INTRODUCTION:

Fungi species that cause fungal infections can cause serious health problems that impact people with compromised immune systems, resulting in elevated morbidity and high fatality rates. Subcutaneous mycosis is a condition that arises from persistent fungal infections that target the dermis and subcutaneous tissue^1,2. One of the major tropical illnesses caused by the fungal development of Sporothrix schenckii is sporotrichosis³. Drug distribution obstacles during therapeutic treatment and restricted drug access to the right locations have an impact on patient compliance. Because the formulation type regulates drug absorption rates to obtain an optimal treatment duration, it affects the therapeutic value of topical antifungal medications^4,5.

In 1991, scientists created SLNs, an inventive pharmaceutical device for contemporary drug delivery systems. Drug bioavailability can be greatly enhanced by employing nanoparticles with sizes ranging from 10 to 1000 nm. The SLN formulation is a key factor in the current era of colloidal drug carrier systems^6,7.

The modern antifungal medication luliconazole has been licensed by the FDA (USA) for broad use. Topical administration techniques are not an option for luliconazole due to its bioavailability barrier. Healthcare professionals must use both cutaneous and subcutaneous encapsulation techniques to attain the highest possible drug concentration at the target site in order to obtain appropriate drug penetration abilities for fungal infections treatment. While patient non-compliance is still a major issue, several topical medications that contain luliconazole that are currently on the market show low skin permeability along with short retention times⁸. Because nano formulations may store large drug loads with little additives, have stable drug characteristics, lower toxicity, and simplify production procedures, the pharmaceutical industry is currently seeing significant expansion in this area⁹. SLNs have characteristics range wide that enable them to assist sustain drug presence at the infection site and facilitate drug penetration through the skin¹⁰.

In this study, we present the formulation and characterization of a topical solid lipid nanoparticle gel containing luliconazole.

MATERIALS AND METHODS:

Reagents and chemicals:

We purchased luliconazole from SMS Pharmaceuticals in India. Other analytical-grade reagents and excipients utilized in this study were purchased from approved vendors.

Preformulation studies:

Absorption maximum in ethanol:

With minor adjustments, used standard procedure to determine maximum amount of luliconazole that could be absorbed. In conclusion, 1mg/ml of luliconazole was produced as a stock solution in methanol. After that, it was serially diluted to reach concentrations of 6, 2, 8, 4 and 10μg/ml. After that, the samples were examined at wavelength 299nm using UV spectrophotometry. Every measurement was carried out three times, and statistical analysis was performed on the collected data.

Assessment of Aqueous Solubility:

The Saturation Shake-Flask method was used to evaluate luliconazole's aqueous solubility. A suitable amount of luliconazole was dissolved in a pH 5.5 acetate buffer and distilled water. After that, the mixture was vortexed and centrifuged for 48hours at 37°C and 50rpm. All measurements were made in triplicate, and the resultant solution was filtered before being subjected to spectrophotometric analysis at 299nm.

Lipophilicity Evaluation:

With minor adjustments to the normal procedure, the conventional method shake-flask assessed the lipophilicity of luliconazole. A system of n-octanol and water was used to calculate the partition coefficient. A conical flask with specified amounts of n-octanol and an aqueous buffer solution was filled with a determined amount of luliconazole. For 48hours, the flask was shaken frequently to bring it into balance. To help the mixture separate into two separate layers, it was then moved to a separating flask, shook once more, and let to stand undisturbed. The log10P ratio was computed by spectrophotometrically analyzing the observations of both phases at 299nm. Every qualification was carried out three times.

Fourier Transform Infrared Spectroscopy:

Using an infrared spectrophotometer, the luliconazole and stearic acid spectra were evaluated. The analyzer prepared sample solutions using potassium bromide, which were then subjected to spectroscopy in the 4000–400 cm−1 spectral region.

Preparation of drug loaded solid lipid nanoparticle:

Using the solvent diffusion approach, luliconazole-containing solid lipid nanoparticles were produced after various adjustments. Stearic acid and luliconazole were combined by boiling them in a water bath at 60±3.0°C while suspended in 5milliliters of ethanol. The resultant mixture was then combined with 5 milliliters of aqueous poloxomer 188 solutions and agitated using a syringe at 4 to 8 degrees Celsius under 2000rpm on a magnetic stirrer. The resulting solid lipid nanoparticles (SLN) were gathered. Using an APV 2000 homogenizer set to 1200 bars of pressure, a heterogeneous mixture was homogenized at high pressure. Clear nanocrystals were created by allowing the resulting mixture to settle at ambient temperature. Information gathered in Table 1.

Table 1: Formulation of solid lipid nanoparticles

SLN code	API % (w/v)	Various concentrations of primary reagents for the synthesis of SLN
SLN code	API % (w/v)	Stearic acid % (w/v)	Poloxomer % (w/v)
F1	1	0.5	1
F2	1	0.7	1
F3	1	1	1
F4	1	2	1
F5	1	1	0.5
F6	1	1	0.7
F7	1	1	1.5
F8	1	1	2

SLN Evaluations:

Evaluation of Entrapment efficiency:

Used a significantly modified version of the given procedure to define percentages of drug encapsulation in SLN. Before being filtered through a 0.22μm syringe filter, 5mg of room-temperature dried SLN was combined with 10ml of HPLC-grade ethanol. At a wavelength of 299nm, the concentration of luliconazole was analyzed. Best result chosen for further evaluation after the percentage entrapment measurement was duplicated three times. The following formula was used to determine entrapment efficiency:

% EE = {[W of Added drug –W of free drug] / W of Added drug} x 100

W of added drug is used in the equation to quantify the amount of drug added to the SLN preparation, and W of free drug determine amount of free drug in the supernatant separation.

Physico-Chemical Property:

Color, odor, pH, and the solubility of SLN F6 in an aqueous media evaluate physico-chemical characteristics of SLN dispersions.

Zeta Potential and Particle size:

The described procedure, which called for some minor adjustments, to evaluate particle size average also zeta potential. A zeta potential/particle size analyzer was used to measure the zeta potential and particle size at room temperature. Phosphate-buffered saline with a pH of 7.4 was used to analyze solution F6.

Gel Preparation:

With very minor modifications, the researchers created the gel solution agreement with reference technique. After adding carbopol 934P to a predetermined volume of distilled water, it was continuously stirred for 30 minutes at 600rpm for methyl paraben sodium (0.02% w/v) and propyl paraben sodium (0.1% w/v). The prepared gel base was left to set undisturbed for a full day. Prior to being added to carbopol gel bases, the SLN F6 was mixed with propylene glycol (5% w/w) and ethanol (1%, 20% w/w) while being shaken at 1000rpm for 30 minutes. In order to stabilize the medication, TEA was added to keep the pH between 5.5 and 6.5 while swirling thoroughly to create a transparent gel.

For ideal homogenous gel with uniform texture while preserving stable physicochemical properties that influence the leading moiety release rates, this production method is being used to four gel formulations that use varied amounts of carbopol and different target amounts. Table 2 lists the various standards for SLN gel compositions^16,17.

Table 2: Formulations of SLN gels

Formulation code	% (w/v) Carbopol 934
G-1	0.5
G-2	1
G-3	1.5
G-4	2

Gel Characterization:

Determination of pH:

Standard methodology pH measurement of gel evaluated using the digital pH meter. A pH meter's glass electrode was used to monitor the pH of an optimized SLN gel composition as the meter rotated.

Determination of Viscosity:

A standard procedure evaluation that contained particular adjustments was applied to the gel viscosity. The properties physical of SLN gel were assessed first, also then viscosity of gel measured using a Brookfield viscometer.

Determination of Entrapment Efficiency:

By measuring free drug amount in the centrifuged gel solution, the percentage of encapsulated drug (EE) in various gel batches was ascertained. To obtain adequate drug extraction from the solution, combined one gram of gel to ethanol, vortexed five minutes. The resultant mixture underwent a 60-minute 15,000rpm centrifugation at 4°C. To get quantitative data, the supernatant from the centrifuged combination was subjected to spectrophotometric 299nm examination. The same equation as previously stated was applied.

Spreading ability:

The gel spread experiment was conducted using a defined process with certain adjustments. A second plate was arranged concentrically on top of acrylic plate, which had a total of 500mg of standardized formulation in the middle center. The measurement meter for circle width was the major width of the gel spread area. By measuring the diameter increase brought on by gel dispersion, the gel spread ability was measured after a 500g weight placed on top plate for a few minutes.

In-vitro release kinetics of drug:

In-vitro drug release techniques, particularly the dialysis bag technique, were used to evaluate drug release also kinetic profiling for the enhanced formulation of SLN G-3gel. After carefully weighing one gram of the gel sample, it was put within a cellulose dialysis membrane, secured with thread, and placed in a flask with fifty milliliters of a solution of phosphate and ethanol buffer. This configuration was kept at 37°C on stirrer magnetic while being continuously stirred at 50rpm. One milliliter of samples was taken out at intervals prearranged i.e. 1, 4, 0.25, 8, 0.5, 2, 3, 6, 12, 24hours, and the volume taken out was replaced with new dissolving media. Using a reference blank, the amount of API released by the SLN was spectrophotometrically measured at 299nm wavelength. Every measurement was carried out three times. Several kinetic models, including zero, first order, Higuchi, also Korsmeyer Peppas models, were used to statistically examine the in-vitro release profiles of drug the API-loaded SLN gel formulation. A regression coefficient value high, suggests a great effectiveness for the initiation and acceptance of the kinetic commands. These kinetic models statistically determined to clarify the mechanics underlying the drug release profile^18-20.

SEM/Scanning Electron Microscope study:

Scanning electron microscopy (SEM) was used to perform the SLN G-3 morphological examination, with some alterations to a standard methodology. A glass stub was covered with a tiny bit of gel and vacuum-dried. The sample-containing stub was then placed inside the SEM chamber and covered with a layer of gold-palladium. After that, the sample was inspected under a microscope at a quickening 10kV voltage.

RESULT AND DISCUSSION:

Drug Preformulation evaluation:

Maximum API absorption in ethanol:

Using maximum absorption of luliconazole at wavelength of 299nm (λmax) within a concentration range of 2–10μg per ml, the drug absorption potential was evaluated in accordance with conventional techniques. With a coefficient of determination of 0.998, the regression equation that was produced was 0.0664x - 0.0478 (Figure 1, Table 3). Finding maxima absorption of luliconazole is the main goal of this investigation, which also aims to validate the methodology for qualitative also quantitative research.

Figure 1: Luliconazole Absorption maxima and regression coefficient graphs.

Table 3: Absorbance of luliconazole at different concentration

S. No.	Concentration	Absorbance
1	2	0.205
2	4	0.308
3	6	0.511
4	8	0.609
5	10	0.745

Solubility Profile:

To evaluate the physicochemical properties of luliconazole, physicochemical studies were conducted. The purpose of these investigations was to assess luliconazole's lipophilic and hydrophilic compatibility. According to the data, luliconazole has a low solubility in water (0.00174 ± 0.182 mg/ml). Its non-aqueous solubility in n-octanol, on the other hand, was determined to be 12.565 ± 0.31 mg/ml.

FTIR analysis:

The compatibility of luliconazole and stearic acid as the main ingredients was assessed using FTIR both before and after formulation. According to Figure 2; Table 4, the main IR absorption peaks that identify luliconazole in spectra are 2979.43 cm-1 (C-H stretch), 2198.82 cm-1 (C≡N stretch), 1554.35 cm-1 (C-H aromatics stretch), 1471.35 cm-1 (C=C-C aromatic ring stretch), 820.41 cm-1 (para-C–H distribution), and 759.46 cm-1 (C-Cl stretch). The sample matched the reference report and purity specifications of genuine luliconazole, as demonstrated by the primary peaks found during analysis.

Table 4: FTIR interpretation of luliconazole

Characteristics Peaks	Reported (cm^-1)	Observed (cm^-1)
Stretch C-H	2850 to 3000	2979.43
Stretch C≡N	2100 to 2400	2198.82
Aromatic C=C stretch	1450 to 1650	1554.35
Aromatic ring C=C-C stretch	1510 to 1450	1471.35
Distribution C-H para	860 to 800	820.41
Stretch C-Cl	600 to 800	759.46

Figure 2: Drug Luliconazole FTIR spectrum

Stearic acid produces the primary IR absorption bands at 2915.20 cm^-1 (C–H stretch alkanes), 2848.02 cm^-1 (C-H stretch aldehyde), 1700.89 cm^-1 (C=O stretch saturated), 1471.59 cm^-1 (C-C stretch), 1295.47 cm^-1 (C-O stretch, aromatic aster), 936.42 cm^-1 (O-H bend), and 719.89 cm^-1, according to an FTIR spectrum that interprets stearic acid and is shown in Figure 3 and Table 5. The analysis's main peaks matched the data that had been published and showed that the stearic acid was genuine and pure.

Table 5: FTIR interpretation Stearic acid

Characteristics Peaks	Reported (cm^-1)	Observed (cm^-1)
Alkanes C–H stretch	2850 – 3000	2915.20
Aldehyde C-H stretch	2800 – 2860	2848.02
Saturated C=O stretch	1700 – 1730	1700.89
Stretch C-C	1400 – 1500	1471.59
Aromatic aster C-O stretch	1250 – 1310	1295.47
Bend O-H	910 – 950	936.42
Bend C=C	665 – 730	719.89
Stretch C-I	500 – 600	547.03

Figure 3: Stearic acid FTIR spectrum

Luliconazole loaded SLN Formulation:

To maximize SLN functionality with respect to luliconazole EE at two experimental stages (nano-precipitation and cooling sonication probe), the protocol employs various modified nano-precipitation techniques. Throughout the procedure, the temperature remained between 4°C and 25°C in both segments. The solvent-anti-solvent interaction causes rapid precipitation when organic solution is added right away to the aqueous solution that has been chilled to 4°C. The product formed uniformly as a result of temperature control during the initial nano-precipitation stage. High-pressure homogenization reduces the size of bigger crystals and stops bead grinding aggregation, which results in uniform homogeneity. +++ Stearic acid and poloxomer 188 concentrations were changed step-by-step from 0.5 to 2% w/v as part of the SLN optimization process. To ascertain the percentage of active moiety entrapment in each of the successfully coded produced groups of SLN, a spectrophotometric examination was performed at 299 nm. For additional assessment, the optimized SLN with the highest luliconazole entrapment will be chosen.

Formulated SLN Evaluation:

The efficiency of SLN entrapment:

The physical and spectral assessment of luliconazole was necessary for the pre-formulation stage. The efficiency of luliconazole excipients was determined by the creation of several batches of nanoparticles. The percentage was calculated via a spectrophotometric analysis of EE at a wavelength of 299nm. Based on the results, SLN F6 and SLN F1 exhibit the highest and lowest percentages of EE of luliconazole-loaded SLN by 92.13% ±0.975 and 53.78%±1.052 w/w, respectively. According to the Kaur et al. investigation, the highest percentage of EE was 90–95% w/w¹¹. The percentage of drug entrapment results measured in each SLN group was shown in Figure 4 and Table 6.

Table 6: Luliconazole SLN formulations Entrapment Efficiency

Preparations	Entrapment efficiency (%±SD)
F1	53.78 ± 1.20
F2	73.56 ± 1.30
F3	89.97 ± 1.43
F4	91.13 ± 1.34
F5	90.38 ± 1.23
F6	92.13 ± 1.23
F7	88.32 ± 0.54
F8	88.79 ± 1.34

Figure 4: SLN Entrapment efficiency %

The best drug entrapment values led to the selection of optimized SLN F6, and additional testing will examine its physicochemical characteristics and gel forming potential.

Physico-chemical Evaluation:

In addition to its aromatic scent and 6.95 pH stability, the SLN F6 had a white, clear appearance with a homogenous texture and uniform structure. Its water solubility was 0.01819±0.035mg/ml higher than that of unconcentrated luliconazole.

Assessment of Zeta potential, PDI, and particle size:

The zeta potential and particle size of luliconazole SLN were successfully identified using the nano ZS90 zetasizer device. One important metric for assessing the possible stability of nanoparticles in physical settings is the zeta potential. Because the deterrent force between nanoparticles rises with high zeta potential values, stable nanoparticle systems are indicated. According to the zeta potential measurement, SLN has a very strong value of about 18.8mV, which confirms the nano system's long-term stability (Fig. 5). With a mean particle diameter of around 344.3 nm, a unimodal distribution pattern, 0.168 PDI, 0.98 intercept value, and a 92% intensity peak, the SLN analysis produced results. The nanoparticle scattering level is indicated by the PDI parameter, which stays low when the PDI value is less than 0.5.

Figure 5: PDI, particle size and zeta potential F-6 SLN formulation

Comparability of the drug and excipients in FTIR:

The stretching frequencies of luliconazole compounds are shown in the FTIR spectrum of SLN F6 at 2956.75 cm^-1 for C-H stretching, 2523 and 2647 cm^-1 for S-H stretching, 2202.52 cm^-1 for C≡N stretching, along with C=N at 1556.90 cm^-1, the C=C aromatic ring at 1471.88 cm^-1, and 720.33 and 1101.29 cm^-1 for C-Cl stretching. The CH₂ asymmetric and symmetric stretching vibrations are represented by the high-frequency bands at 2914.97 cm^-1 and 2848.05 cm^-1 in the stearic acid spectrum, whereas the COOH stretching vibration is seen in the low-frequency zone at 1698.03 cm^-1. Following the successful manufacturing of SLN, spectral analysis of the improved SLN revealed no further alterations in luliconazole. The values in the reporting source correspond to the spectral data.

Table 7: FTIR interpretation of SLN F6

Characteristics Peaks	Reported (cm^-1)	Observed(cm^-1)
Stretch C-H	2850 to 3000	2956.75, 2913.97, 2847.05
Stretch C≡N	2100 to 2400	2202.52
Alkene stretch C=C	1650 to 2000	1699.03
Aromatic stretch C=C	1450 to 1650	1464.82
Stretch C-Cl	550 to 850	608.29

Figure 6: F6-SLN FTIR spectra

Optimization of SLN gels:

When carbopol 934 was used as the gelling agent utilizing the stirring method, the topical gel manufacturing process including luliconazole-loaded SLN was successful. The technique for creating various SLN gel products turned out to be stable and useful. All four SLN gel formulations (G1, G2, G3, and G4) were subjected to a 299nm spectrophotometric evaluation of % entrapment.

Table 8: Entrapment Efficiency of various Gel formulations of luliconazole SLN

Gel Preparations	Entrapment efficiency (%±SD)
G1	85.38 ± 0.344
G2	75.32 ± 1.343
G3	91.39 ± 0.187
G4	73.56 ± 1.787

Figure 7: Entrapment Efficiency of various Gel formulations

When 1.5% carbopol w/w was used as the gelling agent in SLN G-3, the percentage of drug entrapment was 91.39%±0.187. Testing was done on the physiochemical properties of improved formulation G-3 to ascertain its viscosity, spreading ability, pH value, and appearance.

According to the research results, the pH of G-3 gel is 6.12±0.255 and its viscosity reaches 369 cP at measurement. With a spreading ability factor of 4.5, the produced SLN gel exhibits exceptional spreading ability for a topical formulation. To keep patients compliant, every topical medication formulation needs to have strong spreading ability.

Table 9: Evaluation of various physicochemical parameters studied

S. No.	Formulation	pH	Viscosity (cP)	Spreadability (cm²)
1	G-3	6.12±0.255	369 ± 6.21	4.5 ± 0.34

In vitro Release Kinetics of Drug:

When analyzing release profiles utilizing buffer systems that have been created using dialysis bag techniques for 24hours, the statistical models act as instruments to predict the release mechanism. The de-solvation percentages of luliconazole from SLN increased gradually over time, as seen in Figure 7 and Table 10. Effective regulated drug delivery properties are demonstrated by the developed SLN, according to results from release profile research. Minorities of SLN use a uniform drug distribution pattern across their whole structure to accomplish drug release.

Ekambaram et al. claim that uniform drug distribution throughout the lipid material leads to controlled drug release¹². Because Poloxamer 407 has a higher HLB value than Cremophor RH40, it is more successful at controlling the drug release rate. Poloxamer 407's high external spreadable qualities lessen the interfacial tension between the dissolving liquid and SLN. Because of its use, the rate of drug breakdown rises while the buildup of drug particles falls.

The amount of lipid in SLN regulates the size of the nanoparticles and improves drug desolvation. When lipid encases a nanoparticle, the drug dissociation period lengthens, resulting in a prolonged duration of drug release¹³.

Table 10: G-3 vs control gel drug % release profile.

Sr. No.	Time (hrs)	Drug% release of G-3	Drug% release of control
1	0	0	0
2	0.25	7.465±0.14	1.821± 0.02
3	0.5	14.103±0.14	2.153± 0.16
4	1	22.163±0.13	3.143± 0.17
5	2	32.387±0.14	3.283± 0.13
6	3	40.521±0.13	5.193± 0.13
7	4	47.147±0.12	7.716± 0.21
8	6	55.681±0.14	8.607± 0.22
9	8	62.408±0.12	9.288± 0.12
10	12	69.838±0.16	9.136± 0.22
11	24	79.679±0.214	9.773± 0.158

Figure 8: SLN gel vs control gel API release profile In-vitro

Through in-vitro testing, the improved formulation's drug release profile was assessed using zero-order, first-order, Higuchi, and Krosmayer-Peppas kinetic models. A statistical examination of the collected data yielded estimates of the rate constants and the highest correlation values, which led to the evaluation of drug release kinetics. With the exception of zero-order, every model under examination has a best-fitting line. The results obtained provide an explanation for the regulated distribution of medicines from homogenous matrix systems at slower speeds.

Based on the data, SLN G3 is an extremely effective topical formulation for prolonged drug administration. The outcomes are consistent with the findings of previous studies on virtuous covenant. The kinetics order of the SLN G3 gel is shown graphically in Figure 9.

Figure 9: SLN G-3 preparation kinetics

SEM study:

According to SEM analysis, the improved formulation looks like the one shown in Figure 10. Vesicles have a vast internal fluid space, a suitable spherical shape, and well-defined boundaries. Because the suspension was diluted before SEM images were taken, the SEM analysis revealed a low density of nanoparticles. The luliconazole-loaded SLN in gel produced spherical nanoparticles with a smooth surface, according to SEM examination.

Figure 10: SLN G-3 gel SEM outcomes

These findings were consistent with earlier literature reports by Kapileshwari et al. in 2020¹⁵ and Sharma et al. in 2021¹⁴ as well.

CONCLUSION:

Delivering adequate medication quantities to the right bodily site while sustaining its therapeutic effect for a predetermined duration of time is the primary goal of topical drug delivery. Our current study examines the effects of introducing solid lipid nanoparticles (SLN) containing luliconazole to topical gel formulations based on carbopol 934, which has strong skin-adherence qualities, on skin penetration and controlled drug administration at specific areas. There is no chemical reaction between luliconazole and the other ingredients in the formulation, according to the spectro-scopical examination. The gel's microscopic analysis using optical and scanning electron microscopy revealed a consistent distribution of SLN with suitable drug release kinetics.

Given that patients must apply the formulation twice or three times a day, the currently available luliconazole 1% cream product (marketed as LUZU) has limited skin penetration and a brief residence period. Solid lipid nanoparticles (SLNs) containing luliconazole were created because the lipid base of these particles was anticipated to enhance medication penetration through skin barriers. The medicine stayed on the skin longer because to the drug-loaded SLNs that were placed in gel.

CONFLICT OF INTEREST STATEMENT:

The authors declare that there is no conflict of interest regarding the publication of this study.

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Received on 14.06.2025 Revised on 12.07.2025

Accepted on 05.08.2025 Published on 18.10.2025

Available online from November 03, 2025

Res. J. Pharma. Dosage Forms and Tech.2025; 17(4):239-246.

DOI: 10.52711/0975-4377.2025.00033

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