Differentiated Medicines and Polymeric Nanoparticles SENT · – Natrah Arifin – Anja Mirenska...
Transcript of Differentiated Medicines and Polymeric Nanoparticles SENT · – Natrah Arifin – Anja Mirenska...
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Differentiated Medicines from Polymeric Nanoparticles
Ijeoma F. UchegbuUCL School of Pharmacy
Nanomerics Ltd
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Academic Collaborations - Acknowledgements• University College London
– Andreas G. Schätzlein– Simon Gaisford– Gary Parkinson– John Malkinson– Lorenzo Capretto– George Wang– Aikaterini Lalatsa– David Workman– Vicky Lozano– Lisa Godfrey– Antonio Iannitelli– Jay Freeman– Mariarosa Mazza– Dolores Lopez– Funmilola Fisusi– Margarida Carlos – Ramesh Soundararajan– Abdullah Alamoudi– Sunish Patel– Nicholas Hobson– Xiang Wen Jen– Abdulrahman Halwani
• School of Pharmacy, University of London– Marie Christine Jones– Kar Wai Chooi– Adeline Siew– Thi Bich Hang Le– Steven McLellan – Natrah Arifin – Anja Mirenska – Jayanant Iemsang-Arng
• Exeter University– Julian Moger– Natalie Garrett– Nick Stone– Francesca Palombo
• Strathclyde University– Wei Wang– Vitaliy Khutoryanskiy– Xueliang Hou– Xiaozhong Qu– Lee Martin – Maureen Brown– Christine Dufes– Tony Brownlie– Lubna Sadiq– Soryia Siddique– Pei Lee Kan – Abdul Elouzi– Bernd Zinselmeyer – Woei Ping Cheng– Dennis Wong– Pui Ee Wong– Mazen El-Hammadi– Katherine Bolton– Samina Ahmad
• University of Arizona– Frank Porrecca
• University of New England– Tamara King Deeney
• University of Nottingham– Martyn Davies– Clive Roberts
• Universidad Complutense De Madrid– Juan Torrado
• Universidad Cardenal Herrera-CEU– M. Auxiliadora Dea-Ayuela
• Universitat Rovira i Virgili– Josep Guarro
• Cambridge University– Jeremy Baumberg
• Rutherford Laboratories– Pavel Matousek
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Summary
• Academic investigations– Nanoparticle fabrication and characterisation
• Commercialisation– Strategy– Technology– Licensing
• Nasal and ocular assets– Oral dosage form case Studies
• Current academic focus– Diagnostics
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Building Blocks
OO
OO
NHO
O
HO
NH
O
HO
O O
NH2
O
HO
OHOO
NH2
O
HO
HOO
O
uv
wx
HOO
N
O
HO
HO OO
O
HO
NHHO
O
yz
Cl
N
N
NN
NH2N
HN
H2NH2N
NH2N
NH2N
H2N
H2N
N
N
N N
N HN
NH2
NH2NH2
NNH2
N NH2
NH
NH2
OO
O
Wang et al (2004) Macromolecules, 37: 9114 - 9122.Qu et al (2008) Langmuir, 24: 9997–10004Chooi et al (2010) Langmuir, 26: 2301 – 2316Ahmad et al (2010) J Royal Society Interf, 2010, 7: S423 – S433 Siew et al (2012) Mol Pharmaceutics, 9: 14 – 28.Lalatsa et al (2012) Mol Pharmaceutics, 9: 1665-1680Mazza et al (2013) ACS Nano, 7, 1016 – 1026Lalatsa et al (2015) J Control Rel, 197: 87 – 96Fisusi et al (2016) Pharm Res, 33: 1289-1303.Godrey et al (2017) J Control Rel, 270, 135-144Hobson et al (2019) Nanomedicine, 14, 1135-1152
Dendrimer amphiphiles
Carbohydrate combs
Claws
OH
O
NH
HN
NHH2N
O
HN
O
NH
OHN
O
NH
O
H2N
O
O
Peptide amphiphile prodrugs
O OOH
O
O
OH
N
x
OOOH
O
O
OH
N
y
CH3CH3CH3
O
OH
CH2OH
CH2
O
OOH
O O OH
N
x
O
O
OH
O O OH
N
y
CH3
CH3
CH3
OOH
CH2OH
O
OOH
OOOH
N
x
O
CH2
O
OOH
O
O
OH
N
x
O
O
OH
O
O
OH
N
y
CH3CH3
CH3
O
OH
CH2OH
NHCH2
O
OOH
O
O
OH
N
x
O
O
OH
O
O
OH
N
y
CH3
CH3
CH3 O
OH
CH2OH
C
y
OOH
CH2OH
NHCH2
O
OOH
O
O
OH
N x
O
O
OH
O
O
OH
Ny
CH3CH3
CH3
O
OH
CH2OH
NH2
N
NH2
NN
NH2
NH
N
N
N
NH
NH2
NH
N
NH
NH2N
NH
NH2
N N
N N
NH2
N
N
N
NH2
CH2
OOOH
O
O
OH
N
x
O OOH
O
O
OH
N
y
CH3
CH3CH3
O
OH
CH2OH
HCH2
CH2
O
O OH
O
O
OH
N
x
O
O
OH
O
O
OH
N
y
CH3
CH3
CH3O
OH
CH2OH
H2
O
OH
OOOH
N CH3
CH3
CH3
+
+
+
+
+
+
+
+
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Polymeric, Dendrimer and Peptide Nanoparticles
Dense Spheres
200nm500nm
Vesicles
100nm
Polymeric Micelles
200nm
Discs
1000nm
Worm-like Wang et al (2004) Macromolecules, 37: 9114 - 9122.Qu et al (2008) Langmuir, 24: 9997–10004Lalatsa et al (2012) J Control Rel, 161: 523 – 536. Mazza et al (2013) ACS Nano, 7: 1016-1026
200 nm
Peptide Nanofibres
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Intracranial Tumours
Fisusi et al, 2016, Pharm Res, 33, 1289-303.
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Pro
port
ion
of
an
imals
su
rviv
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CONTROL ETOH QLOM
Tumour
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Day 1 Day 7 Day 14 Day 21 Day 28Pla
tele
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Time
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Nanoparticles prolong survivalNo differences in femoral, white and red cell countsBoth treatments cause a change in platelets
Lomustine polymer Nanoparticles (13 mg kg-1) nEthanolic lomustine (1.2 mg kg-1) nUntreated animals �
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Pharma Market Challenges as Drivers
Loss of patent protection• US$194 billion in lost sales 2017-2022 • US$31 billion in lost sales in 2018 alone
Increasing cost of NEW drugs• Low Productivity• Total cost increase to >US$ 2.5 billion
Wrapping drugs with Nanomerics’ Molecular Envelope Technology (MET) creates:
• improved ‘known’ medicines, rescued new chemical entities• Patent protected and premium pricing
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Solution: Molecular Envelope Technology (MET) Engineered from scratch for enhanced delivery
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Molecular Envelope Technology
1. Non-covalent Encapsulation 2. High drug loading: 9 – 50% w/w3. Highly stable nanoparticles: low micromolar CMC
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MET Formulation Space• Data mapped on www.drugbank.ca
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Nanomerics Solution• Molecular Envelope Technology (MET) wrapping of
known drugs: – Creates better medicines for patients– Gives patent protection and retains/creates value
Poorly soluble drugs + Molecular EnvelopeTechnology
= Better Drugs + Patent protection
5-38 x
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Royal Society of Chemistry Award 2017
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MET Safety Demonstrated in GLP Regulatory Toxicology Studies Test OutcomeSingle intravenous dose in the rat Maximum tolerated dose = 150 mg kg-1
7 Day repeat intravenous dose study in the rat Maximum tolerated dose = 100 mg kg-1
GLP Mutagenicity testing Ames test NegativeGLP Mutagenicity testing Mouse Lymphoma Test NegativeGLP Intravenous Rat Irwin Study Nothing abnormal detected at 100 mg kg-1
GLP Intravenous respiratory safety pharmacology in the rat
NOAEL = 40 mg kg-1
Oral 7 day repeat dose ranging dog study NOAEL = 300 mg kg-1 (top dose studied)GLP oral 28 day repeat dose dog study NOAEL = 150 mg kg-1 (top dose studied)Oral 7 day repeat dose ranging rat study NOAEL = 200 mg kg-1
GLP oral 28 day repeat dose rat study NOAEL = 200 mg kg-1 (top dose studied)
Intranasal 7 day repeat dose ranging rat study NOAEL = 30 mg kg-1 (Reduced weight gain at 50 mg kg-1)
GLP 28 day intranasal dose in the rat NOAEL = 18 mg kg-1
6 day topical Ocular tolerability study in the rabbit NOAEL = 40 mg mL-1 (top concentration studied)
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FDA 505(b)(2) FDA Pre-IND Guidance Summary
ü Polymer sufficiently characterised ü Target product profile and specifications ü Preclinical PK data ü First in Human Safety and Tolerability Study Designü Manufacturing guidance and pilot batch data for NDA
statedü Pivotal study design
– Two clinical efficacy studies with a limited number of primary end points
ü Advice on analytical qualification & later stage CMC meeting
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Licensed assets
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Nose-to-brain delivery
Spray dried micro-particles
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Loaded Nanoparticles Naltos™ Powder Device
Cyclonic Plume
⑤ Olfactory deposition into nano-particles
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Olfactory bulb
Brain transport & activity
Thalamus Cortex
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NM127 – Peptide replacement of opiates
Nose to brain 505(b)(1) NCE - endogenous API
– opiate analgesic replacement– Fast pain relief for the
treatment of acute and chronic pain
– Endogenous peptide delivered non-invasively to the brain
– As potent as opiates but avoids the side effects
– No habit forming potential– Enkephalin is active in humans
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Paw
With
draw
al Th
resh
old in
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mple
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eund
's Ad
juvan
t Pain
Mod
el (g
)
Time (minutes)
Intravenous vehicle
Intranasal NM0127 (7.5 mg/ kg)
Intravenous morphine (2.5mg/ kg)
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Opioid sparing pain killer
• NM127
– Enkephalin based pain killer for acute and chronic pain
– No analgesic tolerance or risk of addiction– Active in all preclinical pain models– Licensed to Virpax Pharmaceuticals
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MET Application - Ocular delivery
Proposed mechanism
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Non-irritant ocular medicine
• NM133
– Cyclosporine A eye drops for dry eye disease– Superior to the market leader• Vehicle is non-irritant• Delivers 5 – 8 times more drug to tissues• Clear aqueous liquid – oil free
– Clear regulatory pathway: FDA pre-IND guidance – Licensed to Iacta Pharmaceuticals
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The oral route
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Oral Griseofulvin
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Bloo
d co
ncen
tratio
n(µ
g m
L-1 )
Time
Griseofulvin
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Oral Cyclosporine
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cycl
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cen
trati
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mL-1
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Time (hours)
Cyclosporine
Neoral
Cyclosporine Ananoparticles
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Oral Amphotericin B
0102030405060708090
-10 10 30 50
Plasm
a Co
ncen
tratio
n (n
g m
L-1)
Time (h)
METAmphizone
Ambisome
NM0147
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Oral formulation of Phase II anti-cancer drug
01020304050607080
0 4 8 12 16 20 24Plas
ma
Conc
entra
tion
(ng
mL-1
)
Time (Hours)
MET Formulation
Clinical Formulation
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MET – Proposed Mechanism
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Mucus penetration
Control 30 min 1 h
2h 4 h
Siew et al, Mol Pharm, 9, 14-28 (2012)
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~ 250 µm
A B
DC
X-Y
X-Y
X-Y-Z
Y-Z
25 µm
25 µm
MET particle uptake in intestinal villi
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MET Particles by CARS Microscopy in the GITLiver Stomach Jejenum
Ileum Duodenum Gall Bladder
Garrett et al (2012) J Biophotonics, 5: 458-468Garrett et al (2012) J Raman Microscopy, 43: 681-688
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MET Particle Bioavailability
0.00E+002.00E+014.00E+016.00E+018.00E+011.00E+021.20E+021.40E+021.60E+021.80E+022.00E+02
0 4 8 12 16 20 24
Plasm
a Lev
els (m
g mL-
1)
Time (h)
OralIntravenous
Bioavailability = 24%
Lalatsa et al (2012) Mol Pharm, 9: 1764-1774.
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MET Competitive Advantage – Nanoparticle Technologies
Attributes MET Pegylated Liposomes
Poly-(L-lactide-co-glycolide)-co-poly(ethylene glycol) nanoparticles
Albumin stabilised nanoparticles
Oral particle uptake and tablet formulationsNose to brain deliveryNon-irritant ocular drug delivery and penetration enhancementIntravenous drug deliveryHydrophobic drug deliveryHydrophilic drug deliveryAmphiphilic drug deliveryEase of manufacture Unknown UnknownMarketed Products
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Summary of MET Advantages– GLP safety studies conducted - no safety issues– High API payload: 10 – 50% w/w– Stable system: micromolar CMC– Liquid and solid formulations– Bioavailability enhancement: 5 - 38 fold higher– Drug targeting
• Oral to the lung and spleen• Nasally to the brain
– Enables peptide bioavailability• Limits degradation of drug cargo• Enhanced transport across epithelial barriers
– Multiple routes of administration• Topical to the eye• Intranasal to the brain• Oral to the liver, lungs and spleen
– Multiple molecules• Hydrophobic drugs• Amphiphilic peptides
Qu, et al (2006) Biomacromolecules, 7, 3452-3459Siew et al (2012) Mol Pharmaceutics, 9: 14 – 28.Lalatsa et al (2012) Mol Pharmaceutics, 9: 1665-1680Serrano et al (2015) Mol Pharmaceutics, 12,: 420-431,Lalatsa et al (2015) J Control Rel, 197: 87 – 96Fisusi et al (2016) Pharm Res, 33: 1289-1303.Godrey et al (2017) J Control Rel, 270, 135-144
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Iron Oxide Imaging
Good visualisation of the liver vasculature 1 hour after dosing
Hobson et al (2019) Nanomedicine (Lond), 14, 1135-1152
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RaNT Programme Grant
EPSRC Raman NanoTheranostics Programme Grant£5.7 million
Nick StoneExeter University
Julian MogerExeter University
Pavel MatousekRutherford Laboratories
Jeremy Baumberg Cambridge University
Andreas Schätzlein UCL
Ijeoma UchegbuUCL
Francesca PalomboExeter University
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Thank you