Day 1 :
Keynote Forum
Dieter Lubda
Director, Merck KGaA, Germany
Keynote: New manufacturing technologies and excipients will change future drug production
Time : 12:20-13:00
Biography:
Dr. Dieter Lubda is director of R&D Operations of Actives and Formulation within Merck KGaA (Germany) Life Science business unit. The Formulation R&D teams at global sites within the franchise are mainly focusing on the development and solid and liquid formulations of excipients for oral and parental administration of drugs. During his career of more than 30 years with Merck KGaA/ Germany mainly working in R&D and “Global Operations” Dr. Dieter Lubda has contributed to 77 Peer-reviewed publications and as one of the inventors to more than 50 patents filed or granted.
Dr. Dieter Lubda holds a Ph.D. degree in Chemistry from the University of Vienna, Austria and had got the degree “Diploma Engineer of Chemistry” after finalizing his thesis at the Technical University of West-Berlin, Germany
Abstract:
The requirements of customers with regard to convenience and range of application for oral and liquid administration of active pharmaceutical ingredients (APIs) have increased significantly in recent years. In addition, solubility and bioavailability of APIs for oral administration has become a main issue of pharmaceutical industry.
Nearly all new chemical entities (NCE’s) under development are suffering in aqueous solubility during pharmaceutical drug product development therefore showing limited oral bioavailability. At least, in the preclinical stage every 3rd drug candidate offers poor bioavailability. Different strategies to enhance the drug's bioavailability are commonly used showing beneficial effect. Therefore, technologies to address these challenges have never been more important! But although there are a number of approaches to improving solubility, bioavailability and dissolution rates, they have, for the most part, remained unchanged for decades. The use of drug carriers (such as mesoporous silica), spray drying and hot melt extrusion (HME) are all effective technologies, but as we move into a new era of pharmaceutical development, the excipients used in formulation should be as advanced as the emerging techniques being seen in other areas of the pharma industry. For example, future trends and key drivers of the industry point towards continuous manufacturing, personalized medicine, 3D printing, and increased importance on amorphous solid dispersion, with the goal of dispersing or dissolving an API in a polymeric matrix in the amorphous state. These technologies have the potential to disrupt the market as we know it.
The presentation will give an overview about trends of products and technologies used nowadays to address delivery challenges of small and biomolecules focusing on excipients and technologies for oral administration. Technologies exemplary described increasing bioavailability through enhancement of solubility or trying to address user convenience.
Keynote Forum
Tamara Bukeyeva
Senior Researcher, Kazakhstan, Almaty
Keynote: DIFFERENTIAL EFFECT OF IODINE BIOORGANIC MOLECULAR COMPLEX ON HOST DEFENSE IN BALB/c and C57BL/6 MICE
Time : 14:00-14:30
Biography:
In 2004 she graduated from Kazakh National University. Al-Farabi, Faculty of Biology, Department of Human and Animal Physiology and Biophysics with a Master of Biology. The total scientific experience is more than 16 years. The main research areas are in the field of cell and molecular biology. She is an experienced specialist in conducting cultural work with tumor cell lines, hematopoietic stem cells, and the isolation and cultivation of immunocompetent cells.
Abstract:
Statement of the Problem: Long experience in the use of various iodine preparations has shown that while possessing pronounced antibacterial and antiviral properties, wide-spectrum antimicrobial activity, and lacking mutagenic and teratogenic effects, they are toxic when introduced to the human body, which significantly narrows the scope of their clinical application. The search for alternative ways to solve the problem of high toxicity of inorganic iodine compounds has led to the development of iodine-containing organic complexes. The manifestation of the phagocytic response is a significant indicator of the body reactivity state and level of its immune activity. The coordination compound of iodine with alpha-dextrin and polypeptides was synthesized at the Scientific Center for Anti-Infectious Drugs JSC, the effect of which on the phagocytic activity of granulocytes and monocytes in BALB/c and C57BL/6 mice was studied. Phagocytosis is considered as one of the major host defense function, which is a fundamental component of the innate immune response /1/.
Materials and methods: The animals of each line were divided into 3 groups of 10 mice, including 5 females and 5 males. Two doses of the drug were used in the study: 1/20 of maximum tolerated dose (MTD) is 125 mg/kg and 250 mg/kg (1/10 MTD) of animal weight. Blood was collected on day 14 after the administration of the drug. The analysis was performed by flow cytometry. Findings: It was shown that a new complex of iodine with bioorganic molecules upon repeated oral administration for 14 days in the examined doses did not affect the phagocytosis in BALB/c mice. The findings indicated that a new complex of iodine with bioorganic molecules at a dose of 250 mg/kg increased the phagocytic activity of both granulocytes and monocytes in C57BL/6 mice.
Conclusion & Significance: One of the explanations for the differential effect of a new complex of iodine with bioorganic molecules on different lines of mice may be based on the genetic characteristics of these animals. Macrophages of BALB/c mice are known to be of M-2 type, which inhibits inducible NO synthesis and stimulates cell division. Macrophages of C57BL/6 mice are of M-1 type, which produces NO and inhibit cell division, and increases the cytostatic or cytotoxic activity of phagocytes
/2 - 4/. We can therefore conclude that a new complex of iodine with bioorganic molecules enhances the cellular factors of the natural resistance in the prototype mouse strains Th1 (C57BL/6), but not Th2 (BALB/c). This, in turn, fits into the single mechanism of action of the studied complex, namely, the activation of phagocytic cells through the induction of IFN-γ production and the ability of the complex to switch T cells to the Th1-type response path.
Keynote Forum
Abhinav Mehta
Associate Professor, Dr Harisingh Gour University, India
Keynote: Development and Characterization of pH sensitive liposomes for macrophage targeting using prime-boost vaccination strategy for Pulmonary Tuberculosis
Biography:
Dr. Abhinav Mehta is currently Associate Professor at R C Patel Institute of Pharmaceutical Education and Research at Shirpur, Maharashtra, India. He has 26 publications in peer reviewed journals. He has h-index of 13 and an i10-index of 16 with more than 570 citations. He has supervised 12 M. Pharm students and co-supervised 1 PhD student. He has to his credit 1 Govt. sponsored project on Drug delivery system and Tuberculosis. He has 1 year postdoctoral experience. His current recent research interest is on the development of stimuli responsive drug delivery system
Abstract:
Tuberculosis (TB) caused by the bacterium Mycobacterium tuberculosis remains a major health problem worldwide. Although BCG seems to provide protection against miliary tuberculosis, its effect on pulmonary TB in adults is poor, and needs a better vaccine regimen to combat the disease. Various strategies have been postulated for the development of the tuberculosis vaccine viz. improving the current BCG vaccine, over expression of the immunodominant antigens, endosomal escape, recombinant fusion proteins and a hybrid approach which is a multiphase vaccine that can be administered regardless of the infection status of the individual and with activity both in naïve and already infected individuals.
The present investigation was aimed to develop liposome based DNA prime-protein boost vaccine regimen against pulmonary tuberculosis. The rationale behind the use of liposomes as delivery systems in intracellular infections such as mycobacteria is selective uptake by the macrophages, following systemic administration and versatility to engineer to target the specific site in the body via binding to specific receptors.
Two types of multilamellar liposomes (MLVs) were prepared, one ligand directed while the other pH sensitive cationic. Liposomes were developed using DRV (dehydration-rehydration vesicles) and film hydration technique using trehalose dibehenate (TDB) as a protein stabilizer. O-palmitoyl mannan (OPM) was used to coat the ligand directed liposomes to impart them the desired targetability for the alveolar macrophages. Plasmid DNA encoding genes for Ag85A were adsorbed on the preformed pH sensitive cationic liposomes whereas rAg85A was entrapped in the ligand directed (OPM coated) liposomes.
The optimized formulation was evaluated for various physico-chemical parameters such as vesicle size, shape, entrapment/loading efficiency of the bioactive, their structural integrity by SDS-PAGE followed by confirmation with the western blot and agarose gel electrophoresis and in vitro release. In-vivo immune responses were obtained in terms of antibody responses, isotype titers as well as cytokine profile.
- Biopharmaceutics
Location: Rome, Italy
Chair
Stefania Petralito
Professor
Session Introduction
Stefania Petralito
“Sapienza†University of Rome, Italy
Title: Non -thermal electromagnetic fields to trigger On-Demand drug release from High-Tm Magnetoliposomes
Biography:
Stefania Petralito received the Laurea degree in pharmacy, the Ph.D. degree in Pharmaceutical Science and a Postgraduate Diploma in Hospital Pharmacy from the Sapienza University of Rome, in 1997, 2000 and 2003 respectively. In 2005, she joined the Department of Drug Chemistry and Technologies, Sapienza, as a researcher. Her current research interests include preparation and characterization of vesicular systems as drug delivery systems. She is a member of the Controlled Release Society Italian Chapter (C.R.S.), of the Società Chimica Italiana (SCI)-Division of Pharmaceutic Technology, of the Association of Italian Doctors, and Researchers of Pharmaceutical Technology and Legislation (A.D.R.I.T.E.L.F.).
Abstract:
Magnetic nanoparticles with superparamagnetic properties have attracted increased attention for applications in biomedicine, as they exhibit a strong magnetization only when an external magnetic field is applied. Magnetoliposomes (MLs) are the combination of liposomes with encapsulated magnetic nanoparticles. These hybrid nanocarriers have been showing significant biomedical application possibilities. However, it is essential that nanoparticles exhibit superparamagnetism, this causes nanoparticles to become susceptible to strong magnetization. When the magnetic field is applied, they orient toward this field, but do not retain permanent magnetization in the absence of magnetic field. The magnetic properties of super paramagnetic iron oxide nanoparticles (SPIONs)-based magnetoliposomes allow for alternative therapies through magnetically controlled drug delivery and hyperthermia. In this way they can be viewed as trigger-responsive carriers as they have the potential to act as "remote switch" that can turn on or off the effects of the therapeutics, based on the presence or absence of the stimulus. Recently, a pilot study has demonstrated the feasibility of smart controlled delivery through a magnetic field with intensity significantly lower than the ones usually reported in literature. In this way, a controlled release has been obtained through a magneto-nanomechanical approach without any macroscopic temperature increase. Specifically, signals generated by non-thermal alternating magnetic fields (AMFs) or non-thermal pulsed electromagnetic fields (PEMFs) were applied to high-transition temperature magnetoliposomes (high-Tm MLs) entrapping hydrophilic SPIONs, proving to be interesting and promising stimuli-controlled drug delivery systems
- Drug Targeting & Design
Location: Rome, Italy
Chair
Marta Ruano Aldea,
Professor
Session Introduction
Marta Ruano Aldea
University of Strathclyde, UK
Title: Comparison of the physical characteristics of cubosomes prepared using different manufacturing methods
Biography:
Marta Ruano is a Chemical Engineer who obtained a PhD from the Physical-Chemistry Department of University Complutense of Madrid with the thesis entitled Fabrication of liposomes and polymeric microcapsules. She has 5 years expertise in drug delivery systems for food, cosmetics, and nutraceuticals: liposomes, polymeric micro and nano microparticles with different actives after years dedicated to this research in a R&D technology center. In 2018, she started the KTP project in Glasgow where AB Vista and the University of Strathclyde are involved. The aim of this project is the development of novel nano-delivery systems incorporating bioactive lipids and peptides in animal food formulation with effective antimicrobial stewardship to reduce antibiotic resistance in the food chain.
Abstract:
Background: Cubosomes are cubic lyotropic Liquid Crystalline structures consisting of polar lipids, such as glycerol monooleate (GMO) or glycerol monolaurate (GML) that provide the capability of carrying both hydrophilic and lipophilic compounds1-3. The most straightforward method of producing cubic phase particles is the agitation of both phases (oil and water) with a magnetic stirrer resulting in a coarse dispersion. This produces a polydisperse and unstable solution. Further post-manufacture modifications are required to control dispersity and size: ultrasonication5, homogenisation6, and microfluidics7.
Aims: The aim of the present study was to formulate cubosomes (see Figure 1)4 in the presence of ethanol (hydrotrope) prepared comparing the three post-manufacture methods.
Methods: Three samples were prepared using GMO and GML dissolved in ethanol (oil phase) and the surfactant (F127) dissolved in water (water phase). One sample was sonicated for 5 minutes using 30-40% of the maximum power. The second sample was homogenised for 10 minutes at 8000 rpm. The third sample was prepared using a Neonano device from Neofluidics for 1 minute. The samples were examined by Scanning Electron Microscopy to determine if cubosomes had been formed, and evaluated by Dynamic Light Scattering (DLS) for measurement of particle size and Zeta potential using a Zetasizer Nano ZS90 system to provide a comparison of average droplet size and polydispersity index between all the samples and the measurements of zeta potential showed which method provides better colloidal stability during storage for three months at 4, 25 and 37ºC.
Results: The dispersions examined under Scanning Electronic Microscope showed non-aggregated particles confirming the nanoparticle formation for all three methods. The sample produced by microfluidics showed low polydispersity with no variation of the zeta potential over three months.
Conclusion: Microfluidics avoids the heat gradient and it reduces the manufacture time with high reproducibility
- Pharmaceutical Formulations
Location: Rome, Italy
Chair
Kármen Szabó
Professor
Session Introduction
Kármen Szabó
University of Debrecen, Debrecen, Hungary
Title: Study on the promiscuous nature and aggregation-tendency of 4- thiazolidinone derivatives
Biography:
Kármen Szabó is a doctoral candidate at the Inorganic and Analytical Chemistry Department of the University of Debrecen (Debrecen, Hungary). She is a member of a biochemical research group, which primarily focuses on the investigation and inhibition of carbohydrate-active enzymes (glycoenzymes). Kármen has dealt with the examination of natural and synthetic compounds that could be applied as medicaments for the treatment and/or the prevention of type 2 diabetes mellitus and its complications. She has recently been concerned with the identification and interpretation of drug promiscuity, especially for known and potential anti-diabetic agents. Drug promiscuity, which can be defined as the outstanding inhibitory effect of a compound on various unrelated target enzymes, can lead to financial losses for pharmaceutical industry if it is recognized too late. Therefore, her work can be feasible for eliminating these promiscuous inhibitors even at an early stage in drug development.
Abstract:
Statement of the Problem: According to the International Diabetes Federation (IDF), type 2 diabetes mellitus as well as its complications caused the death of about 4.2 million adults in 20191. Although many effective drugs are currently available, their diverse and often severe side effects require the development of new, safer alternative therapies2. The inhibition of aldose reductase (AR) enzyme can ease or even prevent the development of such longterm complications of diabetes as kidney failure, blindness, or cardiovascular diseases. 4-thiazolidinone derivatives were designed as potential AR-inhibitors3; however, the promiscuous nature of these compounds must be investigated before applying them as drugs.
Methodology & Theoretical Orientation: Our research aimed to determine whether these 4-thiazolidinone derivatives meet the criteria of promiscuity found in the literature. These criteria are as follows: (1) time-dependence, (2) sensitivity both to the change in enzyme concentration as well as to the presence of a detergent, and (3) a considerable inhibitory effect on target enzymes with significantly different mechanisms and/or functions4-5. Activity measurements were carried out spectrophotometrically, using a chromophore-containing substrate and porcine pancreatic α-amylase as enzyme. Since aggregation can be a reason of promiscuity, in the case of those inhibitors that had turned to be promiscuous, I also examined their aggregation-tendency by HPLC.
Findings: Three out of the seven tested inhibitors found to be promiscuous. In these cases, IC50 values increased due to the presence of a detergent and the use of diverse enzyme concentrations, they were able to inhibit efficiently three unrelated enzymes, and IC50 values decreased under the influence of enzymeinhibitor pre-incubation.
Conclusion & Significance: Three out of the seven synthetized AR-inhibitors are not proposed to use as drugs due to their promiscuous nature, whereas the remaining four are worth further testing
Patricia Hegger
Sanofi Aventis Deutschland GmbH, Frankfurt, Germany
Title: In Vitro in Vivo Correlation (IVIVC) of Subcutaneous Formulations
Biography:
Dr. Patricia Hegger has completed her PhD on “Hyaluronan Based ECM-Mimetics with Tunable Charge Densities – Physico-Chemical Properties and Biological Implications” from Max-Planck-Institute for medical research in 2017. Before starting her career in industry she took over an interim-groupleader position at the Max-Planck-Institute for medical research continuing her studies on hyaluronic acid. She is now a labhead in the biopharmacy group of the TIDES Drug Product department of Sanofi-Aventis Deutschland GmbH, a global pharmaceutical company.
Abstract:
The uptake of subcutaneous (s.c.) administered formulations into the systemic circulation is a function of numerous quite diverse processes like active pharmaceutical ingredient (API) dissolution from the formulation and disintegration to monomers (“liberation”), local metabolism and the permeation through the interstitium and endothelium into the blood vessels (“absorption”). The determination of these parameters prior to launch of the drug is the field of biopharmacy, with its three pillars: In silico, in vitro and in vivo assessment combined with in vivo - in vitro correlation.
For s.c. administered formulations however there is only a limited number of systematically applied biopharmaceutical in vitro - in silico tools for characterization of those processes. For example the first in vitro methods for biopharmaceutical evaluation was published in 2015, whereas comparable methods for orally administered small molecules are established since the 1960s. Taken into account, that around 70 % of the marketed drugs today are s.c. applied, this is a highly evolving field with the potential of improvement for (I) molecule selection, (II) formulation selection and optimization and (III) understanding as well as prediction of in vivo findings in animals and humans.
- Pharmaceutical Nanotechnology
Location: Rome, Italy
Chair
Dr. Patricia Hegger
Scientist
- Novel Drug Delivery System
Location: Rome, Italy
Session Introduction
Annalisa Dalmoro
Università degli Studi di Salerno, Dipartimento di Farmacia, Fisciano (SA) Italy
Title: Process innovation in the production of smart lipid-polymeric release systems
Biography:
Annalisa Dalmoro graduated in Chemical Engineering, summa cum laude, in March 2009 at the University of Salerno (Italy), then she gained the Ph.D. degree in Science and Technologies for chemical, pharmaceutical and food industry in 2013. Starting from April 2013 she works as post-Doc researcher in TPP group (http://gruppotpp.unisa.it/en/) at the University of Salerno (Italy). Moreover, she is co-founder of the company Eng4Life srl, spin-off for technology transfer approved by the University of Salerno (http://www.eng4life.it/), established in January 2018. She has published about 40 research articles in international journals indexed on Scopus, WoS. She is also author of 2 patents..
Abstract:
Liposomes are the most versatile carriers for the delivery of a large variety of both lipophilic and hydrophilic drug molecules, being biocompatible and biodegradable. Despite their great advantages, their tendency to degrade and aggregate in biological fluids as well as in storage conditions drove the research towards new preparative approaches for liposomes stabilization, essentially based on superficial coatings or inclusion in polymeric materials. However the most used techniques, such as spraying, layering, sometimes by exploiting supercritical fluids, require complex and expensive apparatuses. Therefore, this work was developed with the idea to overcome typical liposomes stabilization limits, by choosing the consolidated wet granulation process as a method to obtain granules containing liposomes in a single step, by spraying on powder the liposomal suspension, previously produced by a novel continuous and rapid similmicrofluidic method. Literature highlights, although with only few works, the use of wet granulation as method to stabilize polymeric nanoparticles suspensions, by adding them in the binder phase. Instead, there are not experimental evidences about the use of liposomes suspensions as binder phase in wet granulation for both their stabilization and incorporation in pharmaceutical solid forms. Thus, this novel combination between wet granulation and the use of liposomes suspension spray as binder phase, allowed to reach both easy and cheap liposomes stabilization and the production of smart solid multiparticulate dosage forms, which could be ideal candidates for a combined fast/slow release of active ingredients, enhancers, fortifiers.
Drljaca Jovana
University of Novi Sad , Faculty of Medicine, Novi Sad; Serbia
Title: Karnozin EXTRA® alters mitochondrial respiration through its activity on oxidative phosphorylation
Biography:
Abstract:
Carnosine, an endogenous peptide, has been demonstrated to play an antitumorigenic role in certain types of cancer, suppressing glycolysis in cultured tumour cells1,2. Recent evidence suggests that l-carnosine can interfere with oxidative phosphorylation as well3. However, its underlying mechanism is unclear.
The capsule of Karnozin EXTRA® (Carnomed) is a unique patented formula of l-carnosine, in combination with vitamin E, coenzyme Q10, l-carnitine, northern blueberries extract and grape seed extract.
This food supplement was tested on two continuous cell lines with different energy pathways, MRC-5 (human embryo lung fibroblasts) and MCF-7 (human breast cancer cells), to evaluate its effects on mitochondrial respiration and certain mitochondrial respiratory chain complexes of the cells. Cells were treated for 24 hours with different concentrations of aqueous solution of the capsule Karnozin EXTRA® (Carnomed) corresponding to concentrations of pure l-carnosine from the capsule of 2, 5, and 10 mM. Afterwards, we investigated basal respiration of intact cells and the activities of mitochondrial respiratory chain complexes I, II and IV. All measurements were performed using the Hansatech Oxygraph+ instrument (England).
The results showed that Karnozin EXTRA® (Carnomed) exerted a significant reduction in the oxygen consumption in both cell lines in a dose-dependent manner. Moreover, the activities of mitochondrial electron transport chain complexes I, II and IV in both cell lines were compromised. The strongest inhibitory action was shown on the activity of complex II of mitochondrial electron transport chain.
The present study highlights a novel role of this capsule as a regulator of tested cells energy metabolism both in the anaerobic and aerobic pathways, which may give renewed impetus for its development as antitumor agent.
Biography:
Deepesh Lall has curiosity for the development and design of formulation which have much increased Bioavailability and optimistic rate of absorption. I am from starting wanted to overcome several disadvantage of conventional dosage form of Medicament, give an good outcome with novel drug delivery system specially Nanoparticles attracted more towards into NDDS. This Review plays an important role in the field of Pharmaceutic.
Abstract:
Ocular drug delivery still a challenging practice an attempt made to overcome the conventional dosage form with improving the Bioavailability and Concerning Therapeutic desired rate of Anterior Segment Delivery. Drug Delivery to the eye still a challenging practice to overcome Nanoparticles incorporating for optimal Therapeutic activity, as drug molecules treated with the nanoparticles which help to cross from ocular barriers without causing permanent tissue damage. At present availability for the Ocular Anterior segment delivery the conventional dosage forms available with their limitations Bioavailability rate for example solutions, suspensions and some ointments, while novel dosage forms playing important role for achieving more percentage of Bioavailability and rate of absorption without causing optical irritation, for example liposomes, nanoparticles, and implants. Aim of this work also come under the conclusion 80% to 90% of the available formulations present in the market are conventional dosage forms, and they have limited bioavailability due to precorneal clearance and very short duration of action while novel drug delivery system Nanoparticles possess advanced drug delivery medium. On study of certain literature review study conclusion found that major researcher is going with the development of sustained release and control release systems with higher precorneal Bioavailability. Such systems can improve the ocular bioavailability of drugs and provide high patient compliance. With going through several literature review study found therapy into an eyes either by solutions, ointments dropping deteriorating by age, but nanoparticles like micelle, liposomes, Nano sponge’s and dendrimers hydrogel concluded efficient medium for chitosan, hyaluronic acids and antiglaucoma and these novel formulation have ability to deliver drugs in sustain and control release of medicaments. objective of this review is by using nanoparticles overcome the barriers of Ocular Anterior segment delivery with increase and optimistic Bioavailability with crossing Ocular barriers.