lipid nanoparticles – solid lipid nanoparticles • produced from 1 solid lipid nlc –...

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PharmaSol The Solubility People Lipid Nanoparticles for the delivery of actives in pharma, cosmetics & consumer care PharmaSol GmbH No. 1 No. 1 Cornelia M. Keck PharmaSol GmbH Berlin / Germany NLC ® Nanopearls ®

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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

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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?

&

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No. 13

&

What are the benefits of NLC?

PharmaSolThe Solubility PeopleChemical stabilisation

Stability of Retinol: NLC vrs. Emulsion1

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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 (β modification) ⇒⇒⇒⇒ drug expulsion

Problems of “old” SLN

days

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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

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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

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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

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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 (>40°C) & dissolve active compound

2. Disperse active-containing lipid melt

Principle: High pressure homogenization

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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

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No. 21

conc: from 10% to about 50%

PharmaSolThe Solubility People

AF-MICROGRAPH of Q10-loaded Nanoparticles

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No. 22

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LAB 40 discont. - 40 g batch

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No. 23

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LAB 60 - 2-10 kg batch

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No. 24

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Gaulin 5.5 - 150 kg/h

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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

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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

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No. 28

comparison:

• SLN dispersion vs.

• Sandimmun® Neoral vs

PharmaSolThe Solubility People

one of the volunteers

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No. 29

PharmaSolThe Solubility People

Oral cyclosporine - blood profiles

cyclosporine SLN

Sandimmun Neoral

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No. 30

PharmaSolThe Solubility People

Oral drug delivery with lipid nanoparticles

What are the mechanisms?

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No. 31

What are the advantages?

PharmaSolThe Solubility People

Mechanisms of oral lipid nanoparticles

general adhesiveness of very fine particles (nanoparticles)

adhesion processes very reproducible (= little

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adhesion processes very reproducible (= little variation in bioavailability)

lipids known to support absorption of a number of drugs* (Trojan horse)

* W. N. Charman, Proc. of 26 th Int. Symp. of CRS, Boston 1999

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. 33

No. 33

oral bioavailibility – case studies

- cyclosporine and testosterone undecanoate (TU)

dermal application

Make-ability of products – products in the market

Lipid Nanoparticles versus liposomes

Summary

PharmaSolThe Solubility People

oral testosterone formulation on the market

use as testosterone supplement therapy in case of lack of endogene production

regular dose: 4 capsules a day

Product Andriol

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No. 34

regular dose: 4 capsules a day

very fragile & sensitive product:

• has to be kept away from light and

• stored at temperatures between 15°C-25°C

PharmaSolThe Solubility People

comparison of Andriol vrs NLC

3 groups of 4 male Wistar rats were used

animals were deprived from food 12 hours prior to sample administration

Parameters of in vivo study

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to sample administration

oral administration by using a feeding needle

blood sampling was performed at t=0h, 1h, 2h, 3h, 4h, 6h, and 8h after administration. Approx. 400µl of blood were collected

serum was stored at -80°C directly after

centrifugation

PharmaSolThe Solubility People

6000

8000

10000

12000

14000

AU

C [

pg

*h/m

l|]

AUC values after 8 hours

Results:

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No. 36

0

2000

4000

6000

NLC 30% approx. 200nm

NLC 30% approx. 600nm

Andriol Testocaps

AU

C [

pg

*h/m

l|]

smaller size (200 nm) is more effective

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. 37

No. 37

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

water

Oil droplets NLC

How work NLC in cosmetic creams and lotions?

Cream

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No. 38

Skin

PharmaSolThe Solubility People

damaged areas of lipid film

Lipid film on skin

Situation on damaged skin

thin film

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No. 39

Reduced protection, moisture loss, distorted cell function

Skin

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Action of NLC in creams

Rehydration

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No. 40

Repair !Re-inforce !

Skin

NLC film

Rehydration

PharmaSolThe Solubility People

Film formation on skin - principle mechanism

H2O evaporation

tightly packed

layer of lipid-

nanoparticles

Occlusion effectlarge lipid

microparticles

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No. 41

small

"capillary pores"

skin

200 nm

Top view:

large pores

2 µm

PharmaSolThe Solubility People

Occlusion effect Cream vs. Cream with Nanopearls®

30

40

50

60

6 hours

24 hours

48 hours

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No. 42

Occlusion factor of a commercial o/w cream (left) and a cream with incorporated Nanopearls® (right) as a function of time.

(Dingler et al., J. Microencapsulation, 1999)

0

10

20

cream cream + Nanopearls

PharmaSolThe Solubility People

Penetration of:

coenzyme Q10 and Tocopherol

into the stratum corneum (SC) from aqueous

Increased penetration of actives

40

50

60

70

80

90

microparticle

nanoparticle

Tocopherol coenzyme

Conte

nt

acti

ve

[10 %

]

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(SC) from aqueous

NLC® dispersion

vs.

solid lipid microparticlesdispersion

(cumulative amount of skin strips 2-9; skin strip 1 = non-penetrated fraction).

0

10

20

30

fractionpenetratedin SC

fractionpenetratedin SC

Tocopherol coenzyme Q 10

Conte

nt

acti

ve

[10 %

]

PharmaSolThe Solubility People

Principle mechanisms of UV protection

Particular sunscreen: UV

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No. 44

• Molecular sunscreen:heat, light

synergistic effect: sunscreen in NLC

PharmaSolThe Solubility People

Protection by incorporation of TiO2 in NLC

Potential Problem: TiO2 might penetrate into skin, side effects

Solution: firm encapsulation of TiO2 into NLC

should avoid/ minimize potential penetration into the skin

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No. 45

Titanium dioxide

10-20 nmNLC

400 nm

should avoid/ minimize potential penetration into the skin

PharmaSolThe Solubility People

Summary: Performance & Effects on Skin

adhesiveness to skin

film formation, repair of stratum corneum

occlusion effect

skin hydration ↑

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skin hydration ↑

wrinkle depth ↓

increased / modulated penetration of actives

UV protection system

⇒ i.e. skin healing, caring & protective effects!

PharmaSolThe Solubility People

Examples for use in consumer care

sunscreen products (more efficient, “safe-nano”)

mouth sprays/washs

tooth pastes

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No. 47

hair conditioning products

disinfectant sprays

insect repellents

fabric softeners…….etc…etc…….

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. 48

No. 48

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

Lipid Nanoparticles in the German Pharmaceutical Press

Lipid Nanoparticles

Smart delivery system

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No. 49

Smart delivery system

for dermal actives

PharmaSolThe Solubility People2005

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No. 50

PharmaSolThe Solubility People2005

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No. 51

PharmaSolThe Solubility People

Measurement of skin hydration: Corneometer

• Not invasive method

• Measuring time: 1 sec

• Principle: capacity changes

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changes

• Capacity changes are dependent upon the water content in stratum corneum (ε = 78 at 32 oC)

MPA5 with Corneometer 825(Courage and Khazaka, Köln)

Nanopearls®

PharmaSolThe Solubility People

Q10 skin hydration in vivo: NLC vs. NLC-free

20

25

30

Can

ges [

%]

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no NLC

w ith NLC

0

5

10

15

Can

ges [

%]

Long-term study, 42 days,

measurement 12 h after last application

PharmaSolThe Solubility People

South Korean

Top Model no. 1

for the introduction of the

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NLC Supervital products

in the pretigous line

IOPE

by Amore Pacific

1. Sept. 2006

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No. 55

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No. 56

PharmaSolThe Solubility PeopleProducts under PharmaSol license

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PharmaSolThe Solubility People

Dr. Rimpler GmbH – partner of PharmaSol for introducing NLC technology

Dr.Rimpler GmbH

Neue Wiesen 10

D-30900 Wedemark

Founded 1986 by Prof. Dr. Manfred Rimpler

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Health & Care development, production

Cosmetic-GMP & approved by §13 AMG

Company Profile

54 employees

Production capacity 2500 kg per shift

www.Rimpler.de

PharmaSolThe Solubility People

Examples of commercially available loaded NLC

Coenzyme Q10

Vitamin E

Tocotrienol

Retinol

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No. 59

Retinol

Black current oil (BCO)

KuKui oil

Makui oil

use of special lipids: e.g. Carnauba wax

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. 60

No. 60

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

Technical advantages of NLC vs. liposomes

Problems of liposomes:

1. physical stability in o/w systems

2. quantitative analysis difficult

3. chemical stability of labile actives

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3. chemical stability of labile actives

Advantages of NLC:

1. high physical stability due to solid state of particle matrix

2. physical stability easy to prove (DSC)

3. chemical stabilisation of actives due to solid character

PharmaSolThe Solubility People

aequeous Nanopearls®

Nanopearls® in o/w creamEnthalpy[m W ]

o/w cream

Physical stability: Incorporation into cream

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30 40 50 60 70 °C

^endotherm

Tem perature [°C]

Melting peaks of Nanopearls® aqueous dispersion and after its incorporation into an o/w cream

(reference: DSC thermogram of cream - no melting event).

PharmaSolThe Solubility People

Chemical stability of incorporated actives

Nanoemulsions and Liposomes:

Limited protection of actives because:

• lipophilic actives are in exchange with water due to fluid

character of oil droplet / liposome bilayer

• hydrophilic actives in liposome core diffuse through bilayer in

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• hydrophilic actives in liposome core diffuse through bilayer in

outer water phase

NLC:

Enhanced protection of actives:

• solid state minimizes exchange of actives with

water phase (diffusional law by Einstein)

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. 64

No. 64

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

• NLC can be made with regulatory accepted excipients

• NLC are produced with production technology already available in pharmaceutical industry

Summary Pharmaceuticals

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No. 65

• Make-ability of technology proven by cosmetics products on the market

• primary delivery routes:

- dermal application

- oral administration (poorly soluble drugs)

PharmaSolThe Solubility People

• unloaded NLC have own skin effects

• loaded NLC increase chemical stability & “bioactivity” of actives

• NLC can easily be incorporated into creams, etc.

Summary Cosmetics/Consumer Care

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• NLC can easily be incorporated into creams, etc.

• physical stability high, easy to prove quantitatively

• extremely short time from invention to market (6 years)

• Products: > 40 in about 4 years

(including La Prairie /Beiersdorf group)

PharmaSolThe Solubility People

• increase bioavailibility of poorly soluble plant actives

• increase bioavailability of actives like coenzyme Q10 (nano Q10 is 100% available!)

Perspectives for Nutraceuticals

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No. 67

• delivery of unsaturated fatty acids (incl. fish oil NLC)

• NLC for delivery of lipophilic vitamins in a diet

• NLC as physically stable taste enhancer?

PharmaSolThe Solubility People

NLC Product Examples

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No. 68

PharmaSolThe Solubility People

Lipid nanoparticles can be made with regulatory accepted excipients (lipids, surfactants)

they are produced with production technology already available in pharmaceutical industry

Summary – SLN/NLC in general

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No. 69

already available in pharmaceutical industry

Make-ability of technology proven by cosmetics products on the market

primary delivery routes:

- dermal application

- oral administration (poorly soluble drugs)

- intravenous (replacement of liposomes !)

PharmaSolThe Solubility People

NLC proved effective in BA enhancement of the drugs cyclosporine, fenofibrate, T and TU

fenofibrate: competitive products to exclusive nanocrystal products are possible by using NLC as alternative technology

Summary – NLC for oral delivery

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alternative technology

especially for TU:

- a competitive product to Andriol seems feasible:

same BA, but only 1 tablet (NLC – lipid 1)

- higher BA with NLC also possible by optimizing

NLC - lipid 2: smaller particle size

PharmaSolThe Solubility People

increase bioavailability of poorly soluble plant actives (e.g. rutin, hesperidin etc….)

increase bioavailability of actives like coenzyme Q10 (nano Q10 is 100% available!)

Summary – perspectives for Nutraceuticals

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Q10 (nano Q10 is 100% available!)

delivery of unsaturated fatty acids

• incl. fish oil NLC

NLC for delivery of lipophilic vitamins in a diet

NLC as physically stable taste enhancer?