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Nanostructured Nanostructured lipid lipid based liquid based liquid Nanostructured Nanostructured lipid lipid-based liquid based liquid crystaline crystaline systems for controlled release systems for controlled release of drug substances of drug substances September 2010 September 2010 Catalin Nistor Catalin Nistor Research Director, Camurus AB, Lund, Sweden Research Director, Camurus AB, Lund, Sweden Research Director, Camurus AB, Lund, Sweden Research Director, Camurus AB, Lund, Sweden www.camurus.com www.camurus.com 1

Nanostructured lipid-based liquid crystalinecrystaline …Nanostructured lipid-based liquid crystalinecrystaline systems for controlled release systems for controlled release of drug

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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

    1

  • Topics

    • Brief company presentation

    T h l • Technology

    • FluidCrystal® Injection Depot

    • FluidCrystal® Nanoparticles

    2

  • 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

  • Camurus - Advancing pipeline

    COMPANY4

  • Controlling lipid self-assembly

    GDOGDO

    L2

    ReversedReversed micellarmicellar cubiccubic, , spacespace group group Fd3mFd3m

    I2

    2

    ReversedReversed hexagonalhexagonal

    H2

    Water PCL

    TECHNOLOGY6

  • 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

  • Camurus’ Drug Delivery Platforms

    TECHNOLOGY8

  • ”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

  • 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

  • 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

  • Illustration of depot product principle

    FluidCrystal® Injection depot13

  • LC phase structure vs time

    GDO

    I

    L2

    I2

    Water PC

    H2

    L

    14 FluidCrystal® Injection depot

  • 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

  • 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

    1616 FluidCrystal® Injection depot

  • 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 )

  • 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

  • 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

  • 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

  • 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

    2121 FluidCrystal® Injection depot

  • 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)

    22

    S ( y )

    22 FluidCrystal® Injection depot

  • 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

  • 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.

    2424 FluidCrystal® Injection depot

  • 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)

    FluidCrystal® Injection depot25

  • 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

    2626 FluidCrystal® Injection depot

  • 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)

    FluidCrystal® Injection depot27

  • 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)

    28 FluidCrystal® Injection depot

  • 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

  • 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

  • Easy manufacturing by standard processesEasy manufacturing by standard processes

    FluidCrystal® Injection depot31

  • 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.

    FluidCrystal® Injection depot32

  • 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

    FluidCrystal® Injection depot33

  • 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

    34 FluidCrystal® NP

  • 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

    35 FluidCrystal® NP

  • 36