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1
Campbell, K. C. "Novel systems for transdermal drug delivery". Thesis, Queen's University Belfast, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.368758.
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Park, Jung-Hwan. "Polymeric microneedles for transdermal drug delivery". Diss., Available online, Georgia Institute of Technology, 2004:, 2004. http://etd.gatech.edu/theses/available/etd-06072004-131324/unrestricted/park%5Fjung-hwan%5F200405%5Fphd.pdf.
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Roxhed, Niclas. "A Fully Integrated Microneedle-based Transdermal Drug Delivery System". Doctoral thesis, Stockholm : Kungliga Tekniska högskolan, 2007. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-4484.
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Zaid, Alkilani Ahlam. "Polymeric microneedle systems for transdermal drug delivery". Thesis, Queen's University Belfast, 2013. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.603301.
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Delivery across skin offers many advantages compared to oral or parenteral routes e.g. non-invasive, avoiding first-past metabolism, improved bioavailability and reduction of systemic side effects. Microneedle (MN) are minimally-invasive devices that painlessly by-pass the skin's stratum corneum, which is the principal barrier to topically-applied drugs. Polymeric MN delivery systems were designed and evaluated to transdermally deliver two model drugs, the small water soluble drug ibuprofen sodium and the large protein ovalbumin (OVA). A range of hydrogel forming materials for MN production was evaluated to identify the most suitable super swelling hydrogel MN array that are hard in the dry state but, upon insertion into skin, rapidly take up interstitial fluid. The MN themselves contain no drug, but instead drug are loaded into lyophilized patches. Novel super swelling hydrogel forming MN arrays were fabricated from aqueous blends containing 20% w/w poly(methyl vinyl ether co maleic acid) (Gantrez® S97), 7.5% w/w poly(ethylene glycol) (PEG) and 3% sodium carbonate (Na2C03). In addition, dissolving MN arrays loaded with a high dose of non-potent therapeutic drug were fabricated from aqueous blends of 70% w/w Gantrez® AN139 (PH 7) and 30% ibuprofen sodium. Successful drug delivery was achieved in this research work using novel polymeric MN, super swelling hydrogel MN and dissolving MN. The in vitro studies has been shown first ever example of polymeric MN being loaded with a NSAIDs. The novel concept of super swelling hydrogel MN integrated with lyophilized patches loaded with ovalbumin was evaluated. They enabled the sustained delivery of the ibuprofen sodium and ovalbumin both in vitro and in vivo. Gamma sterilization can be done without compromising polymeric MN properties. Finally, hydrogel forming MN arrays can be successfully and reproducibly applied by human volunteers given appropriate instruction so the use of MN applicator devices may not be necessary, thus possibly enhancing patient compliance.
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Kim, Yeu Chun. "Transdermal Drug Delivery Enhanced by Magainin Peptide". Diss., Georgia Institute of Technology, 2007. http://hdl.handle.net/1853/19738.
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The world-wide transdermal drug delivery market is quite large, but only a small number of agents have FDA approval. The primary reason for such limited development is the difficulty in permeating the stratum corneum layer of human skin.
In our study, we developed a novel percutaneous delivery enhancing approach. Magainin peptide was previously shown to disrupt vesicles from stratum corneum lipid components and this ability of magainin allows us to propose that magainin can increase skin permeability. Therefore, we tested the hypothesis that magainin, a pore-forming peptide, can increase skin permeability by disrupting stratum corneum lipid structure and that magainin¡¯s enhancement requires co-administration of a surfactant chemical enhancer to increase magainin penetration into the skin. In support of these hypotheses, synergistic enhancement of transdermal permeation can be observed with magainin peptide in combination of N-lauroyl sarcosine (NLS) in 50% ethanol-PBS solution. The exposure to NLS in 50% ethanol solution increased in vitro skin permeability to fluorescein 15 fold and the addition of magainin synergistically increased skin permeability 47 fold. In contrast, skin permeability was unaffected by exposure to magainin without co-enhancement by NLS-ethanol.
To elucidate the mechanism of this synergistic effect, several characterization methods such as differential scanning calorimetry, Fourier transform infrared spectroscopy, and X-ray diffraction were applied. These analyses showed that NLS-ethanol disrupted stratum corneum lipid structure and that the combination of magainin and NLS-ethanol disrupted stratum corneum lipids even further. Furthermore, confocal microscopy showed that magainin in the presence of NLS-ethanol penetrated deeply and extensively into stratum corneum, whereas magainin alone penetrated poorly into the skin. Together, these data suggest that NLS-ethanol increased magainin penetration into stratum corneum, which further increased stratum corneum lipid disruption and skin permeability.
Finally, skin permeability was enhanced by changing the charge of magainin peptide via pH change. We modulated pH from 5 to 11 to change the magainin charge from positive to neutral, which decreased skin permeability to a negatively charged fluorescein and increased skin permeability to a positively charged granisetron. This suggests that an attractive interaction between the drug and magainin peptide improves transdermal flux.
6
Easley, Christina A. "Electrically-assisted enhancement of transdermal drug delivery using magainin peptides". Thesis, Georgia Institute of Technology, 2002. http://hdl.handle.net/1853/21419.
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Zeng, Jianming. "Constrained crystallization and depletion in the polymer medium for transdermal drug delivery system". Diss., Georgia Institute of Technology, 2004. http://hdl.handle.net/1853/5102.
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Transdermal drug delivery systems (TDS) are pharmaceutical devices that are designed to deliver specific drugs to the human body by diffusion through skin. The TDS effectiveness suffers from crystallization in the patch when they are kept in storage for more than two years. It has been reported that there are two types of crystals in the patch: needle and aggregate, and growth of drug crystals in TDS generally occurs only in the middle third of the polymer layer. In our study, fluorescence microscopy, EDS (SEM) and Raman microspectroscopy were used to further characterize the crystals. The results show that the needle crystals most probably contain estradiol and acrylic resin conjugate. The FTIR spectrum of the model sample proved the occurrence of a reaction between estradiol and acrylic resin. Crystal growth in an unstressed matrix of a dissolved crystallizable drug component was simulated using a kinetic Monte Carlo model. Simulation using Potts model with proper boundary condition gives the crystals in the middle of matrix in the higher temperature. Bond fluctuation model is also being implemented to study representative dense TDS polymer matrix. This model can account for the size effect of polymer chain on the crystal growth. The drug release profile from TDS was also studied by simulating the diffusion of drug molecules using Monte Carlo techniques for different initial TDS microstructure. The release rate and profile of TDS depend on the dissolution process of the crystal. At low storage temperature, the grains are evenly distributed throughout the thickness of the TDS patch, thus the release rate and profile is similar to the randomly initiated system. Further work on stress induced crystallization is currently under development. Although the study was specifically done for drug in a polymer medium, the techniques developed in this investigation is in general applicable to any constrained crystallization in a polymer medium.
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Narayanaswamy, Variankaval. "Characterization of phase transitions in transdermal drug delivery systems". Thesis, Georgia Institute of Technology, 1997. http://hdl.handle.net/1853/8645.
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Chik, Zamri. "Pharmacokinetic studies for the development of transdermal drug delivery systems". Thesis, Queen Mary, University of London, 2007. http://qmro.qmul.ac.uk/xmlui/handle/123456789/1766.
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This thesis mainly describes a series of Phase I pharmacokinetic studies conducted on the TDS®d elivery systemw hich combinedw ith lidocaine,t estosteronea, nd a new drug, Melanotan-I for the transdermal drug delivery. Pharmacodynamic studies have also been carried out in certain areas to support the pharmacokinetics. The initial challenge was the development and validation of a method to analyse lidocaine in human plasma by LCMS-MS. The sensitivity and reliability of the developed method has enabled the analysis of lidocaine plasma levels from the TDS®- Lidocaine study. The results from the study have shown that the TDS® system has been able to deliver the drug effectively through the skin. This finding had a positive impact on the future development of the TDS® system in combination with other drugs. The combination of the TDS® system with testosterone had been successfully tested in 12 healthy male subjects. TDS®-Testosterone was found to be bioequivalent to Androgel®. This result gave an insight into further development of this preparation if it is to be regarded as an alternative treatment for hypogonadism. Various methods of correcting for endogenous testosterone were performed on the data and the influence on bioequivalence was studied. Testosterone was used as a model drug and used to explore potential guidelines for the bioequivalence assessment of endogenous compounds. Finally, the TDS® system has been combined with a new, peptide derived drug, Melanotan-I (MT-I). This drug is currently under development for the cosmetic purposes and the treatment of various skin conditions related to sun allergies. A dose escalation study of TDS®-Melanotan for the protective tanning of skin was carried out and the result was presented. In addition, in vivo techniques, such as microdialysis and tape stripping, have also been explored to investigate the feasibility of measuring pharmacokinetic of a transdermal drug instead of using the conventional systemic measurements.
10
Oladiran, Gbolahan S. "Development and formulation of wax-based transdermal drug delivery systems". Thesis, Aston University, 2008. http://publications.aston.ac.uk/11060/.
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Topical and transdermal formulations are promising platforms for the delivery of drugs. A unit dose topical or transdermal drug delivery system that optimises the solubility of drugs within the vehicle provides a novel dosage form for efficacious delivery that also offers a simple manufacture technique is desirable. This study used Witepsol® H15 wax as a abase for the delivery system. One aspect of this project involved determination of the solubility of ibuprofen, flurbiprofen and naproxen in the was using microscopy, Higuchi release kinetics, HyperDSC and mathematical modelling techniques. Correlations between the results obtained via these techniques were noted with additional merits such as provision of valuable information on drug release kinetics and possible interactions between the drug and excipients. A second aspect of this project involved the incorporation of additional excipients: Tween 20 (T), Carbopol®971 (C) and menthol (M) to the wax formulation. On in vitro permeation through porcine skin, the preferred formulations were: ibuprofen (5% w/w) within Witepsol®H15 + 1% w/w T; flurbiprofen (10% w/w) within Witepsol®H15 + 1% w/w T; naproxen (5% w/w) within Witepsol®H15 + 1% w/w T + 1% C and sodium diclofenac (10% w/w) within Witepsol®H15 + 1% w/w T + 1% w/w T + 1% w/w C + 5% w/w M. Unit dose transdermal tablets containing ibuprofen and diclofenac were produced with improved flux compared to marketed products; Voltarol Emugel® demonstrated flux of 1.68x10-3 cm/h compared to 123 x 10-3 cm/h for the optimised product as detailed above; Ibugel Forte® demonstrated a permeation coefficient value of 7.65 x 10-3 cm/h compared to 8.69 x 10-3 cm/h for the optimised product as described above.
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Pywell, E. J. "Studies on some polymeric matrices for use in transdermal drug delivery systems". Thesis, University of Manchester, 1987. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.378309.
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Van, Dyk Christina Petronella. "Transdermal delivery of 5-Fluorouracil with PheroidTM technology / C.P. van Dyk". Thesis, North-West University, 2008. http://hdl.handle.net/10394/1905.
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Kuduğ, Emre Batıgün Ayşegül. "Use Of Fibroin/Hyaluronic Acid Matrices As A Drug Reservoir In Iontophoretic Transdermal Delivery/". [s.l.]: [s.n.], 2004. http://library.iyte.edu.tr/tezler/master/kimyamuh/T000297.pdf.
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Reynecke, Sonique. "A comparative study of lamellar gel phase systems and emzaloids as transdermal drug delivery systems for acyclovir and methotrexate / Sonique Reynecke". Thesis, North-West University, 2004. http://hdl.handle.net/10394/665.
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The skin forms an attractive and accessible route for systemic delivery of drugs as alternative
to other methods of administration, such as the oral and parental methods because of the
problems associated with last mentioned methods. The lipophilic character of the stratum
corneum, coupled with its intrinsic tortuosity, ensures that it almost always provides the
principal barrier to the entry of drug molecules into the skin.
Due to the fact that methotrexate (MTX) and acyclovir (ACV) have poor penetration
properties through the skin, the aim of this study was to enhance the permeation of
methotrexate and acyclovir with the use of two lamellar gel phase systems (LPGS)
(Physiogel® NT and Physiogel® Dermaquadrille) and with Emzaloid® as transdermal drug
delivery systems.
Three different sets of experiments were done in this study: 1) the viscosity of the two
Physiogel® creams was measured as an indication of stability and to determine whether the
internal structure of the Physiogel® creams were affected by the investigated drugs; 2) the
drug release rate from the three drug delivery vehicles was measured with a Vankel ®
dissolution apparatus; 3) in vitro permeation studies were preformed using vertical Franz
diffusion cells with human epidermal skin clamped between the donor and receptor
compartments. The skin was hydrated with PBS buffer for one hour before 1% mixtures of
the drugs in both the Physiogel® creams and Emzaloid® were applied to the donor chamber.
Samples were taken at 2, 4, 6, 8, 10, 12 and 24 hours. It was then analysed by HPLC for
methotrexate and acyclovir. The fluxes of drug permeation were determined.
The viscosity measurements confirmed that the internal structure of the two Physiogel®
creams was not influenced by the drugs. Acyclovir and methotrexate were both released from
the delivery vehicles. There was an enhancement of acyclovir through the skin from one of
the Physiogel® creams. The permeability of methotrexate in the presence of the two
Physiogel® vehicles was not significantly enhanced. Emzaloid® as delivery vehicle increased
the penetration of both drugs through the skin significantly.
The lamellar gel phase system mimics the structure of the stratum corneum, but does not
improve the drug permeation through the stratum corneum significantly. The utilisation of
Emzaloid® as a drug delivery system could be advocated from these findings. As could be
seen from the penetration profiles Emzaloid® was a superior delivery system for methotrexate
and acyclovir compared to the lamellar gel phase systems.Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2005.
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Goswani, Tarun. "Sublingual drug delivery : in vitro characterization of barrier properties and prediction of permeability". Scholarly Commons, 2008. https://scholarlycommons.pacific.edu/uop_etds/708.
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Santos, Lúcia Isabel Ferreira. "Physical supports for immobilization of drug particles or controlled drug delivery systems by bioinspired pollination". Master's thesis, Universidade de Aveiro, 2017. http://hdl.handle.net/10773/22604.
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Mestrado em Biotecnologia Industrial e AmbientalNos últimos anos, a administração transdérmica de fármacos foi aponte como uma via de libertação de fármacos de sucesso devido às suas enumeras vantagens. Relativamente aos sistemas convencionais, este é um sistema não doloroso, apresenta menos efeitos secundários e possibilita uma dose menos frequente. Os pensos representam a maior quota do mercado de sistemas de libertação transdérmica de fármaco. No entanto, a sua aplicação tem sido restringida pelos atuais problemas associados à sua administração passiva. Com base no conceito de biomimetismo, um novo e otimizado sistema para administração transdérmica de fármacos é aqui proposto, bioinspirado na capacidade das abelhas aprisionarem e, consequentemente, libertarem o pólen durante o processo de polinização. Assim, foi desenhado um penso hierárico biomimético obtido a partir de polidimetilsiloxano (PDMS) com um micropadrão de pilares (imitando o pêlo presente nas patas das abelhas). A otimização do sistema foi obtida pela conjugação de micropilares espaçados com a mesma distância que o diâmetro das partículas de fármaco. Obteve-se assim uma eficiência de aprisionamento de 24,8 ± 0,4 mg/cm2, estando acima dos valores obtidos para os pensos atualmente disponíveis no mercado, bem como na maioria dos trabalhos até aqui efetuados. A tetraciclina, um antibiótico modelo, foi aqui utilizado para determinar o perfil de libertação de dois sistemas diferentes: pensos com tetraciclina em pó ou com micropartículas de alginato encapsuladas com esse mesmo fármaco. Enquanto o pó de tetraciclina foi rapidamente libertado, o sistema mais complexo permitiu uma libertação controlada do composto ativo durante 5 dias. Os pensos foram caracterizados por microscopia eletrónica de varrimento, microscopia de fluorescência e resistência à tração. Além disso, a atividade antimicrobiana também foi também verificada. Em suma, os resultados obtidos propõem a aplicação deste penso a nível clínico, proporcionando uma elevada concentração de fármaco que poderá resolver os problemas atuais associados aos sistemas de administração passiva de fármacos.
In the last years, transdermal drug delivery has been exploited as a successful controlled drug release route due their several advantages (e.g. no painful, less frequent dosage and side effects), being the patches the largest market share of such systems. Nevertheless, current problems associated with passive delivery patches have been limiting their application. Based on the insights behind the biomimetics concept, herein we propose as novel and optimized system for transdermal drug delivery purposes, a bioinspired patch based on the remarkable bee’s ability to catch and release the pollen during pollination. For this purpose, a hierarchical biomimetic polydimethylsiloxane (PDMS) micropatterning patch with micropillars (mimicking the hair of bee’s legs) was engineered. An optimized system was obtained through the combination of patch with micropillars spaced with the same distance as drug microparticles' diameter. In fact, an entrapment efficiency of 24.8 ± 0.4 mg/cm2 was achieved, being above the actual commercially available patches and most of the current research works. The release profile was determinate to two different systems: patches with either tetracycline hydrochloride powder or tetracycline loaded alginate microparticles, a model antibiotic. While tetracycline powder was immediately release, the most complex system allowed for a controlled and sustained release of the active pharmaceutical ingredient (API) for 5 days. The engineered patches were characterized by SEM, fluorescent microscopy, tensile strength and antimicrobial activity was also verified. The results herein obtained suggest that the optimized patch could be further developed for clinical applications, providing high drug concentration that could solve the current problems associated with passive drug delivery patches.
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Tettey-Amlalo, Ralph Nii Okai. "In vitro release of ketoprofen from proprietary and extemporaneously manufactured gels". Thesis, Rhodes University, 2005. http://eprints.ru.ac.za/295/.
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Talbi, Yassine. "Conception d'un patch transdermique intelligent pour le monitoring et l'aide à la prise de médicament". Thesis, Toulouse, INSA, 2018. http://www.theses.fr/2018ISAT0005/document.
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La surveillance personnalisée est une ambition émergente pour les technologies de la santé qui répond aux besoins des patients et des professionnels de santé. L'objectif de ce travail est d'aller jusqu’aux soins, en utilisant un actionneur télécommandé pour mettre en œuvre automatiquement une prescription médicamenteuse. Un système transdermique intelligent est conçu, sous la forme d’un patch, pour administrer de manière contrôlée des médicaments. Des expérimentations sont réalisées pour démontrer l’intérêt des techniques d’aide à la diffusion en termes de contrôle et d’amélioration de la quantité délivrée. Le contrôle de la dose administrée est corrélé à l’actionneur intégré via une loi de commande. Une modélisation et une simulation numérique de la diffusion transdermique est mise en place en liaison avec les résultats obtenus lors d’expérimentations sur une cellule de Franz, ce modèle est appliqué sur une structure planaire "patch classique". Différents scénarios de stimulations électriques et de facteurs de formes ont été conduits pour obtenir un profil d’administration optimal. La conception du système électronique est présentée d’adapter la dose administrée selon les besoins du patient est présentée. Un premier prototype est réalisé, intégrant des fonctions d’actionnement, et de récupération de données issues de capteurs intégrésPersonalized monitoring is an emerging ambition for health technologies responding the needs of patients and healthcare professionals. In this regard, the purpose of this work is to propose a e-health care device offering active control and permanent actuating link able to control the amount of drug delivered. A first part presents our motivations related to the problems of the aging of the population, recalls the current approaches for the monitoring of the elderly and describes the need in the systems of actuations in particular for the aid to the taking of drugs. From these needs, a state of the art is proposed on the techniques for controlling the delivery of drugs. Experiments are carried out to demonstrate the efficiency of diffusion techniques controlling and improving the quantity delivered. The control of the administered dose is correlated to the integrated actuator via a control command. We present a modeling and a numerical simulation of the transdermal diffusion related to the results obtained during experiments on a Franz cell, and the transposition of the model on a planar structure. Different scenarios of electrical stimulations and shape factors have been conducted to obtain optimal administration profile. Finally, the last part is devoted to technological locks and to the design of the intelligent system which adapt the dose administered according to the needs of the patient. A prototype is made, integrating actuation functions, and data recovery from integrated sensors
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Gadiraju, Priya D. "Laminated chemical and physical micro-jet actuators based on conductive media". Diss., Atlanta, Ga. : Georgia Institute of Technology, 2008. http://hdl.handle.net/1853/26611.
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Thesis (Ph.D)--Chemical Engineering, Georgia Institute of Technology, 2009.Committee Chair: Allen, Mark; Committee Member: Allen, Sue; Committee Member: Glezer, Ari; Committee Member: Koros, Williams; Committee Member: Prausnitz, Mark. Part of the SMARTech Electronic Thesis and Dissertation Collection.
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Junior, Abdo Salomão. "Infusão transdérmica de fármaco no tratamento do melanoma murino B16F10". Universidade de São Paulo, 2017. http://www.teses.usp.br/teses/disponiveis/5/5167/tde-03012018-111449/.
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A incidência de casos de melanoma tem aumentado em todo o mundo sendo que, apesar do diagnóstico precoce e do advento das terapias moleculares, o número de pacientes que morrem com a doença em estágio avançado continua em elevação. Deste modo as pesquisas atuais têm focado no desenvolvimento de diferentes estratégias para a disponibilização de terapias eficazes e acessíveis. Nesse contexto, a via de administração transdérmica constitui uma alternativa promissora para aumentar a eficácia local e sistêmica de fármacos, incluindo agentes antitumorais. Diversos métodos têm sido desenvolvidos para maximizar a permeação cutânea de fármacos, destacando-se, entre esses, a ablação térmica por radiofrequência (RF). Esse processo resulta na criação de vários microcanais entre a epiderme e a derme, pelos quais diversas moléculas podem passar em direção às camadas mais profundas da pele. Nesse estudo, a eficácia da infusão transdérmica de etoposídeo por dispositivo de radiofrequência fracionada foi avaliada em modelo de melanoma murino. Camundongos da linhagem C56BL/6 foram divididos nos seguintes grupos experimentais: 1) controle; 2) tratados com radiofrequência; 3) tratados com a aplicação tópica de etoposídeo; e 4) tratados com radiofrequência e posterior aplicação tópica de etoposídeo. Os tratamentos foram realizados durante o período de 28 dias. O peso corpóreo, o volume tumoral e o perfil hematológico foram avaliados semanalmente. Ao término do tratamento os animais foram eutanasiados e procedeu-se a coleta da massa tumoral e dos órgãos (pulmão, baço, rins, linfonodos e fígado) para análise histopatológica. As células tumorais obtidas das massas tumorais foram analisadas quanto às alterações do ciclo celular e do potencial transmembrânico mitocondrial. Os resultados demonstraram que o tratamento com etoposídeo isolado reduziu a sobrevida dos animais e ocasionou alterações histológicas indicativas de toxicidade. Em contrapartida, a infusão transdérmica do etoposídeo por dispositivo de radiofrequência promoveu redução significativa do volume tumoral, em comparação com todos os grupos experimentais, sem ocasionar mortalidade. Esse tratamento também diminuiu a plaquetocitose e elevou o número de eritrócitos em comparação com os outros grupos. A análise histopatológica dos órgãos dos animais tratados com RF + etoposídeo evidenciou que não houveram alterações significativas na arquitetura tecidual. Ainda, o grupo tratado com RF + etoposídeo foi o que apresentou o maior percentual de células estacionadas na fase S/G2M e com mitocôndrias inativas, evidenciando o aumento da eficácia demonstrada no estudo in vivo. O conjunto de resultados sugere que o tratamento com a radiofrequência seguida do etoposídeo resulta em melhor resposta antitumoral do quimioterápico, com baixos índices de toxicidade sistêmicaThe incidence of melanoma cases has increased worldwide and, despite early diagnosis and targeted molecular therapy, the number of patients dying from metastatic disease continues to rise. Thus, current research has focused on the development of different treatment strategies to provide efficient and accessible solutions. In this sense, transdermal delivery is a promising alternative enhancing the local and systemic efficacy of drugs, including antitumor agents. Several methods have been developed to improve the skin permeation of drugs, highlighting, among those, the radiofrequency thermal ablation (RFA). This process results in the creation of many microchannels between the epidermis and the dermis through which several molecules can pass towards the deeper layers of the skin. In this study, the efficacy of the transdermal delivery of etoposide by a fractional radiofrequency device was evaluated in a murine melanoma model. C56BL/6 lineage mice were divided into the following experimental groups: 1) control; 2) treated with radiofrequency; 3) treated with topical applications of etoposide; and 4) treated with radiofrequency followed by topical applications of etoposide. The animals were treated for 28 days and the body weight, tumor volume and hematological profile were analyzed weekly. At the end of the treatments, the animals were euthanized and the tumor mass and organs (lung, spleen, kidneys, lymph nodes and liver) were collected for histopathological analysis. Tumor cells obtained from the tumor masses were analyzed for changes in the cell cycle and mitochondrial transmembrane potential. The results showed that the treatment with etoposide alone reduced the survival of the animals and caused histological changes indicating toxicity. On the other hand, the transdermal delivery of etoposide by a radiofrequency device resulted in a significant reduction of the tumor volume, in comparison with all the experimental groups, not causing mortality. This treatment also decreased thrombocytosis and increased the number of red blood cells compared to the other groups. The histopathological analysis of the organs from animals treated with RFA + etoposide demonstrated that there was no significant change in tissue architecture. Furthermore, the group treated with RFA + etoposide presented the highest percentage of cells with inactive mitochondria and interruption at the S/G2M stage, corroborating the increased efficacy of the in vivo study. The set of results indicates that the treatment with radiofrequency followed by etoposide results in better antitumor responses of chemotherapy, with low toxicity rates
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Zucchini, Lorenzo. "Microaghi e Micropompe per Dispositivi TDDS". Bachelor's thesis, Alma Mater Studiorum - Università di Bologna, 2019. http://amslaurea.unibo.it/18627/.
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I Sistemi ad Infusione di Farmaco Transdermica (TDDS) sono estremamente promettenti ed in rapida evoluzione negli ultimi due decenni. La terza ed ultima generazione sfrutta le tecnologie produttive e i materiali tipici dei MEMS, per questo sono considerabili come facenti parte della categoria BioMEMS, cioè sistemi micro-elettromeccanici applicati alla clinica e alla medicina. Fra i più notevoli vantaggi vi sono la sicurezza del trattamento, le migliori capacità terapeutiche a parità di dose di farmaco, la regolazione automatica e tempo-dipendente del rilascio anche seguendo un feedback biologico. I TDDS in particolare costituiranno un'alternativa più sicura ed efficace all'uso degli aghi ipodermici, ad esempio nel trattamento di patologie croniche gravi quali il diabete. Organi fondamentali dei dispositivi TDDS sono i microaghi e le micropompe, entrambi oggetto di una fiorente ricerca su scala mondiale. I traguardi principali della ricerca a breve termine sono il miglioramento dell'efficienza e della capacità di lavoro per le micropompe, e una migliore biocompatibilità per i microaghi. La presente discussione si concentra su microaghi e micropompe, analizzandone le numerose tipologie al momento disponibili, ponendo l'attenzione sui requisiti di progettazione e sulle prestazioni di ogni caso.
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Andrews, Samantha Nacole. "Microdermabrasion for transdermal drug delivery". Diss., Georgia Institute of Technology, 2010. http://hdl.handle.net/1853/37150.
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The skin serves as a semi-permeable barrier that protects the body from pathogens and water loss. The stratum corneum, the upper 10-15 µm layer of skin, is the primary barrier layer. Due to its structure, only drugs that are lipophilic and with a low molecular weight (<500 Da) can penetrate intact skin. This study examines the use of microdermabrasion as a method of removing the stratum corneum to increase the skin's permeability to hydrophilic molecules, proteins, and vaccines. Microdermabrasion is a FDA-approved cosmetic skin resurfacing procedure that removes the stratum by bombarding it with abrasive particles under vacuum. The aims of this thesis are focused on optimizing the microdermabrasion conditions that will selectively remove stratum corneum, evaluating the transport of different sized molecules through abraded skin in vitro, examining drug efficacy in vivo by delivering insulin to diabetic rats, and examining the rate of skin healing after treatment. Microdermabrasion can be used as a non-invasive transdermal drug technique to safely remove stratum corneum to make the skin more permeable to waters soluble drugs and proteins.
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McAllister, Devin Vincent. "Microfabricated needles for transdermal drug delivery". Diss., Georgia Institute of Technology, 2000. http://hdl.handle.net/1853/11031.
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Henry, Sʹebastien. "Microfabricated device for transdermal drug delivery". Thesis, Georgia Institute of Technology, 1997. http://hdl.handle.net/1853/20707.
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Santos, Paulo Antonio Fernandes Gomes. "Transdermal drug delivery using spray formulations". Thesis, University College London (University of London), 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.497653.
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Long, C. P. "Transdermal drug delivery to the neonate". Thesis, Queen's University Belfast, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.269128.
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Sharma, Ashish. "Electroporative transdermal drug delivery : optimization and safety /". Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape11/PQDD_0015/MQ54909.pdf.
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Lamb, Keith A. "Cell culture models for transdermal drug delivery". Thesis, University of Nottingham, 1992. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.334854.
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Nyambi, Dorothy Affiong. "In vitro transdermal drug transport using iontophoresis". Thesis, King's College London (University of London), 1992. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.246212.
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Gupta, Jyoti. "Microneedles for transdermal drug delivery in human subjects". Diss., Georgia Institute of Technology, 2009. http://hdl.handle.net/1853/34770.
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Microneedles have been developed as a minimally invasive alternative to painful hypodermic needles to deliver modern biotherapeutics. Previously, several in-vitro and in-vivo animal studies have been conducted to show that microneedles increase skin permeability to a wide range of molecules that cannot cross the skin using conventional transdermal patches due to the skin's stratum corneum barrier. However, only a limited number of studies have been performed to study microneedle-based drug delivery in human subjects. Therefore, the objective of this study was to perform the first-in-humans microneedle studies to: a) characterize skin repair responses to solid microneedle insertion to determine the extent of increased skin permeability coupled with predictions of pharmacokinetics of drug delivered through premeabilized skin, b) determine the effect of hollow microneedle-based infusion parameters on flow conductivity of skin and pain and thereby identify barriers to fluid flow into the skin from hollow microneedles, c) assess the safety and efficacy of systemic therapeutic effects through measurement of pharmacokinetic parameters, pain and irritation for microneedle-based insulin delivery in type 1 diabetes subjects, and d) assess the safety and efficacy of local therapeutic effects though delivery of lidocaine to the skin. Results showed for the first time that solid microneedle-treated skin reseals rapidly (< 2 h) in the absence of occlusion whereas occluded skin reseals slowly (3-40 h) depending on microneedle geometry as determined by skin impedance measurements. Increased microneedle length, number, and cross-sectional area led to slower recovery kinetics in the presence of occlusion. This thesis also demonstrated that the flow conductivity of skin decreased as fluid was infused to the dermis through hollow microneedles due to the dense structure of the dermis. Microneedle retraction, low flow rates, and the addition of hyaluronidase helped increase flow conductivity. Microneedles were able to deliver 800 µl of saline to the dermis without causing significant pain. Further, microneedle-based insulin delivery in type 1 diabetes subjects revealed that microneedles provided faster pharmacokinetics and improved glycaemic control than conventional subcutaneous catheters. Lastly, microneedle-based lidocaine injection demonstrated that microneedles were less painful, as effective, and more preferred than hypodermic needles in anesthetizing clinically relevant areas.
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Dwaikat, Mai Al. "The Effect of Ultrasound on Transdermal Drug Delivery". Thesis, Coventry University, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.492372.
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Thakur, R. R. S. "Swellable Hydogel Microneedle Arrays for Transdermal Drug Delivery". Thesis, Queen's University Belfast, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.527897.
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Angel, Aimee B. (Aimee Brigitte) 1977. "A controllable, nano-volumetric, transdermal drug delivery device". Thesis, Massachusetts Institute of Technology, 2002. http://hdl.handle.net/1721.1/89352.
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Mitragotri, Samir. "Ultrasound-mediated transdermal drug delivery : mechanisms and applications". Thesis, Massachusetts Institute of Technology, 1996. http://hdl.handle.net/1721.1/11263.
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Courtenay, Aaron John. "Microneedle-mediated transdermal drug delivery of biotherapeutic macromolecules". Thesis, Queen's University Belfast, 2016. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.706298.
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In the last 20 years biotherapeutic macromolecules have become the fastest growing sector within pharmaceutical industry. Their development, facilitated by the introduction of advanced molecular engineering techniques, has led to improved treatment options for patients with autoimmune conditions, various cancer types, and infectious disease. The complex molecular structure of these drugs render them susceptible to degradation and, as a result, many commercially available products are suitable for parenteral drug delivery only. Subsequently, the hypodermic needle and syringe has remained the device of choice for biotherapeutic delivery, despite the many drawbacks associated with this method. Transdermal delivery has been an attractive alternative for many pharmaceutical formulators. However, few drugs possess the appropriate physicochemical properties required for crossing the human skin barrier. Microneedle (MN) technology combines micro-engineering and material sciences to fabricate micron scale projections manufactured onto a platform. That, when pressed against the skin, create aqueous apertures allowing drug delivery directly into the dermal tissue. This thesis explores the development of polymeric MN-based drug delivery systems, capable of facilitating intradermal and transdermal passage of biotherapeutic macromolecules. The model protein ovalbumin was incorporated into polymeric MN systems using commonly employed industrial manufacturing techniques and sterility was successfully demonstrated. Further these MN platforms were evaluated for intradermal delivery in vivo, highlighting the potential adjuvant effects of Gantrez® S-97. Subsequently, through industrial collaboration with market leading transdermal manufacturing company, Lohmann Therapie Systeme AG, the commercially available vaccine Pentavac® was successfully incorporated into dissolving MN arrays. This study has provided significant learnings for both academia and industrial partners, in relation to industrial manufacture of MN and biotherapeutic macromolecules. Finally, polymeric MN platforms were evaluated in vitro and in vivo for transdermal delivery of a therapeutically relevant monoclonal antibody, bevacizumab. This thesis provides significant evidence to support polymeric MN arrays, as minimally invasive intradermal and transdermal delivery platforms of biotherapeutic macromolecules. Focused input from key stakeholders, including: academia, industry, regulators, healthcare professionals and patients will be needed to ensure successful MN commercialisation
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Calcutt, Joshua J. "Modelling Transdermal Drug Delivery and Drug Transport in the Viable Skin". Thesis, Griffith University, 2021. http://hdl.handle.net/10072/404469.
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Viable skin transport is critical to consider when applying transdermal drugs. Predicting concentration in the viable skin is highly essential for both toxicological and therapeutic reasons. The concentration is also vital for drugs that target topical relief of skin diseases. Furthermore, the viable skin has a significant impact on solutes that are highly lipophilic and have low molecular weight. In these cases, the viable epidermis may even become the rate-limiting barrier. Enhancement of transdermal techniques and a better understanding of drug physiochemistry has also enhanced other drug's ability to permeate through the stratum corneum The second chapter, Chapter 2, highlighted the need for further modelling of the viable skin by performing a literature review. Within the study, the previous methods of modelling the vasculature were described. From the analysis, it was seen that the implementation of a sink condition or the use of a distributed elimination model was insufficient to estimate the impact of the capillary network. Therefore, it was concluded that to get a better representation of experimental data; the capillary loops had to be considered more explicitly.
The central research question of this thesis was the impact the vasculature network had on drug transport within the viable skin. However, micropora- tion of the skin and its effect on drug transport was the second research ques- tion. Chapter 3 investigated the latter case by considering drug transport after the stratum corneum had been microporated. A three-dimensional model was developed, and the different impact micropore parameters had on transport was identified. Capillary loops were then introduced into the model. The shape and size of the loops were varied to determine if they affected the transport profile. Furthermore, the effect of changing the ratio of capillary loops to pores or the recruitment of the capillary loops was identified.
The capillary loop model developed in Chapter 3 was enhanced in Chapter 4. The chapter aimed to determine the role the capillary loops play in viable skin transport. The different capillary loop parameters were investigated, and their impact on a homogenous model's effective depth of a sink condition was identified. The new capillary model's concentration profile was also compared to experimental data and the most prevalent mathematical models. From the results, the new capillary model was much more effective at estimating the Econazole concentration. However, it failed to account for the plateauing of concentration in the deeper dermal regions.
Chapter 5 enhanced the modelling in the previous chapter by considering the blood
ow and permeability barrier of the capillary loop. The permeability barrier was assumed on the surface of the capillary loops and represented the endothelial lining. The results of incorporating these two variables produced a more accurate estimation of dermal transport. The enhanced model was able to estimate the plateauing trend evident in both Hydrocortisone and Econazole. The chapter also discussed the importance of considering a dispersion coefficient instead of a diffusion coeffcient. Finally, the transient profile of the model was five-fold faster than previous mathematical models, which matched the seven-fold increase in experimental data.
Chapter 6 further investigated the vasculature network by modelling the subpapillary plexus. However, in this model, the plexus was not modelled explicitly and instead generalised through the introduction of one compartment. The one-compartment generalisation gave an estimation for the subpapillary plexus. When the plexus was introduced, a much higher concentration for the deeper dermal region was evident. The impact of different parameters associated with the plexus was also analysed. The capillary models developed in previous chapters were compared, and the strengths and limitations of each model were identified. However, the modelling of the plexus was preliminary and needs further investigation in the future.
Chapter 7 looked at using compartments to estimate the concentration after microporation. A three-dimensional approach was developed to determine concentration. Compartments were utilised as they provided a more straightforward solution than the previous chapters. They also require significantly less computational power. The accuracy of the approach was determined by comparing the model to the Comsol model developed in Chapter 3. From the comparison, a reasonable estimation of concentration was evident when a sufficient number of compartments were employed. Furthermore, the computational time required to solve the system decreased significantly when the compartment approach was applied.Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Environment and Sc
Science, Environment, Engineering and Technology
Full Text
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Quinlan, Nathan J. "Gas and particle dynamics in transdermal powdered drug delivery". Thesis, University of Oxford, 1999. http://ora.ox.ac.uk/objects/uuid:f6a9a058-911a-43c5-bc19-95dc866543df.
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Transdermal powdered drug delivery is an emerging technology for the injection of drugs through human skin, in which particles of solid drug are entrained in a high-speed gas flow and directed towards the skin at a high enough velocity to penetrate the outer layer of dead cells. Hand-held devices based on this idea offer a means of safe, painless and effective delivery of many drugs and vaccines. This thesis describes a programme of research into the fluid dynamics which determine the particle velocity distribution, the most important mechanical characteristic of the system, in prototype drug delivery devices. Pressure measurements are described which enable characterisation of the gas flow in the drug delivery devices. These are complemented by optical particle detection experiments, which provide a record of the timing of drug particle delivery with respect to the gas flow. Doppler Global Velocimetry (DGV) has been used to measure the velocity field of drug particles. Various tasks involved in the application of DGV to these flow-fields are described. In particular, the use of time-integrated DGV for measurements of unsteady, short-duration flows is discussed. Time-integrated DGV, applied at a range of operating conditions, has provided information on the variation of particle delivery velocity with particle size and with total mass of particles. Time-resolved DGV measurements reveal that particles first emerge in a slow-moving cloud which is driven by transient starting process in the gas flow, followed by a faster stream of particles entrained in a quasi-steady gas flow. The experimental results are complemented by numerical computations of certain aspects of the drug delivery flows. These computations are compared with experimental results, and used to gain additional information on the functioning of the system as a whole.
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Johnson, Mark E. "Biophysical aspects of transdermal drug delivery and chemical enhancement". Thesis, Massachusetts Institute of Technology, 1996. http://hdl.handle.net/1721.1/10912.
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Olatunji, Ololade. "Modelling and optimization of microneedles for transdermal drug delivery". Thesis, Loughborough University, 2011. https://dspace.lboro.ac.uk/2134/9016.
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Microneedle mediated drug delivery is an amalgam of the conventional transdermal patch and the hypodermic needle injection. It offers an improved drug delivery technique without the limitations of the above methods. The ability of microneedles to increase permeability of substances in the skin has been established in the literature. However, a quantitative method for predicting the performance of microneedle devices prior to their fabrication is yet to be fully developed. The contribution of this research is a theoretical framework for modelling and optimizing microneedle array design to obtain desired drug delivery rate while taking into account the transport and mechanical properties of the skin. This is achieved by exploring various theories surrounding transdermal drug transport. The existing theories are then used to develop models to link the microneedle array design parameters with drug transport properties such as permeability and drug concentration in blood. Numerical simulations and theoretical analyses that are carried out in this PhD research indicate that microneedle design has a significant effect on drug delivery. An algorithm was developed for solving the series of equations presented, thus obtaining a framework which is applied to predict performance of microneedle arrays in vivo. Some practical scenarios are also simulated to demonstrate the applicability of the developed framework. For example, numerical simulations of transdermal delivery of Fentanyl show that varying the design parameters such as penetrated length of microneedle and the tip radius of microneedles affected the peak blood concentration. Similarly, the developed framework was used to obtain the optimum microneedle design to calculate the desired peak blood concentration similar to that obtained using conventional patch system. This study is relevant as it provides a better understanding of microneedle mediated drug delivery process and it orchestrates the design and hence, fabrication of more efficient microneedle based drug delivery devices.
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Al-Qallaf, Barrak. "Mass transfer analysis of transdermal drug delivery using microneedles". Thesis, University of Oxford, 2009. http://ora.ox.ac.uk/objects/uuid:19b5221f-f3a6-4fd6-9263-2eecd39acfcd.
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Microneedle is a promising technique for delivering high molecular weight drugs across skin. The microneedles can offer a number of benefits over other drug delivery methods. For example, the drugs only diffuse over a short distance before reaching the blood circulation which enhances the absorption of drugs by the tissue. However, the drug transport behaviour in skin is affected by a complex interplay of many parameters (e.g., microneedle geometries, permeability across skin, etc). In this thesis, many aspects of the microneedle field were examined. A mathematical model for drug transport from microneedle systems into skin was developed. Issues such as microneedle penetration, surface area of the microneedle arrays, etc. were investigated. This work helped us to focus into optimizing the design of microneedles by developing an in-house algorithm to enhance the performance of transdermal drug delivery using microneedles. Following the development of this algorithm, the influence of skin thickness with its classification (i.e., age group, race, etc.) on drug permeability across skin was studied. Attention was then given to determine the effective permeability (Peff) and the effective skin thickness (Heff) for various solid microneedle models. The outcome of this research allowed us to study the influence of microneedle dimensions on the drug concentration in blood (Cb). Furthermore, the 'pattern' (shape) of the microneedles array (i.e., square or rectangular) and the 'distribution' (arrangement) of the microneedles inside an array (i.e., triangular or diamond) were investigated to identify the optimum microneedle models. Finally, the effect of skin metabolism on both the patch (without microneedles) and the microneedle arrays on drug intake were examined.
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Justin, Richard. "Chitosan-graphene nanocomposite microneedle arrays for transdermal drug delivery". Thesis, University of Sheffield, 2015. http://etheses.whiterose.ac.uk/9544/.
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The project focused on the hypothesis that degradable, polymer microneedle arrays are a promising alternative to traditional drug delivery routes, offering the patient a painless, high concentration, and quick delivery of therapeutics through the skin. This project explored chitosan-graphene nanocomposites as potential materials for microneedle arrays; the addition of graphene to chitosan is believed to yield improved mechanical properties and electrical conductivity over pristine chitosan, which will allow for long and slender microneedles and for electrically stimulated drug delivery, and may positively affect the degradation and drug delivery properties of chitosan. Graphene derivatives, such as graphene oxide, reduced graphene oxide, graphene quantum dots, and magnetic graphene quantum dots were synthesised and then characterised, before they were used as the filler within chitosan nanocomposites. Their effect at varying concentrations upon the mechanical properties, electrical conductivity, drug release, and enzymatic degradation rate of chitosan were assessed. It was determined that reduced graphene oxide was the optimum nanoparticle to reinforce chitosan, achieving the best mechanical and electrical conductivity properties of the nanocomposites. Chitosan-graphene nanocomposite microneedle arrays were shown to passively release small molecular weight drugs at a high delivery quantity and rate. Conductive chitosan-graphene nanocomposite microneedles were tested to determine the effect of electrical stimulation on the release of large molecular weight drugs from the nanocomposite, with substantial improvements in the release rate of large molecular weight drugs when compared to passive diffusion. The microneedle arrays were shown to survive the force of insertion through compressive loading. The depth of penetration of the microneedles was determined through cross-sectional analysis of chicken skin.
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Tuan, Mahmood Tuan Mazlelaa. "Polymeric microneedle-mediated transdermal drug delivery : application to paediatric dosing". Thesis, Queen's University Belfast, 2013. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.602944.
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Development of formulations and drug delivery strategies for paediatrics use is scientifically challenging due the broad age ranges presented within this population, resulting in varying requirements in achieving optimised patient outcomes. Though the oral route of drug delivery remains the preferred option for patients due to its convenience, there are a number of problematic issues such as difficulty in swallowing and palatability of the oral medicine that are specific to this population. On the other hand, parenteral route of drug administration is not well accepted in this population due to needle-related fear and pain. For these reasons, a plethora of alternative routes of drug administration have been investigated. One of such approaches is via transdermal route. The readily accessible and large surface area of the skin provides a promising site for delivery of drugs into the body. However, the stratum corneum (SC) offers a formidable barrier to transdermal transport due to its lipophilicity and highly complex cellular architecture. Microneedle (MN) delivery has been proposed as a strategy to breach the SC barrier function in order to facilitate effective transport of molecules across the skin. This strategy involves the use of micron-sized needles fabricated from different materials and using different geometries to create transient aqueous conduits across the skin. In this present study, . poly(methyl vinyl ether/maleic acid) (PMVE/MA)-based polymeric MNs, namely soluble MN and hydrogel forming MN, were fabricated using a micromoulding technique and incorporating two model drugs commonly used in paediatric patients, i.e. caffeine and lidocaine hydochloride. The feasibility and efficacy of these MNs for potential paediatric dosing were investigated in a series of in vitro and in vivo studies, by employing. The views pertaining MN technology were sought among school children in Northern Ireland (via focus groups discussion), members of UK general public and UK paediatrician (through online surveys), in order to determine the perceived perceptions, acceptance, barriers and concerns for future adoption of this technology. In this thesis, polymeric MNs have been shown to dramatically enhance the skin permeability of the model therapeutic molecules either in vitro or in vivo. Furthermore, this thesis also highlighted a large consensus on the opinions of MN technology among schoolchildren, UK paediatricians and the general public, with respect to its potential usefulness of delivering various types of therapeutic substances for the benefit of paediatric population
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Rytlewski, Francesca Elizabeth. "In vitro investigations into needleless injections and transdermal drug delivery". Thesis, King's College London (University of London), 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.401874.
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Schoellhammer, Carl M. (Carl Magnus). "Use of physical enhancers for gastrointestinal and transdermal drug delivery". Thesis, Massachusetts Institute of Technology, 2015. http://hdl.handle.net/1721.1/98714.
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Thesis: Ph. D., Massachusetts Institute of Technology, Department of Chemical Engineering, 2015.Cataloged from PDF version of thesis.
Includes bibliographical references.
The research presented in this thesis represents a significant advance in the field of transdermal- and gastrointestinal (GI)-based drug delivery. With regards to the former, previous work has led to a thorough mechanistic understanding of ultrasound (US)-enhanced transdermal drug delivery. Despite these investigations, it was previously not possible to maximize the efficiency of the permeabilization, or to decrease the required treatment time. In this area, this thesis presents work on the use of a new US treatment modality to both maximize the area of skin that is permeabilized while simultaneously minimizing the required treatment time. This new method involves the simultaneous use of low- (< 100 kHz) and high- (> 1 MHz) frequency US. A proof-of-concept of this method is presented in Chapter 2. Specifically, through the use of aluminum foil pitting experiments, the mechanism of enhancement is elucidated, confirming an increase in transient cavitational events. This method is further shown to lead to enhanced delivery of model permeants to porcine skin in vitro. The new method is further explored in Chapter 3. Specifically, a physiologically relevant experimental setup, utilizing the receiver chamber of a Franz diffusion cell is developed. With this setup, fundamental studies are carried out to investigate the enhancement in localized transport region (LTR) formation versus the enhancement in the resulting skin permeability in vitro. The most important finding is that the enhancement in permeability is greater than the enhancement in LTR formation, suggesting that dual-frequency US results in more permeable LTRs, in addition to larger LTRs. This phenomenon was not previously realized. Furthermore, the safety of this method is assessed through blinded histological evaluation of skin samples treated both in vitro and in vivo. This investigation demonstrated that dual-frequency US results in no greater histological disruption of the skin than that observed using 20 kHz US alone. The power of physical enhancers, such as US, is underscored by their ability to permeabilize a tissue layer, such as the skin, which is designed to serve as a barrier. The use of physical enhancers in a tissue that lacks this barrier, such as the GI tract, presents an intriguing opportunity to maximize drug delivery while minimizing treatment times. In Chapters 4 and 5, the use of microneedles and US to facilitate GI-based drug delivery are explored. Specifically, in Chapter 4, the implementation of an ingestible device containing microneedles is investigated. Studies in pigs demonstrated that microinjections of a model biologic in the GI tract results in superior kinetics compared to traditional subcutaneous injection. A model device containing radially protruding microneedles was also found to be capable of being excreted naturally without any adverse events. Chapter 5 explores the use of US to facilitate rapid delivery to all tissue types of the GI tract. US is demonstrated to be safe and well tolerated. Further, it is found to enable the delivery of a broad range of permeants with a wide range of molecular weights. The clinical use of such a technology is examined in a model of inflammatory bowel disease, and the tolerability and efficacy of rectalbased drug delivery is studied in both small and large animal models in vivo. This thesis advances the current understanding of the use of physical enhancers in skin and GI tissue. In the area of transdermal drug delivery, the insights gained here could lead to more clinically viable devices by reducing the required skin treatment time to achieve a certain level of permeabilization. With respect to the GI tract, this thesis advances for the first time the use of physical enhancers, including investigating the mechanism of enhancement and the cellular and histological effects. This should open the door to a previously unexplored line of research. Indeed, this research could lead to improved therapies and expansion of research techniques applied to the GI tract, as well as to new medical devices to enable local rectal delivery and, eventually, oral administration using ingestible devices.
by Carl M. Schoellhammer.
Ph. D.
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Chadha, Gurkishan S. Parsons Daniel L. Ramapuram Jayachandra B. "Transdermal delivery of genistein as a chemoprotective drug for melanoma". Auburn, Ala, 2009. http://hdl.handle.net/10415/1778.
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Browning, Cassandra A. "Enhancing transdermal delivery of drug-infused particles using electrostatic pulse". Thesis, Boston University, 2013. https://hdl.handle.net/2144/12718.
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Thesis (Ph.D.)--Boston University
PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you.Transdermal delivery is an ever-increasing field of research because it has many advantages over other methods. Currently, transdermal systems for hormone replacement therapy, smoking cessation, and pain management are common. However, there have been challenges in expanding use of the technology due to difficulty penetrating the skin at the levels or rates that achieve a significant therapeutic effect. Therefore, conventional passive transdermal delivery has been applicable to only small, lipophilic ('lipid or fat loving') substances. Recent research has focused on "needle-free" methods to breach the skin barrier for the purpose of delivering larger molecules and more dose volume. Electroporation is one method typically used to permeabilize a membrane transiently by the application of a single or multiple short electric pulses. This method has been used extensively to permeabilize cells for the purpose of delivering molecules into cells. The application to transdermal delivery, however, is a more recent area of research. Our eventual research goal was to enhance transdermal vaccine delivery by using nanoparticles and an applied voltage pulse to electroporate the skin, followed by interlayer diffusion of the drug-laden nanopatiicles. The approach to developing this delivery method began with initial modeling of the electric fields and their time evolution in each of various layers of the skin. Until very recently, research regarding electroporation of the skin has relied almost exclusively on standard experimental methods without the valuable contribution of an electrostatic-field model upon which to base the experimental work. This analysis assisted us in the selection among the many variables associated with transdermal drug delivery via electroporation: pulse application and parameters, electrode design and placement. Electroporation protocols were explored for the purpose of efficiently and effectively propelling the charged drug-encased nanoparticles in such a way as to enhance movement through the skin while also targeting a specific skin layer. A basic delivery method and parameters were developed to achieve our eventual goal, and the model was tested experimentally with micron particles for validation.
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Wells, Aaron M. "The Effects of Low Frequency Ultrasound in Transdermal Drug Delivery". BYU ScholarsArchive, 2010. https://scholarsarchive.byu.edu/etd/2560.
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Objective: Determine if varying ultrasound frequency affects the delivery of 10% hydrocortisone concentrations during phonophoresis. Utilize intramuscular microdialysis probe for drug collection, thus improving the experimental model. Methods: Thirty one (10 in groups 1 and 2, 11 in group 3) healthy subjects participated in this study. Interventions: Subjects were randomly assigned to one of three treatment groups receiving 10 minute ultrasound treatments applied to a standardized area of the gastrocnemius muscle of the right leg. The ultrasound was performed over the treated area using a 10% hydrocortisone compound mixed with standard ultrasound gel. The contralateral limb served as the control (no mixed compound or treatment) for all groups. Group one received sham ultrasound. Medicated gel was placed on the treatment site, the sound head moved, but no ultrasound was applied. Group two received 45 KHz at .056 w/cm2. Group three received 1 MHz at 1.0 w/cm2 at a 50 % duty cycle. Results: There was no difference in cortisol concentration change during treatment between the three treatment groups on the treated limbs (sham = 1.1 ±7.5 ng/ml, 45 KHz = 1.1 ± 1.5 ng/ml, 1 MHz = 4.1 ± 7.8 ng/ml; F2,22 = .34, P = .72) or control limbs (sham = 1.65 ± 6.6 ng/ml, 45 KHz = -1.3 ± 2.7 ng/ml, 1 MHz = 0.37 ± 8.1 ng/ml; F2,22 = .67, P = .546). No difference was found in cortisol concentration change during treatment between the treatment limbs and the control limbs (treatment = 2.1 ± 6.2 ng/ml, control = 0.20 ± 5.9 ng/ml; F1,22 = .9, P = .35). The following factors were found to influence cortisol concentrations levels in dialysate collected during treatment: depth of muscle in the treatment limbs (F1,22 = 6.4, P = .02), microdialysis probe depth in the control limbs (F1,22 = 4.1, P = .05), and pre treatment cortisol level in the control limbs (F1,22 = 10.1, P = .004. Conclusions: There was no evidence altering ultrasound frequency from 45 KHz to 1 MHZ enhanced the delivery of 10% hydrocortisone to treatment tissues under these experimental conditions.
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Chu, Leonard Yi. "Dissolving microneedles for cutaneous drug and vaccine delivery". Diss., Georgia Institute of Technology, 2009. http://hdl.handle.net/1853/37177.
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Currently, biopharmaceuticals including vaccines, proteins, and DNA are delivered almost exclusively through the parenteral route using hypodermic needles. However, injection by hypodermic needles generates pain and causes bleeding. Disposal of these needles also produces biohazardous sharp waste. An alternative delivery tool called microneedles may solve these issues.
Microneedles are micron-size needles that deliver drugs or biopharmaceuticals into skin by creating tiny channels in the skin. This thesis focuses on dissolving microneedles in which the needle tips dissolve and release the encapsulated drug or vaccine upon insertion. The project aimed to (i) design and optimize dissolving microneedles for efficient drug and vaccine delivery to the skin, (ii) maintain vaccine stability over long-term storage, and (iii) immunize animals using vaccine encapsulated microneedles. The results showed that influenza vaccine encapsulated in microneedles was more thermally stable than unprocessed vaccine solution over prolonged periods of storage time. In addition, mice immunized with microneedles containing influenza vaccine offered full protection against lethal influenza virus infection.
As a result, we envision the newly developed dissolving microneedle system can be a safe, patient compliant, easy to-use and self-administered method for rapid drug and vaccine delivery to the skin.
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Chen, Tao. "CNT MEMBRANE PLATFORMS FOR TRANSDERMAL DRUG DELIVERY AND APTAMER MODULATED TRANSPORT". UKnowledge, 2014. http://uknowledge.uky.edu/cme_etds/34.
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CNT membrane platforms are biomimetic polymeric membranes imbedded with carbon nanotubes which show fast fluid flow, electric conductivity, and the ability to be grafted with chemistry. A novel micro-dialysis probe nicotine concentration sampling technique was proposed and proved in vitro, which could greatly improve the efficiency and accuracy of future animal transdermal studies. To enhance the scope of transdermal drug delivery which was limited to passive diffusion of small, potent lipophilic drugs, a wire mesh lateral electroporation design was also proposed which could periodically disrupt the skin barrier and enhance drug flux.
It was shown that AMP binding aptamer at the tip of carbon nanotubes may act as gatekeepers and regulate ionic transport through CNT membrane. Multiple cycle gating of ionic transport upon AMP binding/unbinding which changes the aptamer conformation was displayed. This CNT membrane-aptamer system closely mimics how protein ion channels modulate ion flow by responding to stimuli, which may have significant impact on active membrane transport.
Finally an enhanced electroosmosis concept by “ratchet” functionalization at both ends of carbon nanotubes in was discussed. Direct observation of water transport by electroosmosis was made possible through enhanced flow in vertically aligned high flux CNT membranes.
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Seto, Jennifer Elizabeth. "Experimental strategies for investigating passive and ultrasound-enhanced transdermal drug delivery". Thesis, Massachusetts Institute of Technology, 2011. http://hdl.handle.net/1721.1/65765.
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Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 2011.Cataloged from PDF version of thesis.
Includes bibliographical references (p. 159-167).
Transdermal drug delivery offers many advantages over traditional drug delivery methods. However, the natural resistance of the skin to drug permeation represents a major challenge that transdermal drug delivery needs to overcome in a safe and reversible manner. One method for enhancing transdermal drug delivery involves the application of ultrasound (US) to skin to physically overcome the skin's barrier properties. To advance this method, the focus of this thesis has been to develop novel experimental strategies and data analyses that can be utilized in in vitro investigations of passive and US-enhanced transdermal drug delivery. US treatment is often combined with a chemical enhancer such as the surfactant sodium lauryl sulfate (SLS). The simultaneous application of US and SLS (referred to as US/SLS) to skin exhibits synergism in enhancing transdermal drug delivery and has been utilized in clinical settings. In order to study the delivery of therapeutic macromolecules into US/SLS-treated skin, e.g. vaccine delivery to the Langerhans cells or drug delivery to the blood capillaries near the epidermis-dermis junction, it would be desirable to conduct in vitro US/SLS-enhanced transdermal diffusion experiments using split-thickness skin (STS) models, in which much of the dermis is removed in order to simulate the in vivo transdermal diffusion to the desired skin component. Therefore, STS was evaluated as an alternative to the well-established US/SLStreated full-thickness skin (FTS) model for the delivery of hydrophilic permeants. The skin permeabilities and the aqueous pore radii of US/SLS-treated pig FTS, 700-pm-thick pig STS, human FTS, 700-pm-thick human STS, and 250-pm-thick human STS were compared over a range of skin electrical resistivity values. The US/SLS-treated pig skin models were found to exhibit similar permeabilities and pore radii, but the human skin models did not. Furthermore, the US/SLS-enhanced delivery of gold nanoparticles and quantum dots (two model hydrophilic macromolecules) was found to be greater through pig STS than through pig FTS, due to the presence of less dermis that acts as an artificial barrier to macromolecules. In spite of greater variability in correlations between STS permeability and resistivity, the results strongly suggest the use of 700-pm-thick pig STS to investigate the in vitro US/SLS-enhanced delivery of hydrophilic macromolecules. After the validation of the pig STS for US/SLS studies, this skin model was used to study the transdermal delivery of nanoparticles. While nanoparticles have potential as transdermal drug carriers, many studies have shown that nanoparticle skin penetration is limited. Therefore, the US/SLS treatment was evaluated as a skin pre-treatment method for enhancing the passive transdermal delivery of nanoparticles. Quantitative and qualitative methods (elemental analysis
(cont.) and confocal microscopy, respectively) were utilized to compare the delivery of 10-nm and 20- nm cationic, neutral, and anionic quantum dots into US/SLS-treated and untreated pig STS. The findings include: (a) ~0.01% of the quantum dots penetrated the dermis of untreated skin (which was quantified for the first time), (b) the quantum dots fully permeated US/SLS-treated skin, (c) the two cationic quantum dots studied exhibited different extents of skin penetration and dermal clearance, and (d) the quantum dot skin penetration is heterogeneous (which was determined using a novel application of confocal microscopy). Routes of nanoparticle skin penetration are discussed, as well as the application of the methods described herein to address conflicting literature reports on nanoparticle skin penetration in the context of nanoparticle skin toxicity. US/SLS treatment is concluded to significantly enhance quantum dot transdermal penetration by 500 - 1300%. The findings suggest that an optimum surface charge exists for nanoparticle skin penetration, and motivate the application of nanoparticle carriers to US/SLS-treated skin for enhanced transdermal drug delivery. The final investigation of this thesis focused on chemical penetration enhancers, which are used to enhance drug delivery through several biological membranes, particularly the stratum corneum of the skin. However, the fundamental mechanisms that govern the interactions between penetration enhancers and membranes are not fully understood. Therefore, the goal of this work was to identify naturally fluorescent penetration enhancers (FPEs) in order to utilize well-established fluorescence techniques to directly study the behavior of FPEs within the skin. In this study, 12 FPE candidates were selected and ranked according to their potency as skin penetration enhancers. The best FPEs found compared well to SLS, a well-known potent skin penetration enhancer. Based on the ranking of the FPEs, FPE design principles are presented. In addition, to illustrate the novel, direct, and non-invasive visualization of the behavior of FPEs within skin, three case studies involving the use of two-photon fluorescence microscopy are presented, including visualizing glycerol-mitigated and US-enhanced FPE skin penetration. Previous two-photon fluorescence microscopy studies have indirectly visualized the effect of penetration enhancers on skin by using a fluorescent permeant to probe the transdermal pathways of the penetration enhancer. These effects can now be directly visualized and investigated using FPEs. The combination of FPEs with fluorescence techniques represents a useful new approach for elucidating the mechanisms involved in penetration enhancement and membrane irritation, and for improving structure-activity relationships for penetration enhancers. The new physical insights obtained using FPEs will aid in designing effective penetration enhancers for drug delivery applications, including penetration enhancers to be combined with US for synergistically enhancing transdermal drug delivery. The experimental strategies presented in this thesis pave the way for investigations in several transdermal fields, including evaluating nanoparticle skin toxicity, designing nanoparticle drug delivery carriers, evaluating ultrasound-assisted transdermal vaccination, elucidating mechanisms of chemical penetration enhancer-induced skin irritation, designing topical formulations with penetration enhancers, and elucidating mechanisms of ultrasound and penetration enhancer synergism in enhancing skin permeability.
by Jennifer Elizabeth Seto.
Ph.D.