New Excipients for

Dermopharmaceutical Formulations

Dermoschool – January 10th 2012

An affiliate of
 Table of content

1 Dermopharmaceutical market

2 Marketed drug forms

3 Emulsology Theory

4 Emulsology Application

5 SEPPIC’s New Excipients

 *** Definitions ***
*Topical
Drug that acts locally when applied on the skin or on
the mucosa

*Transdermal
That goes through the derm. All drug forms applied on
the skin and whose target is beyond the derma
(hormonal patches for instance). Some transdermal
drugs are systemic (hormons) and some acts localy
(anti-inflammatory)

*Cutaneous form
Preparation for skin application aiming at delivering
API locally or through the skin.
1 Dermopharmaceutical
market
 Dermopharmaceutical
Market
Pharmaceutical market:
824 billion $ in 2010 (620 billion €)
A 4 to 7% growth is expected until 2013, especially in new
markets (Central Europe, AAA and Latin America)
6 emerging countries represent 20% of the growth (Russia,
Turkey, South Korea, China, India and Brasil)
Prescription
OTC
Dermopharmacy: Patches

Around 20 billion $ 13%

Mainly OTC 37%

50%
 Dermopharmaceutical
Market
Skin application benefits
Local or systemic treatment
Good patient compliance especially when the skin feeling is good
Non invasive
No hepatic first pass
None or slight adverse effect

Main uses
Anti-acne
Anti-aging
Alopecia treatment
Fungal infection
Antisepsis
Anti-inflammatoty
Dermatosis (psoriasis, eczema, pruritis…)
Hormonal treatment
…
 Dermopharmaceutical
Market
anti-acne
SAI + NSAI
anti-fungal
antibiotics
others
15%
29%
15%

16% 25%
Turn-over of dermopharmaceutical drugs
according to the use
Companies involved in the
market
2 Marketed Drug forms
 What is *Cutaneous penetration?

• It is the progress of the API from stratum corneum to its diffusion in

the derma or in the blood

EXCIPIENTS
• Parameters
Enhance or decrease the cutaneous
absorption
Decrease the absorption
•Cationic polymers (gels)
•Mineral oils (vaseline, silicons…)
Enhance the permeability
•Vegetal oils
•Surfactants
•Liposomes
•Emulsions, multiple emulsions
 What is *Cutaneous penetration?

• It is the progress of the API from stratum corneum to its diffusion in

the derma or in the blood

• Parameters
SKIN STATE
The cutaneous barrier efficiency
must be decreased
Use of detergents
Cutaneous moisturisation (patches)
Absorption enhancers
Vasodilators (nicotinates)
Skin disease
Premature
 What is *Cutaneous penetration?

• It is the progress of the API from stratum corneum to its diffusion in

the derma or in the blood

• Parameters
API
Cutaneous penetration depends on
the nature of the API
Size (low MW = higher
penetration)
Shape
Nature (hydrophilic, lipophilic,
amphiphilic)
 What is *Cutaneous penetration?
Different Ways through the skin:

Transcellular (hydrophilic molecule,

moisturized stratum corneum)
Intercellular (lipophilic or amphiphilic molecules)
Transfollicular
Through sweat gland

Penetration kinetics
According to Fick’s law
J = flow
Kp = permeability coefficient

Km . D . ∆c ∆c = difference of concentration

J = Kp . ∆c = Km = partition coefficient between stratum corneum and

excipients
e D = diffusion coefficient
e = thickness of stratum corneum
 What is *Cutaneous penetration?

J = flow
Kp = permeability coefficient
Km . D . ∆c ∆c = difference of concentration
J = Kp . ∆c = Km = partition coefficient between
e stratum corneum and excipients
D = diffusion coefficient
e = thickness of stratum corneum

• Main points of the formula:

The flow increases with the concentration of API
If Km is high, the affinity for the skin is high
(octanol/water partition coefficient)
D reflects the mobility of the API
Kp is the diffusion speed
 What is *Cutaneous penetration?

Franz’s cell:
In-vitro cutaneous penetration model

Human or young pig skin

shaved and washed

6 cells

Absorption in % of API found

in the chamber compared to
the amount applied

Possibility to determine the

penetration in the different
skin layer
 Drug forms

Gel

Semi-solid

Ointment

Monophase

Liquid solution
 Drug forms

Cream

Gel –
Semi-solid Cream

Foam
Gel In
Multiphase
Oil

Fluid
Liquid
emulsion
 Drug forms

Solid Powder

Particles Semi-solid paste

Liquid suspension
 Marketed forms

Plaster Gel
Powder

Solution

Ointment
Cream Foam

Fluid
Gel Cream Suspension Emulsion
3 Emulsiology Theory
 Emulsion Theory
*Emulsion = Stable mixture of oil and water

Why?
To obtain a specific sensorial profile
To obtain specific technical characteristics

Oil in Water (O/W) or Water in Oil (W/O)

 Emulsion Theory
Key parameters
The surface tension between the 2 phases must be very low

The size of the droplets must be very small to avoid creaming or

Coalescence

The more the interfacial film is optimized, the more stable the
emulsion

High viscosity Optimized interfacial film

Small size
Low tension
 Emulsion Theory
Stability of the emulsions creaming
Stockes’ law and sedimentation

2.r².g. (d1-d2) V = sedimentation speed

V= r = droplets radius
9η g = gravity
d1 and d2 = density of the 2 phases
η = viscosity of external phase

More stable if:

Droplets radius is small

The density of the 2 phases is similar
The viscosity of the external phase is important

Creaming Sedimentation
 Emulsion Theory
Interfacial film
Surfactants

Non-ionic surfactant
Steric hindrance Polymeric emulsifier

Lamellar phase
- (liquid cristal)
Ionic surfactant
Steric hindrance and
-
electrostatic repulsion
-
Insoluble particles
(Pickering’s emulsion)
 Emulsion Theory
Non-ionic surfactants
*Non ionic-surfactants

W
W
O

O
 Emulsion Theory
Non-ionic surfactants
*Non ionic-surfactants
It is compulsory to work with a pair of surfactant
Creaming or coalescence if not stable

Water

Oil
Hydrophilic
surfactant

Lipophilic
surfactant
 Emulsion Theory
Non-ionic surfactants

HLB: Hydrophilic/Lipophilic Balance

Molecular Weight MH
Molecular Weight ML

MH/(MH+ML) The higher HLB is,

HLB = the more hydrophilic the
5 surfactant is

Every emulsion has a required HLB.

To calculate is fast but you need to know the HLB of every component
and the required HLB (very rare)
 Emulsion Theory
Non-ionic surfactants
HLB: Hydrophilic/Lipophilic Balance
The most used way to find the required HLB is empiric testing

% lipophilic 0% 1% 2% 3% 4% 5%

% hydrophilic 5% 4% 3% 2% 1% 0%

% total 5% 5% 5% 5% 5% 5%

Microscopic
aspect

Viscosity J1 50 cps 50 cps 10 cps 600 cps 10000 cps 15000 cps

Oil Oil Stable Water

Stability J1 Stable Stable
exudation exudation granules exudation
 Emulsion Theory
Non-ionic surfactants
HLB: Hydrophilic/Lipophilic Balance
The most used way to find the required HLB is empiric testing

% lipophilic 2.1% 2.2% 2.3% 2.4% 2.5% 2.6% 2.7% 2.8% 2.9%

%
2.9% 2.8% 2.7% 2.6% 2.5% 2.4% 2.3% 2.2% 2.1%
hydrophilic

% total 5% 5% 5% 5% 5% 5% 5% 5% 5%

Microscopic
aspect

Viscosity 10 cps 10 cps 10 cps 10 cps 10 cps 10 cps 10 cps 60 cps 300 cp
Stability J1 Stable Stable Stable Stable Stable Stable Stable Stable Stable
 Emulsion Theory
Non-ionic surfactants

HLB Solubility of the surfactant Main uses

18-20 Fully soluble in water Solubilizer

15 Soluble in water Emulsifier OW More than 14C

Foaming agent Less than 14 C
12 Soluble in water Emulsifier OW

9 Dispersible in water Wetting agent C8-C10 chains

6 Dispersible in oil Emulsifier WO

3 Soluble in oil Emulsifier WO

0 Fully soluble in oil Anti-foaming

 Emulsion Theory
Different types of emulsion

Visible
Clear Bluish White
droplets

Particules size

10 nm 100 nm 1 µm 100 µm

Micellar Nano Mini (Macro)

solution emulsion emulsion emulsion Foam
4 Emulsion Application:
Focus on some specific forms
 Focus on some specific forms
Nanoemulsions
Emulsion with nano sized droplets

BENEFITS CHARACTERISATION

The nanoemulsion DRAWBACKS Droplet size

increases the
(granulometry)
bioavailability
High amounts of
Can be used for surfactants
Clear or bluish tint
injectables

Fast cutaneous Process should be

penetration well mastered

Encapsulation
properties

High stability
 Focus on some specific forms
Microemulsions
Thermodynamically stable emulsion:
Formulator’s dream!

BENEFITS
Single homogeneous phase
Solubilizing properties
Newtonian behaviour
Nanoemulsion Microemulsion

DRAWBACKS

High amounts of surfactants

Very fluid (can be a constraint)

DIFFICULTY TO FORMULATE
Spontaneous formation with the right composition
 Focus on some specific forms
Gels
Gelifying polymers

Polysaccharrides (agar-agar, carraghenates,

alginate, gums, cellulose derivatives)
Acrylic polymers (PVP, carbomers)
PEG

Water, Heating,…
 Focus on some specific forms
Gel Gels
Single phase, hydrophilic actives

Gel cream
2 phases without emulsion process

Anhydrous gel
For water sensitive API (with polar solvents)

Hydroalcoolic gel
Ethanol up to 60%, often used to increase API solubility

Gel-in-Oil
Sustained release form
Nice skin feeling
5 SEPPIC’s New Excipients

Multi functional Polymers:

SEPINEO ™ P600

SEPINEO ™ SE 68
 Challenges

Comfort
CHALLENGES

COMPLIANCE = increase treatment effectiveness

Effectiveness

SOLUBILISATION of Pharmaceutical Active

PENETRATION of molecules into the skin

Process

EASE of handling at industrial scale

 Multifunctional Polymer
DEFINITION SEPINEO™ P 600
SEPINEO™ P 600 is a pre-neutralized polymer inverse
emulsion form
Very easy to handle.
It forms instantaneously non-tacky gels
 Multifunctional Polymer
DEMONSTRATION SEPINEO™ P 600

1- slight shear of the water phase 2- addition of SEPINEO™ P 600

3- moderate shear stress ~10 seconds 4- gelification occurs within seconds

 Multifunctional Polymer
SEPINEO™ P 600
Viscosity in function of the concentration of SEPINEO™ P 600

200000

150000
Viscosité mPa.s

100000

50000

0
0.5 1 1.5 2 2.5 3 3.5 4 4.5 5

% SEPINEO™ P 600

The viscosity increases with the amount of

SEPINEO™ P 600
 Multifunctional Polymer
SEPINEO™ P 600 - Thickener
Water
+ Mix at room
SEPINEO™ P 600 temperature Aqueous Gel
(1 to5%)

Water
+ Mix at room addition
SEPINEO™ P 600 temperature of Ethanol or Solvents
(1 to 5%) (acetone, glycols, glycerin…)

ADVANTAGES Hydroalcoholic Gel

or
No need to neutralise Gel rich in solvents
No need for dispersion
Easy to handle
Non tacky gels
Stable from pH 2 to 12

Nota: possibility to formulate anhydrous gels

 Multifunctional Polymer
SEPINEO™ P 600 - ???
Oily Phase
+
surfactants Heating 75°C
Addition of +
SEPINEO™ P 600 Water

Mixing of the phases 70-75°C

Cooling down

Concentrations of use:
0.5 à 2.0%
SEPINEO™ P 600 is not sensitive to shear
SEPINEO™ P 600 helps keeping the viscosity over time
 Multifunctional Polymer
SEPINEO™ P 600 - Surfactant
Oily phase
+ Room temperature
SEPINEO™ P 600 (1-5%)

Addition of cold water

Mix at room temperature

Gel cream
ADVANTAGES
Room temperature
No high shear stress
No need of surfactants
No HLB calculation
 Multifunctional Polymer
SEPINEO™ P 600: Formules

SEPINEO SE 68 5%
HUILE MINERALE 8%
HUILE D’AMANDE DOUCE 7% Placebo cream
Eau QSP 100 %
SEPINEO P600 0.2%

C8-C10 TRIGLYCERIDES 15 %
Eau QSP 100 % Gel - Cream
SEPINEO P600 3%

PROPYLENE GLYCOL
SEPINEO P600
100 %
3%
Anhydrous gel

ETHANOL
Eau QSP
60 %
100%
Hydroalcoholic
SEPINEO P600 4% gel
 Multifunctional Polymer
SEPINEO™ SE68
*SEPINEO SE 68 is:
a gluco-lipidic emulsifier from vegetal raw materials

Glucose is from OGM free sources (manioc..)

Fatty alcohols are from vegetal oils (noix de coco…)

The linkage between the hydrophilic and lipophilic part gave a

high stability to the product
 Multifunctional Polymer
SEPINEO™ SE68
Emulsion with SEPINEO SE 68 have
a good rheo-fluidity and are moderately thixiotropic
300,0
Courbe d'écoulement / Flow curve -25°C 100000 Courbe d'écoulement / Flow curve -25°C
Plan strié / Rough plate 4cm - entrefer / gap 100µm Plan strié / Rough plate 4cm - entrefer / gap 100µm

250,0 10000

200,0

viscosité (Pa.s)
1000
contrainte (Pa)

150,0 100,0

Emulsion SEPINEO™ SE 68 5% / oily phase 20%

100,0 10,00

Emulsion SEPINEO™ SE 68 5% / oily phase 20%

50,00 1,000
6703BECO.04F-montee
6703BECO.04F-palier 6703BECO.04F-montee
6703BECO.04F-descente 6703BECO.04F-palier
6703BECO.04F-descente
0 0,1000
0 200,0 400,0 600,0 800,0 1000 1,000E-3 0,01000 0,1000 1,000 10,00 100,0 1000
gradient (1/s) gradient (1/s)

Good spreading on the skin

 Multifunctional Polymer
SEPINEO™ SE68

SEPINEO™ SE 68 can form liquid crystals

whatever the oily phase

Photograph: liquid crystals Lamellar phase

(polarized light, 400x)
X 1000

Liquid crystals form a shell around the droplets leading

to skin moisturization and good stability
Multifunctional Polymer
SEPINEO™ SE68
 Multifunctional Polymer
SEPINEO™ SE68 - Preparation

Heat the 2 phases (Sepineo SE 68

in the oily phase)
Mix the water in the oily phase

Mix with a rotor stator for 4 min

(SILVERSON TYPE/3000rpm). Let cool down to
60°C Cool down to room temperatue with an anchor
 Multifunctional Polymer
SEPINEO™ SE68 - Formules

DICLOFENAC SODIUM SALT 1.0%

SEPICIDE CI (conservateur) 0.2%
SEPICIDE HB (conservateur) 0.3%
Diclofenac
Eau QSP 100 %
Cream
LANOL 1688 8.0 % FATTY PHASE
SEPINEO SE 68 5.0%

HYDROCORTISONE 0.5%
SEPICIDE CI (preservative) 0.2%
SEPICIDE HB (preservative) 0.3%

WATER QSP 100 %

Hydrocortisone
PRIMOL 352 8.0 %
Cream
FATTY PHASE
SEPINEO™ SE 68 5.0%
 THANK YOU
Nota
Les seules spécifications analytiques garanties sont celles figurant dans le bulletin d’analyse fourni à chaque livraison de produit.
SEPPIC* ne donne aucune garantie, implicite, expresse ou légale, autre que la garantie limitée décrite ci-dessus, pour le produit objet de ce document. Sans préjudice
des dispositions qui précèdent, SEPPIC* ne donne aucune garantie quant à la qualité loyale et marchande du produit ou à son aptitude à un usage particulier.
L’utilisation et/ou la vente du produit, seul ou associé à d’autres marchandises, se feront sous la seule responsabilité du client. Les informations contenues dans ce
document sont fournies gracieusement, et sont données à titre indicatif ; elles sont basées sur l’état des connaissances de SEPPIC* relatives au produit à cette date et
sont données de bonne foi. Ces informations sont destinées à des personnes ayant une compétence technique et les utilisant à leurs risques et périls. Etant donné
que l’utilisation de ces informations est en dehors du contrôle de SEPPIC*, SEPPIC* ne donne aucune garantie, implicite ou expresse, et n’assume aucune
responsabilité quant à l’utilisation de ces informations. En particulier, le client devra vérifier qu’il ne contrevient pas à des brevets existants.

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