Periodic Reporting for period 1 - ORBIS (Open Research Biopharmaceutical Internships Support)
Berichtszeitraum: 2018-03-01 bis 2020-02-29
Society needs a constant supply of new more effective medicines with decreased side effects. The current process of medicine development is cumbersome, lengthy, and often inefficient as only 1 in approximately 10,000 drug molecules will make it to the market. Studies demonstrated that the irreproducibility of preclinical research ranges from 51% to 89%, translating into over €25 billion wasted annually. Improvements could be achieved by advanced training programs to reinforce best practices related to core skills, technologies, and methods.
Thus, the vision of the ORBIS network is to form a multidisciplinary transnational team that will establish improved competencies and characterization approaches for pharmaceutical research evaluating drug substances and dosage forms.
The participants exchange skills and knowledge, which allow them to progress towards key advances in pharmaceutical sciences. They strengthen collaborative research between the different countries and sectors. The practical and economy-driven approach by industry is combined with scientific excellence to benefit European society with the implementation of scientific methods to solve practical problems and to inspire scientists to expand knowledge in line with industrial needs.
A gap analysis has been performed and technological solutions are proposed by the team to improve the processes of drug synthesis, preformulation, dosage form design, and biopharmaceutical properties. This supports Europe’s aspiration to become a global leader in providing innovative, efficient, safe, patient-friendly, and affordable medicinal products. To achieve this, we planned collaborative, complementary, and industrial application-driven research, leading to a substantial and sustainable improvement of the medicine development process. The educational mission of the project is to enhance the skills and expertise of staff involved in academic and industrial pharmaceutical R&D activities, especially early-stage researchers. The project is increasing their employability and the overall competence of the sector.
Knowledge exchange underpins the following major activities: research & commercialisation, teaching & learning as well as knowledge dissemination to the wider community. Due to the diversity of the group and multiplicity of geographic locations, a number of tools and approaches is used for knowledge sharing within the team. Summer Schools are executed on an annual basis (four in total) for all participants and responsibility for organising the events is circulated. Annual workshops as smaller events support collaboration within the project.
Thus, the vision of the ORBIS network is to form a multidisciplinary transnational team that will establish improved competencies and characterization approaches for pharmaceutical research evaluating drug substances and dosage forms.
The participants exchange skills and knowledge, which allow them to progress towards key advances in pharmaceutical sciences. They strengthen collaborative research between the different countries and sectors. The practical and economy-driven approach by industry is combined with scientific excellence to benefit European society with the implementation of scientific methods to solve practical problems and to inspire scientists to expand knowledge in line with industrial needs.
A gap analysis has been performed and technological solutions are proposed by the team to improve the processes of drug synthesis, preformulation, dosage form design, and biopharmaceutical properties. This supports Europe’s aspiration to become a global leader in providing innovative, efficient, safe, patient-friendly, and affordable medicinal products. To achieve this, we planned collaborative, complementary, and industrial application-driven research, leading to a substantial and sustainable improvement of the medicine development process. The educational mission of the project is to enhance the skills and expertise of staff involved in academic and industrial pharmaceutical R&D activities, especially early-stage researchers. The project is increasing their employability and the overall competence of the sector.
Knowledge exchange underpins the following major activities: research & commercialisation, teaching & learning as well as knowledge dissemination to the wider community. Due to the diversity of the group and multiplicity of geographic locations, a number of tools and approaches is used for knowledge sharing within the team. Summer Schools are executed on an annual basis (four in total) for all participants and responsibility for organising the events is circulated. Annual workshops as smaller events support collaboration within the project.
The works were carried out simultaneously in three complementary areas of interest.
We have
(1) optimized physicochemical properties of some poorly soluble active substances
• We succesfully cocrystalized and charcterised poorly water soluble isoflavone substance used in prophylaxis and treatment of cancer for the improvement of its solubility.
• Cocrystallisation studies with subsequent product characterisation were also performed using a potential anticancer API
• We successfully improved the poor biopharmaceutical properties of itraconazole (antifungal drug with an extremely low solubility) by cocrystallization with a range of dicarboxylic acids as coformers
• We studied solubility and dissolution of lidocaine multicomponent phases
• We applied the quench-cooling method for preparation of co-amorphous cardiovascular drug system. The co-amorphous systems were then extensively characterised and the short-term stability was studied.
• We determined the effect of different polymeric excipients on precipitation of two poorly soluble weak bases.
• Synthesis of thiol derivatives of selected APIs (to be used to produce API-functionalised gold nanoparticles) was performed, with purification and characterisation of the products.
(2) developed and evaluated the innovative oral dosage forms (minitablets, 3D printing films) and drug delivery systems (among other: nanospheres with tyrosine, microemulsions and microemulsion-based systems containing non-steroidal anti-inflammatory drugs, delivery of terbinafine from nanoparticles in treatment of onychomycosis, liposomal formulations and transdermal patches)
(3) proposed novel methodologies of biopharmaceutical evaluation, including among other (i) development and validation of new bioanalytical methods of the determination of selected APIs in human serum (pregabalin); human plasma (cefazolin and cefoxitin; tazobactam and piperacillin) and fat tissue (cefazolin and cefoxitin); (ii) development of predictive and biorelevant dissolution/release methods for preclinical evaluation of biopharmaceutical safety and reliability (dissolution tests of novel oral ibuprofen free acid tablets, optimisation of testing the in vitro dissolution of budesonide from oral tablets in biorelevant conditions, application of new biorelevant dissolution method for very challenging ER formulations); (iii) development and validation of innovative tools for calculation and modelling of PK data and enzymatic reactions)
European Medicines Agency (EMA) and U.S. Food and Drug Administration (FDA) bioanalytical method validation recommendations were compared and a novel statistical model for incurred sample reanalysis was developed. Worth noting is the fact, that we actively participated, sharing our knowledge and experience, in public consultation of the EMA documents:
• EMA Reflection paper on investigation of pharmacokinetics and pharmacodynamics in the obese population (EMA/CHMP/535116/2016)
• Draft guideline on quality and equivalence of topical products (CHMP/QWP/708282/2018)
• ICH guideline M10 on bioanalytical method validation (EMA/CHMP/ICH/172948/2019)
We have
(1) optimized physicochemical properties of some poorly soluble active substances
• We succesfully cocrystalized and charcterised poorly water soluble isoflavone substance used in prophylaxis and treatment of cancer for the improvement of its solubility.
• Cocrystallisation studies with subsequent product characterisation were also performed using a potential anticancer API
• We successfully improved the poor biopharmaceutical properties of itraconazole (antifungal drug with an extremely low solubility) by cocrystallization with a range of dicarboxylic acids as coformers
• We studied solubility and dissolution of lidocaine multicomponent phases
• We applied the quench-cooling method for preparation of co-amorphous cardiovascular drug system. The co-amorphous systems were then extensively characterised and the short-term stability was studied.
• We determined the effect of different polymeric excipients on precipitation of two poorly soluble weak bases.
• Synthesis of thiol derivatives of selected APIs (to be used to produce API-functionalised gold nanoparticles) was performed, with purification and characterisation of the products.
(2) developed and evaluated the innovative oral dosage forms (minitablets, 3D printing films) and drug delivery systems (among other: nanospheres with tyrosine, microemulsions and microemulsion-based systems containing non-steroidal anti-inflammatory drugs, delivery of terbinafine from nanoparticles in treatment of onychomycosis, liposomal formulations and transdermal patches)
(3) proposed novel methodologies of biopharmaceutical evaluation, including among other (i) development and validation of new bioanalytical methods of the determination of selected APIs in human serum (pregabalin); human plasma (cefazolin and cefoxitin; tazobactam and piperacillin) and fat tissue (cefazolin and cefoxitin); (ii) development of predictive and biorelevant dissolution/release methods for preclinical evaluation of biopharmaceutical safety and reliability (dissolution tests of novel oral ibuprofen free acid tablets, optimisation of testing the in vitro dissolution of budesonide from oral tablets in biorelevant conditions, application of new biorelevant dissolution method for very challenging ER formulations); (iii) development and validation of innovative tools for calculation and modelling of PK data and enzymatic reactions)
European Medicines Agency (EMA) and U.S. Food and Drug Administration (FDA) bioanalytical method validation recommendations were compared and a novel statistical model for incurred sample reanalysis was developed. Worth noting is the fact, that we actively participated, sharing our knowledge and experience, in public consultation of the EMA documents:
• EMA Reflection paper on investigation of pharmacokinetics and pharmacodynamics in the obese population (EMA/CHMP/535116/2016)
• Draft guideline on quality and equivalence of topical products (CHMP/QWP/708282/2018)
• ICH guideline M10 on bioanalytical method validation (EMA/CHMP/ICH/172948/2019)
The main achievements beyond the state of the art concerned:
• development of the strategy of crystallization of izoflavones
• development of novel potential nano-carriers of drug substance for transdermal delivery
• the novel statistical model for better understanding of incurred sample reanalysis
• the new biorelevant dissolution method for very challenging ER formulations
The first two achievements could impact the improvement of efficacy and safety of therapies of important civilization morbidities such as cancer, cardiovascular diseases as well as other chronic diseases. The third achievement may contribute to simplify international recommendations concerning bioanalytical method validation. Potential savings could be used to relocate resources for faster drug discovery and development. The fourth achievement could significantly reduce for ER formulations the risk of failure in bioequivalence trials as a result of long gastric residence times and susceptibility to food effects.
Additionally, an application of green chemistry strategies for drug synthesis and new drug carries development will improve the quality of our environment on the local and global scale.
• development of the strategy of crystallization of izoflavones
• development of novel potential nano-carriers of drug substance for transdermal delivery
• the novel statistical model for better understanding of incurred sample reanalysis
• the new biorelevant dissolution method for very challenging ER formulations
The first two achievements could impact the improvement of efficacy and safety of therapies of important civilization morbidities such as cancer, cardiovascular diseases as well as other chronic diseases. The third achievement may contribute to simplify international recommendations concerning bioanalytical method validation. Potential savings could be used to relocate resources for faster drug discovery and development. The fourth achievement could significantly reduce for ER formulations the risk of failure in bioequivalence trials as a result of long gastric residence times and susceptibility to food effects.
Additionally, an application of green chemistry strategies for drug synthesis and new drug carries development will improve the quality of our environment on the local and global scale.