Perspective Impact of Gelling Agents on the Permeation Behavior for the Topical Delivery of Itraconazole Gel

Fungal infections (mycoses) are caused by fungi that invade and grow on or inside the body. These infections can range from mild to life-threatening, depending on the type of fungus and the host’s immune status [1]. Itraconazole is a wide-spectrum antifungal agents belongs to tri-azoles class that can be used to treat various fungal infections. Furthermore, in contrast to other antifungal therapies, the azole groups' preference for the cytochrome P-450 enzymes of fungi rather than mammals allows for highly selective antifungal action with relatively little adverse effects. As a result, higher ITZ concentrations have been attained using standard oral dosages of 200–400 mg daily [2]. However, a number of reproductive issues, liver damage, and nephrotoxicity have all been linked to the high systemic concentration of ITZ that results [3]. Because topical administration of ITZ has fewer side effects than oral administration, it may be beneficial for site-specific delivery. This could be ascribed to its high molecular weight (705.64?g/mol), low aqueous solubility and high lipophilicity (LogP?=?5.66). Gums play a crucial role in gel preparation by acting as thickening and gelling agents, enhancing viscosity, stability, and texture. They prevent phase separation, improve moisture retention, and enable controlled release of active ingredients, making them valuable in pharmaceutical and cosmetic formulations. Large-scale availability of natural polymers and additives, which deliver an effective dosage of medicine for extended times, has led to greater success in designing the most advanced treatment systems today. These days, natural polymers derived from plant gums and fibers are used as gel-forming agents to advance research into these gums and are being documented for their use in formulation development. To examine how polymers regulate the release of API in a formulation, we are utilizing three different types of gums with various polymers. i) Xanthan gum ii) Guar gum iii) Carbopol. Xanthan gum and guar gum are natural polymers, whereas Carbopol is typically a manufactured or semi-synthetic polymer [4]. Xanthan gum is a natural polymer that can play a vital role in sustain release of a gel formulation. Because of its distinct rheological characteristics, xanthan gum is frequently utilized as a sustained-release polymer in gel compositions. By forming a matrix network that slows down drug diffusion, it produces a viscous, stable gel that regulates drug release. common synthetic polymer used in gel formulations as a controlled-release matrix and gelling ingredient is Carbopol. It has outstanding swelling capabilities, creating a very viscous gel that can hold and release medications gradually over time.  A natural polysaccharide, guar gum is frequently utilized in gel formulations as a gelling and sustained-release ingredient. Its superior swelling and water-absorbing qualities create a thick gel matrix that delays drug diffusion and extends release. Additionally, guar gum improves bioadhesion, which increases medication retention at the application site. [5]

 This experiment is done mainly to check how the gums or polymers play a crucial role in the sustain or control release of active ingredients in the gel formulation and find out the best gum among these which is play a crucial role in control release of APIs in gel.

MATERIAL AND METHODS

MATERIALS

The API is Itraconazole, different gums such as Guar gum, Xanthan gum and Carbopol, sodium meta bisulphate, propylene glycol (PG) and Distilled Water.

Methods of preparation of gel formulations

The necessary quantity of gum polymers was added to warm distilled water (no more than 50°C) while stirring (2000 rpm) to prevent air entrapment in order to create gel solutions. For optimal absorption and elimination of trapped air bubbles, the gel was left to soak for 24 hours.  Following separate weighing, the necessary amounts of methyl paraben (0.2 gm) and propyl paraben (0.1 gm) were dissolved in 5 ml of propylene glycol and added to the gel solutions while being continuously stirred. 1 ml of distilled water was used to dissolve 0.1 grams of sodium metabisulphite, which was then added to the gel solution while being constantly stirred. Then the drug Itraconazole (2gm) was added in 10 ml of water but for its poorly soluble property it is sonicated then the mixture of API and water was added to the gel solution. Finally, to maintain the volume of mixtures, the remaining amount of distilled water was added while being agitated at 2000 rpm until homogenous gels were created. [6]

Using 3 different gum solution, three different gel formulation was prepared.

       
           
       
Evaluation [7,8]

The following procedures were used to evaluate and optimize formulations at various type gums:

Appearance:

Clarity, color, homogeneity, consistency, and the presence of aggregates and particles were all evaluated in gel compositions. Using a compound microscope (CETI), homogeneity and clarity were assessed. A small amount of gel was applied between the thumb and index finger, and its behaviour and consistency were noted. In order to determine whether any settled-down particles were present during centrifugation, the formulations were also centrifuged at 2000 rpm using a centrifuge.[9]

Determination Of PH:

A calibrated digital pH meter operating at a constant room temperature range of 24± 2°C was used to measure the pH of the gel compositions.[10]

Moisture Content:      

The oven-dry method was used to determine the gel compositions' moisture content. A petri-dish containing the weighed formulation was placed in an oven set at 105°C. The sample was dried in the oven repeatedly until the formulation's weight remained constant.[11]

Spreadability:

Spreadability was measured using a formula and stated as the amount of time (seconds) it took for two slides (10 cm x 10 cm) to separate from gel that was placed between the slides when a specific load (25 gram) was applied. S = (M.L/T) where S stands for Spreadability, M for weight attached to the higher slide, L for glass slide length, and T for time spent separating the slides. [12,13]

Viscosity: 

The viscosity of the formulation was measured with the Brookfield digital viscometer equipped with spindle S64. The viscosity was measured at room temperature (between  25°C ± 2°C) while revolving at 50 rpm after the gel compositions had settled in the sample container of the viscometer for five minutes. [14]

Evaluation Of Microbial Growth

By dissolving 100 mg of gel in 1 ml of distilled water and then spreading it over an agar plate, the produced formulations were assessed for microbial resistance. The plates were incubated for 24 days at 37°C±1°C to see if any microbial growth was present.

In Vitro Drug Permeation of Gel Formulations [15,16,17]

In vitro permeation study-

The eggshell membrane was used for in vitro permeation studies. The Franz diffusion cell is a frequently used piece of equipment for in vitro permeation investigations the integrity of the reservoir patch is lost because larger surface area patches cannot be placed into the donor chamber of the cell without cutting. At first Franz diffusion cell apparatus was placed properly. The eggshell membrane was attached on the top of the Franz diffusion cell apparatus after filling it with the buffer solution.  The samples of each gel was placed on the eggshell membrane. The temperature was maintained at 37 ± 0.2?C and the rotation of apparatus was adjusted at 300 rpm. This study performed in the duration of 2hr and the sample was collected 10 mins of interval from starting to end of the experiment. Total 12 sample from each gel were collected by using micropipette. These sample was evaluated though UV-spectrometry.

       
           
       
Figure 4 (Franz diffusion cell

RESULT:

The evaluation of gels was done. The evaluation was mainly based on the comparisons in the aspects of permeation between different types of gums. The characteristics of the gels was given on the table 2.

Table 2: Characteristics of different gel formulations

In Vitro Skin Permeation Analyses:

After performing In vitro skin permeation study, according to the data we can conclude that formulations based on xanthan gum have superior permeability properties. As per data, the below graph is plotted.