Penetration Enhancers for

Trans--dermal Application
Trans

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2012-11
NIKKO CHEMICALS CO., LTD .
1-4-8 NIHONBASHI-BAKUROCHO, CHUOKU, TOKYO, 103-0002, JAPAN Email: inter@nikkol.co.jp www.nikkol.co.jp

Trans--dermal Drug Delivery

Trans

Why trans-dermal delivery is important?

Trans-dermal delivery of drugs or active ingredients through the skin to the
systemic circulation provides a convenient route of administration for a
variety of clinical indications.

Trans-dermal Application
Plaster / Tape Ointment, Cream Lotion, Stick Oral Care Products

Processes for Percutaneous Absoption

1. Release drug from the formulation.
2. Penetration into the stratum corneum and permeation/diffusion through it.
3. Partitioning from the stratum corneum into the viable epidermis before
reaching the capillaries located in the dermis.
dermis

Obstacles for delivery across human skin

The application of trans-dermal delivery to a wider range of drugs is limited
due to the significant barrier to penetration across the skin which is
associated primarilyy with the outermost stratum corneum layer y of the
epidermis.

Stratum
corneum

2012-11
NIKKO CHEMICALS CO., LTD .
1-4-8 NIHONBASHI-BAKUROCHO, CHUOKU, TOKYO, 103-0002, JAPAN Email: inter@nikkol.co.jp www.nikkol.co.jp

Nikko Solution
Solution:: Penetration Enhancers and Vehicles

What is a good penetration enhancer?

Enhance the
Good delivery
Safe / No permeation
of the active to
irritation though stratum
target
corneum

Nikko Chemicals provides various type of penetration enhancers such as

oils, surfactants and polybasic acid esters. They can be used in wide
range of pharmaceutical / skin care applications.

Product
P d t Component
C Name
tN
NIKKOL PDD Propylene glycol fatty acid ester (Propylene Glycol Dicaprate)
NIKKOL SEFSOL-218 Propylene glycol fatty acid ester (Propylene Glycol Caprylate)
NIKKOL SEFSOL-228 Propylene glycol fatty acid ester (Propylene Glycol Dicaprylate)
NIKKOL TRIFAT S-308 Glycerin triisooctanoate (Triethylhexanoin)
NIKKOL TRIESTER F-810 Medium-chain triglyceride (Caprylic/Capric Triglyceride)
NIKKOL
O CIO
CO Cetyl ethylhexanoate
Cety et y e a oate
NIKKOL DES-SP Diethyl sebacate
NIKKOL DID Diisopropyl adipate
NIKKOL DIS Diisopropyl sebacate
NIKKOL EOO Ethyl oleate
NIKKOL ICIS Hexadecyl isostearic acid
NIKKOL IPM-EX Isopropyl myristate
NIKKOL IPP
IPP-EX
EX I
Isopropyll palmitate
l it t
NIKKOL Syncelane 4SP -olefin oligomer
NIKKOL Squalane Squalane
NIKKOL TO-10MV Polysorbate 80
NIKKOL TL-10 Polysorbate 20
NIKKOL GO-460V Polyoxyethylene sorbitol tetraoleate (Sorbeth-60 Tetraoleate)
NIKKOL SO-15MV
SO 15MV Sorbitan sesquioleate
NIKKOL BL-9EX Polyoxyethylene Alkyl Ether (Laureth-9)
2012-11
NIKKO CHEMICALS CO., LTD .
1-4-8 NIHONBASHI-BAKUROCHO, CHUOKU, TOKYO, 103-0002, JAPAN Email: inter@nikkol.co.jp www.nikkol.co.jp

Penetration Enhancer s Properties

I. Releasing Ability
The releasing ability was evaluated with various type of vehicles from Nikkol.
I d
Indomethacin
th i 0.5%
0 5% solution
l ti off indomethacin
i d th i released
l d through
th h silicone
ili
membrane was determined.

Vehicles Indomethacin (0.5%)

Silicone membrane

IPM-EX

IPP-EX

TRIFAT S
S-308
308
SEFSOL-228
DIS
DID

CIO
PDD

DES SP
DES-SP
ICIS
SEFSOL-218

* N = 3: number of repetitions
Receiver solution: PBS ((-))
Silicone membrane: LTC-S1-75 (75 m, manufactured by Lintec Corporation)

The results shown that Nikkol IPM IPM--EX has the highest amount of
Indomethacin release
release.. It is suitable for quick efficacy application
application..
Meanwhile, other vehicles provide various celerity . Optimum vehicles
can be selected for specific materials / drugs
drugs..

2012-11
NIKKO CHEMICALS CO., LTD .
1-4-8 NIHONBASHI-BAKUROCHO, CHUOKU, TOKYO, 103-0002, JAPAN Email: inter@nikkol.co.jp www.nikkol.co.jp

Penetration Enhancer s Properties

II. Solubility
Solubility of Indomethacin in various vehicles
Indomethacin 0.5% was diluted with various type of vehicles from Nikkol.
Solubility of Indomethacin was investigated at room temperature.

Oil Surfactant

50
5.0

4.5
methacin (%)

4.0

3.5

3.0
Solubility of Indom

2.5

2.0

1.5

1.0

0.5

0.0

The results show that Nikkol TOTO--10

10MV
MV and Nikkol Sefsol
Sefsol--218 have the
highest solubility profile
profile.. The variety of solubility profiles allows to
choose proper co
co--solvent for specific formulations
formulations..

2012-11
 NIKKO CHEMICALS CO., LTD .
1-4-8 NIHONBASHI-BAKUROCHO, CHUOKU, TOKYO, 103-0002, JAPAN Email: inter@nikkol.co.jp www.nikkol.co.jp

Penetration Enhancer Properties

Solubility of actives in various solubilizer
Six different active molecules typically used via transdermal administration
(Indomethacin Diclofenac Sodium,
(Indomethacin, Sodium Felbinac,
Felbinac Fluriprofen,
Fluriprofen Terbinafine
Hydrochloride and Cholesterol) were examined in 15 vehicles from Nikkol.
Vehicles are shown in order of increase of solubility properties.

Indomethacin * Surfactant Flurbiprofen

DID Sefsol-228
Sepsol-228

DES-SP DIS

TO-10MV * BL-9EX *

Sefsol-218
Sepsol-218 DES-SP

BL-9EX * Sefsol-218
Sepsol-218

0 5 10 15 0 10 20 30 40 50
Drug concentration(%) Drug concentration(%)
Diclofenac Sodium Terbinafine Hydrochloride

GO-460V * Other

TO-10MV
TO 10MV *
SO-15MV *

Sefsol-218
Sepsol-218

Sefsol-218
Sepsol-218
BL-9EX *

0 2 4 6 0 2 4 6
Drug concentration(%) Drug concentration(%)

Felbinac Cholesterol
IPP-EX
TO-10MV *
IPM-EX
Sefsol-218
Sepsol-218 DIS
DID
GO-460V * DES-SP
CIO
DES-SP
PDD
BL-9EX * SO-15MV *
Sepsol-218
Sefsol-218
0 5 10 15
0 5 10 15 20 25
Drug concentration(%) Drug concentration(%)

Room Temp
Temp. 80C
80 C.

Nikkol Sefsol-
Sefsol-218 has very good solubility for various actives.
2012-11
Penetration Enhancers for
Trans--dermal Application
Trans
Study: Indomethacin
Indomethacin(IDM)
(IDM) with Nikkol Sefsol 218
NIKKO CHEMICALS CO., LTD .
1-4-8 NIHONBASHI-BAKUROCHO, CHUOKU, TOKYO, 103-0002, JAPAN Email: inter@nikkol.co.jp www.nikkol.co.jp

Percutaneous Absorption of Drug

Various physical and chemical enhancement strategies are impelemnted to

assist in the transdermal delivery of drugs. Diffusion through skin, controlled
by the stratum corneum (SC),
(SC) is often regarded as diffusion through a
passive membrane described by Flicks second law of diffusion.

av : Thermodynamic activity of drug in base

Base Cv : Concentration of drugg in base
D
Drug

Horny cell layer K : Partition Coefficient between

dermis and base
Epidermis
D : Diffusion Coefficient of drug in base

Dermis

s : Skin activity Coefficient A : Application area

L : Skin thickness P : Transmission Coefficient
dQ KC v DA a v DA
Skin Penetration Rate : = = PC v =
dt L sL
To increase of percutaneous absorption Increase av value

Strategies to Influence Thermodynamic Activity

As flux through
g the membrane is driven byy the chemical p
potential g
gradient, the
higher concentrations of drugs in base (vehicle) induce the flux in system to
increase proportionally. Supersaturated system gains driving force, which
enables molecules to better permeate across the SC. However, such system
is typically unstable, with material in excess of the solubility limit usually
crystallizing out.
Drug
g activityy in base = Dissolved concentration / Saturated Solubilityy

av = 1 av = 1 av < 1
Supersaturation
p Saturation Solution

Supersaturation in a topical formulation can occur by evaporation of a

solvent or co-solvent from system.
2012-11
 NIKKO CHEMICALS CO., LTD .
1-4-8 NIHONBASHI-BAKUROCHO, CHUOKU, TOKYO, 103-0002, JAPAN Email: inter@nikkol.co.jp www.nikkol.co.jp

Percutaneous Absorption of Drug

Evaluation of Releasing ability from Oil Mixture

To evaluate the releasing ability of Indomethacin (IDM),
(IDM) Sefsol-218,
Sefsol 218 Sefsol-228
Sefsol 228
and IPM-EX were taken to mix with sqaulane (as inert oil) at ratios:
100, 82, 64, 46, 28 and 010 in 0.5% IDM solution.
Squalane Sefsol-218 Sefsol-228 IPM-EX

Saturation solubility (%) Saturation solubility (%) Saturation solubility (%)

IDM Released mg//3h

60 0 1.0 2.0 3.0 4.0 5.0 0 0.2 0.4 0.6 0.8 1.0 0 0.1 0.2 0.3 0.4 0.5
150
300
120
40
90 200

20 60
100
30
0 0 0
0 20 40 60 80 100 0 20 40 60 80 100 0 20 40 60 80 100
The ratio of Sefsol-218 (%) The ratio of Sefsol-228 (%) The ratio of IPM-EX (%)

The results show that combination of oil enhanced releasing ability of IDM until
it reaches the optimum point. Sefsol-218 has the highest solubility. We selected
it as candidate to examine the effect with higher IDM concentrations.

IDM Concentration 0.5% IDM Concentration3.0%

Saturation solubility (%) Saturation solubility (%)
mg/3h

0 1.0 2.0 3.0 4.0 5.0 0 1.0 2.0 3.0 4.0 5.0
mg/3h

60 60
IDM Released m
IDM Released

40 40

20 20

0 0
0 20 40 60 80 100 0 20 40 60 80 100
The ratio of Sefsol-218 (%) The ratio of Sefsol-218 (%)

With the combination of squalane and Sefsol

Sefsol--218 used at the saturation
solubility levels, the 3% IDM solution showed a high release effect
effect..

The same delivery can be achieved with different drug concentrations

depending on thermodynamic activity of oil.

2012-11
 NIKKO CHEMICALS CO., LTD .
1-4-8 NIHONBASHI-BAKUROCHO, CHUOKU, TOKYO, 103-0002, JAPAN Email: inter@nikkol.co.jp www.nikkol.co.jp

Percutaneous Absorption of Drug

Evaluation of Drug Releasing from Emulsified Formulation

The formulations were p prepared
p using
g an oil emulsion,, Sefsol-218 and
squalane mixed in a ratio of each 10:0, 8:2, 6:4, 4:6, 2:8 and 0:10. IDM
release from the formulation was evaluated. The formulation is shown below.

Sefsol-218 Ratio 0% 20% 40% 60% 80% 100%

MGS-AMV 0.70 0.70 0.70 0.70 0.70 0.70
C t
Cetanol
l 0 50
0.50 0 50
0.50 0 50
0.50 0 50
0.50 0 50
0.50 0 50
0.50
N-SPV 1.00 1.00 1.00 1.00 1.00 1.00
Squalane 20.00 16.00 12.00 8.00 4.00 0.00
Sefsol-218 0.00 4.00 8.00 12.00 16.00 20.00
Indomethacin 0.50 0.50 0.50 0.50 0.50 0.50
TL 10
TL-10 1 30
1.30 1 30
1.30 1 30
1.30 1 30
1.30 1 30
1.30 1 30
1.30
Cabopol 981 (2%) 12.50 12.50 12.50 12.50 12.50 12.50
1,3-BG 5.00 5.00 5.00 5.00 5.00 5.00
Purified water 57.75 57.75 57.75 57.75 57.75 57.75
KOH (10%) 0.75 0.75 0.75 0.75 0.75 0.75

Formulation Drug
25
Emulsion
IDM Released mg/3h

20

15
Sefsol-218 Ratio (%) 0 20 40 60 80 100
10
The saturation solubility
0 1.0 2.0 3.0 4.0 5.0
in oil (%)
5
The saturation solubility
0 0.2 0.4 0.6 0.8 1.0
in the formulation (%)
0
0 20 40 60 80 100
The ratio of Sefsol-218 (%)
The combination of squalane and 40% 40% Sefsol
Sefsol--218 ratio in the
formulation provided the highest IDM released .

Similarly to the evaluation of releasing ability from oil mixture, drug

delivery is subject to thermodynamic activity of oil in the emulsion type
formulation..
formulation
2012-11
 NIKKO CHEMICALS CO., LTD .
1-4-8 NIHONBASHI-BAKUROCHO, CHUOKU, TOKYO, 103-0002, JAPAN Email: inter@nikkol.co.jp www.nikkol.co.jp

Percutaneous Absorption of Drug

Percutaneous absorption Evaluation using EpiSkin-LM

EpiSkin models are obtained by culturing adult human keratinocytes on a
collagen substrate in conditions which permit their terminal differentiation and the
reconstruction of an epidermis with a functional horny layer.

Human Skin EpiSkinTM

Horny cell layer

Granular
G l layer
l
Stratum spinosum
Basal layer

0.5 % Indomethacin
Percutaneous absorption test HPLC
Emulsion 20 % oil in formulation
Formulation (Sefsol -218
218 and Squalane)

EpiSkin

PBS

Receiver
Epidermis model three-dimensional culture : EpiSkin -Large Model (EpiSkin -LM, manufactured by Skin Ethic)
Liquid receiver : PBS
Sample : Emulsion formulation with squalane and Sefsol-218
Temperature : 37 degrees Celsius
Time sample application : 24 h (Skin and receiver recovery after the test)

200
he skin

80
24h)
Skin permeation

250
IDM amount in th
amount (mg/2

Receiver 60 EpiSkin
(mg/24h)

200

150 40

100
20
50

0 0
0 20 40 60 80 100 0 20 40 60 80 100
The ratio of Sefsol-218 (%) The ratio of Sefsol-218 (%)

The highest IDM release from the formulation and the most efficient skin
permeation were observed with 40% use level of Sefsol-
Sefsol-218.

Based on its solubility and penetration profile, Sefsol-

Sefsol-218 is a good
candidate for Trans
Trans--dermal Drug Delivery.
2012-11
NIKKO CHEMICALS CO., LTD .
1-4-8 NIHONBASHI-BAKUROCHO, CHUOKU, TOKYO, 103-0002, JAPAN Email: inter@nikkol.co.jp www.nikkol.co.jp

Summary

T increase
To i the
th percutaneous
t absorption
b ti
of lipophilic drugs

S
Select suitable bases / enhancers

Solubility Releasing ability

Increase Thermodynamic activity

Co-solvent Saturated solubility

Formulation

Good stabilizer Sustain supersaturation

2012-11
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Email: nk
Email: nkpharma@nikkol.co.jp
pharma@nikkol.co.jp
http://www.nikkol.co.jp/en/
Edited by JTS/ 2012-02