Nanomedicine and Advanced Drug Delivery

Rachel E. Sully obtained her undergraduate diploma in Chemistry MChem from the School of Physical Sciences at the University of Kent in July 2018. Her masters project was on the synthesis of functionalised L-proline precursors which could be advantageous for the synthesis of functionalized N-Carboxy Anhydride (NCA) monomers with Dr Palma from the University of Kent. In September 2018, she joined the postgraduate programme at the Medway School of Pharmacy at the University of Kent. She is now working on an interdisciplinary project, jointly designed and supervised by Dr Gubala/Prof. Podoleanu from the University of Kent and Dr Loizidou/Prof.Garelick from the Middlesex University, London

Melanoma affects over 200,000 people in the UK alone, with survival rates of around 86%. Over the last decade melanoma skin cancer incidence rates for males and females combined increased by 50%. The current main treatments of skin-cancer are surgery to remove the affected area, as well as chemotherapy/radiotherapy and immunotherapy to kill the tumour cells. However, around 33,000 people still die within the first five years after diagnosis and treatment. The purpose of this study is to explore the possible development of a new nanomedicine technology that uses anti-cancer drug doped-nanoparticles (Figure a) to kill tumour cells. Nanoparticles1 are held in solution which can lead to aggregation, making them undesirable as drug delivery systems. The proposed solution to this is to formulate the nanoparticles into a microneedle array made from methylcellulose gels2. In solution, nanoparticles are subject to Brownian motion and tend to aggregate (Figure b), however when formulated into a gel-like microneedle patch (Figure c), the aggregation is prevented. Methylcellulose is used specifically because it is biodegradable and will degrade by enzymatic reaction in the epidermis, thus releasing nanoparticles into the microenvironment. Microneedle patches have been used widely in cosmetics3, as well as for insulin delivery4. To observe the disintegration of microneedles and the release of the drug-doped nanoparticles in the skin5, optical coherence tomography (OCT) will be used6. OCT is a non-invasive imaging technique used to take cross-section images of tissues. Although OCT has been used widely in ophthalmology, the use of OCT to image the skin is still relatively new7. We will also present a detailed synthesis of silica nanoparticles, used as the nanocarriers, as well as their characterization by Dynamic Light Scattering, Fluorescence Spectroscopy, Transmission Electron Microscopy and Scanning Electron Microscopy.

Mzoughi Jihane is a PhD student at the Institute of Materials Science of Mulhouse IS2M. I have a background in chemical engineering, materials and surface functionalization. Currently, I’m working on a project devoted to the development of a novel approach of chronomodulated therapy which takes into account the circadian biorythm of the human body. The release of drug will be programmed via complex spatial distribution of the drug in the biopolymer capsules

Our study investigates the influence of thermal1 and enzymatic2 crosslinking methods on the mechanical, thermal and physiochemical properties3 of gelatin which is known for its good properties in pharmaceutical application namely as a media of drug delivery4. Initially, focus is given first to thermal crosslinking optimization in terms of temperature and heating time.It is found that, in a specific range of these parameters, this treatment decreases the surface polarity and the hydrophilicity of the film. The films treated during less than 5 hours at 150°C exhibited a decrease in water absorption rate measured by Goniometry (~0.13 µL/min) comparing to untreated films (~0.18 µL/min) and films treated over night (~0.33 µL/min) (The thickness of the film is 50 µm and the volume of the water drop deposited is 3 µL). Differencial scanning calorimetry showed decrease in crystallinity after thermal treatment which can be explained by an increase of cross-linking bridges number favorising an amorphous structure. The polymer became insoluble in aqueous medium at 37°C. Swelling capacity is reduced and contact angle is increased.Tensile testing showed an increase in Young’s Modulus of the film after thermal crosslinking, thus, enhanced mechanical stability. We have also started systematic study of enzymatic crosslinking by mTransglutaminase mTG. The gelatin films enzymatically crosslinked were obtained by mixing 4 mL of mTG (10%) with 100 mL of bovin gelatin solution (5%) prepared in deionized water. The surface of enzymatically crosslinked gelatin films observed by AFM showed a less surface roughness (0.98 nm) comparing to thermally crosslinked matrix (1.2 nm) with relief form (hollows).Untreated surfaces seem to present the lowest roughness (0.67 nm).

Blanca Lorenzo-Veiga is a PhD student at the Faculty of Pharmaceutical Sciences at the University of Iceland. Currently, she is in the last year of her PhD. She is first author of two articles in high impact factor journals. Her passion is conducting research in novel drug delivery systems and nanotechnology using advanced materials and nanocarriers to design innovative medicines. During her PhD, she had participated in several international conferences. Her main interests included ocular drug deliver and biomaterials. She is member of AAPS and Biomaterials. She is interested in being part of a pharmaceutical company to expand her research in the previous topics.

Statement of the Problem: Topical eye drops are the most common and convenient dosage form of the drug to the eye. Nevertheless, due to eye barriers, poor drug absorption and low bioavailability make the development of an optimal formulation a challenge. Different strategies have been proposed to address these problems. Cyclodextrin-based nanoaggregates have emerged in recent years as a new platform for drug delivery to the anterior and even posterior segment of the eye. Cyclodextrins are natural cyclic oligosaccharides that have the ability to form water-soluble inclusion complexes holding in their cavities lipophilic drug molecules as guests. The purpose of this study was to investigate the effect of three water-soluble polymers (PVP, PVA, and tyloxapol) widely used in eye drops formulations on the solubility of complexes containing a single CD(gamma-CD) or a mixture of CDs(gammaCD/HPBetaCD) and nepafenac as a model drug. Methodology & Theoretical Orientation: The effect of these polymers on apparent solubility of the complex was analyzed by UHPLC. Moreover, size, osmolarity, and viscosity of these systems were analyzed. Findings: the addition of PVA led to the greatest increase in solubility in both single and mixture CDs. In the case of a single CD, the size was around 163-296 nm but in the case of mixtures of CDs, PVP and tyloxapol showed in some cases a size higher than 1µm. In all cases, the addition of these polymers led to an increase in the viscosity and osmolarity. Conclusion & Significance: This is the first time that the effect of different polymers on nepafenac/CD complexes using a mixture of CDs have been studied. Results showed that the addition of water-soluble polymers such as PVA, PVP or tyloxapol could be a good strategy for the formulation of eye drops containing nepafenac

Ernesto Caballero-Garrido, is a distinguished researcher in biochemistry and animal behavior, he grew up in Madrid (Spain) and received his Bachelor's Degree in Biochemistry by the Universidad Autónoma de Madrid. He obtained his Master's Degree in Microbiology, but completed his doctorate in endondrinology (plasticity of the endocrine pancreas) in the University Miguel Hernández of Elche. Dr. Caballero-Garrido went to the US (to the University of New Mexico, department of neurosurgery) and began his research in the area of neurobiology on miRNA and cerebral microvasculature. Furthermore, he has developed several projects on animal behaviour. In parallel, Dr. Caballero-Garrido wrote various books about the history of science and developed projects of scientific outreach, both scientific programs of Radio and TV. Miguel Hernández University of Elche awarded Dr. Caballero-Garrido for his outreach projects. Currently he is working as a Non-clinical Assessor for the Spanish Agency of Medicines and Medical devices (Spanish Government)

The non-clinical assessment first marketing approval of a pharmaceutical in the European Union mainly includes several tests developed in the International Council for Harmonisation (ICH) and European Medicines Agencies (EMA) guidelines. The recommendations in ICH guidelines further harmonise the non-clinical studies among the regions of the European Union (EU), Japan and the United States. These guidelines represent the consensus reached regarding the type and duration of non-clinical studies to support human clinical trials and marketing authorization for pharmaceutical products. More specifically, in the EU, the rationale and requirements for animal testing in the development of medicinal products for human use are defined in Directive 2001/83/EC as amended. UE directive and EMA guidelines should be read in conjunction with ICH guidelines before applying for a clinical trial or marketing authorization in the EU. The goals of the nonclinical studies generally include a characterization of toxic effects concerning target organs, dose dependence, relationship to exposure, and, when appropriate, potential reversibility. These data should help to define the estimated therapeutic dose, the maximum dose, and dose steps and intervals for clinical trials in humans. The objectives of the non-clinical studies are to define pharmacological and toxicological effects not only before the initiation of human studies but throughout clinical development. The non-clinical studies recommended to support marketing authorization for pharmaceuticals are conducted all along the drug development process. It means that’s the requirements that must be satisfied by the non-clinical studies before each of the clinical trial phases is different for each phase. The guideline ICH M3 (R2) delivers practical recommendations for timing or when to conduct which safety studies. We summarize the main non-clinical studies required by EMA before clinical development and marketing authorization in the European Union.