Emulsifiers For New Dermacare Formulations

Product mini-monographs

Introduction
Topical 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- patients choice and brand loyalty play an increasingly important role in product selection. The cosmetic aspect of a topical formulation therefore needs to be considered. Gattefoss Dermacare brochure contains mini-monographs describing the properties of the following emulsiers Apil, Gelot 64, Sedefos 75, Plurol Diisostearique and Tefose 63. For each of them, a placebo cream is presented for its enhanced sensorialproperties. The sensorial analysis carried out on these selected placebos uses validated methodology. Gattefoss has an internal sensorial panel composed of trained experts to evaluate the specic 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 dening the sensorial prole 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, Gattefoss 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

A P I F I L
Product characteristics
O/W emulsier Drop point: 67.5C PEG-8 Beeswax Packaging: 25kg cardboard box (250g sample) Light amber waxy pellets HLB 9

Key benets
A powerful emulsier 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
Lotion Cream requiring gelling agent in the aqueous phase Cream

Amount of Apil

5%

7%

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

Manufacturing process
70-80C Moderate stirring

1 Add Apil to oily phase 2 Heat both oily and aqueous phases at 70-80C 3 Pour the oily phase into the aqueous phase under moderate stirring 4 Cool down the emulsion to 25C while stirring.

Apifil + Oily phase

Aqueous phase

O/W emulsion

Dermacare formulation
Ingredients

mini-monograph
OilPhasePlus
Functionality % W/W
Emulsier
Emulsier Oily phase

Apil Emulcire 61 wl 2659 Mineral oil

5.00 3.00 30.00

61.60 0.10 0.20 0.05 0.05 100.00

Demineralized water Aqueous phase Carbomer Gelling agent Sodium hydroxide (10% sol.) Neutralizing agent Sorbic acid Preservative Methyl paraben sodium salt Preservative

Apil is a powerful emulsier ideal for formulations incorporating a high volume of oil and lipophilic API.

Appearance: White compact cream Characteristics: pH 5.3 - Viscosity (50s-1 at 25C): 5110 mPa. s
Thickness
10 9 8 7 6 5 4 3 2 1 0

Greasy afterfeel

Greasiness

Soft afterfeel

Softness

Gloss afterfeel Film residue

Spreadability

Sensorial ID Apil

From light and non-greasy to rich textures

Easy spreading

Softness during application

G E L O T
Product characteristics
O/W emulsier

6 4
Drop point: 59.0C

Glycerol monostearate (and) PEG-75 palmitostearate Packaging: 25kg cardboard box (250g sample) Beige waxy pellets HLB 10

Key benets
Trouble-shooting emulsier for difcult 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
Cream requiring gelling agent in the aqueous phase Cream

Amount of Gelot 64

3%

8%

Formulation tips
Use Gelot 64 with Emulcire 61 WL 2659 (Gattefoss) - ratio 1: 1 - to provide a soft, velvet touch during application. Add an aqueous gelling agent if level of Gelot 64 is below 8%.

Manufacturing process
70-80C Moderate stirring

1 Add Gelot 64 to oily phase 2 Heat both oily and aqueous phases at 70-80C 3 Pour the oily phase into the aqueous phase under moderate stirring

GelotTM 64 + Oily phase

Aqueous phase

O/W emulsion

4 Cool down the emulsion to 25C while stirring.

mini-monograph
Ingredients

ChallengePlus
Functionality
Emulsier
Emulsier Texture agent Oily phase Oily phase

% W/W
3.00 3.00 3.00 2.00 10.00
78.85 0.10 0.05 100.00

Gelot 64 Emulcire 61 wl 2659 Cetyl alcohol Labral M 1944 CS Mineral oil

Demineralized water Aqueous phase Sorbic acid Preservative Methyl paraben sodium salt Preservative

Gelot 64 is a trouble-shooting emulsier for difcult to formulate API including acids and alcohol extracts.

Appearance: Semi-uid white cream Characteristics: pH 4.5 - Viscosity (50s-1 at 25C): 3910 mPa. s
Thickness
10 9 8 7 6 5 4 3 2 1 0

Greasy afterfeel

Greasiness

Soft afterfeel

Softness

Gloss afterfeel

Spreadability

Film residue

Sensorial ID Gelot 64

Rich consistency

Velvet touch with good spreadability

Thin and non-greasy lm residue

PLUROL DIISOSTEARIQUE
Product characteristics
W/O emulsier

Triglycerol diisostearate

Packaging: 25kg drum (200g sample) Viscous liquid

HLB 4.5

Key benets
Water-in-oil, PEG-free emulsier particularly useful for thermosensitive or hydrosoluble API. Flexible processing conditions: emulsication using a cold process or a hot process. Ideal for formulations containing mineral oil level up to 25%.

Level of use
Lotion Amount of Plurol Diisostearique 3% Cream

Formulation tips
The 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 (Gattefoss) or hydrogenated castor oil as a consistency agent. For cold processing, Plurol Oleique CC 497 (Gattefoss) can be used as a co-emulsier to enhance stability. Requires the presence of NaCl and MgSO4 (from 1 to 2%) to stabilize the emulsion.

Manufacturing process
Room temperature 70-80C Rapid stirring Moderate stirring

Aqueous phase

Plurol Diisostearique + Oily phase

W/O emulsion

1 Add Plurol Diisostearique to oily phase 2 For hot process: heat both aqueous and oily phases at 70-80C 3 Pour the aqueous phase into the oily phase Mixing speed is faster for cold process 4 If necessary, cool down the emulsion to 25C while stirring.

mini-monograph
WinOHotPlus (Hot process)
Ingredients Functionality
Emulsier Oily phase Texture agent Preservative Preservative
Aqueous phase Stabilizer Stabilizer

WinOColdPlus (Cold process)

Ingredients Functionality
Emulsier Co-emulsier Oily phase Preservative Preservative
Aqueous phase Stabilizer Stabilizer

% W/W
5.00 20.00 2.00 0.25 0.15

% W/W
4.00 2.00 15.00 0.25 0.15
76.60 1.00 1.00 100.00

Plurol Diisostearique Mineral oil Compritol 888 Pellets Methyl paraben Propyl paraben Demineralized water NaCl MgSO4.7H2O

Plurol Diisostearique Plurol Oleique CC 497 Mineral oil Methyl paraben Propyl paraben

71.60 Demineralized water 0.50 NaCl 0.50 MgSO4.7H2O

100.00

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

Appearance Characteristics

WinOHotPlus Compact and bright white cream WinOColdPlus WinOHotPlus Viscosity (50s-1 at 25C) 5040 mPa. s WinOColdPlus 7825 mPa. s
Thickness
10 9 8 7 6 5 4 3 2 1 0

Greasy afterfeel

Greasiness

Soft afterfeel

Softness

Gloss afterfeel Film residue

Spreadability

Sensorial ID Plurol Diisosterarique

Firm consistency

Creamy texture

Thin lm after application

S E D E F O S 75
Product characteristics
O/W emulsier Drop point: 47.5C Triceteareth-4 phosphate (and) Ethylene glycol palmitostearate (and) Diethylene glycol palmitostearate Packaging: 25kg cardboard box (250g sample) White waxy pellets HLB 10

Key benets
An effective emulsier 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 Amount of Sedefos 75 6% Cream

Formulation tips
Anhydrous 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%.

Manufacturing process
70-80C Moderate stirring

1 Add Sedefos 75 to oily phase 2 Heat both oily and hydrophilic phases at 70-80C 3 Pour the oily phase into the hydrophilic phase under moderate stirring

SedefosTM 75 + Oily phase

Hydrophilic phase

O/W emulsion

4 Cool down the emulsion to 25C while stirring.

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

mini-monograph
AnhydroPlus

ResolvPlus
% W/W
9.00
25.00 66.00 100.00

Ingredients
Sedefos 75 Sweet almond oil

Functionality
Emulsier Oily phase

Ingredients

Functionality
Emulsier Oily phase
Preservative Preservative Aqueous phase

% W/W
9.00 25.00
0.10 0.05 55.85 10.00 100.00

Sedefos 75 Mineral oil

Sorbic acid Methyl paraben sodium salt Demineralized water

Glycerine Aqueous phase

Solvent Transcutol P

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

Appearance Characteristics

AnhydroPlus ResolvPlus AnhydroPlus ResolvPlus

White translucid emulsion Semi-uid white emulsion Viscosity (50s-1 at 25C): 9360 mPa. s pH 4.7 - Viscosity (50s-1 at 25C): 1465 mPa. s
Thickness
10 9 8 7 6 5 4 3 2 1 0

Greasy afterfeel

Greasiness

Soft afterfeel

Softness

Gloss afterfeel Film residue

Spreadability

Sensorial ID Sedefos 75

Rich texture Light texture

High emolliency during application Good spreadability

Ideal for dry skin Very good softness after application

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T E F O S E
Product characteristics
O/W emulsier PEG-6 palmitostearate (and) Ethylene glycol palmitostearate (and) PEG-32 palmitostearate Packaging: 10 and 20kg iron pail (450g sample) White waxy solid

63
Drop point: 48.0C

HLB 9-10

Key benets
A multi-functional emulsier 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
Lotion Cream requiring gelling agent in the aqueous phase Cream

Amount of Tefose 63

5%

8%

Formulation tips
Use Tefose 63 with Labral M1944 CS (Gattefoss) - 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%.

Manufacturing process
70-80C Moderate stirring

1 Add Tefose 63 to oily phase 2 Heat both oily and aqueous phases at 70-80C 3 Pour the oily phase into the aqueous phase under moderate stirring

Tefose 63 + Oily phase

Aqueous phase

O/W emulsion

4 Cool down the emulsion to 25C while stirring.

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

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mini-monograph
MicrobicidePlus
Ingredients

Functionality
Emulsier Oily phase Texture agent

% W/W
8.00 18.00 2.00
71.90 0.05 0.05 100.00

Tefose 63 Mineral oil Cetyl alcohol

Demineralized water Aqueous phase Sorbic acid Preservative Methyl paraben sodium salt Preservative

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

Appearance: white cream Characteristics: pH 4.7 - Viscosity (50s-1 at 25C): 2640 mPa. s
Thickness
10 9 8 7 6 5 4 3 2 1 0

Greasy afterfeel

Greasiness

Soft afterfeel

Softness

Gloss afterfeel Film residue

Spreadability

Sensorial ID Tefose 63

Light and thin texture

Good spreadability

Softness during application

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Guidelines to formulate drugs for dermal drug delivery

Targeted drug solubility
The initial approach for selecting the right emulsier 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? W  hich emulsier can emulsify that amount of solubilizer? Gattefoss has determined the maximum amount of lipophilic or hydrophilic phases that each emulsier is able to disperse. This evaluation was done for emulsier concentration corresponding to those of the Dermacare placebo formulations. The results are presented in the following tables.
Table1: Matching emulsiers with lipophilic phases

Max amount of excipient to be emulsied by: Apil Gelot 64 Tefose 63 Sedefos 75 Plurol Diisostearique

Medium Chain Triglyceride Mineral oil Sweet Almond oil 30% 12% 18% 25% <4% 40% 30% 18% 40% 30% 30% 20% 18% 25% <4%

Labral 30% 12% 10% 25% <4%

Table2: Matching emulsiers with hydrophilic phases

Max amount of Glycerine Propylene glycol excipient to be associated with: Apil 15% 20% Gelot 64 20% 20% Tefose 63 5% <30% Sedefos 75 Complete substitution 20% Plurol Diisostearique 25% <3%

Ethanol

Transcutol P

PEG 300

10% 10% 10% 10% 5%

<5% 10% 10% <20% 10%

<10% <5% 5% <20% <5%

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Targeted sensorial prole

Another way of selecting the right emulsier 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.

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

APIFIL.......................................................................... PEG-8 beeswax EMULCIRE 61 WL 2659.................................................... 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 M1944 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
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 tness for a particular use is given, nor is freedom from patent infringement to be inferred. It is offered solely for your consideration, investigation and verication. 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 Gattefoss product, or any other product mentioned in this literature, read, understand and follow the information contained in most recent Material Safety Data sheet.

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Technical support
For more information on Gattefoss products, please contact your local Gattefoss representative to obtain: D  ermacare kit containing samples of selected placebos O  ur excipients for Dermal Drug Delivery brochure F  urther product handling, regulatory and toxicology information D  etails 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).

Contact

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

G attefoss

36 chemin de Genas - BP 603 F-69804 Saint-Priest CEDEX - FRANCE Tel. +33 4 72229800 Fax +33 4 78904567 E-mail: infopharma@gattefosse.com

Derma -135-7-D0