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Ciba ® TINODERM Nanotopes Ultra Small Carriers Ciba Specialty Chemicals Personal Care

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Page 1: Ciba TINODERM - showme.physics.drexel.edushowme.physics.drexel.edu/.../Encapsulation/Nanotopes_Ciba.pdf · Please note that Ciba Patents of the Nan- ... • Maximal skin contact of

Ciba® TINODERM™

Nanotopes™ Ultra Small Carriers

Ciba Specialty Chemicals

Personal Care

Page 2: Ciba TINODERM - showme.physics.drexel.edushowme.physics.drexel.edu/.../Encapsulation/Nanotopes_Ciba.pdf · Please note that Ciba Patents of the Nan- ... • Maximal skin contact of

Nanotopes™

TINODERM™ A

TINODERM™ E

TINODERM™ P

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3TINODERM™ • Nanotopes™ 3

Introduction 4

Description 5

3-Dimensional Structure 5Membrane Architecture 6Nanotopes™ versus Liposomes 7

Stability 8

Surfactant Stability of Nanotopes™

Particle size and skin penetration 10

Electron Micrograph of Nanotopes™ andConventional Liposomes 12

Efficacy Study 14

D-Panthenol delivered by Nanotopes™

Application 16

Formulation Guidelines 16

Day Cream with TINODERM™ E 16Electron Micrograph of Cream Formulation 17

Features and Benefits of Nanotopes™ 18

TINODERM™ Product Range 19

TINODERM™ A: Nanotopes™ with Vitamin A palmitateTINODERM™ E: Nanotopes™ with Vitamin E acetateTINODERM™ P: Nanotopes™ with D-Panthenol

Table of Contents

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4 TINODERM™ • Nanotopes™

Introduction

Cosmetic actives for skin care must pene-trate into the skin in order to utilize theirfull potential. Only few cosmetic actives,such as sun filters are effective on the skinsurface. When such actives remain onlyon the surface, they do not enter the skinin a sufficient concentration to create thedesired effect. Hence, specific carrier sys-tems have been developed to transportcosmetic actives into the skin. These sys-tems ease the transport of activesthrough the skin barrier and, further-more, deliver these actives in a sufficientconcentration to the site of interaction.

The barrier protecting the lower skinlayers from penetrating molecules isthe horny layer (or stratum corneum). Itconsists of flat corneocytes, i. e. cornifiedkeratinocytes, and inter-corneocyte lipidlayers. The structure of the horny layer isoften described as the «brick and mortarmodel».

Cosmetic actives need to be transport-ed through the inter-corneocyte lipids;the inter-corneocyte pores with a width

of about 50 nm. This small width effec-tively limits choices of a carrier system. TINODERM™ Nanotopes™ are carrierswhich have been developed with a parti-cle size smaller than the inter-corneocyte(50 nm). Such nano-sized carriers allowan even distribution of actives on the skinsurface. They generate the highest possi-ble number of active hits and provide fastand efficient transport through the skinbarrier.

TINODERM™ Nanotopes™ are charac-terized by their specific unilamellarmembrane consisting of cone-like andcylinder-like molecules. The alternatingcone and cylinder sequence provideshighly stable particles and further pro-tects the encapsulated active. Addition-aly, this structure strongly resists mole-cules associating with membranes, suchas surfactants or preservatives.

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5TINODERM™ • Nanotopes™

Active Ingredient Oil

Co-surfactant

Water

Lecithin

Membrane architecture: Lecithin/co-surfactant monolayer

Encapsulated core: Oil; cosmetic active

External phase: Water

Mean diameter: 20–40 nm

Description

Nanotpes™ are ultra small carriers with a unilamellar membraneof a diameter between 20–40 nm. They can encapsulatecosmetic actives, as well as, oils.

3-Dimensional Structure

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6 TINODERM™ • Nanotopes™

Description

Nanotopes™ encapsulate a lipid core bya phospholipid/co-surfactant monolayermembrane. The membrane consistsof cylindric (phospholipid molecules)and cone-like (co-surfactant) molecules.These constituents create a very denselypacked membrane of small sized, stableparticles.

Such particles, i. e. Nanotopes™, arehighly resistant against surface activemolecules and tolerant to elevated ionicstrength, this in contrast to conventionalbilayer membranes (liposomes). Conse-

quently, Nanotope™ particles are compat-ible with many emulsifiers and surfactantsand tolerant to electrolytes and pH. The mean size of Nanotopes™ dependson the encapsulated active, but, typicallyfrom 20 nm to 40 nm. Nanotopes™ arenot only homogeneous in size, but have avery narrow particle size distribution.

Nanotope™ constituents specified meetInternational Pharmacopoeia standardsand manufactured according to GMP.Please note that Ciba Patents of the Nan-otopes™ delivery system are pending.

Membrane Architecture

Co-surfactant

Lecithin

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7TINODERM™ • Nanotopes™

Description

Liposomes consist of an aqueous coresurrounded by a phospholipid bilayermembrane. The membrane is solelyconsisting of cylindric molecules (phos-pholipids) which attain their higheststability as sheet-like structures. This liposome formation of such lamellaerequires bending, resulting in a looserpackaging of the membrane. Surfaceactive molecules can intercalate the phos-

pholipid bilayers and, impact the liposomes function by forming mixedmicelles. Liposome membranes are sensi-tive to emulsifiers and surfactants.

The consequence of this curvature-induced membrane structure, results in amean size diameter of 150–250 nm,demonstrating a broad particle size distri-bution.

Nanotopes™ versus Liposomes

Lecithin

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8 TINODERM™ • Nanotopes™

Stability

Nanotopes™ Liposomeswithout Sodium Laurylsulfate (SDS)

Nanotopes™ Liposomeswith 2% SDS added

100

90

80

70

60

50

40

30

20

10

00.0% 2.5% 5.0% 10.0%

SDS Concentration

inta

ct N

ano

top

es™/L

ipo

som

es [

%]

LiposomesSodium dodecyl sulfate (SDS, synonymfor sodium lauryl sulfate) intercalateseasily into the liposome bilayer andspontaneously forms mixed micelles withthe phospholipid molecules. The appear-ance changes from opaque to fullytransparent.

Nanotopes™

Neither Nanotope™ membranes arechanged nor effected by SDS. Theappearance of the translucent Nanotopedispersion remains unchanged.

The above graph shows that the population of Nanotopes™

stays intact, even at concentrations of >5% SDS. Liposomes aredestroyed quickly at low SDS concentrations.

Surfactant Stability of Nanotopes™

Nanotopes™ (blue) and Liposomes (red) in Presence of SDS

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9TINODERM™ • Nanotopes™

• Nanotopes™ membranes are resistant to the integration of surfactants

• Nanotopes™ are compatible with many surfactants/emulsifiers

• Liposomal membranes can be attacked by surfactants (intercalation)

• Liposomes can form mixed micelles in the presence of surfactants

Surfactant Critical surfactant conc. Critical surfactant conc.ccrit for Nanotopes™ ccrit for liposomes

Sodium dodecyl 7% 1%sulfate (SDS)

PEG-20 hydrogenated >20% 1%tallow amine

Laureth-11 6% 1%carboxylic acid

Cocamidopropyl >20% 4%betaine

Trideceth-8 10% 2%

Stability

Stability of Nanotopes™ and Liposomes in the Presence ofSurfactants:

assessed by ccrit turbidity measurements and expressed in terms ofcritical surfactant concentration

Intact populations of liposomes andNanotopes™ can be calculated by turbid-ity measurements even in the presence ofsurfactants /emulsifiers. The stability ofthe carrier particles can be expressed by

the critical surfactant concentrationccrit, the highest surfactant/emulsifierconcentration at which Nanotopes™/liposomes remain stable.

Surfactant Stability of Nanotopes™

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10 TINODERM™ • Nanotopes™

mean size: d = 1/8 d0512 particles encapsulate the volume V0(e.g. Nanotopes™)

The picture demonstrates the relation between the particle size and the corresponding core

volume. An active ingredient offered to the skin in a particle of 160nm diameter has 500 times

the volume of a particle with 20nm diameter.

While 500 particles of 20 nm diameter can be evenly spread over a certain skin surface, the one

particle of 160 nm just covers a small «spot».

mean size: d = d01 particle encapsulates the volume V0(e.g. conventional carriers)

mean size: d = 1/2 d08 particles encapsulate the volume V0

mean size: d = 1/4 d064 particles encapsulate the volume V0

Particle Size and Skin Penetration

Carrier systems are more effective if theyprovide an even and homogeneous parti-cle size distribution to the skin surface.The picture demonstrates the importanceof the particle size in relation to the num-ber of particles which transport a definedamount of a cosmetic active.

If a active is offered to the skin by a parti-cle of a size of 160 nm (conventionalcarrier) 500 times more particles areneeded to transport the same amount ofan active, than if the particles have a sizeof 20 nm (Nanotopes™ ).

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11TINODERM™ • Nanotopes™

The high number of particles per cm2 of skin area includes:

• Maximal skin contact of active encapsulated into Nanotopes™

• Increased flux of active into the skin

• Enhanced efficacy of the applied active

Penetration of active (red) into the skin

Distribution of active (red) on the skin

Conventional carriers Nanotopes™

Particle Size and Skin Penetration

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12 TINODERM™ • Nanotopes™

Nanotopes™ Cryo Electron Micrograph, bar: 100 nm; mean diameter: 20 nm

Particles with sizes smaller than 300 nmcan only be detected by electronmicroscopy. The special method used isthe Cryo electron microscopy (transmis-sion electron microscopy) of ultra rapidly

frozen samples (no water crystallization).This method enables us to detect nanosized particles in a native state withoutartifacts caused by sample preparation.

The electron micrograph demonstrates the even distributionand the small size of Nanotopes™. The high number of particlespresent in the defined area can easily be calculated.

Particle Size and Skin Penetration

Electron Micrograph of Nanotopes™

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13TINODERM™ • Nanotopes™

Conventional Liposomes Cryo Electron Micrograph, bar: 100 nm; mean size: 80–100 nm

Particle Size and Skin Penetration

The high resolution electron micrographdemonstrates the mean size and typicalparticle size distribution of a population

of liposomes. The dense membranes ofthe liposomes are caused by the bilayervs the monolayer of the Nanotopes™.

The number of liposomes in the area of the graph is muchsmaller in comparison to the Nanotopes™ photo on the lefthand side.

Electron Micrograph of Conventional Liposomes

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14 TINODERM™ • Nanotopes™

Efficacy Study

0

-2

-4

-6

-8

-10

-12

-14

-16

-18

6 24 48

Erythema assessment via microcirculation:

hours after UV-irradiation

red

ucti

on

of

mic

roci

rcul

atio

n

Nanotopes™ 5% P

Nanotopes™ 0.5% P

Nanotopes™ 0.05% P

empty Nanotopes™

ointment 0.1%hydrocordisone

ointment 5% P

Three different concentrations of D-Pan-thenol loaded Nanotopes™ were testedin a study on human volunteers by artifi-cially inducing a UV-erythema. A creamcontaining 5% D-Panthenol as neatingredient and a 0.1% hydrocortisone

ointment served as controls. The efficacyof the active was assessed by colorimetryvia the reduction of redness and bymeasuring the change of microcircula-tion by a Laser Doppler flow meter usingthe a* value and the erythema index..

D-Panthenol delivered by Nanotopes™

Study design: (randomized, double-blind; on sixteen human volunteers)

Treatments:TINODERM™ P (5% P); 10-fold and 100-fold dilutions (0.5% P, 0.05% P); empty Nanotopes™.Controls: D-Panthenol ointment (5% P) and Hydrocortisone ointment (0.1% Hydrocortisone).

Dose:8 mg/cm2 applied 2 x daily to specific sites ( 6.25 cm2) on back, after irradiation by 2 MED(40–60 mJ/cm2, Philips TL 0.1).

Measurement of erythema:Difference in redness of treated and untreated skin areas registered by spectrophotometry asa*-value and via erythema scale. Differences in microcirculation by laser Doppler flow meter.

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Efficacy Study

15TINODERM™ • Nanotopes™

0

-0.5

-1.0

-1.5

-2.0

-2.5

6 24 48

Erythema assessment via a* value

hours after UV-irradiation

red

ucti

on

in r

edn

ess

[a*]

6 24 48

Erythema assessment via erythema index

hours after UV-irradiation

red

ucti

on

in r

edn

ess

[ery

them

a in

dex

]Nanotopes™ 5% P

Nanotopes™ 0.5% P

Nanotopes™ 0.05% P

empty Nanotopes™

ointment 0.1%hydrocordisone

ointment 5% P

Nanotopes™ 5% P

Nanotopes™ 0.5% P

Nanotopes™ 0.05% P

empty Nanotopes™

ointment 0.1%hydrocordisone

ointment 5% P

0

-0.5

-1.0

-1.5

-2.0

-2.5

-3.0

D-Panthenol (P) loaded Nanotopes™ (5%P and 0.5%) consistently demonstratedthe highest effect on erythema reductionin comparison to the controls at 6h, 24hand 48h after UV irradiation. The efficacy

TINODERM™ P reduces UV-induced ery-thema in a dose- and time-dependentmanner. The superior efficacy of D-Pan-thenol loaded Nanotopes™ following(6h) UV irradiation may be attributed tothe small size of the carrier facilitating thetransport of the active to deeper layers ofthe stratum corneum.

The results demonstrate the highlight

of TINODERM™ P for use in after sunproducts and products against irritatedskin.

The results also demonstrate the effica-cy of a carrier system in comparison tothe neat active ingredient. The same car-rier, loaded with another active ingredi-ent still works in the same way as demon-strated with the D-Panthenol example.

of the 1:100 dilution of D-Panthenolloaded Nanotopes™ (0.05% P) provedcomparable to that of a conventional 5% D-Panthenol ointment.

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16 TINODERM™ • Nanotopes™

Application

Manufacturing ProcedureHeat phase 1 and phase 2 up to 75°C. Add phase 1 to phase 2under stirring and homogenizing. At 65°C–70°C add part 3.Cool down under stirring to 40°C. Add phases 4, 5 and 6 oneafter the other under stirring. Cool down to 28°C.

Trade Name/Supplier INCI %

1 Brij 72 Steareth-2 2,00Brij 72l Steareth-21 1,30Cetiol SN Cetearyl Isononanoate 3,00Finsolv TN C12–15 Alkyl Benzonate 3,00Fitoderm Squalane 2,00Arlamol E PPG-15 Stearyl Ether 3,00

2 Deionised Water Deionised Water 71,20Komplexon III Disodium EDTA 0,10Pemulen TR-1 Acrylates/C10–30 Akryl 0,30

Acrylate CrosspolymerGlycerin Glycerin 3,00

3 DC 245 Clycometicone 4,50

4 NaOH 10% Sodium Hydroxide Sol. 10% 1.00

5 Euxyl K400 Phenoxyethanol &Methyldibrome Glutaronitrile 0,10

Phenonip Phenoxyethanol & Parabens 0,50

6 TINODERM™ E 5,00

Day Cream with TINODERM™ E

O/W Emulsion with Tinoderm™ EDay cream, preventing the damage of skin caused by free radicals

Appearance white LotionpH value after manufacturing 6,3

Formulation Guideline

Nanotopes™ should be added to thewater phase. Neither short term heatingto approx. 80° C nor homogenizationwill destroy the particles. Preferably Nan-

otopes™ should be added to the formula-tion during the cooling phase togetherwith other sensitive actives.

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17TINODERM™ • Nanotopes™

Application

Intact Nanotope™ particles in a finalformulation can be detected by freezefracture electron microscopy. The frac-

ture of these small particles goes throughthe particle and not along the inter-phase.

The freeze fracture electron micrograph shows the oil-phase and the water phase of the creamformulation with TINODERM™ E. The bar represents 100 nm.

In the water phase of the above cream formulation the Nanotopes™ canbe seen in a homogeneous distribution and a size of about 20 nm.

Electron Micrograph of Cream Formulation

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18 TINODERM™ • Nanotopes™

Features and Benefits of Nanotopes™

Properties and Characteristics

Particle size of 20–40 nm, what issmaller than the width of the inter-corneocyte pores of the skin.

Maximal number of active particlesper skin area. The smaller the carriersize the more particles encapsulatethe same amount of active.

Homogeneous particle sizedistribution.

Cylinder/cone architecture of theNanotopes™ membrane

Benefits for Use in Cosmetics

Efficient uptake of the carriers by thehorny layer.

Highly efficient transport of actives tothe target side of the skin.

Increased affinity of the actives to theskin.

Optimized distribution of actives tothe skin.

More particles enhance the probabili-ty of active hits, i.e. a higher chanceto reach their target, giving a higherefficacy of the encapsulated active.Nanotopes™ deliver an active in app.500 more particles than conventionalcarriers to allow an even distribution.

Nanotopes™ provide an even distribu-tion of the cosmetic active from thewater phase of an emulsion formula-tion.

The architecture of the Nanotopes™

membrane provides high stability atthe presence of surfactants and emul-sifiers within a wide pH range.

The Nanotope™ membrane protectsthe encapsulated actives on the wayto the targeted skin layers.

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19TINODERM™ • Nanotopes™

TINODERM™ Product Range

Ciba Tinoderm™ A

Nanotopes™ withencapsulated Vitamin Apalmitate

Vitamin A palmitate is a precursor ofVitamin A which is known as the active toprevent skin aging. Nanotopes™ transportthe Vitamin A palmitate to the target skinlayers, allowing enzymes to transfer itinto active Vitamin A, thus, initiatingan anti-aging and anti-wrinkle activity.TINODERM™ A is used in skin care prod-ucts with anti-wrinkle properties and pre-vents skin from premature aging.

The recommended use concentration isbetween 2–5 % in a formulation. Typicalapplications are skin care products likeday and night creams, gels or lotions.

Ciba Tinoderm™ P

Nanotopes™ withD-Panthenol.

Panthenol is known as a cosmetic activewith anti inflammatory and soothingproperties. It is used in products forsensitive, irritated and stressed skin. In a human study TINODERM™ P showeda 100 fold increase in anti-inflammatoryefficacy compared to non-encapsulatedPanthenol. The speed of action of TINODERM™ P shows it’s optimal /pre-fered use in after sun formulations.

The recommended use concentration isbetween 2–5 % in a formulation. Themajor applications are skin care productsfor irritated skin, after sun products andafter shave skin care products.

Ciba Tinoderm™ E

Nanotopes™ withencapsulated Vitamin Eacetate.

Vitamin E acetate is a stabilized Toco-pherol precursor. Vitamin E is often calledthe «protection vitamin» of the skin. Itshows anti-inflammatory properties andpositively influences skin moisture prop-erties and wound healing. Vitamin E pre-vents the skin from premature aginginduced by UV irradiation and lipid per-oxidation. Nanotopes™ transport theprecursor of Vitamin E to the target skinlayers where it protects the cell mem-branes from damage of free oxygenradicals, and at the same time, acts as askin moisturizer.

The recommended use concentration isbetween 2–5 % in a formulation. Typicalapplications are sun care and after sunproducts.

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Headquarters/Europe

Ciba Specialty Chemicals Inc.Home & Personal CareCH-4002 BaselSwitzerland

Telephone: +41 61 636 24 14Telefax: +41 61 636 31 [email protected]

© Ciba Specialty Chemicals Inc.Pub. No. TM.TB.0001.e.01Edited in Switzerland

Ciba Specialty ChemicalsPersonal Care

ASEAN/ANZ/South AsiaCiba Specialty Chemicals (Singapore) Pte Ltd.4 Fourth Lok Yang RoadSingapore 629701Telephone: +65 265 36 22Telefax: +65 663 83 [email protected]

North East AsiaCiba Specialty Chemicals K.K.Kansai Head Office10-66, Miyuki-choJ-TAKARAZUKA 665Telephone: +81 797 77 29 12Telefax: +81 797 77 29 [email protected]

North America (Canada, USA)Ciba Specialty Chemicals Corporation4090 Premier DriveUSA-High Point, NC 27265Telephone: +1 336 801 22 37Telefax: +1 336 801 20 [email protected]

Central America (Mexico, Central America)Ciba Especialidades QuÍmicas Mexico, S.A. de C.V.Calzada de Tlalpan 3058, Col. Sta. Ursula CoapaMEX-04850 Mexico, D.F.Apartado Postal 22-115MEX-14001 Mexico, D.F.Telephone: +52 5 422 60 00Telefax: +52 5 677 66 [email protected]

South AmericaCiba Especialidades Químicas Ltda.Av. Prof. Vincente Rao, 90BR-04706-900Caixa Postal 21.421BR-04602-970 São Paulo-SPTelephone: +55 11 532 41 81Telefax: +55 11 543 72 [email protected]

Trademarks are either registered or pending and property ofCiba Specialty Chemicals.

The information given in our circulars is based on the presentstate of our knowledge. It shows without lability on our part theuses to which our product can be put.

IMPORTANT: The following supersedes Buyer’s documents. SELL-ER MAKES NO REPRESENTATION OR WARRANTY, EXPRESS ORIMPLIED, INCLUDING OF MERCHANTABILITY OR FITNESS FOR APARTICULAR PURPOSE. No statements herein are to be construedas inducements to infringe any relevant patent. Under no circum-stances shall Seller be liable for incidental, consequential or indirectdamages for alleged negligence, breach of warranty, strict liability,tort or contract arising in connection with the product(s). Buyer’ssole remedy and Seller’s sole liability for any claims shall be Buyer’spurchase price. Data and results are based on controlled or lab workand must be confirmed by Buyer by testing for its intended condi-tions of use. The product(s) has not been tested for, and is thereforenot recommended for, uses for which prolonged contact withmucous membranes, abraded skin, or blood is intended; or for usesfor which implantation within the human body is intended.

Ciba Specialty Chemicals

Ciba Specialty Chemicals is a global leader in the discovery,manufacture and marketing of innovative specialty chemicals.Our products hold leading positions in their chosen markets. Weadd value beyond chemistry for our customers, employees andshareholders through our state-of-the-art environmentally com-patible technologies and proven international marketing exper-tise.