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………….
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1986 Introduction of first cosmetic product to market:
Capture® by Dior
…..to learn from history for future innovative products
PharmaSolThe Solubility People
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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
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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
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• examples: nanoemulsions
microemulsions
multiple emulsions
transfersomes (by Cevc / Munich, Germany)
PharmaSolThe Solubility People
2005The novel approach in cosmetics & pharma:
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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
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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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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.
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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)
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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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&
What are the benefits of NLC?
PharmaSolThe Solubility PeopleChemical stabilisation
Stability of Retinol: NLC vrs. Emulsion1
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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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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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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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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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Production Technology - Basics
basic mixture:
1. solid lipid
2. liquid lipid NLC
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2. liquid lipid
3. emulsifier
4. (co-emulsifier)
5. water
(according to SLN patent: solid lipids, 0.1% - 30% solid)
NLC solid content > 30%
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Production
1. Melt lipid (>40°C) & dissolve active compound
2. Disperse active-containing lipid melt
Principle: High pressure homogenization
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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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conc: from 10% to about 50%
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AF-MICROGRAPH of Q10-loaded Nanoparticles
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LAB 40 discont. - 40 g batch
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LAB 60 - 2-10 kg batch
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PharmaSolThe Solubility People
Gaulin 5.5 - 150 kg/h
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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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“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
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Oral administration - cyclosporine study
animal: pigs (n=3)
application: via gastric catheter
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comparison:
• SLN dispersion vs.
• Sandimmun® Neoral vs
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one of the volunteers
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PharmaSolThe Solubility People
Oral cyclosporine - blood profiles
cyclosporine SLN
Sandimmun Neoral
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PharmaSolThe Solubility People
Oral drug delivery with lipid nanoparticles
What are the mechanisms?
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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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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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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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Skin
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damaged areas of lipid film
Lipid film on skin
Situation on damaged skin
thin film
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Reduced protection, moisture loss, distorted cell function
Skin
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Action of NLC in creams
Rehydration
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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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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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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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• 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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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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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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Smart delivery system
for dermal actives
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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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PharmaSolThe Solubility PeopleProducts under PharmaSol license
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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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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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• 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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• 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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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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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?