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  • PharmaSolThe Solubility People

    Lipid Nanoparticles for the delivery of actives

    in pharma, cosmetics & consumer care

    PharmaSol GmbH No. 1

    No. 1

    Cornelia M. KeckPharmaSol GmbH

    Berlin / Germany NLC

    Nanopearls

  • PharmaSolThe Solubility PeopleContent

    Short look into history of liposomes

    Definitions & special features

    Structure of lipid particle matrix

    Production process & large scale production lines

    oral bioavailibility case studies

    PharmaSol GmbH No. 2

    No. 2

    oral bioavailibility case studies

    - cyclosporine and testosteronundecanoate (TU)

    dermal application

    Make-ability of products products in the market

    Lipid Nanoparticles versus liposomes

    Summary

  • PharmaSolThe Solubility People

    1968 Invention of liposomes by Bangham

    (liposome size in nanometer range, i.e. liposomes were nanotechnology)

    Let us go back in cosmetic history.

    PharmaSol GmbH No. 3

    No. 3

    1986 Introduction of first cosmetic product to market:

    Capture by Dior

    ..to learn from history for future innovative products

  • PharmaSolThe Solubility People

    PharmaSol GmbH No. 4

    No. 4

  • PharmaSolThe Solubility People

    Extraordinary market success:

    Most people did not know what a liposome is

    but

    they bought the product when the name liposome was on the

    PharmaSol GmbH No. 5

    No. 5

    they bought the product when the name liposome was on the packaging!

    Association: liposome = qualityAssociation: liposome = quality

  • PharmaSolThe Solubility People

    Nanocarrier history since the liposomes

    many attempts to develop a similar successful system

    examples: nanoemulsions

    PharmaSol GmbH No. 6

    No. 6

    examples: nanoemulsions

    microemulsions

    multiple emulsions

    transfersomes (by Cevc / Munich, Germany)

  • PharmaSolThe Solubility People

    2005The novel approach in cosmetics & pharma:

    PharmaSol GmbH No. 7

    No. 7

    NLC = Nanostructured Lipid Carriers

  • PharmaSolThe Solubility PeopleContent

    Short look into history of liposomes

    Definitions & special features

    Structure of lipid particle matrix

    Production process & large scale production lines

    oral bioavailibility case studies

    PharmaSol GmbH No. 8

    No. 8

    oral bioavailibility case studies

    - cyclosporine and testosteronundecanoate (TU)

    dermal application

    Make-ability of products products in the market

    Lipid Nanoparticles versus liposomes

    Summary

  • PharmaSolThe Solubility PeopleDevelopment of

    lipid nanoparticle concept

    Traditional Carriers Lipid Nanoparticles

    1970ies 1950ies 1991 1999/2000

    PharmaSol GmbH No. 9

    No. 9

    Polymeric nanoparticles

    polymer(solid)

    liquid lipid(=oil)

    o/w emulsion

    solid lipid

    SLN1st generation

    solid lipid

    blend

    NLC2nd generation

    surfactant/ stabilizer layer

  • PharmaSolThe Solubility People

    Lipid Nanoparticles in solid state:

    derived from o/w emulsions

    simply replacing the liquid lipid (= oil) by a solid lipid

    (i.e. solid at body temp.)

    Definitions

    PharmaSol GmbH No. 10

    No. 10

    SLN Solid Lipid Nanoparticles

    produced from 1 solid lipid

    NLC Nanostructured Lipid Carriers:

    produced from blend of solid and liquid lipids

    but particles are in solid state at body temperature

  • PharmaSolThe Solubility PeopleFeatures

    Lipid nanoparticles with solid matrix

    Mean particle diameter: 80 - 1000nm

    Production by dispersion techniques, e.g. high pressure homogenization

    Loading* with active compounds, e.g.

    PharmaSol GmbH No. 11

    No. 11

    Loading* with active compounds, e.g.

    1-2% prednicarbate, prednisolone, cyclosporine etc

    10% Benzophenone-3, Allure

    6% Retinol (Vitamin A)

    24% Tocopherol (Vitamin E)

    (* calculated as %age of solid lipid matrix)

  • PharmaSolThe Solubility PeopleNLC Technology / Nanopearls

    novel particulate carrier

    for pharmaceutical / cosmetic / nutraceutical products

    Nanoparticles based on

    regulatory accepted excipients

    physiological / natural solid lipids (renewable resources)

    PharmaSol GmbH No. 12

    No. 12

    Application examples:

    protection of chemically labile active compounds &

    controlled release (CR) - because of solid matrix

    penetration enhancement of actives

    dermal CR (e.g. drugs, perfumes, repellents)

    oral absorption enhancement

  • PharmaSolThe Solubility PeopleNLC versus SLN

    What exactly is the improvement?

    &

    PharmaSol GmbH No. 13

    No. 13

    &

    What are the benefits of NLC?

  • PharmaSolThe Solubility PeopleChemical stabilisation

    Stability of Retinol: NLC vrs. Emulsion1

    PharmaSol GmbH No. 14

    No. 14

    NLC: Compritol ATO 888 10% stabilized with Miranol C32 Emulsion: 10% Miglyol,1.5% Tween 80

    1 V. Jenning (1999), Ph.D. thesis, Free University of Berlin

  • PharmaSolThe Solubility People

    formation of perfect crystalline structure during storage ( modification) drug expulsion

    Problems of old SLN

    days

    PharmaSol GmbH No. 15

    No. 15

    drug in imperfections

    drug betweenFA chains

    days

    months

  • PharmaSolThe Solubility PeopleNLC the more intelligent system

    SLN:

    tendency to form perfect crystals active expulsion

    e.g. tristearin

    PharmaSol GmbH No. 16

    No. 16

    mixture solid & liquid lipids

    NLC:

    inhibit crystallization process by mixing spatially very different molecules imperfections in lattice more space for drug

    drug

  • PharmaSolThe Solubility PeopleContent

    Short look into history of liposomes

    Definitions & special features

    Structure of lipid particle matrix

    Production process & large scale production lines

    oral bioavailibility case studies

    PharmaSol GmbH No. 17

    No. 17

    oral bioavailibility case studies

    - cyclosporine and testosteronundecanoate (TU)

    dermal application

    Make-ability of products products in the market

    Lipid Nanoparticles versus liposomes

    Summary

  • PharmaSolThe Solubility People

    PharmaSol Production Technology

    Basic principle:

    high pressure homogenization

    equipment can be qualified & validated

    PharmaSol GmbH No. 18

    No. 18

    equipment can be qualified & validated

    accepted by regulatory authorities in production lines used for pharmaceutical parenterals

    existing industrial production lines for cosmetics / i.v. pharmaceutical parenteral emulsions can be used

  • PharmaSolThe Solubility People

    Production Technology - Basics

    basic mixture:

    1. solid lipid

    2. liquid lipid NLC

    PharmaSol GmbH No. 19

    No. 19

    2. liquid lipid

    3. emulsifier

    4. (co-emulsifier)

    5. water

    (according to SLN patent: solid lipids, 0.1% - 30% solid)

    NLC solid content > 30%

  • PharmaSolThe Solubility People

    Production

    1. Melt lipid (>40C) & dissolve active compound

    2. Disperse active-containing lipid melt

    Principle: High pressure homogenization

    PharmaSol GmbH No. 20

    No. 20

    2. Disperse active-containing lipid meltin hot surfactant solution = pre-emulsion

    cooling solidification

    NLC

    3. Homogenize pre-emulsionat >40oC, 250 bar, 2 cycles = nanoemulsion

  • PharmaSolThe Solubility People

    Lipid nanoparticles of increasing concentration

    PharmaSol GmbH No. 21

    No. 21

    conc: from 10% to about 50%

  • PharmaSolThe Solubility People

    AF-MICROGRAPH of Q10-loaded Nanoparticles

    PharmaSol GmbH No. 22

    No. 22

  • PharmaSolThe Solubility People

    LAB 40 discont. - 40 g batch

    PharmaSol GmbH No. 23

    No. 23

  • PharmaSolThe Solubility People

    LAB 60 - 2-10 kg batch

    PharmaSol GmbH No. 24

    No. 24

  • PharmaSolThe Solubility People

    Gaulin 5.5 - 150 kg/h

    PharmaSol GmbH No. 25

    No. 25

  • PharmaSolThe Solubility PeopleContent

    Short look into history of liposomes

    Definitions & special features

    Structure of lipid particle matrix

    Production process & large scale production lines

    oral bioavailibility case studies

    PharmaSol GmbH No. 26

    No. 26

    oral bioavailibility case studies

    - cyclosporine and testosteronundecanoate (TU)

    dermal application

    Make-ability of products products in the market

    Lipid Nanoparticles versus liposomes

    Summary

  • PharmaSolThe Solubility PeopleOral administration

    Example: cyclosporine

    annual sales: appr. 1.2 billion US $

    old Sandimmun: problem: variation in BA

    new Sandimmun: problem: high plasma peak

    PharmaSol GmbH No. 27

    No. 27

    new Sandimmun: problem: high plasma peak (microemulsion) (> 1000 ng/ml)

    target of previously developed SLN:combine advantage of old & new Sandimmuni.e. no plasma peak & low variation in bioavailability

  • PharmaSolThe Solubility People

    Oral administration - cyclosporine study

    animal: pigs (n=3)

    application: via gastric catheter

    PharmaSol GmbH No. 28

    No. 28

    comparison:

    SLN dispersion vs.

    Sandimmun Neoral vs

  • PharmaSolTh

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