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ÖgeDevelopment of controlled release tablets and evaluation of release behavior for the treatment of Multiple Sclerosis (MS)(Graduate School, 2025-02-10)Polymers have played an integral role in advancing drug delivery technology by providing controlled release of therapeutic agents at fixed doses over long periods of time, cyclic dosing, and adjustable release of both hydrophilic and hydrophobic drugs. In the field of pharmaceuticals, achieving controlled and targeted drug release is of paramount importance. Over the years, researchers and scientists have explored various approches to optimize drug delivery systems. Among these innovative strategies, polymers effect has emerged as a game-changer. Polymers, with their unique propeties and versatile nature, have revolutionized on drug release within the body. The aim of this study is to develop a controlled drug release mechanism for the active ingredient fampridine, used in the treatment of multiple sclerosis (MS), by designing three different prototypes and presenting the release behavior results of fampridine. The first of the prototypes designed for this purpose encompasses modifications to the unit formulation of the reference product, Fampyra (10 mg extended-release tablets, Biogen Pharmaceuticals). This aims to observe the effect of the type and amount of polymer on the release of fampridine in the conventional dry blending process. Fampridine-containing tablets were prepared using the dry blending process and were compressed at 6-6.5 KN, 20 RPM. In vitro release tests were performed using USP Apparatus II (Paddle). The receptor media contained phosphate buffer pH 6.8, and tests were performed under the conditions of 37°C ± 0.5°C, 50 RPM for 24 hours. In vitro release tests were conducted using Waters HPLC with a UV or PDA detector. For the column, Waters Symmetry C18 100×4.6×3.5μ was used. All methods are validated according to ICH guidelines. Different types of Hydroxypropyl Methyl Cellulose (HPMC), known as K100LV, K100M, and K200M, were used as a polymer filler at various ratios in tablet formulations. All results were compared with the reference product, Fampyra. The purpose of this prototype is to determine how much the cellulose-based polymer present in the reference product affects the release of fampridine. It aims to investigate the impact of using different polymers on both the release of fampridine-containing tablets and the morphological characteristics of the tablets. The significance of this prototype lies in its ability to prevent patented excipients in the unit formula of original products from becoming an obstacle in the development of generic drugs, and to create a generic drug formulation that can achieve a similar effect without infringing on patents. Initially, the unit formula of the reference product was used directly; however, different excipients have been included in the unit formula to address the issues arising in the formulation of the generic drug. 1st prototype's results showed that the type and proportion of polymer used in the unit formulation during the conventional dry blending process significantly affect the release of fampridine. As the viscosity of the polymer and its proportion in the formulation increased, adhesive problems occurred in the tablets, making the release of fampridine more challenging. Since delaying the release of fampridine was a desired outcome, aerosil, which has higher effectiveness than Avicel as a diluent in the formulation, was used to resolve the adhesion issues associated with the use of K200M, which has the highest viscosity. The time period during which the fampridine concentration is stabilized in the solvent medium was 12 hours for the reference product, while it has been extended to 18 hours in the revised unit formula of the generic drug formulation. The results are reproducible, and the methods used have been validated according to ICH guidelines. Second prototype delves into both the formulation of bio-based microspheres containing fampridine for the treatment of multiple sclerosis (MS) and provide an alternative way for the commercially available product (Fampyra 10 mg, Biogen). Encapsulation of fampridine was achieved using polyvinyl alcohol (PVA) and two different polymers know as sodium alginate (Na-Alg) and Chitosan (CS). According to the type of microsphere, Glutaraldehyde (GA) and hydrochloric acid (HCl) or glutaraldehyde and sodium hydroxide (NaOH) were used as cross-linking agents. Polymer ratio (PVA: Na-Alg and PVA:CS), drug: polymer (d: p) ratio, cross-linking agent ratio, and cross-linking time were evaluated on fampridine release. Release studies were analyzed using an ultraviole- visible (UV) spectrophotometer. The microspheres were characterized using scanning electron microscopy (SEM), differential scanning calorimetry (DSC), and Fourier-transform infrared spectroscopy. (FT-IR). The particle size of fampridine-loaded microspheres were determined by the laser-light-scattering device. The purpose of preparing the second prototype is the lack of any studies in the literature regarding fampridine encapsulated by biological polymers, which have been gaining importance recently. By obtaining microspheres with increasingly effective biological polymers, a comparison of the release behaviors with tablets containing fampridine produced by classical methods has been achieved. This will enable the production of an alternative generic drug using a manufacturing method that does not exist in Turkey or even in the world for fampridine. As for results, the study was seperated into two sections. The first one is PVA:Na-Alg microspheres; it was determined that the highest release of fampridine obtained with microspheres prepared with PVA: Na-Alg (w: w) ratio as 1:1, drug: polymer ratio (w: w) as 1:2, cross-linking agent concentration as 2.5% GA + 3% (v:v) HCl, and cross-linking time as 5 minutes. It was observed that all microspheres have 300- 800 μm particle size and the particule size of the microspheres increases d: p ratio paralelly. The second one is PVA:CS microspheres, the highest release of fampridine obtained with microspheres prepared with a PVA:CS (w: w) ratio as 2:1, drug: polymer ratio as 1:2 (w: w), cross-linking agent concentration as 2.5% (v:v) GA + 1M NaOH, and cross-linking time as 5 minutes. It was observed that the release behavior of microspheres does not conform to Fick's Law, as typically seen in release systems created with hydrogels. The aim of the third prototype was to design oral controlled release osmotic pump tablets of fampridine and optimize the drug release profile using response surface methodology, Box Behnken Method. Ostmotic pump tablets were prepared by direct compression with using variying amount of polyoxhyethylene (PoE) which has different molecular weight (Mw) as 300,000 g/mole and 900,000 g/mole and punched as 1 mm and 2 mm with mini tablet punching machine. Constant amount of Celluloce based Opadry EC (10%) (w: w) was used as coating solution. Formulation of tablets and release optimization evaluated with Box Behnken design. 3 factors and 15 levels were used to optimize drug release profile. PoE amount and hole diameter were taken as the independent variables. Response surface plots and contour plots were drawn, and optimum formulations were selected. The Box-Behnken analysis results showed that the optimum release of fampridine occurred when PoE amount was approximately 300 mg. (Mw=300,000 g/mole), with a 2 mm hole diameter. These results are consistent with existing literature and experimental studies and regarding the kinetic results, all tablets exhibited zero-order kinetic. As for evaluating the release of fampridine in the three designed prototypes, it was found that in the first prototype, the release of fampridine was extended by 6 hours compared to the reference product due to minor changes in the polymer and diluent within the formulation. Although promising results were observed in the other prototypes as well, the differentiation of the generic drug's form from the original drug will necessitate clinical studies. Therefore, it is expected that the efficacy of the microspheres will need to be demonstrated through long-term stability studies and that the clinical trials will yield positive results in order to establish them as an alternative to the reference product. This thesis is significant both in the treatment of MS and in research related to the active ingredient fampridine, as such a comprehensive study has not been conducted before. The methodologies employed aim to enhance the comfort of patients suffering from MS and improve the side effect profile of the medication. If the clinical trials of the designed prototypes against the reference product are successful, this research will provide an alternative therapeutic option accessible to patients.
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ÖgeOlefin/paraffin separation in polymer/mof mixed-matrix membranes(Graduate School, 2023-12-22)Membranes, due to their low cost, high energy efficiency and ease of processing, have aroused great interest in the field of gas separation. Polymer membranes currently occupy a dominant position in the commercial market, despite the existing tradeoff between permeability and selectivity associated with their use. Over the past decade a novel class of inorganic-organic porous materials, Metal-Organic Frameworks (MOFs), has emerged as a new research domain in solid state materials. These hybrid nanoporous materials formed by the self-assembly of metal ions or clusters, linked together via a variety of bridging ligands, creating stable open structures with sufficiently large pores for industrially-important applications, such as in gas adsorption, storage and separation. Indeed, a number of recent studies have demonstrated that MOFs could be optimal candidates for membrane-based gas separation processes. In addition, owing to the remarkable properties of MOFs, an alternative strategy to overcome the selectivity/permeability trade-off limits of polymer membranes is to make mixed-matrix membranes (MMMs), in which MOF particles are incorporated into polymer matrices. Typically, the alkane/alkene separation is highly topical since it was identified recently as one of the "7 chemical separation to change the world". Propylene (C3H6) is with ethylene (C2H4), the largest feedstock in petrochemical industries with a global production that exceeds 200 million tons per year, with these chemicals mostly used to produce polymer-grade and plastic products, particularly the widely utilized polypropylene. The objective of the PhD will be to predict the separation performances of a series of MMMs for diverse olefin/paraffin separation based on atomistic models constructed for the corresponding MMMs using a combination of force field and quantum calculations. More specifically, we implement an MC/MD simulation scheme to perform simulations of membrane permeation processes. This prediction will pave the way towards the development of the corresponding MMM and their separation testing by collaborators.
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ÖgeMitoksantron taşıma amaçlı BSA-kaplı, folik asit ile hedeflendirilmiş manyetik karbon nanotüplerin geliştirilmesi(Lisansüstü Eğitim Enstitüsü, 2025-01-10)Günümüzde yılda 15 milyondan fazla insana kanser teşhisi konulmaktadır. Vücutta bölgesel olarak başlayan kanser zamanla uzak bölgelere yayılır ve tedavi edilemez hale gelir. Mevcut tedavi yöntemlerinde her geçen gün gelişmeler yaşansa da hastalığın tedavisi halen istenen optimum yöntemlerden uzaktır. Kanser tedavisinde en kritik nokta, ilacın sağlıklı dokulara zarar vermesini engelleyip, tümörlü dokularda birikmesini sağlamaktır. Kanser tedavisine yönelik yapılan çalışmalar; malzeme, moleküler biyoloji, genetik, mühendislik, biyokimya ve cerrahi gibi birçok farklı alanda çalışan araştırmacıların katkısını kapsar ve optimum çözüme ulaşmada bunlardan hiçbiri tek başına başarılı olamaz. Mitoksantron (MTO), kanser tedavisinde yaygın olarak kullanılan antrasendion bazlı bir antikanser ilacıdır. Fakat sağlıklı hücreler/dokular üzerindeki spesifik olmayan etkileri ve çözünürlüğünün düşük olması nedeniyle klinik kullanımı sınırlıdır. Son yıllarda kanser tedavisine yönelik en önemli yaklaşımlardan biri, MTO benzeri ilaçların toksisitesini azaltmaya yönelik hedefli ilaç taşıyıcı nanosistemlerdir. Bu çalışma, dünyada kalp ve damar hastalıklarından sonra ölüme en çok neden olan kanser hastalığının tedavisine katkı sağlayacak MTO taşıyıcı sistemlerin tasarlanması amacıyla kurgulanmıştır. Literatürdeki benzer çalışmalara kıyasla tez çalışması kapsamında geliştirilen nanotaşıyıcı sistemin hem manyetik özellik hem de ligand içerecek şekilde tasarlanması ile ilacın sağlıklı hücrelere kıyasla kanserli hücrelerde salımının gerçekleşmesinin sağlanması hedeflenmiştir. Böylelikle mevcut tedavi yöntemlerinin neden olduğu en büyük sınırlamalardan biri olan sağlıklı hücrelere olan toksik etkinin de minimum seviyede tutulması amaçlanmıştır. Pasif hedefleme ile kanserli ve sağlıklı hücreler arasındaki yapısal farklılıklardan (pH, sıcaklık, geçirgenlik vb.) yararlanılırken, aktif hedefleme için kanserli bölgede reseptörünün fazla olması nedeniyle folik asit bağlı ve manyetik özelliğe sahip nanotaşıyıcılar hazırlanmıştır. Biyolojik uygulamalardaki potansiyellerini artırmak amacıyla son yıllarda manyetik özelliğe sahip karbon nanotüpler (mKNT) geliştirilmiş ve böylece uygulama alanları daha spesifik hale getirilmiştir. mKNT'ler, ilacın harici bir manyetik alan altında tümör bölgesine hedeflenmesini kolaylaştırabilirken, tümör bölgesinin sıcaklığını 46 °C'ye kadar artırarak hipertermi etkisi sağlayabilir. Böylelikle mKNT'ler kanser tedavisinde kemoterapi ilacının yan etkilerinin azaltılması, ilacın hedefe iletilmesi ve dış uyarıcılar ile hipertermi etkisiyle hedef hücrenin/dokunun ortadan kaldırılmasını sağlayarak çok yönlü taşıyıcılar olarak kullanılabilir ve tedavi aşamasında ilaçtan maksimum verim alınması sağlanabilir. Karbon yapıların ilaç taşıyıcı sistemlerde iskelet olarak kullanılabilmesi için istenen özelliklere sahip olması gerekmektedir. Saf KNT hidrofobik ve toksik özellik gösterir. Bu durumu gidermek için; kovalent veya kovalent olmayan yöntemlerle çeşitli moleküller KNT'ye bağlanarak KNT'nin toksik özelliği iyileştirilebilir. Plazmada en bol bulunan protein olan sığır serum albümin (BSA) biyouyumlu olması nedeniyle kaplama malzemesi olarak dikkat çekmektedir. BSA'nın yapısal konfigürasyonu çeşitli ligand bağlanma bölgeleri sağlar ve BSA, KNT'lerin sitotoksisitesini önemli ölçüde azaltabilir. Yayınlanan çalışmalarda antikanser ilaçların kanser hücrelerine karşı seçiciliğini artırmak için hazırlanan nanotaşıyıcılara manyetik özelliğin yanı sıra birçok aktif hedefleme ligandı da konjuge edilmiştir. Bu ligandlar arasında folik asit (FA), düşük maliyeti, toksik olmaması ve yüksek stabilitesi nedeniyle en duyarlı hedefleme moleküllerinden biridir. Ayrıca FA'nın folat reseptörüne (FR) bağlanma afinitesi yüksektir ve FR'ler birçok farklı kanser hücresinde aşırı eksprese edilir. Çalışmanın ilk aşamasında sentezlenen mKNT'ler, BSA ile kovalent yöntemle fonksiyonelleştirilmiştir. BSA-kaplı mKNT (mKNT-BSA), Fourier dönüşümlü kızılötesi (FT-IR) spektroskopisi, Raman spektroskopisi, X-ışını fotoelektron spektroskopisi (XPS), termogravimetrik analiz (TGA), titreşimli örnek manyetometresi (VSM) ve geçirimli elektron mikroskobu (TEM) gibi ileri analiz teknikleriyle karakterize edilmiştir. Analiz sonuçları mKNT'nin BSA ile kovalent modifikasyonunun başarılı olduğunu göstermiştir. Bir sonraki aşamada, BSA-kaplı mKNT'ler, hedeflenen dağıtıma yönelik spesifik olmamaları nedeniyle FA ile fonksiyonelleştirilmiştir (mKNT-BSA-FA). FA-bağlı nanotaşıyıcılar FT-IR, taramalı elektron mikroskobu (SEM), XPS, VSM ve TGA teknikleri kullanılarak karakterize edilmiştir. mKNT-BSA-FA'nın karakterizasyon sonuçları, nanotaşıyıcının doyum manyetizasyon değerinin manyetik hedefli ilaç dağıtım sistemlerinde kullanımı için uygun olduğunu ortaya koymuştur. Sonraki aşamada, mKNT'lerin MTO yükleme ve salım profilleri değerlendirilmiştir. Saf ve kaplanmış mKNT'ler için pH 9'da ilaç yükleme ve fizyolojik (pH 7,4) ve lizozomal pH'ta (pH 5,5) salım deneyleri gerçekleştirilmiştir. mKNT-BSA-FA'nın en düşük ilaç yükleme kapasitesine ve en yüksek ilaç salım (%) miktarına sahip olduğu görülmüştür. Bu duruma mKNT'nin protein ve folik asit ile fonksiyonelleştirilmesinden sonra hidrofilik özellik kazanması neden olmuştur. Nanotaşıyıcıların sitotoksik etkileri sağlıklı HEK293T ve kanserli MDA-MB-231 hücre hatlarında incelenmiş ve her iki hücre hattı üzerinde de doza bağlı sitotoksik etkileri olduğu görülmüştür. Biyouyumlu BSA ve FA ile yapılan fonksiyonelleştirme mKNT'lerin toksisitesini azaltmıştır. Ayrıca, MTO yüklü mKNT, mKNT-BSA ve mKNT-BSA-FA'nın MDA-MB-231 hücrelerinin canlılığını önemli ölçüde azaltmasına rağmen aynı konsantrasyondaki serbest MTO'ya göre daha az sitotoksik etki gösterdiği belirlenmiştir. Sonuçlar, mKNT-BSA-FA'nın çift hedefleme özelliği nedeniyle geleneksel tedavi yöntemlerine kıyasla daha verimli bir ilaç dağıtım sistemi olabileceğini göstermektedir. İlaç taşıma amaçlı tasarlanan malzemenin süperparamanyetik özelliği, harici manyetik alan uygulanarak ilacın hedeflenen bölgeye iletilmesini ve geleneksel kanser tedavisinin neden olduğu kısıtlamaların giderilmesini sağlar. pH'a duyarlı salım, gelişmiş dispersiyon ve süperparamanyetik özelliğe sahip mKNT-BSA-FA, MTO taşıma amaçlı bir nanosistem olarak düşünüldüğünde iyi bir seçim ve umut verici bir adaydır.
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ÖgeInvestigation of the mechanisms of hERG1 blocker toxins as anti-cancer agent with molecular modeling techniques(Graduate School, 2024-02-20)Ion channels are membrane-inserted proteins which regulate the movement of ions through cell membrane. Potassium (K+) ion channels ubiquitously exist in almost all species and locate in cell membranes. Members of this channel family play important roles in cellular signaling, including various processes. It is well-known that K+ ion channels involved in signaling pathways lead to cell proliferation or apoptosis. Because of their location on cell surface and their well-known pharmacology, they can be used as potential targets in anticancer therapies. The human ether-a-go-go related gene 1 (hERG1) K+ channels play crucial role in the heart, different regions of brain, endocrine cells, smooth muscle cells, and numerous tumor cells. It is known that the inherited mutations of hERG1 gene may lead to the disorder of cardiac repolarization (i.e., long QT syndrome (LQTS)), which may result in sudden cardiac death. It is known that K+ ion channels involved in signaling pathways lead to cell proliferation or apoptosis and some specific toxins were investigated for diverse therapeutic applications on targeting the hERG1 K+ channel. Thus, investigation of channel/toxin interactions mechanisms in atomic level is an important topic for the development of toxin-based therapeutics. Thus, in the first part of this thesis, the interaction mechanisms of two toxins named as BeKm-1 and BmTx3b with the closed-state hERG1 channel have been studied by using different molecular modeling techniques including protein-protein docking and molecular dynamics (MD) simulations. The crucial residues of toxins in channel interactions have been elucidated. It is found that R1, K6, K18, R20, K23 and R27 residues in BeKm-1 and F1, K7, K19, K20 and K28 in BmTx3b are the important residues involved in the strong interactions with the closed-state hERG1 K+ channel. The results of this study can be used by medicinal chemists in the designing of diverse therapeutic applications of natural or synthetic peptides targeting the closed state hERG1 K+ channels. In the second part of the thesis, the information that obtained from hERG-BeKm-1 and hERG-BmTx3b interactions, was used to design de novo peptides. The designed de novo peptides were investigated on open-state hERG. In addition to de novo peptides, peptidomimetics and FDA-approved molecules were included in the study to increase the number of molecules studied. It is believed that the data obtained in the thesis study will provide guidance for hERG inhibition for therapeutic purposes. In this way, it is expected to be able to eliminate various types of disease without causing sudden cardiac death.
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ÖgeOptimization of wastewater and sludge treatment plants regarding efficiency, flexibility and reduction of CO2 emissions(Graduate School, 2024-04-18)After the 2015 Paris Agreement, most of the countries have taken actions to decrease their greenhouse gas (GHG) emissions. Some of them such as the European Union have even aimed to be climate-neutral by 2050. To achieve these results, the share of renewables in electricity has started to be increased. However, this increase may result in fluctuations in the grid depending on the nature of the renewables. This situation must be handled cleverly. Wastewater treatment plants (WWTPs) have a share of 56% of the GHG emissions in the water industry. Direct carbon dioxide (CO2) emissions of WWTPs are considered to be biogenic and not included in the GHG calculations. However, indirect CO2 emissions, which are produced by usage of electricity, contribute to the GHG emissions. WWTPs need 3-5% of global electricity to operate and this is predicted to increase in the near future. Demand side management is a suitable method to deal with the future electricity grid with a high share of renewables. WWTPs are good candidates to take part within this approach. They have flexible processes to produce and/or consume energy and storage options. If they can be operated flexibly based on the CO2 emission factor of the grid, the share of the renewables in the grid can be increased and the CO2 emissions can be reduced. In this thesis, an optimization model of the WWTP of Krefeld city (in Germany) was built and investigated to decrease its indirect CO2 emissions by flexible operation. This WWTP applies a two-stage biological treatment, named A-B process, to the wastewater. As a result of this process, A- and B-sludge are produced. These sludge streams are dewatered and fed to digesters, which are additionally supplied with co-substrates, to produce biogas. The digested sludge leaving digesters is further treated in centrifuges and dryers to obtain dried sludge. The WWTP is integrated to a waste incineration plant on the same site, which burns the dried sludge and the biogas produced in the WWTP along with the waste, and supplies steam to the WWTP. The units of the WWTP that need power and/or electricity were determined. Only the units with more than 30 kW demand were included in the optimization model. After a detailed analysis of the units, it was found that only 29.5% share of the total energy consumption of the WWTP could be flexibly operated due to operational reasons. A software program called TOP-Energy, which applies mixed integer linear optimization, was used to build and optimize the WWTP. This software has some common units such as water pumps, mixers etc. in its library, but the rest of the units, especially WWTP-specific units such as aeration/activation tanks, sedimentation tanks, filters etc. are missing, so they were created by using the Template Editor of the software within this thesis. GUROBI was used as a solver. The WWTP model was optimized to minimize its indirect CO2 emissions that are generated by usage of electricity from grid. To do this the CO2 emission factor of the grid was used. This factor shows the total amount of the CO2 emissions generated during the production of electricity. It is dependent on the source that is used for the electricity production. As the share of the renewables in the electricity grid increases, the CO2 emission factor decreases. The idea is to shift the operation of the WWTP to the times when the CO2 emission factor is relatively low. Inlet and outlet temperature and pressure values of the units were fixed initially. Solid mass fraction of the sludge and organic mass fraction of the total solid within the sludge were defined for each fuel stream as fixed values ("fuel" represents sludge, co-substrate and biogas.). The minimum and the maximum mass flow rates and power consumption values of the units were given as boundary conditions. All these data were taken from the internal documents of the WWTP. The inlet mass flow rates of the wastewater and the co-substrate into the plant were defined as hourly time series for the whole year 2017. The CO2 emission factor of the German electricity grid and the outside temperature values of Krefeld were also used in the model as hourly time series. The optimization model could not be run for the whole year since the model was very detailed and would take extremely long time to solve.
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