Molecules 21 01709 v2 PDF

molecules
Review
Natural Terpenes as Penetration Enhancers for
Transdermal Drug Delivery
Jun Chen 1,2, *, Qiu-Dong Jiang 2 , Ya-Ping Chai 2 , Hui Zhang 2 , Pei Peng 1 and Xi-Xiong Yang 1, *
1 Hubei Collaborative Innovation Center of Targeted Antitumor Drug, Jingchu University of Technology,
Jingmen 448000, China; pengpei2011@126.com
2 Pharmaceutical Research Laboratory of Chinese Medicine, School of Pharmacy,
Nanjing University of Chinese Medicine, Nanjing 210023, China; qiudong_J@126.com (Q.-D.J.);
15951837195@163.com (Y.-P.C.); zh20150908@sina.com (H.Z.)
* Correspondence: chenjun75@163.com (J.C.); yxixiong163@163.com (X.-X.Y.); Tel.: +86-25-8581-1769 (J.C.);
+86-724-235-5813 (X.-X.Y.); Fax: +86-25-8581-1524 (J.C.); +86-724-235-5813 (X.-X.Y.)
Academic Editor: Derek J. McPhee

Received: 18 October 2016; Accepted: 6 December 2016; Published: 11 December 2016
Abstract: The greatest hindrance for transdermal drug delivery (TDD) is the barrier property of skin,
especially the stratum corneum (SC). Various methodologies have been investigated and developed
to enhance the penetration of drugs through the skin. Among them, the most popular approach is
the application of penetration enhancers (PEs), including natural terpenes, a very safe and effective
class of PEs. In the present paper, we focused on terpenes as skin PEs for TDD. The mechanism of
their action, the factors affecting their penetration enhancement effect, as well as their possible skin
toxicity were discussed. Terpenes abundant in nature have great potential in the development of PEs.
Compared to synthetic PEs, natural terpenes have been proved to possess higher enhancement activity.
Interaction with SC intercellular lipids is the main mechanism of action for terpenes. The key factor
affecting the enhancement effect is the lipophilicity of both terpenes and drug molecules. In addition,
a lot of terpenes have also been proved to be much less toxic compared to azone, the classic synthetic
PE. In summary, terpenes may be preferred over the chemically synthesized compounds as safe and
effective PEs to promote the percutaneous absorption of drugs.
Keywords: terpenes; penetration enhancer; transdermal drug delivery; stratum corneum
1. Introduction
Transdermal drug delivery (TDD) has become a viable alternative to conventional routes of drug
administration since it can avoid the hepatic first pass effect, improve the compliance of patients,
decrease the administration frequency, and reduce the gastrointestinal side effects. Despite its great
potential, delivery of most drug molecules via a transdermal route remains one of the major challenges
in the development of transdermal drug delivery systems (TDDS). The principal barrier to TDD is
located in the stratum corneum (SC), the outermost layer of the skin, thereby limiting percutaneous
absorption [1]. The SC is composed of 15~20 layers of flattened cells with no nuclei and cell organelles
separated by an intercellular lipid domain. The structure of the SC can be described in terms of
a so-called “brick-and-mortar” model, with the keratin-filled corneocytes as the bricks and the
intercellular lipids as the mortar. The lipids, comprised of 50% ceramides, 25% cholesterol, 15%
free fatty acids, as well as low levels of phospholipids [2], are organized in orderly-arranged lamellar
layers and thus form an impermeable barrier to drug diffusion [2–5].
There are mainly three possible routes for percutaneous penetration of drug molecules, which
include intracellular diffusion across the SC corneocytes, permeation through the SC intercellular lipid
spaces, and penetration through skin appendages [6]. Among these options, the scientific community
Molecules 2016, 21, 1709; doi:10.3390/molecules21121709 www.mdpi.com/journal/molecules

Molecules 2016, 21, 1709 2 of 22
agrees that the intercellular lipid domain of the SC is the main pathway for the skin penetration of
most drug molecules [1,7].
To achieve therapeutically effective drug levels at the proper site following TDD, the barrier
properties of the SC must be modified to enable sufficient drug permeation. A lot of approaches
have been used to alter the SC barrier properties, and the most commonly applied approach is the
application of penetration enhancers (PEs), which have been used in TDDS since the 1960s [8]. Until
now, efforts have been directed at identifying desirable PEs which possess safe yet effective properties.
Due to their high enhancement effect and low skin irritation, terpenes of natural origin are
now receiving much attention in pharmaceutical and cosmetic formulations as PEs [8,9]. Terpenes,
primarily extracted from medicinal plants, are volatile compounds with molecular components
that are composed of only carbon, hydrogen and oxygen atoms. The basic chemical structure of
terpenes consists of a number of repeated isoprene (C5 H8 ) units which are used to classify terpenes.
They are generally regarded to be safer compared to synthetic Pes which include surfactants, fatty
acids/esters, and solvents [9]. Furthermore, a few terpenes (e.g., 1,8-cineole, menthol, and menthone)
are included in the list of Generally Recognized As Safe (GRAS) agents issued by the US Food and
Drug Administration [10].
This review aims to give an overview of terpenes as PEs for use in TDD, which will be helpful to
researchers working on TDDS in the selection of a suitable terpene.
2. Skin Penetration Enhancement Effect

Many publications have already provided substantial evidence that terpenes are capable of
enhancing percutaneous absorption [11–16].
Compared to conventional synthetic PEs (e.g., oleica acid, azone, dimethyl sulfoxide (DMSO),
ethanol), natural terpenes have been shown to improve the permeation of both lipophilic and
hydrophilic compounds. One study was focused on bulfalin which is a drug molecule suitable
for TDD (molecular weight = 386.5, log P = 2.78). The feasibility of using different PEs to reduce the
permeation barrier was evaluated. The results of skin permeation studies of bulfalin demonstrated
that terpenes (1,8-cnieole, D-limonene, and L-menthol) were the most effective among different PEs.
The enhancement ratios (ERs) of 5% 1,8-cineole, D-limonene, and L-menthol were determined to
be 17.1, 22.2, and 15.3, respectively. In comparison, other synthetic PEs at the same concentration
increased the flux of bulfalin by less than 6-fold. The ER values were determined to be 5.1, 5.2, 2.5, 2.4,
1.4, and 5.3 for oleic acid, lauric acid, SDS, azone, ethyl oleate, and ethyl lauric acid, respectively [11].
In another study, different PEs were incorporated into the gel to improve the skin permeation of
hydrophilic lidocaine hydrochloride. The ER values of DMSO, urea, sodium lauryl sulfate (SLS), and
menthol were determined to be 1.13, 1.72, 2.59, and 3.72, respectively [12]. In addition, the synergistic
effect of terpenes and iontophoresis has been demonstrated and utilized to increase the percutaneous
absorption of oligonucleotides [13].
The effects of PEs on the bioavailability of meloxicam (MLX) gels were investigated and compared
after TDD to rabbits. After application of the control gel without PE, the drug was detectable but
not quantifiable in plasma. In contrast, after administration of the gel containing 5% menthol, MLX
appeared in plasma immediately and reached the maximum peak concentration in about 4 h. It was
found that the 5% menthol gel delivered 3.93 ± 0.85 mg of MLX into the systemic circulation compared
to 1.41 ± 0.24 mg of MLX delivered by 1% oleic acid gel [14].
Using 1% 1,8-cineole as a PE, valsartan transdermal gel was prepared and evaluated.
The pre-clinical evaluation of the antihypertensive efficacy of the valsartan gel was carried out using
experimental hypertensive rats. The gel was applied to the rat abdominal skin area and the blood
pressure values from the tail were recorded at different intervals up to 24 h. The valsartan gel containing
1% 1,8-cineole was found to reduce the blood pressure remarkably (p < 0.001) to about the normal
value and maintain its level for 24 h. Conversely, no reduction in blood pressure was observed with
the control gel without a PE [15].
Molecules 2016, 21, 1709 3 of 22
Propranolol hydrochloride (PH) can be used to treat infantile hemangiomas. To formulate the PH
gel, nine terpenes were compared and 3% farnesol was found to be the most effective. The final PH
gel used hydroxypropyl methylcellulose (HPMC) as the matrix material and used 3% farnesol as the
Molecules 2016, 21, 1709 3 of 21
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Tableof1.28Terpenes
(89.29%) terpenes
applied are limonene, menthone,
oxygen-containing
as penetration enhancers nerolidol, and others. It
terpenes.
Boiling(PEs).
should be noted that
Type25 out ofChemical
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(89.29%)
Chemical terpenes areLog
oxygen-containing
a penetration Chemical
terpenes.
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Terpene
should be noted that
Terpene 25 Table
Type out of1.
Table 28Terpenes
1. (89.29%)
Formula
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as
terpenes areLog PP enhancers
oxygen-containing
asapenetration Point (◦ C)
enhancers
Boiling terpenes.
Chemical
(PEs). Structure
Structure
Ref.Ref.
Terpene Formula applied
Type Table 1. Terpenes
Chemical MW aaas penetration
Log P Point (°C) (PEs).
enhancers
Boiling Chemical Structure Ref.
Terpene TypeTable 1. Terpenes
Formula applied
Chemical MWas penetration
Log P enhancers
Point (°C) (PEs).
Formula applied
Chemical MWas a penetration
Log P enhancers
Point (°C) (PEs).
Chemicalapplied
Formula MWas a penetration
Log P enhancers
Point (°C) (PEs).
Terpene Type Formula
Chemical MWa a Log P Point (°C)
Terpene Type Formula MW Log P Point (°C) Chemical Structure Ref.
Anethole
Anethole
Terpene Monoterpene
Monoterpene
Type C10Chemical
H C H12O 148.202
1210O
Formula
Chemical 148.202
MW a Log3.17
3.17
P
Boiling
Point237.5
237.5
(°C)
Boiling Chemical Structure [16–18]
[16–18]
Ref.
Anethole
Terpene Monoterpene
Type C10 H12O
Formula 148.202
MW a 3.17P
Log 237.5
Point (°C) Chemical Structure [16–18]
Ref.
Anethole Monoterpene C10H12O
Formula 148.202 3.17 237.5
Point (°C) [16–18]
Anethole Monoterpene C10H12O 148.202 3.17 237.5 [16–18]
α-Bisabolol Sesquiterpene C15H26O 222.366 5.07 314.5 [19]

α-Bisabolol
α-Bisabolol Sesquiterpene
Sesquiterpene C15 H
C15
26HO26O 222.366
222.366 5.07
5.07 314.5
314.5 [19]
[19]
Borneol Monoterpene C10H18O 154.249 2.71 212 [16,19,20]

Borneol
Borneol Monoterpene
Monoterpene C18
C10 H 10H
O18O 154.249
154.249 2.71
2.71 212212 [16,19,20]
[16,19,20]
Borneol
Camphor Monoterpene
Monoterpene CC10H18O
10H16O
154.249
152.233 2.71
2.13 212
207.4 [16,19,20]
[19,21]
Borneol
Camphor Monoterpene
Monoterpene C
C 10H18O
10H
154.249 2.71 212 [16,19,20]
Borneol Monoterpene C 18O
H16 O 152.233
154.249 2.13
2.71 207.4
212 [19,21]
[16,19,20]
Camphor Monoterpene C10
10H16O 152.233 2.13 207.4 [19,21]
Camphor
Camphor Monoterpene
Monoterpene C10 H
C10
16 HO16O 152.233
152.233 2.13
2.13 207.4
207.4 [19,21]
[19,21]
Camphor Monoterpene C10H16O 152.233 2.13 207.4 [19,21]
Carvacrol
Camphor Monoterpene
Monoterpene CH
C10 10H 14O
16O 150.22
152.233 3.28
2.13 237.7
207.4 [22]
[19,21]
Carvacrol Monoterpene C10H14O 150.22 3.28 237.7 [22]
Carvacrol
Carvacrol Monoterpene
Monoterpene C10
C10 H HO14O 150.22
150.22 3.28
3.28 237.7
237.7 [22]
[22]
Carvone Monoterpene C10H14O 150.218 2.265 230.5 [23,24]
Carvone
Carvone Monoterpene
Monoterpene C10 HC1410O
H14O 150.218
150.218 2.265
2.265 230.5
230.5 [23,24]
[23,24]
Carvone Monoterpene C10H14O 150.218 2.265 230.5 [11,15,
[23,24]
1,8-Cineole
Carvone Monoterpene
Monoterpene CH
C10 10H 18O
14O 154.249
150.218 2.82
2.265 174
230.5 [23,24]
[11,15,
1,8-Cineole Monoterpene C10H18O 154.249 2.82 174 22–29]
[11,15,
[11,15,
[11,15,
[11,15,
[11,15,
1,8-Cineole
1,8-Cineole Monoterpene
Monoterpene C10 H
C10
18HHO18O 154.249
154.249 2.82
2.82 174174 22–29]
[11,15,22–29]
[11,15,
1,8-Cineole Monoterpene C10 18O 154.249 2.82 174 22–29]
[11,15,
1,4-Cineole
Monoterpene CH
C10 10H 18O
18O 154.249
154.249 2.58
2.82 173.5
174 [16,28,29]
22–29]
1,4-Cineole Monoterpene C10H18O 154.249 2.58 173.5 22–29]
[16,28,29]
1,4-Cineole Monoterpene C10H18O 154.249 2.58 173.5 [16,28,29]
1,4-Cineole
Monoterpene C10 H1018HO18O
C 154.249
154.249 2.58
2.58 173.5
173.5 [16,28,29]
[16,28,29]
Cymene Monoterpene C10H14 134.22 4.02 173.9 [24]
Cymene
Cymene Monoterpene
Monoterpene C10
C10 H 14H14 134.22
134.22 4.02
4.02 173.9
173.9 [24]
[24]
Eugenol Monoterpene C10H12O2 164.201 2.2 255 [17]
[11,15,
1,8-Cineole Monoterpene C10H18O 154.249 2.82 174
22–29]
Molecules 2016, 21, 1709 4 of 22

Table 1. Cont.

Chemical Boiling Chemical
Terpene Type MW a Log P Ref.
Formula Point (◦ C) Structure
Molecules 2016, 21, 1709 4 of 21

Molecules 2016, 21, 1709 4 of 21
Eugenol
Eugenol Monoterpene
Monoterpene C12
C10 H 10H
O122O2 164.201
164.201 2.2
2.2 255255 [17][17]
Molecules 2016, 21, 1709 Table 1. Cont. 4 of 21
Molecules 2016, 21, 1709 Chemical Table 1. Cont. Boiling 4 of 21
Terpene
Molecules 2016, 21, 1709 Type Chemical Table
MW a 1. Cont.
Log P Boiling Chemical Structure Ref.
4 of 21
Terpene Formula Point (°C)
Molecules 2016, 21, 1709 Type Chemical
Formula
MW a 1. Cont.
Table Log P
Boiling
Point (°C)
Chemical Structure Ref.
4 of 21
Molecules 2016, 21, 1709 Type
Terpene Chemical
Formula Tablea 1. Cont. P
MW a Log Boiling
Point (°C)
Chemical Structure Ref.
4 of 21
Terpene
Molecules 2016, 21, 1709 Type Chemical MW 1. Cont.
Table Log P Boiling Chemical Structure Ref.
4 of 21
Terpene Type Formula MW a 1. Cont.
Log P Point (°C) Chemical Structure Ref.
Chemical
Formula Table Boiling
Point (°C)
Terpene Type Chemical MW 1. Cont.
Table a Log P Boiling Chemical Structure Ref.
Terpene Type Formula MW a Log P Point (°C) Chemical Structure Ref.
Chemical
Formula Boiling
Point (°C)
Terpene
Farnesol
Farnesol Type
Sesquiterpene
Sesquiterpene C15Chemical
HC26
15HO26O MW a
222.366
222.366 Log P
5.31
5.31 Boiling
283.4
283.4 Chemical Structure Ref.
[16][16]
Terpene
Farnesol Type
Sesquiterpene Formula
C15H26O MW a
222.366 Log
5.31P Point (°C)
283.4 Chemical Structure Ref.
[16]
Formula Point (°C)
Farnesol Sesquiterpene C15H26O 222.366 5.31 283.4 [16]
Fenchone Monoterpene C10H16O 152.23 2.13 193.5 [24]
Fenchone
Fenchone Monoterpene
Monoterpene C10 HC16
10H
O16O 152.23
152.23 2.13
2.13 193.5
193.5 [24]
[24]
Geraniol Monoterpene C10H18O 154.249 3.28 229.5 [16,24]
Geraniol
Geraniol Monoterpene
Monoterpene C10 HC18
10HO18O 154.249
154.249 3.28
3.28 229.5
229.5 [16,24]
[16,24]
[11,16,
[11,16,
Limonene Monoterpenes C10H16 136.234 4.45 175.4 23–25,
[11,16,
Limonene Monoterpenes C10H16 136.234 4.45 175.4 [11,16,
27,30]
23–25,
27,30]
[11,16,
Limonene
Limonene Monoterpenes
Monoterpenes C10H16
C10 H16 136.234
136.234 4.45
4.45 175.4
175.4 23–25,
[11,16,23–25,27,30]
27,30]
23–25,
27,30]
[11,16,
27,30]
23–25,
27,30]
[11,16,
27,30]
Linalool
Limonene Monoterpene
Monoterpenes CC1010HH1816O 154.25
136.234 3.28
4.45 198.5
175.4 [26]
23–25,
Linalool Monoterpene C10H18O 154.25 3.28 198.5 27,30]
[26]
Linalool Monoterpene C10H18O 154.25 3.28 198.5 27,30]
[26]
Linalool Monoterpene C10H18O 154.25 3.28 198.5 [26]
Linalool
Linalool Monoterpene
Monoterpene C18
C10 H 10H O18O 154.25
154.25 3.28
3.28 198.5
198.5 [26][26]
[11,16,22,
[11,16,22,
Menthol
Linalool Monoterpene
Monoterpene C10
C 10H20O 156.265 3.2 215.4 23,26,31,
[11,16,22,
Menthol Monoterpene C10H H1820O
O 154.25
156.265 3.28
3.2 198.5
215.4 [26]
23,26,31,
[11,16,22,
Menthol Monoterpene C10H20O 156.265 3.2 215.4 32]
23,26,31,
Menthol Monoterpene C10H20O 156.265 3.2 215.4 32]
[11,16,22,
23,26,31,
32]
[11,16,22,
Menthol Monoterpene C10H20O 156.265 3.2 215.4 23,26,31,
32]
Menthol Monoterpene C10 [11,16,22,
Menthol Monoterpene C10 H 20H O20O 156.265
156.265 3.2
3.2 215.4
215.4 23,26,31,
[11,16,22,23,26,31,32]
32]
[11,16,22,
Menthol Monoterpene C10H20O 156.265 3.2 215.4 23,26,31,
[17,22,26,
32]
Menthone
Menthol Monoterpene C10
10H20 18O 154.249
156.265 2.63
3.2 205
215.4 [11,16,22,
[17,22,26,
23,26,31,
Menthone Monoterpene C10H H2018O
O 154.249 2.63 205 32]
31,32]
[17,22,26,
Menthol
Menthone Monoterpene
Monoterpene C
C10
10H18O
156.265
154.249 3.2
2.63 215.4
205 23,26,31,
31,32]
32]
[17,22,26,
31,32]
Menthone Monoterpene C10H18O 154.249 2.63 205 32]
[17,22,26,
Menthone Monoterpene C10H18O 154.249 2.63 205 31,32]
[17,22,26,
31,32]
Menthone Monoterpene C10H18O 154.249 2.63 205 [17,22,26,
Menthone Monoterpene C10 31,32]
Menthone Monoterpene C10 H 18H O18O 154.249
154.249 2.63
2.63 205205 [17,22,26,31,32]
[17,22,26,
[16,24,26,
31,32]
Menthone
Nerolidol Monoterpene
Sesquiterpene CC1015H O
H1826O 154.249
222.366 2.63
5.32 205
276 [16,24,26,
[17,22,26,
Nerolidol
Menthone Sesquiterpene
Monoterpene CC1015HH1826O
O 222.366
154.249 5.32
2.63 276
205 31,32]
27,32]
[16,24,26,
Nerolidol Sesquiterpene C15H26O 222.366 5.32 276 27,32]
31,32]
[16,24,26,
[16,24,26,
27,32]
Nerolidol Sesquiterpene C15H26O 222.366 5.32 276 [16,24,26,
[16,24,26,
27,32]
α-Pinene
Nerolidol Sesquiterpene C15H26O 222.366 5.32 276 [16,24,26,
α-Pinene
Nerolidol
Nerolidol Monoterpene
Sesquiterpene
Sesquiterpene C
C15 HC10H16O
15H O26O 152.23
222.366
222.366 2.11
5.32
5.32 188.6
276276 [26]
27,32]
[16,24,26,27,32]
oxide
α-Pinene Monoterpene C26
10H16O 152.23 2.11 188.6 [16,24,26,
[26]
27,32]
Nerolidol
oxide
α-Pinene Monoterpene
Sesquiterpene C 15H
C10 H16
26O O 152.23
222.366 2.11
5.32 188.6
276 [26]
oxide Monoterpene C10H16O 152.23 2.11 188.6 27,32]
[26]
α-Pinene
oxide
α-Pinene Monoterpene C10H16O 152.23 2.11 188.6 [26]
oxide Monoterpene C10H16O 152.23 2.11 188.6 [26]
α-Pinene
oxide
α-Pinene Monoterpene C10H16O 152.23 2.11 188.6 [26]
oxide
Pulegone Monoterpene CC1010HH1616O
O 152.233
152.23 2.56
2.11 224
188.6 [32]
[26]
α-Pinene
α-Pinene
oxide
Pulegone Monoterpene C10HO H16O 152.233 2.56 224 [32]
Pulegone Monoterpene
Monoterpene
Monoterpene C
C10 HC10
10H16
16 16OO 152.23
152.23
152.233 2.11
2.11
2.56 188.6
188.6
224 [26]
[32][26]
oxide
oxide
Pulegone Monoterpene C10H16O 152.233 2.56 224 [32]
[17,22,26,
Menthone Monoterpene C10H18O 154.249 2.63 205
31,32]
Molecules 2016, 21, 1709 5 of 22

[16,24,26,
Nerolidol Sesquiterpene C15H26O 222.366 5.32 276
27,32]
Table 1. Cont.
α-Pinene
Monoterpene Chemical
C10H16O 152.23 2.11 Boiling
188.6 Chemical [26]
Terpene
oxide Type MW a Log P Ref.
Formula Point (◦ C) Structure
Molecules 2016, 21, 1709 5 of 21

Molecules 2016, 21, 1709
Pulegone Monoterpene 5 of 21
Pulegone
Molecules 2016, 21,Monoterpene
1709 C10 HC16
10H
O16O 152.233
152.233
Table 2.56
2.56
1. Cont. 224224 [32][32]
5 of 21
Molecules 2016, 21, 1709 Chemical Table 1. Cont. Boiling 5 of 21
Terpene
Molecules 2016, 21, 1709 Type Chemical MW a 1. Cont.
5 of 21
Terpene 2016, 21, 1709Type
Molecules Formula MW a 1. Cont.
Table Log P Point (°C) Chemical Structure Ref.5 of 21
Chemical
Formula Boiling
Point (°C)
Terpene
Molecules 2016, 21, 1709 Type Chemical MW 1. Cont.
Table a Log P Boiling Chemical Structure Ref.
5 of 21
Terpene Type Formula MW a Log
Table 1. Cont. P Point (°C) Chemical Structure Ref.
Chemical
Formula Boiling
Point (°C)
Terpene Type Chemical MW a 1. Cont.
RoseRose
oxide
oxide
Terpene Monoterpene
Monoterpene
Type Formula
C10 H O18O
CChemical
10H 154.249
154.249
MW a 3.13
3.13
Log P Point (°C)
196.7
196.7 Chemical Structure [28,29]
[28,29]
Ref.
18
Formula Boiling
Point (°C)
Rose oxide
Terpene Monoterpene
Type C10H18O
Chemical 154.249
MWa 3.13
Log P 196.7
Boiling Chemical Structure [28,29]
Ref.
Rose oxide
Terpene Monoterpene
Type C10Formula
H18O 154.249
MW a 3.13P
Log Point
196.7 (°C) Chemical Structure [28,29]
Ref.
Rose oxide Monoterpene Formula
C10H18O 154.249 3.13 Point (°C)
196.7 [28,29]
Rose oxide Monoterpene C10H18O 154.249 3.13 196.7 [28,29]
Rose oxide Monoterpene C10H18O 154.249 3.13 196.7 [28,29]
Safranal
Rose oxide Monoterpenes
Monoterpene C10CH1014HO18O 150.218
154.249 2.93.13 217.3
196.7 [28,29]
[28,29]
Safranal
Safranal
Rose oxide Monoterpenes
Monoterpenes
Monoterpene C HC
10 C10 H
O
14H18O
10 14 O 150.218
150.218
154.249 2.9
2.9
3.13 217.3
217.3
196.7 [28,29]
[28,29]
[28,29]
Safranal Monoterpenes C10H14O 150.218 2.9 217.3 [28,29]
Safranal
Terpinen-4-ol Monoterpenes C 10 H 14 O 150.218 2.9 217.3 [28,29]
Safranal
Terpinen-4-ol Monoterpenes
Monoterpenes C 10CH 18
10 HO14 O 154.249
150.218 2.992.9 209
217.3 [24,25]
[28,29]
(4-terpinenol)
Safranal Monoterpenes
Monoterpenes C1010H
C H1418OO 154.249
150.218 2.99
2.9 209
217.3 [24,25]
[28,29]
Terpinen-4-ol
Terpinen-4-ol
(4-terpinenol)
Terpinen-4-ol Monoterpenes
Monoterpenes C10 H C10
18HO18O 154.249
154.249 2.99
2.99 209209 [24,25]
[24,25]
(4-terpinenol)
(4-terpinenol)
Terpinen-4-ol Monoterpenes C10H18O 154.249 2.99 209 [24,25]
(4-terpinenol) Monoterpenes C 10H18O 154.249 2.99 209 [24,25]
Terpinen-4-ol
(4-terpinenol)
Terpinen-4-ol Monoterpenes C10H18O 154.249 2.99 209 [24,25]
(4-terpinenol) Monoterpenes C10H18O 154.249 2.99 209 [24,25]
Terpinen-4-ol
(4-terpinenol) Monoterpenes C10H18O 154.249 2.99 209 [24,25]
α-Terpineol
(4-terpinenol) Monoterpenes C10H18O 154.25 2.79 217.5 [24]
α-Terpineol Monoterpenes C10H18O 154.25 2.79 217.5 [24]
α-Terpineol
α-Terpineol Monoterpenes C10 H
Monoterpenes C10
18HO18O 154.25
154.25 2.79
2.79 217.5
217.5 [24]
[24]
Tetra-
Tetra- Monoterpene C10H22O 158.281 3.64 212.5 [16]
hydrogeraniol Monoterpene C10H22O 158.281 3.64 212.5 [16]
Tetra-
hydrogeraniol
Tetra- Monoterpene C 10 H 22 O 158.281 3.64 212.5 [16]
hydrogeraniol Monoterpene C 10H22O 158.281 3.64 212.5 [16]
Tetra-
hydrogeraniol
Tetra-hydrogeraniol
Tetra- Monoterpene C10 H
Monoterpene C10
22H O22O 158.281
158.281 3.64
3.64 212.5
212.5 [16]
[16]
Tetra-
hydrogeraniol
Tetra- Monoterpene C 10H22O 158.281 3.64 212.5 [16]
hydrogeraniol
Thymol Monoterpenes C10H14O 150.22 3.28 233 [21,23]
Thymol
Thymol Monoterpenes C10 H
Monoterpenes C14
10H O14O 150.22
150.22 3.28
3.28 233233 [21,23]
[21,23]
Valen-cene
Thymol Sesquiterpene
Monoterpenes CC 15H24
10H14O
204.351
150.22 6.28
3.28 270.5
233 [27,28]
[21,23]
Valen-cene
Thymol Sesquiterpene
Monoterpenes CC 15H24
10H14O
204.351
150.22 6.28
3.28 270.5
233 [27,28]
[21,23]
Valen-cene Sesquiterpene C15H24 204.351 6.28 270.5 [27,28]
Verbenon-e
Valen-cene Monoterpenes
Sesquiterpene CC1015HH1424O 150.22
204.351 1.97
6.28 227.5
270.5 [23]
[27,28]
Verbenon-e Monoterpenes
Sesquiterpene C15C
Valen-cene Sesquiterpene
Valen-cene H1024H1514H
C O24 204.351
150.22
204.351 1.97 6.28
6.28 227.5
270.5
270.5 [23]
[27,28][27,28]
Verbenon-e
Valen-cene Monoterpenes
Sesquiterpene CC1015HH1424O 150.22
204.351 1.97
6.28 227.5
270.5 [23]
[27,28]
Verbenon-e Monoterpenes C10H14O a 150.22 1.97 227.5 [23]
Verbenon-e Monoterpenes C10H Note:
14O a
MW = molecular
150.22 1.97 weight.227.5 [23]
Verbenon-e Monoterpenes C10H Note:
14O a
MW = molecular
150.22 1.97 weight.227.5 [23]
Verbenon-e Monoterpenes Note:
C10H14Oa MW = molecular
150.22 weight.
1.97 227.5 [23]
The
Verbenon-e penetration enhancement
Monoterpenes C10 H C10 Note:
effect MW
of =
these molecular
terpenes weight.
is summarized in Table 2.
Verbenon-e Monoterpenes
The penetration enhancement effect 14H O14O a 150.22
Note: of MW150.22
these
1.97
1.97
= molecular 227.5
terpenesweight. 227.5
is summarized in Table 2.
[23]
[23]
The penetration enhancement effect ofa these terpenes is summarized in Table on
It should be emphasized that the
Note:penetration
a MW = molecularenhancementweight. effect of terpenes 2. the SC may be
It should
The be emphasized
penetration enhancementthat the penetration
Note:
effect MW =terpenes
oftothese enhancement
molecular isweight. effect of terpenes
summarized on the SC may be
in Tableproperties
2.
different
The in
It should different
penetration vehicle
be emphasized systems
that the
enhancement due
Note:penetration
effect
adue ofMW
a the
these differences
enhancement
= molecular
terpenes in
weight.
is in physico-chemical
effect of terpenes
summarized 2. the SC of
on
in Tableproperties maythese
be
different
It
The in
should different
be
penetration vehicle
emphasized systems
that
enhancement Note:
the MW to=
penetration
effect of the
these differences
molecular weight.
enhancement
terpenes is physico-chemical
effect
summarized of terpenes
in Table on
2. the SC of
maythese
be
solvents
different
It and
in
should their
different
be interactions
vehicle
emphasized thatwith
systems thethe
due SCto [16].
penetrationthe Co-solvents
differences
enhancement inlike propylene
physico-chemical
effect of glycol
terpenes (PG)
properties
on the or
SC ethanol
of
maythese
be
solvents
differentThe inpenetration
and their
different enhancement
interactions
vehicle with effect
the SCtoofterpenes.
these
[16]. terpenes in
Co-solvents is like
summarized
propylene inglycol
Table 2.
(PG) or of
ethanol
Itsynergistic
haveThe
solvents
different
should
and be effects
penetration
their
in different whensystems
emphasized that
enhancement
interactions
vehicle added
with
systems
the due
to
effect
the
duethe the
penetration
oftothese
SC [16].
differences
enhancement
In addition,
terpenes
Co-solvents
the differences is in
physico-chemical
effect
otheroffactors
summarized
like propyleneterpenes
in Table
physico-chemical
properties
glycolon the SC
including
2. (PG)
properties skin
or maythese
ethanol
of
be
type,
these
have It should
synergistic be emphasized
effects when that
added the
to penetration
the terpenes. enhancement
In addition, effect
other of terpenes
factors on
including the SC
skin may
type,be
Thesolvents
penetration
different
pH
have values,and
in their
different
and
Itsynergistic
should
interactions
enhancement
vehicle
formulation
be effects
emphasized
with of
effect
systems the
due
ingredients
when that
added thethe
SC
these
to [16].
should
topenetration
the terpenes.
Co-solvents
terpenes
the also is
differencesbe
enhancement
like
summarized
in
taken
In addition,
propylene
into
effect
other in
physico-chemical
account
offactors
glycol
Table
terpenes 2.
as (PG)
properties
the
on(PG)
including
or of
ethanol
sources
the SC
skinmaythese
of
be
type,
solvents
different and their
inand interactions
different vehicle with
systems SC should
[16].theCo-solvents like propylene glycol or ethanol
pH
have
It should
values,
synergistic
solvents be
experimentaland their formulation
effects
emphasized when
interactions
variabilities.that added
with
the to due
ingredients
the the
SC
penetration
to
terpenes.
[16].
differences
also
Co-solvents
enhancement
be taken
In addition, in physico-chemical
like into factors
other account
propylene
effect of
asproperties
glycol
terpenes
the sources
including
(PG)
on skin
or
the
oftype,
these
ethanol
SC
of
may
different
pH
have values, in different
andtheir
synergistic vehicle
effects whensystems
formulation added due
ingredients
to theto the differences
should
terpenes. also be in physico-chemical
taken
In addition, into
other properties
accountglycol
factors as the
including of these
sources
skin of
type,
solvents
experimental
pH and interactions
variabilities. with the SC [16]. Co-solvents like propylene (PG) or ethanol
havevalues,
be different in and effects
synergistic
different formulation
vehiclewhen ingredients
added
systems to
duethe
SCto
should
terpenes. also be taken other
In addition,
theCo-solvents
differences into factors
accountincluding
in propylene
physico-chemical as the sources
skin of
type,
solvents
experimental
pH values,
have
andandtheir
synergistic
interactions
variabilities.
formulation with the
effects wheningredients
added to the
[16].
should
terpenes.
like
alsoInbeaddition,
taken into
otheraccount
factors as theproperties
glycol (PG)
including
or ethanol
sources of of
skin type,
experimental
pH values, variabilities.
and formulation ingredients should also be taken into account as the sources ofor
have
these solvents synergistic
and
experimental theireffects when added
interactions
variabilities. with to the
the terpenes.
SC [16]. In addition, other
Co-solvents likefactors including
propylene skin(PG)
glycol type,
pH values, and formulation ingredients should also be taken into account as the sources of
experimental variabilities.
ethanol pH
have values, and formulation
synergistic
experimental effects when
variabilities.
ingredients
added to the should also beIntaken
terpenes. addition,into other
account as the
factors sources skin
including of
type, pH values, and formulation ingredients should also be taken into account as the sources of
Molecules 2016, 21, 1709 6 of 22
Table 2. Skin penetration enhancement effect of terpenes applied as PEs.
Vehicle (Terpene
Terpene Drug Parameters Skin Receptor Liquid ER a Proposed Mechanism Ref.
Concentration)
Propranolol log P = 1.53, hydroxypropyl methylcellulose Enhancing diffusion through the
Piglet abdominal skin pH 7.4 PBS 1.8 [16]
hydrochloride MW = 295.804 (HPMC) gel (3%) intercellular lipids
log P = 4.5, Ethanol:pH 7.4 isotonic Ethanol:pH 7.4 Extracting stratum corneum (SC) lipids and
Anethole Valsartan Rat abdominal skin 4.4 [17]
MW = 435.519 PBS = 40:60 (1%) isotonic PBS = 40:60 breaking the hydrogen bonds
log P = 3.59, Carboxyl methyl cellulose
Etodolac Rat abdominal skin pH 7.4 PBS 1.52 Interacting with lipid components of the SC [18]
MW = 287.35 (CMC)-Na gel (1%)
Propranolol log P = 1.53, Increasing lipid fluidity and improving the
α-Bisabolol 66.7% ethanol (5%) Rat dorsal skin pH 7.4 PBS 6.29 [19]
hydrochloride MW = 295.804 partition into the SC
1% = 3.77
log P = −0.95,
5-Fluorouracil 3% = 7.49
MW = 130.08
5% = 10.57
1% = 6.51
log P = 0.23,
Antipyrine 3% = 19.18
MW = 188.23
5% = 32.84
1% = 5.12
log P = 1.23,
Aspirin 1% Brij98 in isotonic 3% = 13.31 Disrupting and extracting part of SC
MW = 180.04 PG:water = 70:30 (1%, 3%, 5%) Rat abdominal skin [20]
PBS (pH 7.2) 5% = 19.81 intercellular lipids
Borneol
1% = 2.40
log P = 2.25,
Salicyclic acid 3% = 8.10
MW = 138.12
5% = 12.76
1% = 1.55
log P = 3.51,
Ibuprofen 3% = 5.18
MW = 206.28
5% = 9.78
Propranolol log P = 1.53, Enhancing diffusion through the
HPMC gel (3%) Piglet abdominal skin pH 7.4 PBS 1.5 [16]
hydrochloride MW = 295.804 intercellular lipids
Propranolol log P = 1.53, Increasing lipid fluidity and improving the
66.7% ethanol (5%) Rat dorsal skin pH 7.4 PBS 5.01 [19]
hydrochloride MW = 295.804 partition into the SC
Molecules 2016, 21, 1709 7 of 22
Table 2. Cont.
Vehicle (Terpene
Concentration)
log P = 3.80,
Indometacin 3.97
MW = 357.79
log P = 2.56,
Lidocaine 5.68
MW = 234.34
log P = 1.23,
Aspirin 9.82
MW = 180.04
Perturbing the regular organization of SC
log P = 0.23,
Antipyrine PG:water = 70:30 (3%) Rat abdominal skin Isotonic pH 7.2 PBS 17.80 lipids or directly extracting part of the SC [21]
Camphor MW = 188.23
lipids; improving the partition into the SC
log P = −0.48,
Tegafur 15.98
MW = 200.17
log P = −0.95,
5-Fluorouracil 11.87
MW = 130.08
Propranolol log P = 1.53, Increasing lipid fluidity and improving
Ethanol:water = 2:1 (5%) Rat dorsal skin pH 7.4 PBS 3.67 [19]
hydrochloride MW = 295.804 the partition into the SC
3.9 (1.2 mM)
log P = 1.76, pH 7.4 Human epidermal 6.6 (1.8 mM)
Carvacrol Corticosterone pH 7.4 PBS SC intercellular lipid fluidization [22]
MW = 346.46 PBS (1.2/1.8/3.0/3.5 mM) membrane 9.5 (3.0 mM)
14.7 (3.5 mM)
log P = 2.94, 0.01 MPBS
Genistein MC gel (0.4%) Human skin 4.78 Disrupting the SC lipid bilayers [23]
MW = 270.237 (pH 7.4):ethanol = 8:2
Carvone log P = 1.43, Hairless mouse Isotonic PBS Disrupting the hydrophobic lipid
Hydrocortisone HPMC gel (2%) 13.1 [24]
MW = 362.46 abdominal skin (pH 7.2) packing of the SC
Molecules 2016, 21, 1709 8 of 22
Table 2. Cont.
Vehicle (Terpene
Concentration)
1.9 (2.0 mM)
log P = 1.76, Human epidermal
Corticosterone pH 7.4 PBS (2.0/3.0/4.0 mM) pH 7.4 PBS 3.2 (3.0 mM) SC intercellular lipid fluidization [22]
MW = 346.46 membrane
3.6 (4.0 mM)
log P = 2.94, 0.01 MPBS
Genistein MC gel (0.4%) Human skin 7.41 Disrupting the SC lipid bilayers [23]
MW = 270.237 (pH 7.4):ethanol = 8:2
log P = 1.43, Hairless mouse Disrupting the hydrophobic lipid
Hydrocortisone HPMC gel (2%) Isotonic PBS (pH 7.2) 14.5 [24]
MW = 362.46 abdominal skin packing of the SC
log P = 3.85,
Osthole 2.27
MW = 244.34
log P = 2.34,
Tetramethylpyr-azine 2.16
MW = 136.20 Perturbing and extracting the SC lipids;
pH 7.2 PBS, 3% Brij98
log P = 1.26, altering the keratin conformation [25]
Ferulic acid PG:water = 80:20 (3%) Rat abdominal skin added for osthole 1.22
MW = 194.18 to some extent
log P = −0.35,
Puerarin 0.60
MW = 432.38
log P = −1.01,
Geniposide 2.80
MW = 388.37
1,8-Cineole Flux = 28.8 ± Increasing the fluidity of SC lipids; causing
(eucalyptol) Lomerizine log P = 4.8, Hairless mouse 0.5% Tween80 in 0.9%
PG (10%) 8.5 µg/cm2 /h disorder of the stacking arrangement of the [26]
dihydro-chloride MW = 541.457 dorsal skin NaCl solution
control = 0 lipid bilayers
Ondansetron log P = 2.07,
Chitosan gel film (1%) Porcine dorsal skin 0.9% Saline solution 3.23 Increasing lipid fluidity of the SC [27]
hydrochloride MW = 329.824
2.15 (0.5%)
2.34 (0.75%)
log P = 4.5, Ethanol:isotonic IPB (pH 7.4) = Ethanol:isotonic IPB Extraction of SC lipids and keratin
Valsartan Rat abdominal skin 6.4 (1%) [28]
MW = 435.519 40:60 (0.5%, 0.75%, 1%, 3%, 5%) (pH 7.4) = 40:60 denaturation in the SC
4.2 (3%)
3.7 (5%)
log P = 4.5, ethanol:isotonic PBS Disrupting the intercellular packing of the
Valsartan Carbopol940 gel (1%) Rat abdominal skin 4.53 [15]
MW = 435.519 (pH 7.4) = 40:60 SC lipids
1.11 (0.5%)
Propranolol log P = 1.53, Ethanol:isotonic PBS (pH 7.4) = Extraction and disruption of SC lipid
Rat abdominal skin PBS pH 7.4 1.20 (0.75%) [29]
hydrochloride MW = 295.804 20:80 (0.5%, 0.75%, 1%) bilayers and keratin denaturation in the SC
2.07 (1%)
log P = 2.78, Hairless mouse Modifying the intercellular packing and
Bufalin PG/water = 50/50 (5%) PEG:PG:water = 40:30:30 17.1 [13]
MW = 386.5 dorsal skin disrupting highly ordered structure of lipids
Molecules 2016, 21, 1709 9 of 22
Table 2. Cont.
Terpene Drug Parameters Vehicle (Terpene Concentration) Skin Receptor Liquid ER a Proposed Mechanism Ref.
1.38 (0.5%)
Propranolol log P = 1.53, Ethanol:isotonic PBS Extraction and disruption of SC lipid
Rat abdominal skin PBS pH 7.4 1.95 (0.75%) [29]
hydrochloride MW = 295.804 (pH 7.4) = 20:80 (0.5%, 0.75%, 1%) bilayers and keratin denaturation in the SC
3.07 (1%)
1,4-Cineole 2.77 (0.5%)
3.39 (0.75%)
log P = 4.5, MW Ethanol:isotonic PBS (pH 7.4) = Ethanol:isotonic Extraction of SC lipids and keratin
= 435.519 40:60 (0.5%, 0.75%, 1%, 3%, 5%) PBS (pH 7.4) = 40:60 denaturation in the SC
6.1 (3%)
5.4 (5%)
log P = 1.43, Hairless mouse Isotonic PBS Disrupting the hydrophobic lipid
Cymene Hydrocortisone HPMC gel (2%) 22.9 [24]
log P = 4.5, MW Ethanol:pH 7.4 isotonic Ethanol:pH 7.4 Extracting SC lipids and breaking the
Eugenol Valsartan Rat abdominal skin 3.0 [17]
= 435.519 PBS = 40:60 (1%) isotonic PBS = 40:60 hydrogen bonds
Farnesol HPMC gel (3%) Piglet abdominal skin pH 7.4 PBS 3.9 [16]
Fenchone Hydrocortisone HPMC gel (2%) 10.1 [24]
Geraniol
Molecules 2016, 21, 1709 10 of 22
Table 2. Cont.
Vehicle (Terpene
Concentration)
log P = 3.3,
Terbinafine Carbopol 934P gel (5%) Porcine dorsal skin pH 5.8 PBS 1.36 Lipid bilayer disruption in the SC [30]
MW = 291.43
Increasing the skin diffusivity by
log P = 2.78, Hairless mouse PEG/PG/ modifying the intercellular packing and
Bufalin PG/water = 50/50 (5%) 22.2 [11]
MW = 386.5 dorsal skin water = 40/30/30 disrupting highly ordered
structure of lipids
log P = 3.85,
Osthole 10.55
MW = 244.34
log P = 2.34,
Limonene Tetramethylpyrazine MW = 136.20 9.61
pH 7.2 PBS, 3% Brij98
log P = 1.26,
Ferulic acid PG:water = 80:20 (3%) Rat abdominal skin added for osthole 53.78 Perturbing and extracting the SC lipids [25]
MW = 194.18
log P = −0.35,
Puerarin 18.40
MW = 432.38
log P = −1.01,
Geniposide 5.70
MW = 388.37
Chitosan gel film (1%) Porcine dorsal skin 0.9% Saline solution 0.94 - [27]
log P = 2.94, Methyl cellulose (MC) 0.01 MPBS
Genistein Human skin 1.73 Disrupting the lipid bilayers of the SC [23]
MW = 270.237 gel (0.4%) (pH 7.4):ethanol = 8:2
Increasing the fluidity of SC lipids;
Lomerizine log P = 4.8, Hairless mouse 0.5% Tween80 in 0.9% Flux = 16.6 ± 4.1 µg/cm2 /h
Linalool PG (10%) causing disorder of the stacking [26]
dihydrochloride MW = 541.457 dorsal skin NaCl solution control = 0
arrangement of the lipid bilayers
Molecules 2016, 21, 1709 11 of 22
Table 2. Cont.
Vehicle (Terpene
Concentration)
Ligustrazine log P = 1.26, Film composed of PVA and Flux = 6.30µg/cm2 /h Disturbing and extracting SC lipids and
Porcine dorsal skin Water [31]
hydrochloride MW = 172.655 CMC-Na (3%) Azone = 0.74 µg/cm2 /h hydrogen bond connection
log P = 3.85,
Osthole 1.21
MW = 244.34
log P = 2.34,
Tetramethylpyrazine 3.92
MW = 136.20
Disordering the ordered organization of
log P = 1.26, PG:water = 80:20 (3%) Rat abdominal skin Isotonic 0.01 M PBS
Ferulic acid 35.32 SC lipids and extracting part of [32]
MW = 194.18 (pH 7.2)
the SC lipids
log P = −0.35,
Puerarin 66.40
MW = 432.38
log P = −1.01,
Geniposide 32.20
MW = 388.37
Menthol log P = 2.94, 0.01 MPBS
Genistein MC gel (0.4%) Human skin 9.59 Disrupting the lipid bilayers of the SC [23]
MW = 270.237 (pH 7.4):ethanol = 8:2
2.8 (1.0 mM)
log P = 1.76, Human epidermal
Corticosterone pH 7.4 PBS (1.0/1.5/2.0 mM) pH 7.4 PBS 3.8 (1.5 mM) SC intercellular lipid fluidization [22]
4.9 (2.0 mM)
Lomerizine log P = 4.8, Hairless mouse 0.5% Tween80 in 0.9% Flux = 28.4 ± 6.6 µg/cm2 /h
PG (10%) causing disorder of the stacking [26]
dihydrochloride MW = 541.457 dorsal skin NaCl solution control = 0
Increasing the skin diffusivity by
log P = 2.78, Hairless mouse PEG/PG/ modifying the intercellular packing and
Bufalin PG/water = 50/50 (5%) 15.3 [11]
MW = 386.5 dorsal skin water = 40/30/30 disrupting highly ordered
structure of lipids
Molecules 2016, 21, 1709 12 of 22
Table 2. Cont.
Vehicle (Terpene
Concentration)
log P = 4.5, Ethanol:pH 7.4 isotonic Ethanol:pH 7.4 Extracting SC lipids and breaking
Valsartan Rat abdominal skin 4.0 [17]
MW = 435.519 PBS = 40:60 (1%) isotonic PBS = 40:60 the hydrogen bonds
log P = 3.85,
Osthole 5.82
MW = 244.34
log P = 2.34,
MW = 136.20
log P = 1.26, Isotonic 0.01 M PBS Disordering the ordered organization of SC
Ferulic acid PG:water = 80:20 (3%) Rat abdominal skin 20.42 [32]
MW = 194.18 (pH 7.2) lipids and extracting part of the SC lipids
log P = −0.35,
Puerarin 293.80
MW = 432.38
Menthone log P = −1.01,
Geniposide 31.60
MW = 388.37
Increasing the fluidity of SC lipids; causing
Lomerizine log P = 4.8, Hairless mouse 0.5% Tween80 in Flux = 20.6 ± 2.5 µg/cm2 /h
PG (10%) disorder of the stacking arrangement of the [26]
dihydro-chloride MW = 541.457 dorsal skin 0.9% NaCl solution control = 0
lipid bilayers
3.8 (2.0 mM)
log P = 1.76, pH7.4 PBS (2.0/2.6/3.0 mM) Human epidermal pH 7.4 PBS SC intercellular lipid fluidization
Corticosterone 4.6 (2.6 mM) [22]
5.9 (3.0 mM)
Ligustrazine log P = 1.26, Film composed of PVA and Flux = 5.37 µg/cm2 /h Disturbing and extracting SC lipids and
Porcine dorsal skin Water [31]
hydrochloride MW = 172.655 CMC-Na (3%) Azone = 0.74 µg/cm2 /h hydrogen bond connection
log P = 3.3,
Terbinafine Carbopol 934P gel (5%) Porcine dorsal skin pH 5.8 PBS 4.13 Lipid bilayer disruption in the SC [30]
MW = 291.43
Increasing the fluidity of SC lipids; causing
Lomerizine log P = 4.8, Hairless mouse 0.5% Tween80 in Flux = 14.2 ± 3.0 µg/cm2 /h
PG (10%) disorder of the stacking arrangement of the [26]
dihydrochloride MW = 541.457 dorsal skin 0.9% NaCl solution control = 0
lipid bilayers
Nerolidol
Chitosan gel film (1%) Porcine dorsal skin 0.9% Saline solution 0.85 - [27]
log P = 1.43, Hairless mouse Isotonic PBS Disrupting the hydrophobic
MW = 362.46 abdominal skin (pH 7.2) lipid packing of the SC
Molecules 2016, 21, 1709 13 of 22
Table 2. Cont.
Vehicle (Terpene
Concentration)
α-Pinene Lomerizine log P = 4.8, Hairless mouse 0.5% Tween80 in Flux = 23.1 ± 1.9 µg/cm2 /h
PG (10%) causing disorder of the stacking [26]
oxide dihydro-chloride MW = 541.457 dorsal skin 0.9% NaCl solution control = 0
log P = 3.85,
Osthole 2.87
MW = 244.34
log P = 2.34,
Tetra-methylpyrazine 2.67
MW = 136.20
log P = 1.26, Isotonic 0.01 M PBS
Pulegone Ferulic acid PG:water = 80:20 (3%) Rat abdominal skin 3.07 Extracting part of the SC lipids [32]
MW = 194.18 (pH 7.2)
log P = −0.35,
Puerarin 2.60
MW = 432.38
log P = −1.01,
Geniposide 2.70
MW = 388.37
1.78 (0.5%)
2.11 (0.75%)
log P = 4.5, Ethanol:isotonic PBS (pH 7.4) = Ethanol:isotonic Extraction of SC lipids and keratin
MW = 435.519 40:60 (0.5%, 0.75%, 1%, 3%, 5%) PBS (pH 7.4) = 40:60 denaturation in the SC
6.1 (3%)
Rose oxide
6.4 (5%)
1.06 (0.5%) Extraction and disruption of SC lipid
Propranolol log P = 3.77, Ethanol:isotonic PBS (pH 7.4) =
Rat abdominal skin PBS pH 7.4 1.13 (0.75%) bilayers and keratin denaturation [29]
hydrochloride MW = 295.804 20:80 (0.5%, 0.75%, 1%)
1.71 (1%) in the SC
1.49 (0.5%)
2.05 (0.75%)
log P = 4.5, Ethanol:isotonic PBS (pH 7.4) = Ethanol:isotonic Extraction of SC lipids and keratin
MW = 435.519 40:60 (0.5%, 0.75%, 1%, 3%, 5%) PBS (pH 7.4) = 40:60 denaturation in the SC
3.4 (3%)
Safranal
3.0 (5%)
1.03 (0.5%) Extraction and disruption of SC lipid
Propranolol log P = 3.77, Ethanol:isotonic PBS (pH7.4) =
1.20 (1%) in the SC
Molecules 2016, 21, 1709 14 of 22
Table 2. Cont.
Vehicle (Terpene
Concentration)
log P = 3.85,
Osthole 1.90
MW = 244.34
log P = 2.34,
MW = 136.20
log P = 1.26, pH 7.2 PBS, 3% Brij98
Ferulic acid PG:water = 80:20 (3%) Rat abdominal skin 2.02 Perturbing and extracting the SC lipids [25]
Terpinen-4-ol MW = 194.18 added for osthole
(4-terpinenol) log P = −0.35,
Puerarin 0.40
MW = 432.38
log P = −1.01,
Geniposide 2.00
MW = 388.37
α-Terpineol Hydrocortisone HPMC gel (2%) Isotonic PBS (pH 7.2) 13.3 [24]
Tetra-hydrogeraniol HPMC gel (3%) Piglet abdominal skin pH 7.4 PBS 3.3 [16]
Thymol 3.1 (1.0 mM)
log P = 1.76, pH 7.4 Human epidermal 5.5 (1.8 mM)
Corticosterone pH 7.4 PBS SC intercellular lipid fluidization [22]
MW = 346.46 PBS (1.0/1.8/3.0/4.0 mM) membrane 10.9 (3.0 mM)
17.2 (4.0 mM)
1.96 (0.5%)
2.14 (0.75%)
log P = 4.5, Ethanol:isotonic PBS (pH 7.4) = Ethanol:isotonic PBS Extraction of SC lipids and keratin
MW = 435.519 40:60 (0.5%, 0.75%, 1%, 3%, 5%) (pH 7.4) = 40:60 denaturation in the SC
4.3 (3%)
Valencene 2.6 (5%)
1.19 (0.5%) Extraction and disruption of the SC lipid
Propranolol log P = 3.77, Ethanol:isotonic PBS (pH 7.4) =
2.20 (1%) in the SC
Verbenone Hydrocortisone HPMC gel (2%) Isotonic PBS (pH 7.2) 11.5 [24]
Note: a The enhancement ratio (ER) was calculated as follows: ER = flux of the drug with terpene/ flux of the drug without terpene.
Molecules 2016, 21, 1709 15 of 22
3. Mechanism of Action
It is widely agreed that PEs may enhance the skin penetration of a drug molecule by acting on the
SC intercellular lipids via extraction or fluidization and/or by increasing the SC partitioning of the
drug and/or by modifying the keratinized protein conformations [10]. As demonstrated in Table 2,
terpenes possess high enhancement activity for both hydrophilic and lipophilic drugs even at low
concentration. It seemed that terpenes interact with SC components by more than one mechanism,
although their interactions with SC intercellular lipids could be the key mechanism.
3.1. Effect on SC Lipids

The effect of terpenes on SC lipids mainly involves the interactions at two sites, namely the
lipophilic tails of the intercellular lipid and the polar head groups, affecting both lipoidal intercellular
and polar transcellular pathways. Nowadays, the former route has attracted more attention.
To elucidate the mechanism of action, attenuated total reflection-fourier transform infrared
spectroscopy (ATR-FTIR) or FT-IR spectrometry studies were often applied to investigate the
biophysical alterations of the skin barrier which could be attributed to its capability of obtaining
the conformation information of the SC lipids and keratins. Stretching peaks near 2850 cm−1 (C-H
symmetric stretching absorbance frequency peak), 2920 cm−1 (C-H asymmetric stretching absorbance
frequency peak), 1640 cm−1 (Amide I), and 1540 cm−1 (Amide II) are usually detected following the
administration of terpenes to the SC [33]. The shift to a higher frequency of C-H stretching peaks
(~2850 and ~2920 cm−1 ) occurs when methylene groups of the SC lipid alkyl chains change from trans to
gauche conformation, indicating the perturbation of SC lipids. The stronger the perturbation, the higher
the C-H stretching peak position. The areas and heights of these two peaks (~2850 and ~2920 cm−1 ) are
proportional to the amount of the SC lipids. So any extraction of the lipids by terpenes results in a
decrease of peak area and peak height.
Both menthol and menthone, the classic terpenes as PEs, can enhance the skin permeability by
extracting SC lipids [31,32]. Revealed by ATR-FTIR studies, compared with the control, the shift of
asymmetric or symmetric C-H stretching to higher wave number was observed after treatment with
menthol or menthone, despite the fact that the alteration of these peak positions was relatively weak.
The results indicated that menthol and menthone could slightly interact with the lipophilic tails of skin
lipids, which could contribute to the transdermal absorption of lipophilic drugs. Remarkably, menthol
and menthone resulted in the significant decrease of peak areas of C-H stretching absorption peaks,
indicating that they could directly extract part of the SC lipids to weaken the skin permeability barrier
provided by the SC lipids. Moreover, no significant difference in the peak positions nor peak areas of
two amide bonds could be observed after treatment with menthol and menthone, suggesting they had
little effect on the keratin in corneocytes [32]. In addition, it was demonstrated that the capacity of
menthone in disturbing and extracting lipids was higher than that of menthol and azone [31].
Similar results were obtained with other terpenes [28,29]. There were obvious differences in the
FT-IR spectra of the control and the terpene-treated (1,8-cineole, 1,4-cineole, rose oxide, safranal, and
valencene) SC samples. Considering the peak height and area of asymmetric and symmetric C-H
stretching peaks, these terpenes were demonstrated to enhance permeation of valsartan by directly
extracting SC lipids [28]. However, they did not fluidize the SC lipids as the peak shift to a higher
wave number was not observed [29].
For other terpenes, the mechanism might be reversed. ATR-FTIR study results showed nerolidol
produced significant blue shift of asymmetric and symmetric C-H stretching peaks. But the decrease
of peak heights and areas for CH2 asymmetric and symmetric stretching peaks were statistically
insignificant. It could be concluded that nerolidol fluidized rather than extracted the SC lipids [30].
In order to further investigate the interaction between SC lipids and terpenes, molecular dynamics
simulations could be used to reveal the detailed mechanism [34].
Molecules 2016, 21, 1709 16 of 22
3.2. Effect on Hydrogen Bond Connection

A large number of ceramides are tightly arranged in the SC lipid bilayer via hydrogen bonding.
It is the hydrogen bond connection that forms the network at the head of ceramide. The hydrogen
bonding makes the lipid bilayer strong and stable, and it is needed in order to maintain the barrier
trait of the SC. The tight network may be loosened by the terpenes with a functional group that can
donate or accept a hydrogen bond.
It was found that menthol had the better penetration enhancement effect on ligustrazine
hydrochloride than that of menthone. The structures of menthol and menthone only differed by
the attached group. The hydroxy group of menthol forms a hydrogen bond with an amide group,
which is much easier to form than with the ketone group of menthone. This loosens the network of SC
to improve the permeation flux of the drug [31].
ATR-FTIR studies using a simple SC lipid model have revealed that the presence of 1,8-cineole
and L-menthol reduces the amide I stretching frequency, indicating that they act mainly on polar lipid
headgroups and break inter- and intra-lammellar hydrogen bonding networks [10,35].
Among the terpenes evaluated (menthol, nerol, camphor, methyl salicylate), nerol was found to
produce the highest level of disruption of the SC lamellae. A hydroxyl group in the terpene molecule
can form a hydrogen bond, leading to disruption of existing hydrogen bonds between the ceramide
head groups in the SC bilayer [5].
3.3. Effect on SC Partition of Drugs

The partition of drug molecules into the SC is the first step of transdermal drug delivery, and it
lays down the foundation for penetration enhancement. Therefore, increasing the partition coefficient
has become one of the action mechanisms of PEs [36]. A positive correlation between terpene uptake
(menthol, thymol, carvacrol, menthone and cineole) into the SC intercellular lipid and β-estradiol
partitioning enhancement was found. This indicated that terpene dissolved in the intercellular lipid
domain can help to improve drug partitioning into the SC [22].
To measure the SC partition, the dried SC sheets were pulverized into powders. The partition
coefficient of propranolol hydrochloride in the SC powder with terpenes ((+)-borneol, (+)-camphor and
α-bisabolol) was found to be significantly higher than that with vehicle (p < 0.05). It is suggested that
the interaction between the drug and terpenes via hydrogen bonding contributes to the enhancement
of the partition coefficient. Following treatment with terpenes, the concentration of PH in the SC
increased as a result of a molecular complex formation between the drug and the terpene [19].
Modelling studies suggest that either hydrocarbon or oxygen-containing terpenes could form
complexes with drugs. It was proposed that hydrocarbon terpenes could interact with drug molecules
by donor/acceptor interactions, van der Waals forces, and HBD (hydrogen bond donor)-π interactions,
while oxygen-containing terpenes could interact with drugs by forming hydrogen bonds [37].
The effect on the SC partition may depend on the lipophilicity of the drug. A series of model drugs
with a wide span of lipophilicity, namely indometacin (log P = 3.80), lidocaine (log P = 2.56), aspirin
(log P = 1.23), antipyrine (log P = 0.23), tegafur (log P = −0.48), and 5-fluorouracil (log P = −0.95)
were employed to study the penetration enhancement effects of camphor. The enhancement ratios
of the SC/vehicle partition coefficients of model drugs were measured to be 1.68 (indometacin), 2.04
(lidocaine), 1.21 (aspirin), 0.98 (antipyrine), 1.05 (tegafur), and 0.96 (5-fluorouracil). It was indicated
that lipophilic camphor could facilitate the partition of lipophilic drugs into the SC [21].
3.4. Effect on Physiological Reactions

Indeed, some terpenes can induce physiological reactions in the living skin, such as vasodilatation
and increase of skin temperature, that can affect their efficacy as PEs.
Menthol’s ability to chemically trigger the cold-sensitive transient receptor potential cation
channel subfamily M member 8 (TRPM8) receptors in the skin is responsible for the well-known
Molecules 2016, 21, 1709 17 of 22
cooling sensation after its application to the skin. In addition, menthol can stimulate skin nociceptors
and initiate an axon reflex with subsequent release of vasodilator peptides [38]. Moreover, an increase
in skin temperature has been found after dermal administration of a mixture containing menthol [39].
4. Factors Affecting the Penetration Enhancement Effect
4.1. Lipophilicity of the Drug

The skin permeability of drug molecules is closely associated with their physicochemical
properties, such as lipophilicity, molecular weight, and melting point. It is generally accepted that
the optimal logP for a drug to penetrate the SC is in the range of 1~3 and the upper limit on MW is
about 500 [40]. A quantitative structure-activity relationship (QSAR) model had been proposed to
predict skin permeability of the drug: log kp = −6.3 + 0.71 log P − 0.061 MW (r2 = 0.67), where kp is
the skin permeability coefficient, and MW is the molecular weight [41]. Based on the model, the drug
lipophilicity appears to be the predominant factor affecting the skin permeability of drugs.
A parabolic curve relationship was found to exist between logP values of model drugs and
the ER values of terpenes. The ER of limonene was in a parabolic curve relationship roughly with
the lipophilicity of model drugs (ER = −4.89 (log P)2 + 12.34 log P + 25.87, r = 0.682), implying
that limonene could achieve the optimum permeation effect for moderate lipophilic drugs (an
estimated log P value of 1.0) [25]. Similar results were obtained with borneol [20]. The correlation
analysis displayed that the ER values were roughly in a parabolic curve relationship with the
logP values of model drugs, 1% borneol: ER= −0.46 (log P)2 + 0.41 log P + 5.18 (r = 0.86); 3% borneol:
ER = −1.57 (log P)2 + 2.64 log P + 13.58 (r = 0.79); 5% borneol: ER= −2.46 (log P)2 + 4.43 log P + 21.37
(r = 0.70). Based on the analysis results, borneol could achieve the optimum permeation-enhancing
performance for moderately hydrophilic drugs (an estimated logP value of −0.5~0.5). A parabolic
curve was also obtained after plotting the ER of camphor against the drug log P values [21]. The
optimal regression equation was obtained from regression analysis: ER= −0.43 (log P)2 − 1.26 log P
+ 13.95 (r = 0.86), indicating that the best log P value of the drug was about 0 to obtain the highest
penetration enhancement effect using camphor as a PE. Therefore, increasing enhancement effects
of terpenes are much more likely to be observed for hydrophilic or amphiphilic drugs rather than
hydrophobic drugs.
4.2. Lipophilicity of the Terpene

In addition to the lipophilicity of the drug, the lipophilicity of the terpene also plays an important
role in determining the penetration enhancement effect. It is anticipated that hydrocarbon terpenes,
such as limonene, exhibit a better penetration enhancement effect for lipophilic drug molecules,
and conversely, the polar group containing terpenes, such as menthol, 1,8-cineole, provide a better
penetration enhancement effect for hydrophilic drug molecules [11,28,42].
For highly lipophilic drugs, lipophilic terpenes with larger logP values seemed to be more
effective as it was easier for them to mix with the SC intercellular lipids, thus, fluidizing or perturbing
the integrity of the barrier function of the SC and, thereby, facilitating the skin penetration of the
drugs. Among tested terpenes, anethole (log P = 3.39) was proved to be the most satisfactory PE for
the permeation of lipophilic valsartan (log P = 4.5) followed by menthone (log P = 2.63). Eugenol
(log P = 2.30) was the least effective terpene enhancer [17]. However, it should be noted that high
lipophilicity of terpenes may have resulted in the decreased partitioning of ondansetron (log P = 2.07)
into the SC [27].
For most drugs, amphiphilic terpenes such as nerolidol possess a high penetration enhancement
effect because the amphiphilic structure is appropriate for the disruption of the highly organized lipid
packing in the SC [16,30].
Molecules 2016, 21, 1709 18 of 22
Extracting SC lipids is one of the key mechanisms of terpenes as PEs. The lipid extraction ability
is enhanced for terpenes with high log P values (e.g., nerolidol) or terpenes that can form highly
hydrophobic micellar structures with membrane lipids (e.g., limonene) [43].
4.3. Concentration of the Terpene

As presented in Table 2, the applied concentrations of the terpenes were in the range of 0.4%~15%.
Most terpenes were applied in the range of 1%~5% in TDDS. For different terpenes, the optimum
concentration may be different.
The penetration enhancement effect initially increased drastically with the increase in terpene
concentration. However, the drug penetration was not significantly enhanced with the further
increase in terpene concentration. The increase in ER values of the drug with the increase of terpene
concentration is normally attributed to the ability of the terpene to modify the skin barrier properties,
while the reduction of drug permeation at higher terpene concentrations could be attributed to the
interaction between terpene and the drug [16].
4.4. Chemical Structure of the Terpene

Generally, the percutaneous absorption of hydrophilic drugs is better improved by terpenes with
polar functional groups, which enable them to interact with the amide groups of the SC ceramides
more competitively than do the terpenes with a carbonyl group. This leads to the disruption of the
barrier provided by hydrogen bonding between lipid bilayers, and facilitate the diffusion of drugs
through the SC [28].
A chain structure of a terpene may help increase the penetration enhancement effect better than a
ring structure. It was found that terpenes with a ring structure, such as menthol and camphor, have
less of an effect when compared to terpenes with a long chain alkyl structure, such as nerol and oleic
acid [5]. Moreover, the chain molecule farnesol showed greater penetration enhancement effects for
hydrophilic drugs than cyclic terpenes, probably due to its lower vaporization energy [16]. Terpenes
with a low boiling point have relatively weaker intermolecular cohesive forces, which means the
oxygen of the functional group is mostly free. Therefore, competitive hydrogen bonding between the
functional groups of terpenes and the skin ceramides is facilitated [16].
The boiling point of a terpene is found to be inversely related to its skin penetration enhancement
effects, as the penetration enhancement of zidovudine, 1,8-cineole with a boiling point of 173 ◦ C
was proved to be the most effective compared to other terpenes with higher boiling points (carvone:
230 ◦ C; pulegone: 224 ◦ C; menthone 210 ◦ C; α-terpineol 217 ◦ C; and menthol 215 ◦ C) [44].
5. Skin Irritancy and Toxicity

Despite most PEs performing fairly well in TDDS, only a few of them have been approved for
clinical application due to their skin toxicity or irritation. Generally, the potency of PEs parallels their
potential for skin irritation and skin toxicity. It is challenging to maintain the balance between safety
and potency of PEs.
Terpenes obtained from natural sources are generally considered to be less toxic compared to
synthetic PEs, such as azone. The toxicities of terpenes were examined using an MTT assay in two
skin cell lines including keratinocytes and fibroblasts. It was found that the IC50 values of borneol
were markedly higher in both HaCaT keratinocytes (4.1150 ± 0.1489 mmol/L) and CCC-HSF-1
fibroblasts (4.9427 ± 0.2992 mmol/L) in comparison to those of the known standard enhancer azone
(0.1169 ± 0.0086 mmol/L in HaCaT cells and 0.2425 ± 0.0233 mmol/L in CCC-HSF-1 cells), indicating
that borneol had relatively low toxicity in skin cells [20]. Camphor, another monoterpene, was
also proved to have low irritancy potential. In a cytotoxicity assay, the IC50 values of camphor
were significantly higher in both keratinocytes (5.35 vs. 0.20 mmol/L) and fibroblasts (5.21 vs.
0.33 mmol/L) compared to azone [21]. Similar results were also obtained with limonene, terpinen-4-ol,
and 1,8-cineole [25]. The IC50 values of limonene, terpinen-4-ol, and 1,8-cineole against HaCaT
Molecules 2016, 21, 1709 19 of 22
keratinocytes were determined to be 2.207 ± 0.035, 0.908 ± 0.033, and 1.400 ± 0.139 mg/mL,
respectively. The IC50 values of limonene, terpinen-4-ol, and 1,8-cineole against CCC-ESF-1 fibroblasts
were determined to be 0.938 ± 0.059, 0.745 ± 0.063, and 1.391 ± 0.113 mg/mL, respectively. Their
previous studies [45] showed that the IC50 values of azone were 0.047 and 0.048 mg/mL in HaCaT
cells and CCC-ESF-1 cells, respectively. In summary, the natural terpenes possessed relatively low
skin irritation potential compared with azone. The effect of sesquiterpene nerolidol and various
monoterpenes (α-terpineol, carvone, limonene, menthone, menthol, pulegone, and 1,8-cineole) on
membrane fluidity in erythrocyte and fibroflast cells was studied and compared [46]. It was found
that the effect of sesquiterpene was significantly greater than that of the monoterpenes. In both tests,
nerolidol was among the most aggressive of terpenes and 1,8-cineole was among the least aggressive.
The toxicity of sesquiterpenes seemed to be higher than that of monoterpenes.
Six terpene compounds, namely menthol, limonene, 1,8-cineole, methone, terpinen-4-ol, and
pulegone, were proved to possess low cytoxicity in comparison with azone. Furthermore, the potential
mechanisms of these terpenes were also investigated. Terpene penetration enhancers perhaps changed
the membrane fluidity and potentials of HaCaT cells by altering the Ca2+ balance of the cell inside
and outside, resulting in an increase in the drug transdermal absorption [47]. Determination of
transepidermal water loss (TEWL) can be an effective index to represent the health of the skin
barrier function. Consequently, TEWL was determined in the investigation to evaluate the skin
irritation. The actual alteration in the TEWL (∆TEWL) value was increased up to 10.32-fold and
24.05-fold after topical application of 5% borneol and azone, respectively. However, no significant
differences were observed between 1% and 3% borneol and the control, suggesting the borneol had a
relative weak impact on TEWL in a certain concentration range. The results indicated that borneol
at an appropriate concentration did not produce obvious skin irritation [20]. However, although the
non-oxidized terpenes were non-irritating, both linalool and limonene were found to be more irritating
after oxidation compared with the pure terpene compounds [48]. Skin irritancy can be defined as
reactions to a particular irritant that results in inflammation of the skin and itchiness. It should be
noted that some terpenes, for example, α-bisabolol, can be applied as useful therapeutic candidates for
the treatment of skin inflammation [49].
6. Discussion and Conclusions

Terpenes belong to a large class of the most abundant natural compounds and are commonly
present in plants as constituents of essential oils. While it is difficult to synthesize novel chemical
PEs, terpenes seem to possess great potential for use as PEs. Until now, at least 28 terpenes have been
evaluated and applied as PEs in TDDS (Table 1). Among them, the most commonly used terpenes are
1,8-cineole, menthol, limonene, menthone, and nerolidol.
Compared to conventional synthetic PEs, natural terpenes have been shown to possess higher
enhancement activity of both lipophilic and hydrophilic compounds. Results of in vitro skin
permeation studies, in vivo pharmacokinetics, and pharmacological evaluation have demonstrated
that terpenes can act as potential PEs due to their high enhancement activity and low toxicity.
Interaction with SC intercellular lipids is the key factor determining the effectiveness of terpenes
as PEs. The effect of terpenes on SC lipids mainly involves the interactions at two sites, namely the
lipophilic tails of the intercellular lipids and the polar head groups. They can fluidize and/or extract
the SC lipids to weaken the skin permeability barrier provided by the SC lipids. In the SC, a large
number of ceramides are tightly arranged in the lipid bilayer due to the hydrogen bonding network.
The tight hydrogen bonding network can be loosened by the terpenes with a functional group that can
donate or accept a hydrogen bond. Consequently, most (89.29%) terpenes which can be used as PEs
are oxygen-containing terpenes. Oxygen-containing and hydrocarbon terpenes could form complexes
with drug molecules, which help in the SC partition of the drug. Their effect on the SC partition may
depend on the lipophilicity of the drug. Furthermore, the physiological activity of terpenes in the
living skin can also affect their efficacy as PEs.
Molecules 2016, 21, 1709 20 of 22
The key factors affecting the enhancement effect are the lipophilicity of both terpenes and drug
molecules. For most drugs, amphiphilic terpenes exert a high penetration enhancement effect because
the amphiphilic structure is appropriate for the disruption of the highly organized lipid packing in the
SC. Chain structure and low boiling point may help to improve the penetration enhancement effect
of terpenes. Moreover, terpenes should be applied in optimum concentration. Most terpenes were
applied in the concentration range of 1%~5% in TDDS.
Revealed by skin cell viability assay and TEWL measurement, terpenes from natural sources are
generally proven to be safer as PEs with very low irritancy potential compared to azone, the classic
chemical skin PE. Until now, no correlation between skin toxicity and penetration enhancement effect
has been found.
Acknowledgments: The authors acknowledge the financial support from the Key Project of Jiangsu Collaborative
Innovation Center of Chinese Medicinal Resources Industrialization (ZDXMHT-1-15) and the Open Project
Program of Hubei Key Laboratory of Drug Synthesis and Optimization, Jingchu University of Technology
(No. OPP2015ZD03).
Conflicts of Interest: The authors declare no conflict of interest.
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© 2016 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
(CC-BY) license (http://creativecommons.org/licenses/by/4.0/).

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Academic Editor: Derek J. McPhee

Keywords: terpenes; penetration enhancer; transdermal drug delivery; stratum corneum

Molecules 2016, 21, 1709; doi:10.3390/molecules21121709 www.mdpi.com/journal/molecules

2. Skin Penetration Enhancement Effect

α-Bisabolol Sesquiterpene C15H26O 222.366 5.07 314.5 [19]

Borneol Monoterpene C10H18O 154.249 2.71 212 [16,19,20]

Molecules 2016, 21, 1709 4 of 22

Cymene Monoterpene C10H14 134.22 4.02 173.9 [24]

Molecules 2016, 21, 1709 4 of 21

Molecules 2016, 21, 1709 5 of 22

Molecules 2016, 21, 1709 5 of 21

Table 2. Skin penetration enhancement effect of terpenes applied as PEs.

3.1. Effect on SC Lipids

3.2. Effect on Hydrogen Bond Connection

3.3. Effect on SC Partition of Drugs

3.4. Effect on Physiological Reactions

4. Factors Affecting the Penetration Enhancement Effect

4.1. Lipophilicity of the Drug

4.2. Lipophilicity of the Terpene

4.3. Concentration of the Terpene

4.4. Chemical Structure of the Terpene

5. Skin Irritancy and Toxicity

6. Discussion and Conclusions

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