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Adrenaline-containing double layered lipidvesicles for use in the treatment of
Cardiopulmonary Resuscitation
Theodoros XanthosMD, PhD, FHEA, FAcadMed, FCP, FERC, FESC
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Nichol G, et al. JAMA. 2008;300(12):1423-1431
CARDIAC ARREST
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Systolic Pressure
Diastolic Pressure
CARDIOPULMONARY RESUSCITATION
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CORONARY PERFUSION PRESSURE (CPP)
CPP= Diastolic Ao-RA
Adrenalineincreases CPP
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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
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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
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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)
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TECHNOLOGICAL CHARACTERIZATION OF THEFORMULATION
• Encapsulation efficiency• Drug release• Biocompatibility
High repeatabilityof the production
process
Slow releasekinetic
Componentsapproved for
human clinicaluse
Safeformulation
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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
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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
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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
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CONTACTS:Theodoros Xanthos and Sergio Murgia
Liason Office: Orsola Macis [email protected]
www.knowledge-share.eu/en/patent/liposomes-for-treatment-of-cardiac-arrest/