- Email: [email protected]
Enhanced dissolution and skin permeation profiles of epalrestat with β-cyclodextrin derivatives using a cogrinding method
European Journal of Pharmaceutical Sciences 106 (2017) 79–86
Contents lists available at ScienceDirect
European Journal of Pharmaceutical Sciences journal homepage: www.elsevier.com/locate/ejps
Enhanced dissolution and skin permeation profiles of epalrestat with βcyclodextrin derivatives using a cogrinding method
MARK
Takayuki Furuishia,⁎, Shoma Takahashib, Noriko Ogawac, Mihoko Gunjia, Hiromasa Nagased, Toyofumi Suzukib, Tomohiro Endoe, Haruhisa Uedaa,f, Etsuo Yonemochia, Kazuo Tomonob a
Department of Physical Chemistry, School of Pharmacy and Pharmaceutical Sciences, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan Laboratory of Pharmaceutics, School of Pharmacy, Nihon University, 7-7-1 Narashinodai, Funabashi-shi, Chiba 274-8555, Japan c Department of Pharmaceutical Engineering, School of Pharmacy, Aichi Gakuin University, 1-100 Kusumoto-cho, Chikusa-ku, Nagoya, Aichi 464-8650, Japan d Central Research Laboratories, School of Pharmacy and Pharmaceutical Sciences, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan e School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo, 192-0392, Japan f Department of Pharmaceutical Sciences, Nihon Pharmaceutical University, 10280 Komuro, Ina-machi, Kitaadachigun, Saitama, 362-0806, Japan b
A R T I C L E I N F O
A B S T R A C T
Keywords: Epalrestat Cyclodextrin Solubility Skin permeation Cogrinding Enhancer
Epalrestat (EPL) is a water-insoluble drug (14 μM) that inhibits aldose reductase. This study investigated the interactions between β-cyclodextrin (CD) derivatives and EPL to determine the solubilizing effect on EPL from phase solubility diagrams. We improved the solubility of EPL in water by adding β-CD derivatives. Moreover, the solubility of EPL mixed with β-CD derivatives by cogrinding in a ball mill method was about 2–3 times higher than those of EPL with the same CD concentration (5 mM) calculated from phase solubility diagrams. In addition, we investigated the effect of β-CD derivatives on in vitro percutaneous absorption of EPL through hairless mouse skin. Among the coground mixtures of EPL and β-CD derivatives, the mixture containing methyl (ME)-β-CD showed the strongest enhancement of EPL skin permeation. Furthermore, adding 10 wt% urea as a skin permeation enhancer after cogrinding with ME-β-CD improved the flux of EPL 300 times compared to the flux of EPL alone. This result indicates the ME-β-CD ground mixture system with urea has potential as a new transdermal drug delivery system of EPL for diabetic neuropathy.
1. Introduction Diabetic neuropathy is one of the most common long-term complications in patients with diabetes mellitus, with 30%–90% of patients with diabetes experiencing peripheral neuropathy (Callaghan et al. 2012). It is known that hyperglycemic conditions result in accumulation of sorbitol in nerves (Ohmura et al. 2009), which poorly penetrates the cell membranes and contributes to the progression of diabetic complications, such as neuropathy, retinopathy, and nephropathy (Ohmura et al. 2009; Chylack and Kinoshita, 1969; Kinoshita et al. 1981; Oates and Mylari, 1999). Epalrestat (EPL, Fig. 1) is a carboxylic acid derivative that inhibits aldose reductase (Terashima et al. 1984), an enzyme in the polyol pathway. Under hyperglycemic conditions, EPL reduces intracellular sorbitol accumulation, which can be effective in treating diabetic neuropathy (Ramirez and Borja, 2008). In Japan, EPL is currently administered through an oral dosage (Kinedac® Tablets 50 mg and many generics). Hotta et al. reported that long term treatment with EPL is well tolerated and can effectively delay the progression of diabetic ⁎
Corresponding author. E-mail address: [email protected] (T. Furuishi).
http://dx.doi.org/10.1016/j.ejps.2017.05.047 Received 12 February 2017; Received in revised form 2 May 2017; Accepted 22 May 2017 Available online 22 May 2017 0928-0987/ © 2017 Elsevier B.V. All rights reserved.
neuropathy and ameliorate associated symptoms of the disease (Hotta et al. 2006). Unfortunately, the oral EPL formulation is usually administrated three times a day and the dosing is usually long term (Hotta et al. 1996; Uchida et al. 1995; Maladkar et al. 2009). Reducing the frequency of oral dosage may improve adherence to therapies among patients (Srivastava et al. 2013). Hence, there may be a clinical need for increased availability of EPL as a long-acting formulation for diabetic neuropathy. The transdermal delivery of drugs provides several therapeutic advantages due to avoidance of hepatic first-pass metabolism, reduced frequency of drug administration, longer duration of action, reduced side effects, and improved patient compliance (Prausnitz & Langer, 2008). However, the stratum corneum (SC), the outermost layer of the epidermis, is the principal rate-limiting barrier to percutaneous absorption. The SC is composed of keratin-rich cells embedded in multiple lipid bilayers, which are mainly comprised of ceramides, cholesterol, and free fatty acids (van Smeden et al. 2014). It is widely accepted that the intercellular lipid domain is the main penetration pathway through the SC for most drugs.
European Journal of Pharmaceutical Sciences 106 (2017) 79–86
T. Furuishi et al.
studies were performed, which confirmed that complexation with various CDs actually enhanced EPL solubility between EPL and CDs in aqueous solution. Second, we studied the physicochemical properties of a ground mixture (GM) of EPL and β-CD and its derivatives using the ball-mill method by particle size analysis, differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), and Fourier transform infrared spectroscopy (FTIR). Finally, after dispersing the coground sample in an aqueous medium, we used the EPL suspension with and without a skin permeation enhancer to determine skin permeation behavior.
Fig. 1. Chemical structure of Epalrestat (EPL).
In the pharmaceutical industry, cyclodextrins (CDs) have mainly been used as complexing agents to increase aqueous solubility, availability, and stability of drugs (Brewster and Loftsson 2007). CDs are cyclic α-(1,4)-linked oligosaccharides of α-D-glucopyranose containing a relatively hydrophobic central cavity and a hydrophilic external surface. The most common CDs are α, β, and γ-CD, which consist of six, seven, and eight α-D-glucopyranose units, respectively (Szejtli 1998; Loftsson and Duchene 2007). In addition to the potential for CDs to enhance solubility, they can be used to increase membrane permeability, especially in skin permeation and as enhancers and stabilizers (Loftsson et al. 2007), and therefore CDs play an important role in optimizing local and systemic dermal drug delivery (Loftsson and Masson 2001). Using CDs in transdermal drug delivery has the following benefits (Matsuda and Arima 1999; Bentley et al. 1997; Lopez et al. 2000): i. ii. iii. iv. v. vi.
2. Materials and methods 2.1. Materials EPL (2-[(5Z)-5-[(E)-3-phenil-2-methylprop-2-enylidene]-4-oxo-2thioxo-3-thiazolidinyl]acetic acid) was kindly gifted from Kobayashi Kako Co., Ltd. (Fukui, Japan). α-, β-, γ-, Hydroxypropyl (HP)-β- (degree of substitution (D.S.): 4.5) and hydroxybuthyl (HB)-β-CD (D.S.:3.8) (Ishiguro et al. 2010) were provided by Nihon Shokuhin Kako Co., Ltd. (Tokyo, Japan). Sulfobutylether (SBE)-β-CD (Captisol®, D.S. ~7.0) was a gift from Ligand Pharmaceuticals Inc. (San Diego, CA, USA). Methylated (ME)-β-CD (D.S. 1.6–1.9) was gifted from Ensuiko Sugar Refining Co. Ltd. (Tokyo, Japan). N-methyl-2-pyrrolidone (NMP) was provided from ISP TECHNOLOGIES Inc. (Tokyo, Japan). Polyoxyethylene lauryl ether (POE, NONION® K-204) was a gift from NOF Corporation (Tokyo, Japan). Sucrose fatty acid ester 1816 (SE 1816, sucrose stearate, HLB = 16) and 1216 (SE 1216, sucrose laurate, HLB = 16) were gifted from Mitsubishi-Kagaku Foods Corporation (Tokyo, Japan). Propylene glycol (PG) and urea were purchased from Wako Pure Chemical Industries, Ltd. (Osaka, Japan). All other solvents and reagents were commercial products of analytical grade and were used without further purification.
Enhancing drug release and/or permeation. Stabilizing drugs in the formulation or at the absorptive site. Enhancing solubilization of lipophilic drugs. Alleviating drug-induced local irritation. Providing sustained release of drugs from the vehicle. Altering drug bioconversion in the viable skin.
EPL is also a water-insoluble drug (14 μM, measured value), thus improving the aqueous solubility and skin permeation of EPL is required for a transdermal drug delivery system. The complexation of EPL with CD would improve not only the dissolution profile, but also enhance EPL skin permeation. Mechanochemistry is a dynamic interdisciplinary research field in material science and solid state chemistry that improves time constraints, simplicity, costs, and waste reduction (Ranu and Stolle 2014). Mechanical activation from solid-state grinding not only prepares the amorphous solids, polymorphs, and solid dispersions, but also induces drug–drug or drug–excipient interactions, resulting in modified physico-chemical properties, such as dissolution rate and the bioavailability of drugs (Boldyrev 2004; Chieng et al. 2009; Janssens and Van den Mooter 2009). In the case of CDs, some authors show through the mechanical grinding process that molecular encapsulation of a guest compound into CDs can successfully increase the solubility of hydrophobic drugs (Arias et al. 1997; He et al. 2013; Mennini et al. 2014). A recent cogrinding technique known for amorphization can also reduce the particle size of a solid to enable dissolution of insoluble compounds in water since dissolution rate depends strongly on particle size (Wongmekiat et al. 2007). Reduced particle size is a product of strong grinding force on a solid, resulting in influenced the surface free energy and distortion of the crystal lattice. Moreover, reduced particle size of drugs affects skin permeation behavior (Moribe et al. 2010; Try et al. 2016). Therefore, we predicted that the solubility and skin permeation of EPL could be improved by cogrinding with CDs. Indeed, to the best knowledge of the authors, no research has yet been performed on enhancing the solubility and skin permeation of EPL with CDs and cogrinding treatment. In this paper, we proposed to improve the dissolution behavior and percutaneous absorption of EPL by CDs using a ball-milling method based on a solid–solid mechanochemical reaction. First, phase solubility
2.2. Phase solubility diagram Phase solubility diagrams were conducted according to the method of Higuchi and Connors (Higuchi and Connors 1965). The EPL was dissolved in 1 mL methanol and the EPL/methanol solution (3 mM) was added to a lightproof glass tube. Methanol was evaporated from the glass tube using a dry thermo bath (MG-200, EYELA, Tokyo, Japan). Two milliliters of β-CD and its derivatives aqueous solutions (1–10 mM) were added to an excess of the EPL and the suspension was then mixed using a vortex mixer and sonicated for 20 min. The mixture was mechanically shaken (100 strokes/min, NTS-1300, Tokyo Rikakikai Co., Ltd., Tokyo, Japan) for 3 days at 25 °C. The suspension was centrifuged at 25 °C and 3000 rpm (CF9RX, Hitachi Koki Co., Ltd. Tokyo, Japan) for 10 min. The supernatant was filtered (pore size, 0.45 μm) and the EPL concentration was determined by HPLC. The phase solubility diagram was constructed by plotting the total dissolved drug concentration against the total CD concentration. For the 1:1 drug/CD complex, the apparent stability constant could be estimated from the slope of the phase solubility diagram (Eq. (1)) (Loftsson et al. 2005).
KC =
slope S0·(1−slope)
(1)
where slope was the slope of the phase solubility diagram, KC was the apparent stability constant, and S0 was the equilibrium solubility of EPL in water in the absence of CDs. 2.3. Analytical method The HPLC system was comprised of a PU-2080 Plus Intelligent HPLC Pump, a UV-2075 Intelligent UV/VIS Detector, a CO-2065 Plus Intelligent Column Oven, an AS-2055 Plus Intelligent Sampler, and a 80
European Journal of Pharmaceutical Sciences 106 (2017) 79–86
T. Furuishi et al.
solution.
ChromNAV Chromatography Data System (all from JASCO Co., Tokyo, Japan). The analytical column, an Inertsil ODS-3 (150 mm × 4.6 mm i.d.; particle size 5 μm; GL Sciences Inc., Tokyo, Japan) was used at room temperature. The mobile phase consisted of 0.05 M phosphate buffer (pH 6.5) and acetonitrile (60:40, v/v) at a flow rate of 1.0 mL/ min. The column eluate was monitored using a visible wavelength of 389 nm.
2.9. Skin permeation studies of ME-β-CD GM systems with permeation enhancers We prepared 3 mL of EPL/ME-β-CD GM suspension with or without percutaneous enhancers (1 or 10 wt%) in water. Six permeation enhancers were selected for testing in GM suspensions; NMP (Koizumi et al. 2004), POE (Park et al. 2000), SE 1216 and 1816 (Okamoto et al. 2005), PG, and urea. After adding 3 mL of water, the suspensions were incubated at 25 °C for about 3 days. We then added 500 μL of each suspension to the donor cell. The skin permeation studies were performed using the same method as “Skin permeation studies of GM systems”.
2.4. Solubilization of EPL with cogrinding EPL (5 mg) was weighed into a lightproof glass vial. The physical mixture (PM) of EPL and β-CD derivatives was prepared at a molar ratio of 1:1 using a vortex mixer. For the preparation of the ground mixture, EPL and β-CD derivatives at 1:1 molar ratio (using 5 mg EPL) were placed in a lightproof glass vial with 20 glass balls (diameters of 5 mm). The mixtures were coground at 120 rpm at 25 °C for 24 h using the desktop ball-mill equipment (model V-1 M; Irie Shokai Co., Ltd., Tokyo, Japan). After adding 3 mL of water, the solution was incubated at 25 °C for about 3 days. The EPL concentration in PM or GM was determined via the same method as the “Phase Solubility diagram” section.
2.10. Data analysis The cumulative amount of drug that had permeated through the skin (Q) was plotted as a function of time. The steady state flux was then calculated from the slope of the linear region of this plot and expressed as (μg/cm2/h). The lag time (h) was calculated by extrapolating the linear region of the curve to the X-axis. The permeability coefficient (Kp) was calculated using Eq. (2) (Zhao et al. 2008):
2.5. Differential scanning calorimetry (DSC) DSC was carried out with a DSC8230 (Rigaku Co., Tokyo Japan). Samples were placed into an aluminum-crimped pan and measured at a speed of 5 °C/min from 30 to 250 °C under atmosphere. Al2O3 was used as reference.
Kp = Flux S
(2)
where S is the saturation solubility of the drug in the donor solution. 2.11. Statistical analysis
2.6. Powder X-ray diffractometry (PXRD)
All experiments were run in triplicate. The results were analyzed by one-way analysis of variance (ANOVA), followed by the modified Fisher's least-squares difference method. The level of statistical significance was set at p < 0.05.
PXRD was performed with a Miniflex with a Cu-Kα radiation source (Rigaku Co.). Data were collected at a scan rate of 4.2° min− 1 over a 2θ range of 5°–35°. The accelerating voltage was 35 kV and the current was 15 mA.
3. Results and discussion
2.7. Fourier transform infrared spectrometry (FTIR)
3.1. Improving the dissolution property of EPL with β-CDs (phase solubility diagram and cogrinding method)
FTIR spectra of samples were obtained on a FTIR spectrometer (model 230, Jasco Co., Ltd) using the KBr disc method. Spectra (16 scans at 4 cm− 1 resolution) were collected in the 4000–400 cm− 1 range.
The complexing behavior of EPL with various CDs in water was studied by the phase solubility method. Fig. 2 shows the phase solubility diagrams of EPL with various CDs. The solubility of EPL did not increase enough with α- and γ-CD (data not shown). The EPL/β-CD system displayed a typical BS-type solubility curve according to the classification system of Higuchi and Connors (Higuchi and Connors 1965), where the initial rising portions were followed by plateau regions, after which the total EPL concentration decreased. From
2.8. Skin permeation studies of GM systems All animal experiments were performed in accordance with the guidelines of the Institutional Animal Care and Use Committee (School of Pharmacy, Nihon University, Chiba, Japan). The full-thickness dorsal skin of male hairless mice (5–8 weeks of age), sacrificed by ether, was excised and adherent fat and other visceral debris were removed from the undersurface. In vitro skin permeation studies were performed with Franz cells (Vertical diffusion cell™, Hanson Research Corporation, CA, USA). Franz cells were mounted in a Microette™ Plus system (Hanson Research) equipped with a thermostatic bath, injection system, vacuum pump, agitation clamp, archive samples in Mulitfull™ collector, and autosampler. The EPL GM suspension (500 μL) in water with or without various β-CD derivatives (all concertation is 5 mM) was added to the donor cell. EPL GM with/without β-CD derivatives suspension was prepared via the “Solubilization of EPL with cogrinding” method. The effective area of diffusion was 1.77 cm2 and the receiver cell volume was 7 mL. The receiver cell was filled with phosphate buffered solution (PBS, pH 7.4) and stirred at 650 rpm using a magnetic stirrer. The entire system was maintained at 32 ± 0.5 °C with a circulating water jacket. The amount of EPL that permeated the skin into the receiver cell was quantitated by collecting 0.5 mL samples from the receiver cell at the designated time intervals and analyzing these by HPLC. The volume of receiver cell fluid withdrawn at each interval was replaced with PBS
Fig. 2. Phase solubility diagrams of EPL/CDs systems.
81
European Journal of Pharmaceutical Sciences 106 (2017) 79–86
T. Furuishi et al.
PM could be interpreted as an approximate superposition of EPL and βCD derivatives. It was revealed that no interaction occurred between EPL and β-CD derivatives by physical mixing alone. When EPL was coground with various β-CD derivatives at a 1:1 molar ratio, respectively, the PXRD showed a halo pattern and no diffraction peak appeared. Crystalline EPL became amorphous by cogrinding with βCD derivatives (Fig. 5). It is suggested that the crystalline structure of EPL was disrupted and that EPL molecules were substantially converted into amorphous states, but did not form a crystalline complex.
Fig. 2, the length of the plateau region indicated a stoichiometry of 1:2, possibly 1:3 (EPL:β-CD). The solubility of EPL with 6 mM β-CD was about 5 times higher than intact EPL in aqueous solution. Moreover, the solubility profiles of EPL with all β-CD derivatives were classified as AL-type, indicating the formation of a 1:1 stoichiometry complex. Since the solubility of EPL increased linearly from about 10 (β-CD) to 21 (HB-β-CD) times greater than EPL alone, water-soluble complexes could be formed within the range of CD concentrations examined. The value of the apparent stability constant (Kc) of the EPL-β-CD and their derivative complexes increased in the order of β-(470) < HP-(810) < SBE-(1135) ≅ ME(1135) < HB-β-CD (1850 M− 1). These results suggest that HB-β-CD contribute the most to increasing the solubility of EPL. In the phase-solubility diagrams (Fig. 2), the solubility of EPL increased using β-CD derivatives, but the simple dissolution test with CDs, namely the addition of the water insoluble drug into the CD solution, would not sufficiently enhance the dissolution behavior of the water insoluble drug. The cogrinding technique is widely used for improving dissolution rate and/or solubility. In an attempt to further enhance EPL solubility, we applied this method of obtaining a ground mixture for solubilizing EPL using β-CD derivatives. Fig. 3 shows the concentration of EPL by β-CD derivatives with or without the cogrinding method. The concentration of EPL from the GM was about 3 times greater than PM (p < 0.05, ANOVA). These values were also about 2–3 times larger than the concentration of EPL with the same CD concentration (5 mM) calculated from the phase solubility diagrams (Fig. 2). From this result, we reaffirmed that the coground technique is very useful in reducing the addition of β-CDs derivatives and thus improving dissolution behavior.
3.4. FTIR measurements FTIR revealed the molecular interaction between EPL and β-CD derivatives. Fig. S1 shows the FTIR spectra of EPL/β-CD derivative systems. For EPL alone, characteristic absorption peaks were observed near 1743, 1674, and 1556 cm− 1 from carboxyl, amide, and thiocarbonyl stretching vibrations, respectively. All of these characteristic peaks were observed and did not shift in PM and GM systems. As the results, it is considered that EPL is dispersed in the β-CD derivatives but difficult to determine to be included in that. Taken together with DSC and PXRD measurements, it is likely that specific molecular interactions between EPL and β-CD derivatives did not occur and EPL dispersed in β-CD derivatives in an amorphous state.
3.5. Effect of various β-CD derivatives on the skin permeation of EPL As we described in the introduction, using the CD for transdermal has some advantage. β-CD derivatives are used as skin permeation enhancers, because some β-CD derivatives alter the structure of SC lipid due to extract significant amounts of some lipophilic components from the skin (Bentley et al. 1997; Legendre et al. 1995). Moreover, Ventura et al. reported that histological analysis of treated human SC and epidermis showed a protective effect of the ME- and HP-β-CD towards an invasive action shown by celecoxib on SC, even though the both CD enhanced the flux of celecoxib through human SC and epidermis (Ventura et al. 2006). Therefore, it is conceivable that β-CD derivatives are useful and safety skin permeation enhancer. The skin permeation profiles of EPL coground with various β-CD derivatives are shown in Fig. 6 and Table 1. All the β-CD derivatives, except for SBE-β-CD, increased the flux of EPL rather than EPL alone and PM, respectively. Among the β-CD derivatives in the GM system, the highest permeation rate of 1.07 μg/cm2/h was observed with ME-βCD (p < 0.05, ANOVA), while SBE-β-CD produced the lowest enhancement in EPL flux (0.01 μg/cm2/h). The highest flux value is about 100 times greater than EPL alone. Moreover, the Kp values of EPL with MEβ-CD were highest among the β-CD derivatives. In the phase solubility diagram (Fig. 2), the EPL solubility increased with β-CD derivatives following the order of HP-β-CD < SBE-β-CD ≅ ME-β-CD < HB-β-CD. Furthermore, from results of experiments on cogrinding effects (Fig. 3), EPL solubility increased by cogrinding with β-CD derivatives, but there were no significant differences among them. However, according to results of skin permeation of EPL (Fig. 6), ME-β-CD had substantially enhanced EPL skin permeation. The obtained result can be attributed to the capacity for ME-β-CD to extract lipids, such as cholesterol and triglycerides, from the SC and to complex them, thus temporarily decreasing the skin barrier properties (Ventura et al. 2006; Másson et al., 1999; Lopez et al. 2000; Babu and Pandit 2004). The enhancement effect of ME-β-CD on the skin permeation of EPL was estimated by not only improving the dissolution behavior of EPL, but also by ME-β-CD extracting lipid and/or cholesterol from the SC. For these reasons, skin permeation of EPL would be increased by ME-βCD among the β-CD derivatives used in our experiments.
3.2. DSC measurements DSC measurements were carried out to evaluate the thermal behavior of EPL, β-CD derivatives, PM, and GM, respectively (Fig. 4). One sharp endothermic peak was observed around 224 °C attributed to the fusion of crystalline EPL in the DSC thermogram of EPL. On the other, broad endothermic peaks were observed around 100 °C, which can be explained by dehydration during the heating process in the β-CD derivatives. In the PM system, the endothermic peaks derived from EPL decreased or almost disappeared. These results may be due to low interaction between the pure components in the PMs. Conversely, the sharp endothermic peak corresponding to EPL melting decreased or disappeared in the GM. Water loss from β-CDs also decreased. This indicates that EPL and β-CD derivatives were molecularly dispersed in the amorphous binary mixture. 3.3. PXRD measurements PXRD patterns of EPL, β-CD derivatives, and a PM of EPL and β-CD derivatives (molar ratio 1:1) are presented in Fig. 5. The pattern of the
Fig. 3. Effect of co-grinding with β-CD derivatives on EPL solubility.
82
European Journal of Pharmaceutical Sciences 106 (2017) 79–86
T. Furuishi et al.
Fig. 4. DSC curves of EPL/β-CD derivatives systems showing a) HB-β-CD, b) ME-β-CD, c) SBE-β-CD, and d) HP-β-CD.
permeation enhancers. As shown in Table S1, fluxes of EPL from EPL/ ME-β-CD GM systems with addition of 1 wt% NMP, PG, and Urea were ca. 2.0, 1.4, and 2.0 times higher than in the EPL/ME-β-CD GM system, respectively. In contrast, POE, SE1816, and SE1216 did not enhance the skin permeability of EPL from the EPL/ME-β-CD GM systems. Moreover, Fig. 7 shows the effect of the concentration of NMP, PG, and urea on the skin permeation of EPL, respectively. Table 2 summarizes the skin permeation parameters of EPL with the abovementioned three skin permeation enhancers and ME-β-CD compared 10 wt% with 1 wt% skin permeation enhancers. The flux values of EPL increased with increasing concentrations of these enhancers from 1 to 10 wt%. Among these enhancers, urea markedly enhanced EPL permeability across the skin and the flux value was 2.96 μg/cm2/h, which was about 300 times greater than EPL alone. Enhanced EPL by addition of urea was due to not only a moisturizing effect leading to improved mobility of the SC protein (Alonso et al. 2001), but also by increasing
3.6. Influence of chemical enhancers on the skin permeation of EPL from the ME-β-CD GM system The enhanced skin permeation of ELP is considered limited when the ME-β-CD GM system is used alone. Recent reports show the combination of CD with other drug delivery tools, such as liposome (Alomrani et al. 2014), iontophoresis (Juluri and Narasimha Murthy 2014) and electrophoresis (Sammeta et al. 2010), improve the skin permeation of drug rather than using only CDs, but these techniques are not convenient due to use the special technique and/or equipment. In contrast, improving percutaneous absorption of drug using chemical enhancer is a simple and inexpensive method. It is well known that the combination of various enhancers improves the percutaneous absorption of drugs much greater than either enhancer alone (Ho et al. 1994; Kakubari et al. 2006). Therefore, we tried to enhance the skin permeation of the EPL/ME-β-CD GM system using water-soluble skin
Fig. 5. PXRD patterns of EPL/β-CD derivatives systems for a) HB-β-CD, b) ME-β-CD, c) SBE-β-CD, and d) HP-β-CD.
83
European Journal of Pharmaceutical Sciences 106 (2017) 79–86
T. Furuishi et al.
Fig. 6. Skin permeation profiles of EPL from EPL/β-CD derivatives systems, including a) HP-β-CD system, b) SBE-β-CD, c) HB-β-CD, and d) ME-β-CD. The concentration of all β-CD derivatives is 5 mM. Table 1 Skin permeation parameters of EPL from EPL/β-CD derivatives systems. Sample
PM
GM
EPL intact HB-β-CD ME-β-CD SBE-β-CD HP-β-CD HB-β-CD ME-β-CD SBE-β-CD HP-β-CD
Flux (μg/cm2/h)
Lag time (h)
Q (μg/cm2)
S (μg/mL)
KP (× 10− 3 cm/h)
0.01 0.03 0.18 0.01 0.01 0.28 1.07 0.01 0.03
15.8 ± 3.1 8.1 ± 1.2 13.7 ± 3.6 9.7 ± 1.6 18.6 ± 1.0 14.0 ± 3.1 17.4 ± 0.6 6.4 ± 4.2 3.0 ± 1.0
0.13 0.48 1.65 0.13 0.10 2.78 7.44 0.23 0.52
4.6 ± 1.1 40.4 ± 4.2 31.4 ± 2.8 26.2 ± 0.9 23.3 ± 2.5 117.0 ± 22.8 80.2 ± 21.8 91.8 ± 25.1 95.8 ± 45.5
3.09 ± 0.71 0.75 ± 0.10 5.83 ± 4.36 0.36 ± 0.06 0.47 ± 0.55 2.42 ± 1.18 13.34 ± 4.39 0.14 ± 0.06 0.39 ± 0.23
± ± ± ± ± ± ± ± ±
0.0002 0.002 0.136 0.001 0.013 0.127 0.199 0.005 0.003
± ± ± ± ± ± ± ± ±
0.03 0.08 0.80 0.01 0.08 0.78 1.30 0.05 0.13
Q: amount permeated of EPL; S: solubility; KP: permeability constant; each value is the mean ± S.D. (n = 3).
4. Conclusion
the concentration of EPL. Regardless, the solubility of EPL did not increase by addition of 10% PG, as the flux of EPL improved. This suggested that PG does not contribute to improving the dissolution of EPL. It was reported that PG enhanced the skin permeability of some drugs so that the solvent ‘drag’ may carry permeant into the tissue as PG traverses and there may be some minor disturbance to intercellular lipid packing within the SC bilayers (Williams and Barry 2004). Therefore, this mechanism could support the increasing the flux of EPL by PG. Conversely, using 10% NMP, the flux of EPL decreased with the decreasing solubility of EPL against increasing Kp values. It is suggested that the amount of EPL permeated through the skin decreased due to decreased solubility of EPL in the donor phase. From this result, among these enhancers, we found that 10% urea with ME-βCD accreted the skin permeation of EPL and it was estimated that the mechanism for this effect involves the ability for urea and ME-β-CD to not only enhance the solubility of EPL in aqueous solution, but also to increase mobility of the SC protein, thus enhancing the distribution of EPL into the intercellular region of the SC.
In this study, we characterized the solid state of EPL using β-CD derivatives and demonstrated that the solubility of EPL increased. Phase solubility diagrams showed that β-CD derivatives enhanced the solubility of EPL and we found the cogrinding process was more efficient in increasing the concentration of EPL in aqueous solution, which the dissolution enhancing factors were estimated the complex formation between EPL and β-CD derivatives. Based on a combination of DSC, IR, and PXRD data, we found the crystalline structures of EPL were disrupted and that ELP molecules substantially dispersed into amorphous β-CD derivative in the solid state. The GM system with β-CD derivatives increased the skin permeation of EPL markedly more than EPL alone or the PM system. Moreover, the addition of the skin permeation enhancer into the GM system dramatically enhanced the skin permeability of EPL. Specifically, the maximum flux occurred at 10% urea and the flux value was 300 times greater than with EPL alone without urea. These results indicate the ME-β-CD GM system with urea has potential as a new transdermal drug delivery system of EPL for diabetic neuropathy, but the same ternary system could attempt to 84
European Journal of Pharmaceutical Sciences 106 (2017) 79–86
T. Furuishi et al.
Fig. 7. Effect of enhancer concentration on skin permeation profiles of EPL from the EPL/ME-β-CD system. Table 2 Effect of enhancer concentration on the skin permeation parameters of EPL from EPL/ME-β-CD systems. Enhancers
Flux (μg/cm2/h)
wt%
10
1.0
10
1.0
10
1.0
10
1.0
10
1.0
NMP PG Urea
0.91 ± 0.09 2.76 ± 1.15 2.96 ± 0.34
2.05 ± 0.94 1.38 ± 1.03 2.07 ± 1.02
18.1 ± 0.2 18.0 ± 0.9 17.5 ± 1.6
18.0 ± 0.6 18.2 ± 0.6 18.0 ± 0.8
5.97 ± 0.61 18.4 ± 6.5 20.5 ± 4.6
13.9 ± 7.0 9.31 ± 6.73 14.1 ± 6.7
6.2 ± 0.3 51.8 ± 7.4 219.7 ± 6.9
47.5 ± 15.4 57.1 ± 1.6 87.9 ± 7.4
147.3 ± 16.0 53.3 ± 23.5 13.5 ± 1.6
43.2 ± 24.3 24.2 ± 18.1 23.6 ± 11.8
Lag time (h)
Q (μg/cm2)
S (μg/mL)
KP (× 10− 3 cm/h)
Q: amount permeated of EPL; S: solubility; KP: permeability constant; each value is the mean ± S.D. (n = 3). influence of some cyclodextrins on the stratum corneum from the hairless mouse. J. Pharm. Pharmacol. 49, 397–402. Boldyrev, V.V., 2004. Mechanochemical modification and synthesis of drugs. J. Mater. Sci. 39, 5117–5120. Brewster, M.E., Loftsson, T., 2007. Cyclodextrins as pharmaceutical solubilizers. Adv. Drug Deliv. Rev. 59, 645–666. Callaghan, B.C., Cheng, H.T., Stables, C.L., Smith, A.L., Feldman, E.L., 2012. Diabetic neuropathy: clinical manifestations and current treatments. Lancet Neurol. 11, 521–534. Chieng, N., Aaltonen, J., Saville, D., Rades, T., 2009. Physical characterization and stability of amorphous indomethacin and ranitidine hydrochloride binary systems prepared by mechanical activation. Eur. J. Pharm. Biopharm. 71, 47–54. Chylack Jr., L.T., Kinoshita, J.H., 1969. A biochemical evaluation of a cataract induced in a high-glucose medium. Investig. Ophthalmol. 8, 401–412. He, D., Deng, P., Yang, L., Tan, Q., Liu, J., Yang, M., Zhang, J., 2013. Molecular encapsulation of rifampicin as an inclusion complex of hydroxypropyl-βcyclodextrin: design; characterization and in vitro dissolution. Colloids Surf. B: Biointerfaces 103, 580–585. Higuchi, T., Connors, K.A., 1965. Advances in analytical chemistry and instrumentation, chapter 4. In: Phase Solubility Studies, pp. 117–212. Ho, H.O., Huang, F.C., Sokoloski, T.D., Sheu, M.T., 1994. The influence of cosolvents on the in-vitro percutaneous penetration of diclofenac sodium from a gel system. J. Pharm. Pharmacol. 46, 636–642. Hotta, N., Sakamoto, N., Shigeta, Y., Kikkawa, R., Goto, Y., 1996. Clinical investigation of epalrestat, an aldose reductase inhibitor, on diabetic neuropathy in Japan: multicenter study. Diabetic Neuropathy Study Group in Japan. J. Diabetes Complicat. 10, 168–172. Hotta, N., Akanuma, Y., Kawamori, R., Matsuoka, K., Oka, Y., Shichiri, M., Toyota, T., Nakashima, M., Yoshimura, I., Sakamoto, N., Shigeta, Y., 2006. Long-term clinical
enhance the skin permeability of other water-insoluble drugs. Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.ejps.2017.05.047. Acknowledgements This study was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (25870795) and the Otani prize(Hoshi University, 2013). References Alomrani, A.H., Shazly, G.A., Amara, A.A., Badran, M.M., 2014. Itraconazolehydroxypropyl-β-cyclodextrin loaded deformable liposomes: in vitro skin penetration studies and antifungal efficacy using Candida albicans as model. Colloids Surf. B: Biointerfaces 121, 74–81. Alonso, A., dos Santos, W.P., Leonor, S.J., dos Santos, J.G., Tabak, M., 2001. Stratum corneum protein dynamics as evaluated by a spin-label Maleimide derivative: effect of urea. Biophys. J. 81 (6), 3566–3576. Arias, M.J., Moyano, J.R., Ginés, J.M., 1997. Investigation of the triamterene–βcyclodextrin system prepared by co-grinding. Int. J. Pharm. 153, 181–189. Babu, R.J., Pandit, J.K., 2004. Effect of cyclodextrins on the complexation and transdermal delivery of bupranolol through rat skin. Int. J. Pharm. 271, 155–165. Bentley, M.V., Vianna, R.F., Wilson, S., Collett, J.H., 1997. Characterization of the
85
European Journal of Pharmaceutical Sciences 106 (2017) 79–86
T. Furuishi et al.
Oates, P.J., Mylari, B.L., 1999. Aldose reductase inhibitors: therapeutic implications for diabetic complications. Expert Opin. Investig. Drugs 8, 2095–2119. Ohmura, C., Watada, H., Azuma, K., Shimizu, T., Kanazawa, A., Ikeda, F., Yoshihara, T., Fujitani, Y., Hirose, T., Tanaka, Y., Kawamori, R., 2009. Aldose reductase inhibitor, epalrestat, reduces lipid hydroperoxides in type 2 diabetes. Endocr. J. 56, 149–156. Okamoto, H., Sakai, T., Danjo, K., 2005. Effect of sucrose fatty acid esters on transdermal permeation of lidocaine and ketoprofen. Biol. Pharm. Bull. 28, 1689–1694. Park, E.S., Chang, S.Y., Hahn, M., Chi, S.C., 2000. Enhancing effect of polyoxyethylene alkyl ethers on the skin permeation of ibuprofen. Int. J. Pharm. 209, 109–119. Prausnitz, M.R., Langer, R., 2008. Transdermal drug delivery. Nat. Biotechnol. 26, 1261–1268. Ramirez, M.A., Borja, N.L., 2008. Epalrestat: an aldose reductase inhibitor for the treatment of diabetic neuropathy. Pharmacotherapy 28, 646–655. Ranu, B., Stolle, A., 2014. Ball Milling Towards Green Synthesis: Applications, Projects, Challenges. The Royal Society of Chemistry, London. Sammeta, S.M., Vaka, S.R.K., Murthy, S.N., 2010. Transcutaneous electroporation mediated delivery of doxepin-HPCD complex: a sustained release approach for treatment of postherpetic neuralgia. J. Control. Release 142, 361–367. van Smeden, J., Janssens, M., Gooris, G.S., Bouwstra, J.A., 2014. The important role of stratum corneum lipids for the cutaneous barrier function. Biochim. Biophys. Acta 1841, 295–313. Srivastava, K., Arora, A., Kataria, A., Cappelleri, J.C., Sadosky, A., Peterson, A.M., 2013. Impact of reducing dosing frequency on adherence to oral therapies: a literature review and meta-analysis. Patient Prefer. Adherence. 7, 419–434. Szejtli, J., 1998. Introduction and general overview of cyclodextrin chemistry. Chem. Rev. 98, 1743–1754. Terashima, H., Hama, K., Yamamoto, R., Tsuboshima, M., Kikkawa, R., Hatanaka, I., Shigeta, Y., 1984. Effects of a new aldose reductase inhibitor on various tissues in vitro. J. Pharmacol. Exp. Ther. 229, 226–230. Try, C., Moulari, B., Beduneau, A., Fantini, O., Pin, D., Pellequer, Y., Lamprecht, A., 2016. Size dependent skin penetration of nanoparticles in murine and porcine dermatitis models. Eur. J. Pharm. Biopharm. 100, 101–108. Uchida, K., Kigoshi, T., Nakano, S., Ishii, T., Kitazawa, M., Morimoto, S., 1995. Effect of 24 weeks of treatment with epalrestat, an aldose reductase inhibitor, on peripheral neuropathy in patients with non-insulin-dependent diabetes mellitus. Clin. Ther. 17, 460–466. Ventura, C.A., Tommasini, S., Falcone, A., Giannone, I., Paolino, D., Sdrafkakis, V., Mondello, M.R., Puglisi, G., 2006. Influence of modified cyclodextrins on solubility and percutaneous absorption of celecoxib through human skin. Int. J. Pharm. 314, 37–45. Williams, A.C., Barry, B.W., 2004. Penetration enhancers. Adv. Drug Deliv. Rev. 56, 603–618. Wongmekiat, A., Tozuka, Y., Moribe, K., Oguchi, T., Yamamoto, K., 2007. Preparation of drug nanoparticles by co-grinding with cyclodextrin: formation mechanism and factors affecting nanoparticle formation. Chem. Pharm. Bull. 55, 359–363. Zhao, L., Fang, L., Xu, Y., Liu, S., He, Z., Zhao, Y., 2008. Transdermal delivery of penetrants with differing lipophilicities using O-acylmenthol derivatives as penetration enhancers. Eur. J. Pharm. Biopharm. 69, 199–213.
effects of epalrestat, an aldose reductase inhibitor, on diabetic peripheral neuropathy: the 3-year, multicenter, comparative Aldose Reductase Inhibitor-Diabetes Complications Trial. Diabetes Care 29, 1538–1544. Ishiguro, T., Hirayama, F., Iohara, D., Arima, H., Uekama, K., 2010. Crystallization and polymorphic transitions of chlorpropamide in aqueous 2-hydroxybutyl-βcyclodextrin solution. Eur. J. Pharm. Sci. 39, 248–255. Janssens, S., Van den Mooter, G., 2009. Review: physical chemistry of solid dispersions. J. Pharm. Pharmacol. 61, 1571–1586. Juluri, A., Narasimha Murthy, S., 2014. Transdermal iontophoretic delivery of a liquid lipophilic drug by complexation with an anionic cyclodextrin. J. Control. Release 189, 11–18. Kakubari, I., Nakamura, N., Takayasu, T., Yamauchi, H., Takayama, S., Takayama, K., 2006. Effects of solvents on skin permeation of formoterol fumarate. Biol. Pharm. Bull. 29, 146–149. Kinoshita, J.H., Kador, P., Catiles, M., 1981. Aldose reductase in diabetic cataracts. JAMA 246, 257–261. Koizumi, A., Fujii, M., Kondoh, M., Watanabe, Y., 2004. Effect of N-methyl-2-pyrrolidone on skin permeation of estradiol. Eur. J. Pharm. Biopharm. 57, 473–478. Legendre, J.Y., Rault, I., Petit, A., Luijten, W., Demuynck, I., Horvath, S., Ginot, Y.M., Cuine, A., 1995. Effects of β-cyclodextrins on skin: implications for the transdermal delivery of piribedil and a novel cognition enhancing-drug, S-9977. Eur. J. Pharm. Sci. 3, 311–322. Loftsson, T., Duchene, D., 2007. Cyclodextrins and their pharmaceutical applications. Int. J. Pharm. 329, 1–11. Loftsson, T., Masson, M., 2001. Cyclodextrins in topical drug formulations: theory and practice. Int. J. Pharm. 225, 15–30. Loftsson, T., Hreinsdottir, D., Masson, M., 2005. Evaluation of cyclodextrin solubilization of drugs. Int. J. Pharm. 302, 18–28. Loftsson, T., Vogensen, S.B., Brewster, M.E., Konradsdottir, F., 2007. Effects of cyclodextrins on drug delivery through biological membranes. J. Pharm. Sci. 96, 2532–2546. Lopez, R.F., Collett, J.H., Bentley, M.V., 2000. Influence of cyclodextrin complexation on the in vitro permeation and skin metabolism of dexamethasone. Int. J. Pharm. 200, 127–132. Maladkar, M., Rajadhyaksha, G., Venkataswamy, N., Hariharan, R.S., Lohati, S.R., 2009. Efficacy, safety, and tolerability of epalrestat compared to methylcobalamine in patients with diabetic neuropathy. Int. J. Diabetes Dev. Ctries. 29, 28–34. Másson, M., Loftsson, T., Masson, G., Stefansson, E., 1999. Cyclodextrins as permeation enhancers: some theoretical evaluations and in vitro testing. J. Control. Release 59, 107–118. Matsuda, H., Arima, H., 1999. Cyclodextrins in transdermal and rectal delivery. Adv. Drug Deliv. Rev. 36, 81–99. Mennini, N., Bragagni, M., Maestrelli, F., Mura, P., 2014. Physico-chemical characterization in solution and in the solid state of clonazepam complexes with native and chemically-modified cyclodextrins. J. Pharm. Biomed. Anal. 89, 142–149. Moribe, K., Shibata, M., Furuishi, T., Higashi, K., Tomono, K., Yamamoto, K., 2010. Effect of particle size on skin permeation and retention of piroxicam in aqueous suspension. Chem. Pharm. Bull. 58, 1096–1099.
86
Contents lists available at ScienceDirect
European Journal of Pharmaceutical Sciences journal homepage: www.elsevier.com/locate/ejps
Enhanced dissolution and skin permeation profiles of epalrestat with βcyclodextrin derivatives using a cogrinding method
MARK
Takayuki Furuishia,⁎, Shoma Takahashib, Noriko Ogawac, Mihoko Gunjia, Hiromasa Nagased, Toyofumi Suzukib, Tomohiro Endoe, Haruhisa Uedaa,f, Etsuo Yonemochia, Kazuo Tomonob a
Department of Physical Chemistry, School of Pharmacy and Pharmaceutical Sciences, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan Laboratory of Pharmaceutics, School of Pharmacy, Nihon University, 7-7-1 Narashinodai, Funabashi-shi, Chiba 274-8555, Japan c Department of Pharmaceutical Engineering, School of Pharmacy, Aichi Gakuin University, 1-100 Kusumoto-cho, Chikusa-ku, Nagoya, Aichi 464-8650, Japan d Central Research Laboratories, School of Pharmacy and Pharmaceutical Sciences, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan e School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo, 192-0392, Japan f Department of Pharmaceutical Sciences, Nihon Pharmaceutical University, 10280 Komuro, Ina-machi, Kitaadachigun, Saitama, 362-0806, Japan b
A R T I C L E I N F O
A B S T R A C T
Keywords: Epalrestat Cyclodextrin Solubility Skin permeation Cogrinding Enhancer
Epalrestat (EPL) is a water-insoluble drug (14 μM) that inhibits aldose reductase. This study investigated the interactions between β-cyclodextrin (CD) derivatives and EPL to determine the solubilizing effect on EPL from phase solubility diagrams. We improved the solubility of EPL in water by adding β-CD derivatives. Moreover, the solubility of EPL mixed with β-CD derivatives by cogrinding in a ball mill method was about 2–3 times higher than those of EPL with the same CD concentration (5 mM) calculated from phase solubility diagrams. In addition, we investigated the effect of β-CD derivatives on in vitro percutaneous absorption of EPL through hairless mouse skin. Among the coground mixtures of EPL and β-CD derivatives, the mixture containing methyl (ME)-β-CD showed the strongest enhancement of EPL skin permeation. Furthermore, adding 10 wt% urea as a skin permeation enhancer after cogrinding with ME-β-CD improved the flux of EPL 300 times compared to the flux of EPL alone. This result indicates the ME-β-CD ground mixture system with urea has potential as a new transdermal drug delivery system of EPL for diabetic neuropathy.
1. Introduction Diabetic neuropathy is one of the most common long-term complications in patients with diabetes mellitus, with 30%–90% of patients with diabetes experiencing peripheral neuropathy (Callaghan et al. 2012). It is known that hyperglycemic conditions result in accumulation of sorbitol in nerves (Ohmura et al. 2009), which poorly penetrates the cell membranes and contributes to the progression of diabetic complications, such as neuropathy, retinopathy, and nephropathy (Ohmura et al. 2009; Chylack and Kinoshita, 1969; Kinoshita et al. 1981; Oates and Mylari, 1999). Epalrestat (EPL, Fig. 1) is a carboxylic acid derivative that inhibits aldose reductase (Terashima et al. 1984), an enzyme in the polyol pathway. Under hyperglycemic conditions, EPL reduces intracellular sorbitol accumulation, which can be effective in treating diabetic neuropathy (Ramirez and Borja, 2008). In Japan, EPL is currently administered through an oral dosage (Kinedac® Tablets 50 mg and many generics). Hotta et al. reported that long term treatment with EPL is well tolerated and can effectively delay the progression of diabetic ⁎
Corresponding author. E-mail address: [email protected] (T. Furuishi).
http://dx.doi.org/10.1016/j.ejps.2017.05.047 Received 12 February 2017; Received in revised form 2 May 2017; Accepted 22 May 2017 Available online 22 May 2017 0928-0987/ © 2017 Elsevier B.V. All rights reserved.
neuropathy and ameliorate associated symptoms of the disease (Hotta et al. 2006). Unfortunately, the oral EPL formulation is usually administrated three times a day and the dosing is usually long term (Hotta et al. 1996; Uchida et al. 1995; Maladkar et al. 2009). Reducing the frequency of oral dosage may improve adherence to therapies among patients (Srivastava et al. 2013). Hence, there may be a clinical need for increased availability of EPL as a long-acting formulation for diabetic neuropathy. The transdermal delivery of drugs provides several therapeutic advantages due to avoidance of hepatic first-pass metabolism, reduced frequency of drug administration, longer duration of action, reduced side effects, and improved patient compliance (Prausnitz & Langer, 2008). However, the stratum corneum (SC), the outermost layer of the epidermis, is the principal rate-limiting barrier to percutaneous absorption. The SC is composed of keratin-rich cells embedded in multiple lipid bilayers, which are mainly comprised of ceramides, cholesterol, and free fatty acids (van Smeden et al. 2014). It is widely accepted that the intercellular lipid domain is the main penetration pathway through the SC for most drugs.
European Journal of Pharmaceutical Sciences 106 (2017) 79–86
T. Furuishi et al.
studies were performed, which confirmed that complexation with various CDs actually enhanced EPL solubility between EPL and CDs in aqueous solution. Second, we studied the physicochemical properties of a ground mixture (GM) of EPL and β-CD and its derivatives using the ball-mill method by particle size analysis, differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), and Fourier transform infrared spectroscopy (FTIR). Finally, after dispersing the coground sample in an aqueous medium, we used the EPL suspension with and without a skin permeation enhancer to determine skin permeation behavior.
Fig. 1. Chemical structure of Epalrestat (EPL).
In the pharmaceutical industry, cyclodextrins (CDs) have mainly been used as complexing agents to increase aqueous solubility, availability, and stability of drugs (Brewster and Loftsson 2007). CDs are cyclic α-(1,4)-linked oligosaccharides of α-D-glucopyranose containing a relatively hydrophobic central cavity and a hydrophilic external surface. The most common CDs are α, β, and γ-CD, which consist of six, seven, and eight α-D-glucopyranose units, respectively (Szejtli 1998; Loftsson and Duchene 2007). In addition to the potential for CDs to enhance solubility, they can be used to increase membrane permeability, especially in skin permeation and as enhancers and stabilizers (Loftsson et al. 2007), and therefore CDs play an important role in optimizing local and systemic dermal drug delivery (Loftsson and Masson 2001). Using CDs in transdermal drug delivery has the following benefits (Matsuda and Arima 1999; Bentley et al. 1997; Lopez et al. 2000): i. ii. iii. iv. v. vi.
2. Materials and methods 2.1. Materials EPL (2-[(5Z)-5-[(E)-3-phenil-2-methylprop-2-enylidene]-4-oxo-2thioxo-3-thiazolidinyl]acetic acid) was kindly gifted from Kobayashi Kako Co., Ltd. (Fukui, Japan). α-, β-, γ-, Hydroxypropyl (HP)-β- (degree of substitution (D.S.): 4.5) and hydroxybuthyl (HB)-β-CD (D.S.:3.8) (Ishiguro et al. 2010) were provided by Nihon Shokuhin Kako Co., Ltd. (Tokyo, Japan). Sulfobutylether (SBE)-β-CD (Captisol®, D.S. ~7.0) was a gift from Ligand Pharmaceuticals Inc. (San Diego, CA, USA). Methylated (ME)-β-CD (D.S. 1.6–1.9) was gifted from Ensuiko Sugar Refining Co. Ltd. (Tokyo, Japan). N-methyl-2-pyrrolidone (NMP) was provided from ISP TECHNOLOGIES Inc. (Tokyo, Japan). Polyoxyethylene lauryl ether (POE, NONION® K-204) was a gift from NOF Corporation (Tokyo, Japan). Sucrose fatty acid ester 1816 (SE 1816, sucrose stearate, HLB = 16) and 1216 (SE 1216, sucrose laurate, HLB = 16) were gifted from Mitsubishi-Kagaku Foods Corporation (Tokyo, Japan). Propylene glycol (PG) and urea were purchased from Wako Pure Chemical Industries, Ltd. (Osaka, Japan). All other solvents and reagents were commercial products of analytical grade and were used without further purification.
Enhancing drug release and/or permeation. Stabilizing drugs in the formulation or at the absorptive site. Enhancing solubilization of lipophilic drugs. Alleviating drug-induced local irritation. Providing sustained release of drugs from the vehicle. Altering drug bioconversion in the viable skin.
EPL is also a water-insoluble drug (14 μM, measured value), thus improving the aqueous solubility and skin permeation of EPL is required for a transdermal drug delivery system. The complexation of EPL with CD would improve not only the dissolution profile, but also enhance EPL skin permeation. Mechanochemistry is a dynamic interdisciplinary research field in material science and solid state chemistry that improves time constraints, simplicity, costs, and waste reduction (Ranu and Stolle 2014). Mechanical activation from solid-state grinding not only prepares the amorphous solids, polymorphs, and solid dispersions, but also induces drug–drug or drug–excipient interactions, resulting in modified physico-chemical properties, such as dissolution rate and the bioavailability of drugs (Boldyrev 2004; Chieng et al. 2009; Janssens and Van den Mooter 2009). In the case of CDs, some authors show through the mechanical grinding process that molecular encapsulation of a guest compound into CDs can successfully increase the solubility of hydrophobic drugs (Arias et al. 1997; He et al. 2013; Mennini et al. 2014). A recent cogrinding technique known for amorphization can also reduce the particle size of a solid to enable dissolution of insoluble compounds in water since dissolution rate depends strongly on particle size (Wongmekiat et al. 2007). Reduced particle size is a product of strong grinding force on a solid, resulting in influenced the surface free energy and distortion of the crystal lattice. Moreover, reduced particle size of drugs affects skin permeation behavior (Moribe et al. 2010; Try et al. 2016). Therefore, we predicted that the solubility and skin permeation of EPL could be improved by cogrinding with CDs. Indeed, to the best knowledge of the authors, no research has yet been performed on enhancing the solubility and skin permeation of EPL with CDs and cogrinding treatment. In this paper, we proposed to improve the dissolution behavior and percutaneous absorption of EPL by CDs using a ball-milling method based on a solid–solid mechanochemical reaction. First, phase solubility
2.2. Phase solubility diagram Phase solubility diagrams were conducted according to the method of Higuchi and Connors (Higuchi and Connors 1965). The EPL was dissolved in 1 mL methanol and the EPL/methanol solution (3 mM) was added to a lightproof glass tube. Methanol was evaporated from the glass tube using a dry thermo bath (MG-200, EYELA, Tokyo, Japan). Two milliliters of β-CD and its derivatives aqueous solutions (1–10 mM) were added to an excess of the EPL and the suspension was then mixed using a vortex mixer and sonicated for 20 min. The mixture was mechanically shaken (100 strokes/min, NTS-1300, Tokyo Rikakikai Co., Ltd., Tokyo, Japan) for 3 days at 25 °C. The suspension was centrifuged at 25 °C and 3000 rpm (CF9RX, Hitachi Koki Co., Ltd. Tokyo, Japan) for 10 min. The supernatant was filtered (pore size, 0.45 μm) and the EPL concentration was determined by HPLC. The phase solubility diagram was constructed by plotting the total dissolved drug concentration against the total CD concentration. For the 1:1 drug/CD complex, the apparent stability constant could be estimated from the slope of the phase solubility diagram (Eq. (1)) (Loftsson et al. 2005).
KC =
slope S0·(1−slope)
(1)
where slope was the slope of the phase solubility diagram, KC was the apparent stability constant, and S0 was the equilibrium solubility of EPL in water in the absence of CDs. 2.3. Analytical method The HPLC system was comprised of a PU-2080 Plus Intelligent HPLC Pump, a UV-2075 Intelligent UV/VIS Detector, a CO-2065 Plus Intelligent Column Oven, an AS-2055 Plus Intelligent Sampler, and a 80
European Journal of Pharmaceutical Sciences 106 (2017) 79–86
T. Furuishi et al.
solution.
ChromNAV Chromatography Data System (all from JASCO Co., Tokyo, Japan). The analytical column, an Inertsil ODS-3 (150 mm × 4.6 mm i.d.; particle size 5 μm; GL Sciences Inc., Tokyo, Japan) was used at room temperature. The mobile phase consisted of 0.05 M phosphate buffer (pH 6.5) and acetonitrile (60:40, v/v) at a flow rate of 1.0 mL/ min. The column eluate was monitored using a visible wavelength of 389 nm.
2.9. Skin permeation studies of ME-β-CD GM systems with permeation enhancers We prepared 3 mL of EPL/ME-β-CD GM suspension with or without percutaneous enhancers (1 or 10 wt%) in water. Six permeation enhancers were selected for testing in GM suspensions; NMP (Koizumi et al. 2004), POE (Park et al. 2000), SE 1216 and 1816 (Okamoto et al. 2005), PG, and urea. After adding 3 mL of water, the suspensions were incubated at 25 °C for about 3 days. We then added 500 μL of each suspension to the donor cell. The skin permeation studies were performed using the same method as “Skin permeation studies of GM systems”.
2.4. Solubilization of EPL with cogrinding EPL (5 mg) was weighed into a lightproof glass vial. The physical mixture (PM) of EPL and β-CD derivatives was prepared at a molar ratio of 1:1 using a vortex mixer. For the preparation of the ground mixture, EPL and β-CD derivatives at 1:1 molar ratio (using 5 mg EPL) were placed in a lightproof glass vial with 20 glass balls (diameters of 5 mm). The mixtures were coground at 120 rpm at 25 °C for 24 h using the desktop ball-mill equipment (model V-1 M; Irie Shokai Co., Ltd., Tokyo, Japan). After adding 3 mL of water, the solution was incubated at 25 °C for about 3 days. The EPL concentration in PM or GM was determined via the same method as the “Phase Solubility diagram” section.
2.10. Data analysis The cumulative amount of drug that had permeated through the skin (Q) was plotted as a function of time. The steady state flux was then calculated from the slope of the linear region of this plot and expressed as (μg/cm2/h). The lag time (h) was calculated by extrapolating the linear region of the curve to the X-axis. The permeability coefficient (Kp) was calculated using Eq. (2) (Zhao et al. 2008):
2.5. Differential scanning calorimetry (DSC) DSC was carried out with a DSC8230 (Rigaku Co., Tokyo Japan). Samples were placed into an aluminum-crimped pan and measured at a speed of 5 °C/min from 30 to 250 °C under atmosphere. Al2O3 was used as reference.
Kp = Flux S
(2)
where S is the saturation solubility of the drug in the donor solution. 2.11. Statistical analysis
2.6. Powder X-ray diffractometry (PXRD)
All experiments were run in triplicate. The results were analyzed by one-way analysis of variance (ANOVA), followed by the modified Fisher's least-squares difference method. The level of statistical significance was set at p < 0.05.
PXRD was performed with a Miniflex with a Cu-Kα radiation source (Rigaku Co.). Data were collected at a scan rate of 4.2° min− 1 over a 2θ range of 5°–35°. The accelerating voltage was 35 kV and the current was 15 mA.
3. Results and discussion
2.7. Fourier transform infrared spectrometry (FTIR)
3.1. Improving the dissolution property of EPL with β-CDs (phase solubility diagram and cogrinding method)
FTIR spectra of samples were obtained on a FTIR spectrometer (model 230, Jasco Co., Ltd) using the KBr disc method. Spectra (16 scans at 4 cm− 1 resolution) were collected in the 4000–400 cm− 1 range.
The complexing behavior of EPL with various CDs in water was studied by the phase solubility method. Fig. 2 shows the phase solubility diagrams of EPL with various CDs. The solubility of EPL did not increase enough with α- and γ-CD (data not shown). The EPL/β-CD system displayed a typical BS-type solubility curve according to the classification system of Higuchi and Connors (Higuchi and Connors 1965), where the initial rising portions were followed by plateau regions, after which the total EPL concentration decreased. From
2.8. Skin permeation studies of GM systems All animal experiments were performed in accordance with the guidelines of the Institutional Animal Care and Use Committee (School of Pharmacy, Nihon University, Chiba, Japan). The full-thickness dorsal skin of male hairless mice (5–8 weeks of age), sacrificed by ether, was excised and adherent fat and other visceral debris were removed from the undersurface. In vitro skin permeation studies were performed with Franz cells (Vertical diffusion cell™, Hanson Research Corporation, CA, USA). Franz cells were mounted in a Microette™ Plus system (Hanson Research) equipped with a thermostatic bath, injection system, vacuum pump, agitation clamp, archive samples in Mulitfull™ collector, and autosampler. The EPL GM suspension (500 μL) in water with or without various β-CD derivatives (all concertation is 5 mM) was added to the donor cell. EPL GM with/without β-CD derivatives suspension was prepared via the “Solubilization of EPL with cogrinding” method. The effective area of diffusion was 1.77 cm2 and the receiver cell volume was 7 mL. The receiver cell was filled with phosphate buffered solution (PBS, pH 7.4) and stirred at 650 rpm using a magnetic stirrer. The entire system was maintained at 32 ± 0.5 °C with a circulating water jacket. The amount of EPL that permeated the skin into the receiver cell was quantitated by collecting 0.5 mL samples from the receiver cell at the designated time intervals and analyzing these by HPLC. The volume of receiver cell fluid withdrawn at each interval was replaced with PBS
Fig. 2. Phase solubility diagrams of EPL/CDs systems.
81
European Journal of Pharmaceutical Sciences 106 (2017) 79–86
T. Furuishi et al.
PM could be interpreted as an approximate superposition of EPL and βCD derivatives. It was revealed that no interaction occurred between EPL and β-CD derivatives by physical mixing alone. When EPL was coground with various β-CD derivatives at a 1:1 molar ratio, respectively, the PXRD showed a halo pattern and no diffraction peak appeared. Crystalline EPL became amorphous by cogrinding with βCD derivatives (Fig. 5). It is suggested that the crystalline structure of EPL was disrupted and that EPL molecules were substantially converted into amorphous states, but did not form a crystalline complex.
Fig. 2, the length of the plateau region indicated a stoichiometry of 1:2, possibly 1:3 (EPL:β-CD). The solubility of EPL with 6 mM β-CD was about 5 times higher than intact EPL in aqueous solution. Moreover, the solubility profiles of EPL with all β-CD derivatives were classified as AL-type, indicating the formation of a 1:1 stoichiometry complex. Since the solubility of EPL increased linearly from about 10 (β-CD) to 21 (HB-β-CD) times greater than EPL alone, water-soluble complexes could be formed within the range of CD concentrations examined. The value of the apparent stability constant (Kc) of the EPL-β-CD and their derivative complexes increased in the order of β-(470) < HP-(810) < SBE-(1135) ≅ ME(1135) < HB-β-CD (1850 M− 1). These results suggest that HB-β-CD contribute the most to increasing the solubility of EPL. In the phase-solubility diagrams (Fig. 2), the solubility of EPL increased using β-CD derivatives, but the simple dissolution test with CDs, namely the addition of the water insoluble drug into the CD solution, would not sufficiently enhance the dissolution behavior of the water insoluble drug. The cogrinding technique is widely used for improving dissolution rate and/or solubility. In an attempt to further enhance EPL solubility, we applied this method of obtaining a ground mixture for solubilizing EPL using β-CD derivatives. Fig. 3 shows the concentration of EPL by β-CD derivatives with or without the cogrinding method. The concentration of EPL from the GM was about 3 times greater than PM (p < 0.05, ANOVA). These values were also about 2–3 times larger than the concentration of EPL with the same CD concentration (5 mM) calculated from the phase solubility diagrams (Fig. 2). From this result, we reaffirmed that the coground technique is very useful in reducing the addition of β-CDs derivatives and thus improving dissolution behavior.
3.4. FTIR measurements FTIR revealed the molecular interaction between EPL and β-CD derivatives. Fig. S1 shows the FTIR spectra of EPL/β-CD derivative systems. For EPL alone, characteristic absorption peaks were observed near 1743, 1674, and 1556 cm− 1 from carboxyl, amide, and thiocarbonyl stretching vibrations, respectively. All of these characteristic peaks were observed and did not shift in PM and GM systems. As the results, it is considered that EPL is dispersed in the β-CD derivatives but difficult to determine to be included in that. Taken together with DSC and PXRD measurements, it is likely that specific molecular interactions between EPL and β-CD derivatives did not occur and EPL dispersed in β-CD derivatives in an amorphous state.
3.5. Effect of various β-CD derivatives on the skin permeation of EPL As we described in the introduction, using the CD for transdermal has some advantage. β-CD derivatives are used as skin permeation enhancers, because some β-CD derivatives alter the structure of SC lipid due to extract significant amounts of some lipophilic components from the skin (Bentley et al. 1997; Legendre et al. 1995). Moreover, Ventura et al. reported that histological analysis of treated human SC and epidermis showed a protective effect of the ME- and HP-β-CD towards an invasive action shown by celecoxib on SC, even though the both CD enhanced the flux of celecoxib through human SC and epidermis (Ventura et al. 2006). Therefore, it is conceivable that β-CD derivatives are useful and safety skin permeation enhancer. The skin permeation profiles of EPL coground with various β-CD derivatives are shown in Fig. 6 and Table 1. All the β-CD derivatives, except for SBE-β-CD, increased the flux of EPL rather than EPL alone and PM, respectively. Among the β-CD derivatives in the GM system, the highest permeation rate of 1.07 μg/cm2/h was observed with ME-βCD (p < 0.05, ANOVA), while SBE-β-CD produced the lowest enhancement in EPL flux (0.01 μg/cm2/h). The highest flux value is about 100 times greater than EPL alone. Moreover, the Kp values of EPL with MEβ-CD were highest among the β-CD derivatives. In the phase solubility diagram (Fig. 2), the EPL solubility increased with β-CD derivatives following the order of HP-β-CD < SBE-β-CD ≅ ME-β-CD < HB-β-CD. Furthermore, from results of experiments on cogrinding effects (Fig. 3), EPL solubility increased by cogrinding with β-CD derivatives, but there were no significant differences among them. However, according to results of skin permeation of EPL (Fig. 6), ME-β-CD had substantially enhanced EPL skin permeation. The obtained result can be attributed to the capacity for ME-β-CD to extract lipids, such as cholesterol and triglycerides, from the SC and to complex them, thus temporarily decreasing the skin barrier properties (Ventura et al. 2006; Másson et al., 1999; Lopez et al. 2000; Babu and Pandit 2004). The enhancement effect of ME-β-CD on the skin permeation of EPL was estimated by not only improving the dissolution behavior of EPL, but also by ME-β-CD extracting lipid and/or cholesterol from the SC. For these reasons, skin permeation of EPL would be increased by ME-βCD among the β-CD derivatives used in our experiments.
3.2. DSC measurements DSC measurements were carried out to evaluate the thermal behavior of EPL, β-CD derivatives, PM, and GM, respectively (Fig. 4). One sharp endothermic peak was observed around 224 °C attributed to the fusion of crystalline EPL in the DSC thermogram of EPL. On the other, broad endothermic peaks were observed around 100 °C, which can be explained by dehydration during the heating process in the β-CD derivatives. In the PM system, the endothermic peaks derived from EPL decreased or almost disappeared. These results may be due to low interaction between the pure components in the PMs. Conversely, the sharp endothermic peak corresponding to EPL melting decreased or disappeared in the GM. Water loss from β-CDs also decreased. This indicates that EPL and β-CD derivatives were molecularly dispersed in the amorphous binary mixture. 3.3. PXRD measurements PXRD patterns of EPL, β-CD derivatives, and a PM of EPL and β-CD derivatives (molar ratio 1:1) are presented in Fig. 5. The pattern of the
Fig. 3. Effect of co-grinding with β-CD derivatives on EPL solubility.
82
European Journal of Pharmaceutical Sciences 106 (2017) 79–86
T. Furuishi et al.
Fig. 4. DSC curves of EPL/β-CD derivatives systems showing a) HB-β-CD, b) ME-β-CD, c) SBE-β-CD, and d) HP-β-CD.
permeation enhancers. As shown in Table S1, fluxes of EPL from EPL/ ME-β-CD GM systems with addition of 1 wt% NMP, PG, and Urea were ca. 2.0, 1.4, and 2.0 times higher than in the EPL/ME-β-CD GM system, respectively. In contrast, POE, SE1816, and SE1216 did not enhance the skin permeability of EPL from the EPL/ME-β-CD GM systems. Moreover, Fig. 7 shows the effect of the concentration of NMP, PG, and urea on the skin permeation of EPL, respectively. Table 2 summarizes the skin permeation parameters of EPL with the abovementioned three skin permeation enhancers and ME-β-CD compared 10 wt% with 1 wt% skin permeation enhancers. The flux values of EPL increased with increasing concentrations of these enhancers from 1 to 10 wt%. Among these enhancers, urea markedly enhanced EPL permeability across the skin and the flux value was 2.96 μg/cm2/h, which was about 300 times greater than EPL alone. Enhanced EPL by addition of urea was due to not only a moisturizing effect leading to improved mobility of the SC protein (Alonso et al. 2001), but also by increasing
3.6. Influence of chemical enhancers on the skin permeation of EPL from the ME-β-CD GM system The enhanced skin permeation of ELP is considered limited when the ME-β-CD GM system is used alone. Recent reports show the combination of CD with other drug delivery tools, such as liposome (Alomrani et al. 2014), iontophoresis (Juluri and Narasimha Murthy 2014) and electrophoresis (Sammeta et al. 2010), improve the skin permeation of drug rather than using only CDs, but these techniques are not convenient due to use the special technique and/or equipment. In contrast, improving percutaneous absorption of drug using chemical enhancer is a simple and inexpensive method. It is well known that the combination of various enhancers improves the percutaneous absorption of drugs much greater than either enhancer alone (Ho et al. 1994; Kakubari et al. 2006). Therefore, we tried to enhance the skin permeation of the EPL/ME-β-CD GM system using water-soluble skin
Fig. 5. PXRD patterns of EPL/β-CD derivatives systems for a) HB-β-CD, b) ME-β-CD, c) SBE-β-CD, and d) HP-β-CD.
83
European Journal of Pharmaceutical Sciences 106 (2017) 79–86
T. Furuishi et al.
Fig. 6. Skin permeation profiles of EPL from EPL/β-CD derivatives systems, including a) HP-β-CD system, b) SBE-β-CD, c) HB-β-CD, and d) ME-β-CD. The concentration of all β-CD derivatives is 5 mM. Table 1 Skin permeation parameters of EPL from EPL/β-CD derivatives systems. Sample
PM
GM
EPL intact HB-β-CD ME-β-CD SBE-β-CD HP-β-CD HB-β-CD ME-β-CD SBE-β-CD HP-β-CD
Flux (μg/cm2/h)
Lag time (h)
Q (μg/cm2)
S (μg/mL)
KP (× 10− 3 cm/h)
0.01 0.03 0.18 0.01 0.01 0.28 1.07 0.01 0.03
15.8 ± 3.1 8.1 ± 1.2 13.7 ± 3.6 9.7 ± 1.6 18.6 ± 1.0 14.0 ± 3.1 17.4 ± 0.6 6.4 ± 4.2 3.0 ± 1.0
0.13 0.48 1.65 0.13 0.10 2.78 7.44 0.23 0.52
4.6 ± 1.1 40.4 ± 4.2 31.4 ± 2.8 26.2 ± 0.9 23.3 ± 2.5 117.0 ± 22.8 80.2 ± 21.8 91.8 ± 25.1 95.8 ± 45.5
3.09 ± 0.71 0.75 ± 0.10 5.83 ± 4.36 0.36 ± 0.06 0.47 ± 0.55 2.42 ± 1.18 13.34 ± 4.39 0.14 ± 0.06 0.39 ± 0.23
± ± ± ± ± ± ± ± ±
0.0002 0.002 0.136 0.001 0.013 0.127 0.199 0.005 0.003
± ± ± ± ± ± ± ± ±
0.03 0.08 0.80 0.01 0.08 0.78 1.30 0.05 0.13
Q: amount permeated of EPL; S: solubility; KP: permeability constant; each value is the mean ± S.D. (n = 3).
4. Conclusion
the concentration of EPL. Regardless, the solubility of EPL did not increase by addition of 10% PG, as the flux of EPL improved. This suggested that PG does not contribute to improving the dissolution of EPL. It was reported that PG enhanced the skin permeability of some drugs so that the solvent ‘drag’ may carry permeant into the tissue as PG traverses and there may be some minor disturbance to intercellular lipid packing within the SC bilayers (Williams and Barry 2004). Therefore, this mechanism could support the increasing the flux of EPL by PG. Conversely, using 10% NMP, the flux of EPL decreased with the decreasing solubility of EPL against increasing Kp values. It is suggested that the amount of EPL permeated through the skin decreased due to decreased solubility of EPL in the donor phase. From this result, among these enhancers, we found that 10% urea with ME-βCD accreted the skin permeation of EPL and it was estimated that the mechanism for this effect involves the ability for urea and ME-β-CD to not only enhance the solubility of EPL in aqueous solution, but also to increase mobility of the SC protein, thus enhancing the distribution of EPL into the intercellular region of the SC.
In this study, we characterized the solid state of EPL using β-CD derivatives and demonstrated that the solubility of EPL increased. Phase solubility diagrams showed that β-CD derivatives enhanced the solubility of EPL and we found the cogrinding process was more efficient in increasing the concentration of EPL in aqueous solution, which the dissolution enhancing factors were estimated the complex formation between EPL and β-CD derivatives. Based on a combination of DSC, IR, and PXRD data, we found the crystalline structures of EPL were disrupted and that ELP molecules substantially dispersed into amorphous β-CD derivative in the solid state. The GM system with β-CD derivatives increased the skin permeation of EPL markedly more than EPL alone or the PM system. Moreover, the addition of the skin permeation enhancer into the GM system dramatically enhanced the skin permeability of EPL. Specifically, the maximum flux occurred at 10% urea and the flux value was 300 times greater than with EPL alone without urea. These results indicate the ME-β-CD GM system with urea has potential as a new transdermal drug delivery system of EPL for diabetic neuropathy, but the same ternary system could attempt to 84
European Journal of Pharmaceutical Sciences 106 (2017) 79–86
T. Furuishi et al.
Fig. 7. Effect of enhancer concentration on skin permeation profiles of EPL from the EPL/ME-β-CD system. Table 2 Effect of enhancer concentration on the skin permeation parameters of EPL from EPL/ME-β-CD systems. Enhancers
Flux (μg/cm2/h)
wt%
10
1.0
10
1.0
10
1.0
10
1.0
10
1.0
NMP PG Urea
0.91 ± 0.09 2.76 ± 1.15 2.96 ± 0.34
2.05 ± 0.94 1.38 ± 1.03 2.07 ± 1.02
18.1 ± 0.2 18.0 ± 0.9 17.5 ± 1.6
18.0 ± 0.6 18.2 ± 0.6 18.0 ± 0.8
5.97 ± 0.61 18.4 ± 6.5 20.5 ± 4.6
13.9 ± 7.0 9.31 ± 6.73 14.1 ± 6.7
6.2 ± 0.3 51.8 ± 7.4 219.7 ± 6.9
47.5 ± 15.4 57.1 ± 1.6 87.9 ± 7.4
147.3 ± 16.0 53.3 ± 23.5 13.5 ± 1.6
43.2 ± 24.3 24.2 ± 18.1 23.6 ± 11.8
Lag time (h)
Q (μg/cm2)
S (μg/mL)
KP (× 10− 3 cm/h)
Q: amount permeated of EPL; S: solubility; KP: permeability constant; each value is the mean ± S.D. (n = 3). influence of some cyclodextrins on the stratum corneum from the hairless mouse. J. Pharm. Pharmacol. 49, 397–402. Boldyrev, V.V., 2004. Mechanochemical modification and synthesis of drugs. J. Mater. Sci. 39, 5117–5120. Brewster, M.E., Loftsson, T., 2007. Cyclodextrins as pharmaceutical solubilizers. Adv. Drug Deliv. Rev. 59, 645–666. Callaghan, B.C., Cheng, H.T., Stables, C.L., Smith, A.L., Feldman, E.L., 2012. Diabetic neuropathy: clinical manifestations and current treatments. Lancet Neurol. 11, 521–534. Chieng, N., Aaltonen, J., Saville, D., Rades, T., 2009. Physical characterization and stability of amorphous indomethacin and ranitidine hydrochloride binary systems prepared by mechanical activation. Eur. J. Pharm. Biopharm. 71, 47–54. Chylack Jr., L.T., Kinoshita, J.H., 1969. A biochemical evaluation of a cataract induced in a high-glucose medium. Investig. Ophthalmol. 8, 401–412. He, D., Deng, P., Yang, L., Tan, Q., Liu, J., Yang, M., Zhang, J., 2013. Molecular encapsulation of rifampicin as an inclusion complex of hydroxypropyl-βcyclodextrin: design; characterization and in vitro dissolution. Colloids Surf. B: Biointerfaces 103, 580–585. Higuchi, T., Connors, K.A., 1965. Advances in analytical chemistry and instrumentation, chapter 4. In: Phase Solubility Studies, pp. 117–212. Ho, H.O., Huang, F.C., Sokoloski, T.D., Sheu, M.T., 1994. The influence of cosolvents on the in-vitro percutaneous penetration of diclofenac sodium from a gel system. J. Pharm. Pharmacol. 46, 636–642. Hotta, N., Sakamoto, N., Shigeta, Y., Kikkawa, R., Goto, Y., 1996. Clinical investigation of epalrestat, an aldose reductase inhibitor, on diabetic neuropathy in Japan: multicenter study. Diabetic Neuropathy Study Group in Japan. J. Diabetes Complicat. 10, 168–172. Hotta, N., Akanuma, Y., Kawamori, R., Matsuoka, K., Oka, Y., Shichiri, M., Toyota, T., Nakashima, M., Yoshimura, I., Sakamoto, N., Shigeta, Y., 2006. Long-term clinical
enhance the skin permeability of other water-insoluble drugs. Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.ejps.2017.05.047. Acknowledgements This study was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (25870795) and the Otani prize(Hoshi University, 2013). References Alomrani, A.H., Shazly, G.A., Amara, A.A., Badran, M.M., 2014. Itraconazolehydroxypropyl-β-cyclodextrin loaded deformable liposomes: in vitro skin penetration studies and antifungal efficacy using Candida albicans as model. Colloids Surf. B: Biointerfaces 121, 74–81. Alonso, A., dos Santos, W.P., Leonor, S.J., dos Santos, J.G., Tabak, M., 2001. Stratum corneum protein dynamics as evaluated by a spin-label Maleimide derivative: effect of urea. Biophys. J. 81 (6), 3566–3576. Arias, M.J., Moyano, J.R., Ginés, J.M., 1997. Investigation of the triamterene–βcyclodextrin system prepared by co-grinding. Int. J. Pharm. 153, 181–189. Babu, R.J., Pandit, J.K., 2004. Effect of cyclodextrins on the complexation and transdermal delivery of bupranolol through rat skin. Int. J. Pharm. 271, 155–165. Bentley, M.V., Vianna, R.F., Wilson, S., Collett, J.H., 1997. Characterization of the
85
European Journal of Pharmaceutical Sciences 106 (2017) 79–86
T. Furuishi et al.
Oates, P.J., Mylari, B.L., 1999. Aldose reductase inhibitors: therapeutic implications for diabetic complications. Expert Opin. Investig. Drugs 8, 2095–2119. Ohmura, C., Watada, H., Azuma, K., Shimizu, T., Kanazawa, A., Ikeda, F., Yoshihara, T., Fujitani, Y., Hirose, T., Tanaka, Y., Kawamori, R., 2009. Aldose reductase inhibitor, epalrestat, reduces lipid hydroperoxides in type 2 diabetes. Endocr. J. 56, 149–156. Okamoto, H., Sakai, T., Danjo, K., 2005. Effect of sucrose fatty acid esters on transdermal permeation of lidocaine and ketoprofen. Biol. Pharm. Bull. 28, 1689–1694. Park, E.S., Chang, S.Y., Hahn, M., Chi, S.C., 2000. Enhancing effect of polyoxyethylene alkyl ethers on the skin permeation of ibuprofen. Int. J. Pharm. 209, 109–119. Prausnitz, M.R., Langer, R., 2008. Transdermal drug delivery. Nat. Biotechnol. 26, 1261–1268. Ramirez, M.A., Borja, N.L., 2008. Epalrestat: an aldose reductase inhibitor for the treatment of diabetic neuropathy. Pharmacotherapy 28, 646–655. Ranu, B., Stolle, A., 2014. Ball Milling Towards Green Synthesis: Applications, Projects, Challenges. The Royal Society of Chemistry, London. Sammeta, S.M., Vaka, S.R.K., Murthy, S.N., 2010. Transcutaneous electroporation mediated delivery of doxepin-HPCD complex: a sustained release approach for treatment of postherpetic neuralgia. J. Control. Release 142, 361–367. van Smeden, J., Janssens, M., Gooris, G.S., Bouwstra, J.A., 2014. The important role of stratum corneum lipids for the cutaneous barrier function. Biochim. Biophys. Acta 1841, 295–313. Srivastava, K., Arora, A., Kataria, A., Cappelleri, J.C., Sadosky, A., Peterson, A.M., 2013. Impact of reducing dosing frequency on adherence to oral therapies: a literature review and meta-analysis. Patient Prefer. Adherence. 7, 419–434. Szejtli, J., 1998. Introduction and general overview of cyclodextrin chemistry. Chem. Rev. 98, 1743–1754. Terashima, H., Hama, K., Yamamoto, R., Tsuboshima, M., Kikkawa, R., Hatanaka, I., Shigeta, Y., 1984. Effects of a new aldose reductase inhibitor on various tissues in vitro. J. Pharmacol. Exp. Ther. 229, 226–230. Try, C., Moulari, B., Beduneau, A., Fantini, O., Pin, D., Pellequer, Y., Lamprecht, A., 2016. Size dependent skin penetration of nanoparticles in murine and porcine dermatitis models. Eur. J. Pharm. Biopharm. 100, 101–108. Uchida, K., Kigoshi, T., Nakano, S., Ishii, T., Kitazawa, M., Morimoto, S., 1995. Effect of 24 weeks of treatment with epalrestat, an aldose reductase inhibitor, on peripheral neuropathy in patients with non-insulin-dependent diabetes mellitus. Clin. Ther. 17, 460–466. Ventura, C.A., Tommasini, S., Falcone, A., Giannone, I., Paolino, D., Sdrafkakis, V., Mondello, M.R., Puglisi, G., 2006. Influence of modified cyclodextrins on solubility and percutaneous absorption of celecoxib through human skin. Int. J. Pharm. 314, 37–45. Williams, A.C., Barry, B.W., 2004. Penetration enhancers. Adv. Drug Deliv. Rev. 56, 603–618. Wongmekiat, A., Tozuka, Y., Moribe, K., Oguchi, T., Yamamoto, K., 2007. Preparation of drug nanoparticles by co-grinding with cyclodextrin: formation mechanism and factors affecting nanoparticle formation. Chem. Pharm. Bull. 55, 359–363. Zhao, L., Fang, L., Xu, Y., Liu, S., He, Z., Zhao, Y., 2008. Transdermal delivery of penetrants with differing lipophilicities using O-acylmenthol derivatives as penetration enhancers. Eur. J. Pharm. Biopharm. 69, 199–213.
effects of epalrestat, an aldose reductase inhibitor, on diabetic peripheral neuropathy: the 3-year, multicenter, comparative Aldose Reductase Inhibitor-Diabetes Complications Trial. Diabetes Care 29, 1538–1544. Ishiguro, T., Hirayama, F., Iohara, D., Arima, H., Uekama, K., 2010. Crystallization and polymorphic transitions of chlorpropamide in aqueous 2-hydroxybutyl-βcyclodextrin solution. Eur. J. Pharm. Sci. 39, 248–255. Janssens, S., Van den Mooter, G., 2009. Review: physical chemistry of solid dispersions. J. Pharm. Pharmacol. 61, 1571–1586. Juluri, A., Narasimha Murthy, S., 2014. Transdermal iontophoretic delivery of a liquid lipophilic drug by complexation with an anionic cyclodextrin. J. Control. Release 189, 11–18. Kakubari, I., Nakamura, N., Takayasu, T., Yamauchi, H., Takayama, S., Takayama, K., 2006. Effects of solvents on skin permeation of formoterol fumarate. Biol. Pharm. Bull. 29, 146–149. Kinoshita, J.H., Kador, P., Catiles, M., 1981. Aldose reductase in diabetic cataracts. JAMA 246, 257–261. Koizumi, A., Fujii, M., Kondoh, M., Watanabe, Y., 2004. Effect of N-methyl-2-pyrrolidone on skin permeation of estradiol. Eur. J. Pharm. Biopharm. 57, 473–478. Legendre, J.Y., Rault, I., Petit, A., Luijten, W., Demuynck, I., Horvath, S., Ginot, Y.M., Cuine, A., 1995. Effects of β-cyclodextrins on skin: implications for the transdermal delivery of piribedil and a novel cognition enhancing-drug, S-9977. Eur. J. Pharm. Sci. 3, 311–322. Loftsson, T., Duchene, D., 2007. Cyclodextrins and their pharmaceutical applications. Int. J. Pharm. 329, 1–11. Loftsson, T., Masson, M., 2001. Cyclodextrins in topical drug formulations: theory and practice. Int. J. Pharm. 225, 15–30. Loftsson, T., Hreinsdottir, D., Masson, M., 2005. Evaluation of cyclodextrin solubilization of drugs. Int. J. Pharm. 302, 18–28. Loftsson, T., Vogensen, S.B., Brewster, M.E., Konradsdottir, F., 2007. Effects of cyclodextrins on drug delivery through biological membranes. J. Pharm. Sci. 96, 2532–2546. Lopez, R.F., Collett, J.H., Bentley, M.V., 2000. Influence of cyclodextrin complexation on the in vitro permeation and skin metabolism of dexamethasone. Int. J. Pharm. 200, 127–132. Maladkar, M., Rajadhyaksha, G., Venkataswamy, N., Hariharan, R.S., Lohati, S.R., 2009. Efficacy, safety, and tolerability of epalrestat compared to methylcobalamine in patients with diabetic neuropathy. Int. J. Diabetes Dev. Ctries. 29, 28–34. Másson, M., Loftsson, T., Masson, G., Stefansson, E., 1999. Cyclodextrins as permeation enhancers: some theoretical evaluations and in vitro testing. J. Control. Release 59, 107–118. Matsuda, H., Arima, H., 1999. Cyclodextrins in transdermal and rectal delivery. Adv. Drug Deliv. Rev. 36, 81–99. Mennini, N., Bragagni, M., Maestrelli, F., Mura, P., 2014. Physico-chemical characterization in solution and in the solid state of clonazepam complexes with native and chemically-modified cyclodextrins. J. Pharm. Biomed. Anal. 89, 142–149. Moribe, K., Shibata, M., Furuishi, T., Higashi, K., Tomono, K., Yamamoto, K., 2010. Effect of particle size on skin permeation and retention of piroxicam in aqueous suspension. Chem. Pharm. Bull. 58, 1096–1099.
86