Hindawi

International Journal of Polymer Science

Volume 2017, Article ID 1476270, 7 pages
https://doi.org/10.1155/2017/1476270

Research Article
Effect of Film-Forming Polymers on Release of Naftifine
Hydrochloride from Nail Lacquers

Indr{ Šveikauskait{ and Vitalis Briedis

Department of Clinical Pharmacy, Lithuanian University of Health Sciences, SukilėliJ Pr. 13, 50161 Kaunas, Lithuania

Correspondence should be addressed to Indrė Šveikauskaitė; [email protected]

Received 4 November 2016; Revised 11 January 2017; Accepted 23 January 2017; Published 16 February 2017

Academic Editor: Jaume Garcia-Amorós

Copyright © 2017 Indrė Šveikauskaitė and Vitalis Briedis. This is an open access article distributed under the Creative Commons
Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is
properly cited.

The successful topical therapy of onychomycosis depends on effective drug release and penetration into nail, which can be achieved
by using an adequately developed delivery system. This study evaluated and compared effect of film-forming polymers Eudragit
RL100, Eudragit RS100, and ethyl cellulose on naftifine hydrochloride release from experimental nail lacquer formulations. Quality
of formulations was evaluated by determining drying time and water resistance. Interactions between active pharmaceutical
ingredient and excipients were investigated using microcalorimetry and FT-IR. Optimization of nail lacquer formulations was
performed by naftifine hydrochloride release testing. Release of naftifine hydrochloride increased with increasing concentration of
Eudragit RL100. Plasticizer triacetin affected the release of naftifine hydrochloride, when Eudragit RS100 polymer was used. Ethyl
cellulose polymer was determined to be not applicable for naftifine hydrochloride nail lacquer formulations. Two compositions of
nail lacquers were optimized and could be used in further development of transungual delivery systems.

1. Introduction deliver therapeutic doses of active substances remains critical

for efficient onychomycosis treatment [7, 9, 10].
Onychomycosis is a fungal infection of nails that causes Mechanical characteristics and water resistance make
discoloration, thickening, and separation from the nail bed. nail lacquers a promising alternative for onychomycosis
It affects up to 14% of the population and is responsible topical treatment. Lacquer film is formed during solvents
for almost 50% of nails diseases [1]. Oral antifungal therapy evaporation after lacquer application. Films formed by nail
remains the most often used for onychomycosis treatment; lacquers have to establish attachment to the nail surface
however, it has significant disadvantages: long systematic which is a necessary prerequisite of efficient drug delivery
treatment can cause serious side effects, liver damage, and [11]. The increase of drug concentration depends on the
only tiny drug fraction could reach a target because of limited volatile fraction in the nail lacquer [12]. This system is
blood circulation [2]. Therefore, topical therapy is often considered to be efficient for onychomycosis therapy as a film
considered as reasonable alternative. Topical delivery systems creates a reservoir of the drug substance in the infected nail
offer many benefits in dermatology; however, gel, cream, plate. This leads to achieving continuous penetration of drug
or liquid formulations are not adequate for the transungual substance, required for an effective treatment [13–15].
delivery since they are easily removed by washing or rubbing. Reservoir properties and release characteristics are
This phenomenon at the site of application accounts for their affected by nature of the polymer used for film formation.
inefficacy [3–6]. Polymeric film can form an external reservoir, control a
Few days lasting drug delivery is considered as essential release of drug substance, and (or) limit the supply of drug
requirement for pharmaceutical formulations applied topi- [16]. Differences in film-forming system technology can affect
cally on the nail [7, 8]. Film-forming systems for transungual film affinity to keratin and nail permeation [17]. Drug release
drug delivery are used in clinical practice, but their ability to from film-forming systems is affected by several factors:
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2 International Journal of Polymer Science

Table 1: Composition of 1% naftifine hydrochloride nail lacquers.

N1 N2 N3 N4 N5 N6 N7 N8 N9 N10 N11 N12 N13 N14 N15 N16 N17 N18 N19 N20
API 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1
Solvents system 83.4 84 81.5 81.5 84 81.2 85 79 85 81.2 84 81.5 83.4 84 81.5 81.5 84 81.2 85 79
(1 : 1 : 1)
Triacetin 2.8 0 5 2.5 5 3.9 2 5 2 3.9 5 2.5 2.8 0 5 2.5 5 3.9 2 5
Eudragit RL100 12.8 15 12.5 15 10 13.9 12 15 — — — — — — — — — — — —
Eudragit RS100 — — — — — — — — — — — — 12.8 15 12.5 15 10 13.9 12 15
Ethyl cellulose — — — — — — — — 12 13.9 10 15 — — — — — — — —

active substance physicochemical properties, type and con- Table 2: Conditions and duration of the microcalorimetric testing.
centration of a polymer and plasticizer, and incorporation of
other excipients [18, 19]. Temperature ranges Change speed Duration
The aim of this study was to evaluate the effect of film- 20–100∘ C 1 K/min 4800 s
forming polymers on quality characteristics of nail lacquers 100–200∘ C 0.5 K/min 12 000 s
and naftifine hydrochloride release. Optimization of lacquer 200–20∘ C 1.2 K/min 9000 s
formulations was performed referring to naftifine hydrochlo-
ride release data.
spreading the sample on a glass slide and rising it vertically
2. Materials and Methods [20].
The water resistance test was conducted by applying a nail
2.1. Materials. Naftifine hydrochloride was purchased from lacquer onto a glass slide, allowing it to dry, then immersing
Chemical Point (Deisenhofen, Germany). Ethanol 96% (AB a glass slide with the lacquer film in water for 7 days [21].
Stumbras, Lithuania), butyl acetate, and ethyl acetate were Changes in film discoloration, turbidity, and resistance to
obtained from Sigma-Aldrich Chemie GmbH (Steinheim, water were evaluated every 24 hours. Structural changes
Germany) and used as solvents system. Triacetin which of films were visualized by means of inverted microscope
was used as plasticizer was kindly supplied by Lanxess Olympus IX71 combined with LCAchNYOXPH lens.
(Germany). Film-forming polymers Eudragit RL100 and A ratio of released and adsorbed heat of developed for-
Eudragit RS100 were kindly gifted by Evonik Industries AG mulations was determined using microSC microcalorimeter
(Essen, Germany), while ethyl cellulose Ethocel Standard 20 (Setaram Instrumentation, France). Experiment was carried
Premium was obtained from Colorcon (UK). out in two phases: heating and cooling of experimental
formulations. Conditions of the experiment are presented in
Table 2.
2.2. Methods
FT-IR spectra were used to evaluate the possible existing
2.2.1. Preparation of Nail Lacquers. The experimental nail molecular interactions between drug and film-forming poly-
lacquers were formulated by dissolving appropriate amount mer. Drug-excipients compatibility studies were performed
of naftifine hydrochloride in a base lacquer, containing by scanning from 4000 to 400 cm−1 in a FT-IR Spectrum Two
ethanol (96%), butyl acetate, ethyl acetate, triacetin, and spectrophotometer (PerkinElmer, USA). Peak matching was
one of the film-forming polymers: Eudragit RL100, Eudragit done to detect any possible interactions of components.
RS100, or ethyl cellulose. Experimental compositions of 1%
naftifine hydrochloride nail lacquers are presented in Table 1. 2.2.3. In Vitro Naftifine Hydrochloride Release Testing. Nafti
Naftifine hydrochloride was mixed with solvent system fine hydrochloride release experiments were carried out at
using magnetic stirrer at 1000 rpm until the drug substance 32∘ C measuring drug quantity diffusing through 1 cm2 cupro-
was completely dissolved. Polymer was added and mixed phan dialysis membranes (MWCO – 10000 Da). Diffusion
until a clear solution was obtained. The plasticizer was added membrane was mounted on the diffusion cell and 50 𝜇L of
on the final step of the lacquer formulation. lacquer experimental formulation was applied uniformly on
the surface of the membrane and left for 4 hours till complete
2.2.2. Physical Characterization of Nail Lacquers. Quality of lacquer drying and film formation. Drying time of 4 hours
nail lacquers was evaluated by measuring drying time, water was experimentally proven to be sufficient to achieve dry
resistance, compatibility of drug with excipients, and ratio of lacquer film under ambient conditions by determining weight
released and absorbed heat. loss kinetics. Dry film was protected from external factors
Drying time was determined by applying a liquid film of by aluminum foil cover. Naftifine hydrochloride solubility
experimental sample on a glass plate and time till obtaining in water at 32∘ C was determined to be 950.1 𝜇g/mL and
dry-to-touch condition at room temperature (20 ± 2∘ C) water (15 mL) was used as acceptor phase for establishing
was measured. A smoothness of flow was determined by sink conditions. At predefined time points, 2 mL of acceptor
 9484, 2017, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1155/2017/1476270 by Dr. Pallavi K NGSMIPS - Ab Shetty Memorial Institute Of Dental Sciences , Wiley Online Library on [21/03/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
International Journal of Polymer Science 3

Table 3: Quantitative ranges of components in nail lacquer formulations.

Component Function Amount (%)

Ethanol (96%) : ethyl acetate : butyl acetate Solvents system 79–85%
Eudragit RL100/Eudragit RS100/ethyl cellulose Film-forming polymer 10–15%
Triacetin Plasticizer 0–5%

medium was withdrawn and the same amount of a fresh containing 0–2% plasticizer was less than 60 seconds, and
medium was added to maintain a constant volume of acceptor formulations with 5% plasticizer amount were drying in
liquid. The amount of released drug was determined by 3-4 minutes.
UV spectrophotometry at 294 nm wavelength in triplicate. Published results have demonstrated the effect of the
The released drug amount was calculated and results were viscosity of the film-forming polymer solution on the
denoted as the means ± SD. smoothness of the formed film [11]. The viscosity of ethyl
cellulose solution was in the range from 18 to 22 mPas when
2.2.4. Optimization of Compositions. The compositions of concentration of the film-forming component ranged from 10
nail lacquers for optimization were generated by applying to 15%, respectively. Ethyl cellulose showed poor solubility in
D-optimal design model according to quantitative ranges the mixture of organic solvents. It formed clear, opalescent,
of components (Table 3). Eight different compositions were viscous solutions. When the concentration of ethyl cellulose
generated for each film-forming polymer. Optimization of was higher than 12.5%, precipitates containing white film
experimental nail lacquers formulations was performed by have been formed. Addition of triacetin plasticizer to ethyl
setting in vitro release results as the critical criteria. cellulose solution resulted in shorter drying times of the
films. Nevertheless, the drying time of ethyl cellulose films
ranged from 8 to 10 minutes, and the formed films remained
2.2.5. Statistical Analysis. Nail lacquers optimization was sticky.
performed using experiment planning software Design- Presence of plasticizer in film-forming solution results
Expert 6.0.8, D-optimal design model. Statistical analysis in a stronger and flexible film [23]. Results of film testing
of experimental data was performed using SPSS software demonstrated the ability of plasticizer to affect mechanical
(version 19.0) and Microsoft Office Excel 2015. Spearman’s properties of the film and its increased resistance to water.
rank coefficient was used for correlation analysis. Statistically Plasticization reduces the glass transition temperature of the
significant difference was determined when value of 𝑃 < 0.05. polymers and provides film with higher flexibility, strength,
and resistance [7, 11, 23]. Results of water resistance testing
3. Results and Discussion showed that film resistance depended on the amount of film-
former, plasticizer, and their ratio. Maximum stability and
Suitability of hydrophobic polymers for film formation from resistance to water were determined when lacquer formu-
experimental formulations of nail lacquers and transungual lations contained 13.9% Eudragit RL100 polymer and 3.9%
delivery of naftifine hydrochloride was evaluated. The solu- triacetin. Film color change to yellowish was determined
bility of the film-forming polymer defines whether dispersion on the 5th day of testing. When formulations contained
or solution of polymer will be applied for film formation, no plasticizer, they were washed away in 24 hours. Films,
which in turn affects mechanical properties and appearance produced from 15% ethyl cellulose and 2.5% plasticizer
of formed film [7, 11] as well as drug release rates [22]. containing formulations, were washed away in 48 hours. The
As the solvents evaporate the polymer chains come into wash-out times were confirmed by microscopic evaluation of
closer contact in solutions resulting in formation of a smooth film surface.
and water resistant film [7, 16]. The choice of the film- Chemical interactions of film-forming polymers and
forming polymers was made considering their solubility and plasticizer can result in the changes of film properties. Drug
the characteristics of the formed solutions. Eudragit RL100 interactions with film-forming system can cause reduced
and Eudragit RS100 polymers are freely soluble in the mix- release of the drug from the produced film. Possible inter-
tures of organic solvents. These polymers formed clear, low actions of the nail lacquer components were evaluated by
viscosity, and runny solutions. Clear and homogenous film microcalorimetry and FT-IR spectroscopy. Nail lacquer for-
was produced by controlling polymer and plasticizer con- mulations containing Eudragit RL100 and Eudragit RS100
centrations in nail lacquer. The characteristics of polymeric showed no change in absorbed thermal energy when com-
films formed by experimental nail lacquer formulations are pared with naftifine hydrochloride free formulations (Fig-
presented in Table 4. The viscosity of solutions increased ure 1(a)). New peaks were observed in all thermographs of
as the concentration of the polymer was increased [11]. ethyl cellulose polymer films containing naftifine hydrochlo-
The increase of polymer concentration resulted in longer ride when temperature was raised to 190∘ C. Changes of
duration of film formation, but it had effect on dried lacquer polymer concentration had no effect on thermal behavior of
film characteristics. Film drying time was also affected by tested films. FT-IR analysis revealed no chemical interaction
addition of plasticizer. The drying time for the formulations between naftifine hydrochloride and film-forming polymers
 4

Table 4: Characteristics of tested nail lacquer films.

Concentration range; Nail lacquer film
Polymer Solution characteristics
% w/w Max. drying time Esthetic characteristics Water resistance Common surface structure

10 Resistance depends on amount of

Clear, runny solution. Low Clear, slightly glossy, not
Eudragit RL100 12.5 ≤2 min. film-former, plasticizer, and both
viscosity. sticky.
15 their ratios.

10 Resistance depends on amount of

Clear, runny solution. Low Clear, slightly glossy,
Eudragit RS100 12.5 ≤4 min. film-former, plasticizer and both
viscosity. sticky.
15 their ratios.

Film starts washing out on 3rd day

10
Opalescent, thick solution. of an experiment. No significant
Ethyl cellulose 12.5 ≤8 min. From clear to white.
Hardly runny. difference while changing polymer
15
or plasticizer amount.
International Journal of Polymer Science

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International Journal of Polymer Science 5

100 8 Exo Exo 8

98 6 6
96
94 4 4

HeatFlow 1 (mW)

HeatFlow 2 (mW)
92
90 2 2
88 0 0
86
%T

84 −2 −2
82
80 −4 −4
78
76 −6 −6
74 −8 −8
72
70 −10 −10
4000 3500 3000 2500 2000 1500 1000 500 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5 6 6.5
Wavenumbers (cm−1 ) Time (h)
(a) (b)

Figure 1: (a) FT-IR spectra of formulation N6. Red, API-free formulation; pink, naftifine hydrochloride nail lacquer. (b) Microcalorimetric
thermograph of formulation N6. Dark blue, API-free formulation; light blue, naftifine hydrochloride nail lacquer. Duration of testing is
approximately 6.5 h.

Table 5: Naftifine hydrochloride release, polymer Eudragit RL100.

Formulation number
(h)
N1 N2 N3 N4 N5 N6 N7 N8
0.25 27 ± 1.2 37.5 ± 0.5 33.5 ± 0.92 26.9 ± 1.23 26 ± 0.8 35 ± 0.79 39.7 ± 1.12 42.7 ± 0.81
0.5 39.7 ± 1.1 47.2 ± 0.6 45.2 ± 0.71 35.25 ± 1.31 31 ± 0.71 47.2 ± 0.91 45.3 ± 1.31 52.4 ± 0.93
1 49.1 ± 1 62.3 ± 0.51 53.8 ± 0.82 49.6 ± 1.4 45 ± 0.9 58.2 ± 0.8 57.8 ± 1.24 69.3 ± 0.72
2 55.3 ± 1.3 70.8 ± 0.82 56.9 ± 0.95 62.2 ± 1.2 49.4 ± 0.85 67 ± 1.13 65.4 ± 1.13 78 ± 0.85
3 58.7 ± 0.9 75.3 ± 0.73 63.2 ± 0.75 72 ± 1.15 52.3 ± 0.62 67 ± 0.42 69.9 ± 1 86 ± 0.67
4 63.7 ± 1 77.9 ± 0.6 68.5 ± 0.8 74.4 ± 1.2 58.2 ± 0.75 68 ± 0.93 70 ± 1.32 94 ± 0.97
5 66.7 ± 1.2 84.1 ± 0.7 73.1 ± 0.72 77 ± 1.25 60.2 ± 0.82 73 ± 1.21 72 ± 1.25 98 ± 0.82
6 70.5 ± 1.3 90 ± 0.62 77.8 ± 0.61 80.9 ± 1.5 66 ± 0.91 77 ± 1.32 72.5 ± 1.31 98.5 ± 0.86

(Figure 1(b)). Microcalorimetry revealed possible naftifine lacquer was decreased (Table 6). This effect can be related to
hydrochloride and ethyl cellulose can have internal inter- structural differences of Eudragit RL100 and Eudragit RS100
actions when the temperature was increased. These results as higher number of quaternary ammonium substitution is
suggest unsuitability of ethyl cellulose use as a film-forming present in Eudragit RL100 if compared to Eudragit RS100.
polymer for naftifine hydrochloride delivery. Possibility of using ethyl cellulose for film formation has
Published results confirm that the nature of chosen film- been demonstrated with fluconazole [24]. Films produced
forming polymer can affect mechanical, cosmetic properties from 10-11% ethyl cellulose containing formulations showed
of dried film, and drug release kinetics from formed system more than 90% release of fluconazole in less than 10 hours.
[7, 21, 22]. In vitro release studies demonstrated signifi- Film formation is influenced by used solvent system which
cant differences between tested polymeric films. Statistically should efficiently dissolve the film-forming components and
significant correlation was determined between increasing drug substance. Ethyl cellulose formulations delayed the
Eudragit RL100 concentration and increased amount of release of naftifine hydrochloride as only 40% of the drug was
released naftifine hydrochloride (Table 5). Hydrophobic poly- released in 72 h. This result should be considered acceptable,
mers can produce a “burst” release of the active substance but the film wash away occurred in 72 h.
and have ability to form a drug reservoir in biological Considering naftifine hydrochloride release in vitro
membrane [16]. Highest release of drug substance (98.5% results, formulations with Eudragit RL100 and Eudragit
in 6 hours) was achieved from nail lacquer film containing RS100 were chosen for further optimization studies. Opti-
15.0% Eudragit RL100. In this case, presence of plasticizer mization was performed by applying desirability function.
had no effect on naftifine hydrochloride release rate, thus Desirability of in vitro release parameter ranged between 0
indicating it had no effect on the drug-polymer interaction and 1, with values verging towards 1 considered the most
in the formed polymeric film. However, plasticizer enhanced desired. Optimal compositions of nail lacquers are presented
release of drug when Eudragit RS100 was used. Statistically in Figure 2.
significant correlation (𝑃 < 0.05) was established between Predicted in vitro release results were checked by per-
increased polymer-plasticizer ratio and increased release rate forming in vitro release testing (Table 7). Optimized formu-
of naftifine hydrochloride. lations were tested by evaluating drying time, water resis-
Conversely, the release of naftifine hydrochloride tance, drug-excipients compatibility, and ratio of released and
increased when concentration of Eudragit RS100 in nail absorbed heat.
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6 International Journal of Polymer Science

Table 6: Naftifine hydrochloride release, polymer Eudragit RS100.

Formulation number
(h)
N13 N14 N15 N16 N17 N18 N19 N20
0.25 12.6 ± 1.22 22 ± 0.82 16 ± 0.87 16 ± 0.75 25 ± 0.87 19 ± 0.97 21 ± 1.25 24 ± 0.67
0.5 23.9 ± 1.11 23 ± 0.91 24 ± 0.96 16.4 ± 0.84 32 ± 0.97 21 ± 0.91 26 ± 1.12 25 ± 0.87
1 43.8 ± 1.2 24.5 ± 0.71 32 ± 0.78 20 ± 0.87 42 ± 0.68 28 ± 0.84 35.9 ± 1.14 33.1 ± 0.91
2 52.8 ± 1.34 27 ± 0.62 46.4 ± 0.89 26 ± 0.75 46 ± 0.78 33 ± 0.79 41.3 ± 1.08 43.8 ± 0.84
3 62.8 ± 1.22 30.1 ± 0.87 56.2 ± 0.87 31.5 ± 0.94 52 ± 0.89 40 ± 0.84 48.7 ± 1.89 54.3 ± 0.67
4 71.5 ± 1.25 32 ± 0.89 61.5 ± 0.86 34.3 ± 0.78 62 ± 0.95 61 ± 0.94 59 ± 1.7 71.6 ± 0.87
5 76.1 ± 1.31 33.5 ± 0.75 66.3 ± 0.87 40.1 ± 0.68 63 ± 0.78 62 ± 0.74 62 ± 1.54 72.8 ± 0.57
6 78 ± 1.15 36.5 ± 0.96 69.35 ± 0.64 51 ± 0.79 66 ± 0.87 64 ± 0.85 67 ± 1.34 73 ± 0.97

Table 7: Characteristics of optimized nail lacquer formulations.

Components of formulation
Optimized formulation Designed in vitro release value Determined in vitro release value
Solvents Polymer Triacetin
OPT-1 79% 15% 5% 96.19% 98%
OPT-2 83.4% 10.6% 5% 81.38% 80.5%

A: solvents A: solvents
89.0 89.0

86.7
Prediction 81.38
0.0 81.0
10.0 0.0 44.4 10.0
51.4
75.2 69.5 58.4
72.4
65.4

81.0

86.7

Prediction 98.19

20.0 79.0 10.0 20.0 79.0 10.0

B: polymer C: triacetin B: polymer C: triacetin
(a) (b)

Figure 2: Areas of optimal composition of nail lacquers with highest desirability parameter: (a) OPT-1 formulation, Eudragit RL100 polymer;
(b) OPT-2 formulation, Eudragit RS100 polymer.

4. Conclusions testing presented the possibility of evaluating the suitability

of tested polymers for formulation of nail lacquers. The
Antifungal formulations for transungual drug delivery rep- results provided reliable arguments for choosing Eudragit
resent complex systems, influenced by solubility character- RL100 and Eudragit RS100 for further lacquer composition
istics of used polymers, plasticizers, and physicochemical optimization studies. Optimization resulted in definition of
characteristics of the drug. System of evaporating solvents quantitative composition of nail lacquers, containing both
used in formulation of lacquers should ensure dissolution Eudragit RL100 and Eudragit RS100 as film-forming poly-
of formulation components and formation of homogeneous mers, and suitability of designed formulations was confirmed
product before and after film drying. Application of adequate by in vitro biopharmaceutical testing. The application of opti-
quality testing methods provides reliable information on mization technology proved to be efficient tool in designing
possible interactions of lacquer system components and for and identifying naftifine hydrochloride lacquer compositions
biopharmaceutical characterization of the drug containing with predefined quality parameters. Quality of optimized nail
film. Testing of drying time, water resistance, microcalori- lacquer formulations should be confirmed by performing
metric analysis, compatibility studies, and in vitro release transungual naftifine hydrochloride delivery studies.
 9484, 2017, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1155/2017/1476270 by Dr. Pallavi K NGSMIPS - Ab Shetty Memorial Institute Of Dental Sciences , Wiley Online Library on [21/03/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
International Journal of Polymer Science 7

Competing Interests antimycotic activity,” British Journal of Dermatology, vol. 162,

no. 2, pp. 311–317, 2010.
The authors declare that there are no competing interests. [14] S. T. Tanriverdi and Ö. Özer, “Novel topical formulations of
Terbinafine-HCl for treatment of onychomycosis,” European
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The authors are thankful to Lanxess, Evonik Industries AG, [15] K. R. Shireesh, S. B. Chandra, P. Vishnu, and M. V. V. Prasad,
and Colorcon for generous supply of chemical substances. “Ungual drug delivery system of ketoconazole nail lacquer,”
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