Falsified medicines, verify before you buy

Treballs Finals de Grau de Farmàcia, Facultat de Farmàcia, Universitat de Barcelona, 2017. Tutor/a: Marián Carretero.[eng] Counterfeit medicines are a global public health risk. From February 9th, 2019, the new legislation will regulate the pharmaceutical products for human consumption, which aims to avoid into the supply chain, identity drug counterfeit, background or origin, requiring individual packaging identification of all prescription drugs sold on the Spanish market. The pharmaceutical industry, wholesalers and pharmacy offices should be able to adapt to requirements that are in constant transition. Despite of the existence of the Delegated Regulation (EU) 2016/161, which shows the unification of the strategies to follow, the differences remain important enough to detect all illicit products on the market. In this review, it has analyzed the evolution of European legislation and safety devices. The detection of spurious products, regularization and control and their consequences, advice for the patient and the incidence rate, are topics covered in depth in this review. Other aspects, such as the factors that influence the counterfeiting are also reviewed. It is urgently needed, improvements in surveillance, including the detection of breaches of security, collection, analysis and dissemination of data to address the needs of public health to combat the global trade of counterfeit medicines. The main purpose of the current legislation is the safety of the consumer and harmonization within the EU.[cat] Los medicamentos falsificados representan un riesgo para la salud pública mundial. A partir del 9 de febrero de 2019, la nueva normativa comunitaria regulará los productos farmacéuticos para el consumo humano. Ésta tiene por objetivo, evitar en la cadena de suministro, medicamentos falsificados en su identidad, trayectoria u origen, obligando a la identificación individual de los envases de todos los medicamentos de prescripción vendidos en el mercado español. La industria farmacéutica, mayoristas y oficinas de farmacia deben ser capaces de adaptarse a unos requisitos que se encuentran en constante transición. A pesar de la existencia del Reglamento Delegado (UE) 2016/161, que muestra la unificación de las estrategias a seguir, las diferencias siguen siendo lo suficientemente importantes como para detectar todos los productos ilícitos en el mercado. En esta revisión, se ha analizado la evolución de la legislación Europea entorno a los medicamentos falsificados, y luego se ha establecido disposiciones detalladas relativas a los dispositivos de seguridad. La detección de productos espurios, la regularización, control y sus consecuencias, consejos para el paciente y el índice de incidencia, son los temas tratados en profundidad en el trabajo. También se repasan otros aspectos como los factores que influyen en la falsificación. Se precisan urgentemente mejoras en la vigilancia, incluida la detección de infracciones de seguridad, recopilación, análisis y difusión de datos para abordar las necesidades de salud pública con el fin de combatir el comercio mundial de medicamentos falsificados. La finalidad principal de la legislación actual es garantizar la seguridad del consumidor y la armonización dentro de la UE

Wine Cunterfeiting: Development of fast, non-destructive and multifactorial laser-based spectrochemical methods for authentication of bottled wine

378 p.La presente Tesis Doctoral pretende avanzar en el desarrollo de una herramienta analítica que permita certificar la autenticidad de un vino de forma inequívoca mediante técnicas analíticas no invasivas (es decir, prácticamente inapreciable a simple vista) como son la ablación laser con plasma de acoplamiento inductivo-espectrometría de masas (LA-ICPMS) y las espectroscopias Raman e Infrarroja, que permiten el análisis de una muestra sólida sin necesidad de procesarla y sin inducir degradación o alteración apreciable alguna. Mediante la metodología desarrollada se pretende establecer el perfil elemental y molecular del vidrio, el papel, la tinta y la cápsula de las botellas de vino

Wine Cunterfeiting: Development of fast, non-destructive and multifactorial laser-based spectrochemical methods for authentication of bottled wine

378 p.La presente Tesis Doctoral pretende avanzar en el desarrollo de una herramienta analítica que permita certificar la autenticidad de un vino de forma inequívoca mediante técnicas analíticas no invasivas (es decir, prácticamente inapreciable a simple vista) como son la ablación laser con plasma de acoplamiento inductivo-espectrometría de masas (LA-ICPMS) y las espectroscopias Raman e Infrarroja, que permiten el análisis de una muestra sólida sin necesidad de procesarla y sin inducir degradación o alteración apreciable alguna. Mediante la metodología desarrollada se pretende establecer el perfil elemental y molecular del vidrio, el papel, la tinta y la cápsula de las botellas de vino

Citotoxicidade in vitro da ticlopidina em linhas celulares Hep G2 e Caco 2

The present dissertation is divided into 3 parts. In the Part I is described the research work conducted at the Health Sciences Research Center of the University of Beira Interior (CICS–UBI, Covilhã) with the aim of evaluating the cytotoxicity of ticlopidine and Hypericum perforatum extractin hepatic and intestinal epithelium cell lines. Ticlopidine is a prodrug mainly used in the prophylaxis of thromboembolic complications in patients with thromboembolic disease, especially if they are aspirin-intolerant. It is associated with multiple drug interactions, mostly via cytochrome P450 (CYP)-inhibition. H. perforatum has been widely used as an antidepressant, anti-inflammatory and antimicrobial agent, being considered, however, responsible for numerous herb-drug interactions due to the induction of CYP enzymes and P-glycoprotein expression. Given the predisposition of both these compounds to induce interactions when co-administered with other substances, it was considered relevant to study their cytotoxicity, alone and in combination, in hepatic – Hep G2 – and intestinal epithelium – Caco 2 – cell lines. The cells were incubated with various concentrations of ticlopidine and/or H. perforatum extract at various periods of time and the putative cytotoxicity induced by each incubation condition was assessed through cellular viability (MTT) assays. Overall, the results showed that ticlopidine may be cytotoxic in both Hep G2 and Caco 2 cells, depending on its concentration and period of incubation, and that the simultaneous incubation of cells with both the compounds promotes a similar pattern to that observed when cells are incubated with the extract alone and it is dose-, time- and cell line-dependent. The Part II refers to the hospital pharmacy internship performed at the Istituti Fisioterapici Ospedalieri, in Rome, between February 2nd and April 29th 2015. Finally, the Part III refers to the community pharmacy internship carried out in the Nunes Feijão Pharmacy, near Barreiro, between May 11th and August 10th 2015.A presente dissertação encontra-se dividida em 3 partes. Na Parte I encontra-se descrito o trabalho de investigação realizado no Centro de Investigação em Ciências da Saúde da Universidade da Beira Interior (CICS-UBI, Covilhã) com o objetivo de avaliar a citotoxicidade da ticlopidina e de um extrato de hipericão em células hepáticas e do epitélio intestinal. A ticlopidina é um pró-fármaco oral apresentado apenas na forma de comprimidos e utilizado essencialmente na profilaxia de eventos cardiovasculares major em pessoas com doença tromboembólica, especialmente se forem intolerantes ao ácido acetilsalicílico. Requer bioativação in vivo pelas enzimas do citocromo P450 (CYPs) para formar o seu metabolito ativo, que se liga irreversivelmente ao recetor P2Y12 nas plaquetas, inibindo a sua ativação e agregação induzidas pela adenosina difosfato (ADP) de uma forma tempo- e dose-dependente. Tratando-se de um potente inibidor mecanismo-dependente de algumas CYPs, inibindo até o seu próprio metabolismo, a ticlopidina está associada a múltiplas interações farmacológicas e não farmacológicas. Além disso, apresenta diversas reações adversas hematológicas, pelo que o seu uso deve ser monitorizado nos primeiros três meses de tratamento. Os efeitos adversos são reversíveis após a retirada do fármaco. O hipericão, uma das mais antigas e bem estudadas plantas medicinais, tem sido amplamente utilizado como agente antidepressivo, anti-inflamatório e antimicrobiano. Apresenta-se sob diversas formas farmacêuticas, sendo os extratos considerados como a mais importante. Barato e fácil de obter, torna-se uma alternativa às terapias farmacológicas comuns, sem apresentar efeitos adversos major. Encontram-se identificados mais de 150 constituintes: a hipericina é considerada o composto farmacologicamente mais importante, enquanto à hiperforina é atribuída a responsabilidade pela maioria das interações medicamentosas. De facto, o hipericão é um potente indutor das CYPs e da expressão da glicoproteína-P (P-gp). De acordo com o efeito farmacológico demonstra diversos mecanismos de ação; enquanto antidepressivo, atua de uma forma semelhante aos inibidores seletivos da recaptação de serotonina, podendo originar um síndrome serotoninérgico ou interações farmacodinâmicas se coadministrado com fármacos que aumentam a sinalização deste neurotransmissor. Dada a predisposição de ambos os referidos compostos para induzir interações quando coadministrados com outras substâncias considerou-se relevante estudar a sua citotoxicidade, sozinhos e em associação, em células hepáticas – Hep G2 – e do epitélio intestinal – Caco 2. As células foram incubadas com várias concentrações de ticlopidina e/ou de extrato de hipericão durante vários períodos de tempo e a citotoxicidade putativa induzida por cada condição de incubação foi avaliada através de ensaios de viabilidade celular (MTT). No geral, a ticlopidina mostrou-se significativamente citotóxica em ambas as linhas celulares apenas na concentração de 200 µM; todavia, as células revelaram uma recuperação da viabilidade celular após 24 h de incubação. Quanto ao hipericão, apresentou maior toxicidade na linha celular hepática, comparativamente aos resultados obtidos para a linha celular intestinal. Mais uma vez, as células recuperaram e voltaram a proliferar após 72 h de incubação. Da incubação com ambos os compostos obtiveram-se resultados semelhantes aos obtidos na incubação apenas com hipericão, principalmente nas células Caco 2. Nas células Hep G2, a incubação com ambos os compostos mostrou-se menos citotóxica que a incubação com hipericão sozinho. A recuperação da viabilidade celular apresentada por ambas as linhas celulares na incubação com os compostos sozinhos ou em combinação sugere, nas células Hep G2, a formação de conjugados de glutationa não tóxicos e, nas células Caco 2, um mecanismo de efluxo pela P-gp. Em suma, os resultados obtidos mostraram que a ticlopidina pode ser citotóxica em ambas as linhas celulares Hep G2 e Caco 2, dependendo da sua concentração e do período de incubação, e que a incubação simultânea das células com ambos os compostos promove um padrão similar ao observado quando as células foram incubadas com o extrato sozinho, sendo a toxicidade dependente da dose, do tempo e da linha celular. A Parte II refere-se ao estágio em farmácia hospitalar realizado nos Istituti Fisioterapici Ospedalieri, em Roma, entre 2 de fevereiro e 29 de abril de 2015. Finalmente, a Parte III refere-se ao estágio em farmácia comunitária feito na Farmácia Nunes Feijão, perto do Barreiro, entre 11 de maio e 10 de agosto de 2015

An Integrated Control and Data Acquisition System for Pharmaceutical Capsule Inspection

Pharmaphil Inc. manufactures two-part gelatin capsules for the pharmaceutical industry. Their current methods of quality control of their product is by performing manual inspection of every carton of capsules prior to shipment. In today\u27s modern manufacturing world, more efficient and cost-effective means of quality control exist. It is Pharmaphil\u27s desire to develop a custom machine vision system to replace manual inspection with a potential opportunity in the capsule manufacturing quality control market. In collaboration with the Electrical and Computer Engineering Department at the University of Windsor, a novel system was developed to achieve this goal. The objective was to develop a system capable of inspecting 1000 capsules per minute with the ability to detect holes, cracks, dents, bubble, double caps and incorrect colour or size. Using an antiquated machine vision system for capsule inspection from the mid-nineties as a base, a modern inspection system was developed that performed faster and more thorough inspections. As a measure to minimize the overall system cost as well as to increase flexibility, a full custom design was undertaken. The resulting system follows a traditional machine vision system whereby the main components include an image acquisition component, a processing unit and machine control. The designed system uses custom USB2.0 cameras to acquire images, a standard desktop PC to process image data and a custom machine control board to perform machine control and timing. The system operates with four identical quadrants operating in parallel to increase throughput. The final system developed provided a proof-of-concept for the approach taken. The machine control and image acquisition component of the system yielded a maximum throughput of 1200 capsules per minute. After incorporating image inspection, the final result was a system that was capable of inspecting capsules at a rate of about 800 capsules per minute with high accuracy. With optimizations, the system throughput can be further improved. The findings throughout the development of the prototype system provide an excellent basis from which the first generation commercial unit can be designed

Polymers in pharmaceutical additive manufacturing: A balancing act between printability and product performance

Materials and manufacturing processes share a common purpose of enabling the pharmaceutical product to perform as intended. This review on the role of polymeric materials in additive manufacturing of oral dosage forms, focuses on the interface between the polymer and key stages of the additive manufacturing process, which determine printability. By systematically clarifying and comparing polymer functional roles and properties for a variety of AM technologies, together with current and emerging techniques to characterize these properties, suggestions are provided to stimulate the use of readily available and sometimes underutilized pharmaceutical polymers in additive manufacturing. We point to emerging characterization techniques and digital tools, which can be harnessed to manage existing trade-offs between the role of polymers in printer compatibility versus product performance. In a rapidly evolving technological space, this serves to trigger the continued development of 3D printers to suit a broader variety of polymers for widespread applications of pharmaceutical additive manufacturing

Advanced Materials in Drug Release and Drug Delivery Systems

Development of new drug molecules is costly and requires longitudinal, wide-ranging studies; therefore, designing advanced pharmaceutical formulations for existing and well-known drugs seems to be an attractive device for the pharmaceutical industry. Properly formulated drug delivery systems can improve pharmacological activity, efficacy and safety of the active substances. Advanced materials applied as pharmaceutical excipients in designing drug delivery systems can help solve problems concerning the required drug release—with the defined dissolution rate and at the determined site. Novel drug carriers enable more effective drug delivery, with improved safety and with fewer side effects. Investigations concerning advanced materials represent a rapidly growing research field in material/polymer science, chemical engineering and pharmaceutical technology. Exploring novel materials or modifying and combining existing ones is now a crucial trend in pharmaceutical technology. Eleven articles included in the the Special Issue “Advanced Materials in Drug Release and Drug Delivery Systems” present the most recent insights into the utilization of different materials with promising potential in drug delivery and into different formulation approaches that can be used in the design of pharmaceutical formulations

Study of computational method, Biopharmaceutics, Pharmacokinetics and Develop a Integrated Computational Prototype as Bioinformatics Application

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Microgel Suspensions for Tissue Engineering and Tumor Models

Human tissues are complex materials with hierarchical organizations of a variety of different cell types and matrix properties. Capturing these properties in vitro has been a chief goal of tissue engineering since its inception. However, full recapitulation of native tissue structures and functions remains unresolved. This thesis explores a new methodology to capture native tissue’s complexity using hydrogel matrices composed of microgel suspensions. In this thesis, I developed a new microgel particle using a water in oil emulsion technique with methacrylated gelatin. The mechanics and size of individual microgels are readily tunable. Packing particles tight enough forms jammed suspensions that enable direct extrusion of the particles as a 3D printing ink. And exposure to purple light photocrosslinks microgels together into annealed cell-laden matrices for long term culture. When jammed, microgels also function as a support bath for 3D printing. To demonstrate the utility of a microgel support bath, I created a model tumor microenvironment to study cancer metastasis. Direct writing of a Pluronic sacrificial ink into a stromal cell-microgel suspension was used to form endothelialized vessel structures. Further 3D printing of melanoma cancers enabled freeform spatial control over tumor architectures and relative distances to vessel structures. Tumor cells were found to migrate into the prototype vessels as a function of distance. I next explored microgel suspensions as a platform for stem cell differentiation. Current efforts to recapitulate native tissue structures using stem cells lack tight spatial control over cell locations and matrix architectures. To address this issue, I first demonstrate how modifications to microgel properties can direct stem cell differentiation. By combining varied microgels together, I created gradients of microgel sizes and stiffness to spatially direct cell lineage using adipose derived stromal cells (ADSCs) as a model stem cell system. Further optimizations of cell printing enabled high spatial control over cell location and differentiation outcomes. As a final demonstration, I created heterogenous matrices of microgels with interspersed or directly printed functional microcapsules. The novel capsule design enabled the highest recorded loading of protein in a microscale volume, accommodating up to 40 mg/mL of biologically active species within a single microcapsule. By adding in enzymes, gas releasing hydrogels, and nanoparticles, I successfully perturbed the local gas concentrations within the matrix. I demonstrate the capsules capacity as a 3D printable ink, enabling spatial control over gradients of gas release to direct secondary messenger signals. The modularity of the system was demonstrated through several potential applications including attenuation of peroxide activity to combat radiation damage, and creating hypoxic cell culture conditions for wound healing and tumor microenvironment mimicry Together, these findings demonstrate the versatility of GelMa microgel suspensions as a tool with unique advantages for biofabrication and scaffolding for tissue engineering. This work has scope across the fields of material science, bioengineering, regenerative medicine, and cancer modeling

Electrodeless electro hydrodynamic printing of personalized drug dosages

There is compelling evidence that variability in drug efficacy in individuals depends on their genetic fingerprints. These observations have given rise to the concept of personalized therapy whose ultimate goal is to develop medicinal agents designed for each niche of the population and individual patients according to their genetic background. The drawback in current pharmaceutical technologies is that most processes are designed to target large population and are unable to meet the demand of small-scale manufacturing of tailored therapeutics with diverse range of physical properties. One of the major challenges lie in developing efficient and cost effective methods of manufacturing personalized treatments. Noncontact drop-on-demand (DOD) systems (i.e., drops are formed only as required) appear to be the most promising platform technology for small-scale manufacturing of personalized treatments. As a digital technology, DOD dosing is able to deposit precisely controlled amounts of material at exact locations without waste, rendering it especially attractive for use with expensive pharmaceutical products. It would provide the capability to form an individual dosage unit by printing a vast array of predefined amounts of therapeutics arranged in a specific pattern on a carrier substrate to achieve a desired drug release profile. However, current DOD methods developed for chemically and thermally stable, low-viscosity inks are of limited use for pharmaceuticals due to fundamentally different functional requirements. In this dissertation, a recently developed DOD method for gentle printing of personalized medicines is presented. To eliminate adverse effects of electrochemical reactions at the fluid-electrode interface, the fluid was infused into an electrically insulating nozzle to form a pendant drop that served as a floating electrode capacitively coupled to external electrodes. A short voltage pulse was applied to the electrodes to stretch the drop into a liquid bridge that broke up creating a sessile drop on the substrate which could be post-processed into a final dosage form. Versatility was proved in experiments on fluids spanning over three orders of magnitude in viscosity and electric conductivity. This method can be used for printing fluids of different physical properties in pharmaceutical, biomedical, and biotechnology applications. Model for pendant drop and scaling analysis which captured the essential physics of electrodless electrohyrodynamic drop dynamics is presented. This analysis describes the characteristics of the operating regimes and provides critical design guideline. To demonstrate the capability of electrodeless DOD for printing personalized dosages, assembled unit dosages were prepared by precisely loading porous hydroxy methylcellulose film matrix with controlled drops of model drugs dissolved in lowly volatile polyethylene glycol carrier. Dissolution tests were performed following United States Pharmacopeia (USP) protocol, and the drug release data was analyzed to identify the underlying drug release mechanisms from the assembled unit dosages. Data showed that the DOD method met the reproducibility requirement critical for content uniformity and that the porous film rapidly disintegrated resulting in instant release of drug which could be useful in fast orally dissolvable medicinal film dosage forms