rainer h. müller nanopearls · rainer h. müller no. 2 content • short look into cosmetic...

PharmaSol GmbH No. 1AmsterdamFree University Technology Presentation 2007Rainer H. MüllerNo. 1

Lipid Nanoparticles for Improved Formulationof

Cosmetic and Pharmaceutical Actives

Rainer H. Mü[email protected]

NLC®

Nanopearls®


Content• Short look into cosmetic history• Definitions & special features• Production process & large scale production lines• Pharma / nutritional supplements: oral bioavailibility

enhancement• Pharma & Cosmetic: Performance on skin• Cosmetics: products on the market & performance

• Access to NLC products• Summary


Let us go back in cosmetic history………….

1968 Invention of liposomes by Bingham(liposome size in nanometer range, i.e. liposomes were nanotechnology)

1986 Introduction of first cosmetic product to market:

Capture® by Dior

…..to learn from history for future innovative products


Extraordinary market success:

Most people did not know what a liposome is

but

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

Association: Association: liposomeliposome = = qualityquality


Dermal history since the liposomes

• many attempts to develop a similar successful system

• examples: nanoemulsions

microemulsions

multiple emulsions

MDS - microsponge delivery systems

transfersomes (by Cevc / Munich, Germany)


2005The novel approach in cosmetics & pharma:

NLC = Nanostructured Lipid Carriers


Development of lipid nanoparticle concept

Polymericnanoparticles

polymer(solid)

liquid lipid(=oil)

o/w emulsion

solid lipid

SLN / Lipospheres1st generation

solid lipidblend

NLC2nd generation

surfactant/ stabilizer layer

Traditional Carriers Lipid Nanoparticles


Definitions• 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.)

• SLN – Solid Lipid Nanoparticlesproduced from solid lipids

• NLC – Nanostructured Lipid Carriers:produced from blend of solid and liquid lipids, but particles are in solid state at body temperature


FeaturesLipid nanoparticles with solid matrixMean particle diameter: 80 - 1000nmProduction by dispersion techniques, e.g. high pressurehomogenizationLoading* with active compounds, e.g.

1-2% prednicarbate, prednisolone, cyclosporine etc…10% Benzophenone-3, Allure6% Retinol (Vitamin A)

24% Tocopherol (Vitamin E)(* calculated as %age of solid lipid matrix)


NLC Technology / Nanopearls®

novel particulate carrier for pharmaceutical / cosmetic products

Nanoparticles based on regulatory accepted excipients, physiological / natural solid lipids (renewable resources)

Application examples: protection of chemically labile active compounds &controlled release (CR) - because of solid matrixpenetration enhancement of activesdermal CR (e.g. drugs, perfumes, repellents)oral absorption enhancement


NLC the more intelligent system

SLN: tendency to form perfect crystals active expulsione.g. tristearin

NLC: inhibit crystallization process by mixing “spatially” very different molecules imperfections in lattice

mixture solid &liquid lipids


Nanostructure of NLC

imperfection (“holes” in lattice)

The particle matrix of NLC is composed of spatially very different molecules whichcannot form a perfect lipid crystal


The Production Technology

Basic principles:

high pressure homogenization

• 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


Production Technology - Basics

basic mixture:solid lipidliquid lipidemulsifier(co-emulsifier)water

(SLN: solid lipids, 0.1% - 30% solid)

solid content> 30%


Production by high pressure homogenization

Melt lipid (>40°C) and dissolve active compound

Disperse active-containing lipid melt in hot surfactantsolution = pre-emulsion

Homogenize pre-emulsion at >40oC, 250 bar, 2 cycles = nano-emulsion

cooling, solidification

NLC / Nanopearls®


“old” SLN vs. novel NLC


Gaulin 5.5 - 150 kg/h


Oral application example: cyclosporine annual sales: appr. 1.2 billion US $ “old” Sandimmun: problem of variation in

bioavailability “new” Sandimmun: high plasma peak (microemulsion) (> 1000 ng/ml) target of previously developed SLN: combine advantage of “old” & “new” Sandimmun, i.e.

no plasma peak and low variation in bioavailability


Oral delivery: cyclosporine study

animal: pigs (n=3)

application: via gastric catheter

comparison: SLN dispersion vs. Sandimmun® Neoralcyclosporine particles


Oral cyclosporine - blood profiles

0

400

800

1200

1600

2000

0 2 4 6 8 10 12 14 16 18 20 22 24tim e [h]

cycl

ospo

rine

con

c. [n

g/m

l] cyclosporine SLNSandimmun Neoral


Oral drug delivery with lipid nanoparticles

What are the mechanisms?

What are the advantages?


Mechanisms of oral lipid nanoparticles

general adhesiveness of very fine particles (nanoparticles)

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


Technical advantages of NLC vs. liposomesProblems of liposomes:1. physical stability in o/w systems

2. quantitative analysis difficult

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


Physical stability: DSC analysis• Determine melting enthalpy of solid lipid matrix of

Nanopearls®

this allows– to prove molecular loss of lipid particles during

incorporation in cosmetic product

– to prove 100% presence of intact, undissolvedNanopearls® during shelf live of product(„standard“ stability in cosmetics: 3 months)


Chemical stability of incorporated activesNanoemulsions and Liposomes:Limited protection of actives because:• lipophilic actives are in exchange with water due to fluidcharacter of oil droplet / liposome bilayer

• hydrophilic actives in liposome core diffuse through bilayer inouter water phase

NLC:Enhanced protection of actives:• solid state minimizes exchange of actives withwater phase (diffusional law by Einstein)


Chemical stability of incorporated actives

Nanoemulsion Nanoparticle dispersion

e.g. polymericnanoparticle or NLC

modified after Rolf Petersen, Berlin


Chemical stabilisation effect of NLCStability of Retinol

in Nanopearls® dispersion(Compritol ATO 888 10% stabilized with Miranol C32) versus Miglyol emulsion (10% oil,1.5% Tween 80).

Reference: V. Jenning, Ph.Dthesis, 1999, Free Univ. of Berlin

020406080

100

cont

ent[

%]

RT

020

406080

100

0 20 40 60 80 100 120 140 160 180time [days]

cont

ent[

%] 40°C

N

N

E

E


Film formation on skin - principle mechanism

Interparticle space:= identical (24 %)

however: different hydrodynamics

nanoparticle pores: capillary condensationeffect (similar to dryingagent silica gel!)

H2O evaporation

small"capillary pores"

skin

200 nm

Top view:

large pores

tightly packedlayer of lipid-nanoparticles

Occlusion effectlarge lipidmicroparticles

2 µm


How work NLC in cosmetic creams and lotions?

NLCOil dropletsCream

water

Skin


Situation on damaged skin

damaged areas of lipid film

Lipid film on skin thin film

Skin

Reduced protection, moisture loss, distorted cell function


Action of NLC in creams

Repair !Re-inforce !

Skin

NLC film


Occlusion effect - in vitro test1. Filter paper on beaker with water2. Apply formulation onto filter3. Measure amount of water evaporated4. Reference: beaker with filter only5. Calculate occlusion factor F: 0 = evaporation from ref.

100 = no evaporation at allfilter

formulationH2O H2O

REFH20 H20

Literature: method after de Vringer, 1992; company: Yamanouchi


Occlusion factor of a commercial o/w cream (left) and a cream withincorporated Nanopearls® (right) as a function of time. (Dingler et al., J. Microencapsulation, 1999)

Occlusion effectCream vs. Cream with Nanopearls®

0

10

20

30

40

50

60

cream cream + Nanopearls

6 hours24 hours48 hours

Occ

lusi

onfa

ctor


Penetration of:

coenzyme Q10 and Tocopherolinto the stratum corneum(SC) from aqueous

Nanopearls® dispersionvs. solid lipid microparticlesdispersion

Increased penetration of actives

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

0

10

20

30

40

50

60

70

80

90

fractionpenetratedin SC

fractionpenetratedin SC

microparticlenanoparticle

Tocopherol coenzyme Q 10

Con

tent

activ

e[1

0 %

]


Principle mechanisms of UV protection

• Particular sunscreen:UV

• Molecular sunscreen: heat, light

synergistic effect: sunscreen in NLC


Release of molecular sunscreen and side effects

0

2

4

6

8

10

0 5 10 15 20 25

time [h]

Rel

ease

[%]

Nanopearls Emulsion

Release of benzophenone-3 from emulsion is twice as high as fromNanopearls® dispersion*

* Wissing, Ph.D. thesis, Free University of Berlin, 2001


Performance & Effects on skin

• adhesiveness to skin• film formation, repair of stratum corneum• occlusion effect• skin hydration ↑• wrinkle depth ↓• increased / modulated penetration of actives• UV protection system

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



enhancement• Pharma & Cosmetic: Performance on skin• Cosmetics: products on the market & performance• Access to NLC products• Summary


Lipid Nanoparticles in the German Pharmaceutical Press

Lipid Nanoparticles

Smart delivery systemfor dermal actives

Application to the skin is the keyto release the actives


Nanopearls® in cosmetic products• Lotions• Creams & Gels• Decorative cosmetics• Sprays

• Mode of incorporation

Blend NLC concentrate with existing product / newformulation


Present state of commercialisation

• 1st non-exclusive license sold for cosmetic finalproducts in 2005 to:

Dr. Rimpler GmbH

• 1st product launch announced at the PCIE in Paris2005

• presentation of first 2 NLC products on the world at thecosmetic trade fair „Beauty“ in Munich, autumn 2005


Composition of NLC coenzyme Q10 suspension

Coenzym Q10 4.8 %

Cetylpalmitat

Miglyol 812

surfactant

Water up to 100.0 %


In vivo penetration of Q10: NLC vs. references

0

5

10

15

20

25

1 2 3 4 & 5 6 & 7 8 & 9

Tape number

Cum

ulat

ive

%ag

e Q

10

NLCEmulsionParaffinum liquidum


Measurement of skin hydration: Corneometer

• Not invasive method• Measuring time: 1 sec• Principle: capacity

changes• Capacity changes are

dependent upon the watercontent in stratumcorneum (ε = 78 at 32 oC)

MPA5 with Corneometer 825(Courage and Khazaka, Köln)

Nanopearls®


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

no NLCw ith NLC

0

5

10

15

20

25

30

Can

ges

[%]

Long-term study, 42 days,measurement 12 h after last application


Examples of available loaded NLC• Coenzyme Q10

• Vitamin E

• Tocotrienol

• Retinol

• Black current oil (BCO)

• KuKui oil

• use of special lipids: e.g. Carnauba wax

also service forcustomer tailor-made

NLC available


South Korean

Top Model no. 1

for the introduction of the

NLC Supervital products

in the pretigous line

IOPE1. Sept. 2006


Cosmetic products in the series by Amore Pacific: SuperVital cream (left), SuperVital serum (middle) and SuperVital eye cream (right).


Product name Producer/ distibuter

Market introduction

main active ingredients

Cutanova Cream Nano Repair Q10Intensive Serum NanoRepair Q10Cutanova Cream NanoVital Q10

Dr. Rimpler/ Germany

10/200510/200506/2005

Q 10, polypeptide, Hibiscusextract, ginger extract, ketosugarQ 10, polypeptide, mafane extractQ 10, TiO2, polypeptide, ursolicacid, oleanolic acid, sunflowerseed extract

SURMER Crème Legère Nano-ProtectionSURMER Crème Riche Nano-RestructuranteSURMER Elixir du Beauté Nano-VitalisantSURMER Masque Crème Nano-Hydratant

Isabelle Lancray/ France

11/2006 kukuinut oil, Monoi Tiare Tahiti®, pseudopeptide, milk extract from coconut, wild indigo, noni extractkukuinut oil, Monoi Tiare Tahiti®, pseudopeptide, milk extract from coconut, wild indigo, noni extractkukuinut oil, Monoi Tiare Tahiti®, pseudopeptide, milk extract from coconut, wild indigo, noni extractkukuinut oil, Monoi Tiare Tahiti®, pseudopeptide, milk extract from coconut, wild indigo, noni extract

Reference: Euro Cosmetics 2007


SuperVital- Cream- Serum- Eye cream(line: IOPE)

Amore Pacific/South Korea

09/2006 coenzyme Q10, ω-3 and ω-6 unsaturated fatty acids

NLC Deep Effect Eye SerumNLC Deep Effect Repair CreamNLC deep effect reconstruction serum

BeateJohnen/ GermanyHSE 24

12/200605/2007

coenzyme Q10, highly active oligo saccharidesQ10, TiO2, highly active oligosaccharidesQ10, actyl hexapeptide-8, highly active oligo saccharides

Regenerationscreme Intensiv

Scholl/ Germany

03/2007 urea, avocado oil, macadamia nuts oil

Reference: Euro Cosmetics 2007


Finished Cosmetic Products• PharmaSol owns world wide IP rights for finished

cosmetic products [email protected]

• Purchase license on a product-by-products base

• Produce own NLC suspensions or source out production of:

- NLC concentrate or- complete production of NLC productto cooperation partner of PharmaSol


Dr. Rimpler GmbH – partner of PharmaSolfor introducing NLC-technology

Dr.Rimpler GmbHNeue Wiesen 10

D-30900 Wedemark

Founded 1986 by Prof. Dr. Manfred Rimpler

Health & Care development, production

Cosmetic-GMP & approved by §13 AMG

Company Profile54 employees

Production capacity 2500 kg per shift

www.Rimpler.de


Service by Dr. Rimpler GmbH

• Development of customized NLC in cooperation with PharmaSol

• Contract manufacturing of NLC concentrate for licensees of PharmaSol (finished products)

• Production of bulk product (creams, lotions etc. with NLC)

• Ready-made products incl. packaging

• Cosmetic testing via external partners


Production machines

Unimix LM 3

First step for scaling up from laboratory

Unimix SRM 250

Batch from 60 to 250 kg

Unimix SRC 1000

Batch from 250 to 1000 kg


Filling equipment

Jar - Fillpack

60 jars/min

Tube - Norden 400

2 machines with 40 tubes/min

Bottle - Fillpack

120 bottles/min

Airless - Valois

10 bottles/min


Summary Pharmaceuticals• NLC can be made with regulatory accepted

excipients

• NLC are produced with production technology 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)


Summary Cosmetics• unloaded NLC have own skin effects

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

• NLC can easily be incorporated in creams, lotion etc

• physical stability high, easy to prove quantitatively

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

• Products: about 20 in about 1.5 years


NLC Product Examples

rainer h. müller nanopearls · rainer h. müller no. 2 content • short look into cosmetic...

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