Chen Xiao. / "April 2003." / Thesis (Ph.D.)--Chinese University of Hong Kong, 2003. / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Mode of access: World Wide Web.

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A completely automatic continuous flow dissolution procedure was developed and tested. Pertinent dissolution conditions were investigated and chosen to study the dissolution characteristics of seven brands of phenylbutazone tablets. A pumping system enabled the simulated digestive fluid to flow from the dissolution vessel into the flow cell of a recording spectrophotometer for a continuous recording of the drug concentration in the dissolution medium, which was gradually changed from an acidic medium to a basic one. From the "in vitrott” data obtained by this test procedure, a T₅₀% value of 120 minutes was chosen as a limit of acceptance for the test products. The "in vivo" characteristics of six of the brands were compared with those observed for a pharmaceutically acceptable product. Of the seven test products, only four were acceptable on the basis of both the "in vitro" and the "in vivo" data. Correlation of the "in vitro" and the "in vivo" data resulted in "least squares" lines with negative slopes. / Pharmaceutical Sciences, Faculty of / Graduate

Thesis (Ph.D.)--University of Wollongong, 2005. / Typescript. Includes bibliographical references: leaf 239-252.

Chitin Microparticles (CMPs, 1-10um), a special form of the ubiquitous and nontoxic polysaccharide Chitin (GlcNAc), is capable of inducing a switch in macrophages from the wound-healing M2 phenotype to the classically activated pro-inflammatory M1 phenotype; which has therapeutic implications in allergy and cancer. We hypothesized that TLR2 forms a complex with CMPs and Chitin-Binding Proteins (CBPs) at the surface of peritoneal macrophages and remains with that complex after internalization to initiate downstream signaling events, leading to the production of the M1 cytokine, TNFalpha. Our results from experiments performed in RAW 264.7 cells show that TLR2 and TLR1, but not TLR6, are associated with the CMP binding fraction, and that both TLR1 and TLR2 might be important for M1 activation as a result of CMP phagocytosis. This project sheds light on CMP as a potential therapeutic agent and provides more evidence for a phagocytosis-dependent TLR2 signaling pathway. / Includes bibliography. / Thesis (M.S.)--Florida Atlantic University, 2016. / FAU Electronic Theses and Dissertations Collection

Phenylpropanolamine (PPA), a sympathomimetic amine, has been widely used over the past 40 years as a decongestant and, in much larger dosages, as an appetite suppressant. Considerable interest has recently been shown in this drug due to its increasing popularity as an over-the-counter anorectic agent. Much controversy exists concerning the unfavourable side-effects of PPA resulting from the higher doses required for appetite suppression and the potential of this drug for abuse. A literature search revealed a paucity of information concerning the determination of PPA in biological fluids and, most noticeably, on the pharmacokinetics of this drug. An original method for determining PPA in serum and urine using high performance liquid chromatography (HPLC) which has increased sensitivity over other published HPLC methods is presented here. The simplicity of the extraction from biological fluids and subsequent determination by HPLC, enables concentrations of PPA to be monitored after a single dose of the drug. This method is therefore readily applicable to bioavailability and pharmacokinetic studies. The dissolution profiles of 4 sustained-release formulations of PPA were determined in a modified USP rotating paddle apparatus and the samples analysed using HPLC. A mathematical equation was applied to these data which are expressed in terms of dissolution parameters. Oral test dosage forms and solutions of PPA were investigated in bioavailability trials using the developed HPLC method to analyse the urine and serum samples. Linear one body compartment kinetics were assumed and the WagnerNelson method used to transform in vivo serum data to absorption plots which were then fitted to the well known Weibull equation. In order to more appropriately characterize the kinetic processes of absorption, distribution and elimination, a more complex model was utilized which involved numerical integration of a series of differential equations. The data were fitted to these models using nonlinear regression techniques. The pharmacokinetics of PPA are shown to exhibit some evidence of nonlinearity. The absorption of the drug appears to be di scontinuous and PPA seems to favour a two body compartment model.

The study involves the investigation of the chemical composition of some marine organisms. This entails collecting the organism, extracting compounds from it and separation, characterization and identification of these compounds. Marine chemistry has been ignored by many scientists in the past and it is for this reason that these organisms have been investigated, with the aim of discovering their chemistry and also finding new compounds which might be of value in our society. Such value may be the medicinal benefit and/or the understanding of some toxicological effect of some species. This study was conducted on Codium extricatum, Palythoa natalensis, Zoanthus sansibaricus and Zoanthus durbanensis all of which were collected from reefs situated at the southern part of Durban in KwaZulu-Natal (KZN). Carpobrotus edulis was another organism that was used in this work. The plant normally occurs on sand dunes. This, however, was collected from the terrestrial environment within the premises of University of Natal (Durban). Sterols, i.e., compound l, 2 and compound 4 were obtained from both the Codium and Zoanthus genera. Zoanthus also gave compounds which are derivatives of genetic material and these include inosine nucleoside, adenine nucleoside and guanine nucleoside. Zoanthus further gave a compound which is aromatic in nature i.e., compound 5 and this belongs to a class of compounds known as the tyramines. Cinnamic acid was found from Carpobrotus edulis. The structures of all compounds were elucidated by conducting a number of experiments using spectroscopic methods. These included nuclear magnetic resonance spectroscopy (n.m.r), mass and infrared spectroscopy. / Thesis (M.Sc.)-University of Natal, Durban, 2000.

Lung cellular disposition and anti-inflammatory pharmacology of inhaled corticosteroids (ICSs) is complex, comprised of a cascade of aerosol deposition and dissolution, followed by cellular uptake for local pharmacological action. This project hypothesized that the kinetics of dissolution for certain ICS aerosols generated from inhaler products were kinetically rate-determined for their cellular uptake and local pharmacological action. A novel dissolution testing system was developed to determine the dissolution kinetics for the ICS aerosols. A total of 5 ICSs aerosols generated from 6 inhaler products were collected in 2.1-3.3 or 4.7-5.8 µm of aerodynamic diameters at 0.7-19.8 µg on filter membranes by impaction using the Andersen cascade impactor. The filter membrane was then placed on the donor side of the transwell insert, with its face down, and the ICS dissolution in the limited 40 µL of the donor fluid was monitored over time. The dissolution kinetics overall conformed to the rank order of the aqueous solubility, while also being affected by ICS aerosol’s mass, size, formulation and dosage forms. For the readily soluble triamcinolone acetonide (TA), the kinetics was first-order, reaching ≥89 % dissolution in 5 h. In contrast, for the least soluble fluticasone propionate (FP), the kinetics was zero-order, reaching only 3 % dissolution in 10 h. The project then developed an air-interface culture of human bronchial epithelial cell line, Calu-3. Well-differentiated monolayers were formed with sufficiently “tight” barrier for restrictive solute diffusion while their mucosal surface was maintained semi-dry with 39.7±12.1 µL of the mucosal lining fluid in the 4.5 cm2 transwells. These monolayers were transfected with reporter plasmid of pNFκB-Luc to assess in vitro anti-inflammation via repression of pro-inflammatory NFκB by direct FP or TA aerosol deposition. The FP aerosols at 0.9 µg successfully exhibited significant 35.7±6.3 % repression. Notably, however, an identical ~0.5 µg of FP and TA aerosols caused comparable 15.5±2.2 and 10.4±2.6 % repression, respectively, despite FP’s 10-fold greater “intrinsic” anti-inflammatory potency over TA, reported in the literature. This was attributed to FP’s slow dissolution resulting in only 4.7 % cellular uptake, compared to 32.6 % for the TA aerosols. Hence, the FP aerosols were shown to be rate-determined by dissolution on the lung cell surface, resulting in reduced anti-inflammatory actions, which was not the case for the readily soluble TA aerosols.

A absorção oral de um fármaco é fundamentalmente dependente da solubilidade aquosa e da permeabilidade gastrintestinal. Estes são fatores determinantes da biodisponibilidade e, consequentemente, da eficácia clínica de um medicamento. O Sistema de Classificação Biofarmacêutica (SCB), fundamentado nas propriedades de solubilidade e permeabilidade, consolidou-se nos últimos anos como ferramenta de auxílio na predição da biodisponibilidade de fármacos e tem sido empregado no desenvolvimento de formas farmacêuticas, contendo novos fármacos ou não, bem como no registro de medicamentos genéricos. O emprego do SCB para a isenção dos estudos de biodisponibilidade relativa/bioequivalência para algumas classes de fármacos vem sendo adotado e discutido, uma vez que os ensaios de biodisponibilidade apresentam limitações técnicas, econômicas e éticas. Assim, nos últimos anos, Agências Regulatórias têm utilizado o SCB para permitir que testes de dissolução in vitro sejam usados para estabelecer bioequivalência no caso de fármacos altamente solúveis e altamente permeáveis. O presente trabalho tem como objetivos revisar e reunir a literatura relacionada ao SCB com vistas a discutir a possibilidade de isenção dos estudos de biodisponibilidade relativa / bioequivalência para os medicamentos. Com esta proposta, foram pesquisadas as bases de dados Pubmed, Medline, Legislações Brasileiras indexadas no Visalegis e Legislação Internacional. Buscou-se a literatura pertinente publicada no período entre 1980 e o primeiro semestre de 2009. Desde a introdução do SCB existe uma relutância na aplicação das bioisenções para o registro de genéricos uma vez que as indústrias farmacêuticas não querem arriscar uma rejeição à sua solicitação nos países onde esse sistema ainda não é aceito, principalmente devido à falta de harmonização da legislação global. No Brasil, o SCB não é aceito para isenção de estudos de biodisponibilidade relativa/bioequivalência, pois os dados de permeabilidade são escassos na literatura científica para a grande maioria dos fármacos e ainda não existem protocolos validados para os estudos de permeabilidade. Além disto, o país ainda não possui um sistema de registro e controle de qualidade de princípios ativos e excipientes, ou seja, até o momento, não há regulamentação técnica para registro de matérias-primas de produtos farmacêuticos e cosméticos, ao contrário do que existe nos Estados Unidos. Para uma melhor aplicabilidade do SCB nas bioisenções as seguintes questões devem ser destacadas: continuidade do suporte científico para assegurar bioisenções para fármacos da Classe III; suporte científico para as metodologias de determinação de permeabilidade, com o objetivo de determinar a classificação biofarmacêutica dos fármacos; discutir a aplicação da Classificação Biofarmacêutica na fase de pesquisa e desenvolvimento de novas moléculas. / The oral absorption of a drug is fundamentally dependent on the aqueous solubility and gastrointestinal permeability. Those are determinant factors of the bioavailability of a drug and of the clinical efficacy of a pharmaceutical product. The Biopharmaceutics Classification System (BCS) is based on the properties of solubility and permeability and has been developed as a tool to predict bioavailability of drugs. BCS has also been used in the development of new dosage forms, including new molecules or not, as well as in the registration of generic drugs. The use of BCS as a \"waiver\" of in vivo bioavailability and bioequivalence studies for some drug classes has been discussed, since bioavailability studies represent technical, economical and ethical limitations. Therefore, in the last years the Regulatory Agencies have used BCS to allow that in vitro dissolution tests be used to establish bioequivalence in the case of highly soluble and highly permeable drugs. The present study has the objective to review the literature related to BCS, focusing in the discussion of biowaivers. The research was conducted using the following databases: Pubmed, Medline, Brazilian legislation indexed in the ANVISA website (VISALEGIS) and international legislation. The research period was between 1980 and the first semester of 2009. Since the introduction of BCS there is reluctance in the application of a biowaiver because the pharmaceutical companies do not want to risk a rejection of their biowaiver request in the countries where this system has not been established yet and also due to the lack of global legislation harmonization. In Brazil the BCS is not accepted for waiving bioequivalence studies, since permeability data are not very common in the scientific literature, for the great majority of drugs. Besides, the country does not have a regulatory framework for the registration of active pharmaceutical ingredients and raw materials, as it happens in the United States. In order to give a better applicability of BCS in biowaiver requests, the following questions must be pointed out: continuity of scientific support to assure biowaivers for Class III drugs; scientific support for permeability methodologies determination; discuss the applicability of BCS in early development phase studies for new molecular entities.

A Política de Saúde no Brasil, que inclui a Política Nacional de Medicamentos, a criação da Agência Nacional de Vigilância Sanitária (ANVISA), a promulgação da Lei de Medicamentos Genéricos, bem como a publicação das Resoluções que estabelecem os critérios técnicos para seu registro, revolucionou o mercado farmacêutico brasileiro na última década, introduzindo vários conceitos como Equivalência Farmacêutica e Terapêutica, Biodisponibilidade e Bioequivalência. Tais conceitos constituem as bases científicas para a implantação dos medicamentos genéricos, aliados à certificação de Boas Práticas de Fabricação e Controle de Qualidade (BPFs). Após cinco anos, os medicamentos genéricos representam cerca de 10% do mercado farmacêutico brasileiro em unidades com redução mínima de 35% no preço do genérico em relação ao medicamento de referência, em função de que o fabricante não necessita investir em estudos clínicos para comprovação da eficácia e segurança, garantidas pela comprovação da equivalência terapêutica com o medicamento de referência. O mercado brasileiro de genéricos é muito atrativo, pois 86% dos fármacos registrados no país não são patenteados e mais de 50% da população brasileira não tem acesso a medicamentos por problemas econômicos. Por outro lado, 70% do mercado farmacêutico brasileiro é composto por medicamentos similares, que somente em 2003 passaram a ter regulamentação técnica específica para comprovação da eficácia e segurança. Dessa forma, apesar de vasta literatura existente, justifica-se a sistematização dos aspectos técnicos e científicos que fundamentam a regulamentação técnica de biodisponibilidade relativa e bioequivalência com aplicabilidade na XXIII capacitação de recursos humanos em Biofarmacotécnica e na área regulatória no país. A análise da implantação e evolução das regulamentações técnicas, bem como, das conclusões dos estudos de bioequivalência e biodisponibilidade relativa avaliados pela ANVISA, torna-se ferramenta essencial para a compreensão dos aspectos regulatórios dos estudos de biodisponibilidade relativa e bioequivalência adotados. Considerando-se, ainda, a importância da racionalização de recursos e a necessidade de manutenção da qualidade dos medicamentos genéricos e similares no Brasil, com base na literatura científica mundial e no Banco de Dados da ANVISA, avaliou-se a viabilidade do emprego do Sistema de Classificação Biofarmacêutica (SCB), proposta elaborada por Amidon et al. (1995), para isenção da necessidade de realização de estudos de biodisponibilidade relativa/bioequivalência para o registro e pós-registro de medicamentos no Brasil. Assim sendo, concluiu-se que: a implantação de medicamentos genéricos no Brasil significou grande avanço técnico-científico para as áreas regulatória, acadêmica e industrial; a implementação e o aprimoramento da regulamentação técnica para medicamentos genéricos ocorreu devido à sua revisão contínua e publicação de quatro novas versões no período de 2.000 a 2.004; a experiência adquirida foi a base para a elaboração da regulamentação para medicamentos similares; a reprovação de estudos de bioequivalência de fármacos da Classe I do SCB é um alerta para que um estudo aprofundado das causas e da aplicação desse sistema na isenção de estudos in vivo visando o registro de medicamentos no Brasil seja realizado. / Health Policy in Brazil, which includes the National Policy on Medicines, the creation of the National Agency for Sanitary Vigilance (ANVISA), the promulgation of the Generic Medicines Law, as well as the publication of Resolutions establishing technical criteria for their registration, has revolutionized the Brazilian pharmaceutical market over the past decade introducing a number of concepts such as Pharmaceutical and Therapeutic Equivalence, Bioavailability and Bioequivalence. Such concepts have comprised the scientific basis for the implementation of generic medicines, in conjunction with the certification of Good Manufacturing and Quality Control Practices (BPFs). Five years on, generic medicines account for around 10% of the Brazilian pharmaceutical market in units, with a price cut in generics of at least 35% compared with the corresponding reference medicine, as a result of manufacturers not having to invest in clinical trials to prove efficacy and safety which are guaranteed by proof of therapeutic equivalence to the reference medicine. The Brazilian generics market is highly attractive since 86% of active principles registered in the country are not patented, and given that more than 50% of the Brazilian population does not have access to medicines for economic reasons. However, 70% of the Brazilian pharmaceutical market is made up of similar medicines, which only gained specific technical regulation for proof of efficacy and safety in 2003. Therefore, despite the vast body of literature available, a systematic approach for technical and scientific aspects underlying the technical regulation of relative bioavailability and bioequivalence is warranted, where this may also apply to both training of human resources in Biopharmaceutics and to the regulatory area in the country. Analysis of the XXVI implementation and evolution of technical regulations, along with the conclusions of ANVISA-assessed bioequivalence and relative bioavailability trials, have become an essential tool in understanding the regulatory aspects of the studies on relative bioavailability and bioequivalence adopted. Furthermore, given the continuing importance of rationalizing resources and the need to maintain the quality of generic medicines and similars in Brazil, the viability of employing the Biopharmaceutical Classification System (SCB) proposed by Amidon et al. (1995) dispensing with the need to run relative bioavailability/bioequivalence studies for the registration and post-registration of medicines in Brazil, has been assessed based on world scientific literature and ANVISAs database. Thus it was concluded that the implementation of generic medicines in Brazil has represented a major technical and scientific step forward for the regulatory, academic and industrial areas. Moreover, the implementation and refining of the technical regulations for generic medicines has taken place as a result of ongoing review and publication of four new versions between 2000 and 2004. The experience gained has provided the foundation in devising technical regulations for similar medicines. Finally, the rejection of bioequivalence studies for medicines from Class 1 SCB may serve as a warning that more in-depth studies into the root causes, and the application of this system in the absence of in-vivo studies for registration of medicines in Brazil, should be undertaken.