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Aljayyoussi, Ghaith. "Dendrimer biopharmaceutics : toward active dendrimer-cannabinoid drugs." Thesis, Cardiff University, 2011. http://orca.cf.ac.uk/14220/.
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The ultimate aim of the work described in this thesis was to (1) utilise PAMAM dendrimers as a tool to achieve differential transport across the intestinal mucosa and the blood brain barrier, where these dendrimers can be used to achieve oral bioavailability but avoid BBB penetration and CNS access and (2) to create cannabinoid-dendrimer conjugates that are active in their own right and whose penetration to the brain is prevented but whose intestinal activity is afforded for the treatment of IBD. Overall, the work described in this thesis has promoted a strategy whereby an active polymer (dendrimer)-drug conjugate could be formed that is active in its own right and where the polymer can serve to provide differential biological barrier transport which with regard to cannabinoid pharmacology obviates adverse CNS effects. The work in this thesis describes the design and synthesis of novel and active cannabinoid structures that should have commercial interest. These novel compounds served to further elucidate SAR in amino alkyl indole cannabinoids. SAR findings have revealed a site on these cannabinoids that can be functionally altered without loss of pharmacological activity. Additionally, studies in this thesis have led to the development of a novel radiolabelling strategy for anionic polymers that offers a number of distinct advantages over other approaches. Ultimately, a novel stable Dendrimer-cannabinoid conjugate has been synthesised but to date has not shown biological activity in the models utilised in this work.
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Skinner, Michael Fredrick. "Biopharmaceutics and pharmacokinetics of the macrolide antibiotic Josamycin." Thesis, Rhodes University, 1992. http://hdl.handle.net/10962/d1003269.
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The investigations detailed herein have been conducted to address various aspects of the biopharmaceutics and pharmacokinetics of josamycin which to-date, have received little or no attention in the literature. Areas of investigation have included the selective determination of josamycin in serum and urine samples, the stability of josamycin in stored biological samples, intrinsic dissolution rates, solubility, acid and alkali stability and bioavailability and pharmacokinetics after dosing with a solution, powder and tablets. High performance liquid chromatography (HPLC) was used as the main analytical tool throughout these studies and proved to be highly versatile for the determination of josamycin in a number of different media. HPLC analysis afforded simple yet accurate determination of josamycin in samples from dissolution, solubility, tablet content and stability studies. Furthermore, the specificity afforded by HPLC was particularly useful for the separation of josamycin from degradation products formed in acid and alkali media. Since metabolites of josamycin are microbiologically active, microbiological assays do not determine the concentration solely of josamycin. An analytical method capable of the selective determination of josamycin in serum and urine samples is therefore required for the procurement of reliable bioavailability and pharmacokinetic data. HPLC affords this selectivity and a method for the selective determination of josamycin in serum and urine was successfully developed. The assay was simple yet precise, accurate and sensitive. Furthermore, it was well suited to the determination of josamycin in a large number of biological samples. Its success was largely due to the use of a solid phase extraction step using C₁₈ extraction columns, with a highly specific wash sequence followed by a phase separation step after elution from the extraction column. Chromatography was performed on a C₁₈ reversed-phase analytical column with UV detection of josamycin and internal standard at 231 nm and at 204 nm respectively using a programmable multi-wavelength detector. Only slight modification of the assay described should enable the selective determination of the metabolites of josamycin. This assay, therefore, lays the groundwork for future investigations into the pharmacokinetics of these metabolites. The re-usability of extraction columns was assessed in an attempt to reduce the cost of sample analysis. It was found that extraction columns could be used twice for the extraction of serum samples and up to four times for the extraction of urine samples. The difference between the re-usability of extraction columns for serum and urine samples was ascribed to various differences in the composition of the sample matrix. The stability of josamycin in stored serum and urine samples was also assessed.
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Walton, Carol Julie. "Stakeholder influences on the commercialisation and delivery of cell-based medicinal products." Thesis, University of Cambridge, 2013. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.648388.
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Lindenberg, Marc. "A biopharmaceutics classification scheme for the development of new drugs." Aachen Shaker, 2007. http://d-nb.info/987761897/04.
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Lindenberg, Marc. "A biopharmaceutics classification scheme for the development of new drugs /." Aachen : Shaker, 2008. http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&doc_number=016726181&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA.
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Faragalla, Jane Eliza. "Development of isoflavonoid-derived anti-prostatic cancer agents." Access electronically, 2005. http://www.library.uow.edu.au/adt-NWU/public/adt-NWU20060516.121728/index.html.
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Terespolsky, Susan Ann. "A study of the biopharmaceutics and pharmacokinetics of the macrolide antibiotic, erythromycin." Thesis, Rhodes University, 1992. http://hdl.handle.net/10962/d1003273.
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Erythromycin, a macrolide antibiotic isolated from Streptomyces erythreus, was first introduced into clinical medicine in 1952. It is active against most gram-positive bacteria, some gram-negative bacteria and is currently the agent of choice for Legionella pneumophila. Erythromycin is an acid-labile compound rapidly degrading in acidic solutions such as the acid environment of the stomach. As such, erythromycin absorption following oral administration of solid dosage forms is relatively poor. Accordingly there have been various approaches used to protect the drug against gastric inactivation. These precautions include enteric-coating of tablets, capsules or pellets of erythromycin base, the synthesis of acid stable 2' esters of erythromycin (ethylsuccinate and propionate) and salts of these esters (erythromycin estolate), and more recently, the synthesis of a range of new acid-stable, semi-synthetic macrolide antibiotics. The 2' esters are antimicrobially inactive or much less active than the parent compound and must be converted to the free erythromycin base in vivo in order to exhibit antibacterial activity. Intrinsic dissolution rates determined on raw material can provide extremely useful information relating to the gastrointestinal absorption of drugs from solid dosage forms. The large inter- and intrasubject variability associated with erythromycin base has, to date, mainly been attributed to gastric acid inactivation of the drug. However, changes in duodenal pH resulting in altered solubility and intrinsic dissolution rates may account for the observed variability. Thus, the intrinsic dissolution rates of erythromycin base at pH 6.0, 6.5, 7.0, 7.5 and 8.0 were compared in order to investigate the possible effects of pH changes which may occur in the duodenal contents, on the in vivo dissolution and subsequent absorption of this compound. The standard intrinsic dissolution rate test procedure employing a rotating disc of pure erythromycin base powder which only allows for dissolution from a constant surface area, was adapted and the drug quantitatively determined by reversed phase high performance liquid chromatography (HPLC) using ultraviolet detection. Results of intrinsic dissolution studies at both 22°C and 37°C indicate that the solubility, and therefore the rate of dissolution of erythromycin base is pH dependent, being more soluble at pH 6.0 than pH 8.0 (an approximate 800 times and 1000 times reduction in the amount dissolved after 30 minutes, at 22°C and 37°C respectively, when the pH of the medium was increased from 6 to 8). Although the stability of erythromycin and its ester derivatives in aqueous acidic solutions has been well documented, very little has been reported on the compound's stability in organic solvents. Methanol is recommended by official drug compendia (U.S.P. and B.P.) for use in erythromycin identification tests as well as in the sample preparation steps during assay procedures. Thus, the effect of methanol and acetonitrile, organic solvents of similar polarities and densities, on the stability of erythromycin base, erythromycin ethylsuccinate, propionyl erythromycin and erythromycin estolate at room temperature (22°C ± 0.5°C), using HPLC with electrochemical detection, was investigated. Erythromycin base is relatively stable in both methanol and acetonitrile, remaining intact for over 168 hours in acetonitrile and showing less than 5% degradation in methanol over the same period. Erythromycin ethylsuccinate in acetonitrile shows less than 5% degradation over 168 hours whereas in methanol, rapid hydrolysis occurs resulting in almost total conversion to base within 40 hours. Approximately 87% of erythromycin propionyl ester remained intact after 168 hours in acetonitrile whilst methanol caused rapid hydrolysis to erythromycin base (35% remaining after 28 hours). Erythromycin estolate appeared to be unstable in both acetonitrile and methanol. In acetonitrile, only 13% of the estolate remained intact after 168 hours, whereas in methanol, the reaction was much more rapid with 35% of the estolate remaining after 28 hours. The use of methanol as a solvent for erythromycin estolate reference standards is thus contraindicated. A number of conflicting reports on the half- life as well as the body compartment model that best describes erythromycin base serum concentration-time profiles (lBCM generally used to describe orally administered erythromycin, whilst a 2BCM has been used to describe erythromycin administered intravenously), appear in the literature. These differences may be largely attributed to the sampling period (between 6 and 12 hours) used in the repective studies. The objective of this study was to determine the body compartment model that best describes erythromycin base serum concentration-time curves by increasing the sampling time to 24 hours. In addition, the effect of chronic dosing of erythromycin on erythromycin pharmacokinetics, in the same group of subjects, was investigated. The single and multiple oral dose pharmacokinetics of erythromycin enteric coated base pellets within a gelatin capsule (250mg), were studied in 6 healthy, normal volunteers (19.5 ± 0.76 years, 71.5 ± 8.18 kg, 180.33 ± 5.99 cm). Furthermore, steady state concentrations were predicted using the pharmacokinetic parameters obtained from the single dose study, and compared with those obtained in the multiple dose study. Plasma concentrations were determined using a sensitive high-performance liquid chromatographic method with electrochemical detection. For the single dose study, after a tlag of 2.5 ± 0.71 hr, Cmax (1.12 ± 0.47 μ/ml) was reached at a tmax of 4.08 ± 0.93 hr post dose, with serum concentrations ranging from 0.31 - 1.62 μ/ml. The half-life was found to be 5.42 ± 1.31 hr. On multiple dosing (250mg six hourly), serum concentrations for the fifth, ninth and thirteenth dosing intervals ranged from 0.67 - 2.92 μ/ml, 1.69 - 3.65 μ/ml and 0.61 - 3.01 μ/ml, occurring at 3.75 ± 0.69 hr, 3.17 ± 1.03 hr and 3.17 ± 1.03 hr post dose with a Cmax of 1.89 ± 0.68 μ/ml, 2.35 ± 0.70 μ/ml and 1.94 ± 0.74 μ/ml, respectively. The area under the serum concentration- time curve for the single dose study (AUC₀₋∞) was 4.67 ± 0.88 hr.μ/ml, whilst the AUC₀₋τ. for the fifth, ninth and thirteenth dosing intervals of the multiple dose study were 5.77 ± 1.76 hr.μ/ml, 6.46 ± 1.33 hr.μ/ml and 5.97 ± 2.36 hr.μ/ml respectively, indicating an approximately 33% increase in AUC on chronic dosing of erythromycin. The observed increase in AUC may be a result of increased bioavailability or a decrease in clearance on chronic dosing.
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Lindenberg, Marc [Verfasser]. "A biopharmaceutics classification scheme for the development of new drugs / Marc Lindenberg." Aachen : Shaker, 2008. http://d-nb.info/116434238X/34.
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ARORA, DEEPIKA. "IN VITRO MODELS FOR INHALED CORTICOSTEROID (ICS) AEROSOLS: A STUDY OF THEIR BIOPHARMACEUTICS AND PHARMACOLOGY." VCU Scholars Compass, 2008. http://scholarscompass.vcu.edu/etd/1650.
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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.
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Arora, Deepika. "In vitro models for inhaled corticosteroid (ICS) aerosols : a study of their biopharmaceutics and pharmacology /." Not available unti 12/11/2013, 2008. http://hdl.handle.net/10156/2340.
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Filho, Pedro de Lima. "Estudos da biodisponibilidade e bioequivalência de medicamentos com alimentação: fundamentos e critérios de execução." Universidade de São Paulo, 2005. http://www.teses.usp.br/teses/disponiveis/9/9139/tde-09012018-115505/.
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A biodisponibilidade é definida pelos parâmetros de velocidade e extensão com que o fármaco atinge a circulação sistêmica a partir da forma farmacêutica, sendo uma propriedade não somente do fármaco, mas também da formulação, representando o desempenho in vivo da qualidade do medicamento. O medicamento genérico, para ser intercambiável com sua referência (geralmente o inovador registrado após comprovação de eficácia e segurança), deve ser considerado pelas autoridades regulatórias como seu equivalente terapêutico. A bioequivalência é o estudo comparativo das biodisponibilidades entre medicamentos, empregado para comprovação de equivalência terapêutica, baseada no princípio de que a similaridade dos perfis sanguíneos de concentração-tempo proporciona similares resultados quanto à eficácia e segurança. O presente trabalho compreendeu uma abordagem sobre os estudos de biodisponibilidade e bioequivalência com alimentação, com objetivo de sistematização dos fundamentos científicos e critérios normativos nacionais e internacionais, avaliação da necessidade e elaboração de diretrizes para condução destes estudos. Foi pesquisada a literatura científica sobre o tema, com ênfase nas publicações dos últimos dez anos, e também as diretrizes regulatórias nacionais e internacionais vigentes. Foram avaliados os efeitos do alimento na absorção gastrintestinal de fármacos, os fatores envolvidos na interação fármaco-alimento e os mecanismos físico-químicos e fisiológicos envolvidos. O alimento pode influenciar a absorção dos fármacos e promover aumento, retardo ou redução de absorção, devido a diferentes efeitos, por exemplo: prolongamento do tempo de esvaziamento gástrico, interação direta do fármaco com constituintes do alimento, aumento da viscosidade do conteúdo intestinal, alteração do pH, aumento do fluxo sanguíneo esplâncnico e interação com transportadores. A interação fármaco-alimento pode resultar em alterações farmacocinéticas e farmacodinâmicas. O efeito do alimento é mais significativo nas fases de absorção e metabolismo do fármaco, podendo resultar em perda de eficácia ou toxicidade. As interações fármaco-alimento são influenciadas pela natureza do alimento, constituição e quantidade da refeição, tempo entre alimentação e medicação e pela formulação. A refeição altamente gordurosa tem maior potencial de alteração da fisiologia gastrintestinal, principalmente aumentando o tempo de esvaziamento gástrico, o fluxo sanguíneo e a secreção biliar. Esses efeitos podem afetar significativamente a absorção de fármacos, sendo especialmente críticos para as formulações de liberação modificada. O efeito total do alimento na farmacocinética é resultante da interação de múltiplos efeitos relacionados ao fármaco, à formulação, à fisiologia gastrintestinal e à refeição. Devido à variabilidade e difícil previsibilidade dos efeitos do alimento sobre a velocidade e extensão de absorção dos fármacos, devem ser conduzidos estudos de efeito do alimento para novos fármacos e novas formulações. A pesquisa resultou na compilação das diretrizes para avaliação do efeito do alimento na biodisponibilidade, incluindo-se os desenhos dos estudos. É apresentado um esquema para avaliação da necessidade dos estudos de biodisponibilidade e bioequivalência, com base nas características do fármaco e nos tipos de formulações. As diretrizes para requerimento e condução dos estudos foram sistematizadas em uma proposta de guia para estudos de biodisponibilidade e bioequivalência com alimentação a ser empregado no caso de registro e alterações pós-registro para medicamentos novos, genéricos e similares no Brasil.Bioavailability is defined by rate and extension parameters with which the drug reaches the systemic circulation from its dosage form, being not only a property of such drug, but also of the formulation, representing the in vivo quality of the medicine. In order to be interchangeable with its reference drug (usually the innovative drug registered after efficacy and safety proof), the generic drug must be considered as its therapeutic equivalent. Bioequivalence is the comparative study between drugs\' bioavailabilities, used for the proving of therapeutic equivalence, based on the principle that the similarity between blood concentration-time profiles generates similar efficacy and safety results. This work is a discussion about the food-effect bioavailability and fed bioequivalence studies, aiming at systematizing the scientific fundaments and national and international regulatory criteria, necessity evaluation and elaboration of de guidelines for studies execution. Research was done on scientific literature on the subject, with emphasis on publications over the last ten years, and also on current regulatory guidelines. The effects of food on the gastrointestinal absorption of the drugs, the factors related to the food-drug interaction and the physical-chemical and physiological mechanisms involved were evaluated. Food may influence the drug absorption and cause drug absorption increase, delay or reduction due to different factors, for example: gastric emptying time increase, direct drug interaction with food constituents, intestinal content viscosity increase, pH alterations, spleen blood flow increase and transporter interaction. The food-drug interaction may cause pharmacokinectic and pharmacodynamics alterations. Food\'s effect is most significant during the absorption and metabolic phases of the drug and may result in efficacy loss or toxicity. The food-drug interaction is influenced by the nature of the food, meal constitution and quantity, feeding and medication interval time and formulation. A high-fat meal has greater gastrointestinal physiology alteration potential, especially increasing the gastric emptying time, the blood flow and bile secretion. These effects may significantly impact the drugs\' absorption being especially critical for the modified-release formulations. Toe total food effect on pharmacokinectic is the result of the interaction of multiple effects related to the drug, the formulation, the gastrointestinal physiology and the meal. Due to its variability and the difficulty to predict the effects of food on the rate and extension of drugs\' absorption effect studies must be carried out for new drugs and new formulations. The research resulted in the compilation of the guidelines for the evaluation of food effects on bioavailability, including the studies\' designs. A scheme is presented for the evaluation of the necessity of bioavailability and bioequivalence studies based on the drug\'s characteristics and the types of formulations. The guidelines for the requirement and conduction of the studies were systematized in a guide proposal for bioavailability and bioequivalence studies of medicines with feeding to be used in the case of registration, and post-registration changes for new, generic and similar drugs in Brazil.
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Magri, Agnes. "Extração e purificação do biofármaco antileucêmico L-asparaginase (ASNase) utilizando sistemas aquosos bifásicos com polímeros e líquidos iônicos /." Araraquara, 2019. http://hdl.handle.net/11449/181238.
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Orientador: Jorge Fernando Brandão PereiraBanca: Carlota de Oliveira Rangel Yagui
Banca: Marlus Chorilli
Banca: Ariela Veloso de Paula
Banca: Luis Henrique Souza Guimarães
Resumo: A L-asparaginase destaca-se como um importante biofármaco utilizado no tratamento de leucemia, além da sua utilização na indústria alimentícia. Seu alto custo de produção se deve principalmente às etapas de purificação, que correspondem em geral a mais de 70% do valor do produto final. Assim, novos processos de extração líquido-líquido, como a aplicação de Sistemas Aquosos Bifásicos (SABs), surgem como técnicas alternativas de extração/purificação mais econômica e biocompatível. Nesse sentido, este trabalho avaliou um processo alternativo para a purificação de baixa resolução da enzima L-asparaginase (ASNase) utilizando-se SABs com polímeros e sais ou líquidos iônicos (LIs). Inicialmente, foi realizado um estudo comparativo de diferentes metodologias de quantificação da atividade da ASNase comercial, a fim de compreender as interferências dos métodos em diferentes condições, e assim estabelecer um método de quantificação adequado para determinação da atividade de ASNase nos SABs. A seguir, a estabilidade da ASNase foi avaliada frente aos diferentes componentes de fases dos SABs. Dessa forma, LIs derivados de colinas e polímeros foram testados como solventes alternativos na biocatálise, e a fim de compreender o efeito do tamanho da cadeia do ânion dos LIs sob a estabilidade da enzima, foram testadas soluções aquosas contendo as colinas com os seguintes ânions: cloreto ([Ch]Cl); acetato ([Ch][Ac]); propanoato ([Ch][Pro]); butanoato ([Ch][But]) e hexanoato ([Ch][Hex]). O aumento... (Resumo completo, clicar acesso eletrônico abaixo)
Abstract: L-asparaginase (ASNase) is an important biopharmaceutical used in the treatment of leukemia, as well in industrial food processes. Its high production costs are mainly due to purification steps, in general, up to 70% of the final product value. Therefore, new liquid-liquid extraction processes, such as Aqueous Biphasic Systems (ABS), have appeared as more economical and biocompatible extraction/purification alternatives. In this work an alternative process for the purification of the enzyme L-asparaginase (ASNase) using ABS composed of polymers and salts or ionic liquids (ILs) was evaluated. In the first stage, a comparative study of different activity quantification methods of the commercial ASNase was carried out. This study intended to determine the interferences of the quantification methods and to establish the most adequate method for the quantification of ASNase activity after the extraction with different ABS. Further, the stability of the ASNase in the presence of different type and concentration of phase-forming agents, namely cholinium based-ILs ([Ch]+ -ILs) and polymers, was evaluated. Thus, in order to understand the effect of the increase of anion alkyl chain length of the ILs in the enzyme stability, aqueous solutions of [Ch]+ -ILs, with the following anions, were tested: chloride ([Ch]Cl), acetate ([Ch][Ac]), propanoate ([Ch][Pro]), butanoate ([Ch][But]) and hexanoate ([Ch][Hex]). The increase of the anion alkyl chain length had a negative effect on the enzymatic activity due to the affinity of these compounds to the protein structure. [Ch]Cl and [Ch][Ac] were selected as the best alternative solvents, because of their ASNase stability aptitude, as well enzymatic activity enhancing effect. The stability and activity of ASNase in aqueous solutions of polyethylene glycol... (Complete abstract click electronic access below)
Doutor
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Bueno, Marcia Martini. "Implantação, evolução, aspectos técnicos e perspectivas da regulamentação técnica de biodisponibilidade relativa e bioquivalência de medicamentos genéricos e similares no Brasil." Universidade de São Paulo, 2005. http://www.teses.usp.br/teses/disponiveis/9/9139/tde-02022009-101019/.
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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.
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Almeida, Nicholas Tadeu Vannuchi da Costa. "Triagem de moléculas inibitórias da peroxirredoxina II humana, visando o tratamento da leucemia linfoide aguda (LLA) /." São Vicente, 2017. http://hdl.handle.net/11449/149981.
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Orientador: Marcos Antônio de OliveiraCoorientador: Wagner Vilegas
Resumo: O Instituto Nacional do Câncer (INCA) estima que em 2016 sejam registrados cerca de 12.600 novos casos pediátricos de câncer, sendo que 25% devem ser representados pela leucemia linfoide aguda (LLA). Todos os quimioterápicos utilizados no tratamento da LLA levam a diversos efeitos colaterais como: mutagenicidade, teratogenicidade, efeitos citotóxicos e alergias, sendo premente a necessidade da descoberta de novas drogas com efeitos indesejados reduzidos ou ausentes. Já foi demonstrado que em células tumorais a expressão de peroxidases é aumentada de modo a manter níveis adequados para o crescimento e evitar a apoptose. Em mamíferos, a peroxidase denominada de peroxirredoxina II (PrxII) aparenta ter papel fundamental na progressão e manutenção das células tumorais e e estudos recentes indicam que esta enzima possui altos níveis de expressão em células neoplásicas ao passo que sua inibição é capaz de tornar células neoplásicas mais suscetíveis ao tratamento com radioterapia ou mesmo induzir a diferenciação celular das células tumorais. Foi descoberto que o diterpenóide natural, adenantina (Adn), é capaz de inibir de forma bastante eficaz o crescimento celular in vitro e in vivo de células de LLA atuando sobre PrxII. Entretanto, não se tem informações de seus efeitos na leucemia linfoide aguda. O projeto tem como objetivos avaliar efeitos inibitórios em PrxII humana de moléculas isoladas em projetos anteriores, incluindo aquelas similares a Adn, oriundas da biota brasileira e t... (Resumo completo, clicar acesso eletrônico abaixo)
Abstract: Not available
Mestre
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PROCÓPIO, José Valdilânio Virgulino. "Estudos de correlação in vitro-in vivo em formulações contendo fármacos de diferentes classes biofarmacêuticas." Universidade Federal de Pernambuco, 2015. https://repositorio.ufpe.br/handle/123456789/22228.
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FACEPE
Há vários relatos científicos de modificações in vitro, nas características de Insumos farmacêuticos ativos (IFAs) em formulações contendo celulose microcristalina (CMC), porém há escassez de estudos para avaliar sua influência in vivo. Este trabalho teve como objetivo avaliar a influência da celulose microcristalina de diferentes origens e tamanhos de partícula na estabilidade, cinética de liberação in vitro e correlacionar com estudos in vivo utilizando IFAs de diferentes classes biofarmacêuticas. Foram utilizados lotes de CMC de dois diferentes fabricantes (A e B), com diferentes tamanhos CMC101 e CMC102, três lotes dos IFAs sinvastatina (Sinv) e fluconazol (Fluc) e um lote do ibuprofeno (Ibup). Foram obtidos dezesseis lotes de comprimidos dos IFAs com as celuloses. As técnicas analíticas: difração de raio X, análise térmica, microscopia eletrônica de varredura, cromatografia líquida de alta eficiência e dissolução permitiram a caracterização dos IFAs, CMCs e comprimidos. Estudos de biodisponibilidade foram realizados utilizando coelhos Nova Zelandia como modelo, após avaliação e aprovação ética, Certificado n° 0308/11, e validação dos métodos bioanalíticos. As CMCs apresentaram diferenças nas características de degradação térmica, nas análises microscópicas e de cristalinidade em função da origem e/ou do tamanho de partícula. A Sinvastatina mostrou diferenças entre os lotes no comportamento de fusão, decomposição térmica e dissolução intrínseca. Os comprimidos contendo sinvastatina apresentaram liberação conforme o modelo matemático de El-Yazigi e houve diferenças nas características de estabilidade e dissolução em função do tipo de celulose utilizada na sua produção. Foi estabelecida correlação direta entre a quantidade liberada na dissolução e os dados de estabilidade térmica para todos os comprimidos contendo a Sinv com todas as CMCs, exceto para a CMC101B, que apresentou cristalinidade diferente das demais. O Fluconazol não apresentou diferenças significativas entre os lotes na dissolução, fusão e decomposição térmica. Os comprimidos contendo Fluc e CMC101 dos diferentes fabricantes apresentaram liberação conforme o modelo matemático de El-Yazigi, os perfis de dissolução em água foram semelhantes, no entanto diferiram in vivo, de modo que não foi estabelecida correlação in vitro/in vivo, sendo o modelo in vivo mais eficiente no sentido de detectar a diferença existente entre as formulações. O ibuprofeno apresentou perda de massa em uma única etapa na termogravimétria e através do DSC-fotovisual e pirólise acoplada a espectrometria de massa foi possível confirmar que ela ocorreu por vaporização. Os comprimidos contendo Ibuprofeno e CMC101 dos diferentes fabricantes não apresentaram diferenças entre os perfis de dissolução utilizando tampão fosfato pH 7,2. Utilizando água, como meio de dissolução, a liberação ocorreu conforme o modelo matemático de Higuchi havendo diferença na liberação em função da origem da CMC101 utilizada. Foi estabelecida correlação in vitro/in vivo utilizando água como meio de dissolução. Houve diferença na liberação e absorção do ibuprofeno, a partir dos comprimidos, em função da celulose microcristalina utilizada para sua produção. Esses resultados mostram a importância e necessidade de estudos mais amplos que os farmacopéicos, incluindo estudos de correlação in vitro-in vivo, na avaliação da influência dos excipientes, em função da origem, na cinética de liberação dos comprimidos e biodisponibilidade durante a qualificação de fornecedores.
There are several scientific reports of in vitro changes in the characteristics of various active pharmaceutical ingredients (APIs) in Formulaçãos containing microcrystalline cellulose (MCC), but there are few studies to evaluate its influence in vivo. This study aimed to evaluate the influence of microcrystalline cellulose from different Fontes and particle size to stability, in vitro release kinetics and correlate with in vivo studies using APIs of different biopharmaceutical classes. Were used two different lots of MCC by manufacturers (A and B) with different sizes CMC101 and CMC102, three lots of APIs simvastatin (Sinv) and fluconazole (Fluc) and one lot of ibuprofen (Ibup). Sixteen batches of tablets were obtained by direct compression of APIs with cellulose. The analytical techniques: X-ray diffraction, thermal analysis, scanning electron microscopy, high performance liquid chromatography and dissolution efficiency allowed the characterization of APIs, CMCs and tablets. Bioavailability studies were conducted using rabbits New Zealand as a model, after analysis and approval Certificate No. 0308/11, and validation of bioanalytical methods. The MCCs showed different characteristics of thermal degradation, the microscopic analysis and crystallinity according to the origin and / or size. The Simvastatin showed differences between batches behavior during melting, thermal decomposition and intrinsic dissolution. Tablets containing simvastatin showed release as a mathematical model El-Yazigi were differences in the stability and dissolution characteristics depending on the type of MCC used in its production, was established a direct correlation between the amount released in the dissolution and stability data Thermal for all Sinv tablets containing CMC with all except for the CMC-101B, which has different crystallinity characteristics. The Fluconazole no showed significant differences between the lots in the dissolution, melting and thermal decomposition. Tablets containing Fluc and CMC101 from different manufacturers presented equal release (El-Yazigi) and dissolution profiles in water however differed in vivo, correlation of data in vivo / in vitro is not established. The in vivo model was more efficient in order to detect the difference between the formulations containing fluconazole. Ibuprofen showed weight loss in one step by the thermogravimetry and DSC-fotovisual and pyrolysis-mass spectrometry it was that it is vaporization. Tablets containing Ibup and CMC101 from different manufacturers showed no differences between the dissolution profiles using pH 7.2 phosphate buffer. Using water as the dissolution medium, the release occurred as the mathematical model of Higuchi and showed difference in the release as to the origin of CMC101, correlation of data in vitro / in vivo is established and showed differences in absorption. These results show the need for studies beyond pharmacopoeial methods, including correlation studies in vitro-in vivo, at the evaluation of the excipients, depending on the origin, the release kinetics of tablets and bioavailability during qualifying suppliers.
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Munday, Dale Leslie. "Design, development and evaluation of encapsulated oral controlled release theophylline mini-tablets." Thesis, Rhodes University, 1991. http://hdl.handle.net/10962/d1003255.
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Conventional solid dosage forms often lead to fluctuations which exceed the maximum safe therapeutic level and/or decline below the minimum effective level. It is recognised that many drugs for chronic administration should be administered on a schedule that maintains plasma drug concentration within the therapeutic window. Research in controlled release dosage forms aims at designing a system with a zero-order input (eg, ideally to deliver 8.33% of the dose per hour over a 12 hour duration), producing steady state plasma drug levels. Oral dministration of drugs prepared as a controlled release formulation is extremely popular, and has attracted the attention of pharmaceutical scientists during the last decade. This has been due to the simultaneous convergence of various factors (eg, discovery of novel polymers and devices, better understanding of formulation and physiological constraints, expiration of existing patents, prohibitive cost of developing new drug entities), involved in the development of these delivery systems. Controlled release oral products can be formulated as single or multiple unit dosage forms and the relative merits of multiple unit forms with their own rate controlling systems are well established. This work describes the development of a relatively inexpensive multiple-unit capsule dosage form of theophylline containing coated mini-tablets for drug delivery throughout the gastrointestinal tract. Preformulation studies on theophylline anhydrous included solubility and dissolution rate determinations. Techniques including X-ray powder diffraction, differential scanning colorimetry and infrared spectroscopy provided no evidence of true polymorphism after recrystallisation from various solvents. However, scanning electron micrographs showed the effects of solvent polarity and cooling rate on the size and shape of recrystallised particles. Theophylline granules were manufactured by using various binders and were film coated by fluidised bed technology with various proportions of ethylcellulose, containing varying amounts of PEG 1540. In vitro release rates were dependent upon coating thickness and the proportion of PEG, which, being water soluble, created pores in the coating during dissolution studies as observed by a scanning electron microscope. However, substantial proportions of the drug remained unreleased from the granules. In order to overcome the problems of drug retention, plain granules were used and theophylline mini-tablets (3 mm diameter, weighing 15 - 20 mg) were manufactured and film coated with various Eudragits ® and other polymeric mixtures (soluble and insoluble). In vitro dissolution profiles from samples enclosed in hard gelatin capsules were determined using the USPXXI paddle apparatus in test media at pH 1.2 (HCI), pH 5.4 and 7.4 (phosphate buffers) at 37'C. Monitoring of in vitro theophylline release over 12 h, under identical hydrodynamic conditions, showed that the dissolution rate at pH 1.2 is substantially greater (95% of total drug content released in < 10 h) than that in phosphate buffers. The maximum release after 12 h was approximately 20 and 30% of total drug content of the tablet at pH 5.4 and 7.4, respectively. However, in vivo bioavailability after oral administration of tablets to rabbits corresponded to over 95% of total drug, compared with the same dose administered intravenously. The retarded drug release during in vitro dissolution in phosphate buffer was attributed to a possible interaction of phosphate ions with theophylline molecules at the tablet core-coat interface. These findings indicate that both rate and extent of theophylline release from the slow release coated mini-tablets are highly sensitive to phosphate buffers. The data also emphasise the usefulness of an animal model for assessment of in vivo drug release and subsequent absorption during the development of modified release dosage forms. Mini-tablets were subjected to isothermal and cyclic stresses to reach conditions for up to 6 months at different temperatures and relative humidity. The film integrity was maintained but ageing of the coating occurred which impeded dissolution. Reduced drug release was temperature related while the effect of relative humidi% was insignific~t. Encapsulated mini-tablets (uncoated and coated with Eudragit RL and RS 2% w/w) equivalent to a 300 mg dose, were evaluated both in vitro and in vivo using beagle dogs. The pharmacokinetic parameters from single and multiple dose studies showed several advantages over Theo-Dur® 300 mg tablets. Precise dosage titration is possible by careful adjustment of the number of encapsulated mini-tablets. This multiple unit mini-tablet delivery system will allow for greater flexibility in dosage adjustment compared to the currently available preparations, allowing individualised fine dose titration in those patients requiring therapeutic drug monitoring. The developmentof the multiple unit mini-tablet formulation appears to provide an optimal dosage form with maximum flexibility in respect of dose, duration range and ease of production.
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Bonamici, Denise. "Sistema de classificação biofarmacêutica e bioisenções." Universidade de São Paulo, 2009. http://www.teses.usp.br/teses/disponiveis/9/9139/tde-29032010-151226/.
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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.
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Bustos, Salgado Paola. "Biopharmaceutical study of therapeutic efficacy of nanostructured formulations made from products of natural origin." Doctoral thesis, Universitat de Barcelona, 2021. http://hdl.handle.net/10803/673940.
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This research work was aimed at the characterization in vitro, ex vivo and in vivo of nanostructured systems which independently contain a natural flavanone extracted from Eysenhardtia platycarpa and another four flavanones obtained through semi-synthesis of the first flavanone with the objective of providing evidence of their efficaciousness as anti-inflammatory cutaneous agents. Initially the flavanone was isolated from its natural source, and following on from this, the derivatives were obtained through chemical reactions of acetylation, methylation, cyclization and vinyl cyclization. Calculations were made in silico using computational programs like Molinspiration and PASS Online. These gave the theoretical physio-chemical properties of the flavanones and estimated the profile of their probable anti-inflammatory activity. An analytical methodology was used for the quantification of the flavanones with High Performance Liquid Chromatography (HPLC) in samples that crossed human skin in an ex vivo study. The objective was to demonstrate that an analytical method had been selected that did not cause any interference from the biological components due to the tissue with which we worked. The results showed that the method was lineal, exact and precise in the assayed concentrations interval (1.56 - 200 µg/mL). Afterwards, nano-structured formulations were prepared individually: they contained each flavanone at 0.5 % and the excipients were: Labrasol®, Labrafac® lipophile, Propylene glycol and Plurol Oleic®. These formulations were morphologically and physio-chemically characterized. The results obtained revealed that the flavanones formulations (FF) were suitable for topical administration. An in vitro assay was carried out of the liberation of the flavanones from their individual formulation, using a dialysis membrane with a system of Franz type cells to guarantee that the formulation liberated the flavanones and allowed there to be a sufficient quantity of each component susceptible to being permeated in human skin. Immediately afterwards, ex vivo studies were realized using human skin with the objective of evaluating the permeation profile of the flavanones contained in dissolution individually and in the formulations. The study demonstrated that the quantity of flavanone permeated and retained in the skin was different, depending on the flavanone assayed. This was probably due to the different molecular interactions of the functional groups with the tissue components. The flavanones derived were retained in the skin in greater quantity than natural flavanone. Finally, an in vivo assay was carried out on the anti-inflammatory efficaciousness in a model of rat’s auricular edema induced by arachidonic acid. The results demonstrated that the flavanones were capable of reducing the edema (swelling) and the formulation excipients did not influence in the biological activity. The formulations turned out to be more effective than the reference pharmaceutical drug used in this study (sodium diclofenac gel). It was shown that the structural modification of the natural flavanone improved the therapeutic activity in which the derived methylated and cyclized vinyl stood out. These results are in concordance with the results obtained in the evaluation of the cytokines expression (IL-1β, IL-6 y TNF-α) carried out, and moreover allowed the advantage of the use of nano-structured systems in making the flavanones more effective to be shown in comparison with flavanones assayed in dissolution.El presente trabajo de investigación versa sobre la caracterización in vitro, ex vivo e in vivo de sistemas nanoestructurados que contienen de forma independiente una flavanona natural extraída de Eysenhardtia platycarpa y cuatro flavanonas obtenidas mediante semi-síntesis de la primera, con el objetivo de evidenciar su eficacia como agentes antiinflamatorios cutáneos. Inicialmente se aisló la flavanona de su fuente natural seguida de la obtención de los derivados mediante las reacciones químicas acetilación, metilación, ciclación y vinilo ciclación. Se realizaron cálculos in silico utilizando programas computacionales como Molinspiration y PASS Online para obtener las propiedades fisicoquímicas teóricas de las flavanonas y estimar su probable perfil de actividad antiinflamatoria. Se validó una metodología analítica para la cuantificación de las flavanonas por cromatografía líquida de alta eficacia (HPLC) en muestras que atravesaron piel humana en un estudio ex vivo. Lo anterior con el objeto de demostrar una selectividad del método analítico planteado sin que hubiese ninguna interferencia provocada por los componentes biológicos propios del tejido con el que se trabajaría. Los resultados mostraron que el método es lineal, exacto y preciso en el intervalo de concentraciones ensayadas (1.56 - 200 µg/mL). Posteriormente, se prepararon individualmente las formulaciones nanoestructuradas que contenían al 0.5 % cada flavanona y como excipientes: Labrasol®, Labrafac®, Propilenglicol y Plurol Oleico®. Dichas formulaciones fueron caracterizadas morfológica y fisicoquímicamente. Los resultados obtenidos revelaron que las formulaciones de las flavanonas (FF) eran adecuadas para su administración tópica. Se llevó a cabo un ensayo in vitro de liberación de las flavanonas desde su formulación individual, utilizando una membrana de diálisis en sistemas de celdas tipo Franz para garantizar que la formulación libera las flavanonas y permite disponer de cantidad suficiente de cada compuesto susceptible de ser permeado en piel humana. Seguidamente, se realizaron estudios ex vivo utilizando piel humana con el propósito de evaluar el perfil de permeación de las flavanonas contenidas en disolución de forma individual y en las formulaciones. El estudio demostró que la cantidad de flavanona permeada y retenida en la piel fue diferente dependiendo de la flavanona ensayada; probablemente debida a las diferentes interacciones molecular de sus grupos funcionales con los componentes del tejido. Las flavanonas derivadas se retuvieron en mayor cantidad en piel que la flavanona natural. Finalmente, se desarrolló un ensayo in vivo de eficacia antiinflamatoria en un modelo de edema auricular de rata inducido por ácido araquidónico. Los resultados demostraron que las flavanonas fueron capaces de reducir el edema y los excipientes de las formulaciones no influyeron en la actividad biológica. Las formulaciones resultaron ser más efectivas que el fármaco de referencia usado en este estudio (gel de diclofenaco sódico). Se comprobó que la modificación estructural de la flavanona natural mejoró la actividad terapéutica destacando los derivados metilados y vinilo ciclizados. Estos resultados se encuentran en concordancia con los obtenidos de la evaluación de expresión de las citosinas (IL-1β, IL-6 y TNF-α) realizado y además, permitió evidenciar la ventaja del uso de sistemas nanoestructurados para disponer las flavanonas, en comparación con las flavanonas ensayadas en disolución.
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Issa, Michéle Georges. "Avaliação do impacto de diferentes variáveis no ensaio de dissolução intrínseca de metronidazol." Universidade de São Paulo, 2011. http://www.teses.usp.br/teses/disponiveis/9/9139/tde-15072011-104145/.
Full textAbstract:
O objetivo do presente trabalho foi avaliar o impacto de diferentes variáveis no ensaio de dissolução intrínseca de metronidazol. Inicialmente, as amostras, com diferentes graus de micronização, foram submetidas à caracterização físico-química, sendo realizados ensaios de solubilidade, tamanho de partícula, análise térmica (DSC/ TG), infravermelho por transformada de Fourier (FTIR), difratometria de raios X (DRX), análise de área superficial pelo método BET, microscopia óptica, densidade verdadeira e densidade compactada. Na sequência, foram realizados os ensaios de dissolução intrínseca segundo um planejamento experimental do tipo fatorial fracionado, sendo cada fator avaliado em três níveis. Para o delineamento, utilizou-se o programa Statistica 8.0. e os fatores estudados foram: velocidade de rotação, pressão utilizada na formação do compactado do fármaco, meio de dissolução e grau de micronização. Os resultados mostraram alteração nas propriedades reológicas do material conforme o aumento do grau de micronização, enquanto as demais propriedades não foram afetadas. Entre os fatores estudados no delineamento, a velocidade de rotação e o meio de dissolução, foram aqueles que exerceram influência significativa na dissolução intrínseca do metronidazol. Embora a solubilidade do fármaco não sofra influência do tamanho de partícula, valores superiores foram observados em HCl 0,1 M, meio em que também foram obtidas as mais elevadas velocidades de dissolução intrínseca (VDIs).The purpose of this study is to evaluate the impact of different variables in the intrinsic dissolution test of metronidazol. Initially, the samples, with different levels of micronization, underwent physicochemical characterization, whereby they were tested for solubility, particle size, thermal analysis (DSC/TG), Fourier transform infrared (FTIR) spectroscopy, X-ray diffractometry (DRX), surface area analysis by the BET method, optical microscopy, true density and tapped density. Then, intrinsic dissolution tests were carried out according to fractional factorial experimental planning, with each factor being evaluated on three levels. The Statistica 8.0 software program was used for design, and the factors studied were: rotational velocity, pressure used in the formation of the compressed drug, dissolution medium and level of micronization. The results indicated alterations in the rheological properties of the material, as the level of micronization increased, while the remaining properties were unaffected. Among the factors studied in the design, the rotation speed and the dissolution medium were the factors that exercised the most significant influence on the intrinsic dissolution of metronidazol. Although the solubility of the drug is not influenced by particle size, higher values were observed in HCl 0.1 M, the medium in which the highest intrinsic dissolution rates (IDRs) were also obtained.
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Petri, Niclas. "Involvement of Membrane Transport Proteins in Intestinal Absorption and Hepatic Disposition of Drugs Using Fexofenadine as a Model Drug." Doctoral thesis, Uppsala University, Department of Pharmacy, 2005. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-5808.
Full textAbstract:
The aims of this thesis were to study the in vivo relevance of membrane transporters for intestinal absorption and the hepatic disposition of drugs in humans and preclinical models. Fexofenadine is a substrate for ABCB1 (P-glycoprotein) and members of the organic anion transporting polypeptide (OATP/SLCO) family. It is marginally metabolised in humans.
The influence of known inhibitors of ABCB1 and OATPs on the membrane transport and pharmacokinetics of fexofenadine was investigated in Caco-2 and porcine models and in humans. The permeability of fexofenadine remained low, even when significantly altered by the addition of an inhibitor. Using the Loc-I-Gut® technique in vivo in humans, it was possible to see that the jejunal effective permeability of fexofenadine was unchanged when given with verapamil. However, the systemic exposure and apparent absorption rate of fexofenadine increased. This suggests that the first-pass liver extraction of fexofenadine was reduced by verapamil, probably through the inhibition of sinusoidal OATP-mediated and/or canalicular ABCB1-mediated secretion. The unchanged permeability can be explained by simultaneous inhibition of jejunal apical OATP-uptake and ABCB1-efflux, which would leave fexofenadine to be transported by passive trancellular diffusion. A Loc-I-Gut® perfusion in the porcine model enabling blood sampling in the portal and hepatic veins and bile collection revealed increased jejunal permeability, but no subsequent verapamil-induced elevation in the systemic exposure of fexofenadine. This indicates a species-related difference in the localisation of and/or the substrate specificity of fexofenadine for the transporters involved. The absence of an effect on the first-pass liver extraction in the porcine model might be caused by the observed lower liver exposure of verapamil.
Finally, a novel intubation technique enabling dosing of fexofenadine in the jejunum, ileum and the colon showed that fexofenadine was absorbed less along the length the intestine in agreement with the properties of a low permeability drug.
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Mesquita, Leonardo Mendes de Souza. "Fitoterápicos padronizados para o tratamento de doenças crônicas : Rhizophora mangle /." São Vicente, 2017. http://hdl.handle.net/11449/150682.
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Orientador: Wagner VilegasResumo: As espécies vegetais contendo substâncias bioativas são, cada vez mais, objeto de pesquisas, levando a alternativas para tratamentos terapêuticos ou revelando substâncias que posteriormente possam ser exploradas com o intuito de produzir fármacos. Estudos de plantas são de grande importância, em razão do vasto número de metabólitos secundários que podem ser encontrados. Eles têm cada vez mais atraído a atenção da sociedade, mostrando-se uma fonte alternativa aos altos custos dos medicamentos alopáticos. Mas, para que as plantas sejam usadas com eficácia e segurança, são necessários estudos multidisciplinares. A Agência Nacional de Vigilância Sanitária e o Ministério da Saúde aprovaram o uso de 71 plantas medicinais no tratamento contra diabetes, úlceras, inflamações e outras doenças crônicas. Contudo, essa é uma lista ainda limitada, pois várias espécies não são disponíveis o ano todo e/ou nas várias regiões do Brasil. Em contrapartida, Rhizophora mangle (Rhizophoraceae, popularmente conhecida como mangue vermelho) é uma espécie que ocorre no Brasil desde o Pará até Santa Catarina. É comumente utilizada pelas populações tradicionais costeiras, principalmente para o tratamento de diabetes, hemorroidas, analgesia e dores estomacais. Recentemente, nosso grupo de pesquisa verificou que o extrato acetônico das cascas de R. mangle possui atividades antioxidante e antiulcerogênica, e é eficaz no tratamento da colite experimental. Contudo, foi realizada apenas uma avaliação prelimina... (Resumo completo, clicar acesso eletrônico abaixo)
Abstract: Plant species containing bioactive compounds are continuously being investigated, in order to search for alternative therapeutic treatments. These studies can reveal substances that can be explored in order to produce new drugs. Investigation of plants are of great importance, because of the large amounts of secondary metabolites that can be found. They have increasingly attracted the attention of the society, proving to be an alternative source to the high costs of allopathic medicines. However, multidisciplinary studies are necessary to ensure that plants are used with effectively and safety. The National Sanitary Surveillance Agency and the Ministry of Health have approved 71 medicinal plants to be used against diabetes, ulcers, inflammation and other chronic diseases. However, this list is still limited because several species are not available year-round and/or in the various regions of Brazil. In contrast, Rhizophora mangle (Rhizophoraceae, popularly known as red mangrove) is a Brazilian species that occurs from Pará to Santa Catarina. It is commonly used by traditional coastal populations, mainly for the treatment of diabetes, hemorrhoids, analgesia and stomach pains. Recently, our research group verified that the acetone extract of R. mangle barks has antioxidant and antiulcerogenic activities and it is also effective in the treatment of the experimental colitis. However, only a preliminary evaluation of the chemical composition of the barks was previously carried out... (Complete abstract click electronic access below)
Mestre
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Hamdani, Jamila. "Développement de formes orales divisées à libération prolongée par la technique de la pellétisation thermoplastique." Doctoral thesis, Universite Libre de Bruxelles, 2005. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/211027.
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L’étude des caractéristiques physico-chimiques du Compritol® (béhénate de glycérol) et du Précirol® (palmito-stéarate de glycérol) a été effectuée. Les méthodes d’évaluation consistaient en la calorimétrie différentielle à balayage, la microscopie sur platine chauffante et la rhéologie dans un rhéomètre capillaire à pression variable. Cette étude a montré une évolution de la structure cristalline de ces deux corps gras en fonction du temps et de la température de stockage. En effet, ces composés, après fusion et refroidissement, « recristallisent » sous une structure partiellement amorphe, qui évolue avec le temps en structure cristalline. Il est également ressorti de cette évaluation que ces deux excipients lipidiques présentent des plages de fusion bien distinctes. Cette caractéristique est conservée lorsqu’ils sont en mélanges binaires. Enfin, ces corps gras se déforment sous l’action de fortes forces de cisaillement à des températures inférieures à leurs plages de fusion. L’utilisation du Compritol® et du Précirol® comme corps gras lipophiles pour former des microbilles à libération prolongée a alors été envisagée. Nous avons procédé moyennant une technique de fabrication simple et rapide appelée « la pelletisation thermoplastique ». Il s’agit d’un procédé en une étape qui met à profit le pouvoir liant des corps gras facilement fusibles et se passe ainsi de l’usage de l’eau ou de solvants organiques. L’appareillage utilisé est de type mélangeur granulateur à haute vitesse.
Nous nous sommes basés sur les renseignements fournis par l’étude de préformulation afin d’optimaliser les conditions de fabrication des microbilles. Le contrôle de la température du mélange est très important pour la réussite du procédé de pelletisation thermoplastique. La vitesse du bras du mélangeur, la température de la double paroi et le temps de sphéronisation constituent les paramètres clés pour réussir la pelletisation du mélange. Nous avons mis au point des formulations contenant 15% (m/m) de Précirol® et une quantité croissante de Compritol® variant de 3 à 65 % (m/m). La libération du chlorhydrate de phényléphrine, employé comme agent traceur, a déjà été ralentie pour les formulations contenant 25 % (m/m) de corps gras. Face à ces résultats encourageants, nous avons mis au point des formulations contenant 75 % (m/m) de différents principes actifs (chlorhydrate de ciprofloxacine, théophylline et kétoprofène) et 25 % (m/m) de corps gras. Ces formulations ont abouti à la fabrication de microbilles à libération prolongée. Une étude de stabilité menée sur certaines des formes finies a montré la stabilité des microbilles lipidiques pour autant que le principe actif incorporé dedans ne soit par lui-même facilement dégradable.
Afin d’élargir le champ d’application du procédé de fabrication, nous avons mis au point des microbilles flottantes à libération prolongée. Les formulations proposées contiennent comme excipients :les deux corps gras, un mélange effervescent (bicarbonate sodique/ acide tartrique) et du Methocel K100. Leur flottabilité a été prouvée in vitro sur une période de plus de huit heures et In vivo par administration de microbilles de riboflavine flottantes versus non flottantes à des volontaires humains sains.
Doctorat en Sciences biomédicales et pharmaceutiques
info:eu-repo/semantics/nonPublished
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Pande, Rachna. "Globalization of biopharmaceutical manufacturing." Thesis, Massachusetts Institute of Technology, 2011. http://hdl.handle.net/1721.1/68449.
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Thesis (S.M. in Technology and Policy)--Massachusetts Institute of Technology, Engineering Systems Division, Technology and Policy Program, 2011.Cataloged from PDF version of thesis.
Includes bibliographical references (p. 131-134).
The biomanufacturing industry is changing due to increasing globalization. However, it is changing differently from other high tech industries like software/ semiconductor/ automobiles. In this study we use global biomanufacturing investment data, industry survey data as well as interviews with members of industry and academia to understand the extent of microbial biomanufacturing activity (total volume, number of facilities, type of facilities) and nature of biomanufacturing activity (complexity of products and processes across both mammalian and microbial production) in different regions of the world today. The study shows that traditional centers of expertise in US and EU still house most of the worlds biomanufacturing capacity. The facilities in US and EU perform a larger number of operations within their facilities and also more technically complex operations than facilities in Asia. US facilities support the most complex products (median unit operations =13) and processes (cell culture, purification) and maximum average products per facility(12.2). Asian facilities support simpler products (median unit operations =7), simpler processes (fermentation, fill/finish) and fewer products per facility on average (3.25). These results support the idea that managing technical complexity is one of the biggest challenges in biomanufacturing today and it can determine where a biologic can be manufactured. While economic forces push manufacturing of biologics to low cost locations, the need to develop expertise may prevent manufacturing from scattering across the world. Instead, there may be a more guided flow to locations with an expertise in certain types of products and processes.
by Rachna Pande.
S.M.in Technology and Policy
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Novais, Joana Lobo Fernandes. "Economic and engineering aspects of disposables-based bioprocessing." Thesis, University College London (University of London), 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.270590.
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Wei, Tzu-Hsiang Biotechnology & Biomolecular Sciences Faculty of Science UNSW. "Transient production of biopharmaceutical proteins." Publisher:University of New South Wales. Biotechnology & Biomolecular Sciences, 2009. http://handle.unsw.edu.au/1959.4/43708.
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The creation of stable mammalian cell lines for biopharmaceutical production often require several months, and is unfavourable for the rapid production of multiple drug candidates for screening in the early stages of development. Biopharmaceutical production by transient transfection provides a possible alternative of quickly producing these early stage drug candidates. The Epi-CHO transient expression system, which consists of a Chinese hamster ovary (CHO) cell line (CHO-T) expressing the murine polyomavirus Large T-Antigen (LT), emonstrated enhanced transient recombinant protein production. The aim of this study was to prolong transient recombinant protein prod.Jction of the Epi-CHO expression system by creating a CHO cell line expressing both LT and EBNA1 (ECHO-T). The pEBNA1-LT expression vector encoding LT and EBNA1 was constructed and transfected into CHO-K1. A total of 20 clones were isolated from the antibioticresistant pool and screened for the expression of functional LT and EBNA1. PCR analysis showed 16 of the 20 clones was positive for EBNA1 and LT DNA. Of the 16 clones, six were positive for EBNA1 and LT expression by RT-PCR. Detection of LT and EBNA1 by immunofluorescence showed positive staining for the P7-G3 clone. Western blotting suggested the P7-G3 clone was: positive for EBNA1, and clones P3-C7 and P7-E2 were positive for LT. A plasmid replication assay confirmed the expression of functional LT in all six clones. Plasmid maintenance assay confirmed clone P7-G3 as the ECHO-T clones to express functional EBNA1. The P7-G3 clone demonstrated prolonged and sustained transient recombinant protein expression when compared to CHO-T. The P7-G3 clone achieved sustained transient protein expression for 32 days in the absence of selection, the longest currently reported for CHO cells.
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Steltenpohl, Kurt Maus. "Variation reduction in biopharmaceutical manufacturing." Thesis, Massachusetts Institute of Technology, 1999. http://hdl.handle.net/1721.1/80012.
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Thesis (S.M.)--Massachusetts Institute of Technology, Sloan School of Management; and, (S.M.)--Massachusetts Institute of Technology, Dept. of Mechanical Engineering, 1999.Includes bibliographical references (p. 45).
by Kurt Maus Steltenpohl.
S.M.
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Lakhdar, K. "Production planning of biopharmaceutical manufacture." Thesis, University College London (University of London), 2006. http://discovery.ucl.ac.uk/1444912/.
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Multiproduct manufacturing facilities running on a campaign basis are increasingly becoming the norm for biopharmaceuticals, owing to high risks of clinical failure, regulatory pressures and the increasing number of therapeutics in clinical evaluation. The need for such flexible plants and cost-effective manufacture pose significant challenges for planning and scheduling, which are compounded by long production lead times, intermediate product stability issues and the high cost - low volume nature of biopharmaceutical manufacture. Scheduling and planning decisions are often made in the presence of variable product titres, campaign durations, contamination rates and product demands. Hence this thesis applies mathematical programming techniques to the planning of biopharmaceutical manufacture in order to identify more optimal production plans under different manufacturing scenarios. A deterministic mixed integer linear programming (MILP) medium term planning model which explicitly accounts for upstream and downstream processing is presented. A multiscenario MILP model for the medium term planning of biopharmaceutical manufacture under uncertainty is presented and solved using an iterative solution procedure. An alternative stochastic formulation for the medium term planning of biomanufacture under uncertainty based on the principles of chance constrained programming is also presented. To help manage the risks of long term capacity planning in the biopharmaceutical industry, a goal programming extension is presented which accounts for multiple objectives including cost, risk and customer service level satisfaction. The model is applied to long term capacity analysis of a mix of contractors and owned biopharmaceutical manufacturing facilities. In the final sections of this thesis an example of a commercial application of this work is presented, followed by a discussion on related validation issues in the biopharmaceutical industry. The work in this thesis highlighted the benefits of applying mathematical programming techniques for production planning of biopharmaceutical manufacturing facilities, so as to enhance the biopharmaceutical industry's strategic and operational decision-making towards achieving more cost-effective manufacture.
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Ben, Jebara Marouen. "Essays on Biopharmaceutical Supply Chains." University of Toledo / OhioLINK, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=toledo1438776838.
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Angkawinitwong, Ukrit. "Novel biopharmaceutical formulations from electrohydrodynamic atomisation." Thesis, University College London (University of London), 2018. http://discovery.ucl.ac.uk/10042642/.
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Biopharmaceutical forms a new class of medicine which is biologically active and produced by recombinant technology or obtained from living organisms. It can be diversified into a range of subtype of drugs such as therapeutic enzymes, monoclonal antibodies, subunit proteins, nucleic acid and genetic materials. They have been used extensively for clinical application involving disease treatments, prevention and diagnosis. Unlike small molecule compounds, their chemical structures are more complex and can crucially influence their activity. However, these highly ordered conformation are often transformed upon exposure to physical stress during manufacturing such as extreme temperature, pH and high shear. This posses a challenge for the development of biologics and highlights the need of a more friendly formulation technique for macromolecules. Electrohydrodynamic atomisation (EHDA) is a process where using electrical energy to break up a bulk liquid into fine jets. The process allows the fabrication of micro to nano-scaled structures including particles or fibres without using heat involved. This can avoid the thermally induced degradation emerged during the formulation of macromolecules. Additionally, numerous materials can be fabricated by EDHA such as polymers, hydrogels and ceramic, thus enabling the design of various drug delivery systems. The aim of this PhD project is to undertake a conceptual study using EHDA to formulate biopharmaceuticals. Four biologics, alkaline phosphatase (ALP), bevacizumab (Avastin®; a whole-length monoclonal antibody used for neovascularization treatment), poly(inosinic-cytidylic acid) (poly-IC; an immunopotentiator), and ovalbumin (a model vaccine antigen) were processed into composites with polymers including poly(vinylpyrollidone) (PVP), poly(ε- caprolactone) (PCL) and poly(lactide-co-glycolide) (PLGA). Micron-nano sized fibres and particles for implantable biologic formulations were produced. Material properties and the activity of the developed formulation were characterised to identify the best formulation for biopharmaceutics.
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Wagner, Alice Elizabeth 1980. "Understanding risk in a biopharmaceutical portfolio." Thesis, Massachusetts Institute of Technology, 2011. http://hdl.handle.net/1721.1/68469.
Full textAbstract:
Thesis (S.M.)--Harvard-MIT Division of Health Sciences and Technology, 2011.Cataloged from PDF version of thesis. "Pages 65-70 contain illegible text. This is the best copy available"--P. after t.p.
Includes bibliographical references (p. 63-64).
Investors have difficulty funding the life sciences because of the high risks involved in research and development and commercialization of new products. Risk in the biopharmaceutical industry is the result of scientific, regulatory and economic uncertainty. The nature of the biopharmaceutical industry introduces many challenges. Each of these challenges incorporates a measure of risk into drug development. The level of understanding of technical success interdependencies has not been fully investigated. These interdependencies (correlations) could lead to an overall greater risk to the company's portfolio than previously expected. A better understanding of the risks that lead to success or failure in drug development might encourage more investment in the life sciences and specifically in the biopharmaceutical industry, and a greater awareness of the correlations between risks and products might lead to more informed decision making on a biopharmaceutical portfolio leading increased productivity. A dataset was collected from Thomson Reuters. The dataset is the oncology portfolio from a biopharmaceutical company, Genentech Inc. Logistic regression was used to determine if any of the defined variables contributed to the success or failure of the oncology products. The chi-square value was 7.738 with the degrees of freedom equal to 5 and with a p-value of 0.17. Therefore, none of the variables significantly contributed to the outcome. More research should be performed in this area in order to better understand the risk in a biopharmaceutical portfolio.
by Alice Elizabeth Wagner.
S.M.
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Cosby, Samuel T. (Samuel Thomas). "Process Analytical Technology in biopharmaceutical manufacturing." Thesis, Massachusetts Institute of Technology, 2013. http://hdl.handle.net/1721.1/80911.
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Thesis (M.B.A.)--Massachusetts Institute of Technology, Sloan School of Management; and, (S.M.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering; in conjunction with the Leaders for Global Operations Program at MIT, 2013.This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections.
Cataloged from student-submitted PDF version of thesis.
Includes bibliographical references (p. 83-85).
Process Analytical Technology (PAT) became a well-defined concept within the pharmaceutical industry as a result of a major initiative by the FDA called "Pharmaceutical cGMPs for the 21st Century: A Risk-Based Approach." The FDA defines PAT as "a system for designing, analyzing, and controlling manufacturing through timely measurements (i.e., during processing) of critical quality and performance attributes of raw and in-process materials and processes, with the goal of ensuring final product quality." The biotechnology industry has started incorporating PAT in manufacturing, because of regulatory pressure and because the previous blockbuster-oriented business model is becoming less viable. This thesis proposes a methodology for evaluating PAT systems and delivers guidance on how to develop and implement them to effectively manage risk in biopharmaceutical manufacturing. The methodology includes guidance regarding identifying opportunities, evaluating and implementing novel analytical technology, appropriately applying acquired data, and managing change associated with PAT implementation. Experimental results from a novel PAT system that acquires light scattering and UV absorbance data to control chromatography during large-scale manufacturing are presented as a case study. The case study follows the methodology to show how a system optimized for a laboratory can be scaled for use in biopharmaceutical manufacturing.
by Samuel T. Cosby.
S.M.
M.B.A.
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Terblanche, Thersia. "Change Management in a biopharmaceutical company." University of Western Cape, 2020. http://hdl.handle.net/11394/8003.
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Magister Pharmaceuticae - MPharmThis study aimed to review the change management implemented in a Biopharmaceutical company in Cape Town in the light of existing literature on change management theory. Three main constructs were identified: process of change, readiness for change and climate of change. A quantitative pencil-and-paper survey were used to explore and describe employee experience of the change management process within a single department of a biopharmaceutical company in Cape Town. Cronbach alpha coefficient confirmed internal reliability (α = 0.94) of the questionnaire constructs. Employees across all ages reported average scores for all constructs (M ≥ 2.5 < 4), indicating a similar experience regardless of age. A medium-strong positive correlation (p < 0.01; r = 0.49) was observed between process of change and climate of change.
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McCartney, Sharmila. "Mechanical characterisation of freeze-dried biopharmaceuticals." Thesis, Imperial College London, 2014. http://hdl.handle.net/10044/1/29743.
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This thesis presents comprehensive investigations into the mechanical behaviour of freeze dried (FD) biopharmaceuticals with respect to processing conditions (freezing rate, mode of ice nucleation and primary drying temperature). The contribution of formulation composition, cake density and individual excipients on the mechanical properties were studied. The interactive effect of processing conditions and model formulation composition was also studied using statistically designed experiments. A mechanical indentation test using a flat faced punch was developed and validated to test fragile freeze-dried cakes in-situ (within vial) without any sample preparation. FD cakes were made from sucrose, trehalose, mannitol and model formulations with lysozyme and bovine serum albumin (BSA) under typical industrial FD process conditions. Freeze-dried cakes exhibited failure by a brittle crushing mechanism. An initial near linear rise in the stress-strain curve represented cake elastic behaviour and transitioned into a steady stress plateau as strain was increased, with intermittent cracking and crushing failures representative of cells failures in the z axial direction. FD trehalose, sucrose and mannitol have distinctly different Young's modulus and maximum stresses at failure. Higher primary drying temperature (-40°C) causes cell micro-collapse hence reduces the Young's modulus and crushing stress compared to -50°C. Cakes manufactured at faster cooling rates (0.9°C/min) produce smaller pore sizes but more in number resulting in higher Young's modulus and crushing stress compared to slower cooling rates of 0.09°C/min with less numerically but larger pore sizes. Controlled nucleation creates a narrow pore size distribution resulting in a uniform Young's modulus and similar crushing stress compared to cakes with wider pore size distributions (spontaneous nucleation). FD lysozyme and BSA products cakes are strongest when mannitol and sucrose are used in combination at ~1:1 ratio compared to other formulation compositions. In summary, the findings offer a systematic understanding of the relationship of mechanical behaviour of FD cakes, processing conditions and formulation composition. The mechanical test method developed can potentially provide a quantitative critical quality attribute related to internal FD cake structure hence its robustness for handling and transportation. It will provide information on suitability of biopharmaceutical formulations including excipients for manufacture of robust FD cakes.
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Zhou, Zhou. "Novel experimental techniques for biopharmaceutical analysis." Thesis, University of Strathclyde, 2016. http://digitool.lib.strath.ac.uk:80/R/?func=dbin-jump-full&object_id=27842.
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Drug solubility and dissolution are important attributes controlling the bioavailability (BA) of oral dosage forms and can be determined in vivo, however it is expensive and can generate ethical issues. In vitro tests have been introduced utilising simulated gastrointestinal (GI) fluids, capturing the GI composition and conditions. However, individual variation and food-induced changes of the GI environment affecting drug BA have been recognised and in-depth knowledge is required to understand their effects on drug absorption. A fractional factorial design of experiment (DoE) and a 4-component mixture design (4MD) were used to investigate drug equilibrium solubility in media presenting in different levels of pH, concentration of amphiphiles, buffer, salt and pancreatin. Poorly soluble acidic, basic and neutral drugs with various physiochemical properties were tested. Solubility results correlate well with literature values, indicating they explored the solubility variation in the biorelevant space. Except pancreatin, all factors showed significant impacts on drug solubility. The descending order of average effect magnitude is pH, amphiphiles, buffer and salt, some of which also displayed remarkable drug specific interactions. Changing amphiphile ratios in 4MD further indicated that solubilisation is not a simple accumulative solubilisation of individual amphiphiles, but interactions between amphiphile-amphiphile and drug-amphiphiles. Powder dissolution using various biorelevant media indicates intrinsic dissolution rates (IDR) are positively correlated with equilibrium solubility and the diffusion coefficient of drugs in different ionisation states and interactions with amphiphiles. The above studies illustrate the convoluted nature of the GI fluids and provide a visualisation of how solubility/dissolution map varies within the ranges of GI fluid parameters. Statistical approaches can systematically detect critical factors affecting drug solubility and dissolution, and the output can potentially be applied in physiologically based pharmacokinetic (PBPK) model to achieve better in vivo-in vitro correlation (IVIVC).
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Zhang, Junge Foley Joe Preston. "Quantitative biopharmaceutical applications of capillary electrophoresis /." Philadelphia, Pa. : Drexel University, 2009. http://hdl.handle.net/1860/3166.
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Tan, Kei Xian. "Aptameric Formulation for Enhanced Biopharmaceutical Delivery." Thesis, Curtin University, 2018. http://hdl.handle.net/20.500.11937/68408.
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This research work developed a novel polymeric carrier system for targeted drug delivery to specific body sites. It utilized unique molecular probes called aptamers that navigate the complexity of mammalian cell systems and present drug molecules to desired locations. The aptamer molecules were tagged onto polymer drug carriers as binding ligands to direct an efficient path towards targeted delivery, avoiding unwanted effects on nontargeted cells and potentially addressing side effects of chemotherapy.
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McGarvey, O. S. "Calorimetric, structural and spectroscopic studies on trehalose as a protein cryoprotectant." Thesis, Queen's University Belfast, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.273088.
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Sullivan, Sean Padraic. "Polymer microneedles for transdermal delivery of biopharmaceuticals." Diss., Georgia Institute of Technology, 2009. http://hdl.handle.net/1853/33873.
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Biopharmaceuticals, including proteins, DNA and vaccines, are one of the fastest growing segments of the overall pharmaceutical market. While the hypodermic injection, the most common delivery method for these molecules, is effective, it also has limitations, including low patient compliance, need for medically trained personnel and biohazardous sharps after delivery. The overall goal of this thesis was to develop a new delivery system for biopharmaceuticals, based on dissolving polymer microneedles, which is effective and more patient compliant than the hypodermic needle.
Microneedles are microscopic needles that are large enough to insert into the skin to deliver drugs effectively, while being short enough to avoid the pain causing nerves deep in the skin. An additional benefit of polymer microneedles is that the needles completely dissolve in the skin, leaving behind no biohazardous sharps. There are significant material and fabrication issues that must be overcome in the development of this new device.
The first part of this thesis focused on the development of a new fabrication process, based on in situ photopolymerization, for the creation of polymer microneedles. These microneedles were shown to successfully insert into the skin, dissolving within a minute to deliver the encapsulated cargo, and retain full activity of encapsulated proteins.
Next, we applied the microneedle technology to the delivery of the influenza virus. We found that the reformulation process required to encapsulate the influenza virus in polymer microneedles did not affect the antigenicity or immunogenicity of the virus. In addition, we used coated metal microneedles to successfully immunize mice with the influenza virus, verifying the delivery capabilities of a microneedle system.
Finally, we used the dissolving polymer microneedles to successfully immunize mice with the influenza virus, resulting in full protection against lethal challenge after one immunization. This immune response was equivalent to the control intramuscular injection. In conclusion, we have developed dissolving polymer microneedles as an effective and patient compliant delivery system for biopharmaceuticals. This system could be especially applicable to mass immunization efforts or home use, since it can be self-administered and allows for easy disposal with no biohazardous sharps.
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Rajapakse, Thiaga Anuradha. "Biopharmaceutical drug development modelling and portfolio management." Thesis, University College London (University of London), 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.413689.
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Chen, Fei Ph D. Massachusetts Institute of Technology. "Magnetically enhanced centrifugation for continuous biopharmaceutical processing." Thesis, Massachusetts Institute of Technology, 2009. http://hdl.handle.net/1721.1/51565.
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Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 2009.Includes bibliographical references.
Effective separation and purification of biopharmaceutical products from the media in which they are produced continues to be a challenging task. Such processes usually involve multiple steps and the overall product loss can be significant. As an integrative technique, high gradient magnetic separation (HGMS), together with the application of functional magnetic particles, provides many advantages over traditional techniques. However, HGMS has a number of drawbacks; and its application is limited because it is inherently a batch process and it is difficult to recycle the magnetic nanoparticles. This thesis explores the development of a new type of continuous magnetic separation process, called magnetically enhanced centrifugation (MEC), which exploits the interactions of magnetic particles with magnetic field gradients, forced convective flows and large centrifugal forces. Magnetically susceptible wires in a uniform magnetic field facilitate the capture and aggregation of magnetic particles on wires, and a centrifugal force perpendicular to the magnetic force conveys the particle sludge parallel to the wires in a continuous mode. The primary focus of this thesis is multi-scale modeling and simulation to understand the underlying physics of MEC processes. The potential of MEC as an effective unit operation for biopharmaceutical downstream processing has been demonstrated. Unlike traditional batch-mode HGMS, MEC has a great advantage in that it can be operated continuously as magnetic particles captured on wire surface are constantly removed.
(cont.) A dimensionless model for simulating the trajectories of magnetic particles in combined magnetic and flow fields has been developed. The model was first applied to single wire configurations and then extended to multi-wire arrays. It was shown that modified rhombic arrays can provide high capture efficiency while maintaining low pressure drop. It is also shown that capture efficiencies based on results for clean, particle-free wires, may be seriously in error because the particle buildup that accumulates on the wire significantly distorts the flow and the magnetic fields and thus influences the particle trajectories. The dynamic buildup growth process was treated as a moving-boundary problem. Simulation results have shown that the capture efficiency decreases dramatically as particle buildup volume increases. In addition, the influence of particle chaining under magnetic dipole-dipole forces on separation efficiency has been investigated. Magnetic particles form chains as soon as they enter a background magnetic field, and are captured in the form of particle chains. The hydrodynamic force on particle chains was calculated using a 3-D CFD simulation. The capture radius calculated with considering the chaining effect is few times as great as the capture radius calculated assuming individual particles. Bench-top MEC experiments have shown that magnetic particle buildup generally comprises two layers with distinct structures: a spiky layer with all chains parallel to the magnetic field, and a densely-packed layer near the wire.
(cont.) This unique structure reflects the dominance of magnetic forces near the wire and of magnetic dipole-dipole interactions at locations further from the wire. As more and more particles accumulate on the wire surface, the centrifugal force can overcome the cohesion of the layer or the adhesion of the layer to the wire, leading to movement of the buildup material. The onset of such movement can be achieved either by increasing the centrifugal force or by increasing the buildup height. Energy and force analyses have been carried out to study various scenarios of buildup movement. For monodisperse magnetic particles, four scenarios can be expected: chain-like layer collapsing down (I), rigid body movement (II), buildup breakage (III), and mixed behavior of rigid body movement and buildup breakage (IV). A set of design formulas were derived to predict buildup structure and different scenarios. Useful scenario and operating regime diagrams were obtained. A discrete element modeling (DEM) package was developed to study the dynamics and rheological behavior of highly concentrated magnetic particle systems. For monodisperse magnetic particles, simulation results confirmed the four regions of the scenario diagram as predicted by force arguments. For polydisperse magnetic particles, DEM simulations showed that the buildup exhibits solid-like behavior when centrifugal effects are small, and liquid-like behavior with a continuous velocity profile when centrifugal effects are large.
(cont.) DEM simulations were able to predict the three dimensional effects, including the buildup profiles at the wire tip. Taken together, the results of this work provide a general strategy that can be used as a starting point for the design, evaluation, and optimization of magnetically enhanced processes that are suitable for biopharmaceutical downstream processing.
by Fei Chen.
Ph.D.
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Smith, Stephen E. "Process management applications in biopharmaceutical drug production." Thesis, Massachusetts Institute of Technology, 2011. http://hdl.handle.net/1721.1/66048.
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Thesis (M.B.A.)--Massachusetts Institute of Technology, Sloan School of Management; and, (S.M.)--Massachusetts Institute of Technology, Engineering Systems Division; in conjunction with the Leaders for Global Operations Program at MIT, 2011.Cataloged from PDF version of thesis.
Includes bibliographical references (p. 71-73).
Genzyme's manufacturing and supply chain organization is responsible for the production and delivery of medically necessary medicines for patients with rare diseases around the world. Because of the nature of the products produced at Genzyme, a lapse in operational performance has societal as well as economic impacts. Therefore increased understanding of the complex production systems at Genzyme is helpful to reduce risk and improve performance. This thesis is an analysis of a system of two critical production processes at Genzyme. These processes are studied collectively because shared resources make them a tightly coupled system. The research is presented in three sections. The first section explores the current state of the system and explains general performance trends. The second section examines the impact of scheduling complexity arising from shared resources. The third section discusses how process improvement methodologies could be applied at Genzyme. The following conclusions arise from the work conducted for this thesis. First, the performance of the system has declined due to an increase in utilization and an already high level of variability. Second, variability caused by shared resource conflicts can be minimized using new scheduling techniques. And finally, continuous improvement methods are recommended to further reduce variability and increase overall process performance.
by Stephen Smith.
S.M.
M.B.A.
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Gonçalves, Bianca Leopoldo. "Porous structures for the purification of biopharmaceuticals." Master's thesis, Faculdade de Ciências e Tecnologia, 2014. http://hdl.handle.net/10362/12128.
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This work aimed at the development of a (bio)polymeric monolithic support for biopharmaceuticals purification and/or capture. For that, it was assured that functional groups on its surface were ready to be involved in a plethora of chemical reactions for incorporation of the desired and most suitable ligand. Using cryogelation as preparation method a screening on multiple combinations of materials was performed in order to create a potentially efficient support with the minimal footprint, i.e. a monolithic support with reasonable mechanical properties, highly permeable, biocompatible, ready to use, with gravitational performance and minimal unspecific interactions towards the target molecules, but also biodegradable and produced from renewable materials. For the pre-selection all monoliths were characterized physico-chemically and morphologically; one agarose-based and two chitosan-based monoliths were then subjected to further characterizations before and after their modification with magnetic nanoparticles. These three specimens were finally tested towards adenovirus and the recovery reached 84% for the chitosan-GMA plain monolith prepared at -80°C.
Monoliths based on chitosan and PVA were prepared in the presence and absence of magnetic particles, and tested for the isolation of GFP directly from crude cellular extracts. The affinity ligand A4C7 previously selected for GFP purification was synthesized on the monolith. The results indicated that the solid-phase synthesis of the ligand directly onto the monolith might require optimization and that the large pores of the monoliths are unsuitable for the purification of small proteins, such as GFP.project PTDC/EBB-BIO/118317/2010
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Carlert, Sara. "Investigation and Prediction of Small Intestinal Precipitation of Poorly Soluble Drugs : a Study Involving in silico, in vitro and in vivo Assessment." Doctoral thesis, Uppsala universitet, Institutionen för farmaci, 2012. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-178053.
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The main objectives of the present project were to increase the understanding of small intestinal precipitation of poorly soluble pharmaceutical drugs, investigate occurrence of crystalline small intestinal precipitation and effects of precipitation on absorption. The aim was to create and evaluate methods of predicting crystalline small intestinal drug precipitation using in vivo, in vitro and in silico models. In vivo small intestinal precipitation from highly supersaturated solutions of two weakly basic model drugs, AZD0865 and mebendazole, was investigated in humans and canine models. Potential precipitation of AZD0865 was investigated by examining dose dependent increases in human maximum plasma concentration and total exposure, which turned out to be dose linear over the range investigated, indicating no significant in vivo precipitation. The small intestinal precipitation of mebendazole was investigated from drug concentrations and amount of solid drug present in dog jejunum as well as through the bioavailability after direct duodenal administration in dogs. It was concluded that mebendazole small intestinal precipitation was limited, and that intestinal supersaturation was measurable for up to 90 minutes. In vitro precipitation methods utilizing simulated or real fasted gastric and intestinal fluids were developed in order to simulate the in vivo precipitation rate. The methods overpredicted in vivo precipitation when absorption of drug was not simulated. An in vitro-in silico approach was therefore developed, where the in vitro method was used for determining the interfacial tension (γ), necessary for describing crystallization in Classical Nucleation Theory (CNT). CNT was evaluated using a third model drug, bicalutamide, and could successfully describe different parts of the crystallization process of the drug. CNT was then integrated into an in silico absorption model. The in vivo precipitation results of AZD0865 and mebendazole were well predicted by the model, but only by allowing the fundamental constant γ to vary with concentration. Thus, the in vitro-in silico approach could be used for small intestinal precipitation prediction if the in vitro concentration closely matched in vivo small intestinal concentrations.
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Villa, Adam Daniel. "Lean transformation methodology and implementation in biopharmaceutical operations." Thesis, Massachusetts Institute of Technology, 2008. http://hdl.handle.net/1721.1/44322.
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Thesis (M.B.A.)--Massachusetts Institute of Technology, Sloan School of Management; and, (S.M.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering; in conjunction with the Leaders for Manufacturing Program at MIT, 2008.Includes bibliographical references (p. 77-78).
Amgen's Operations division is responsible for the production, release and distribution of commercial and clinical products. Due to industry consolidation, impending competition and revenue impacts, Amgen is facing the need to rapidly improve the Operations division and align different manufacturing sites. In order to achieve these goals, the Operations Improvement group is leading an initiative to bring about a lean transformation of Amgen's operations.This thesis analyzes the initial operational excellence efforts underway within Amgen Operations. The analysis includes an overview of the process by which the continuous improvement methodology and strategy were constructed, the creation of a training curriculum and the initial implementation of the continuous improvement methodology at specific manufacturing sites. In addition, the thesis explores the environment in which this program operates and the cultural and business drivers that support and detract from the efforts.The following conclusions were developed as a result of the analysis of the lean transformation efforts at Amgen. First, company and industry specific nomenclature is essential to make lean principles contextually relevant for the biopharmaceutical industry. Additionally, relevant metrics are needed to facilitate multi-site alignment and drive the desired behavior. Finally, continuous improvement efforts can effectively leverage a science-based culture by applying it to a new business context.
by Adam Daniel Villa.
S.M.
M.B.A.
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David, Laura [Verfasser]. "Viral clearance for continuous biopharmaceutical processes / Laura David." München : Verlag Dr. Hut, 2020. http://d-nb.info/1219477036/34.
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Leong, Yuen Yoong. "Biopharmaceutical development networks : architecture, dynamic processes and evolution." Thesis, University of Cambridge, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.615052.
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Ashouri, P. "A dynamic simulation framework for biopharmaceutical capacity management." Thesis, University College London (University of London), 2011. http://discovery.ucl.ac.uk/1306173/.
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In biopharmaceutical manufacturing there have been significant increases in drug complexity, risk of clinical failure, regulatory pressures and demand. Compounded with the rise in competition and pressures of maintaining high profit margins this means that manufacturers have to produce more efficient and lower capital intensive processes. More are opting to use simulation tools to perform such revisions and to experiment with various process alternatives, activities which would be time consuming and expensive to carry out within the real system. A review of existing models created for different biopharmaceutical activities using the Extend® (ImagineThat!, CA) platform led to the development of a standard framework to guide the design and construct of a more efficient model. The premise of the framework was that any ‘good’ model should meet five requirement specifications: 1) Intuitive to the user, 2) Short Run-Time, 3) Short Development Time, 4) Relevant and has Ease of Data Input/Output, and 5) Maximised Reusability and Sustainability. Three different case studies were used to test the framework, two biotechnology manufacturing and one fill/finish, with each adding a new layer of understanding and depth to the standard due to the challenges faced. These Included procedures and constraints related to complex resource allocation, multi-product scheduling and complex ‘lookahead’ logic for scheduling activities such as buffer makeup and difficulties surrounding data availability. Subsequently, in order to review the relevance of the models, various analyses were carried out including schedule optimisation, debottlenecking and Monte Carlo simulations, using various data representation tools to deterministically and stochastically answer the different questions within each case study scope. The work in this thesis demonstrated the benefits of using the developed standard as an aid to building decision-making tools for biopharmaceutical manufacturing capacity management, so as to increase the quality and efficiency of decision making to produce less capital intensive processes.
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Ritchie, Elspeth Kathryn. "Application of multivariate data analysis in biopharmaceutical production." Thesis, University of Newcastle upon Tyne, 2016. http://hdl.handle.net/10443/3356.
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In 2004, the FDA launched the Process Analytical Technology (PAT) initiative to support product and process development. Even before this, the biologics manufacturing industry was working to implement PAT. While a strong focus of PAT is the implementation of new monitoring technologies, there is also a strong emphasis on the use of multivariate data analysis (MVDA). Effective implementation and integration of MVDA is of particular interest as it can be applied retroactively to historical datasets in addition to current datasets. However translation of academic research into industrial ways of working can be slowed or prevented by many obstacles, from proposed solutions being workable only by the original academic to a need to prove that time invested in developing MVDA models and methodologies will result in positive business impacts (e.g. reduction of costs or man hours). The presented research applied MVDA techniques to datasets from three scales typically encountered during investigations of biologics manufacturing processes: a single product, dataset; a single product, multi-scale dataset; a multi-product, multi-scale, single platform dataset. These datasets were interrogated in multiple approaches and multiple objectives (e.g. indictors/causes of productivity variation, comparison of pH measurement technologies). Individual project outcomes culminated in the creation of a robust statistical toolbox. The toolbox captures an array of MVDA techniques from PCA and PLS to decision trees employing k-NN. These are supported by frameworks and guidance for implementation based on interrogation aims encountered in a contract manufacturing environment. The presented frameworks ranged from extraction of indirectly captured information (Chapter 4) to meta-analytical strategies (Chapter 6). Software-based tools generated during research ranged from translation of high frequency online monitoring data as robust summary statistics with intuitive meaning (Appendix A) to tools enabling potential reduction in confounding underlying variation in dataset structures through the use of alternative progression variables (Chapter 5). Each tool was designed to fit into current and future planned ways of working at the sponsor company. The presented research demonstrates a range of investigation aims and challenges encountered in a contract manufacturing organisation with demonstrated benefits from ease of integration into normal work process flows and savings in time and human resources.
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Lanova, Nadiia, and Надія Ланова. "Gentiana species as perspective source of biopharmaceutical products." Thesis, National Aviation University, 2021. https://er.nau.edu.ua/handle/NAU/50973.
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1. Hungerer K., Kadereit J. The phylogeny and biogeography of Gentiana L. sect. Ciminalis (Adans.) Dumort.: a historical interpretation of distribution ranges in the European high mountains. Perspect Plant Ecol Evol Syst. 1998;1:121–135.
2. Astamirova M. A.-M. Anatomo-fiziologicheskie adaptatsii kriofil'nykh rasteniy tsentral'noy i vostochnoy chasti glavnogo Kavkazskogo khrebta / M. A.-M. Astamirova, M. U. Umarov, M. A. Taysumov // Vestnik KrasGAU. — 2016. — No 11. –– S. 114––122.The actuality of topic is related with preservation of Red List plants of Ukraine and obtaining target compounds of medicinal application. The aim of work was to analyzed scientific data according Gentiana species as perspective source of biopharmaceutical products.
Актуальність теми пов'язана із захистомрослин з Червоної книги України та отримання цільових сполук ідля їх медичного застосування. Метою роботи було проаналізувати наукові дані стосовно рослин виду Gentiana як перспективного джерела біофармацевтичних продуктів.
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Fung, Ho Ki. "Synthesis and development of manufacturing processes for biopharmaceuticals /." View Abstract or Full-Text, 2003. http://library.ust.hk/cgi/db/thesis.pl?BIEN%202003%20FUNG.
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