Abstracts of keynote and plenary speakers

PLENARY SPEAKERS

Sustainable Pharmacy – A comprehensive approach to sustainability throughout the life cycle of medicines

Mia Siven

Associate Professor

Helsinki Institute of Sustainability Science (HELSUS), Finland

September 12, 2024, at 12:00 - 13:00

Sustainability challenges in the pharmaceutical and healthcare sectors are diverse and relate to the commonly identified concerns of climate change, biodiversity loss and chemicalisation. Economic and social dimensions are present alongside ecological sustainability. Pharmaceuticals are essential for human and animal health. At the same time, they are increasingly recognised as contaminants of emerging concern for the environment and human health when their residues enter the environment. Research is actively addressing the environmental impact of pharmaceuticals and the development of benign-by-design APIs — biodegradable and non-toxic molecules. Also, emissions of greenhouse gases from production and transportation stress sustainability. There is a need for pharmaceutical products that comprehensively take into account sustainability in formulation, manufacture and packaging. Furthermore, the rational use of medicines plays an important role. Sustainable pharmacy is a new transdisciplinary field of research where a comprehensive approach is essential. By definition, sustainable pharmacy aims to identify and develop solutions to sustainability gaps in the entire life-cycle of medicines, from drug discovery and preclinical development to the development, production and distribution of pharmaceutical products, as well as sustainable use of medicines and their end-of-life management. As a researcher and educator, how can you contribute to sustainable pharmacy?

Current Tools for Performance Ranking of Enabling Drug Formulations: Abilities and Limitations

Annette Bauer-Brandl

Professor

Department. of Physics, Chemistry, and Pharmacy; University of Southern Denmark, DK- Odense

September 13, 2024, at 09:00 - 10:00

For oral administration of poorly soluble drug compounds, enabling drug formulations are needed to ensure sufficient drug absorption. For decades, such enabling formulations have been optimized towards improved apparent drug solubility, dispersing the formulations using excipients such as surfactants, cyclodextrins, drug-rich nanoparticles etc, and in biomimetic media (FaSSIF, FeSSIF containing bile salt micelles). Apparent solubility is experimentally accessible by bench top centrifugation and filtration and comprises both free drug fractions (i.e., molecularly dissolved, single drug molecules in hydration shell) and solubilized, colloid-associated drug fractions (1). However, already in the ´60s, in situ experiments indicated that only free drug is readily available for absorption (2). This fact had widely been forgotten until recently, when appreciation of free drug being the driving force for drug absorption was renewed (3). Thus, discrimination between molecularly and apparently dissolved drug fractions is required for predicting of drug product performance. Dialysis, ultracentrifugation, and field-flow fractionation can be used to distinguish molecularly dissolved from colloid-associated drug in static solubility experiments (4,5,6,). These approaches cannot follow supersaturation and precipitation processes during the dissolution of enabling formulations.

In dissolution experiments, again filtration or centrifugation are typically used to separate the non-dissolved fraction, and until recently, there were no alternatives available for time-resolved analysis of the free drug. Dissolution/permeation experiments are successfully used as surrogates (7,8,9). However, in vitro microdialysis sampling provides a close to real-time quantification of molecularly dissolved drug and has recently been introduced for a variety of enabling drug formulations (10-14). Besides novel mechanistic insights into the dissolution processes of enabling formulations, this method also offers new opportunities to parametrize physiologically based biopharmaceutics models (PBBMs) and thus to integrate meaningful vitro data into a mechanistic PBBM for optimized drug development.

Tools and methods will be explained and discussed using case studies.

Bauer-Brandl, A. & M. Brandl, Solubility and Supersaturation, in Solubility in Pharmaceutical Chemistry, C. Saal and A. Nair, Editors. 2019, De Gruyter.
Levy, G. & R. Reuning, Effect of Complex Formation on Drug Absorption I: Complexes of Salicylic Acid wih absorbable and nonabsorbable sompounds. J Pharm Sci, 1964. 53: p. 1471-1475.
Buckley, S.T., et al., Biopharmaceutical classification of poorly soluble drugs with respect to "enabling formulations". Eur J Pharm Sci, 2013. 50 (1): p. 8-16.
Kanzer, J., et al., In situ formation of nanoparticles upon dispersion of melt extrudate formulations in aqueous medium assessed by asymmetrical flow field-flow fractionation. J Pharm Biomed Anal, 2010. 53(3): p. 359-65.
Frank, K.J., et al., Amorphous solid dispersion enhances permeation of poorly soluble ABT-102: true supersaturation vs. apparent solubility enhancement. Int J Pharm, 2012. 437(1-2): p. 288-93.
Frank, K.J., et al., What is the mechanism behind increased permeation rate of a poorly soluble drug from aqueous dispersions of an amorphous solid dispersion? J Pharm Sci, 2014. 103(6): p. 1779-86.
Sironi, D., et al., Dynamic dissolution-/permeation-testing of nano- and microparticle formulations of fenofibrate. Eur J Pharm Sci, 2017. 96: p. 20-27.
Nunes, P.D., et al., In vitro Dissolution/Permeation tools for amorphous solid dispersions bioavailability forecasting II: Comparison and mechanistic insights. Eur J Pharm Sci, 2023: p. 106513.
Nunes, P.D., et al., Insights into the Release Mechanisms of ITZ:HPMCAS Amorphous Solid Dispersions: The Role of Drug-Rich Colloids. Mol Pharm, 2022. 19(1): p. 51-66.
Fong, S.Y.K., et al., A novel microdialysis-dissolution/permeation system for testing oral dosage forms: A proof-of-concept study. Eur J Pharm Sci, 2017. 96: p. 154-163.
Shah, K.B., et al., An improved method for the characterization of supersaturation and precipitation of poorly soluble drugs using pulsatile microdialysis (PMD). Int J Pharm, 2014. 468(1-2): p. 64-74.
Holzem, F.L., et al., Microdialysis and nanofiltration allow to distinguish molecularly dissolved from colloid- associated drug concentrations during biomimetic dissolution testing of supersaturating formulations. Eur J Pharm Sci, 2022: p. 106166.
Holzem, F.L., et al., Combining in vitro dissolution/permeation with microdialysis sampling: Capabilities and limitations for biopharmaceutical assessments of supersaturating drug formulations. European Journal of Pharmaceutical Sciences, 2023.
Eriksen, J.B., et al., In-vitro dynamic dissolution/bioconversion/permeation of fosamprenavir using a novel tool with an artificial biomimetic permeation barrier and microdialysis-sampling. Eur J Pharm Sci, 2023. 181: p. 106366.

From pharmacy practice research to full pharmaceutical care service implementation on the example of Polish case studies during and after COVID-19 pandemic

Piotr Merks

Adjunct Professor

Cardinal Stefan Wyszyński University, Faculty of Medicine, Poland
September 13, 2024, at 13:30 - 14:30

The COVID-19 pandemic highlighted the critical role of pharmacists in healthcare systems worldwide, accelerating the need for comprehensive pharmaceutical care services. During the presentation, show the transition from pharmacy practice research to the full implementation of pharmaceutical care services in Poland. Our research work has been pivotal in illustrating how pharmacy practice, traditionally focused on dispensing medications, has evolved to include a broader spectrum of patient-centered care. The research during and after the pandemic emphasizes the integration of pharmaceutical care into the Polish healthcare system, where pharmacists began to take on enhanced roles in patient counseling, medication management, and public health initiatives.

The case studies reviewed demonstrate how the pandemic served as a catalyst for these changes, with pharmacists in Poland stepping up to meet the increased demands for healthcare services, including vaccination programs, medication therapy management, and patient education. The successful implementation of these services was facilitated by ongoing research that informed policy changes and training programs, ensuring that pharmacists were equipped to handle their expanded responsibilities.

Our research not only underscores the importance of pharmaceutical care in improving patient outcomes but also provides a blueprint for how similar transformations can be achieved in other healthcare systems. The Polish experience offers valuable insights into the challenges and opportunities of integrating pharmaceutical care into routine pharmacy practice, particularly in response to global health crises like the COVID-19 pandemic.

Targeted Systemic Delivery of Payloads Using Homing Peptides

Tambet Teesalu

Professor

University of Tartu, Estonia
September 14, 2024, at 9:00 - 10:00

My laboratory employs in vivo phage display screens to identify homing peptides binding to specific targets in the vasculature. These peptides can be used for precision delivery of drugs, biologicals, and nanoparticles into tumors to enhance their therapeutic efficacy. I will outline current approaches to mapping vascular heterogeneity using in vivo peptide phage display, as well as characterization and validation workflow for candidate vascular homing peptides. Additionally, I will offer a translational perspective by describing the clinical development status of the prototypic tumor-penetrating peptide, iRGD. Lastly, I will discuss our unpublished data on blood-brain-barrier targeting peptides, which have the potential to deliver imaging and therapeutic payloads to glioblastoma and other neurological diseases. This innovative research could help to overcome the significant challenges associated with delivering therapeutic agents to the brain and has the potential to revolutionize the treatment of these devastating conditions.

Keywords: tumor homing peptide, iRGD, Neuropilin, phage display, nanomedicine

KEYNOTE SPEAKERS

Strategies from the field of particle engineering to develop novel formulations; updated overview

Rita Ambrus

Associate Professor

University of Szeged, Hungary, Institute of Pharmaceutical Technology and Regulatory Affairs

September 12, 2024, at 14:00 - 14:30

Introductions

Modern pharmaceutical technology is focused on formulations that are targeted to the exact site at the appropriate time, with maximum efficiency and with reduced side effects. Nanoparticle engineering has been developed and reported for pharmaceutical applications. In this approach, poorly water-soluble compounds are formulated as nanometer-sized (< 1000 nm) drug particles. Nanoparticulate technology offers increased bioavailability, improved absorption, and the potential for drug targeting. The main question of our work is, how can we use and apply the prepared nanosized systems (as predispersions) in drug formulation (to reach local or systemic effect) to get effective therapies for different diseases. Therefore, we should find cost-effective production by new technological processes containing the most important technological and material parameters.

The main focus of our research is the development of modern, innovative particle size reduction processes for the production of predispersions by modification the physico-chemical properties of model active ingredients, Using experimental design to identify technologies that can also be used by industry, as well as by developing test methods (in vitro, ex vivo and in silico) to acquire knowledge that helps the development and production of modern pharmaceutical formulations.

Materials and methods

In this work, different methods were used to decrease particle size into the micro- or the nanosize range. They can be divided into two main categories: bottom-up and top-down techniques. These two categories are not separated sharply, because the combination of the top-down and the bottom-up technique is necessary to control the particle size. Basically, we focused on the following methods: research and development of dry/wet milling; ultrasonic-assisted nanoprecipitation and preparation of nanocarriers by nano spray drying.

We developed formulations for per os, nasal and pulmonary application. The applied model drugs were nonsteroidal anti-inflammatory agents such as meloxicam. Different type of excipients e.g. PVA, PVP, PEG, Leucine, Inhalac, Mannitol, Hyaluronic acid were used. Characterization of micrometric and physicochemical properties, structure, compatibility, stability, in vitro, ex vivo and in silico properties took a part of the scientific evaluations. The innovative formulations could play a significant role in modern therapies.

Results

We monitored the dry/wet grinding parameters and the factors affecting nano-precipitation, used alternative energy sources based on solvent evaporation, designed compositions and production parameters in the 1-5 µm and 100-500 nm particle size ranges. A predispersions (liquid and solid formulations of nanosuspensions) were produced with innovative technological solutions (formation of particles with a specific habit), optimized the products, and in some cases the intermediate product as final products (stabilizers, drying procedures, composition, toxicity) could be used. Furthermore, with preformulation tests, we determined the additives necessary for alternative drug intake (pulmonary, nasal) and their applicable concentrations in the case of different dosageforms. We developed a new preparation protocol for delivering nanoparticles to the lungs by developing a "nano-in-micro" inhalation product (innovative product). In silico aerodynamic model was introduced as a part of inhalation investigation protocol. A horizontal diffusion model for the examination of suspensions and powders (geometric arrangement, real-time analysis, membrane impregnation, small volume). was also used.

Conclusion

Based on these results, we carried out research and development of innovative product compositions containing nano-sized active ingredients, which may be suitable for intranasal and pulmonary intake, e.g. for the treatment of neurodegenerative and paint treatment (nasal powder and nasal spray containing meloxicam) and chronic obstructive pulmonary diseases (inhalation powder containing meloxicam). The results can help the production of extra generic forms, as well as the development of possible original nanomedicines.

Keywords: nanosuspensions, particle engineering, preformulation, nasal and pulmonary drug delivery

Acknowledgement: The work was supported by NKFI OTKA K_146148 project.

Strategies on efficient nanotechnology-based drug delivery in nervous system disorders

Zerrin Sezgin-Bayındır

Associate Professor

Department of Pharmaceutical Technology, Faculty of Pharmacy, Ankara University, Turkey

September 12, 2024, at 16:30 - 17:00

The complex pathophysiology, presence of various barriers such as the blood-brain barrier (BBB) and the progressive nature of neurodegenerative diseases continues to be a significant challenge in their treatment. In response, innovative treatment approaches leveraging non-invasive techniques with higher patient compliance are emerging as promising alternatives and nanotechnology offers a promising path to improve drug delivery to the central nervous system (CNS). This presentation discusses the potential of nanotechnology-based drug delivery systems (NDDS) for the effective treatment of nervous system disorders. By taking advantage of the unique properties of nanoparticles such as small size, versatile surface morphology and the ability to encapsulate various therapeutic agents, NDDS can improve drug bioavailability, targeting and efficacy. In this context, findings on the potential of polymeric micelles and biomimetic nanoparticle systems, which our study groups have been working on, will be presented. These drug delivery systems were found to be promising strategies for the treatment of neurodegenerative diseases. However, the need for further studies to evaluate the suitability of the developed systems for industrial production and their possible toxicity should be taken into consideration.

Fragment-based design in the discovery of new antibacterial leads

Rok Frlan

Associate Professor

University of Ljubljana, Slovenia

September 12, 2024, at 17:00 - 17:30

Fragment-based drug discovery (FBDD) is an effective approach to identify new antibacterial agents, especially in the face of increasing bacterial resistance. This method enables efficient exploration of the chemical space and targets essential bacterial enzymes involved in peptidoglycan biosynthesis. Our research focused on three main areas: the construction and screening of a focused library of fragment-sized thiazoles and thiadiazoles targeting the enzyme D-Ala ligase (Ddl), and the utilization of the DELopen platform for high-throughput screening against the enzymes MurA and DdlB. We identified and validated multiple fragment hits by biochemical inhibition assays and orthogonal biophysical methods such as surface plasmon resonance. Our results emphasize the need for comprehensive hit profiling to exclude non-specific inhibitors and confirm the effect on the target. In addition, the deciphering of compounds from DNA-encoded libraries led to the discovery of new MurA inhibitors with promising antibacterial activity. These findings underline the importance of innovative screening and rational drug design in the development of new antibacterial agents to combat resistant bacterial strains.

Keywords: fragment-based drug discovery, antibacterial agents, thiazoles, D-Ala ligase, DNA-encoded libraries, peptidoglycan biosynthesis, hit profiling, bacterial resistance.

Dissolution and solubility enhancement - nanocrystals, cocrystals or co-amorphous indomethacine?

Leena Peltonen

Professor

Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, Finland

September 13, 2024, at 11:00 - 11:30

The number of drug candidates having solubility issues is increasing, and numerous different techniques to improve the solubility properties are studied a lot. Enhanced solubility and dissolution is mostly based on two approaches: solubilization, like different kind of lipid or surfactant systems, or supersaturation like nanocrystals, amorphous systems or cocrystals. These both approaches have their own benefits and challenges and the selection of solubility enhancement method is dependent on the material properties of the drug candidate.

Nanosizing, amorphous formulations or cocrystallization of drug are all efficient ways to improve the solubility and dissolution properties of a drug candidate. All these systems will lead to supersaturated state after the dissolution, which poses special challenges for bioavailability. Besides, thermodynamic stability challenges are different related to each of these techniques, and for example coamorphous system can crystallize to cocrystalline system during the storage. In order to reach the optimum and stable formulation for a drug candidate, it is utmost important to understand different approaches for solubility enhancement and drug release behavior and especially formulation and stability issues related to maintaining the solubility benefits during the storage and drug release testing as well as bioavailability.

3D printing of enteric formulations

Kristiine Roostar

PhD student

Institute of Pharmacy, University of Tartu, Estonia

September 13, 2024, at 11:00 - 11:30

In modern personalized medicine, the customized medicines with individualized doses is the main topic in the pharmaceutical technology perspective. Modern 3D printing technologies hold great promises for the development of customized medicines and drug delivery systems.

Semi-solid extrusion (SSE) 3D printing is a quite simple 3D printing technology providing many advantages for the printing of pharmaceutical oral solid dosage forms. The printing does not require high temperatures. Only a few excipients are required for a printing operation, and the ink preparation is not complicated, thus making SSE 3D printing a suitable technology to be used for example in a pharmacy to manufacture immediate-release solid oral drug preparations.

In addition to immediate-release drug preparations, many active pharmaceutical ingredients (APIs) are formulated to gastro-resistant (enteric) drug preparations to pass the acidic environment of the stomach and to dissolve in the alkaline environment of the small intestine. The development of such customized preparations using modern pharmaceutical 3D printing technologies is a challenge due to the inappropriateness of the excipients and/or APIs, combining different 3D printing technologies.

Community pharmacist-led medication reviews in improving adherence

Anita Tuula

PhD student

Institute of Pharmacy, University of Tartu, Estonia

September 13, 2024, at 14:30 - 15:00

Medication non-adherence is a common issue in polypharmacy patients. In developed countries, around 50% of patients with chronic illnesses are not using their medicines as prescribed according to WHO (1). Medication review (MR) is a structured evaluation of a patient’s medication regimen which aims to optimize medicine use and improve health outcomes (2). Through patient engagement and promoting medication awareness, MR services have demonstrated to be beneficial in improving adherence (3).

Patients can have many different reasons for not taking their medication as intended. Factors leading to medication non-adherence can be patient-related, condition-related, healthcare system related, therapy-related or socioeconomic status related (1); thus, interventions aimed to improve adherence must offer personalized solutions. Self-reporting questionnaires and patient interviews are considered the most suitable methods to detect reasons for non-adherence during MRs.

In 2019-2021, the community pharmacy based MR pilot was launched in Estonia, Latvia, Poland, Hungary, Romania and Bulgaria. 318 patients using five or more medicines were included in the study. Non-adherence was documented for 50% of study participants by the pharmacist during patient interviews. The main reasons for non-adherence included forgetfulness or memory problems and lack of knowledge regarding medicines. In almost half the cases, the reason for non-adherence was not documented, implying further pharmacist training on promoting adherence could be necessary.

1. World Health Organization. Adherence to long-term therapies: evidence for action. 2003.

2. Griese-Mammen N et al. PCNE definition of medication review: reaching agreement. Int J Clin Pharm. 2018 Oct 1;40(5):1199–208.

3. International Pharmaceutical Federation (FIP). Medicines Use Review: a Toolkit for Pharmacists. 2020.

Personalized drug delivery systems for the treatment of skin diseases

Andrea Heinz

University of Copenhagen, Denmark

September 13, 2024, at 14:30 - 15:00

Inflammatory skin diseases are prevalent and often require complex treatment regimens that challenge patient adherence and therapeutic effectiveness. The presentation will introduce three novel drug delivery systems designed in our research group to overcome these challenges. The first drug delivery system is an electrospun dressing combining the release of salicylic acid and hydrocortisone, offering a controlled, once-daily release to improve adherence in treating inflammatory skin conditions. The dressing shows superior drug penetration and anti-inflammatory effects compared to standard formulations. Another focus of the presentation will be terpene-based eutectic mixtures for dermal drug delivery. Our research demonstrates that the terpene composition, rather than fixed molar ratios, drives drug solubility, viscosity, and skin retention, offering new permeation-enhancing strategies for optimizing transdermal formulations. Finally, protease-responsive hydrogels and microparticles for the treatment of chronic skin conditions will be presented. These PEG-based microparticles release tofacitinib citrate during flare-ups, with tunable properties enabling precise control over drug release and mechanical performance. Overall, the presentation aims at highlighting advancements in patient-friendly, targeted, and responsive therapies for managing challenging skin conditions.

Nano and Multiparticulate Systems in Oral Drug Delivery

Yesim Aktas

Professor

Erciyes Üniversitesi, Turkey

September 13, 2024, at 16:00 - 16:30

Despite of many studies on drug delivery approaches, oral administration still stands as the most convenient route due to its invasive nature, cost-effectiveness, and ease of large-scale production. On the other hand the choice of drug administration route depends not only on convenience but also on the drug's properties and pharmacokinetics. Oral administration have some limitations such as acidic environment, enzymatic degradations, barriers and food interactions in the gastrointestinal tract in addition to physicochemical properties of drugs, including poor water solubility that reduces or prevents the drug absorption. Therefore these problems can be avoided by parenteral administration although the compliance of patients with chronic diseases to oral formulations is generally higher than that to injection. Furthermore manufacturing of parenteral medications requires expensive procedures including sterilisation which may cause unfavourable effects on the active substance such as therapeutic peptides and proteins. Nanocarriers open a new avenue for oral administration with improved therapeutic efficiency and adherence of patients to their treatment.

1. A. des Rieux, V. Fievez, M. Garinot, Y.J. Schneider, V. Préat, Nanoparticles as potential oral delivery systems of proteins and vaccines: A mechanistic approach, J. Control. Release, 2006, 116, 1–27.

2. Y. Aktaş, M.Ç. Tekeli, N. Çelebi, Development and characterization of exendin-4 loaded self-nanoemulsifying system and in vitro evaluation on Caco-2 cell line, J. Microencapsul., 2020, 37, 41–51.

3. S. Ünal, S.C. Öztürk, E. Bilgiç, H. Yanık, P. Korkusuz, Y. Aktaş, J.M., Benito, G. Esendağlı, E. Bilensoy, Therapeutic efficacy and gastrointestinal biodistribution of polycationic nanoparticles for oral camptothecin delivery in early and late-stage colorectal tumor-bearing animal model, Eur. J. Pharm. Biopharm., 2021, 169, 168–177.

4. O.R. Guadarrama-Escobar, P. Serrano-Castañeda, E. Anguiano-Almazán, A. Vázquez-Durán, M.C. Peña-Juárez, R. Vera-Graziano, M.I. Morales-Florido, B. Rodriguez-Perez, I.M. Rodriguez-Cruz, J.E. Miranda-Calderón, J.J Escobar-Chávez, Chitosan Nanoparticles as Oral Drug Carriers, Int. J. Mol. Sci. 2023, 24, 1-17.

Smart formulations

Anssi-Pekka Karttunen ¹

University Lecturer

Henna Noponen ¹, Rim Alrawi ², Atte Junnila ¹, Leena Peltonen ¹

¹ University of Helsinki, Finland,

² Helsinki Vocational College and Adult institute

September 13, 2024, at 16:00 - 16:30

Introduction

Most new drugs have poor aqueous solubility.1 Some common means to overcome this obstacle are amorphous solid dispersion (ASD), and co-amorphous (CA) or co-crystal (CC) form of the drug with a suitable co-former.2,3 Alongside finding solutions to increase the solubility, the final tablet formulation and selection of suitable excipients needs to be considered. In some cases, the stabilizers, for example polymers in case of ASDs, might constitute considerable share of the tablet, leaving only small amount for other excipients. Thus, it is beneficial if multifunctional excipients can be used to suffice the needs for example on processability, solubilization and stabilization of supersaturation.

Another issue in pharmaceutical manufacturing is increasing number of drug shortages. This is often related to active ingredients, but during international crises this could also affect excipients. For this reason, side stream lactose from dairy side stream has been tested for tablet manufacturing.

Materials and methods

Indomethacin (IND) was used as a poorly soluble model drug and HME process with Soluplus® or Kollidon® VA64 was utilized to make ASDs, or with Nicotinamide (NIC) to produce CA or CC. Ball-milling and quench-cooling were also employed in CC and CA manufacture, respectively. The ASD manufacture was evaluated with two API-polymer ratios (50:50 and 30:70 %w/w). To switch between CA and CC in HME process4, barrel temperature was changed between 110 and 150 °C, but same standard concave screw configuration and molar ratio of 1:1 was used for both. Same molar ratio was used also in ball-milling or quench-cooling. Typical excipients were used in making the final tablet formulations with care given for rational selection. DSC, IR and XRPD were utilized to confirm the solid state of materials and single phase of ASDs.

In another study, side stream lactose was used as filler in different ratios with MCC (15/85, 50/50 and 85/15) for direct compression to tablets. Compression profiles, variation in tableting, disintegration and dissolution were used to evaluate success of production.

Results and discussion

ASDs from IND were successfully produced with both polymers and API-polymer ratios. CC and CA between IND and NIC were successfully manufactured by HME through the selection of right processing temperature. Addition of 10% Soluplus® to the IND-NIC formulation made the extrusion easier without changing the IND-NIC co-formation. The manufacture of CC was also successful with ball-milling and CA with quench-cooling. However, it was noticed for quench cooled CA that it transformed to CC within hours. The use of NIC as CC or CA co-former was beneficial from formulation aspect as the weight ratio between IND and NIC was ~3:1, meaning it will not constitute extremely high portion of excipients and allows a reasonable tablet size.

In the formulation side, HPMC was used in tablet formulations made from CC or CA to stabilize the supersaturated state. On the other hand, it also provided stability for the tablet compaction as it decreased the variation in tensile strength. It could have probably worked as sole binder even though PVP was also used in the formulation. Likewise, Soluplus® acted as both processing aid in HME process but also serves as solubility enhancer for the poorly soluble drug. The manufacture of CA IND-NIC with HME was also beneficial since it was more stable than quench-cooled CA. In addition, it provides a better starting material to be grind as granules/pellets for subsequent tableting. By selecting right process and conditions for size reduction of the HME filaments, these granules/pellets can be made rather flowable which decreases the amounts of additional excipients needed.

The side stream lactose proved usable, with certain ground rules, to be used in tablet formulations. Poor flow was an issue when lactose was used as primary filler but the physical quality of the lactose could be improved to tackle this. The ability to use this lactose will secure the national supply also during crises.

Conclusion

Various methods to improve poor solubility of drug substances exist. When selecting the most suitable one, the ability to make the final formulation and process should also be considered. Attention should also be paid to rationale selection of excipients to allow maintaining the tablet size reasonable while allowing the design of robust manufacturing process as well. The presented case studies have provided tools and ideas on rationale formulation design to achieve these goals, by for example selecting multifunctional excipients.

Acknowledgments

Marika Tossavainen, Ulla Moilanen, Satu Kivimäki, Vilhelmiina Harju and Maarit Julkunen are acknowledged for providing the investigational lactose and Eetu Myöhenen and Chee Ng for laboratory studies. (Study was EU funded Kotimaiset bioraaka-aineet terveys- ja hyvinvointituotteissa, FARKOS project #A80468)

1. Jermain, S.V..; Brough, C.; Williams, R.O. Amorphous solid dispersions and nanocrystal technologies for poorly water-soluble drug delivery – An update. Int. J. Pharm., 535, 379-392 (2018).

2. Laitinen, R.; Löbmann, K.; Grohganz, H.; Priemel, P.; Strachan, C.J.; Rades, T. Supersaturating drug delivery systems: The potential of co-amorphous drug formulations. Int J Pharm., 532, 1-12 (2017)

3. Kavanagh, O.N.; Croker, D.M.; Walker, G.M.; Zaworotko, M.J. Pharmaceutical cocrystals: from serendipity to design to application. Drug. Discov. Today, 24, 796-804 (2019)

4. Shen, P.; Zhang, C.; Hu, E.; Gao, Y.; Wei, Y.; Zhang, J.; Qian, S.; Heng, W. Switch between Cocrystal and Coamorphous Forms Depending on Thermal Modulation of Hot-Melt Extrusion. Mol. Pharmaceutics, 20, 3412-3426 (2023)

Capillary electrophoresis – a valuable bioanalytical tool for pharmacology research

Tamás Tábi

Associate Professor

Department of Pharmacodynamics, Semmelweis University, Budapest, Hungary

September 14, 2024, at 11:00 - 11:30

Capillary electrophoresis is a powerful separation and analytical technique that can serve as a complementary tool for the more wide-spread chromatographic and mass spectrometry based assays. In the field of bioanalytics its advantages of high separation efficiency and low sample and reagent requirement are beneficial, while appropriate method development can help to overcome its inferior detection sensitivity.

In the lecture we will present examples to illustrate the applicability of capillary electrophoresis for analysis of biological samples in various fields of pharmacological research.

Capillary electrophoresis is exceptionally appropriate for chiral analysis due to its high separation efficiency and peak capacity. Simultaneous separation of several enantiomer pairs can be achieved. Fine tuning of chemical and chiral selectivity by using dual selector systems will also be shown.

Poor detection sensitivity commonly limits the applicability of capillary electrophoresis for bioanalytics. We will present sensitivity improvement opportunities and their application to biological samples as well. Pros and cons of electrophoretic preconcentration methods and use of the more sensitive laser induced fluorescence detector will be discussed. Examples will be presented from the fields of drug metabolism studies, amino acid analysis and glycolipid biology.

Lyotropic liquid crystals: advanced delivery systems for dermal and subcutaneous application

Mirjam Gosenca Matjaž

Assistant Professor

University of Ljubljana, Faculty of Pharmacy, Department of Pharmaceutical Technology, Slovenia

September 14, 2024, at 11:00 - 11:30

Lyotropic liquid crystals (LLCs) represent an outstanding delivery system with unique properties and functionalities suitable for various applications, including dermal, oral, and parenteral, among others. LLCs are self-assembled, organized mesophases of amphiphilic molecules formed upon contact with an aqueous environment under appropriate temperature and concentration conditions. Despite their relatively straightforward preparation, the versatile mesophases formed - classified as lamellar, hexagonal, and cubic - require in-depth microstructural characterization using various complementary techniques.

The microstructure of LLCs fundamentally relates to their drug delivery potential. While lamellar mesophases present the forefront of dermal drug delivery owning to their structural similarity to the intercellular lipids of the stratum corneum, hexagonal and cubic mesophases present an attractive platform for subcutaneous administration due to their highly ordered microstructure, which enables sustained drug release being particularly relevant for peptide drugs, which often suffer from poor stability and short plasma half-life.

To fully harness the advantages of LLCs for improved therapeutic outcomes and patient adherence, it is crucial to develop LLCs with microstructure tailored to the specific application. The use of bio-based materials is particularly compelling in this context. The lecture will explore all of these aspects, highlighting strategies for optimizing LLCs for dermal and subcutaneous application.