Information from the Human Genome Project is being integrated into the drug discovery and development process to permit novel drug targets to be identified, clinical trial testing to be made more efficient, and efficacious therapeutics to be approved and made widely available. Knowledge of the genome will allow for the description and quantification of disease and susceptibility to disease as informational errors or deficits. The creation and application of knowledge occur through cooperative or competitive interactions, often reflecting the perceived value of the knowledge. The public or private value of the knowledge, both for itself and for potential applications, can be determined through an understanding of the classification and characterization of this knowledge, as well as the position of the knowledge within the drug discovery and development pipeline. The transformation of knowledge from a purely public good to a quasi-private good has highlighted the need for balance between incentives for the market provision of scientific and technological knowledge by an innovator and incentives for the market provision of incremental knowledge by a follow-on developer. It has been suggested that a patent system developed for a discrete model of innovation may no longer be optimal for an information-based, cumulative model of innovation. Consequently, it is necessary to reanalyze models of intellectual property protection and strategies of knowledge sharing in biopharmaceutical discovery research. Under certain conditions, the biotech commons is an efficient institution that can preserve downstream opportunities for multiple researchers fairly and efficiently. A framework for classifying and characterizing discovery knowledge is developed in this research and the role of research consortia in preserving the biotech commons is analyzed. This study also addresses the value of pooling versus unilaterally holding knowledge, the benefits associated with appropriating from the commons, the role of knowledge characteristics in bargaining between licensor and licensee, and the overall management of the biotech commons.

Information from the Human Genome Project is being integrated into the drug discovery and development process to permit novel drug targets to be identified, clinical trial testing to be made more efficient, and efficacious therapeutics to be approved and made widely available. Knowledge of the genome will allow for the description and quantification of disease and susceptibility to disease as informational errors or deficits. The creation and application of knowledge occur through cooperative or competitive interactions, often reflecting the perceived value of the knowledge. The public or private value of the knowledge, both for itself and for potential applications, can be determined through an understanding of the classification and characterization of this knowledge, as well as the position of the knowledge within the drug discovery and development pipeline. The transformation of knowledge from a purely public good to a quasi-private good has highlighted the need for balance between incentives for the market provision of scientific and technological knowledge by an innovator and incentives for the market provision of incremental knowledge by a follow-on developer. It has been suggested that a patent system developed for a discrete model of innovation may no longer be optimal for an information-based, cumulative model of innovation. Consequently, it is necessary to reanalyze models of intellectual property protection and strategies of knowledge sharing in biopharmaceutical discovery research. Under certain conditions, the biotech commons is an efficient institution that can preserve downstream opportunities for multiple researchers fairly and efficiently. A framework for classifying and characterizing discovery knowledge is developed in this research and the role of research consortia in preserving the biotech commons is analyzed. This study also addresses the value of pooling versus unilaterally holding knowledge, the benefits associated with appropriating from the commons, the role of knowledge characteristics in bargaining between licensor and licensee, and the overall management of the biotech commons.

Neaustinė medžiaga gali būti nauja vaisto forma, todėl yra svarbu rasti biofarmacinį tyrimą, kuris būtų tinkamas įvertinti vaistinių medžiagų atsipalaidavimą iš neaustinės medžiagos. Tyrimo tikslas buvo atlikti tirpimo testo modifikacijas siekiant jį pritaikyti nustatant vaistinių medžiagų atpalaidavimą iš neaustinės medžiagos. / Nonwoven fabric can be a new drug form, it is important to find a biopharmaceutical assay, which would be suitable to assess the drug release from nonwoven fabric. Main aim was to carry out the modifications of the dissolution test in order to adapt it to the process of medicinal substance release from nonwoven fabric.

Darbo tikslas: sumodeliuoti apsauginio poveikio rozmarinų puskietes vaisto formas ir įvertinti jų kokybę. Darbo uždaviniai: Išnagrinėti mokslinėje literatūroje kvapniojo rozmarino (Rosmarinus officinalis L.) biologinį poveikį ir pritaikymo galimybes puskiečių preparatų gamyboje; parinkti rozmarinų ištraukų, kaip veikliosios medžiagos, sudėtį ir įvertinti jų kokybę bei ištirti jų biologinį aktyvumą tyrimais in vitro; sumodeluoti puskietes vaisto formas su rozmarinų ištraukomis ir ištirti jų kokybę; nustatyti pagrindo įtaką fenolinių junginių atpalaidavimui iš sumodeliuotų puskiečių vaisto formų su rozmarinų ištraukomis. Metodai: Rozmarinų ištraukų kokybė įvertinta nustatant spektrofotometriniu metodu fenolinių junginių kiekį ir antioksidacinį aktyvumą DPPH radikalų surišimo metodu. Antimikrobinis aktyvumas vertintas pagal Ph Eur. 01/2002, 2.6.12. Rozmarinų puskiečių preparatų kokybė įvertinta nustatant vienalytiškumą, pH reikšmę, antimikrobinį aktyvumą, fenolinių junginių atpalaidavimą iš puskiečių sistemų tyrimu in vitro. Rezultatai: Didžiausias fenolinių junginių kiekis (14,139±0,417mg/ml) nustatytas rozmarinų ištraukose 1:1, kai ekstrahentu naudotas 40 proc. (V/V) etanolis, o mažiausias (2,296±0,268mg/ml) – naudojant 96 proc. (V/V) etanolį. Tyrimų metu nustatyta, kad stipresnis antioksidacinis (EC50=9,63±0,34µg/ml) ir antimikrobinis aktyvumas būdingas rozmarinų ištraukoms 1:1, kai ekstrahentu naudojamas 40 proc. (V/V) etanolis. Rozmarinų puskiečių preparatų pH reikšmė -... [toliau žr. visą tekstą] / Work aim: to model protective effect rosemary semi-hard drug forms and evaluate their quality. Work objectives: To analyze biological effect of sweet rosemary (Rosmarinus officinalis L.) and application opportunities in the production of semi-hard preparations provided in scientific literature; to select the composition of rosemary extracts, as the active substance, and to evaluate their quality as well as analyze their biological activity by in vitro tests; to model semi-hard drug forms with rosemary extracts and to analyze their quality; to determine the influence of the basis on the release of phenolic compounds from the modelled semi-hard drug forms with rosemary extracts. Methods: The quality of rosemary extracts was evaluated spectrophonometrically determining the amount of phenolic compounds and antioxidant activity by DPPH radical bonding method. Antimicrobial activity was evaluated according to Ph Eur. 01/2002, 2.6.12. The quality of rosemary semi-hard preparations was evaluated by determining homogeneity, pH value, antimicrobial activity, release of phenolic compounds from semi-hard systems through in vitro test. Results: The largest amount of phenolic compounds (14,139±0,417mg/ml) was found in rosemary extracts 1:1, when 40 percent (V/V) ethanol was used as the extractant, and the least amount (2,296±0,268mg/ml) – using 96 percent (V/V) ethanol. During the tests it was found that stronger antioxidant (EC50=9,63±0,34µg/ml) and antimicrobial activity is typical to... [to full text]

A cefalexina é um antibiótico semi-sintético, derivado das cefalosporinas, que exibe amplo espectro de ação, sendo largamente empregado por via oral. No Brasil é comercializado na forma de comprimido revestido, por cinco laboratórios farmacêuticos diferentes. No presente estudo foram avaliados, do ponto de vista biofarmacotécnico, 2 especialidades farmacêuticas (A e B), sob a forma de comprimidos revestidos, contendo 500 mg de cefalexina, disponíveis no mercado nacional. A análise in vitro foi realizada para dois lotes (1 e 2) de cada produto (A e B), através de ensaios físicos e físico-químicos (peso médio, dureza, umidade, teor de cefalexina, teste e perfil de dissolução), com a finalidade de verificar sua conformidade com especificações estabelecidas pelos compêndios oficiais. Estudos de cinética de dissolução foram empregados para avaliação mais precisa quanto às características biofarmacotécnicas in vitro das respectivas formulações. Os estudos de bioequivalência entre os produtos A e B (lote 2) empregaram delineamento experimental cruzado aleatório, em dois períodos, utilizando-se 24 voluntários. Os parâmetros farmacocinéticos empregados nesta avaliação foram obtidos a partir de dados de excreção urinária da cefalexina, sendo sua concentração na urina determinada por cromatografia líquida de alta eficiência, através de metodologia desenvolvida e validada no presente estudo. A bioequivalência entre os produtos foi determinada a partir da análise estatística (ANOVA) dos seguintes dados: quantidade de cefalexina acumulada excretada na urina (Du acumulado); quantidade total de cefalexina excretada na urina no tempo infinito (Du∞); velocidade máxima de excreção urinária ([Ddu/dt]max). Os resultados das análises físicas e físico-químicas indicaram que ambos os produtos estudados apresentaram-se dentro das especificações farmacopéicas. Na avaliação da bioequivalência entre os mesmos, obtiveram-se intervalos de confiança dentro dos limites estabelecidos internacionalmente (80 a 125%), para todos os parâmetros avaliados, comprovando, desta forma, que os produtos A e B são bioequivalentes e, portanto, intercambiáveis. / Cephalexin is a semi-synthetic cephalosporin-derived antibiotic which has an extensive action spectrum, widely used by oral administration. In Brazil, where it is largely marketed, in a tablet coated way, five differents brands can be found. The goal of this study was to evaluate from the biopharmaceutic point of view two cephalexin 500 mg tablet brands (A and B) availables in brazilian market. In order to check its accordance with official pharmacopeial specifications, two lots (1 and 2) of each brand (A and B) were analysed in vitro through physical and physical-chemical assays in vitro tests (average weight, hardness, wet, cephalexin content, dissolution test). Both formulations were also submitted to dissolution kinetics studies to reach an accurate evaluation of their in vitro biopharmaceutics features. The bioequivalence studies between A and B brands (Iot 2) was based on an open randomized two period cross over design with twenty-four male and female healthy volunteers. Pharmacokinetics parameters used in this evaluation were obtained from cephalexin urinary excretion data; to assess urine cephalexin concentrations a high performance liquid chromatographic assay developed and validated in this study was used. Bioequivalence was confirmed using a multiway ANOVA and when the 90 % confidence interval for accumulated cephalexin amount excreted in urine (Du accumulated); total amount of cephalexín excreted in urine (Du∞ ) and maximum rate of urinary excretion ([dDu/dt]max), fell within the interval 80-125 %.No discrepancies between both cephalexin brands in physical-chemycal tests were found. Confidence intervals for pharmacokinetics parameters were inside the bioequivalence limits according with the international atandars (80-125%), demonstrating that A and B formulations can be considered bioequivalent and therefore interchangeable.

A biodisponibilidade é o fator determinante da eficácia clínica de um fármaco e depende diretamente das propriedades de solubilidade e permeabilidade da substância ativa. O Sistema de Classificação Biofarmacêutica (SCB), baseado nestas características, consolidou-se nos últimos anos como ferramenta de auxílio na predição da biodisponibilidade de fármacos. O SCB tem sido empregado no desenvolvimento de formas farmacêuticas, contendo novos fármacos ou não, e no registro de medicamentos genéricos, por conta das limitações técnicas, econômicas e éticas para a realização dos ensaios diretos de biodisponibilidade. Assim, a avaliação das propriedades de solubilidade e permeabilidade dos fármacos, embora indiretamente, oferece objetivas indicações sobre a eficácia dos medicamentos, com vantagem de consolidar modelos in vitro, mais facilmente reprodutíveis, sem trazer riscos a voluntários sadios. Dentre os estudos de solubilidade destaca-se o método do equilíbrio que emprega a técnica de shake-flask. Para a determinação da permeabilidade in vitro, diferentes técnicas têm sido empregadas, dentre as quais destacam-se modelos que empregam tecido intestinal de animais. O presente trabalho teve como objetivos a avaliação da solubilidade e da permeabilidade de fármacos antirretrovirais (lamivudina e zidovudina) e o desenvolvimento de protocolo para determinação da permeabilidade em segmentos de intestino de ratos, por meio de modelo in vitro em ensaios com células de Franz. A solubilidade dos fármacos propostos foi caracterizada pela técnica shake-flask e por meio da dissolução intrínseca, sendo que os resultados permitiram concluir que, segundo o SCB, os fármacos zidovudina e lamivudina apresentam alta solubilidade. Os ensaios de permeabilidade demonstram que o método proposto é viável e os valores de permeabilidade da lamivudina e da zidovudina sugerem que ambos os fármacos podem ser classificados como de alta permeabilidade. / Bioavailability is the determinant of the clinical efficacy of a drug and is directly dependent on the properties of solubility and permeability of the active substance. The Biopharmaceutical Classification System (BCS), based on these characteristics, has become in recent years as a tool to aid in predicting the bioavailability of drugs. The BCS has been used in the development of dosage forms, containing new drugs or not, and the registration of generic drugs, since there are technical limitations, economic and ethical guidelines for the testing of direct bioavailability. Thus, the evaluation of the solubility and permeability of the drugs, although indirectly, provides objective indications on the effectiveness of medicines, with the advantages of consolidating in vitro models more easily reproducible without bringing risk to healthy volunteers. Among the solubility studies highlight the shake-flask method, recommended by regulatory agencies. To determine the in vitro permeability, different techniques have been employed, among which stand out models based on intestinal tissue obtained from different animals. This study aims to evaluate the solubility and permeability of antiretroviral drugs (lamivudine and zidovudine), and the development of protocol for the determination of permeability in intestine segments of rats using in vitro model in experimental Franz cells. So far, the solubility of proposed drugs was characterized by shake-flask method and through the intrinsic dissolution. About the solubility, results showed that, according to BCS, the drugs zidovudine and lamivudine has high solubility. About the intrinsic dissolution, results showed agreement with the results of the solubility. Permeability tests showed that the proposed method is feasible and the permeability values of lamivudine and zidovudine suggest that both drugs can be classified as high permeability.

No description available.

No description available.

No description available.

The biopharmaceutical industry has experienced remarkable progress in the upstream production capacity of life-saving proteins. This is while the downstream processing has failed to keep pace, including unit operations which are working close to their physical limit with no economy of scale. Column chromatography which is an integral unit in different stages of downstream purification is considered as the major bottleneck in this section. The packed-bed resin media is costly and the processes are labor-intensive and extremely time consuming. Membrane chromatography which uses a stack of adsorptive membranes as the chromatographic media is one of the most promising alternatives for conventional chromatography techniques. The performance of membrane adsorbers is consistent over a wide range of flow rates which is owing to the dominance of convective solute transport as opposed to the diffusion-based nature of mass transfer within the pores of the resin beads. This translates to much higher productivity and considerably lower buffer consumption (even as high as 95%), leading to much lower overall processing costs. The other advantages are significantly lower footprints and decreased pressure drops, both contributing to diminished capital costs. Membrane adsorbers are greatly scalable and used in a single-use manner. The latter eliminates the cleaning and validation steps and brings about much shorter processing times and higher flexibility in process development. Due to the performance advantages of membrane chromatography, this technique is now widely used in purification of high volumes of samples in late-stage polishing. Currently available membrane adsorbers have radial-flow spiral-wound configuration with high frontal surface area to bed height ratio according to which dilute impurities are removed in a flow-through format at very high flow rates and low pressure drops. Nevertheless, they fail to give high-resolution for bind-and-elute separations which makes them unsuitable for many unit operations, highly restricting their application. Severe design deficiencies such as large dead volumes and varying membrane area over the bed height result in broad and poorly resolved peaks. Herein, a novel device design was successfully developed which addresses the abovementioned shortcomings. The laterally-fed membrane chromatography (LFMC) devices house a stack of rectangular membrane sheets with two rectangular lateral channels on both sides of the stack as the feed and permeate channels. The design offers balanced pressure over the sides of the stack as well as even solute flow path lengths due to which the solute residence time is very uniform. Also, the small dead volumes minimize the dispersion effects. These features make the LFMC technology highly suitable for bind-and-elute applications, the improvement which is brought about by a simple design. The devices are easy to fabricate and highly scalable. The LFMC devices containing cation-exchange (CEX) membranes with 7 mL bed volume were examined for bind-and-elute separation where they outperformed the equivalent commercially available radial-flow devices. The design was further modified to give even lower dead volumes and more cost-effective fabrication. The latest embodiment of the device gave resolutions which were comparable with the ones obtained with the commercially packed resin columns in 1 mL and 5 mL scale with consistency over wide range of flow rates. The results were all acquired using a three component model protein system. Upon the approval of suitability of the device for bind-and-elute separation, the CEX-LFMC was used for purification of monoclonal antibodies (mAbs), the largest class of biopharmaceuticals. The device showed great performance in separation of mAb charge variants when extensively shallow gradients (60 membrane bed volumes) were required. The devices offered very stable conductivity gradients at high flow rates. LFMC devices in three different preparative scales gave great performance in separation of mAb aggregates which was approved for different mAb samples. The other application studied with the CEX-LFMC devices was the single-step preparative purification of mono-PEGylated proteins which is as well very challenging due to the physicochemical similarities between the target molecules and the impurities. Collectively, the LFMC devices combine the high-resolution with high-productivity which is highly desirable in downstream purification of biological molecules with great potential to expand the application of membrane chromatography. Finally, the LFMC devices were modified to adapt the analytical scale where they were integrated with a stack of hydrophilized PVDF membranes. The device successfully delivered ultra-fast separation of mAb aggregates in less than 1.5 minutes based on hydrophobic interaction membrane chromatography (HIMC). The assay times achieved with the HI-LFMC technique outclassed the currently available ultra-high performance chromatography (UPLC) methods at the same time with being extremely cost-effective. The application of the LFMC technology in analytical scale has great potential to offer cheap and rapid analysis in process development and quality control section of biopharmaceutical manufacturing. / Thesis / Doctor of Philosophy (PhD)