1. Introduction
Psoriasis is a skin condition characterized by an abnormally high rate of cell growth. It is not communicable; rather, it is brought on by an overactive immune system. Psoriasis is an inflammatory skin disorder brought on by misguided T lymphocytes. The skin of psoriasis patients may be rough and bumpy because of their high cell turnover [
1]. Psoriatic skin becomes red, flaky, and thick due to an increase in keratinocytes, new blood vessel growth, and immune cell infiltration. Since there is currently no cure and conventional treatments have their limits, natural anti-psoriatic remedies have been the subject of much research. There is not a lot written about using herbs to treat psoriasis. Psoriasis treatments, especially those used topically, need prolonged application [
2]. This is especially challenging when the drugs are taken orally, as liquids are eliminated rapidly via the skin. Tight skin makes it difficult for drugs to enter the body, reducing their efficacy [
3]. Psoriasis treatments have always been limited by these factors. Hydrogels with built-in pharmaceuticals might improve transdermal drug delivery. As a result, improved methods of drug retention and distribution in topical anti-psoriatic medications are urgently required [
4].
Curcumin has a demonstrated ability to mitigate inflammatory responses in a manner akin to the impact of steroids, but devoid of any associated side effects [
5]. The challenges of water insolubility, reduced potency, and instability are common issues encountered in various herbal remedies [
6,
7]. Extensive first-pass metabolism occurs, making it a suitable candidate for topical gel formulations [
8,
9]. Further, tea tree oil possesses significant antimicrobial and anti-inflammatory properties [
10,
11]. Terpinen-4-ol has the potential to inhibit the production of various inflammatory mediators, such as interleukins, by human peripheral blood monocytes [
12]. This finding suggests a plausible mechanism by which tea tree oil might mitigate the typical inflammatory response in conditions like psoriasis by acting beneath the dermal layer. However, there is currently no documented research on the combined effects of both substances in the form of an anti-psoriatic emulgel. Consequently, there is a need for a delivery system that can facilitate transdermal drug release and demonstrate its therapeutic effects.
The first line of defense against psoriasis is a topical therapy [
13]. There is a need for a more effective medication delivery method since patients are less likely to comply with long-term therapy when using the current formulation (ointment), because it is oily and causes irritation. Nanoemulsions are kinetically stable systems with a size range of 20–200 nm, making them suitable for topical delivery [
14]. Since psoriatic skin is rough and encrusted with plaques, their nano-sized nature provides higher penetration and retention into the skin, which is desirable in psoriasis. In addition, nanoemulsions may be readily transformed into a gel, which improves skin hydration and medication delivery into the skin, increases patient compliance thanks to its non-greasy and non-sticky nature, and offers prolonged drug administration.
In our present study, we have developed transdermal preparations loaded with curcumin using tea tree oil, aiming to enhance both the effectiveness and transdermal drug delivery, while exploring the potential synergistic effects of tea tree oil in combination with curcumin.
3. Conclusions
The emulgel system was developed and assessed with the aim of enhancing the solubility, skin deposition, and permeation of curcumin with tea tree oil for the treatment of psoriasis. Our investigation revealed that these formulations exhibited favorable physical properties and demonstrated a significant anti-psoriatic effect. Over a 90-day physical stability test, the curcumin-loaded formulation remained stable, with no significant changes in appearance, pH, viscosity, or drug content. The release kinetics of curcumin from both the gel and emulgel followed a zero-order and Higuchi model, indicating a controlled release profile. In an in vivo study using an IMQ-induced psoriasis model, the curcumin-loaded emulgel displayed superior anti-psoriatic efficacy compared to the curcumin-loaded gel. This suggests that the emulgel formulation holds promise for improving the topical effectiveness of poorly permeable curcumin in the long-term management of psoriasis. Additionally, our data demonstrated that tea tree oil substantially enhanced the in vivo activity of curcumin-loaded formulations, particularly the curcumin-loaded emulgel, highlighting a synergistic effect between curcumin and tea tree oil. In conclusion, the emulgel formulation has the potential to serve as a viable vehicle for the transdermal delivery of curcumin.
4. Materials and Methods
4.1. Materials
The following chemicals and materials were acquired from various sources: curcumin was obtained from Sigma-Aldrich Co. (St. Louis, MO, USA), Tween 80 from Merck Specialities Private Limited (Worli, Mumbai, India), sodium carboxymethylsellulose (NaCMC) and ethanol from Sigma-Aldrich Co. (St. Louis, MO, USA), propylene glycol (PG) from Merck (Schuchardh, Hokenbrunn, Germany), and myrrh oil from Blossoms Aroma Private Limited. All remaining chemicals used were of analytical grade and procured from Sigma, USA.
4.2. Screening of Oils, Surfactants, and Co-Surfactants
A total of 10 mg of curcumin was added to every vial with 1 mL of an acceptable medium, such as an oil, surfactant, or co-surfactant. The mixture was vortexed for 15 min to ensure that the curcumin and the vehicles were properly mixed. After that, the solutions were maintained at 25 °C for 48 h in an orbital shaking incubator to aid with solubilization and reach equilibrium. The solution was centrifuged at 500 rpm for 15 min, and the supernatant phase was filtered using a 0.45 mm membrane filter. The filtered sample was mixed using ethanol. As well, the concentration of curcumin was quantified using a UV spectrophotometer to measure absorbance at 425 nm [
16,
17].
4.3. Development of Gel
The gel base was formulated by introducing NaCMC into water while continuously stirring using a magnetic stirrer (Remi Motors, Mumbai, India) until complete and uniform swelling was achieved, resulting in the formation of a gel base. A measured quantity of curcumin was dissolved in ethanol and vigorously vortexed for 5 min. Subsequently, this curcumin solution was combined with the gel base to create a homogeneous gel [
7,
18]. Detailed compositions of the curcumin-loaded gel can be found in
Table 5.
4.4. Development of Curcumin-Loaded Nanoemulsion and Loading into Gel
The simplest technique of preparing the nanoemulsion is through the spontaneous method, by stirring the emulsion mixture directly without involving any higher energy of emulsification. In the preparation of a curcumin nanoemulsion, tea tree oil was employed in the oil phase, Tween 80 served as the surfactant PG and as the co-surfactant, and ethyl alcohol served as a solvent. Initially, curcumin was mixed with tea tree oil to form the oil phase and vortexed, followed by the addition of the surfactant PG and co-surfactant; then, 20 mL of water was added with continuous stirring to obtain the nanoemulsion.
The base of the gel was produced by dissolving a measured amount of gelling reagent within water. The emulsion loaded with curcumin was gradually mixed with a Heidolph RZR 1 mixer (Heidolph Instruments, Schwabach, Germany) for 5 min at 3000 rpm until a uniform emulgel was achieved [
7]. The specific compositions of the curcumin-loaded emulgel are detailed in
Table 6.
4.5. Characterization of Gel and Emulgel
4.5.1. Visual Inspection
The physical appearance, color, and consistency of the created formulations (gel and emulgel) were assessed visually. The formulation that showed desirable results was selected for further examination and characterization.
4.5.2. Drug Content
A properly weighed amount (one gram) of gel and emulgel was dissolved in 1 mL of methanol. The sample was diluted to measure the absorbance using a UV spectrometer at 425 nm. The drug content of each formulation was determined using the following formula.
Drug content = (concentration × dilution factor × volume taken) × conversion factor [
19].
The formulation that showed the maximum drug content was selected for further examination and characterization.
4.5.3. pH Determination
A calibrated pH meter was used to measure the pH value of the compositions at room temperature. In 100 mL of distilled water, 1 g of the gel and emulgel was distributed, utilizing a digital pH meter to determine the pH value of the dispersion [
15].
4.5.4. Viscosity Measurement
A cone and plate viscometer with spindle 7 (Brookfield Engineering Laboratories) was used to determine the viscosity of the prepared batches. The system was linked to a thermostatically controlled water flow that kept a constant temperature of 25 °C [
20,
21].
4.5.5. Spreadability Determination
A spreadability apparatus, consisting of a wooden board with a scale and two glass slides, was used to test the spreadability of the transdermal preparation. It aids in determining the size of the area across which the mixture can easily spread once administered towards the afflicted area of the skin. A load of 500 g was given for one minute to 1 g of the gel and emulgel combination and was placed between two horizontal glass slides (25 × 25 cm) [
22,
23].
where, S = spreadability, M = weight (in g) tide upper slide, L = length (in cm) of glass slides, and T = time (in sec) taken to separate the two slides completely from each other [
24].
4.5.6. Centrifugation Test
The stability of both the gel and emulgel was evaluated using the centrifugal test. In this test, approximately 5–6 g of the final emulgel and gel formulation were put in a centrifuge tube, then centrifuged at around 5000 rpm for about 10 min at 25 °C. As a result, a visual inspection of the gel and emulgel was conducted to detect signs of phase separation or creaming [
24].
4.5.7. Particle Size, PDI, and Zeta Potential
A dynamic light scattering instrument (Malvern Zetasizer, Nano ZS, Worcestershire, UK) was used to investigate the particle size and polydispersity index (PDI) of the curcumin-loaded gel and emulgel. The compositions were diluted over 100 times with deionized distilled water before testing. Light scattering was evaluated at 90° room temperature. The zeta potential was measured via Laser Doppler Electrophoresis after vigorous mixing and 200-fold dilution in deionized distilled water [
15].
4.5.8. FTIR and DSC of Gel and Emulgel
An FTIR spectroscopy analysis was used to assess the interaction and compatibility of the medication as well as the additional inert ingredients within the composition. The FTIR spectroscopy was carried out using an FTIR spectrometer. When a certain amount of material was mixed with potassium bromide, the FTIR spectra for the pure medicine (curcumin) and excipients were observed (KBr). The transmission mode scanning technique was used, with wavenumbers ranging from 4000 to 400 cm
−1 [
25].
Curcumin dispersion and incorporation in the lyophilized nanoemulsions were measured using the DSC technique [
11]. A total of 10 mL of the nanoemulsion was lyophilized with 5% (
w/
v) mannitol at −20 °C in a freeze-dryer (HetoDrywinner, Copenhagen, Denmark). In summary, 4 mg of the lyophilized sample was heated at 20 °C/min from 40 to 200 °C with 20 mL/min of inert gas nitrogen, using an empty pan as a reference.
4.5.9. In Vitro Drug Release Study
Franz diffusion cells or egg membranes were utilized in the drug release study. One gram of the formulation was distributed on the egg membrane’s surface and clamped between the diffusion cell’s donor and receptor chamber. This included 200 mL of diffusion medium (phosphate buffer, pH 7.4, containing 25% methanol), which had been warmed at 37 ± 1 °C and stirred continuously at 100 rpm with a magnetic stirrer. During various fixed periods, 10 mL of sample were taken through receptor media. Withdrawn samples were replaced with fresh medium in an equivalent amount. The specimen had been compared to a blank around 425 nm utilizing a UV spectrophotometer [
26].
4.5.10. Kinetic Study
The profile of an in vitro release of medication was utilized to examine the correlation coefficient (r
2) and release kinetics of curcumin-loaded compositions. This was achieved by plotting the concentration of the drug with time. The following kinetic models were used in this research [
27].
Zero-order equation Q1 = Q0 + K0 t;
First-order equation lnQ1 = lnQ0 × K0 t;
Higuchi model Q = KH t1/2;
Korsemeyer–Peppas equation Mt/M∞ = Ktn.
Q1 is the initial amount of the drug dissolved at time t, Q0 is the initial amount of the drug in the solution, K0 is the zero-order release rate constant, K1 is the first-order release rate constant, Q is the amount of the drug released at time t per unit area, KH is the Higuchi diffusion rate constant, Mt and M∞ are the amounts of the drug released at time t and infinite time, K is the release rate constant, and n is the drug release exponent.
The model that created a linear plot and had the highest (r
2) value was the best fit for the drug release data [
28].
4.6. Stability Studies
Stability assessments were employed to investigate the physicochemical characteristics of curcumin-loaded products, specifically the gel and emulgel formulations. These compositions were securely stored in sealed containers at relative humidity levels of 60% and temperatures of 4 °C and 25 °C for a duration of three months. Subsequently, an analysis of the physical attributes of the samples was conducted [
29].
4.7. In Vivo Anti-Psoriatic Activity
The potency of the produced curcumin-loaded gel and emulgel was investigated using the animal model of imiquimod-induced psoriasis. The anti-psoriatic activity animal protocol has been approved via the Institutional Animal Ethics Committee (SRMS CET Bareilly, Ref. no 715/PO/Re/S/02/CPCSEA) and the studies were carried out according to their standards. The anti-psoriatic activity of the produced formulations was tested using male Albino rats (6–8 weeks old, weight about 20–30 g). The rats are housed in standard laboratory conditions (temperature: 25 ± 2 °C, relative humidity: 55 ± 5%). The animals had unlimited access to laboratory meals and water.
The topical use of marketed imiquimod cream (5%
w/
w. Glenmark pharmaceutical Ltd., Mumbai, India) was used for producing psoriasis. the dorsal area of male albino rats was shaved. Psoriasis was induced after ten consecutive days of topically applying the imiquimod cream (62.5 mg/day). When psoriasis was induced, the animals were separated into three groups: group A, group B, and group C. Group A received no treatment, while group B and C received the curcumin-loaded gel and curcumin nanogel (equal to 100 mg curcumin), respectively. The medication was continued for 10 days after psoriasis was induced. As described by Mittal et al., 2021, PASI scoring (0, 1, 2, 3, and 4) was used to measure the severity of psoriasis. Symptoms such as redness, thickness, and scaling was assessed as none, mild, moderate, severe, or extremely severe [
15].
4.8. Statistics
The data obtained were presented as mean values with standard deviation (SD) (n = 3). A statistical analysis was conducted using one-way ANOVA tests with GraphPad Prism version 5. A difference was considered statistically significant if the p-value was <0.05.