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
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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
5
“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
6
“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
8
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
9
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⋅
10
“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
11
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
12
“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?
13
“Formulating for Efficacy” identifies the optimal ‘polarity’ of your formulation
driving forcepenetrant
Optimal polarities of formulation
solubilitypenetrantsolubilitypenetrant
morehydrophilic
polarity penetrant
+ PPG- PPG morelipophilic
14
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 ±=
15
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
16
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
17
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
23
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…
25
…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)
26
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
27
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
28
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
29
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
30
“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
31
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
32
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
33
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
34
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
36
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
38
skin
Skin penetration experiments show the effects of the LX emulsifiers…
Pig skin
tapes
trans-dermal
A, B, C or D
39
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
40
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
41
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
42
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
43
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
44
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
45
“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)
47
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
48
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
49
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
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