Nanostructured lipid-based liquid crystalinecrystaline …Nanostructured lipid-based liquid...
Transcript of Nanostructured lipid-based liquid crystalinecrystaline …Nanostructured lipid-based liquid...
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NanostructuredNanostructured lipidlipid based liquid based liquid NanostructuredNanostructured lipidlipid--based liquid based liquid crystalinecrystaline systems for controlled release systems for controlled release of drug substancesof drug substances
September 2010September 2010
Catalin NistorCatalin Nistor
Research Director, Camurus AB, Lund, SwedenResearch Director, Camurus AB, Lund, SwedenResearch Director, Camurus AB, Lund, SwedenResearch Director, Camurus AB, Lund, Sweden
www.camurus.comwww.camurus.com
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Topics
• Brief company presentation
T h l • Technology
• FluidCrystal® Injection Depot
• FluidCrystal® Nanoparticles
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Camurus - Snapshot profile
• Headquarter in Lund, Sweden – “Medicon Valley”• Member of GS Development group
St itt d i t• Strong committed investor• Broad late/mid stage drug product pipeline• Global technology leader in lipid-based drug delivery • Strategic corporate partnerships
COMPANY3
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Camurus - Advancing pipeline
COMPANY4
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Controlling lipid self-assembly
GDOGDO
L2
ReversedReversed micellarmicellar cubiccubic, , spacespace group group Fd3mFd3m
I2
2
ReversedReversed hexagonalhexagonal
H2
Water PCL
TECHNOLOGY6
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Controlling lipid self-assembly
• Nanoparticle formation – FluidCrystal® NP
GDO
L+fragmenting agent,
dil i / h
I2
L2 dilution/shear
H2
Water PCL
Cubosome®, Flexosome®, Hexosome®
TECHNOLOGY7
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Camurus’ Drug Delivery Platforms
TECHNOLOGY8
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”The best dose is the one you don’t give”
Reduced frequency of administrationis vital in an increasingly competitive
k t lmarketplace
–Patient convenience–Increased adherence / compliance–Enhanced safety profile–Dose sparing–Dose sparing–Life-cycle management strategies–Enable development &
i di tinew indication
FluidCrystal® Injection depot10
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Controlled- vs. Immediate-releaseCo t o ed s ed ate e ease
100IR CR
80
100
/m
L
60
trat
ion
, n
gThe
40
ug
Con
cen
t erapeutic wi
20
Dru
indow
00 5 10 15 20 25
Time, h
FluidCrystal® Injection depot11
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Essential requirements
• Compatibility with administration device/route
• Demonstrated safety and tolerability
• Demonstrated in vivo functionality
• Product storage stability • Product storage stability
• Manufacturability at commercial scales
FluidCrystal® Injection depot12
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Illustration of depot product principle
FluidCrystal® Injection depot13
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LC phase structure vs time
GDO
I
L2
I2
Water PC
H2
L
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In vitro release vs composition
20
80
100
ease
15ei
n re
leas
e
20
40
60
% fl
uore
scei
n re
le
5
10
% fl
uore
sce
0100 80 75 65 60 55 50
wt% GMO with respect to SPC
070 65 60 55 50 45 4070 65 60 55 50 45 40
wt% GDO with respect to SPC
FluidCrystal® Injection depot15
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Leuprolide FluidCrystal® Leuprolide FluidCrystal®
• Leuprolide: gonadorelin (LHRH) analogue, linear nonapeptidenonapeptide
The acti e ingredient in Procren® and Eligard® • The active ingredient in Procren® and Eligard®, approved for treatment of prostate cancer
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Leuprolide FluidCrystal®:Leuprolide FluidCrystal®: one month target duration FC leuprolide versus marketed products p p
Ratsn = 6
1000 FC leuprolide 7.5 mgEligard® 7.5 mgFC leuprolide 3 75 mgng
/ml)
100FC leuprolide 3.75 mgProcren® Depot 3.75 mg
ntra
tion
(n
10
de c
once
n
1
leup
rolid
0.10 4 8 12 16 20 24 28
Plas
ma
Time (days)
FluidCrystal® Injection depot17
( y )
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C ®Leuprolide FluidCrystal®: one month target duration - s.c. versus i.m.
Dogsn = 6 (SC)n = 4 (IM)
100
intramuscularg/m
L)
n = 4 (IM)
10
intramuscularsubcutaneous
ratio
n (n
g
1 con
cent
r
0 1eup
rolid
e
0.10 7 14 21 28
Plas
ma
le
Time (days)
FluidCrystal® Injection depot18
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L lid Fl idC t l®Leuprolide FluidCrystal®: Demonstrated long-term release in men
Phase IIa datan/group = 6
100
0 25 ml (7 5 mg) abdominal s c(ng/
mL)
n= 27mean + sd10
0.25 ml (7.5 mg) abdominal s.c. 0.25 ml (7.5 mg) deep s.c.
ntra
tion
(
1
de c
once
n
0 01
0,1
leup
rolid
0,010 7 14 21 28
Ser
um
Time (days)
FluidCrystal® Injection depot19
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L lid Fl idC t lLeuprolide FluidCrystal: Demonstrated testosterone suppression
Phase IIa datan/group = 6700
800
0 25 l (7 5 ) bd i ln (n
g/dL
)
n/group 6n=27
500
600
700 0.25 ml (7.5 mg) abdominal s.c.0.25 ml (7.5 mg) deep s.c.
cent
ratio
n
300
400
one
conc
100
200
test
oste
ro
00 7 14 21 28
Med
ian
t
Time (days)
FluidCrystal® Injection depot20
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Octreotide FluidCrystal® Octreotide FluidCrystal®
• Octreotide: somatostatin analogue, cyclic octapeptideoctapeptide
The acti e ingredient in Sandostatin® and • The active ingredient in Sandostatin® and Sandostatin® LAR® (Novartis), approved for treatment of acromegaly and carcinoid syndrome
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Octreotide FluidCrystal® versus Octreotide FluidCrystal® versus Sandostatin® LAR
0.1 ml (2.45 mg) SC0.3 ml (7.35 mg) SC1 ml (24.5 mg) SC0.3 ml (7.35 mg) IMng
/mL) Phase I
n = 6
100.3 ml (7.35 mg) IMSandostatin® LAR® (20mg)Astruc et al., 2005
tratio
n (n
1
e co
ncen
t
0,1
ctre
otid
e
0,010 7 14 21 28
Ser
um o
Time (days)
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S ( y )
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Octreotide FluidCrystal®:Octreotide FluidCrystal®: Tuning of release duration – 24 hours vs. 1 week
Ratsn = 6 (SC)
1000Saline solution SCFl idC t l® SC dn
g/m
l)
100FluidCrystal® SC one dayFluidCrystal® SC one week
ntra
tion
(
10
de c
once
n
1
octre
otid
0.10 20 40 60 80 100 120 140 160
Pla
sma
Time (hours)
FluidCrystal® Injection depot23
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Somatostatin FluidCrystal® Somatostatin FluidCrystal®
• Somatostatin: peptide hormone (14 amino acids, cyclic) with ubiquitous distribution regulating the cyclic) with ubiquitous distribution, regulating the endocrine system and neurotransmission
• Possible applications in acromegaly, Cushing’s syndrome, different types of cancer, etc.
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S t t ti (1 14) Fl idC t l®Somatostatin (1-14) FluidCrystal®: one week target duration
10
RatsN = 24 (SC)
10 20 mg/kg30 mg/kg40 mg/kgEndogenous SSTn
(ng/
mL)
10
15
20
L/da
ys)
1g
ncen
tratio
n
0
5
10
AU
C (n
g/m
L
0.1
a S
ST
con 015 20 25 30 35 40 45
Dose (mg/kg)
0.010 7 14
Pla
sma
Time (days)
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Buprenorphine FluidCrystal® Buprenorphine FluidCrystal®
• Buprenorphine: partial µ-opioid receptor agonist with a wider safety window than other opioidswider safety window than other opioids
• Existing products: sublingual tablets Subutex® and Subuxone®, and in the s.c implant Probuphine®.
• Aproved for treatment of drug abuse and management of pain
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B hi Fl idC t l®Buprenorphine FluidCrystal®:one month target duration
100015 mg/kg
ml) Rats
100
g g50 mg/kg75 mg/kg
tion
(ng/
m n = 10 (SC)
10
once
ntra
t
10 7 14 21 28P
lasm
a co
0 7 14 21 28P
Time (days)
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Fl idC t l®Buprenorphine FluidCrystal®:one week target duration
Ratsn = 6 (SC)
2005 mg/kg10 mg/kgm
l)
2000( )
15010 mg/kg20 mg/kg50 mg/kg
atio
n (n
g/m
1000
1500
2000
ng/m
l*d)
50
100
once
ntra
0
500
1000
AUC
inf.
(n
0
50
Pla
sma
co 0 0 10 20 30 40 50 60Dose (mg/kg)
0 7 14P
Time (days)
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Peptide storage stability octreotide and leuprolide in prefilled syringes
110
120 OCT 25°C/60%RHOCT 40°C/75%RHLEU 25°C/60%RHn
100
110 LEU 25 C/60%RHLEU 40°C/75%RH
cent
ratio
n
80
90
drug
con
c
60
70
of s
tart
d
500 2 4 6 8 10 12
% o
Time (months)
FluidCrystal® Injection depot29
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SSmall molecule storage stability buprenorphine, benzydamine and diclofenac
110
120on
90
100BUP 25°C/60%RHnc
entra
tio
70
80
90BZD 25°C/60%RHDCF 25°C/60%RH
drug
con
50
60
70
% o
f sta
rt
500 4 8 12 16 20 24
%
Time (months)
FluidCrystal® Injection depot30
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Easy manufacturing by standard processesEasy manufacturing by standard processes
FluidCrystal® Injection depot31
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FluidCrystal® Injection depot: Competitive landscape example
Leuprolide products Octreotide products
Procren® Depot 3.75 mg1 mL/25G/reconstitution/s.c. Sandostatin® LAR® 10, 20, 30 mg
2 5 L/19G/ tit ti /i
Leuprolide products Octreotide products
Prosenze® 7.5 mg
2.5 mL/19G/reconstitution/i.m.
g0.25 mL/27G/ready-to-use/s.c. CAM2029 10, 20, 30 mg
0.33-1.0 mL/25G/ready-to-use/s.c.
Eligard® 7.5 mg0.25 mL/20G/reconstitution/s.c.
Somatuline® Autogel® 60, 90, 120 mg0.3-0.5 mL/16G/ready-to-use/deep s.c.
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FluidCrystal® Injection depot
Key competitive features:
St i t ll t l t• Strong intellectual property• True ready-to-use product design• Easy manufacturing by standard processes• High drug payloads, easily dose adjustable• Subcutaneous and intramuscular administration• Small needle size (23-27 gauge) • Small needle size (23-27 gauge) • Low dose dumping, consistent release• Tuneable duration from one day to several months• Good stability of loaded drug in the lipid matrix• Demonstrated safety in clinical trials
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Self-assembled lipid superstructures: Se asse b ed p d supe st uctu esBeyond emulsions and liposomes
Barauskas J, Johnsson M, Tiberg F NANO LETTERS , 5 (8),1615-1619 , 2005
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Extended somatostatin circulation time by i ti ith i ll biassociation with reverse micellar cubic
phase nanoparticles SPC/GDO/P80 (40/40/20 w/w)
Cervin C, Vandoolaeghe P, et. al.EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCE36 (4-5), 377-385, 2009
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