Formulating for Better Efficacy - The Indian … Efficacy.pdfEstasan 3575 Estol 1512 Estol 1526 Estol 1540 Estol 3609 Pripure 3759 Prisorine 2021 Prisorine 2034 Prisorine 2039 Prisorine

Prof. Dr. Johann W. WiechersIndependent Consultant for Cosmetic ScienceJW Solutions, Gouda, The NetherlandsVisiting Professor at The School of Pharmacy University of London, London, UKTechnical Advisor Cosmetics & Toiletries

Formulating for Better Efficacy

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The answer to better efficacy is simple, don’t you think?

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The answer to better efficacy is simple, don’t you think?

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Can technology provide better answers in financially challenging times?

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“Formulating for Better Efficacy” is a structured approach to formulation design

1. Selection of the drug / active ingredient

2. Selection of the emollient

3. Selection of the emulsifier

4. Selection of adjuvants

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“Formulating for Better Efficacy” is a structured approach to formulation design

1. Selection of the drug / active ingredient

2. Selection of the emollient

3. Selection of the emulsifier

4. Selection of adjuvants

7

Step 1: Can my drug / active penetrate the skin in sufficient amounts?

Select only drugs/ actives that:- MW < 1000, ideally <500- octanol/water partition coefficient of 10-100- non-ionized- melting point below 40 °C- high dipole moment

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Step 1: Can my drug / active penetrate the skin in sufficient amounts?

Calculate the permeability coefficient using the Potts – Guy equation:

log kp (cm/sec) =

- 6.3 + 0.71·log Koct/water - 0.0061·MW

Potts, R.O., and Guy, R.H., Predicting skin permeability, Pharm. Res. 9 (1992) 663-669

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Step 1: Can my drug / active penetrate the skin in sufficient amounts?

Input = Jss = kp · ΔC

Output = Cl · CT

Delivery gap = MEC / CT, ideally ≤ 100

ClC k = C p

TΔ⋅

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“Formulating for Better Efficacy” is a structured approach to formulation design

1. Selection of the drug / active ingredient

2. Selection of the emollient

3. Selection of the emulsifier

4. Selection of adjuvants

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An emollient serves two important functions related to skin delivery

High absolute solubility of the drug in the formulation to ensure that enough is present to reach minimal effective concentrations at target site

Low relative solubility of the drug in the formulation, relative to that in the stratum corneum to ensure a good driving force for the drug to penetrate the stratum corneum

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“Formulating for Efficacy” optimises these two contradictory requirements…

High absolute solubility in formulation:polarities drug and formulation the same

Low relative solubilities in formulation:more soluble in stratum corneum than in formulation, therefore:polarities drug and stratum corneum the samepolarities drug and formulation different

How to cope with such contradiction?

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“Formulating for Efficacy” identifies the optimal ‘polarity’ of your formulation

driving forcepenetrant

Optimal polarities of formulation

solubilitypenetrantsolubilitypenetrant

morehydrophilic

polarity penetrant

+ PPG- PPG morelipophilic

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PPG stands for the penetrant polarity gap…

…and is the difference in “polarity” between drug and stratum corneum

The bigger the PPG, the smaller the skin delivery

Both optimized formulation polarities are equally good from a delivery point of view

Optimized polarity of formulation can be calculated:

gappolaritypenetrantpenetrantofpolaritynformulatioofpolarity ±=

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You need a few more novel definitions to be able to work with this…

PI: Polarity IndexA company-proprietary polarity index but encompassing much more than only polarity

RPI: Relative Polarity IndexDifference in PI between drug and formulation components such as emollients

PPG: Penetrant Polarity GapDifference in PI between drug and stratum corneum

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Now, let’s start to get to “Formulate for Efficacy”…

An emollient with a small RPI……will have a high solubility of your drug in the formulation

An emollient with a large RPI……will have a low solubility of your drug in the formulation and

will increase the partitioning of your drug into skin

Three-step plan:Step 1: Maximize solubility by selecting a

primary emollient Small(est) RPIStep 2: Maximize partitioning by selecting a

secondary emollient Large RPIStep 3: Mix in right proportions to obtain ideal

formulation phase

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What I am doing in the schematic repres-entation of “Formulating for Efficacy”?

driving forcepenetrant

Optimal polarities of formulation

solubilitypenetrantsolubilitypenetrant

morehydrophilic

polarity penetrant

+ PPG- PPG morelipophilic

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First, you need some RPI values when Formulating for Efficacy…

…using octadecenedioic acid as an example

0

5

10

15

20

25

0 2 4 6 8 10

Relative Polarity Index (RPI)

Solu

bilit

y (%

w/v

)

Arlamol EArlamol HDEstasan 3575Estol 1512Estol 1526Estol 1540Estol 3609Pripure 3759Prisorine 2021Prisorine 2034Prisorine 2039Prisorine 2040Prisorine 3505Prisorine 3515

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In Table form, selection of your emollients might actually be easier…

INCI name Calculated RPI valueGlycerin 24.9

Propylene glycol 17.5

Dipropylene Glycol 11.8

Ethanol 11.8

Glyceryl stearate 2.8

Glyceryl Isostearate 2.8

Triethylhexanoin 3.7

Caprylic/capric triglyceride 3.7

Propylene Glycol Isostearate 0.75

Pentaerythrityl Tetraisostearate 4.6

Isopropyl Myristate 4.5

Isopropyl Isostearate 4.8

Ethylhexyl palmitate 5.1

Ethylhexyl isostearate 5.2

Isostearyl Isostearate 5.8

Vegetable Squalane 8.8

2

1

20

Propylene Glycol Isostearate 15.0Triethylhexanoin 3.0Octadecenedioic acid 2.0Steareth-21 5.0Steareth-2 1.0Glycerin 4.0Xanthan gum 0.2Phenoxyethanol (and) Methylparaben (and)

Propylparaben (and) 2-bromo-2-nitropropane-1,3-diol 0.7Aqua ad 100.0

In this way, we get a skin delivery optimised formulation

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Caprylic/Capric triglyceride 10.0Glyceryl stearate SE 3.0Steareth-21 5.0Steareth-2 1.0Cetyl alcohol 2.0Octadecenedioic acid 2.0Glycerin 3.0Benzoic acid 0.22-Amino-2-methyl-1-propanol, to pH 5.5 qsAqua ad 100.0

We had already used and tested another formulation

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Pig skin was dermatomed to 400µm and the two formulations were applied

Pig skin

A or B

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skin

After 24 hours, the application area was split in three separate layers

Pig skin

tapes

trans-dermal

A or B

24

0

5

10

15

Formulation notoptimised for delivery

Delivery optimisedformulation

Dio

ic A

cid

Del

iver

y ( μ

g/cm

2 )

TapesSkinTransdermal3.5-fo

ld

Using this strategy enhances the skin delivery…

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…and therefore also the efficacy of this skin whitening molecule

p < 0.05

3.2-fold

0

0.5

1

1.5

2

2.5

0 2 4 6 8

Time (weeks)

ΔL-v

alue

(rel

ativ

e to

wk

0)

Study 1 (2% non-FFE) Study 2 (2% FFE)

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Using FFE, you can even lower the dose without loss of efficacy…

Propylene Glycol Isostearate 15.0Triethylhexanoin 3.0Octadecenedioic acid 2.0Steareth-21 5.0Steareth-2 1.0Glycerin 4.0Xanthan gum 0.2Phenoxyethanol (and) Methylparaben (and) Propylparaben

(and) 2-bromo-2-nitropropane-1,3-diol 0.7Aqua ad 100.0

7.51.51.0

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Using FFE, you can even lower the dose without loss of efficacy…

0

0.5

1

1.5

2

2.5

0 2 4 6 8

Time (weeks)

ΔL-v

alue

(rel

ativ

e to

wk

0)

Study 1 (2% non-FFE) Study 2 (2% FFE) Study 3 (1% FFE)

p < 0.002

3.9-fold

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Concentration in formulation

Con

cent

ratio

n de

liver

ed a

t tar

get s

ite

Minimum effective concentration

= non skin delivery-optimized formulation= skin delivery-optimized formulation

A

B

C

Formulating for Efficacy has therefore three types of benefits…

A. Create efficacyB. Enhance efficacyC. Reduce concentration

MICMAC

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Emollients determine the extent of skin delivery

…because they influence the thermodynamic activity of the active ingredient

…because they determine the absolute solubility of the active ingredient

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“Formulating for Better Efficacy” is a structured approach to formulation design

1. Selection of the drug / active ingredient

2. Selection of the emollient

3. Selection of the emulsifier

4. Selection of adjuvants

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Four formulations were prepared for the skin delivery studies

A B C DOctadecenedioic Acid 2.0 2.0Propagermanium 0.5 0.5Propylene Glycol Isostearate 15.0 15.0 15.0 15.0Triethylhexanoin 3.0 3.0 3.0 3.0Steareth-21 5.0 5.0Steareth-2 1.0 1.0Sorbitan Stearate (and) Sucrose Cocoate 5.5 5.5Glycerin 4.0 4.0 4.0 4.0Xanthan gum 0.2 0.2 0.4 0.2Preservative 0.7 0.7 0.7 0.7Aqua 69.1 69.6 70.4 71.1

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Two contained the lipophilic active ingredient octadecenedioic acid

A B C DOctadecenedioic Acid 2.0 2.0Propagermanium 0.5 0.5Propylene Glycol Isostearate 15.0 15.0 15.0 15.0Triethylhexanoin 3.0 3.0 3.0 3.0Steareth-21 5.0 5.0Steareth-2 1.0 1.0Sorbitan Stearate (and) Sucrose Cocoate 5.5 5.5Glycerin 4.0 4.0 4.0 4.0Xanthan gum 0.2 0.2 0.4 0.2Preservative 0.7 0.7 0.7 0.7Aqua 69.1 69.6 70.4 71.1

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Two contained the hydrophilic active ingredient propagermanium

A B C DOctadecenedioic Acid 2.0 2.0Propagermanium 0.5 0.5Propylene Glycol Isostearate 15.0 15.0 15.0 15.0Triethylhexanoin 3.0 3.0 3.0 3.0Steareth-21 5.0 5.0Steareth-2 1.0 1.0Sorbitan Stearate (and) Sucrose Cocoate 5.5 5.5Glycerin 4.0 4.0 4.0 4.0Xanthan gum 0.2 0.2 0.4 0.2Preservative 0.7 0.7 0.7 0.7Aqua 69.1 69.6 70.4 71.1

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Formulations A and C contained a non LX-inducing emulsifier system

A B C DOctadecenedioic Acid 2.0 2.0Propagermanium 0.5 0.5Propylene Glycol Isostearate 15.0 15.0 15.0 15.0Triethylhexanoin 3.0 3.0 3.0 3.0Steareth-21 5.0 5.0Steareth-2 1.0 1.0Sorbitan Stearate (and) Sucrose Cocoate 5.5 5.5Glycerin 4.0 4.0 4.0 4.0Xanthan gum 0.2 0.2 0.4 0.2Preservative 0.7 0.7 0.7 0.7Aqua 69.1 69.6 70.4 71.1

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Microscopy of these formulations does not show liquid crystals

Formulation A

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Formulations B and D contained a LX-inducing emulsion system

A B C DOctadecenedioic Acid 2.0 2.0Propagermanium 0.5 0.5Propylene Glycol Isostearate 15.0 15.0 15.0 15.0Triethylhexanoin 3.0 3.0 3.0 3.0Steareth-21 5.0 5.0Steareth-2 1.0 1.0Sorbitan Stearate (and) Sucrose Cocoate 5.5 5.5Glycerin 4.0 4.0 4.0 4.0Xanthan gum 0.2 0.2 0.4 0.2Preservative 0.7 0.7 0.7 0.7Aqua 69.1 69.6 70.4 71.1

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Polarised light microscopy does reveal liquid crystals

Formulation B

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skin

Skin penetration experiments show the effects of the LX emulsifiers…

Pig skin

tapes

trans-dermal

A, B, C or D

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02468

10121416

FormulationA

FormulationB

Dio

ic A

cid

Del

iver

y (μ

g/cm

2 )

TapesSkinTransdermal

Lipophilic: Transdermal delivery increased with LX formulations

LX

Total delivery the same but

more transdermal

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05

101520253035

FormulationC

FormulationDPr

opag

erm

aniu

m D

eliv

ery

(μg/

cm2 )

TapesSkinTransdermal

Total delivery increased with the hydrophilic penetrant

Total delivery has increased

but transdermal still low

LX

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But in different ways!

more transdermal delivery of lipophilic penetrant = faster delivery

more dermal delivery of the hydrophilic penetrant = more delivery

How to explain this scientifically?

LX emulsions enhance both dermal and transdermal delivery

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Hydrophilic active ingredients remained trapped in LX structures

Longer residence time = more penetration

a: hydrophobic partb: trapped waterc: hydrophilic partd: bulk watere: oil

a: hydrophobic partb: trapped waterc: hydrophilic partd: bulk watere: oil

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LX systems may influence packing of skin barrier lipids

more permeable for all penetrants

enhanced transdermal delivery for both polarities

Pilgram et al, JID 117 (2001) 710-717

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Emulsifiers determine the rate of skin delivery…

…because of possible influence on skin lipid packing

Much more experimental data needed before general rules can be established

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“Formulating for Better Efficacy” is a structured approach to formulation design

1. Selection of the drug / active ingredient

2. Selection of the emollient

3. Selection of the emulsifier

4. Selection of adjuvants

46

Another possibility to increase skin penetration is to change the polarity of the stratum corneum

2 formulations with and without 10 % dimethyl isosorbide based on:

Propylene Glycol Isostearate 15.0Triethylhexanoin

3.0Steareth-21

5.0Steareth-2

1.0Propagermanium

0.5Glycerin

4.0Xanthan gum 0.4Phenoxyethanol (and) Methylparaben (and)

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DMI makes the stratum corneum more compatible with the active ingredient

05

101520253035404550

Formulation withoutDMI

Formulation with DMI

Prop

ager

man

ium

del

iver

y(%

app

lied

dose

)

Tape StripsSkinTransdermal

~2-fold

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Let me explain this using RPI terminology...

PI values:Skin (~ n-butanol) estimated at 0.8DMI = -1.6Water-soluble actives < 0

Theory: DMI penetrates skinraises PI of skin making it more compatible with PI of

water-soluble activesin essence, a reduction of the PPGfast penetrating molecules like DMI, PG and TC

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Summarizing, one can easily formulate for better efficacy and save money

Use your brains before you use your hands

Throw away your standard / preferred prototype formulations

Finding MICMAC only worthwhile for expensive drugs / actives or high volume products

Scope and validity of this approach can be calculated