Here we bring the topics overview. Below the overview there are annotations and names of academic supervisor(s), their university/department and project assignments to research area(s) from five key domains in The Parc: Solid state chemistry, Preformulation and solid state analysis, Drug design and process, Biopharmacy and Preclinical in vivo testing. For more information on a specific Ph.D. project, you can contact us at info@theparc.eu or you can contact the academic supervisor directly (find email below each project description).
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PhD topics overview
01/ Controlling of drug crystals properties during crystallization
02/ Development and optimization of continuous production of cocrystals
03/ Optimization of screening process for preparation of solid solutions using HME
04/ Development and optimization of continuous process of wet granulation
05/ Improving powder materials properties
06/ Modelling of drug-excipient molecules interaction during dissolution process
07/ In silico crystal structure predictions for pharmaceutical ingredients
08/ Study of the stability of APIs in mixtures with respect to their processing and composition
09/ Surface energy heterogeneity of particulate matter
10/ Kinetic, thermodynamic and structural aspects of forming solid dispersions of high-melting drugs
11/ Monitoring and prediction of tablet disintegration behavior using texture analysis
12/ Advanced manufacturing concepts for flexible dose combinations
13/ Co-processed active pharmaceutical ingredients for direct compression
14/ Scale-up of wet nanomilling and nanocrystal formulation processes
15/ Liposomal reservoirs for non-equilibrium encapsulation of bioactive compounds
16/ Development of advanced methodology for in vitro testing of long-acting injectable depot systems
17/ Investigation of collective phenomena in lipid membrane permeation
18/ Development of liquisolid systems with controlled drug release
19/ Improving drug solubility via liquisolid systems preparation
20/ Development of nanoparticulate formulations targeting skin cancer
21/ Advanced ceramide formulations for skin barrier recovery
22/ Development of membrane model systems to predict permeability of drugs
23/ Non-hypoglycemic effects of GLP-1 mediation for neuro-humoral and immunological dysregulation in civilization diseases
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1/ Controlling of drug crystals properties during crystallization
Active Pharmaceutical Ingredients (APIs) are commonly small molecules, which are prepared by crystallization process. Properties of prepared crystals (i.e., physico-chemical but also formulation properties) are strongly dependent on the used drug solid form, their size and crystal morphology. Therefore, the focus of this project is to study impact of crystallization process parameters and post-processing step on the prepared drug crystals with respect to size, morphology and polymorphism. Temperature modulated batch crystallization will be combined with wet-milling process to control the shape as well as flow properties of prepared drug crystals. In this project we also investigate possibility to use spherical crystallization, which is an alternative to wet-milling, to prepare spherical particles composed of crystalline API. Significant advantage of this approach is very good particle flowability which is significantly lower for non-spherical crystals prepared by wet-milling. While pharmaceutical industry is typically using batch operation, as a part of this project we will investigate the possibility to prepare same drug crystals as studied in batch mode in a continuous process. Millifluidic reactor utilizing gas-droplet flow will be used to control residence time distribution of crystals in the crystallizer. Process analytical technology capable to measure the crystal size, shape and morphology will be used for analysis of composition via Raman spectroscopy to ensure constant product quality. On-line measurement will be supported by off-line measurement via SEM, IR spectroscopy, XRD and NMR. Student will be also involved in the scale up of developed process.
Supervisor: prof. Ing. Miroslav Šoóš, Ph.D. (Miroslav.Soos@vscht.cz)
University: University of Chemistry and Technology, Department of Chemical Engineering
Parc area: Solid state chemistry
2/ Development and optimization of continuous production of cocrystals
Cocrystals are multicomponent solid forms composed of API and suitable coformer. Process of solid-state transformation is effectively done in the systems, where energy is introduced into the systems, i.e., ball mills. Building on our strong knowledge of mechanochemical preparation of co-crystals we propose to extent study of cocrystal production into continuous process using extrusion system. In addition, due to positive impact of oil-based compounds in the drug product on the drug bioavailability, we propose to use oil based coformers in the process of cocrystal formation. Initially, student will be involved in the small-scale experiments using vibration ball mill. For successful cases process will be transferred to the continuous production using twin screw extruder. For both systems we will cover broad range of process parameters (milling frequency/rotation speed, temperature, residence time, mixing intensity due to presence of milling balls/extruder screw geometry, amount of coformer etc.) to investigate their impact on the physico-chemical properties of prepared solid forms. Obtained powders will be characterized by XRD, DSC and TGA as well as by measurement of drug dissolution coupled with the permeation measurement (application of classical Frantz cell setup or direct measurement of diffusion to the oil phase). In the last stage of the project, we will compare in-vivo behavior of prepared cocrystals to prove possibility of continuous processing.
Supervisor: prof. Ing. Miroslav Šoóš, Ph.D. (Miroslav.Soos@vscht.cz
University: University of Chemistry and Technology, Department of Chemical Engineering
Parc area: Solid state chemistry
3/ Optimization of screening process for preparation of solid solutions using HME
Amorphous solid solutions (ASSs) represent very interesting approach for formulation of drugs with low solubility. They are characterized by formation of amorphous solid typically composed of polymer in which drug is molecularly dissolved. However, optimization of ASSs composition is time consuming process, therefore in the presented project we propose to utilize rheological tests to determine several critical parameters for extraction process. In particular, rheological measurement of the polymer-drug powder mixture or polymer-drug melt can provide information about the melting temperature of powder-melt, glass transition temperature, viscosity of the polymer-drug melt as well as can be used to determine maximum amount of drug loading in the polymer. Last but not least, rheological measurement at elevated temperature can provide information about the residence time of the polymer-drug mixture in the HME before degradation. All these information will be in the next stage used to set up operating parameters for HME process. Significant advantage is that rheological measurement requires fraction of the material amount normally used in the development of HME process. Based on our early stage results we propose to extend this procedure for other drugs or systems containing plasticizers to test method robustness. Rheological tests will be combined with other analytical methods to characterize prepared polymer-drug ASSs including XRD, DSC, TGA, dissolution testing combined with permeability measurements, water sorption and long-term stability testing.
Due to the fact that the selection of a suitable polymer is currently implemented using experimental testing, in the presented project we further propose to use detailed computer simulations (quantum chemical calculations and molecular dynamic simulations) of polymer-drug drug-small molecule interactions in order to reduce the time needed to find a suitable combination. Quantum-chemical calculations of the COSMO-RS type enable the first and relatively quick qualitative estimation of Hansen's solubility parameters and can thus serve in the initial screening of suitable polymers. Molecular dynamic simulations can then be used as a computational-thermodynamic tool that allows verifying the polymer-drug affinity in a real system arrangement (ideally including basic experimental knowledge).
Supervisor: prof. Ing. Miroslav Šoóš, Ph.D. (Miroslav.Soos@vscht.cz)
University: University of Chemistry and Technology, Department of Chemical Engineering
Parc area: Solid state chemistry
4/ Development and optimization of continuous process of wet granulation
Wet granulation process is commonly used to increase of drug particle size, improve of drug particle flowability or its physicochemical properties. Commonly, the wet granulation process is done in a batch mode using high shear granulators. However, during the process scale up there is often difference in the final granule properties including size, composition, homogeneity, porosity etc. All these parameters have impact on the rate of drug product disintegration and drug dissolution. Therefore, the main goal of this work is to develop and optimize process of wet granulation using continuous operation mode via extrusion process. Process parameters will cover ratio of drug particle to binder, binder type, size and surface properties of drug particles, mixing intensity, applied shear rate and residence time in the extruder. As an alternative to water-based binders, we will investigate also possibility to use oil-based binders or water emulsions, targeting higher bioavailability. Obtained granules will be characterized by a combination of various methods including API crystal form stability (XRD), size characterization (optical and electron microscopy, light scattering), porosity measurement (BET, Hg porosimetry, tomography), composition (Raman mapping, FTIR, NIR spectroscopy), powder rheology and granule disintegration kinetic. Collected results will be compared with those measured for granules obtained from batch process, targeting development of criteria for process transfer from small-scale batch process to continuous operation. In the last stage we will investigate in-vivo testing of binder type on the drug bioavailability.
Supervisor: prof. Ing. Miroslav Šoóš, Ph.D. (Miroslav.Soos@vscht.cz)
University: University of Chemistry and Technology, Department of Chemical Engineering
Parc area: Drug design and process
5/ Improving powder materials properties
The production process of tablets is based on powder components containing the drug and the required excipients. The properties of these powders depend on the method of their production and it is often difficult to change it. On the other hand, these properties can negatively affect flow or formulation properties (e.g., stickiness). The dry coating process is based on the adhesion of powders of one substance to the surface of another powder substance without the use of any liquid. In addition to reducing the use of solvents, it is possible to use the process for the preparation of multicomponent powder forms or surface passivation. The dry coating process is typically carried out in batch systems of a specific design, for which registration by regulatory authorities is very difficult. In the presented project, we propose to implement the process in an extruder by mixing suitable powders. The target applications will be the targeted control of tablet disintegration by changing the properties of the powder components and the preparation of multicomponent powders containing two or more drugs. The optimization of the coating process will be realized using a combination of experiments and DEM modeling to analyze the energy required for sufficient adhesion of auxiliary particles on the surface of the main powders. Analysis of the prepared powders will be done via combination of several technique including XRD, DSC, powder rheology, optical microscopy and SEM combined with image analysis for determination of particle size distribution.
Supervisor: prof. Ing. Miroslav Šoóš, Ph.D. (Miroslav.Soos@vscht.cz)
University: University of Chemistry and Technology, Department of Chemical Engineering
Parc area: Preformulation and solid state analysis
6/ Modelling of drug-excipient molecules interaction during dissolution process
Measurement of drug substance dissolution rate is a key parameter in the selection of suitable excipients for development of drug dosage form. However, there is very strong impact of excipients on the dissolution process. In particular, surfactants are commonly used to improve table or drug particle wettability, while polymers are commonly used to stabilize supersaturated drug solutions during the dissolution process. Even though measurement of the dissolution kinetics combined with permeability measurement can reveal information about drug behavior under various conditions this approach is not capable to provide data to understand interactions between drug molecules and various excipients in the solution. Therefore, in this project we propose to use combined approach based on the measurement of drug solubility and permeability and molecular dynamic (MD) modelling. While experimental data will allow systematic investigation of the impact of excipients on drug dosage form dissolution process, MD will provide detailed information about the intermolecular interactions in the liquid phase, identify formation of drug-excipient-water molecules complexes in the dissolution media. Once the MD model will be validated it can be used as a tool to select suitable excipients to maximize drug solubility, prevent its precipitation and maximize its permeability. Preliminary results for systems Valsartan-non-ionic surfactants conform robustness of this approach by identifying intermolecular interaction between alkyl chain of the surfactants and Valsartan molecules. Furthermore, predicted number of Valsartan molecules agrees well with those calculated from CMC point and dynamic measurement of Valsartant particles solubilization after addition of an excess of surfactant.
Supervisor: prof. Ing. Miroslav Šoóš, Ph.D. (Miroslav.Soos@vscht.cz)
University: University of Chemistry and Technology, Department of Chemical Engineering
Parc area: Biopharmacy
7/ In silico crystal structure predictions for pharmaceutical ingredients
Active pharmaceutical ingredients tend to from various polymorphic crystal structures, which differ in their structure, physico-chemical properties, and thus potentially also in their pharmaceutical activity and bioavailability. Computational chemistry offers tools to predict crystal structures in silico only from the knowledge of the molecular formula. Vastness of such in silico generated polymorph landscape can tell whether there would be a single dominant stable polymorph, or rather a more complex interplay of multiple polymorphs could occur for a particular compound. Quantum-chemistry methods enable to rank the predicted candidate polymorph structures of a pharmaceutical ingredient in terms of their relative energy at various conditions (temperature, solvent, etc.) and also to predict kinetic barriers stabilizing any potential meta-stable polymorphs. Such in silico modelling performed at the initial stage of the pharmaceutical research can guide later crystal engineering efforts to reach the most beneficial drug formulation in terms of its stability for storage and transport and subsequent solubility and bioavailability. This computational project aims at assessing the applicability and reliability of diverse theoretical methods for polymorph ranking within the workflow of crystal structure prediction. Aspects of conformational polymorphism, incorporation of ab initio methods into genetic algorithms, impact of a solvent on the polymorph ranking, and the high-throughput feasibility of the predictions will be addressed. The ultimate goal will be the ability to predict and identify in silico a meta-stable polymorph (more soluble by definition) that would be kinetically stabilized by high energy barriers for spurious recrystallization.
Supervisor: doc. Ing. Ctirad Červinka, Ph.D. (Ctirad.Cervinka@vscht.cz)
University: University of Chemistry and Technology, Department of Physical Chemistry
Parc area: Solid state chemistry
8/ Study of the stability of APIs in mixtures with respect to their processing and composition
Drug stability is one of the fundamental qualitative attributes that must be evaluated in the context of drug research and development. Without sufficient information on the stability of the medicinal product, it is not possible to obtain a marketing authorisation and to place the product on the market. Significant effort is invested at the beginning of development to select the optimal API form for further downstream development steps. Understanding the stability of the selected API formulation is important for appropriate choice of manufacturing processes and quality assurance of the finished products. The scope of the work will be to study both the chemical and physical stability of different APIs in terms of formulation composition and type of mixture preparation or process treatment.
Supervisor: Ing. Jan Patera, Ph.D. (Jan.Patera@vscht.cz)
University: University of Chemistry and Technology, Department of Organic Technology
Parc area: Preformulation
9/ Surface energy heterogeneity of particulate matter
Free surface energy is one of the important parameters in industrial applications and processes of powder and fibrous materials. Differences in surface energy affect interfacial interactions such as wetting, cohesion, or adhesion. As the wide range of uses of powders is controlled by surface reactions or interactions, the characterization of surface energies can be important information for improving surface properties (eg surface modification). General theories can only be applied to smooth, molecularly flat solid surfaces or particles. However, most interfaces for particulate matter do not have an ideally smooth surface or an ideally homogenized surface, so the work will focus on determining the heterogeneity of surface properties; heterogeneity of surface energy, and its relation to other properties of these substances.
Supervisor: Ing. Jan Patera, Ph.D. (Jan.Patera@vscht.cz)
University: University of Chemistry and Technology, Department of Organic Technology
Parc area: Preformulation
10/ Kinetic, thermodynamic and structural aspects of forming solid dispersions of high-melting drugs
High melting point drugs present a challenge in the formulation of amorphous solid dispersions, e.g. solid solutions with polymers, because the chemical stability of both the drug and the polymer makes it impossible to safely reach the eutectic melt formation temperature. Thus, solid dispersions are essentially formed by dissolving solid drug in the polymer melt, which creates both residence time and mixing requirements in the molten state, as well as requirements for compatibility of drugs and coformers to prevent undesired crystallization of the drug in the finished product. Therefore, this work will focus on the evaluation of compatibility of drugs and coformers by computational and experimental methods, stability of dispersions as a function of their composition and kinetics of drug dissolution in polymer melt. This main axis will be complemented by the study of the application properties of the formulations prepared with the possible support of an industrial partner. The work assumes a significant contribution to supervision from FHNW Basel.
Supervisor: prof. Ing. Petr Zámostný, Ph.D. (Petr.Zamostny@vscht.cz)
University: University of Chemistry and Technology, Department of Organic Technology
Parc area: Drug design and process
11/ Monitoring and prediction of tablet disintegration behavior using texture analysis
The disintegration kinetics of tablets is a determining step for their overall dissolution behavior, as it determines the size and specific surface area of the fragments produced during their disintegration. This kinetics depends on the rate of penetration of the disintegration medium into the tablet microstructure, both into the pores and swelling components of the tablet, and the ability of the internal dissolution and swelling processes to disrupt the tablet cohesion. The aim of this work is to study the kinetics of water absorption into the tablet as a function of its composition and microstructure by means of textural analysis and microscopic measurements, to study the resistance of the tablet to erosive effects as a function of the amount of absorbed liquid as well as the size of the fragments formed as a result of these processes. The knowledge obtained should then be used to develop a fully or partially predictive model capable of predicting disintegration behavior based on the microstructure of the tablet and the physical properties of its components.
Supervisor: prof. Ing. Petr Zámostný, Ph.D. (Petr.Zamostny@vscht.cz)
University: University of Chemistry and Technology, Department of Organic Technology
Parc area: Preformulation and solid state analyses
12/ Advanced manufacturing concepts for flexible dose combinations
Fixed dose combinations (FDC) are drug products containing two or more active pharmaceutical ingredients whose combined therapeutic effect has been proven to be superior to that of individual components. Numerous clinical studies show significantly improved life expectancy of patients using FDC compared to their individual counterparts, especially in the cardiovascular area. For large therapeutic areas, it is common to develop FDCs e.g. in the form of bi-layer tablets for the most prescribed combinations of drugs and their strengths, e.g. candesartan and amlodipine. However, smaller, or more marginal patient cohorts are not served by this approach. The aim of this project is to develop and implement novel manufacturing concepts based on the post-mixing of mass-produced single-component subunits (e.g. minitablets), and thus achieve flexibility for small batch manufacturing of FDC products with a broader range of dosage strength combinations and/or interchangeable active ingredients.
Supervisor: prof. Ing. František Štěpánek, Ph.D. (Frantisek.Stepanek@vscht.cz)
University: University of Chemistry and Technology, Department of Chemical Engineering
Parc area: Drug design and process
13/ Co-processed active pharmaceutical ingredients for direct compression
Active pharmaceutical ingredients (APIs) in high-dose tablets (e.g. metformin, ibuprofen) would benefit from as little dilution by excipients as possible to keep the tablet weight down, while maintaining processability (bulk density, flow behaviour, compressibility, etc.). Co-processing is a rapidly emerging approach that aims to combine the API with a small amount of excipient while achieving large differences in processability, usually by the modification of surface properties, particle size and morphology. The aim of this project is to explore co-processing concepts for several chosen APIs based on both dry and wet routes, and to demonstrate that co-processed APIs can be manufactured in a scalable and reproducible manner. The ultimate aim is to utilise co-processes APIs in direct compression, i.e. the manufacturing of high-dose tablets without any granulation step.
Supervisor: prof. Ing. František Štěpánek, Ph.D. (Frantisek.Stepanek@vscht.cz)
University: University of Chemistry and Technology, Department of Chemical Engineering
Parc area: Drug design and process
14/ Scale-up of wet nanomilling and nanocrystal formulation processes
Dried nanocrystalline suspensions of poorly soluble active pharmaceutical ingredients (APIs) have been shown to be superior to amorphous solid dispersions in terms of dissolution rate enhancement, stability, excipient dilution, and manufacturing simplicity. The formation of aqueous nanosuspension can be achieved in wet stirred media mills that can be operated in a batch mode during process development and then scaled up to flow-through arrangement either in recirculation or single-pass mode. The suspension can then be easily dried to obtain granular material suitable for direct capsule filling or direct tabletting. The aim of this project is to develop and validate a robust scale-up methodology for the manufacturing of nanocrystal suspensions by flow-though wet milling at the highest possible concentration, subsequent spray during or fluid-bed drying, and processing into a final dosage form (tablets, capsules). For a chosen API, the entire process from raw API to finished products will be demonstrates and the product pharmaceutical performance (stability, in vitro dissolution, in vivo bioavailability) will be evaluated.
Supervisor: prof. Ing. František Štěpánek, Ph.D. (Frantisek.Stepanek@vscht.cz)
University: University of Chemistry and Technology, Department of Chemical Engineering
Parc area: Drug design and process
15/ Liposomal reservoirs for non-equilibrium encapsulation of bioactive compounds
Liposomes are spherical vesicles composed of a phospholipid bilayer surrounding an aqueous cavity. Liposomes can be used as drug carrier systems, but their capacity is limited by the thermodynamic solubility of the encapsulated substance in the aqueous phase and its partitioning into the lipidic membrane. For this reason, the practical applications of liposomes are not as numerous as they could be. The aim of this project is to develop and demonstrate a method of substantially increasing the drug carrying capacity of liposomes and make it independent of thermodynamic solubility of the compound. Strategies for achieving these goals will include simultaneous liposome formation and substance crystallisation from a supersaturated solution either by cooling or by solvent evaporation or building the liposomes around a concentrated nanosuspension of the drug, or hydration of a solid dispersion of the drug in a lipidic matrix. Once such high-load liposomes are formed, they will be tested for bioavailability enhancement of poorly soluble or enzymatically degradable drugs, for side effect elimination of drugs that irritate the GI tract, or for drug application by injection.
Supervisor: prof. Ing. František Štěpánek, Ph.D. (Frantisek.Stepanek@vscht.cz)
University: University of Chemistry and Technology, Department of Chemical Engineering
Parc area: Drug design and process
16/ Development of advanced methodology for in vitro testing of long-acting injectable depot systems
Injectable depot systems (also called Long Acting Injectables -- LAIs) represent an increasingly popular class of drug delivery systems that offer convenience for the patients, good adherence to medication, avoidance of side effects such as gastric irritation, and theoretically 100% bioavailability. However, there are no established methods for in vitro characterisation of drug release from LAI, or for their bioequivalence testing or in vivo-in vitro correlations. Also, there is a need for accelerated in vitro models, especially for LAIs that last for several months under in vivo conditions. Drug release from LAI depots comprises several elementary steps such as particle dissolution, drug diffusion and enzymatic conversion in the surrounding tissues, drug absorption into systemic circulation, and drug elimination. The aim of this project is to develop and test a series of in vitro methods for the characterisation of LAI, which can be based e.g. on hydrogel matrices, hollow-fibre membrane modules, or 3D cell cultures (artificial muscles). The objective will be to test the reproducibility and bio relevance of such models, as well as their incorporation into a typical workflow of a pharmaceutical R&D laboratory.
Supervisor: prof. Ing. František Štěpánek, Ph.D. (Frantisek.Stepanek@vscht.cz)
University: University of Chemistry and Technology, Department of Chemical Engineering
Parc area: Drug design and process
17/ Investigation of collective phenomena in lipid membrane permeation
Permeation of small molecules across lipid bilayer lies at the essence of physiological processes such as cell homeostasis or application processes such as drug delivery. For a long-time, pemeation has been considered a unary property of the permeant, but recent experimental evidence suggests that non-trivial interactions can occur during the co-permeation of multiple solutes simultaneously. Both acceleration and retardation of permetaion has been observed, and the equilibrium water-lipid partitioning coefficient has been affected as well. The aim of this project is to understand the underlying mechanisms that govern solute interaction during co-permeation across lipidic bilayers using computational methods. Using a combination of Molecular Dynamics and appropriate mean-field based approaches, hypothesis regardding co-permeation and co-partitioning will be tested. Specifically, the “crowding out” and “crowding in” hypotheses of co-permeation will be explored computatinoally. The knowledge gained in the simulations will be used for the rational design of co-permeants, for the explanation of potential drug interactinos, and for establishing engineering principles of liposomal formulations.
Supervisor: prof. Ing. František Štěpánek, Ph.D. (Frantisek.Stepanek@vscht.cz)
University: University of Chemistry and Technology, Department of Chemical Engineering
Parc area: Biopharmacy
18/ Development of liquisolid systems with controlled drug release
Liquisolid systems represent novel formulations intended to improve the bioavailability of poorly soluble drugs. Liquisolid systems are commonly used to improve the dissolution rate of poorly soluble drugs. However, controlled release can be achieved for these systems if they are combined with retarding agents. Therefore, the project will focus on developing and evaluating novel liquisolid systems with controlled release of poorly soluble drugs. The main aims of the project will include designing a drug delivery system capable of releasing the drug at the specific site of the gastrointestinal tract (e.g., colon) in a controlled manner.
Supervisor: doc. PharmDr. Barbora Vraníková, Ph.D. (vranikovab@faf.cuni.cz)
University: Charles University, Faculty of Pharmacy, Department of Pharmaceutical Technology
Parc area: Drug design and process
19/ Improving drug solubility via liquisolid systems preparation
Liquisolid systems (LSS) represent novel formulations intended to improve the bioavailability of poorly soluble drugs. Their preparation is based on the sorption of the drug in the liquid state into the porous structure of the carrier material, which is subsequently coated by very fine particles of coating material. The project will focus on the development of liquisolid systems with the aim to reduce the amount of excipients needed for drug conversion and facilitating their production.
Supervisor: doc. PharmDr. Barbora Vraníková, Ph.D. (vranikovab@faf.cuni.cz)
University: Charles University, Faculty of Pharmacy, Department of Pharmaceutical Technology
Parc area: Drug design and process
20/ Development of nanoparticulate formulations targeting skin cancer
Skin tumours are identified with increasing incidence. Currently, topical treatment is substantially limited by low bioavailability of anticancer drugs. The aim of this work is development of nanoparticulate systems (e.g. liposomes, lipid and polymer nanoparticles) and monitoring their potential to target drugs into skin tumours. Nanocarriers loaded with active compounds for cancerous and precancerous stages will be prepared and characterised. Their ability to transport the drug across the skin barrier and interactions with cancer tissue will be studied in vitro and ex vivo. Processing of the most promising systems will be optimized for in vivo experiments in mice cancer models where the drug/nanoparticle transport and release kinetics in the tumour will be monitored. The results will contribute to fundamental understanding of relationships between the nanoformulation, its properties and biological effects in cancer tissue.
Supervisor: doc. Dr. Jarmila Zbytovská (Jarmila.Zbytovska@vscht.cz)
University: University of Chemistry and Technology, Department of Organic Technology
Parc area: Drug design and process, Biopharmacy
21/ Advanced ceramide formulations for skin barrier recovery
Ceramides are essential components of the skin barrier. Many skin diseases, e.g. atopic dermatitis or psoriasis, are connected with their pathological biosynthesis and decreased levels in the stratum corneum, the outermost skin layer. Simple topical application of ceramides shows, however, a basic shortcoming – minimum skin bioavailability. Therefore, development of advanced nanoparticulate formulations targeting ceramides right into the skin barrier seems to be a promising therapeutical procedure.
The aim will be development of advanced nanoparticulate formulations with ceramides. Optimum process procedures, composition, and scale-up possibilities will be screened. Efficiency of the formulations will be studied in vitro in cell cultures and ex vivo in isolated skin. To characterize the mode of action of the formulations, biophysical techniques will be applied on order to monitor interactions with the skin barrier. The best formulations will be tested also in vivo on animal models.
Supervisor: doc. Dr. Jarmila Zbytovská (Jarmila.Zbytovska@vscht.cz)
University: University of Chemistry and Technology, Department of Organic Technology
Parc area: Drug design and process, Biopharmacy
22/ Development of membrane model systems to predict permeability of drugs
The basic step in the absorption of drugs into the body is their permeation across the cell membrane. However, it is difficult to study this phenomenon in complex organ systems. The aim of this thesis will be to establish artificial lipid membrane models that will be used for in vitro study of drug permeation. Different types of lipid systems mimicking the structure of biological membranes of selected tissues (intestinal lumen, sublingual, dermal tissue, etc.) will be developed. Membranes will be characterized in detail at the molecular level using biophysical methods (SAXS, FTIR, Raman spectroscopy, AFM and others). Furthermore, permeation kinetics will be studied on the membranes for a series of active compounds with different physicochemical properties. The data obtained will be correlated with more complex in vitro cellular models and ex vivo models. Correlation with in silico models will also be applied in the collaboration with oth. The main output of the project will be valid model systems that have the potential to predict the permeation behaviour of drugs in more complex biological environments.
Supervisor: doc. Dr. Jarmila Zbytovská (Jarmila.Zbytovska@vscht.cz)
University: University of Chemistry and Technology, Department of Organic Technology
Parc area: Biopharmacy
23/ Non-hypoglycemic effects of GLP-1 mediation for neuro-humoral and immunological dysregulation in civilization diseases
Liraglutide is a peptide GLP-1 receptor agonist, contains 31 amino acids and a bound fatty acid. GLP- 1 is an incretin secreted primarily by enteroendocrine cells of the gastrointestinal tract. Unlike GLP-1, from which liraglutide is derived, it has a biological half-life of approximately 13 hours due to its stability to peptidases and stabilization by binding to albumin, making it suitable for use in clinical practice in the treatment of type 2 diabetes and obesity.
However, there are numerous studies that reported secondary GLP1 dependent alterations of multiple neurohumoral and neuroimmonological regulations. Dysregulation of the neurohumoral and neuroinflammatory crosstalk is believed to be a complex pathophysiological factor in the development of several civilization diseases. If these GLP1 mediated effects become more precisely understood, they may open repurposing pathways for GLP1 analoques in multiple indications related to civilization diseases.
In line with these observations a few GLP1 dual or polyagonist peptides are now in clinical trials or combinations with multiple agents are being tested. Molecular targets include receptors for GLP-2, GIP and glucagon. Currently, tirzepatide (GLP-1/GIP) is the only FDA/EMA approved one. Combinations with a long-acting analogues of amylin or PYY are also being tested. Since liraglutide decreases PCSK9 expression, combinations with PCSK9 inhibitors could also make sense.
The objective of the PhD program is to elaborate on the mechanisms of non-hypoglyceamic effects of GLP1 agonist liragulite to restore dysregulations in neurohumoral effects, mitochondrial metabolism, oxidative stress, senescence, inflammatory or apoptotic pathways related to civilization diseases and short-lived risk. The next step is to test in vivo activity of GLP1 agonist in combination with selected secondary target modulator in specific models of disease and the effect on aging.
Supervisor: prof. MUDr. Ondřej Slanař, Ph.D. (ondrej.slanar@lf1.cuni.cz)
University: Charles University, First Faculty of Medicine, Institute of Pharmacology
Parc area: Preclinical in-vivo testing
April 15. 2024