Journal of Drug Delivery Science and Technology 54 (2019) 101289

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Journal of Drug Delivery Science and Technology

journal homepage: www.elsevier.com/locate/jddst

Formulation design and evaluation of a transdermal drug delivery system T

containing a novel eptazocine salt with the Eudragit® E adhesive
Takayuki Furuishia,∗, Koji Kunimasub, Keita Fukushimac, Takashi Oginod, Kaoru Okamotob,
Etsuo Yonemochia, Kazuo Tomonoc, Toyofumi Suzukic,∗∗
a
Department of Physical Chemistry, School of Pharmacy and Pharmaceutical Sciences, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo, 142-8501, Japan
b
Formulation Research Laboratory, Nippon Zoki Pharmaceutical Co., Ltd., 1093-1 Minamiyama, Furukawa-cho, Ono-shi, Hyogo, 675-1363, Japan
c
Laboratory of Pharmaceutics, School of Pharmacy, Nihon University, 7-7-1 Narashinodai, Funabashi, Chiba, 274-8555, Japan
d
Institute of Bio-Active Science, Nippon Zoki Pharmaceutical Co., Ltd., 442-1, Kawakitayama, Kinashi, Kato-shi, Hyogo, 673-1461, Japan

A R T I C LE I N FO A B S T R A C T

Keywords: We aimed to select an appropriate permeation enhancer for the percutaneous absorption of eptazocine (EPZ) and
Transdermal develop a prolonged-release EPZ transdermal patch using Franz diffusion cells fitted with hairless mouse skin.
Eptazocine We tested several enhancers and found that the effect on the skin permeation of EPZ of an isopropyl myristate
Salt form (IPM) solution system was improved by adding glyceryl monocaprylate (GEFA-C8). The patches had a film
Skin permeation enhancer
former (Eudragit® E) as the matrix backbone, with 10% free EPZ, 10% IPM, and 5% GEFA-C8. The addition of 5%
Eudragit
citric acid to the Eudragit E matrix led to a three-fold increase in the flux of EPZ (31.4 μg/cm2/h). Changing the
form of EPZ loaded onto the patch from the free form to a salt form (hydroxybromide [HBr], hydrochloride,
lactate, oxalate, citrate, and tartrate), with concentrations of 20% EPZ, led to drug retention in the matrix
without crystallization. The patches with 20% EPZ HBr salt, 10% IPM, and 5% GEFA-C8 exhibited the highest
permeation flux (48.3 μg/cm2/h). These results indicate that EPZ HBr salt in a Eudragit® E matrix could be used
as a novel analgesic transdermal drug delivery system.

1. Introduction formulation for postoperative anti-inflammatory pain relief and early

Pain can be controlled using various analgesics, which are selected
depending on the type and extent of the pain. Anesthesiologists must
not only manage postoperative acute pain but also control in-
traoperative anesthesia and analgesia [1,2]. Eptazocine (EPZ) was
synthesized in Japan in 1976 and introduced onto the market in 1987,
and was developed as a narcotic antagonist analgesic [3]. EPZ is a κ-
selective opioid receptor agonist that is currently used for clinical ap-
plications. The analgesic effect of EPZ is similar to or stronger than that
of pentazocine (a narcotic-antagonist analgesic); however, it is weaker
than that of morphine in humans when systemically administered [4,5].
EPZ is used for the management of cancer-related and postoperative
pain due to its limited capacity to induce respiratory depression, phy-
sical dependence, or tolerance [6–8]. The intravenous or subcutaneous
injection formulation of EPZ is commonly used, since this drug has a
half-life of only 2 h [9,10]; hence, the physical burden of frequent in-
travenous or subcutaneous administration is a concern. There may thus
be a clinical need for increased availability of EPZ in a long-acting
functional recovery following surgery such as total knee arthroplasty.
EPZ exhibits a stronger analgesic effect than nonsteroidal anti-in-
flammatory analgesic agents, and has a lower frequency of adverse
effects compared to narcotic analgesic agents such as morphine. It
therefore shows immense potential as an external analgesic preparation
that exhibits excellent characteristics of effectiveness, safety, and long-
term usability.
A transdermal drug delivery system (TDDS) is a painless method of
delivering drugs systemically via the application of drug formulations
to intact skin [11]. TDDSs have several advantages over painful hypo-
dermic injections, since they do not generate dangerous medical waste
or pose a risk of disease transmission via needle reuse (a consideration
especially in developing countries) [12] and can provide a non-invasive
alternative to parenteral routes, thereby circumventing issues such as
needle phobia [13]. TDDS patches were designed to control release of
drugs into the systemic blood circulation over a period of time after
their application to the skin.
To the best of the authors’ knowledge, only one patent has reported

∗
Corresponding author.
∗∗
Corresponding author.
E-mail addresses: t-furuishi@hoshi.ac.jp (T. Furuishi), suzuki.toyofumi@nihon-u.ac.jp (T. Suzuki).

https://doi.org/10.1016/j.jddst.2019.101289
Received 13 May 2019; Received in revised form 30 August 2019; Accepted 15 September 2019
Available online 20 September 2019
1773-2247/ © 2019 Elsevier B.V. All rights reserved.
T. Furuishi, et al. Journal of Drug Delivery Science and Technology 54 (2019) 101289

enhancement of the skin permeation of EPZ [14]. The need for trans- Table 2
dermal delivery of analgesics is likely to continue to increase, with the Formulation of TDDS patches containing free EPZ in an IPM/GEFA-C8 system.
increase in the elderly population, so further design improvement is Adhesive EPZ IPM GEFA-C8 Citric acid Adhesive
desirable [15], and the development of a novel TDDS patch for the
delivery of EPZ would be beneficial for postoperative pain control. Duro-Tak® 10 10 5 – 75
Eudragit® E 10 10 5 – 75
We investigated the percutaneous absorption of the free form (i.e.,
Eudragit® RS/RL 10 10 5 – 75
the non-salt form) of EPZ with isopropyl myristate (IPM) and glycerol Plastoid® B 10 10 5 – 75
esters of fatty acids (GEFAs) through the skin of hairless mice. Novel Eudragit® E + citric acid 10 10 5 5 70
matrix-type transdermal patches for the delivery of free EPZ were
fabricated using acrylic adhesives, and these patches were evaluated in Values are concentration (%) by weight.
vitro. In addition, matrix-type transdermal patches with several salt
forms of EPZ, using Eudragit® E adhesive, were developed and eval- Table 3
uated to improve the dispersion and/or dissolution of the drug in the Formulation of salt-form EPZ TDDS patches based on Eudragit® E.
adhesive. Form of EPZ EPZ IPM GEFA-C8 Eudragit E

Free 20 10 5 65
2. Materials and methods HBr 20 10 5 65
HCl 20 10 5 65
2.1. Materials Lactate 20 10 5 65
Oxalate 20 10 5 65
Citrate 20 10 5 65
The free form of EPZ ((1S, 6S)-1,4-dimethyl-2,3,4,5,6,7-hexahydro- Tartrate 20 10 5 65
1H-1,6-methano-4-benzazonin-10-ol) was isolated from the injection HBr 30 10 5 55
formulation of eptazocine hydrobromide (Sedapain® Inj. 15, Nichi-Iko HCl 30 10 5 55
Lactate 30 10 5 55
Pharmaceutical, Toyama, Japan). The synthesis and characterization of
the salt forms of EPZ are provided in the Supplementary Material. IPM Values are concentration (%) by weight.
was purchased from Wako Pure Chemical (Osaka, Japan). Propylene
glycol (PG) was purchased from Tokyo Chemical Industry (Tokyo, mixed pressure-sensitive adhesive (PSA) solution was cast at a thickness
Japan). Glyceryl monocaprylate (GEFA-C8, Sunsoft® 700P-2), glyceryl of 200 μm on a backing membrane (9742 Scotchpak™, 3M, Maplewood,
monocaprate (GEFA-C10, Sunsoft® 760), glyceryl monolaurate (GEFA- MN, USA) with a film applicator (MULTICATOR™ 411, Erichsen,
C12, Sunsoft® 750), glyceryl monostearate (GEFA-C18, Sunsoft® 8000 V), Hemer, Germany) and heated in an oven at 60 °C for 20 min to remove
and glyceryl dicaprylate (GEFA-DiC8, Sunsoft® GDC-S) were donated by any residual solvent. The dried film was then laminated with a release
Taiyo Kagaku (Mie, Japan). Glyceryl tricaprylate (GEFA-TriC8, liner (CoTran™ 9722, 3M) to protect it from tearing. The resulting
Panacate® 800) and polyoxyethylene lauryl ether (POE-lauryl ether, three-layered sheets were stored at room temperature for 24 h, and
NONION® K-204) were donated by NOF Corporation (Tokyo, Japan). circular patches of 1.13 cm2 (diameter 12 mm) were die-cut before each
Glyceryl monobutyrate (GEFA-C4) and glyceryl monocaproate (GEFA- experiment.
C6) were synthesized in our laboratory following previous studies
[16–18]. Duro-Tak® 87–9301 was donated by Henkel Japan (Tokyo,
2.3. Polarized microscopy
Japan). Eudragit® E PO (butylated methacrylate copolymer), Eudragit®
RL PO, Eudragit® RS PO (ammonio methacrylate copolymer types A
Polarized microscopy measurements of the circular patches were
and B), and Plastoid® B (neutral polymer based on butyl methacrylate
carried out on an Eclipse E600W POL microscope (Nikon, Tokyo,
and methyl methacrylate) were kindly donated by Evonik Japan
Japan) to examine drug crystallization after 24 h of storage at room
(Tokyo, Japan). All other analytical-grade solvents and reagents were
temperature following the manufacturing process.
commercially obtained and used without further purification.
2.4. Skin permeation study
2.2. Synthesis of aminoalkyl copolymer adhesives
All animal experiments were carried out in accordance with the
Eudragit® E, Eudragit® RS/RL (1:1), and Plastoid® B adhesives and guidelines of the Institutional Animal Care and Use Committee (School
transdermal patches were prepared as described in previous studies of Pharmacy, Nihon University, Chiba, Japan), as well as the ARRIVE
[19,20]. Table 1 summarizes the composition of these adhesives. guidelines for the care and use of laboratory animals, UK Animals
Briefly, the polymers were dissolved in acetone/ethanol/2-propanol (Scientific Procedures) Act 1986 and associated guidelines, and EU
(9:5:1) (for Eudragit® E and RS/RL) or acetone (for Plastoid® B), using a Directive 2010/63/EU for animal experiments (Approval number:
mechanical stirrer (MAZELA Z-2100, Tokyo Rikakikai, Tokyo, Japan). AP1904). The excised skin of hairless mice (Labo Skin, HOS: HR-1 Male,
Next, the plasticizer was added to the polymer solution, and the pre- aged 7 weeks, Hoshino Laboratory Animals, Ibaraki, Japan) was used as
parations were mixed for 10 min. For the Eudragit® adhesives, the a permeation membrane for in vitro skin permeation tests. These tests
cross-linker succinic acid was also added (Table 1). were carried out with a Franz diffusion cell (Vertical Diffusion Cell™,
First, appropriate amounts of EPZ, the adhesive, and the enhancers Hanson Research, Los Angeles, CA, USA) at 32 °C. A saturated free EPZ
were mixed and subjected to sonication (Tables 2 and 3). Second, the solution (200 μL) in IPM, with or without of one of the seven GEFA

Table 1
Composition of adhesives based on Eudragit® and Plastoid®.
Polymer (%) Plasticizer (%) Cross-linker (%) Solvent (%)

Eudragit® E Eudragit® E PO (35) Dibutyl sebacate (19) Succinic acid (4) Acetone, ethanol, 2-propanol (35)
Eudragit® RS/RL (1:1) Eudragit® RS PO Dibutyl phthalate (13) Succinic acid (2) Acetone, ethanol, 2-propanol (40)
Eudragit® RL PO (45)
Plastoid® B Plastoid® B (43) Dibutyl phthalate (17) – Acetone (40)

2
T. Furuishi, et al.
compounds added at a 10% (w/v) concentration, was added to the
donor cells. Saturated solutions were used for the diffusion experiments
to assess the maximum thermodynamic activity of the drug [21]. The
effective area of diffusion was 1.77 cm2, and the receiver cell volume
was approximately 7 mL. The receiver cells were filled with McIlvaine
buffer (pH 4.0) [22,23] to maintain sink conditions and stirred at
650 rpm using a magnetic stirrer. The amount of EPZ that permeated
the receiver cells was quantitated by collecting 0.5 mL samples at de-
signated time intervals for high-performance liquid chromatography
(HPLC) analysis. The receiver cell fluid withdrawn at each interval was
replaced with the same volume of McIlvaine buffer.
2.5. Analytical method
The HPLC system was constructed with a PU-2080 Plus Intelligent
HPLC Pump, a UV-2075 Intelligent UV/Vis Detector, and an AS-2055
Plus Intelligent Sampler (Jasco, Tokyo, Japan). A CAPCELL PAK C18-
type MG (150 mm long × 4.6 mm internal diameter, particle size 5 μm;
Shiseido, Tokyo, Japan) analytical column was used at room tempera-
ture. The mobile phase comprised 50 mM phosphoric acid and acet-
onitrile (77:23, v/v) at a flow rate of 1.0 mL/min. The column eluate
was monitored at an ultraviolet wavelength of 278 nm.
2.6. Data analysis
The cumulative quantity of the drug permeating through the skin
(Q) was plotted as a function of time. Skin flux was determined using
Fick's law of diffusion (Equation (1)):
Jss = dQr/Adt,
where Jss is the steady-state skin flux in μg/cm2/h, dQr is the change in
quantity of the drug passing through the skin into the receptor com-
partment in μg, A is the active diffusion area in cm2, and dt is the time
elapsed. The lag time (LT, h) was calculated by extrapolating the linear
region of the curve to the x-axis. The permeability coefficient (P) was
calculated using Equation (2)
P = Jss/S,
where S is the saturation solubility of the drug in the donor solution.
2.7. Statistical analysis
Results are expressed as the mean ± standard deviation (SD) of at
least three independent experiments. Two-group comparisons were
performed using Student's t-test. Multiple-group comparisons were
performed using one-way analysis of variance (ANOVA) and Fisher's
least significant difference. P-values of < 0.05 or 0.01 were defined as
statistically significant.
3. Results
3.1. Skin permeation of free EPZ in combination with various glycerol esters
of fatty acids (GEFAs) and IPM solution
In the first part of this experiment, we investigated the efficacy of
skin permeation enhancers that are used as pharmaceutical additives
for enhancing the skin permeation of free EPZ (Table S1). Although the
Jss and LT of IPM were slightly lower and longer than those of POE-
lauryl ether, the value of P was 5–7 times greater than for the other
solvents (POE-lauryl ether and PG). IPM was thus the most suitable
solvent for this transdermal system for delivery of free EPZ, and it was
therefore selected for all subsequent experiments assessing skin per-
meation.
We then investigated the effect of adding GEFAs to the IPM solution
on the percutaneous absorption of free EPZ. Fig. 1 and Table S2 show
Journal of Drug Delivery Science and Technology 54 (2019) 101289
Fig. 1. Permeation flux (JSS) and permeation coefficient (P) of free EPZ
from an IPM suspension containing one of various GEFAs. Values are
means ± SD (n = 3 or 4).
the Jss and P values and skin permeation parameters for free EPZ, re-
spectively. Compared with IPM on its own, the combination of IPM
with GEFA-C6, C8, or C10 markedly enhanced P. The value of Jss in-
creased with increased GEFA alkyl chain length from GEFA-C4 to GEFA-
C8, but beyond GEFA-C8, Jss decreased once more. GEFA-DiC8 and
GEFA-TriC8 did not enhance the skin permeation of EPZ. GEFA-C8
therefore exhibited the optimal enhancement of EPZ skin permeation,
suggesting that it could be a candidate chemical percutaneous absorp-
(1) tion enhancer.
3.2. Fabrication of TDDS patches incorporating free EPZ and Eudragit® E
adhesive
To optimize the formulation of the free EPZ patches, the effect of
various acrylic PSA matrices containing 10% IPM and 5% GEFA-C8 on
the skin permeation of free EPZ was investigated (Table 2). First we
(2)
used the Duro-Tak® 87-9301 adhesive, but Jss was only 1% of that
obtained using the free EPZ suspension (29.4 μg/cm2/h), and LT was
longer than with the suspension (Table S3).
We then tested the effects of Eudragit® E adhesive, Eudragit® RS/RL,
and Plastoid® B, all of which are acrylate copolymers. The highest flux
(12.0 μg/cm2/h) was obtained with Eudragit® E (Table S3). Despite the
fact that Eudragit® E is based on a basic polymer and Eudragit® RS/RL
and Plastoid® B are based on neutral polymers, drug crystals were ob-
served with all three after the manufacturing process (Fig. 2A). The
differences in the skin permeation of EPZ among these three formula-
tions may therefore have been caused by electrostatic interactions be-
tween the drug and polymer functional group. We also investigated the
effect of citric acid on the Jss of EPZ patches containing Eudragit® E
(Fig. 2B) and found that it was 31.4 μg/cm2/h, which is ~3 times
greater than without citric acid (Table S3). Microscope analysis of these
patches revealed that the crystallization of EPZ did not occur with the
addition of citric acid (Fig. 2A). Thus the addition of citric acid induces
an improvement in EPZ flux and avoids drug crystallization in the
matrix.
3.3. Fabrication of TDDSs using the salt form of EPZ and Eudragit® E
adhesive
Transdermal matrix patches containing Eudragit® E were prepared
to investigate the effect of using various organic salt forms of EPZ on
the drug's steady-state skin flux (Table 3). In these experiments, the
salts were loaded directly onto the patch rather than being added to the
matrix, at a concentration of 20% or 30% by weight. EPZ
3
T. Furuishi, et al. Journal of Drug Delivery Science and Technology 54 (2019) 101289

Fig. 2. (A) Photographs of EPZ crystals in, and (B) permeation flux (JSS) of EPZ from, TDDS patches containing free EPZ with or without citric acid (5%).
Values are means ± SD (n = 3 or 4). Student's t-test was used to determine the statistical significance of differences with respect to the Eudragit® E patch without
citric acid. **P < 0.01.

Fig. 3. Photographs of EPZ crystals in TDDS patches containing salt-form EPZ.

4
T. Furuishi, et al.
Fig. 4. Permeation flux (JSS) of EPZ from TDDS patches containing salt-
form EPZ. Values are means ± SD (n = 3 or 4). ANOVA was used to de-
termine the statistical significance of differences with respect to the free EPZ
patch. *P < 0.05; **P < 0.01; N·S., not significant.
hydroxybromide (HBr), hydrochloride (HCl), and lactate did not exhibit
crystallization in the matrix (Fig. 3), even though they were loaded onto
the patches at concentrations of 20%, double that of the free EPZ that
did exhibit crystallization (Fig. 2A). In contrast, the patches with EPZ
citrate and tartrate did exhibit crystal formation (Fig. 3). The HBr
(48.3 μg/cm2/h), HCl (35.9 μg/cm2/h), and lactate (35.1 μg/cm2/h)
salts of EPZ also yielded a faster flux than free EPZ (Fig. 4, Table S4).
When the loading concentration of the drug in the adhesive was in-
creased from 20% to 30%, however, the Jss values were almost un-
changed (Fig. 4, Table S4), and now a microcrystalline structure was
observed for the HBr and lactate salts, although still not for the HCl salt
(Fig. 3). Thus use of a concentration of more than 20% did not appear to
beneficially affect the drug's skin permeation. Based on these results,
the skin permeation of HBr, HCl, and lactate EPZ salts loaded at 20% in
the TDDS was higher than that of the free form of EPZ in the Eudragit®
E matrix.
4. Discussion
4.1. Skin permeation of the free form of EPZ in combination with various
GEFAs and an IPM solution
When drugs permeate the skin, they penetrate the stratum corneum
(SC) and then pass through the deeper epidermis and dermis without
accumulating in the dermal layer. The SC comprises keratin-rich cells
embedded in multiple lipid bilayers, which mainly consist of ceramides,
cholesterol, and free fatty acids [24,25]. The intercellular lipid domain
is generally thought to be the main pathway for the penetration of most
drugs through the SC [26]. To facilitate the safe, effective delivery of
drugs through the skin [27], skin permeation enhancers may be used.
Ideally, these cause a temporary, reversible reduction in the barrier
function of the SC. There are various GEFAs with different alkyl chain
lengths and/or degrees of substitution, and when used as permeation
enhancers, their structures are predicted to differentially affect the skin
permeation of the drug. Our skin permeation experiments revealed that
a GEFA-C8/IPM system enhanced the skin permeation of EPZ: the
highest permeation rate for free EPZ in solution, 292.5 μg/cm2/h, was
observed with GEFA-C8 (Table S2). The hydrophilic–lipophilic balance
(HLB) values of GEFA-C6, GEFA-C8, and GEFA-C10 are 8.2, 7.2, and 6.5,
respectively [28]. This range (6.5–8.2) was in good agreement with the
reported range for polyoxyethoxylated non-ionic surfactants (7–9) that
act as effective promoters of ibuprofen flux across rat skin [29]. With
5
Journal of Drug Delivery Science and Technology 54 (2019) 101289
respect to the mechanism by which IPM and the combination of GEFA-
C8 with IPM enhance the skin permeation of EPZ, IPM is known to fa-
cilitate the fluidization of SC lipids [30] and the distribution of drugs
into the skin [27]. The synergistic effects of IPM and GEFA-C8 in in-
ducing the loss of stacking order in the SC lipid bilayers have been
reported [30]. It is thus not surprising that the combination of IPM and
GEFA-C8 improved the skin permeation of free EPZ through hairless
mouse skin.
4.2. Free EPZ TDDS patches based on Eudragit E adhesive with and without
citric acid
Matrix TDDS patches incorporate active drugs in a polymer matrix
that regulates the release of the drug via diffusion (i.e., the drug moves
from high to low concentrations). This differs from reservoir systems,
which contain a rate-controlling membrane that is responsible for the
controlled release of transdermal formulations [31]. Simple matrix
systems comprise a single polymer layer that contains the active drug.
Drug-in-PSA systems contain a PSA layer that interacts directly with the
skin and contains the active drug. Since the physicochemical properties
of the PSA significantly affect the skin permeation rate of the drug, the
selection of an appropriate PSA matrix is crucial in TDDS patch design
[32,33]. Drug-in-PSA systems are typically thin and pliable, which may
improve patient adherence.
The combination of IPM and GEFA-C8 improved the percutaneous
absorption of free EPZ (Fig. 1, Table S2). A monolithic adhesive matrix-
type patch was fabricated using free EPZ, IPM, and GEFA-C8, based on a
pressure-sensitive acrylic adhesive, Duro-Tak® 87–9301. Previously, a
TDDS with pentazocine, whose structure is similar to that of free EPZ,
has been reported with Duro-Tak® 87–9301 as the adhesive [20].
Contrary to our expectations, using Duro-Tak® 87–9301 as the adhesive
with EPZ led to a lower flux rate (2.6 μg/cm2/h). Since this matrix was
saturated with free EPZ, the Jss value did not improve even when the
amount of free EPZ in the matrix was increased. We therefore tried
using different acidic, basic, and neutral polymers, and compared their
performance with respect to flux [34]. The diffusion coefficient of drugs
in a PSA matrix is affected by the type of functional group the drug
molecule contains. Drugs with secondary amide and tertiary amine
groups interact with carbonyl groups in the PSA, whereas those with
carbonyl or ester groups do not exhibit strong interactions [35]. Eu-
dragit, methacrylic acid, and methacrylate copolymers are used in the
pharmaceutical industry as film-coating materials for tablets [36], and
they are attracting attention as potential adhesives for transdermal
systems [34,37]. The skin permeation of free EPZ TDDS patches using
Eudragit® E, Eudragit® RS/RL, or Plastoid® B exhibited a higher flux
than those based on the Duro-Tak® 87-9301 adhesive (Table S2). This
indicated that the EPZ was supersaturated in the patch. The solubility of
EPZ decreased in the following order: ethanol > 2-propanol >
acetone > ethyl acetate (Fig. S1). The solvent used to dissolve the
drug in the matrix that exhibited the lowest flux was ethyl acetate
(which is nonpolar), but acetone, ethanol, and 2-propanol (all of which
are polar organic solvents) were used in the Eudragit® E, Eudragit® RS/
RL, and Plastoid® B patches respectively. Thus the flux was higher in
these patches, even though the EPZ content was the same (10%), be-
cause the amount of EPZ dissolved in the matrix was greater. The
amount of succinic acid used as the cross-linker in the Eudragit® E patch
was greater than that used in the Plastoid® B patch, and the skin per-
meation of the drug when combined with a basic polymer (Eudragit® E
patch) was greater than when it was combined with a neutral polymer
(Eudragit® RS/RL and Plastoid® B patches). We therefore suggest that
the differences in the drug's skin permeation summarized in Table S3
were caused by electrostatic interaction between the drug and polymer
functional groups.
The addition of an organic acid improves the skin permeation of
basic non-narcotic analgesic drugs from TDDS patches [14]. The Jss
value for the Eudragit® E TDDS system with citric acid was about three
T. Furuishi, et al.
times higher than for that without citric acid (Fig. 2B, Table S2). This
improvement in EPZ flux was related to the enhanced dissolution of
EPZ in the matrix.
4.3. Salt-form EPZ TDDS patches based on Eudragit® E adhesive
The addition of citric acid improved the skin permeation of EPZ
when used with Eudragit® E adhesive, and it would have generated an
EPZ salt in the matrix. However, the addition of an organic acid into a
transdermal matrix during fabrication would be complicated. On the
other hand, EPZ HBr is used clinically for injection and is solubilized in
ethanol. We therefore postulated that the salt forms of EPZ, including
EPZ HBr, would be readily soluble in the Eudragit® matrix, and thus
tested transdermal matrix patches containing salt-form EPZ, with
Eudragit® E as the adhesive. The EPZ HBr, HCl, and lactate salts loaded
at a 20% concentration onto the patch each exhibited better skin per-
meability than the other salt forms tested (Fig. 4). This was supported
by the fact that crystallization was not observed in the patches con-
taining these salts forms (Fig. 3). In contrast, the patches containing the
citrate and tartrate EPZ salts exhibited crystal formation in the ma-
trices. Combined, these results suggested that the EPZ was super-
saturated in the HBr, HCl, and lactate patches. The skin permeation
profiles of the EPZ citrate and tartrate patches were comparable with
that of the free EPZ patch in terms of Jss (μg/cm2/h) and LT (h), but not
with respect to Q (μg/cm2; Table S4). Since there is a limit to the so-
lubility of EPZ citrate and tartrate in the Eudragit® E matrix, EPZ
crystallization occurred in the matrix. A longer LT (15 h) without
crystallization was observed for the TDDS containing EPZ oxalate
(Table S4). The LT value indicates the time required for a stable diffu-
sion flow to be established, the use of the oxalate salt could possibly
delay the diffusion of EPZ from the matrix relative to the free form of
EPZ (Table S4).
The permeation rate of fentanyl from polyisobutylene matrices
through human cadaver skin exhibits a linear increase up to the sa-
turation concentration [38]. In matrices loaded with high drug con-
centrations, crystallization of the drug is thought to lead to a reduction
in its thermodynamic activity, possibly reducing its flux through the
stratum corneum [38]. The in vitro steady-state flux from amorphous
ketotifen-dispersed matrices through excised hairless mouse skin is
about seven times higher than that from crystalline ketotifen-dispersed
matrices [39]. This enhanced skin permeation of the amorphous form of
ketotifen from a PSA matrix is caused by supersaturation. In a super-
saturated system, the excess drug molecules once full solubility has
been reached are dispersed in the vehicle, leading to a temporarily high
thermodynamic activity and skin permeation. Hence, the skin per-
meation efficiency of the TDDS systems containing EPZ salts suggests
that they are supersaturated in the adhesive matrix.
5. Conclusion
In this study, a novel transdermal patch for the delivery of salt-form
EPZ was developed using the Eudragit® E adhesive polymer and a skin
permeation enhancer comprising 10% IPM and 5% GEFA-C8. Using
concentrations of up to 20% of EPZ HBr, HCl, or lactate salt resulted in
a two-to three-fold increase in the skin permeation of the drug from the
patch relative to that of the free drug, without crystal formation. A
TDDS patch containing EPZ salts may therefore be a potential long-term
release formulation for the management of chronic pain in patients with
arthralgia.
Author contributions
Takayuki Furuishi and Koji Kunimasu contributed equally to this
article.
6
Journal of Drug Delivery Science and Technology 54 (2019) 101289
Conflicts of interest
Koji Kunimasu, Takashi Ogino, and Kaoru Okamoto are full-time
employees of Nippon Zoki Pharmaceutical Co. Ltd., and thus declare a
possible conflict of interest.
Acknowledgements
This study was supported by Hoshi University Grant-in-Aid for
Leading Research Project grants in 2017 and 2018, and by the OTC Self-
Medication Promotion Foundation 2018 (T.F.). In addition, this study
was supported in part by the Private University Research Branding
Project of the Ministry of Education, Culture, Sports, Science, and
Technology of Japan (T.S.).
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://
doi.org/10.1016/j.jddst.2019.101289.
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