Thesis (Ph. D.)--School of Chemical Engineering, Georgia Institute of Technology, 2004. Directed by Mark R. Prausnitz. / Vita. Includes bibliographical references (leaves 151-158).

Thesis (Ph. D.)--Georgia State University, 2007. / Title from thesis title screen. Author's name from thesis title screen. Jerry C. Smith, committee chair; Kathryn Grant, Stuart Allison, committee members. Electronic text (148 p. : ill. (some col.)) : digital PDF file. Description based on contents viewed October 5, 2007. Includes bibliographical references (p. 124-148).

The current world-wide interest in transdermal drug delivery makes the prospect of valid in vitro diffusion cell methodology highly attractive. A new laboratory diffusion cell has been designed and constructed based on theoretical principles and practical permeation reports surveyed in recent literature, and has been applied to the monitoring of betamethasone 17-valerate permeation. The cell performance has been validated with respect to hydrodynamic mixing efficiency and temperature of the receptor phase. The steady-state permeation of this corticosteroid has been monitored through various synthetic and animal membranes in order to select the most appropriate media for in vitro study. The permeation of betamethasone 17-valerate has been monitored from various types of commercial and extemporaneously prepared semisolid topical formulation (cream, lotion, ointment and scalp application), through silicone membrane, human and weanling pig stratum corneum, and full thickness hairless mouse skin, and these in vitro results have been compared to data from in vivo blanching assays, using the same formulations, in an attempt to correlate the findings. This experimental methodology has necessitated the development of ancillary analytical techniques. A column-switching high-performance liquid chromatographic method has been developed for the rapid on-line clean-up and analysis of betamethasone 17-valerate contained in the various topical formulations, which minimizes sample handling and extraction procedures. The method has been modified for the analysis of this corticosteroid in the isopropyl myristate receptor phase used in the in vitro permeation experiments, and scintillation counting of tritium-labelled water has been used to verify the integrity of the animal membranes. The comparison of in vitro permeation and in vivo blanching results indicate good correlation of the data in certain instances. The closest correlations have been observed when the human stratum corneum has been used in vitro and these results are compared to data from the occluded mode of the blanching assay. The results of the porcine and murine media have also correlated with the human in vivo data, whereas the silicone membrane appears applicable only in certain in vitro experiments. The results indicate that valid, comparative percutaneous absorption data may be obtained in vitro by using a well designed, validated diffusion cell system.

The rapidly growing interest in the potential use of topical drug delivery formulations has resulted in increased use of the skin as a vital port for drug delivery. Extensive research has been conducted in designing vehicles capable of delivering a desired amount of drug to a specific site, to produce the desired pharmacological response. Rooperol tetra-acetate is a lipophilic, cytotoxic drug with the potential for use in the treatment of solar keratosis. For effective pharmacological action, delivery of the drug to the epidermal/dermal junction of the skin is required. A study of the topical penetration properties of rooperol tetra-acetate from different topical bases, each possessing different physico-chemical properties, was performed. The assessment involved a comparison of the diffusion properties under occlusive and non occlusive conditions when the drug was formulated into a gel, Cetomacrogol Cream B.P. (oil-inwater), Simple Ointment B.P. and an extemporaneously prepared water-in-oil topical cream. The in vitro experiments were conducted using polydimethylsiloxane and rat membrane mounted in a Franz diffusion cell. The topical permeation kinetics of rooperol tetra-acetate were determined by exploring the release characteristics of the active ingredient from the vehicles formulated and the permeability properties of the drug through the membranes employed. Further studies involved investigating the utilization of supersaturated systems intended to increase the thermodynamic activity of the drug when formulated into a propylene glycol/water vehicle (with and without polymer). To measure the release of rooperol tetra-acetate into the skin from a topical base it was necessary to, firstly, develop a suitable quantitative method for the analysis of the active drug in the aqueous receptor phase of in vitro diffusion cells. The second stage of product development was the design of an effective delivery system to facilitate the release of the diffusant from its base. A high performance liquid chromatographic method was utilized for the identification and quantification of the active drug. As validation is an important aspect in the development and subsequent utilization of an analytical procedure, the developed HPLC technique was validated by determining the precision, accuracy, range, limit of quantitation and sensitivity of the system. Lastly, the stability of rooperol tetra-acetate at elevated temperatures was assessed and a stability profile of the drug was generated for the three-month period of analysis. The results obtained following chromatographic analysis of the receptor phase sampled during the diffusion experiments indicate that the gel and oil-in-water formulations most effectively promoted the diffusion of rooperol tetra-acetate across polydimethylsiloxane membrane. The water-in-oil system exhibited lower flux rates and the ointment showed the least drug release. Occlusion of the topical vehicle increased the diffusitivity of the permeant from all formulations analysed. The permeation assessment results of the supersaturated systems showed enhanced diffusion of rooperol tetra-acetate across polydimethylsiloxane and rat membrane. The high thermodynamic activity existing in supersaturated systems most effectively increased the driving force for drug diffusion resulting in enhanced percutaneous penetration of rooperol tetra-acetate beyond the release and transport limitations of saturated solutions. These results provide the basis on which an effective topical drug delivery vehicle may be designed for this new drug entity.

Chemical exposure of the skin has become a route of entry of some chemicals into the body and has come under major review in recent times. This research aims to develop a method of estimating skin exposure that is both reliable and non-prohibitive in cost. This involved the design and testing of skin patches adaptable for monitoring skin exposure to chemicals using several different types of absorbents which could be easily worn against skin. The final design of the patch used either activated charcoal or tenax as the absorbing medium. The patches were then desorbed with a solvent in order to analyse the chemicals. The results of the study showed that many skin exposures do not have a direct relationship with inhalation exposures, which is important because currently there are no estimates of the levels of skin exposures that may have potential long term health effects. The patch has proved successful for detecting the presence and determining the amount of chemicals that come in contact with the skin. Charcoal patches have the widest application, but are not suitable for all situations and tenax should be used on these occasions. / Doctor of Philosophy (PhD)

Thesis (Ph.D.)--Bioengineering program, Georgia Institute of Technology, 2008. / Committee Chair: Dr. Mark R. Prausnitz; Committee Co-Chair: Dr. Mark Feinberg; Committee Member: Dr. Mark Allen; Committee Member: Dr. Niren Murthy; Committee Member: Dr. Peter Hesketh; Committee Member: Dr. Robert Swerlick

Thesis (Ph. D.)--University of Washington, 2000. / Vita. Includes bibliographical references (leaves 250-284).

Orientadores: Daniele Ribeiro de Araujo, Eneida de Paula / Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Biologia / Made available in DSpace on 2018-08-19T03:33:56Z (GMT). No. of bitstreams: 1 Stoco_SheilaMaria_M.pdf: 3477145 bytes, checksum: 52055c23ee448699937dcc50fc0739fc (MD5) Previous issue date: 2011 / Resumo: Durante muito tempo, acreditou-se que a função primordial da pele era comportar-se como barreira a agentes químicos, físicos e microbiológicos. Hoje, entretanto, esta concepção mudou e verifica-se que a pele apresenta-se como uma estratégia para a administração cutânea de fármacos, possibilitando a utilização de formas farmacêuticas auto-administráveis, o que facilita a adesão ao tratamento quando se necessita de administrações repetidas. A ropivacaína (RVC), objeto desse estudo, é um anestésico local que além de induzir menor toxicidade ao sistema nervoso central e cardiovascular, não apresenta inconvenientes quanto aos efeitos adversos como metemoglobinemia e potencial alergênico causados pela benzocaína e lidocaína. Dessa forma, este trabalho teve por objetivo desenvolver formulações contendo o anestésico local RVC para uso tópico, uma vez que não há forma comercial disponível. Sendo assim, a RVC foi associada a diferentes promotores de absorção ou a carreadores como nanopartículas de alginato-quitosana. Fatores como baixo potencial tóxico, alta permeabilidade através da pele, rápido início de ação e efeito prolongado do bloqueio anestésico foram avaliados para possível aplicação clínica. Os resultados de permeação in vitro mostraram que as formulações de RVC com promotores de absorção (mentol, polietilenoglicol-PEG 600, polietilenoglicol-PEG 400 e PEG 600 associado a Span® 20) apresentaram rápido início de ação. A duração do bloqueio sensorial (tail flick) induzido por essas formulações foi significativo, com tempo de analgesia superior a 400 minutos, o que reflete um período desejável e satisfatório para aplicação tópica. No entanto, em termos de potencial citotóxico, as formulações com PEG 600 e PEG 600 associado a Span® 20 evidenciaram viabilidade celular inferior a 50 % tanto em cultura de fibroblastos quanto em cultura celular de melanoma. Esses dados de citoxicidade mostram potencial irritativo para a pele e podendo inviabilizar essas formulações em termos de aplicação na prática clínica. A formulação com mentol não foi avaliada em termos de citotoxicidade em decorrência da insolubilidade do mentol nos meios de cultura DMEM (fibroblastos) e RPMI 1640 (células de melanoma). A RVC (2%) encapsulada em nanopartículas de alginato-quitosana mostrou o melhor perfil de permeação dentre todas as formulações desenvolvidas neste trabalho tanto em relação à velocidade de permeação e tempo para início de ação. Com referência ao potencial tóxico, a RVC 2% encapsulada em nanopartículas apresentou valores de viabilidade celular que assinalam citotoxicidade inferior a 50% tanto em fibroblastos quanto em células de melanoma Esses dados indicam baixo potencial irritativo na pele e possibilidade de aplicação clínica. Além disso, a avaliação farmacológica mostrou que o tempo de analgesia foi superior a 600 minutos, o qual confirma a efetividade anestésica da formulação desenvolvida para anestesia tópica. Dessa forma, os resultados demonstram que a incorporaçao de RVC em nanopartículas de alginato-quitosana apresenta viabilidade para aplicação clínica devido aos excelentes resultados observados, os quais evidenciam boa penetração através da pele, rápido inicio de ação, toxicidade dérmica reduzida e tempo de analgesia prolongado / Abstract: For a long time, the main function of the skin was acting as a barrier to chemical, physical and microbiological agents. However, nowadays, this concept has changed and the skin is presented as an important strategy as route of administration for several drugs, allowing the use of self-administered dosage forms, which enhances the compliance to the treatment, specially when frequent administrations are necessay. Ropivacaine (RVC), object of this study, is a local anesthetic able to induces less toxicity effects to the cardiovascular and to the central nervous system without inducing adverse effects such as methemoglobinemia neither allergenic potential similar to those of benzocaine and lidocaine. Thus, this work aimed to develop local anesthetic formulations containing the RVC, since there is no topical formulation commercially available for this drug. Therefore, RVC was associated with different permeation enhancers or nanocarriers such as alginate-chitosan nanoparticles. Factors such as low toxic potential, high permeability across the skin, fast onset of action and prolonged effect of anesthesia were evaluated for possible clinical application. Results from in vitro permeation showed that RVC formulations with absorption enhancers (menthol, polyethylene glycol-PEG 400, PEG 600 and PEG 600 associated with Span® 20) showed fast onset of action. The duration of sensory block (tail flick) induced by these formulations was significant, with a time of analgesia than 400 minutes, a period which reflects desirable and suitable for topical application. However, in terms of cytotoxic potential, the formulations with PEG 600 and PEG 600 associated with Span® 20 showed cell viability below 50% both in culture of fibroblasts and melanoma cells. These data show cytotoxicity to skin irritant and can derail these formulations in terms of application in clinical practice. The menthol formulation was not evaluated in terms of cytotoxicity due to the insolubility of menthol in the DMEM culture medium (fibroblasts) and RPMI 1640 (melanoma cells). RVC 2% encapsulated in alginate-chitosan nanocapsules showed the best permeation profile of all the formulations developed in this work in terms of permeation rate and time to onset of action. Regarding to the toxic potential, RVC 2% encapsulated in nanoparticles showed values of cell viability lower than 50% cytotoxicity in melanoma cells and fibroblasts cultures. These data indicate low toxic potential to the skin and possible advantages on clinical application. In addition, the tail-flick test showed that the duration of analgesia was greater than 600 minutes, which confirms the effectivity of this anesthetic formulation for topical anesthesia. Our results demonstrated that RVC encapsulated in alginate-chitosan nanoparticles presented potential for clinical application due to the excellent results regarding to penetration through the skin, fast onset of action, reduced dermal toxicity and prolonged duration of analgesia / Mestrado / Bioquimica / Mestre em Biologia Funcional e Molecular

In the present study, propylene glycol monostearate (PGM), ethoxylated stearyl alcohol (ESA) and combination thereof have been investigated for their film-forming potential. The wettability, strength, and integrity of the films were evaluated by measuring the contact angles and modulus of elasticity. The films of mixed composition had smaller contact angles than the films of either component. The modulus of elasticity of all films tested was in the range of 0.19 - 0.40 Kg/cm2. A series of experiments were conducted in vitro to study the effect of changes in film composition, drug concentration and rate of agitation on cortisol release. Films of varying compositions containing 10 to 20% w/w ESA with corresponding decrease in PGM concentration with 4% w/w cortisol were found to release from 15 to 90% of cortisol during a 12 hour period. Unidirectional drug release from all film matrices was found to follow first-order kinetic profile over the first five hours of drug release. The examination of Q versus t½ plots (granular matrix) revealed linearity for the first five hours of drug release but curvilinear effect beyond. First-order release rate constant was found to increase linearly with rate of agitation.

This research utilizing full thickness human abdominal skin was designed to assess the in vitro percutaneous penetration of benzocaine by 1-dodecylazacycloheptan-2-one (Azone) , dimethylsulfoxide (DMSO) and 2-pyrrolidone (2-P) under conditions of constant thermodynamic activity in the vehicle. The solubilities of benzocaine in Azone and 80/20, 60/40 and 40/60 V/V DMSO/water systems were found to be 254.17, 533.00, 68.60 and 2.51 mg/ml respectively. All three adjuvants demonstrated a significant but concentration- dependent enhancement of benzocaine penetration. On the basis of comparative analysis of the steady-state fluxes, Azone was most effective at the level of 5% V/V when drug concentration was twice the saturation solubility _jn the 20/80 PG/water gel. At higher Azone levels, any penetration enhancement effects were strongly negated by a corresponding decrease in skin/vehicle partitioning. Azone appeared to enhance penetration of benzocaine molecules by directly reducing the barrier function of the stratum corneum. DMSO-induced enhancement of benzocaine penetration was observed over 40/80% V/V DMSO. Pretreatment studies strongly suggested that enhancement by DMSO is due to a significant but temporary effect on the epidermal barrier. The moderate enhancement of benzocaine penetration shown by 80% 2-P in water could be due to a decrease in diffusional resistance of stratum corneum brought on by a slow interaction between the stratum corneum and 2-P.