Дисертації з теми "Transdermal Drug Delivery System"
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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.
Повний текст джерелаPark, 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.
Повний текст джерелаRoxhed, 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.
Повний текст джерелаZaid, 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.
Повний текст джерелаKim, Yeu Chun. "Transdermal Drug Delivery Enhanced by Magainin Peptide." Diss., Georgia Institute of Technology, 2007. http://hdl.handle.net/1853/19738.
Повний текст джерелаEasley, Christina A. "Electrically-assisted enhancement of transdermal drug delivery using magainin peptides." Thesis, Georgia Institute of Technology, 2002. http://hdl.handle.net/1853/21419.
Повний текст джерелаZeng, 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.
Повний текст джерелаNarayanaswamy, Variankaval. "Characterization of phase transitions in transdermal drug delivery systems." Thesis, Georgia Institute of Technology, 1997. http://hdl.handle.net/1853/8645.
Повний текст джерелаChik, 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.
Повний текст джерелаOladiran, Gbolahan S. "Development and formulation of wax-based transdermal drug delivery systems." Thesis, Aston University, 2008. http://publications.aston.ac.uk/11060/.
Повний текст джерелаPywell, 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.
Повний текст джерелаVan, 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.
Повний текст джерелаKuduğ, 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.
Повний текст джерелаReynecke, 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.
Повний текст джерелаThesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2005.
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.
Повний текст джерелаSantos, 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.
Повний текст джерелаNos 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.
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/.
Повний текст джерелаTalbi, 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.
Повний текст джерелаPersonalized 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
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.
Повний текст джерелаCommittee 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.
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/.
Повний текст джерелаThe 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
Zucchini, Lorenzo. "Microaghi e Micropompe per Dispositivi TDDS." Bachelor's thesis, Alma Mater Studiorum - Università di Bologna, 2019. http://amslaurea.unibo.it/18627/.
Повний текст джерелаAndrews, Samantha Nacole. "Microdermabrasion for transdermal drug delivery." Diss., Georgia Institute of Technology, 2010. http://hdl.handle.net/1853/37150.
Повний текст джерелаMcAllister, Devin Vincent. "Microfabricated needles for transdermal drug delivery." Diss., Georgia Institute of Technology, 2000. http://hdl.handle.net/1853/11031.
Повний текст джерелаHenry, Sʹebastien. "Microfabricated device for transdermal drug delivery." Thesis, Georgia Institute of Technology, 1997. http://hdl.handle.net/1853/20707.
Повний текст джерелаSantos, 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.
Повний текст джерелаLong, 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.
Повний текст джерелаSharma, 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.
Повний текст джерелаLamb, 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.
Повний текст джерелаNyambi, 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.
Повний текст джерелаGupta, Jyoti. "Microneedles for transdermal drug delivery in human subjects." Diss., Georgia Institute of Technology, 2009. http://hdl.handle.net/1853/34770.
Повний текст джерелаDwaikat, 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.
Повний текст джерелаThakur, 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.
Повний текст джерелаAngel, 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.
Повний текст джерелаMitragotri, Samir. "Ultrasound-mediated transdermal drug delivery : mechanisms and applications." Thesis, Massachusetts Institute of Technology, 1996. http://hdl.handle.net/1721.1/11263.
Повний текст джерелаCourtenay, 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.
Повний текст джерелаCalcutt, Joshua J. "Modelling Transdermal Drug Delivery and Drug Transport in the Viable Skin." Thesis, Griffith University, 2021. http://hdl.handle.net/10072/404469.
Повний текст джерелаThesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Environment and Sc
Science, Environment, Engineering and Technology
Full Text
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.
Повний текст джерелаJohnson, Mark E. "Biophysical aspects of transdermal drug delivery and chemical enhancement." Thesis, Massachusetts Institute of Technology, 1996. http://hdl.handle.net/1721.1/10912.
Повний текст джерелаOlatunji, Ololade. "Modelling and optimization of microneedles for transdermal drug delivery." Thesis, Loughborough University, 2011. https://dspace.lboro.ac.uk/2134/9016.
Повний текст джерелаAl-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.
Повний текст джерелаJustin, Richard. "Chitosan-graphene nanocomposite microneedle arrays for transdermal drug delivery." Thesis, University of Sheffield, 2015. http://etheses.whiterose.ac.uk/9544/.
Повний текст джерелаTuan, 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.
Повний текст джерелаRytlewski, 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.
Повний текст джерелаSchoellhammer, 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.
Повний текст джерелаCataloged 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.
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.
Повний текст джерелаBrowning, Cassandra A. "Enhancing transdermal delivery of drug-infused particles using electrostatic pulse." Thesis, Boston University, 2013. https://hdl.handle.net/2144/12718.
Повний текст джерелаTransdermal 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.
Wells, Aaron M. "The Effects of Low Frequency Ultrasound in Transdermal Drug Delivery." BYU ScholarsArchive, 2010. https://scholarsarchive.byu.edu/etd/2560.
Повний текст джерелаChu, Leonard Yi. "Dissolving microneedles for cutaneous drug and vaccine delivery." Diss., Georgia Institute of Technology, 2009. http://hdl.handle.net/1853/37177.
Повний текст джерелаChen, Tao. "CNT MEMBRANE PLATFORMS FOR TRANSDERMAL DRUG DELIVERY AND APTAMER MODULATED TRANSPORT." UKnowledge, 2014. http://uknowledge.uky.edu/cme_etds/34.
Повний текст джерелаSeto, 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.
Повний текст джерелаCataloged 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.