Formulation and Evaluation of Mefenamic Acid Emulgel for Topical Delivery

Topical drug delivery systems have gained considerable attention in the pharmaceutical field as effective alternatives to conventional oral administration. Although oral delivery remains the most widely used route, it is often limited by factors such as first-pass metabolism, gastrointestinal irritation, and reduced bioavailability, particularly for hydrophobic drugs1. In contrast, transdermal and topical delivery systems bypass these limitations by providing a non-invasive, site-specific approach that enhances patient compliance and maintains relatively steady plasma drug concentrations2. Among the various topical dosage forms, emulgels have emerged as promising and superior dermatological formulations. Conventional topical preparations such as creams, ointments, and lotions exhibit certain drawbacks. For instance, lotions often possess low viscosity and reduced residence time on the skin, while ointments tend to be greasy and cosmetically less acceptable.3 Emulgels overcome these limitations by combining the advantages of both emulsions and gels. This dual-controlled system facilitates the incorporation of hydrophobic drugs into an oil-in-water (o/w) emulsion, which is subsequently gelled using appropriate polymers. As a result, emulgels exhibit improved stability, enhanced spreadability, a pleasant cooling effect, and better skin penetration4. Mefenamic acid, a potent non-steroidal anti-inflammatory drug (NSAID) belonging to the fenamate class, is widely used for its analgesic and anti-inflammatory effects. However, oral administration of mefenamic acid is frequently associated with gastrointestinal side effects, including gastric irritation, abdominal pain, and peptic ulceration5. Additionally, its poor aqueous solubility poses challenges for effective permeation through the skin when formulated in conventional gel systems6. Therefore, the present study focuses on the development of a Mefenamic acid emulgel to enhance its topical permeability and therapeutic efficacy. Hydrophilic polymers such as sodium alginate and sodium carboxymethyl cellulose were employed as gelling agents, while mentha oil was incorporated as a natural permeation enhancer. This approach aims to develop a stable, effective, and patient-friendly topical formulation for the management of localized pain and inflammation7.

METHODOLOGY

Preformulation Studies

Preformulation studies are essential for evaluating the physicochemical properties of a drug prior to formulation development. These studies help in determining the suitability of the drug for dosage form design and ensure product stability and efficacy 8.

I. Determination of Melting Point

The melting point of pure Mefenamic acid was determined using the capillary method with a Thiele’s tube apparatus. A small quantity of the drug was filled into a sealed capillary tube and placed in the apparatus containing liquid paraffin. The temperature was gradually increased, and the point at which the drug completely melted was recorded. The melting point serves as an indicator of purity; a sharp and narrow melting range confirms the absence of impurities. The experiment was performed in triplicate, and the average value was reported to ensure accuracy and reproducibility 9.

II. Identification of Drug (λmax Determination)

The identification of Mefenamic acid was carried out using UV-visible spectrophotometry by determining its maximum absorption wavelength (λmax). Standard solutions of 10 µg/mL and 20 µg/mL were prepared in distilled water and phosphate buffer (pH 7.4). These solutions were scanned over the UV range of 200–400 nm, and the λmax was observed in the range of 280–285 nm. The analysis was performed against a suitable blank, and the obtained λmax value confirmed the identity and purity of the drug. This method is widely used for qualitative and quantitative drug analysis due to its sensitivity and accuracy10.

III. Solubility Studies

Solubility studies were conducted to determine the solubility profile of Mefenamic acid in different solvents, including distilled water, ethanol, and sodium lauryl sulphate (SLS) solution. An excess amount of the drug was added to each solvent to prepare saturated solutions, which were then subjected to intermittent shaking for 24 hours at room temperature to achieve equilibrium. The solutions were subsequently filtered, and the drug concentration was analysed using a UV spectrophotometer at 285 nm. The results were recorded as the mean of three determinations. These studies are crucial for selecting suitable solvents and excipients for formulation development, especially for poorly water-soluble drugs11.

Preparation of Mefenamic Acid Emulgel

The emulgel formulations were prepared using both natural and semi-synthetic hydrophilic polymers, namely sodium alginate and sodium carboxymethyl cellulose (NaCMC), at varying concentrations (1%, 1.5%, and 2% w/v), to evaluate their effect on formulation properties.

Preparation of Gel Base

Accurately weighed quantities of sodium alginate and Sodium carboxymethyl cellulose were dispersed in purified water and allowed to hydrate under continuous stirring using a mechanical stirrer. The pH of the gel base was adjusted to 6.0–6.5 using triethanolamine (TEA), ensuring compatibility with skin pH and enhancing formulation stability. Proper hydration of polymers is essential to achieve the desired viscosity and consistency of the gel base 12.

Incorporation of Drug

Mefenamic acid (1 g) was dissolved in 95% ethanol to enhance its solubility and ensure uniform distribution within the formulation. The drug solution was then gradually incorporated into the prepared gel base with continuous stirring to obtain a homogeneous mixture. The final weight of the formulation was adjusted to 50 g using purified water13.

Preparation of Emulsion

The emulsion phase was prepared separately and remained constant across all formulations. The oil phase, consisting of mentha oil (acting as a penetration enhancer), Span 80 (lipophilic surfactant), and light liquid paraffin, was heated to 70–80°C. Simultaneously, the aqueous phase containing Tween 80 (hydrophilic surfactant), propyl paraben (preservative), propylene glycol (humectant and co-solvent), and water was heated to the same temperature. The oil phase was then slowly added to the aqueous phase under continuous mechanical stirring to form a stable oil-in-water (o/w) emulsion. Maintaining equal temperatures of both phases is critical to prevent phase separation and ensure uniform emulsion formation14.

Formation of Emulgel

The prepared emulsion was gradually incorporated into the gel base with continuous stirring until a uniform emulgel was obtained. The final formulation was allowed to cool to room temperature, resulting in a stable, homogeneous emulgel with improved spreadability and drug release characteristics. The combination of emulsion and gel systems enhances the delivery of hydrophobic drugs by improving solubilization and penetration through the skin15.

Evaluation of Mefenamic Acid Emulgel

The prepared Mefenamic acid emulgel formulations were evaluated for various physicochemical, in-vitro, and in-vivo parameters to ensure their quality, efficacy, and stability.

1. Physical Evaluation

All formulations were visually inspected for colour, homogeneity, consistency, occlusiveness, washability, phase separation, and odour. These parameters are important indicators of patient acceptability and formulation stability16,17.

2. Determination of pH

The pH of the formulations was determined by dispersing 1% w/v of the emulgel in distilled water. The pH was measured using a calibrated digital pH meter. Maintaining pH within the physiological skin range (approximately 5.5–7.0) is essential to avoid skin irritation and ensure compatibility18.

3. Spreadability

Spreadability of the emulgel was evaluated using a parallel plate method. Approximately 0.1 g of the formulation was placed between two glass slides (marked with 5 mm divisions) and allowed to spread under a specified weight for 5 minutes. The diameter of the spread circle was measured in centimetres. The test was performed in triplicate, and the mean value was reported.

Spreadability was calculated using the formula:

Where:

• S = Spreadability
• M = Weight tied to the upper slide
• L = Length of the glass slide
• T = Time required to separate the slides

Good spreadability indicates ease of application and uniform distribution of the formulation over the skin surface19.

4. Homogeneity and Grittiness

The prepared emulgels were evaluated for homogeneity by visual inspection after setting in the container. A small quantity of gel was also rubbed on the back of the hand to assess uniformity and detect the presence of any aggregates or grittiness. A homogeneous formulation without particulate matter indicates proper mixing and stability20.

5. Phase Separation

Phase separation studies were conducted to evaluate the stability of the emulsion system. Oil-in-water (o/w) emulsions were diluted with water, whereas water-in-oil (w/o) emulsions were diluted with oil to confirm the type of emulsion and check for any instability or separation. The absence of phase separation indicates good formulation stability21.

6. Drug Content Determination

An accurately weighed quantity (100 mg) of emulgel was dissolved in 100 mL of phosphate buffer (pH 7.4) in a volumetric flask. The solution was shaken for 2 hours using a mechanical shaker to ensure complete drug extraction. The solution was then filtered, and the absorbance was measured at 285 nm using a UV spectrophotometer, with phosphate buffer as the blank.

Drug content was calculated using the formula:

Uniform drug content ensures consistent therapeutic efficacy of the formulation22.

7. Permeability Coefficient (Kp)

The permeability coefficient was calculated to evaluate the drug permeation through the membrane using the following equation:

Where:

• Kp = Permeability coefficient
• Jss = Steady-state flux
• Cv = Total drug concentration in the donor compartment

This parameter reflects the efficiency of drug permeation across the membrane23.

8. Fourier Transform Infrared (FTIR) Studies

FTIR analysis was performed to detect any potential drug–polymer interactions. Samples of pure drug, polymers, and optimized formulation were prepared using the KBr pellet method. The spectra were recorded over a range of 4000–400 cm⁻¹ using an FTIR spectrophotometer (Shimadzu 8300, Japan). The obtained spectra were analysed for characteristic peaks and possible interactions24.

9. In-vitro Drug Release Studies

In-vitro drug release studies were performed using a membrane diffusion method. The formulation was applied onto a suitable membrane, which was mounted on a test tube and suspended in a beaker containing phosphate buffer (pH 7.4) as the diffusion medium. The temperature was maintained at 37 ± 0.5°C, and the system was continuously stirred using a magnetic stirrer. At predetermined time intervals, 2 mL samples were withdrawn and replaced with an equal volume of fresh buffer. The samples were analyzed spectrophotometrically at 285 nm, and the cumulative percentage drug release was calculated25.

10. In-vivo Anti-inflammatory Activity

Anti-inflammatory activity was evaluated using the carrageenan-induced paw edema model in albino rats. Edema was induced by sub plantar injection of 1% w/v carrageenan into the left hind paw.

Experimental Groups:

• Group I (Control): Carrageenan only
• Group II (Standard): Diclofenac gel + carrageenan
• Group III (Test): Formulation F3 + carrageenan

The formulations were applied 30 minutes prior to carrageenan injection. Paw volume was measured at 30, 60, 90, and 120 minutes using a plethysmometer.

Percentage inhibition of edema was calculated as:

Where:

• Vc = Paw volume of control group
• Vt = Paw volume of treated group

This method is widely used for evaluating anti-inflammatory activity of topical formulations26.

11. In-vivo Analgesic Activity

Analgesic activity was evaluated using the hot plate method. The latency time (time taken by the animal to respond to thermal stimulus) was recorded.

Experimental Groups:

• Group I (Control): No treatment
• Group II (Standard): Diclofenac gel
• Group III (Test): Formulation F3

An increase in latency time indicates analgesic activity of the formulation27.

12. Skin Irritation Study

Skin irritation studies were conducted using albino rats. The animals were maintained under standard laboratory conditions with free access to food and water. The dorsal surface of the rats was shaved, and an area of approximately 4 cm² was marked. The test formulation was applied to one side, while the other side served as control. The animals were observed for 24 hours for any signs of irritation such as redness, swelling, or changes in skin morphology. Absence of irritation confirms the safety of the formulation for topical use28.

Table 1: Composition of different formulation of Mefenamic Acid Emulgel

Table 2: Preformulation studies of Mefenamic acid pure drug

*Average of three determinations

Table 3: Solubility studies of Mefenamic acid

*Average of three determinations

Table 4:  Percent yield of prepared Mefenamic Acid Emulgel

*Average of three determinations

Table 5: Physical parameters of Mefenamic acid Emulgel

Table 6: Physical parameters of Mefenamic acid Emulgel

Table 7: Drug content of Mefenamic acid Emulgel

*Average of three determinations

Table 8: In-vitro release profile of Mefenamic acid Emulgel F1-F6

Table 9: In-vivo studies for Anti-inflammatory activity: Change in rat paw

Values are expressed as mean + S.E.M and % of inhibition of edema was represented in (n=6)

Table 10: In-vivo studies for Analgesic activity Hot Plate Latency Time (sec)