Derma Monographs

Emulsifiers For NewDermacare Formulations

Product mini-monographs

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IntroductionTopical dosage forms are mostly used to treat dermatological diseases and/or deliver drugs to localized tissues. In an environment where more and more topical formulations are “over the counter“ -OTC- patient’s choice and brand loyalty play an increasingly important role in product selection.

The cosmetic aspect of a topical formulation therefore needs to be considered.

Gattefossé Dermacare brochure contains mini-monographs describing the properties of the following emulsifiers Apifil®, Gelot™ 64, Sedefos™ 75, Plurol® Diisostearique and Tefose® 63. For each of them, a placebo cream is presented for its enhanced ‘sensorial’properties.

The sensorial analysis carried out on these selected placebos uses validated methodology. Gattefossé has an internal sensorial panel composed of trained experts to evaluate the specific sensorial properties of topical formulation including texture, spreadability and post-application feeling. These properties are numerically ranked resulting in the construction of a spider diagram defining the sensorial profile of each formulation.

It is then possible to select a formulation based on the desired and optimized sensorial properties. For example, the treatment of irritated and/or damaged skin demands a formulation that has good spreadability, rapid absorption and soft afterfeel. These features can be enhanced and optimized with the application of sensorial analysis.

The Dermacare kit can accompany this brochure. It contains the 7 different samples of placebo cream described in these mini-monographs. This kit is available upon request.

The information provided in the brochure is only an overview of our extensive body of knowledge on topical formulations. With representatives located throughout the world, Gattefossé is able to share a world of ideas and to provide technical support.

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Contents> APIFIL® ..........................................................................................................4-5

> GeLOT™ 64 ......................................................................................................6-7

> PLUROL® DIISOSTeRARIQUe ...............................................................................8-9

> SeDeFOS™ 75 ................................................................................................. 10-11

> TeFOSe® 63 ................................................................................................... 12-13

> GUIDeLIneS TO FORmULATe DRUGS FOR DeRmAL DRUG DeLIveRy ............................ 14-15

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Product characteristics

a p i f i l®

Key benefitsA powerful emulsifier for formulations requiring a high volume of oil phase (up to 40-50%).Compatible with a wide variety of oils.Compatible with most APIs at a pH between 4.5 and 7.0.

Level of use

Formulation tipsUse Apifil® with emulcire™ 61 WL 2659 (Gattefossé) - ratio 2:1 - for a creamy texture and to improve heat stability.Add an aqueous gelling agent if level of Apifil® is below 7%.Use Compritol® 888 ATO or Pellets, Geleol™ mono and diglycerides nF (Gattefossé), and cetyl alcohol as consistency agents.Avoid stearic acid and hydrogenated castor oil.

Manufacturing process

1 Add Apifil® to oily phase

2 Heat both oily and aqueous phases at 70-80°C

3 Pour the oily phase into the aqueous phase under moderate stirring

4 Cool down the emulsion to 25°C while stirring.Apifil®

+Oily phase

Aqueous phase O/W emulsion

70-80°C Moderate stirring

Amount of Apifil® 5% 7%

Drop point: 67.5°C

Light amber waxy pellets

HLB 9Packaging: 25 kg cardboard box (250 g sample)

PeG-8 Beeswax

O/W emulsifier

Cream requiring gelling agent

in the aqueous phaseLotion Cream

5

mini-monograph

Appearance: White compact creamCharacteristics: pH 5.3 - viscosity (50s-1 at 25°C) : 5 110 mPa. s

Ingredients Functionality % W/W

Apifil® Emulsifier 5.00 Emulcire™ 61 WL 2659 Emulsifier 3.00 mineral oil Oily phase 30.00

Demineralized water Aqueous phase 61.60 Carbomer Gelling agent 0.10 Sodium hydroxide (10% sol.) neutralizing agent 0.20 Sorbic acid Preservative 0.05 methyl paraben sodium salt Preservative 0.05 100.00

Apifil® is a powerful emulsifier ideal for formulations incorporating a high volume of oil and lipophilic API.

Dermacare formulation

Sensorial ID Apifil®

From light and non-greasy to rich textures

easy spreading Softness during application

OilPhasePlus

0123456789

10Thickness

Greasiness

Softness

Spreadability

Film residue

Gloss afterfeel

Soft afterfeel

Greasy afterfeel

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Amount of Gelot™ 64 3% 8%

Key benefitsTrouble-shooting emulsifier for difficult to formulate APIs (acidic APIs, alcohol extracts or essential oils).Compatible with a wide variety of gelling agents and consistency agents. excellent heat stability and stable over a wide range of pH: from 3 to 12.

Level of use

Formulation tipsUse Gelot™ 64 with emulcire™ 61 WL 2659 (Gattefossé) - ratio 1: 1 - to provide a soft, velvet touchduring application.Add an aqueous gelling agent if level of Gelot™ 64 is below 8%.


g e l o t ™ 6 4Drop point: 59.0°C

Beige waxy pellets


Glycerol monostearate (and) PeG-75 palmitostearate

O/W emulsifier

1 Add Gelot™ 64 to oily phase



4 Cool down the emulsion to 25°C while stirring.GelotTM 64+

Oily phase




in the aqueous phaseCream

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mini-monograph

Appearance: Semi-fluid white creamCharacteristics: pH 4.5 - viscosity (50s-1 at 25°C) : 3910 mPa. s


Gelot™ 64 Emulsifier 3.00 Emulcire™ 61 WL 2659 Emulsifier 3.00 Cetyl alcohol Texture agent 3.00 Labrafil® M 1944 CS Oily phase 2.00 mineral oil Oily phase 10.00

Demineralized water Aqueous phase 78.85 Sorbic acid Preservative 0.10 methyl paraben sodium salt Preservative 0.05 100.00

Sensorial ID Gelot™ 64

Rich consistencyvelvet touch with good spreadability

Thin and non-greasy film residue

Gelot™ 64 is a trouble-shooting emulsifier for difficult to formulate API including acids and alcohol extracts.

ChallengePlus

0123456789

10Thickness

Greasiness

Softness

Spreadability

Film residue

Gloss afterfeel

Soft afterfeel

Greasy afterfeel

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plurol® diisostearique

Aqueous phase Plurol® Diisostearique+

Oily phase

W/O emulsion


Room temperature Rapid stirring 1 Add Plurol® Diisostearique to oily phase2 For hot process: heat both aqueous and oily phases

at 70-80°C3 Pour the aqueous phase into the oily phase

mixing speed is faster for cold process4 If necessary, cool down the emulsion to 25°C while

stirring.

Key benefitsWater-in-oil, PeG-free emulsifier particularly useful for thermosensitive or hydrosoluble API.Flexible processing conditions: emulsification using a cold process or a hot process.Ideal for formulations containing mineral oil level up to 25%.

Level of use

Formulation tipsThe oily phase should contain mineral oil, and not more than 5% of other types of oils.For hot processing, use Compritol® 888 ATO or Pellets (Gattefossé) or hydrogenated castor oil as a consistency agent.For cold processing, Plurol® Oleique CC 497 (Gattefossé) can be used as a co-emulsifier to enhancestability.Requires the presence of naCl and mgSO4 (from 1 to 2%) to stabilize the emulsion.


viscous liquid

HLB 4.5Packaging: 25 kg drum (200 g sample)

W/O emulsifier

Lotion Cream

Amount of Plurol® Diisostearique 3%

Triglycerol diisostearate

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mini-monograph

Sensorial ID Plurol® Diisosterarique

Firm consistency Thin film after applicationCreamy texture

Plurol® Diisostearique is a PEG-free, W/O emulsifier ideal for heat-sensitive API when used with a cold process.

0123456789

10Thickness

Greasiness

Softness

Spreadability

Film residue

Gloss afterfeel

Soft afterfeel

Greasy afterfeel

WinOHotPlus (Hot process)

Plurol® Diisostearique Emulsifier 5.00 mineral oil Oily phase 20.00 Compritol® 888 Pellets Texture agent 2.00 methyl paraben Preservative 0.25 Propyl paraben Preservative 0.15

Demineralized water Aqueous phase 71.60 naCl Stabilizer 0.50 mgSO4.7H2O Stabilizer 0.50

100.00

Ingredients Functionality % W/WWinOColdPlus (Cold process)

Plurol® Diisostearique Emulsifier 4.00 Plurol® Oleique CC 497 Co-emulsifier 2.00 mineral oil Oily phase 15.00 methyl paraben Preservative 0.25 Propyl paraben Preservative 0.15

Demineralized water Aqueous phase 76.60 naCl Stabilizer 1.00 mgSO4.7H2O Stabilizer 1.00

100.00


Appearance WinOHotPlus Compact and bright white cream WinOColdPlusCharacteristics WinOHotPlus viscosity (50s-1 at 25°C) 5040 mPa. s WinOColdPlus 7825 mPa. s

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s e d e f o s™ 75

Formulation tipsAnhydrous emulsions can be obtained with hydrophilic phase like glycerine, propylene glycol, PeG,Compatible with all oily phases (up to 40%).Compatible with all gelling agents and consistency agents.One pot process is feasible when amount of Sedefos™ 75 > 9%.


Key benefitsAn effective emulsifier for hydrosensitive APIs and for formulations requiring a large volume of oily phase (up to 40%).excellent compatibility and heat stability.easy-to-use one-pot formulation process or standard processing methods.

Level of use

Lotion Cream

Amount of Sedefos™ 75 6%

Drop point: 47.5°C

White waxy pellets


Triceteareth-4 phosphate (and) ethylene glycol palmitostearate (and) Diethylene glycol palmitostearate

O/W emulsifier

SedefosTM 75+

Oily phase

Hydrophilic phase O/W emulsion

70-80°C Moderate stirring 1 Add Sedefos™ 75 to oily phase

2 Heat both oily and hydrophilic phases at 70-80°C

3 Pour the oily phase into the hydrophilic phase under moderate stirring

4 Cool down the emulsion to 25°C while stirring.

A one-pot process can also be used with Sedefos™ 75

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mini-monograph

Sensorial ID Sedefos™ 75

Rich texture

Light texture

High emolliency during application

Good spreadability

Ideal for dry skin

very good softness after application

Sedefos™ 75 is a problem-solving emulsifier for highly hydrosensitive API, difficult to solubilize API requiring solvents or large amount of oily phase.

0123456789

10Thickness

Greasiness

Softness

Spreadability

Film residue

Gloss afterfeel

Soft afterfeel

Greasy afterfeel

Sedefos™ 75 Emulsifier 9.00 Sweet almond oil Oily phase 25.00

Glycerine Aqueous phase 66.00 100.00

AnhydroPlus

Sedefos™ 75 Emulsifier 9.00 mineral oil Oily phase 25.00

Sorbic acid Preservative 0.10 methyl paraben sodium salt Preservative 0.05 Demineralized water Aqueous phase 55.85

Transcutol® P Solvent 10.00 100.00

ResolvPlus

Appearance AnhydroPlus White translucid emulsion ResolvPlus Semi-fluid white emulsionCharacteristics AnhydroPlus viscosity (50s-1 at 25°C) : 9360 mPa. s ResolvPlus pH 4.7 - viscosity (50s-1 at 25°C) : 1465 mPa. s

Ingredients Functionality % W/W Ingredients Functionality % W/W

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t e f o s e® 63

Key benefitsA multi-functional emulsifier enabling one-pot processing.yields emulsion with medium to high viscosity.excellent mucosal and skin tolerance, ideal for antifungal treatments, widely used in vaginal emulsions.

Level of use

Formulation tipsUse Tefose® 63 with Labrafil® m 1944 CS (Gattefossé) - ratio 2: 1 - for higher heat stability.If level of Tefose® 63 is below 8%, add an aqueous gelling agent.One-pot process is feasible when amount of Tefose® 63 > 12%.


Amount of Tefose® 63 5% 8%

Drop point: 48.0°C

White waxy solid

HLB 9-10Packaging: 10 and 20 kg iron pail (450 g sample)

PeG-6 palmitostearate (and) ethylene glycol palmitostearate (and) PeG-32 palmitostearate

O/W emulsifier

1 Add Tefose® 63 to oily phase



4 Cool down the emulsion to 25°C while stirring.Tefose® 63+

Oily phase




in the aqueous phaseLotion Cream

A one-pot process can also be used with Tefose® 63

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mini-monograph

Appearance: White creamCharacteristics: pH 4.7 - viscosity (50s-1 at 25°C) : 2640 mPa. s


Tefose® 63 Emulsifier 8.00 mineral oil Oily phase 18.00 Cetyl alcohol Texture agent 2.00

Demineralized water Aqueous phase 71.90 Sorbic acid Preservative 0.05 methyl paraben sodium salt Preservative 0.05 100.00

Sensorial ID Tefose® 63

Light and thin texture Good spreadability Softness during application

Tefose® 63 is an ideal emulsifier for anti-fungal treatment due to excellent mucosal tolerance.

MicrobicidePlus

0123456789

10Thickness

Greasiness

Softness

Spreadability

Film residue

Gloss afterfeel

Soft afterfeel

Greasy afterfeel

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Guidelines to formulate drugs for dermal drug deliveryTargeted drug solubility

The initial approach for selecting the right emulsifier for the drug is by drug solubility screening. Two questions have then to be answered:

• How much solubilizer (either hydrophilic or lipophilic) is required to solubilize the drug?• Which emulsifier can emulsify that amount of solubilizer?Gattefossé has determined the maximum amount of lipophilic or hydrophilic phases that each emulsifier is able to disperse. This evaluation was done for emulsifier concentration corresponding to those of the Dermacare placebo formulations. The results are presented in the following tables.

Max amount of excipient Medium Chain Triglyceride Mineral oil Sweet Almond oil Labrafil®

to be emulsified by:Apifil® 30% 40% 30% 30%

Gelot™ 64 12% 30% 20% 12%

Tefose® 63 18% 18% 18% 10%

Sedefos™ 75 25% 40% 25% 25%

Plurol® Diisostearique < 4% 30% < 4% < 4%

Max amount of Glycerine Propylene glycol Ethanol Transcutol® P PEG 300 excipient to be associated with:Apifil® 15% 20% 10% < 5% < 10%

Gelot™ 64 20% 20% 10% 10% < 5%

Tefose® 63 5% < 30% 10% 10% 5%

Sedefos™ 75 Complete substitution 20% 10% < 20% < 20%

Plurol® Diisostearique 25% < 3% 5% 10% < 5%

Table 2: Matching emulsifiers with hydrophilic phases

Table 1: Matching emulsifiers with lipophilic phases

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Targeted sensorial profileAnother way of selecting the right emulsifier can be driven by the sensorial identity of the emulsion it can be built. The sensorial properties of the placebo Dermacare formulations are reported in the spider diagram below.

The information included in this brochure is presented in good faith and we believe that it is correct, but no warranty as to accuracy of results or fitness for a particular use is given, nor is

freedom from patent infringement to be inferred. It is offered solely for your consideration, investigation and verification. The user shall determine under his responsibility, the use and the

security conditions of the information, and will remain the only one responsible in case of damageable consequences. Before using a Gattefossé product, or any other product mentioned in

this literature, read, understand and follow the information contained in most recent material Safety Data sheet.

APIFIL® ......................................................................... PeG-8 beeswax

emULCIRe™ 61 WL 2 659 ................................................... Cetyl alcohol (and) Ceteth-20 (and) Steareth-20

COmPRITOL® 888 ATO & COmPRITOL® 888 PeLLeTS ................. Glycerol dibehenate eP/Glyceryl behenate nF

GeLeOL™ mOnO AnD DIGLyCeRIDeS nF................................. Glycerol monostearate (Type I) eP/mono and diglycerides nF

GeLOT™ 64 ...................................................................... Glycerol monostearate eP/nF (and) PeG-75 palmitostearate

LABRAFIL® m 1 944 CS ...................................................... Oleoyl macrogol-6 glycerides eP/Oleoyl polyoxyl-6 glycerides nF

PLUROL® DIISOSTeARIQUe ................................................ Triglycerol diisostearate eP

PLUROL® OLeIQUe CC 497 ................................................. Polyglyceryl-3 dioleate e475/USFA

SeDeFOS™ 75 .................................................................. Triceteareth-4 phosphate (and) ethylene glycol palmitostearate eP/nF/JPeD (and) Diethylene glycol palmitostearate eP/nF/JPeD

TeFOSe® 63........................................................ ............. PeG-6 palmitostearate (and) ethylene glycol palmitostearate eP/nF/JPeD (and) PeG-32 palmitostearate

List of excipients used in this brochure: chemical description/regulatory status

G AT T E F O S S é36 chemin de Genas - BP 603F-69804 Saint-Priest CeDeX - FRAnCeTel. +33 4 72 22 98 00Fax +33 4 78 90 45 67e-mail: [email protected]

To locate your local Gattefossé representative please visit our website www.gattefosse.com or contact our headquarters below.

Contact

Technical supportFor more information on Gattefossé products, please contact your local Gattefossé representative to obtain :

• Dermacare kit containing samples of selected placebos• Our excipients for Dermal Drug Delivery brochure• Further product handling, regulatory and toxicology information• Details of the technical services offered by our Application Laboratory (extensive database of creams, gels,

ointments and microemulsion formulation developed for various model drugs routinely used in treating skin disorders and muscular pain). De

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