Development and Evaluation of Efinaconazole Containing Potential Permeation enhancer for an enhanced Transungual Drug Delivery
Zaiba khanum
Department of pharmaceutics, MMU College of Pharmacy, Vijaya Nagar, Ramanagara, Karnataka, India.
*Corresponding Author E-mail: ZaibaKhanum705@gmail.com
ABSTRACT:
All over the last time of period the treatment of illness has been carried out by administration drugs to human body by many routes namely oral, topical, inhalation etc. Human nails do not have only protective and decorative act, but can also be regarded as an substitute tract for drug delivery. A nail is a horny structure formed by the invagination of epidermis into the dermis. The maturation and differentiation of the epithelial nail matrix cells make the nail that is tightly attached to the nail bed, which a little bit contribute to nail formation. It is also known as onyx, composed of Keratin protein that is also found in skin and hair. The protein Keratin in nails is harder than the keratin found in hair and skin.
A nail is envelope like covering that covers the dorsal part of the terminal phalanges of fingers and toes in humans, primates and in few other mammals. The nails are similar to claws, hooves and horns, which are also keratinized structures, found on other animals. The success of local topical therapy for onychomycosis depends on the achievement of effective chemical concentrations into/through the human nail plate; therefore, a suitable antifungal drug must be coupled with an appropriate delivery method. The human nail plate consists of three layers; the dorsal and intermediate layer derived from the matrix, and the ventral layer from nail bed. The intermediate layer is three - quarter of the whole nail thickness and consists of the soft keratin. The upper layer, dorsal, are only a few cell layers thick but consisting of hard keratin, with a relatively high sulfur content, mainly in the form of amino acids cysteine, which constitutes 94 % by weight of nail.
Nail Disorders:
Diseases of the nails are from pigmentation or discoloration and inflammation and brittle split nails. The nail plate could seem abnormal as results of, an inherent defect, illness of skin with the nail bed, systematic illness, reduction of blood provide, native trauma, tumors of the nail fold or nail bed, infection of the nail fold, infection of the nail plate.
a. Distal lateral subungual: Spreading of fungi through distal subungual area and lateral nail groove.
b. Proximal subungual onychomycosis: Infection in proximal nail plate due to infiltration from nail cuticle or proximal nail folds in the form of white streak near the nail fold.
c. Superficial onychomycosis: Restricted to toe nails. On nail plate form white spots or specks and become friable and powdery.
d. Endonyx onychomycosis: Caused by infection through nail plate free margin, imparts milky white discoloration on nail plate.
2) Paronychia: Inflammation of proximal and lateral nail folds.
a. Acute paronychia: Caused by staphylococcal bacteria. Damage cuticle and nail folds causing pain and inflammation.
b. Chronic paronychia: Caused by irritant reaction on exposure to environmental irritant or alkali.
3) Nail psoriasis: Signs of patches of raised, red skin and causing irritation and pain Nail matrix shows pitting and appearance of large transverse furrows, while nail bed shows yellow-red nail discoloration under the nail plate and leads to thickening of skin under the nail.
4) Nail plate overgrowth: Commonly showing in elderly people due to their inability or neglect for grooming or cutting of nails causes nail plate to thicken and attain a curved structure which appear ‘claw shaped’ thickened nails pinch the skin causing pain excessive trauma may cause subungual haemorrhage, especially in presence of diabetes mellitus.
5) Leukonychia: Become white spots or line on nail
6) Onychorrhexis: Brittle and rough nail
7) Onychotropia: Atrophy of nail plate.
8) Tinea unguis: Roundworm of the nails is characterized by nail thickening, deformity and eventually ends up in nail plate loss.
Figure 1: Tinea unguis.
Figure 2: leukonychia.
Figure 3: Candida onychomycosis
Etiology of Onychomycosis: The causative pathogens of onychomycosis include dermatophytes, candida and nondermatophytic molds. Dermatophytes are the fungi most commonly responsible for onychomycosis in the temperature western countries, while candida and nondermatophytic molds are more frequently involved in the tropics and subtropics with hot and humid climate.
Diagnosis of Onychomycosis: Conventional methods for identifying fungal organisms in the nail plate of patients with onychomycosis (OM) include direct microscopy, fungal culture, and histopathology. Surgical pathology testing using PAS stain is the current gold standard for the diagnosis of OM. Newer methods for diagnosing OM include polymerase chain reaction, optical coherence tomography, confocal laser scan microscopy, matrix assisted laser desorption/ionization time of flight mass spectrometry and phase contrast hard x-ray microscopy. Confirmation of observations and availability and cost must be considered before these newer methods for diagnosing OM can be incorporated in clinical practice.
Nail Lacquer: Nail polish or nail varnish is applied to human fingernails or toenails to decorate and or protect the nail plate. Conventional nail lacquers have been used as cosmetics since a long time for beautification and protection of nails. Topical nail preparation like lacquers, enamel and varnish are an integral part of today’s beauty treatments. It protects the nail plate, but more importantly it enhances their beauty, imparting colour and luster.
A model nail lacquer should have the following properties:
· It should be harmless to skin and nails.
· It should be convenient and easy to apply.
· It should be stable on storage.
· It should form a satisfactory film on nails.
To achieve satisfactory film it should have the following characteristics:
· It should have good wetting and flow properties so that the film formed is even.
· It should have uniform colour.
· It should have good gloss.
· It should have good adhesive properties.
· It should have sufficient flexibility so that it does not crack or become brittle.
· It should have sufficient hard surface which is resistant to impact and scratch.
· It should have reasonable dry time (1-2 min) without developing bloom.
· It should be able to maintain the above-mentioned properties for a reasonable time.
MATERIALS AND METHODS:
Development of nail lacquer of Efinaconazole:
a. Preparation of nitrocellulose:
About 5 gm of cellulose base was taken in a beaker and 50 ml of concentrated sulphuric acid and 25 ml of 70 % nitric acid was added. The above mixture was cooled to 5 min to obtain cellulose nitrate. Then cotton was removed and washed in cold water with sodium bicarbonate solution to remove all acid residues. Then it was dried at room temperature.
b. Nitrocellulose film former
Table 1: Nitrocellulose film former
|
Formulation code |
Nitrocellulose (% w/v) |
Plasticizers (% w/v) PG Glycerin |
Ethanol (ml) |
|
F1 |
2 |
10 - |
10 |
|
F2 |
4 |
10 - |
10 |
|
F3 |
6 |
10 - |
10 |
|
F4 |
2 |
- 10 |
10 |
|
F5 |
4 |
- 10 |
10 |
|
F6 |
6 |
- 10 |
10 |
Three different concentrations of nitrocellulose, 2%, 4%, 6%, were prepared using two different plasticizes, propylene glycol and glycerin at 10% concentration as per table no 1. The optimum concentration for film formation was determined by evaluating the thickness, tensile strength.
c. Optimization of nitrocellulose film:
Film thickness: The thickness of the film was measured by using screw gauge with a least count of 0.01 mm at different spots of the films. The thickness was measured at five different spots of film and average was taken.
Tensile strength: The instrument used to measure the tensile strength was designed in pharmaceutics laboratory especially for this project work. The instrument is a modification of chemical balance used in normal laboratory. One pan of the balance was replaced with one metallic plate having a hook for attaching the film. The equibrium of the balance was adjusted by adding weight to the right pan of balance. The instrument was modified in such a way that the patch can be fixed up between two hooks of horizontal beams to hold the test film. A film of 2.5 cm length was attached to one side hook of the balance and other side hook was attached to plate fixed up to the pan.
Preparation of Nail Lacquer: The mixture of Efinaconazole and nitrocellulose film was dissolved in ethyl alcohol in the required quantity using a magnetic stirrer at a constant speed. To above clear solution required quantity of 2-HP-β-CD, salicylic acid and propylene glycol were mixed thoroughly and made up to the volume to 100 ml. The prepared nail lacquer was transferred to a narrow mouthed, plastic screw capped glass bottle.
Table 2: Formulation chart of nail lacquer
|
Ingredients (%) |
F1 |
F2 |
F3 |
F4 |
F5 |
F6 |
|
Efinaconazole |
2 |
2 |
2 |
2 |
2 |
2 |
|
Nitrocellulose |
5 |
5 |
5 |
5 |
5 |
5 |
|
Salicylic acid |
5 |
10 |
15 |
20 |
20 |
20 |
|
2-HP-β-CD |
- |
- |
- |
10 |
10 |
10 |
|
Ethyl cellulose |
- |
- |
- |
0.75 |
0.50 |
0.25 |
|
Propylene glycol |
10 |
10 |
10 |
10 |
10 |
10 |
|
Ethanol (q.s) |
100 |
100 |
100 |
100 |
100 |
100 |
Preformulation Studies of Efinaconazole:
a. Solubility Studies: Saturated solubility of Efinaconazole was prepared by using 10 ml of distilled water/ethanol/acetone in 25 ml volumetric flasks in triplicate. A precaution was taken so that drug remains in medium in excess. Then by using mechanical shaker, the flask was shaken for 48 h. The sampling was done on 24 and 48 h. The sample withdrawn (1 ml after filtration) was diluted with appropriate medium.
b. Scanning for drug absorption (λmax) using double beam spectrophotometer: 100 mg of pure drug was taken in a volumetric flask and dissolved in a little of phosphate buffer pH of 7.4 and volume made up to 100 ml. 1 ml of the above solution was taken and further diluted to 100 ml. The above solution scanned for maximum absorbance in double beam UV- visible spectrometer in between the range of 400-200 nm against phosphate buffer pH 7.4 as the blank. Triplicate readings were taken and average was calculated.
c. Development of UV spectrophotometric method for analysis of oxiconazole: The stock solution (1 mg/ml) was prepared by weighed accurately 50 mg of Efinaconazole nitrate and transferred to a 50 ml volumetric flask then makeup the final volume with methanol. Different concentrations (2, 4, 6, 8, and10µg/ml) of solutions were prepared from the stock and measure the absorbance at 210 nm by using UV-Visible spectrophotometer and reagent blank.
d. FTIR Study: IR study was carried out to check purity of drug. It was determined by fourier transform region of 4000 to 400 cm-1 at resolution of 4 cm-1 by dispersing sample in KBr and compressing into disc by applying pressure of 5 tons for 5 min in hydraulic press. The pellet was placed in light path and the spectrum was obtained. Infrared spectrophotometer.
Evaluation parameters:
Drying Time: A film of sample was applied on a glass petri dish with the help of brush. The time to form a dry to touch film was noted using a stopwatch.
Smoothness to flow: The sample was poured on a glass slide on an area of 1.5 square inches and spread on a glass plate by making glass slide to rise vertically. And smoothness of flow was determined by comparing with standard marketed nail lacquer.
Viscosity: The viscosity of nail lacquer was determined using a Brookfield viscometer with spindle no 64. The sample was taken in a closed jar to minimize the solvent evaporation. Sample should be aged at least 8 h at 250 ⁰C before performing the test. At 250⁰C, shake vigorously, start timer, insert spindle into the sample to the scored line, with the motor running at 60 rpm. Spindle should be in correct position in less than 1 min. Read the instrument at the end of 10 min then switch the speed control to 6 rpm and read the instrument again at the end of another 10 min.
Drug content estimation: Nail lacquer equivalent to 200 mg was dissolved in 50 ml phosphate buffer solution of pH 7.4. Then the solution was ultra sonicated for 15 min. The resulting solution was filtered, made up the volume up to 100 ml with phosphate buffer solution of pH 7.4. From the above solution take 10 ml and made up to100 ml with PBS of pH 7.4. Then the diluted solution was estimated spectrophotometrically at wavelength of 210 nm and determined the drug content.
In- vitro transungual permeation studies: In vitro transungual studies were carried out using Franz diffusion cells of volume 25 ml, were performed by using Franz diffusion cell at 37±5°C and phosphate buffer (pH 7.4) fitted with a custom-made Teflon nail holder. Drug solution equivalent to 100 μg prepared in buffer was placed in the donor compartment. The receiver compartment was filled with phosphate buffer (pH 7.4) volume was 25 ml. The active diffusion area was 0.25 cm. The receiver compartment was stirred at 600 rpm with a 3 mm magnetic stir bar. Intermittent samples of 2 ml were drawn from the receiver compartment at 2 h intervals for 36 h and the amount of Efinaconazole transported was measured. Equal volume of fresh buffer was replaced in the receiver compartment followed by each sampling. The drug analysis was by using double‐beam UV spectrophotometer, at 210 nm.
Stability study: Stability studies of nail lacquer were carried out as per ICH guidelines. The samples were stored at the temperature 40±2°C/75±5% RH for 1 month. Then the formulation was evaluated for drying time, non-volatile content, in vitro adhesion, water resistance and drug content.
RESULTS AND DISCUSSION:
Pre formulation studies:
Solubility: Efinaconazole was found to be freely soluble (1-10 parts of solvent required for 1 part of solute) in phosphate buffer of pH 7.4 and methanol, slightly soluble (100-1000 parts of solvent required for 1 part of solute) in ethanol.
Compatibility studies:
Figure 4: FTIR spectra of Efinaconazole
All the characteristic IR peaks related to pure drug, Efinaconazole were also appear in the IR spectrum of mixture of drug-polymer, so there was no any chemical incompatibility between drug and polymer.
Evaluation of Nitrocellulose film:
Table 3: Nitrocellulose film former
|
Nitrocellulose concentration (%w/v) |
1 |
2 |
3 |
4 |
|
Thickness (µm) |
55+0.03 |
57+0.03 |
56+0.04 |
58+0.02 |
|
Tensile strength (kg/cm2) |
2.54+0.02 |
2.58+0.01 |
2.61+0.03 |
2.54+0.02 |
Table 4: Evaluation of nail lacquer
|
Formulation code |
Drying time (sec) |
Viscosity |
Drug content (%) |
|
F1 |
49 |
105±0.45 |
86.49 ± 0.42 |
|
F2 |
51 |
116±0.33 |
87.01 ± 0.35 |
|
F3 |
48 |
122±0.23 |
88.75 ±0.44 |
|
F4 |
128 |
160±0.65 |
92.34± 0.93 |
|
F5 |
57 |
146±0.72 |
91.87 ± 0.78 |
|
F6 |
56 |
152±0.41 |
90.56 ± 0.57 |
*Standard Deviation (n=3)
The viscosity of sample ranged from 100 to 220 centipoises and it was observed that in between 105 to 160 centipoises, the product was clear and glossy. Drying time for formulations F1 to F6 was found between 49 seconds to 128 seconds. It was found that as the polymer concentration increases, the drying time increases respectively. Percentage drug content for all the lacquers was found to be satisfactory and in between 86% to 92%. In vitro permeation studies, it was found that formulation F4 showed release of 89.4% at the end of 12 h.
In vitro transungual permeation studies:
Table 5: In vitro release study of formulations F1-F6 in phosphate buffer pH 7.4
|
Sl. No. |
Time |
Percentage drug release |
|||||
|
(h) |
F1 |
F2 |
F3 |
F4 |
F5 |
F6 |
|
|
1 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
|
2 |
1 |
2 |
3.2 |
3.1 |
4.6 |
3.5 |
3.1 |
|
3 |
2 |
3.39 |
3.6 |
5.06 |
13.2 |
5.4 |
5.07 |
|
4 |
3 |
8.75 |
9.24 |
15.1 |
34.6 |
15.2 |
8.78 |
|
5 |
4 |
12.7 |
12.9 |
32.2 |
41.3 |
32.4 |
16.3 |
|
6 |
5 |
26.3 |
25.4 |
40.2 |
51.9 |
41.1 |
31.2 |
|
7 |
6 |
33.1 |
32.3 |
47.5 |
64 |
56.4 |
39.5 |
|
8 |
8 |
48.9 |
4.74 |
54.6 |
74.7 |
63.2 |
57.1 |
|
9 |
10 |
54.9 |
55.2 |
60.6 |
81.3 |
75.4 |
64.5 |
|
10 |
12 |
65.1 |
62.7 |
69.8 |
89.4 |
85.1 |
82.2 |
Figure 5: In vitro transungual permeation studies
Table 6: Accelerated stability studies for optimized formulation F4
|
Parameters |
Before |
After |
|
Drying time (sec) |
128 |
120 |
|
Drug content (%) |
92.34± 0.93 |
88.75 ±0.44 |
*Standard Deviation (n=3)
The studies were carried out to verify the changes in physical characteristics such as drying time, % drug content at different conditions of higher temperature (4±02⁰C) for 1 month. The results are reported in table no.
CONCLUSION:
The purpose of the present investigation was to prepare and evaluate the Efinaconazole nail lacquer for the treatment of onychomycosis. The formulations were prepared with permeation enhancers (2-hydroxypropyl)- β-cyclodextrin and keratolytic agent and salicylic acid. Then, these lacquers were compared for drying time, drug content and drug diffusion. It can be concluded that medicated nail lacquers proved to be a better tool as a drug delivery system of an antifungal drug in the treatment of onychomycosis. Apart from treating the nail infections, the medicated nail lacquers can be also used for beautification of nails with ease of application. This improves patient compliance and acceptability.
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Received on 18.11.2025 Revised on 07.03.2026 Accepted on 09.05.2026 Published on 27.05.2026 Available online from May 30, 2026 Asian J. Research Chem.2026; 19(3):247-252. DOI: 10.52711/0974-4150.2026.00038 ©A and V Publications All Right Reserved
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