10.5826/dpc.1204a202
Introduction: Onychomycosis is a fungal disorder of the nail which afflicts 5% of the population worldwide. The disease is strenuous to cure as it is chronic, hard to eliminate and tends to recur. Topical therapy is at the forefront for the treatment of many disorders of nail. However, the success rate of topical therapy has been halted owing to the poor permeation of topical therapeutics across densely keratinized nail barrier. Therefore, ungual drug permeation must be improved for an effective topical therapy. An approach to achieve this goal would be the use of terpenes from natural sources as potential penetration enhancers. This study is aimed to explore the effectiveness of some novel terpenes as potential penetration enhancers on transungual delivery of terbinafine.
Methods: Ex-vivo permeation studies were performed by sopping the nail clippings of healthy human volunteers in control and working solutions containing terbinafine (5mg/ml) per se and terbinafine (5mg/ml) with 6% of each terpenes including lavandulol, safranal, rose oxide, limonene, 3-methyl-2-butene-1-ol, and linalool respectively for 48 hours. The terbinafine concentration in nail samples was determined using a HPLC method.
Results: Statistical analysis showed that studied terpenes increase transungual penetration of terbinafine in the following order: linalool &gt; rose oxide &gt; 3-methyl-2-butene-1-ol &gt; safranal&gt; limonene&gt;lavandulol acetate. Accordingly, linalool was found to be the most effective penetration enhancer for the transungual delivery of terbinafine.
Conclusion: It is concluded that linalool can be used as safe and potential penetration enhancer for enhancing the transungual delivery of terbinafine for onychomycosis.
text/xml
2160-9381
2345
en
Yasmin Sultana
https://creativecommons.org/licenses/by-nc/4.0
Dermatology Practical & Conceptual
nail
Investigation on utility of some novel terpenes on transungual delivery of terbinafine for the management of onychomycosis
Text.Serial.Journal
https://dpcj.org/index.php/dpc
Original Article
2022-10-31
2022-01-31
2022-10-31
2022-12-05
e2022202
Dermatol Pract Concept
Introduction: Onychomycosis is a fungal disorder of the nail which afflicts 5% of the population worldwide. The disease is strenuous to cure as it is chronic, hard to eliminate and tends to recur. Topical therapy is at the forefront for the treatment of many disorders of nail. However, the success rate of topical therapy has been halted owing to the poor permeation of topical therapeutics across densely keratinized nail barrier. Therefore, ungual drug permeation must be improved for an effective topical therapy. An approach to achieve this goal would be the use of terpenes from natural sources as potential penetration enhancers. This study is aimed to explore the effectiveness of some novel terpenes as potential penetration enhancers on transungual delivery of terbinafine.
Methods: Ex-vivo permeation studies were performed by sopping the nail clippings of healthy human volunteers in control and working solutions containing terbinafine (5mg/ml) per se and terbinafine (5mg/ml) with 6% of each terpenes including lavandulol, safranal, rose oxide, limonene, 3-methyl-2-butene-1-ol, and linalool respectively for 48 hours. The terbinafine concentration in nail samples was determined using a HPLC method.
Results: Statistical analysis showed that studied terpenes increase transungual penetration of terbinafine in the following order: linalool &gt; rose oxide &gt; 3-methyl-2-butene-1-ol &gt; safranal&gt; limonene&gt;lavandulol acetate. Accordingly, linalool was found to be the most effective penetration enhancer for the transungual delivery of terbinafine.
Conclusion: It is concluded that linalool can be used as safe and potential penetration enhancer for enhancing the transungual delivery of terbinafine for onychomycosis.
Yasmin Sultana
2022/10/31
10.5826/dpc.1204a202
e2022202
Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi
2160-9381
nail
en
e2022202
Abdollahi D, Jafariazar Z, Afshar M. Effect of monoterpenes on ex vivo transungual delivery of itraconazole for the management of onychomycosis. J Cosmet Dermatol. 2020; 19(10):2745-2751. Doi: 10.1111/jocd.13317. Epub 2020 Feb 11. PMID: 32043759.
Investigation on utility of some novel terpenes on transungual delivery of terbinafine for the management of onychomycosis
https://dpcj.org/index.php/dpc/article/download/2345/1762
     Investigation on Utility of Some Novel Terpenes
      on Transungual Delivery of Terbinafine for the
             Management of Onychomycosis
        Isha Gupta1, Syeda Nashvia Adin1, Mohd. Aqil2, Mohd. Mujeeb1, Yasmin Sultana2


1 Department of Pharmacognosy and Phytochemistry, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India
2 Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India



Key words: onychomycosis, transungual, terpenes, penetration enhancer, terbinafine,
Citation: Gupta I, Adin S N, Aqil M, Mujeeb M, Sultana Y. Investigation on utility of some novel terpenes on transungual delivery of terbinafine
for the management of onychomycosis. Dermatol Pract Concept. 2022;12(4):e2022202. DOI: https://doi.org/10.5826/dpc.1204a202
Accepted: February 21, 2022; Published: October 2022
Copyright: ©2022 Gupta et al. This is an open-access article distributed under the terms of the Creative Commons Attribution-
NonCommercial License (BY-NC-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use,
distribution, and reproduction in any medium, provided the original authors and source are credited.
Funding: None.
Competing interests: None.
Authorship: Both Isha Gupta and Syeda Nashvia Adin have equal contribution in this article and should be considered joint first author.
Corresponding author: Mohd. Aqil, Associate Professor, Department of Pharmaceutics, School of Pharmaceutical Education and Research,
Jamia Hamdard (Deemed University), New Delhi, India-110062, Contact: +91-9811798725, E-mail: aqilmalik@yahoo.com




  ABSTRACT              Introduction: Onychomycosis is a fungal disorder of the nail which afflicts 5% of the population world-
                        wide. The disease is strenuous to cure as it is chronic, hard to eliminate and tends to recur. Topical therapy
                        is at the forefront for the treatment of many disorders of nail. However, the success rate of topical therapy
                        has been halted owing to the poor permeation of topical therapeutics across densely keratinized nail bar-
                        rier. Therefore, ungual drug permeation must be improved for an effective topical therapy. An approach
                        to achieve this goal would be the use of terpenes from natural sources as potential penetration enhancers.
                        Objective: This study is aimed to explore the effectiveness of some novel terpenes as potential pene-
                        tration enhancers on transungual delivery of terbinafine.
                        Methods: Ex-vivo permeation studies were performed by sopping the nail clippings of healthy human
                        volunteers in control and working solutions containing terbinafine (5mg/ml) per se and terbinafine
                        (5mg/ml) with 6% of each terpenes including lavandulol, safranal, rose oxide, limonene, 3-methyl-2-
                        butene-1-ol, and linalool respectively for 48 hours. The terbinafine concentration in nail samples was
                        determined using a HPLC (High Performance Liquid Chromatography method.
                        Results: Statistical analysis showed that studied terpenes increase transungual penetration of terbin-
                        afine in the following order: linalool > rose oxide > 3-methyl-2-butene-1-ol > safranal > limonene >
                        lavandulol acetate. Accordingly, linalool was found to be the most effective penetration enhancer for
                        the transungual delivery of terbinafine.
                        Conclusions: It is concluded that linalool can be used as safe and potential penetration enhancer for
                        enhancing the transungual delivery of terbinafine for onychomycosis.




Review | Dermatol Pract Concept. 2022;12(4):e2022202                                                                                          1
Introduction                                                     increasing the diffusion gradient and penetration capacity of
                                                                 the active through the nail plate [15-18].
Onychomycosis is the most prevalent fungal disorder of              Researches from past decades have shown that chemi-
the nails attributable to yeasts (Candida albicans and other     cal penetration enhancers yield higher permeation rates
candida species), non-dermatophyte molds (Scytalidium hy-        than other approaches for effective transungual delivery,
alinum, Scopularicpsis brevicaulis, Acremonium sp., Asper-       but irritancy at the site of application always remains a
gillus Sp., S.dimidiatum), and dermatophytes (Trichophyton       challenge [19,20]. Therefore, research has been oriented to-
rubrum, T. krajdenii, T. mentagrophytes, Epidermophyton          wards finding safe and effective penetration enhancers from
floccosum) [1]. Due to this infection, the patients experience   natural sources. Terpenes acquired from natural sources
a prodrome of nail plate thickening, onycholysis, and nail       have emerged as promising candidates and are considered
discoloration. The afflicted patients experience paresthe-       as clinically acceptable penetration enhancers. In addition,
sia, local pain, and reduced quality of life. The abnormal       many terpenes appear in the list of generally recognized as
appearance of the nails may plague the daily activities and      safe (GRAS) agents published by the USFDA. Terpenes are
stigmatize social life of affected persons [2]. Onychomyco-      used for permeation enhancements of both lipophilic and
sis progression increases with simultaneous inhabitation of      hydrophilic drugs. Their activity depends on their chemical
other conditions like HIV, poor peripheral circulation, dia-     structure and physicochemical properties such as degree of
betes, and immunosuppression [1].                                unsaturation, boiling point, size and chirality, the energy of
    The onychomycosis treatment always remains chal-             vaporization, and lipophilicity [21].
lenging due to the thick impermeable property of the nail           In the present study, we chose terbinafine, an allylamine
and profound infection [3]. However, oral treatment ther-        fungicidal drug that acts by inhibiting squalene epoxidase in
apy remains the priority for the affected patients due to the    the ergosterol biosynthesis pathway and shows higher effi-
accessibility and efficacy of oral therapeutics [2]. The oral    cacy against dermatophytes and many non-dermatophytes
treatment includes anti-fungal drugs from allylamine and         [22]. Topical therapy can eminently treat onychomycosis.
azole classes. The azole class includes ketoconazole, fluco-     The route is highly advantageous attributable to its localised
nazole and itraconazole and the allylamine class includes        effect and minimal adverse effect profile. However, its poten-
terbinafine wherein itraconazole and terbinafine are US FDA      tial is hampered by the rigid keratinous structure of the nail
approved medications for onychomycosis treatment [4-6].          plate which is hard to breach [23].
Terbinafine excels over itraconazole due to higher cure rate
and fewer drug interactions. However, their effectiveness is
                                                                 Objectives
defined/constrained due to their limited availability at the
site of action, which further increases treatment duration,      Therefore, our research has been centered on improvement
treatment cost, side effects like cardiac disturbances and he-   of transungual delivery of terbinafine with the assistance of
patic toxicity, and drug interactions. The topical treatment     natural permeation enhancers ie terpenes viz. lavandulol,
provides an alternative approach to evade the drawbacks          safranal, rose oxide, limonene, 3-methyl-2-butene-1-ol, and
associated with oral medicines and improves the adherence        linalool. The salient features of the studied terpenes have
and localized effect [7-12].                                     been highlighted in Table 1.
    The topical treatments approved by the FDA for effec-
tive treatment of onychomycosis include tavaborole 5%
                                                                 Methods
solution, ciclopirox 8% nail lacquer, and efinaconazole 10%
solution [13-14]. However, their effectiveness is limited due    Terbinafine was purchased from Virupaksha Organ-
to the minimal permeability of the drug across the nail plate.   ics Limited. Lavandulol, safranal, rose oxide, limonene,
The nail impermeability can be accredited to the highly          3-methyl-2-butene-1-ol, and linalool were purchased from
­stable hydrogen bonds and disulfide linkages in the kera-       Sigma-Aldrich. Absolute ethanol, methanol, hydrochlo-
tin network. Moreover, globular proteins and keratin fibres      ric acid, sodium hydroxide, propylene glycol, Tween 80,
make a complex structure that makes the nail plate the most      and HPLC grade methanol were purchased from S.D. Fine
challenging biological barrier [3]. Therefore, extensive re-     Chemicals. All chemicals were of Analytical Reagent grade.
search has been focused on altering the nail plate barrier by
employing various approaches, which include physical meth-       Liquid Chromatographic Conditions
ods, mechanical methods, chemical treatments, and penetra-       HPLC Quaternary System consisting of lichrospher C18
tion enhancers; wherein one of the most commonly used            reverse-phase column of 25 x 4.6 mm with particle size of
approaches is the use of penetration enhancers, which act        5 μm was used for performing HPLC analysis. All analy-
by disrupting the keratinized structure of nail plate thereby    ses were carried out under isocratic conditions at a flow



2                                                                           Review | Dermatol Pract Concept. 2022;12(4):e2022202
                             Table 1. Some Important Properties of Studied Terpenes.
                         Molecular
        Name             Formula                   Structure                      Type              Log P        Boiling Point
 Lavandulol acetate     C12H20O2                                         Monoterpene                 3.1             90 oC




 Safranal               C10H14O                                          Aldehydic terpene           2.1             70 oC




 Rose oxide             C10H18O                                          Monoterpene                 2.9            71-73 oC




 Limonene               C10H16                                           Monoterpene                 3.4             175 oC




 3-methyl-2-buten-      C5H10O                                           Monoterpene                 0.91            140 oC
 1-ol or prenol

 Linalool               C10H18O                                          Monoterpene                 2.7            198.5 oC




rate of 1ml/min using mobile phase methanol: acetonitrile:        the optimal effect of terpenes on transungual delivery of ter-
0.2% triethylamine (55:35:10, %v/v) with U.V. detection at        binafine, terpenes concentration was chosen to be more than
280 nm [24].                                                      4.7%, which emulated the highest concentration of terpene
                                                                  in market formulation viz. Vicks Vaporub® (camphor, 4.7%).
Preparation of Stock and Working Solutions                        The prepared solutions were subjected to nail penetration
In propylene glycol: tween 80: ethanol: dimethyl sulfoxide        studies [25].
(30: 3: 62: 5), the stock solution of terbinafine (25 mg/ml)
was prepared and stored at -20°C. By diluting the stock solu-     Ex-vivo Nail Penetration Studies
tion in water: ethanol (50:50, v/v) five times, terpene-free      Healthy adult volunteers (5 women, 5 men, 18-50-years-old,
working solution (control) was prepared. The concentration        N = 10) who were not on any prescribed drug were chosen
was selected based on the method sensitivity used in the ex-      for sample collection. Nail samples were collected using nail
periment and the terbinafine solubility. Further, 6 working       clippers and scissors. After giving a brief description about
solutions were prepared, each containing 5 mg/ml of terbina-      the experiment, written consent was taken from all partic-
fine stock solution and 6% of terpenes (solution B, C, D, E, F,   ipating individuals. No ethical approval was needed since
and G labelled for lavandulol, safranal, rose oxide, limonene,    nails are waste materials and voluntarily donated by the par-
3-methyl-2-butene-1-ol, and linalool respectively). To assess     ticipants. After collecting nail samples, each nail was cut into



Review | Dermatol Pract Concept. 2022;12(4):e2022202                                                                             3
small pieces; 25 mg of nail sample was used for each exper-           The concentration of terbinafine in nail samples was de-
iment [25]. To remove the adhered dirt from the surface and        termined from the calibration curve plotted using the above
prevent any interference in the study, 20 ml of water was          five calibrators.
added to the nail samples to digest for 20 minutes. Then, nail
samples were washed with methanol three times and then             Statistical Analysis
air-dried. Further, the nail samples were stored at a room         The outcome result of the terbinafine extraction from the
temperature in a sealed plastic bags till analysis.                nail samples of the control solution (without terpene) was
    Eight propylene tubes of 2 ml capacity were taken and          compared individually with the results acquired with each
eight aliquots (each 25 mg) of nail samples of each volunteer      test solution (carrying 6% terpene) by statistical analysis.
were transferred into it. One ml of a drug-free working solu-      Shapiro-Wilk test was employed to determine the normal
tion was taken in the first tube as blank sample (solution A).     distribution of variables using SigmaPlot v 14.0 software.
To determine the effect of terpenes on the penetration of ter-     For comparing the quantitative variables with normally dis-
binafine across the nail samples, 1 ml each of blank solution      tributed and non-normally distributed quantitative variables,
A and working solutions B, C, D, E, F, and G was added to          Paired t-test and Mann-Whitney U test were employed, re-
the remaining tubes and kept at room temperature for 48            spectively, and a P value < 0.05 was considered statistically
hours. Further, nail samples were sonicated for 15 minutes         significant.
with 10 ml methanol thrice to remove the adhered drug res-
idue from the surface.
    Further, the samples were transferred to the centrifuge        Results
tubes. Then, the tubes were incubated after addition of 1ml
                                                                   Sample Preparation and Drug Stability
of 0.5 M NaOH for 12 hours to digest the samples. The
samples were neutralized by adding 0.5 M HCl solution. The         To assess the transungual permeation of the drugs, the nail

samples were then vortexed for 2 minutes and centrifuged at        samples of the human volunteers were digested in various

6000 rpm for 20 minutes. The supernatant was collected and         media [25]. Alkaline, acidic and methanolic digestion meth-

the concentration of terbinafine in 20 uL of each solution         ods were used to hydrolyze the nail matrix. Various digestion

was determined by HPLC analysis.                                   procedures have been reported, including acid digestion by
                                                                   HCl (0.1 – 5.0 M), basic digestion by NaOH (1-10 M), di-
Stability of Terbinafine in the Digestion Procedure                gestion by nitric oxide (5% – 60%), their combination with

In propylene glycol: tween 80: ethanol: dimethyl sulfoxide         methanol and hydrogen peroxide at a temperature between

(30: 3: 62: 5 v/v) vehicle, 1 mg/ml stock solution of terbina-     25-600C and digestion with benzyltrimethyl ammonium

fine was prepared. The 100ul/ml solution of terbinafine was        hydroxide. Stability of terbinafine was determined with the

prepared by diluting the stock solution 10 times in water:         above methods (data not shown); eventually basic digestion

methanol (50:50, v/v). Further, two different solutions were       by NaOH (0.5 M) for 16 hours at room temperature was

prepared using this solution. First, an aqueous solution of        found as the best approach to digest the nail samples. The

5 µl/ml of terbinafine was made by diluting the above solu-        recovery of terbinafine by applying this method was found

tion 20 times, and 20 µL of the prepared aqueous solution          to be 30.7%.

was subjected into the column. Secondly, a 5 µl/ml solution
was made in 0.5 M NaOH and incubated for 12 hours. After           Ex-vivo Nail Penetration and Statistical Analysis
incubation, the solution was neutralized by adding 0.5 M           The experimental data from ex-vivo nail penetration studies
HCl, centrifuged; and 20 µL of this solution was subjected         and statistical analysis are presented in Table 2 and HPLC
for HPLC analysis. To determine the stability of terbinaf-         chromatograms of drug-free (blank), calibrator (standard
ine in the digestion procedure, the experiment was repeated        terbinafine) and sample solution (terpene spiked) are shown
three times to ascertain the stability of terbinafine in the di-   in Figure 1.
gestion procedure by taking into consideration the dilution           The concentration of terbinafine in nail samples of con-
factor and the areas attained after injection of aqueous and       trol, lavandulol, safranal, rose oxide, limonene, 3-methyl-2-
basic solutions.                                                   butene-1-ol, and linalool was found ranging from 3.094 to
                                                                   3.445 µg/mg (3.280 ± 0.122), 3.372 to 3.548 µg/mg (3.486
Preparation of the Calibrators                                     ± 0.051), 3.419 to 3.774 µg/mg ( 3.601 ± 0.115), 4.469 to
In 0.5 M NaOH, five calibrators of different concentrations        4.682 µg/mg (4.554 ± 0.061), 3.502 to 3.605 µg/mg (3.551
of 5, 7.5, 10, 12.5, and 15 µg/ml were prepared from 1mg/ml        ± 0.038), 4.386 to 4.538 µg/mg (4.463 ± 0.041) and 4.708
stock solution of terbinafine. For HPLC analysis of calibra-       to 4.796 µg/mg (4.748 ± 0.028) respectively. After employ-
tors, the aforementioned procedure was employed.                   ing Mann-Whitney U test, the results showed a significant



4                                                                                 Review | Dermatol Pract Concept. 2022;12(4):e2022202
           Table 2. Concentration of Terbinafine (µg mg-1) Found in Nail Samples from Healthy
                          Individuals and the Results from Statistical Analysis.
      Volunteers          Control group A         Group B        Group C        Group D         Group E         Group F        Group G
 1                              3.445               3.544         3.608           4.599           3.579           4.496          4.785
 2                              3.345               3.495         3.492           4.682           3.526           4.386          4.742
 3                              3.125               3.473         3.571           4.564           3.605           4.462          4.721
 4                              3.320               3.372         3.774           4.469           3.502           4.465          4.746
 5                              3.395               3.448         3.546           4.532           3.578           4.436          4.796
 6                              3.142               3.494         3.596           4.486           3.527           4.482          4.746
 7                              3.365               3.521         3.419           4.516           3.553           4.428          4.771
 8                              3.094               3.548         3.549           4.542           3.581           4.538          4.708
 9                              3.325               3.476         3.773           4.569           3.542           4.462          4.727
 10                             3.239               3.486         3.685           4.576           3.515           4.475          4.739
 Mean                           3.280               3.486         3.601           4.554           3.551           4.463          4.748
 SD                             0.122               0.051         0.115           0.061           0.038           0.041          0.028
 Normality test                                    Passed         Passed          Passed          Passed         Passed          Passed
 P value                                            0.437         0.382           0.921           0.517           0.665          0.381

A= terbinafine: B = terbinafine with lavandulol acetate; C = terbinafine with safranal; D = terbinafine with rose oxide; E = terbinafine with
limonene; F = terbinafine with 3-methyl-2-butene-1-ol; G = terbinafine with linalool.



difference between the control group and the lavandulol,                and effective permeation enhancers from natural sources. In
safranal, rose oxide, limonene, 3-methyl-2-butene-1-ol, and             particular, terpenes have gained significant interest and are
linalool groups. The above results reveal that terpenes in-             considered clinically acceptable permeation enhancers [21].
crease transungual penetration of terbinafine in the follow-            These promising candidates are considered effective and
ing order: linalool > rose oxide > 3-methyl-2-butene-1-ol >             constitute a very safe class of permeation enhancers acquired
safranal> limonene > lavandulol acetate.                                from natural sources.
                                                                            Furthermore, a good number of terpenes is incorporated in

Conclusions                                                             the list of generally recognized as safe (GRAS) classified by the
                                                                        US FDA [21]. The penetration enhancement ability of terpenes
Topical therapy is at the forefront for the treatment of many           for hydrophobic and hydrophilic drugs are ascribed to their
disorders of nail and skin due to higher patient compliance             chemical structure in addition to the physicochemical prop-
and lesser side effects accompanied with systemic therapy.              erties, including size and chirality, degree of unsaturation, li-
Howbeit, the nail disorders are frequently strenuous to cure            pophilicity, the energy of vaporization, and boiling point [21].
and require long term therapy. The nail plate is an aggregate               In the past decades, several findings have shown that in
of highly dense keratinized tissue which in turn gives low              vitro transungual studies are used to simulate and charac-
permeability to the diffusing substances [26]. A number of              terize the in vivo nail permeability. Permeation studies using
approaches have been shown to be effective in enhancing                 Franz diffusion cells, measurement of nail swelling and drug
transungual permeation such as mechanical methods (nail                 uptake by nails after soaking nail clippings in drug solutions
abrasion and nail avulsion), physical techniques (U.V light,            are often used. Though, in the recent works, it was found
carbon dioxide laser, iontophoresis, occlusion and hydra-               that keratin guards the analyte present in the nail matrix and
tion, sonophoresis, photodynamic therapy, electroporation               hampers the availability of solvent and other reagents [18].
and acid etching) or use of chemical penetration enhancers              Hence, a digestion step was required to assess the terbinaf-
(keratolytic agents, water, keratinolytic enzymes, urea, mer-           ine concentration in the nail before analysis. In the present
captans, sulfides and hydrogen peroxides) [26].                         study, effect of different terpenes was investigated on the
     Literature and patent search divulged that chemical                transungual permeation of terbinafine and these were found
penetration enhancers excel over other strategies for the               to increase its permeation in following order: linalool > rose
transungual delivery of drugs. Albeit the concentration re-             oxide > 3-methyl-2-butene-1-ol > safranal> limonene > la-
quired to achieve useful levels of permeation enhancements              vandulol acetate. Thus, linalool was found to be the most
may cause irritancy at the site of application [19,20]. Hence,          effective penetration enhancer for the transungual delivery
the investigations have been diverted towards searching safe            of terbinafine.
    A      0.045

           0.040

           0.035

           0.030

           0.025
        A/U




           0.020

           0.015

           0.010

           0.005

           0.000

                    1.00    2.00    3.00     4.00    5.00     6.00     7.00      8.00      9.00    10.00
                                                    MINUTES

    B
          0.110

          0.100

          0.090

          0.080

          0.070

          0.060
    A/U




          0.050

          0.040

          0.030

          0.020

          0.010

          0.000

                   1.00    2.00    3.00     4.00      5.00    6.00     7.00      8.00     9.00      10.00
                                                    MINUTES

    C


          0.025



          0.020



          0.015
    A/U




          0.010



          0.005



          0.000


                   1.00    2.00    3.00     4.00      5.00    6.00     7.00      8.00     9.00      10.00
                                                    MINUTES

    Figure 1. (A) HPLC chromatogram of blank. (B) HPLC chromatogram of standard terbinafine. (C) HPLC
    ­chromatogram of sample terbinafine.



6                                                                Review | Dermatol Pract Concept. 2022;12(4):e2022202
    The present study concludes that terpenes including la-             13. Gupta AK, Scher RK. Oral antifungal agents for onychomyco-
vandulol, safranal, rose oxide, limonene, 3-methyl-2-butene-                sis. Lancet. 1998;351(9102):541-542. DOI: 10.1016/S0140
                                                                            -6736(05)78552-4. PMID: 9492770.
1-ol, and linalool accentuate the transungual penetration of
                                                                        14. Gupta AK, Simpson FC. Routes of drug delivery into the nail
terbinafine and among these, linalool has been found to be
                                                                            apparatus: Implications for the efficacy of topical nail solutions
the most effective penetration enhancer for the transungual                 in onychomycosis. J Dermatolog Treat. 2016; 27(1):2–4. DOI:
delivery of terbinafine. By virtue of their enhancing effect,               10.3109/09546634.2015.1034081. PMID: 25983025.
formulation of terbinafine with one or combination of these             15. Bseiso EA, Nasr M, Sammour OA, Abd El Gawad NA. Novel
terpenes could be beneficial in topical dosage form develop-                nail penetration enhancer containing vesicles “nPEVs” for treat-
                                                                            ment of onychomycosis. Drug Deliv. 2016;23(8):2813-2819.
ment for treatment of onychomycosis.
                                                                            DOI: 10.3109/10717544.2015.1099059. PMID: 26447337.
                                                                        16. Murdan S. Enhancing the nail permeability of topically applied
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Review | Dermatol Pract Concept. 2022;12(4):e2022202                                                                                          7
