Mohamed Sathak AJ College of Pharmacy, Chennai, Tamil Nadu 600119
Onychomycosis, a chronic fungal infection of the nail, presents challenges in topical treatment due to the nail plate’s dense keratin structure and limited drug permeation. Tavaborole, a boron-containing antifungal agent, offers potent activity against dermatophytes but requires optimized formulations for effective transungual delivery. The present study aimed to formulate and optimize pH-responsive in-situ gels of Tavaborole using a Quality-by-Design (QbD) approach and Design of Experiments (DOE) methodology. Tavaborole was characterized as a clear, colorless liquid with no particulate matter, demonstrating purity and stability. Solubility studies revealed poor aqueous solubility but enhanced solubility in ethanol, methanol, and acetone, confirming its hydrophobic nature. UV-visible spectrophotometry at 272 nm provided a reliable method for quantitative analysis, with a linear calibration curve (R² ? 1.0). Various concentrations of Carbopol 934, HPMC K4M, and Triethanolamine were evaluated, significantly influencing viscosity (3426–4717 cps), gelation time (130–228 sec), pH (6.3–6.6), and drug release profiles. Formulations F12, F2, and F10 demonstrated the highest drug release (up to 92.51%) with suitable gelation and viscosity, ensuring effective and sustained topical delivery. FTIR analysis confirmed stable drug-excipient interactions, contributing to gel formation and controlled release behavior. Minimal bias percentages and predictive regression models validated the formulation process. Overall, the study establishes that the synergistic combination of Carbopol 934, HPMC K4M, and Triethanolamine enables the development of stable, patient-friendly, and efficient Tavaborole in-situ gels for onychomycosis treatment, with potential for improved therapeutic outcomes and patient compliance.
Onychomycosis is a persistent fungal infection of the nail unit, primarily caused by dermatophytes, but occasionally by yeasts and non-dermatophyte molds. It is one of the most common nail disorders worldwide, accounting for a significant portion of nail abnormalities seen in clinical practice [1]. The condition not only affects the aesthetic appearance of nails but also poses functional limitations, discomfort, and in some cases, secondary infections, particularly in immunocompromised individuals and patients with diabetes [2]. Treatment of onychomycosis remains challenging due to the dense keratinized structure of the nail plate, which acts as a formidable barrier to drug penetration, and the slow growth rate of nails, which prolongs treatment duration [3]. Conventional systemic antifungal therapies, although effective, are often associated with hepatotoxicity, drug–drug interactions, and other systemic side effects [4], whereas topical treatments typically suffer from poor nail penetration and insufficient retention time, limiting their therapeutic efficacy. Tavaborole, a novel boron-containing antifungal agent, has emerged as a promising candidate for topical treatment due to its potent activity against dermatophytes, favorable safety profile, and ability to disrupt fungal protein synthesis [5]. Despite these advantages, achieving sustained drug release and sufficient permeation through the nail plate remains a significant challenge [6]. This has led to growing interest in innovative drug delivery systems that can enhance drug bioavailability, prolong residence time, and improve patient adherence. In-situ gel systems have garnered considerable attention as a potential solution to these limitations [7]. These formulations are applied in a liquid or semi-liquid state and undergo a sol-to-gel transition in response to specific physiological stimuli such as pH, temperature, or ionic strength. pH-responsive in-situ gels are particularly suitable for topical applications in the nail environment, as the formulation can transform into a gel upon contact with the slightly alkaline pH of the nail bed [8]. This transition not only increases the contact time of the drug at the target site but also facilitates controlled and sustained drug release, improving therapeutic outcomes. Additionally, in-situ gels can enhance patient compliance due to their ease of application, minimal irritation, and non-invasive nature [9]. The development of an optimized pH-responsive in-situ gel requires a systematic approach to formulation design and evaluation. Quality-by-Design (QbD) is an established framework that emphasizes a thorough understanding of formulation and process variables to ensure the desired product quality [10]. Coupled with Design of Experiments (DOE), QbD enables the systematic investigation of critical factors affecting formulation performance, such as polymer type and concentration, viscosity, gelation time, and drug release profile. By applying this structured methodology, it is possible to identify optimal formulation parameters, reduce variability, and ensure reproducibility. This study aims to formulate and optimize a pH-responsive in-situ gel containing Tavaborole for the treatment of onychomycosis, leveraging the principles of QbD and DOE. By integrating advanced formulation strategies with a systematic optimization approach, this study seeks to address the limitations of conventional topical antifungal therapies and provide an effective, patient-friendly solution for onychomycosis management. The findings are expected to contribute to the development of clinically relevant, optimized transungual delivery systems that can enhance drug efficacy, reduce treatment duration, and improve overall patient outcomes.
METHODOLOGY
The organoleptic characteristics of Tavaborole, including its color, odor, and physical appearance, were observed visually under adequate lighting conditions. The drug was examined for any unusual coloration, particulate matter, or odors that might suggest contamination or degradation. These observations provided initial qualitative information about the drug's purity and physical state [11].
Solubility studies were conducted to determine the solubility of Tavaborole in various solvents such as distilled water, ethanol, methanol, phosphate buffer (pH 5.5 and 7.4), and acetone. An excess amount of drug was added to 10 mL of each solvent in separate stoppered conical flasks and shaken continuously in a shaking water bath at 25?±?2°C for 24 hours. The solutions were then filtered through Whatman filter paper, and the filtrate was analyzed spectrophotometrically to determine the amount of drug dissolved in each solvent [11].
A stock solution of Tavaborole was prepared by dissolving an accurately weighed amount of the drug in phosphate buffer (pH 5.5) and scanning the solution in the UV range of 200–400 nm using a UV-Visible spectrophotometer. The wavelength at which the drug exhibited maximum absorbance (λmax) was identified and recorded. This wavelength was used for subsequent quantitative analysis [11].
To construct the calibration curve, a series of standard solutions of Tavaborole were prepared in phosphate buffer (pH 5.5) at concentrations ranging from 2 to 20 µg/mL. The absorbance of each solution was measured at the previously determined λmax using a UV-Visible spectrophotometer. A calibration curve was plotted by taking absorbance on the Y-axis and concentration on the X-axis. The curve was assessed for linearity and the correlation coefficient (R² value) was calculated to confirm reliability for further quantitative estimations [11].
FTIR spectroscopy was used to evaluate possible interactions between Tavaborole and the selected polymers. The spectra of the pure drug, individual excipients, and physical mixtures of the drug with polymers were recorded using an FTIR spectrometer. Each sample was mixed with potassium bromide (KBr), compressed into a pellet, and scanned over a range of 4000–400 cm?¹. The presence, absence, or shifting of characteristic peaks was analyzed to identify any potential chemical interactions [11].
A 2³ full factorial design was employed using Design-Expert® software to systematically evaluate and optimize the formulation variables. The three independent formulation factors selected were:
This design resulted in 8 experimental runs, with 4 center point replicates to ensure model validity and reproducibility, giving a total of 12 runs. The in-situ gel formulations containing Tavaborole were prepared using a cold method. Initially, weighed quantities of Carbopol 934 and HPMC K4M were slowly dispersed in distilled water with continuous stirring using a magnetic stirrer. The dispersion was allowed to hydrate for 12 hours at room temperature to ensure complete swelling of the polymers. Separately, Tavaborole was dissolved in a small volume of ethanol to enhance solubility and was gradually added to the hydrated polymer dispersion under gentle stirring to ensure uniform drug distribution. Triethanolamine was then added dropwise to the mixture to adjust the pH to the physiological range (approximately 6.8–7.4), which facilitates sol-to-gel transition upon application to the nail bed. PEG was added to enhance the penetration. The final volume was made up with distilled water, and the formulation was stirred until a clear and homogeneous solution was obtained. Each batch was labeled (F1–F12) according to the factorial design matrix and stored in airtight containers until further evaluation [12].
Dr. R. Sundhararajan, Pushpamala M., Yuvaraj S.*, Formulation, Optimization, and Evaluation of a pH-Responsive In-situ gel of Tavaborole using Design of Experiments (DOE), Int. J. Sci. R. Tech., 2025, 2 (10), 466-482. https://doi.org/10.5281/zenodo.17454887
10.5281/zenodo.17454887
