Adrenaline-containing double layered lipidvesicles for use in the treatment of

Cardiopulmonary Resuscitation

Theodoros XanthosMD, PhD, FHEA, FAcadMed, FCP, FERC, FESC

Nichol G, et al. JAMA. 2008;300(12):1423-1431

CARDIAC ARREST

Systolic Pressure

Diastolic Pressure

CARDIOPULMONARY RESUSCITATION

CORONARY PERFUSION PRESSURE (CPP)

CPP= Diastolic Ao-RA

Adrenalineincreases CPP

ADRENALI NE

α1 α2 β

Smooth musclecontractionPeripheral

vasoconstrictionImproved circulation

Inhibition oftransmitterrelease

Smoothmusclecontraction

Heart musclecontractionSmooth musclerelaxation

Modification of IgE-medicated allergic reactionsBronchodilation

UNDESIRED EFFECT

Some of these resultsmay be attributed tothe sudden increaseand decrease of the

drug in the body

FORMULATION OF THE ADRENALINE-LOADED LIPOSOMES

Adrenaline loadedin liposomes via aremote loadingtechnique

Adrenaline stabilizedagainst oxidation

Neutral adrenaline freely diffuse throughthe liposomal wall.

Protonated adrenaline remains trapped inthe liposomal core.

pH-gradient liposomes

Patent pending technology: PCT/IB2018/055606

PHYSICOCHEMICAL CHARACTERIZATION OF THEFORMULATION

• Cryo-Electron Microscopy• Small Angle X-ray Scattering• Dynamic Light Scattering

Appropriateadrenalineloading

• Average liposome size: 67 nm• Polidispersity Index: 0.18• Zeta-potential: −6 mV

Cryo-EM SAXS

DLS

Extremely stableformulation

(up to 2 years)

TECHNOLOGICAL CHARACTERIZATION OF THEFORMULATION

• Encapsulation efficiency• Drug release• Biocompatibility

High repeatabilityof the production

process

Slow releasekinetic

Componentsapproved for

human clinicaluse

Safeformulation

0

200

400

600

800

1000

0 1 2 3 4 5 6 7 8 9 10

Classical

Liposomal

Adrenaline(ng/mL)

Time (min)

ADRENALINE CONCENTRATION IN ALIVE PIGS:CLASSICAL VS LIPOSOMAL

In the classicalformulation: All

three pigs developedVentricularTachycardia

In the liposomalformulation: No pigdeveloped any type

of malignantarrhythmia

LIPOSOMAL STILL MAINTAINSTHERAPEUTIC CONCENTRATION

ROADMAP

2017 2018 2019 2020 2021 2022

Formulation development

Physico-chemical and in vitrobiopharmaceutical characterization

Pre-clinical (PK, toxicity)

Pre-clinical (PD, dose optimization)

Production up scale and analytics

GMP production for phase I

Clinical trial application for phase I

Clinical study phase I

FURTHER DEVELOPMENTS

• Animal experiments in alive pigs to better define the pharmacokinetics ofthe human dose

• Animal experiments in both shockable and non shockable rhythms to seewhether the liposomal formulation increases ROSC and whether it affectsthe neurological outcome

• Human trials to see whether the formulation is superior to the classicaladrenaline formulation

CONTACTS:Theodoros Xanthos and Sergio Murgia

Liason Office: Orsola Macis omacis@amm.unica.it

www.knowledge-share.eu/en/patent/liposomes-for-treatment-of-cardiac-arrest/

murgias@unica.it