PharmaSol
The Solubility People
Lipid Nanoparticles
for the delivery of actives
in pharma, cosmetics & consumer care
Cornelia M. Keck
PharmaSol GmbH
Berlin / Germany
PharmaSol GmbH
NLC®
Nanopearls®
No. 1
No. 1
Content
PharmaSol
The Solubility People
Short look into history of liposomes
Definitions & special features
Structure of lipid particle matrix
Production process & large scale production lines
oral bioavailibility – case studies
- cyclosporine and testosteronundecanoate (TU)
dermal application
Make-ability of products – products in the market
Lipid Nanoparticles versus liposomes
Summary
PharmaSol GmbH
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PharmaSol
The Solubility People
Let us go back in cosmetic history………….
1968 Invention of liposomes by Bangham
(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
PharmaSol GmbH
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PharmaSol
The Solubility People
PharmaSol GmbH
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PharmaSol
The 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
packaging!
Association:
PharmaSol GmbH
liposome = quality
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PharmaSol
The Solubility People
Nanocarrier history since the liposomes
• many
attempts to develop a similar successful system
• examples: nanoemulsions
microemulsions
multiple emulsions
transfersomes (by Cevc / Munich, Germany)
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PharmaSol
The Solubility People
2005
The novel approach in cosmetics & pharma:
NLC = Nanostructured Lipid Carriers
PharmaSol GmbH
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No. 7
Content
PharmaSol
The Solubility People
Short look into history of liposomes
Definitions & special features
Structure of lipid particle matrix
Production process & large scale production lines
oral bioavailibility – case studies
- cyclosporine and testosteronundecanoate (TU)
dermal application
Make-ability of products – products in the market
Lipid Nanoparticles versus liposomes
Summary
PharmaSol GmbH
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PharmaSol
The Solubility People
Development of
lipid nanoparticle concept
Traditional Carriers
1970ies
1950ies
polymer
(solid)
liquid
lipid
(=oil)
Polymeric
o/w emulsion
nanoparticles
PharmaSol GmbH
Lipid Nanoparticles
1991
1999/2000
solid
lipid
solid
lipid
blend
SLN
1st generation
NLC
2nd generation
surfactant/ stabilizer layer
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Definitions
PharmaSol
The 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.)
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
PharmaSol GmbH
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Features
PharmaSol
The Solubility People
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.
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)
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NLC Technology / Nanopearls®
PharmaSol
The Solubility People
novel particulate carrier
•
for pharmaceutical / cosmetic / nutraceutical 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 matrix
• penetration enhancement of actives
• dermal CR (e.g. drugs, perfumes, repellents)
• oral absorption enhancement
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NLC versus SLN
PharmaSol
The Solubility People
What exactly is the improvement?
&
What are the benefits of NLC?
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Chemical stabilisation
PharmaSol
The Solubility People
Stability of Retinol: NLC vrs. Emulsion1
NLC: Compritol ATO 888 10% stabilized with Miranol C32
PharmaSol GmbHEmulsion: 10% Miglyol,1.5% Tween 80
1 V.
Jenning (1999), Ph.D. thesis, Free University of Berlin
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PharmaSol
The Solubility People
Problems of “old” SLN
formation of “perfect” crystalline structure during
storage (β modification) ⇒ drug expulsion
days
months
drug in
imperfections
PharmaSol GmbH
drug between
FA chains
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NLC the more intelligent system
PharmaSol
The Solubility People
SLN:
tendency to form perfect crystals active expulsion
e.g. tristearin
NLC:
inhibit crystallization process by mixing “spatially” very
different molecules
imperfections in lattice more space for drug
mixture
solid & liquid lipids
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drug
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Content
PharmaSol
The Solubility People
Short look into history of liposomes
Definitions & special features
Structure of lipid particle matrix
Production process & large scale production lines
oral bioavailibility – case studies
- cyclosporine and testosteronundecanoate (TU)
dermal application
Make-ability of products – products in the market
Lipid Nanoparticles versus liposomes
Summary
PharmaSol GmbH
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PharmaSol
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PharmaSol Production Technology
Basic principle:
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
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PharmaSol
Production Technology - Basics
The Solubility People
basic mixture:
1.
2.
3.
4.
5.
solid lipid
liquid lipid
emulsifier
(co-emulsifier)
water
NLC
solid content > 30%
(according to SLN patent: solid lipids, 0.1% - 30% solid)
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PharmaSol
The Solubility People
Production
Principle: High pressure homogenization
1. Melt lipid (>40°C) & dissolve active compound
2. Disperse active-containing lipid melt
in hot surfactant solution = pre-emulsion
3. Homogenize pre-emulsion
at >40oC, 250 bar, 2 cycles = nanoemulsion
cooling
PharmaSol GmbH
solidification
NLC
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PharmaSol
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Lipid nanoparticles of increasing concentration
PharmaSol GmbH
conc: from 10% to about 50%
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PharmaSol
The Solubility People
AF-MICROGRAPH of Q10-loaded Nanoparticles
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PharmaSol
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LAB 40 discont. - 40 g batch
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PharmaSol
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LAB 60 - 2-10 kg batch
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PharmaSol
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Gaulin 5.5 - 150 kg/h
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Content
PharmaSol
The Solubility People
Short look into history of liposomes
Definitions & special features
Structure of lipid particle matrix
Production process & large scale production lines
oral bioavailibility – case studies
- cyclosporine and testosteronundecanoate (TU)
dermal application
Make-ability of products – products in the market
Lipid Nanoparticles versus liposomes
Summary
PharmaSol GmbH
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PharmaSol
Oral administration
The Solubility People
Example:
cyclosporine
annual sales:
appr. 1.2 billion US $
“old” Sandimmun: problem: variation in BA
“new” Sandimmun: problem: high plasma peak
(microemulsion)
(> 1000 ng/ml)
target of previously developed SLN:
combine advantage of “old” & “new” Sandimmun
i.e. no plasma peak & low variation in bioavailability
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PharmaSol
The Solubility People
Oral administration - cyclosporine study
animal:
pigs (n=3)
application:
via gastric catheter
comparison:
• SLN dispersion vs.
• Sandimmun® Neoral vs
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one of the volunteers
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PharmaSol
The Solubility People
Oral cyclosporine - blood profiles
cyclosporine SLN
Sandimmun Neoral
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PharmaSol
The Solubility People
Oral drug delivery with lipid nanoparticles
What are the mechanisms?
What are the advantages?
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PharmaSol
The Solubility People
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
PharmaSol GmbH
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Content
PharmaSol
The Solubility People
Short look into history of liposomes
Definitions & special features
Structure of lipid particle matrix
Production process & large scale production lines
oral bioavailibility – case studies
- cyclosporine and testosterone undecanoate (TU)
dermal application
Make-ability of products – products in the market
Lipid Nanoparticles versus liposomes
Summary
PharmaSol GmbH
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PharmaSol
Product Andriol
The 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
very fragile & sensitive product:
• has to be kept away from light and
• stored at temperatures between 15°C-25°C
PharmaSol GmbH
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PharmaSol
Parameters of in vivo study
The 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
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
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centrifugation
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Results:
The Solubility People
AUC [pg*h/ml|]
AUC values after 8 hours
14000
12000
10000
8000
6000
4000
2000
0
NLC 30%
approx.
200nm
NLC 30%
approx.
600nm
Andriol
Testocaps
smaller size (200 nm) is more effective
PharmaSol GmbH
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Content
PharmaSol
The Solubility People
Short look into history of liposomes
Definitions & special features
Structure of lipid particle matrix
Production process & large scale production lines
oral bioavailibility – case studies
- cyclosporine and testosteronundecanoate (TU)
dermal application
Make-ability of products – products in the market
Lipid Nanoparticles versus liposomes
Summary
PharmaSol GmbH
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PharmaSol
The Solubility People
How work NLC in cosmetic creams and lotions?
Cream
Oil droplets
NLC
water
Skin
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PharmaSol
The Solubility People
Situation on damaged skin
Lipid film on skin
thin film
damaged areas of lipid
film
Skin
Reduced protection, moisture loss, distorted cell function
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PharmaSol
The Solubility People
Action of NLC in creams
Rehydration
Re-inforce !
Repair !
NLC film
Skin
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PharmaSol
The Solubility People
Film formation on skin - principle mechanism
Occlusion effect
large lipid
tightly packed
microparticles
layer of lipidnanoparticles
H 2 O evaporation
200 nm
2 µm
skin
Top view:
large pores
PharmaSol GmbH
small
"capillary pores"
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PharmaSol
The Solubility People
Occlusion effect
Cream vs. Cream with Nanopearls®
60
6 hours
24 hours
50
48 hours
40
30
20
10
0
cream
cream + Nanopearls
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)
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PharmaSol
The Solubility People
Increased penetration of actives
Penetration of:
NLC®
dispersion
vs.
solid lipid microparticles
dispersion
Content active [10 %]
coenzyme Q10 and
Tocopherol
into the stratum corneum
(SC) from aqueous
90
nanoparticle
80
microparticle
70
60
50
40
Tocopherol
30
20
coenzyme
Q 10
10
0
fraction
penetrated
in SC
fraction
penetrated
in SC
(cumulative amount of skin strips 2-9; skin strip 1 = non-penetrated fraction).
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PharmaSol
The Solubility People
Principle mechanisms of UV protection
Particular sunscreen:
• Molecular sunscreen:
UV
heat, light
synergistic effect: sunscreen in NLC
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PharmaSol
The 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
Titanium dioxide
10-20 nm
NLC
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PharmaSol GmbH
400 nm
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PharmaSol
The Solubility People
Summary: 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!
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PharmaSol
The Solubility People
Examples for use in consumer care
sunscreen products (more efficient, “safe-nano”)
mouth sprays/washs
tooth pastes
hair conditioning products
disinfectant sprays
insect repellents
fabric softeners…….etc…etc…….
PharmaSol GmbH
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Content
PharmaSol
The Solubility People
Short look into history of liposomes
Definitions & special features
Structure of lipid particle matrix
Production process & large scale production lines
oral bioavailibility – case studies
- cyclosporine and testosteronundecanoate (TU)
dermal application
Make-ability of products – products in the market
Lipid Nanoparticles versus liposomes
Summary
PharmaSol GmbH
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PharmaSol
The Solubility People
Lipid Nanoparticles in the German Pharmaceutical Press
Lipid Nanoparticles
Smart delivery system
for dermal actives
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2005
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The Solubility People
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Measurement of skin hydration: Corneometer
• Not invasive method
• Measuring time: 1 sec
• Principle: capacity
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)
PharmaSol GmbH
Nanopearls®
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PharmaSol
The Solubility People
Q10 skin hydration in vivo: NLC vs. NLC-free
30
25
Canges [%]
20
15
10
5
0
no NLC
w ith NLC
PharmaSol GmbH
Long-term study, 42 days,
measurement 12 h after last application
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PharmaSol
The Solubility People
South Korean
Top Model no. 1
for the introduction of the
NLC Supervital products
in the pretigous line
IOPE
by Amore Pacific
PharmaSol GmbH
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1. Sept. 2006
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PharmaSol
Products under PharmaSol license The Solubility People
PharmaSol GmbH
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PharmaSol
The 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
Health & Care development, production
Cosmetic-GMP & approved by §13 AMG
Company Profile
54 employees
Production capacity 2500 kg per shift
www.Rimpler.de
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Examples of commercially available loaded NLC
Coenzyme Q10
Vitamin E
Tocotrienol
Retinol
Black current oil (BCO)
KuKui oil
Makui oil
use of special lipids: e.g. Carnauba wax
PharmaSol GmbH
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Content
PharmaSol
The Solubility People
Short look into history of liposomes
Definitions & special features
Structure of lipid particle matrix
Production process & large scale production lines
oral bioavailibility – case studies
- cyclosporine and testosteronundecanoate (TU)
dermal application
Make-ability of products – products in the market
Lipid Nanoparticles versus liposomes
Summary
PharmaSol GmbH
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The 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
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
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Physical stability: Incorporation into cream
a eq u eo u s N a n op ea rls ®
N an o pe a rls ® in o /w cre am
E n th alp y
[m W ]
o /w cre a m
^e nd othe rm
30
40
50
60
70
°C
T em p era tu re [°C ]
Melting peaks of Nanopearls® aqueous dispersion and after its
incorporation into an o/w cream
(reference: DSC thermogram of cream - no melting event).
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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
outer water phase
NLC:
Enhanced protection of actives:
• solid state minimizes exchange of actives with
water phase (diffusional law by Einstein)
PharmaSol GmbH
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No. 63
Content
PharmaSol
The Solubility People
Short look into history of liposomes
Definitions & special features
Structure of lipid particle matrix
Production process & large scale production lines
oral bioavailibility – case studies
- cyclosporine and testosteronundecanoate (TU)
dermal application
Make-ability of products – products in the market
Lipid Nanoparticles versus liposomes
Summary
PharmaSol GmbH
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The Solubility People
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)
PharmaSol GmbH
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The Solubility People
Summary Cosmetics/Consumer Care
• unloaded NLC have own skin effects
• loaded NLC increase chemical stability & “bioactivity” of
actives
• 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)
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Perspectives for Nutraceuticals
• increase bioavailibility of poorly soluble plant actives
• increase bioavailability of actives like coenzyme 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?
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NLC Product Examples
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The Solubility People
Summary – SLN/NLC in general
Lipid nanoparticles can be made with regulatory
accepted excipients (lipids, surfactants)
they 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)
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PharmaSol GmbH - intravenous (replacement of liposomes
!)
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The Solubility People
Summary – NLC for oral delivery
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
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
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Summary – perspectives for Nutraceuticals
increase bioavailability of poorly soluble plant
actives (e.g. rutin, hesperidin etc….)
increase bioavailability of actives like coenzyme
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?
PharmaSol GmbH
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