catanionic mixtures together with oppositely charged surfactants. These mixtures exhibited interesting phase behaviour, where, among other structures, vesicles and large worm-like or branched micelles were found. The size of these aggregates makes them a potential means of prolonging the drug release from gels, as only monomer drugs in equilibrium with larger aggregates were readily able to diffuse through the gel. When the diffusion coefficient for drug release from the formulation based upon a catanionic mixture was compared to that obtained for the drug substance and gel alone, the coefficient was some 10 to 100 times smaller.
The effects of changes in the pH and ionic strength on the catanionic aggregates was also investigated, and this method of prolonging the release was found to be quite resilient to variations in both. Although the phase behaviour was somewhat affected, large micelles and vesicles were still readily found. The drug release was significantly prolonged even under physiological conditions, that is, at a pH of 7.4 and an osmolality corresponding to 0.9% NaCl.
Surfactants of low irritancy, capric and lauric acid, may successfully be used instead of the more traditional surfactants, such as sodium lauryl sulfate (SDS), and prolonged release can still be obtained with ease.
Some attempts to deduce the release mechanism from the proposed systems have also been made using transient current measurements, dielectric spectroscopy, and modelling of the release using the regular solution theory. In these studies, the previous assumptions made concerning the mechanism responsible for the release were confirmed to a large extent. Only small amounts of the drug existed in monomer form, and most seemed to form large catanionic aggregates with the oppositely charged surfactant.
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Veen, Jacoba van der. "A study on programmed drug release from tablets." [S.l. : [Groningen : s.n.] ; University Library Groningen] [Host], 1993. http://irs.ub.rug.nl/ppn/293023646.
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Paulsson, Mattias. "Controlled Release Gel Formulations for Mucosal Drug Delivery." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2001. http://publications.uu.se/theses/91-554-5173-X/.
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Fetherston, S. M. "Novel Sustained Release Divices for Vaginal Drug Administration." Thesis, Queen's University Belfast, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.527695.
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Dennis, Andrew Barriball. "Sustained drug release from semi-solid capsule formations." Thesis, Cardiff University, 1988. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.328069.
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Hyde, Thomas Miles. "Transport in polymers : application to controlled drug release." Thesis, University of Cambridge, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.363822.
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Chang, Rong-Kun. "Dual Polymer Microsphere Systems to control drug release /." Ann Arbor : University Microfilms International, 1985. http://www.gbv.de/dms/bs/toc/016417453.pdf.
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Niknezhad, Sepideh. "STRATEGIC DESIGN OF NANOFIBER CARRIERS FOR DRUG RELEASE." University of Akron / OhioLINK, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=akron1513257280368733.
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Yeh, Hsi-wei. "Investigation of Polymeric Composites for Controlled Drug Release." VCU Scholars Compass, 2017. http://scholarscompass.vcu.edu/etd/4971.
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The Electrospray (ES) technique is a promising particle generation method for drug delivery due to its capabilities of producing monodisperse PLGA composite particles with unique configurations and high drug encapsulation efficiency. In the dissertation work, the coaxial dual capillary ES was used to generate drug-loaded core-shell PLGA particles to study the effects of particle filling materials, drug loading locations and particle shell thicknesses on the resultant in vitro release behaviors of the hydrophilic and/ or hydrophobic model drugs. Through release profile characterization of drug-loaded PLGA particles (particle size: 400 nm and 1 μm), it was confirmed that the co-encapsulation of Budesonide (BUD, the hydrophobic small-molecule model drug) and Theophylline (THY, the hydrophilic small-molecule model drug) in the particle cores is the most effective drug loading strategy for extended release of the fixed combined BUD and THY. Particles composed of PLGA fillers with lower molecular weights and with greater shell layer thicknesses could release THY in a well controlled fashion. On the other hand, a slower release rate of Bovine Serum Albumin (BSA, the protein model drug) from PLGA particles with greater shell thickness was also observed. Sequential release of BSA and Paclitaxel (PTX, the hydrophobic small-molecule anti-cancer model drug) was achieved by the 400-nm PLGA (Mw: 7,000-17,000 g/mol, LA/GA: 50/50) particles with potential biopharmaceutical applications in cancer therapy.
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Gilligan, Claire A. "Controlled release polymeric films and pellets." Thesis, Queen's University Belfast, 1989. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.336028.
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Patel, Jitandrakumar Ramanbhai. "The kinetics of calcium-induced calcium release in the heart." Thesis, Open University, 1992. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.294077.
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Sutch, Jonathan C. D. "Optimising Microenvironmental pH and Drug Release from Formulations Containing a Weakly Basic Drug." Thesis, University of Nottingham, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.489694.
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The release ofpapaverine, a weakly basic drug, is pH dependent. To allow drug release throughout the changing pH milieu ofthe gastrointestinal tract, weak acid modifiers are often added to modify the microenvironmental pH. A technique to measure the microenvironmental pH by confocal microscopy (CLSMpH) has been optimised to allow accurate measurement in coated pellets. A central composite design was used to investigate the effect of formulation factors on drug release and CLSMpH• Acid modifiers and fillers of varying solubility were also investigated. The solubility and proportion ofthe acid used has a significant effect on drug release. A more soluble acid provides a shorter acidic microenvironment, conversely a greater extent ofdrug release was seen during this time. It is the solubility of the acid and not just the acidity that affects papaverine release. A more soluble excipient may produce a greater internal porosity. Alternately the soluble excipient may increase the internal osmotic pressure. Finally, soluble excipients may partition into the coat and produce pores upon dissolution, however an overlap of mechanisms may occur. The CLSMpH method has provided an insight into the release mechanism from pellets. It would appear an acid less soluble than the drug would be useful to supply a prolonged acidic microenvironment, providing a more soluble excipient is used to allow drug release. Finally, the CLSMpH method has been applied to hydrophilic matrix tablets. Using this technique spatial and temporal measures ofpH can be made. An acidic pH gradient was observed across tablets formulated with acidic excipients. Conversely, the gel layer pH was principally basic in tablets formulated without them. The use of the CLSMpH technique and similar fluorescence techniques could be useful in elucidating the release mechanisms in hydrophilic matrix tablets and as an aid to formulation.
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Velghe, Carine. "Oral controlled drug delivery systems, optimization of release patterns and elucidation of release mechanisms." Thesis, Lille 2, 2013. http://www.theses.fr/2013LIL2S048/document.
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Le développement de nouvelles formes galéniques nécessite la mise au point de protocoles avec variation d’un ensemble de paramètres jouant sur les caractéristiques du dispositif. Au niveau industriel, cela représente une perte importante de temps et d’argent. Avec le développement d’outils permettant la caractérisation des systèmes et à fortiori des mécanismes impliqués dans la libération du principe actif, l’application des modèles mathématiques se voit être de plus en plus grande permettant de prédire la sortie du principe actif hors de son système. L’un des objectifs de ce travail a été de développer un modèle mathématique mécanique réaliste permettant de quantifier la libération de vitamines à partir de matrice lipidique. Deux techniques différentes de formulation : la compression directe et une suite d’extrusion en phase chauffante/ broyage/ compression directe ont permis la préparation de comprimés à base de Compritol 888 (glyceryl dibehenate NF). L’acide nicotinique a été utilisé comme principe actif modèle hautement soluble dans le milieu environnant. Des études de dissolution ont montrée une libération plus accrue pour des comprimés ayant une charge initiale en vitamine plus importante, cela liée à une augmentation de la porosité de la matrice avec l’épuisement graduel de la vitamine. Concernant la technique de préparation, un taux de sortie beaucoup plus faible dans le cas des comprimés préparés par extrusion en phase chauffante préalable, est mesuré, dû à un emprisonnement de la vitamine par la matrice fondue. A partir de ces observations et des connaissances sur les matrices lipidiques, un modèle basé sur les lois de diffusion de Fick et sur la considération de la coexistence d’une partie du principe actif sous forme dissoute ou non dissoute a été élaboré. Ce modèle permet la prédiction de la quantité de vitamine libérée au cours du temps en fonction de l’impact de la composition, de la technique de préparation et de la taille du système. Ces simulations in-silico sont d’une grande aide pour permettre d’accélérer la production de comprimés à base de Compritol 888. Dans le cas de systèmes multiparticulaires, et encore plus dans le cas de formes enrobées, des modèles mathématiques peuvent également être établis mais montrent une complexité plus grande, notamment due à la membrane polymérique. Dans cette optique, le développement de nouveaux outils pour caractériser les systèmes est primordial. Dernièrement la technologie Terahertz voit son potentiel comme nouvel outil dans la caractérisation de systèmes enrobés croissant. Son emploi dans la détection de différence de taille et d’uniformité de films polymériques d’enrobage pour des systèmes multicouches a été réalisé sur des granules de tailles conventionnelles (1mm de diamètre). Un premier enrobage de metoprolol succinate a été réalisé sur des noyaux de sucre, suivi d’un enrobage permettant le contrôle de la fuite du principe actif à base d’un mélange de Kollicoat SR :Kollicoat IR. Des granules avec différentes tailles d’enrobage ont été étudiées par Terahertz. Une taille homogène de la couche de principe actif pulvérisée a été montré dans tous les types de pellets ; alors qu’une taille croissante de l’enrobage polymérique 46 µm, 71 µm et 114 µm a pu être appréhendée. Ces résultats, mis en corrélation avec les méthodes de dissolution traditionnelles, permettront le développement d’une formule prédisant les cinétiques de libération à partir de la lecture non destructive de l’épaisseur d’enrobage par Térahertz.[...]Development of new galenic devices needs series experiments with variation of number parameters. For industrial, it’s a lost in time and money. Food and Drug Administration initiated since several years, Process Analytical Technology (PAT) as a tool to analyze and control pharmaceutical process. These tools can be helpful to determine drug release mechanism and allow application of mathematical model to predict drug release kinetics. One objective of this work is to develop a mechanistically realistic mathematical model allowing for the quantification of vitamin release from Compritol 888 (glyceryl dibehenate NF)-based matrix tablets, prepared either by direct compression or via hot-melt extrusion/grinding/compression. Nicotinic acid has been used as highly soluble drug in surrounding medium. Dissolution studies show vitamin release rates increased with increasing initial niacin content, due to the increased matrix porosity upon vitamin depletion. In all cases, niacin release from tablets prepared via hot-melt extrusion was slower than from tablets prepared by direct compression, due to more intense embedding of the vitamin within the lipid. Importantly, a numerical model based on Fick’s law of diffusion and considering the co-existence of dissolved and non-dissolved vitamin could successfully be used to quantify vitamin release from both types of tablets, irrespective of the initial niacin loading and tablet size. In-silico simulations can be very helpful to accelerate product optimization of Compritol 888-based matrices, saving development time and costs. For multiparticulates systems, and more again for coated forms, mathematical models are more complexes. In this goal, development of new tools to characterize devices is primordial. Technology Terahertz offers an interesting potential. This technique can be used to detect difference in size and uniformity for polymeric film from multilayer pellets of 1 mm diameter. Pellets consisting of a sugar starter core and a metoprolol succinate layer were coated with a Kollicoat® SR: Kollicoat® IR polymer blend. Pellets with several coating thickness are studied. No drug layer thickness difference between batches was observed, and the average coating thicknesses were 46 µm, 71 µm and 114 µm, for the different batches. Terahertz results compared with experimental data from dissolution methods, allow predicting coating thickness results correlated with the subsequent drug release behavior. Multiparticulates systems have important interest: they allow avoiding “dose dumping”. Dose dumping is described as an unintended, rapid drug release in a short period of time of the entire amount or a significant fraction of the drug contained in a modified release dosage form (Meyer, 2005). This phenomenon can be observed in the case of ethylcellulose-based devices in presence with ethanol rich-media. Recently, ethylcellulose:guar gum blend have been reported to provide ethanol-resistant drug release kinetics from coated dosage forms. Theophylline matrix pellets were coated with ethylcellulose: guar gum blends. These granules show no change in drug release profiles upon contact with medium containing 40% of ethanol (v/v). This is because the ethanol insoluble guar gum effectively avoids undesired ethylcellulose dissolution in ethanol-rich bulk fluids. However, so far the importance of crucial formulation parameters, including the minimum amount of guar gum to be incorporated and the minimum required guar gum viscosity, remains unclear. It was found that more than 5% guar gum (referred to the total polymer content) must be incorporated in the film coating and that the apparent viscosity of a 1% aqueous guar gum solution must be greater than 150 cPs to provide ethanol-resistance. [...]
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Wagner, Daniel. "Sustained release formulations for compounds underlying intestinal drug efflux." [S.l.] : [s.n.], 2003. http://deposit.ddb.de/cgi-bin/dokserv?idn=96927890X.
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Shuwisitkul, Duangratana [Verfasser]. "Biodegradable implants with different drug release profiles / Duangratana Shuwisitkul." Berlin : Freie Universität Berlin, 2011. http://d-nb.info/1025490355/34.
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