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Journal of Drug Delivery and Therapeutics

Open Access to Pharmaceutical and Medical Research

Copyright  © 2023 The  Author(s): This is an open-access article distributed under the terms of the CC BY-NC 4.0 which permits unrestricted use, distribution, and reproduction in any medium for non-commercial use provided the original author and source are credited

Open Access   Full Text Article                                                                                                                 Review Article 

Formulation Perspectives in Topical Antifungal Drug Therapy: A Review 

G.R. Godge*¹ , S.C. Bharat¹ , A.B. Shaikh¹ , B.B. Randhawan¹ , M.A. Raskar¹  and S.N. Hiremath² 

¹ Dr. Vithalrao Vikhe Patil Foundation’s College of Pharmacy, Ahmednagar-414111, India

² PRES’s Pravara Rural College of Pharmacy (Diploma), Pravaranagar, Loni-413736, India

INTRODUCTION

A topical application occurs when a drug is administered topically to a specific area of the body. Topical administration, which includes a wide variety of classes such creams, foams, gels, lotions, and ointments, most frequently refers to application to bodily surfaces like the skin or mucous membranes to treat ailments. Numerous topical drugs are administered topically, to the skin.¹ Compared to other drug delivery methods, the topical/transdermal route has several benefits, including continuous medication delivery, less side effects, and increased patient compliance.² Drugs for topical use are meant to be applied externally. They are designed to have a localizing effect on one or more skin layers.³ The wide range of pharmaceutical dosage forms used in topical drug delivery systems includes semisolids, liquid preparations, sprays, and solid powders. Gels, creams, and ointments are the most often utilized semisolid topical drug delivery preparations. ⁴ 

GEL

According to the U.S.P., a gel is a semisolid system made up of a dispersion made up of either large organic molecules or small inorganic particles that are enclosed and contacted by fluids. Gels are a significantly dilute cross-linked system with no flow in the steady-state1822. They are made up of a two-component semi-solid liquid-rich system. Their one distinguishing feature is the existence of a continuous structure that provides solid-like characteristics.⁵ Gels have become a preferred medium for drug delivery formulations due to their biocompatibility, network structure, and molecular stability of the integrated bioactive ingredient.⁶

STRUCTURE OF GELS

A gel is made up of a natural or synthetic polymer that forms a three-dimensional matrix in a dispersion medium or hydrophilic liquid. After application, the liquid evaporates, trapping the medicine in a thin film of the gel-forming matrix that physically covers the skin. The existence of a network produced by the interlocking of gelling agent particles causes a gel to be stiff. The structure of the network and the properties of the gel are determined by the nature of the particles and the kind of form that is responsible for the links. ⁶

Figure 1: Structure of gels

Topical formulations have three main functions ⁷

1. Because of their emollient qualities, they help in skin hydration.
2. To protect the skin from the elements or to repair an undamaged or injured region of skin.
3. To apply medicine to the skin.

ADVANTAGES OF TOPICAL DRUG ADMINISTRATION⁶

1. Avoids issues with gastrointestinal (GI) medication absorption caused by GI pH, enzymatic activity, and drug interactions with food, drink, and other orally delivered medicines.
2. When other methods of administration (e.g., oral administration, intravenous injection) are ineffective, such as with vomiting, swallowing issues, resistant children, or diarrhea, this route is chosen.
3. Patient acceptance is improved since this medication delivery technique is non-invasive, avoiding the discomfort of parenteral therapy.
4. Avoids the first-pass effect, which may result in enzyme inactivation by digestive and liver enzymes.
5. Dose reduction as compared to oral dosing forms.
6. The ability to dissolve a large range of drugs with varying chemical characteristics, allowing for combination treatment with a single transdermal gel.
7. Improves compliance by providing longer treatment with a single application.
8. Drug therapy can be stopped quickly by removing the application from the skin's surface.
9. Less oily and easier to remove from the skin.

DISADVANTAGES OF TOPICAL DRUG ADMINISTRARION¹

1. This route is not suitable for medications that irritate or sensitize the skin.
2. Topical preparations are more costly than traditional dosing forms.
3. The route is constrained by the surface area of the delivery system and the dose that must be administered in the chronic stage of illness.

CLASSIFICATION OF GELS⁷

Figure 2: General Classification of Gels

There are two classification categories for topically administered gels. The first approach categories gels into two kinds of gel systems. These are known as inorganic and organic gel systems, respectively. Most inorganic hydrogels, such as aluminium hydroxide gel and bentonite magma, are two-phase systems. Bentonite has also been utilised as an ointment basis in quantities ranging from 10% to 25%. Most organic gels are single-phase systems that may contain gelling agents such as carbomer and tragacanth as well as organic liquids such as Plastibase. The second classification method separates gels into hydrogels and organogels, with several subcategories in between organic hydrogels, natural and synthetic gums, and inorganic hydrogels are examples of soluble in water components.⁷

CHARACTERISTICS OF GELS^{8, 9}

Gels should possess the following properties

1. Gelling agents for pharmaceutical or cosmetic usage should ideally be inert, safe, and not react with other formulation components.
2. During storage, the gelling ingredient in the preparation should provide an acceptable solid-like character that is easily broken when subjected to shear forces caused by shaking the bottle, squeezing the tube, or during topical application.
3. It should have appropriate antimicrobial action against microbial attack.
4. The topical gel should be non-sticky.
5. Swelling

When a gelling agent comes into contact with a liquid that solvates it, the agent absorbs a significant amount of the liquid and its volume rises. Swelling is the term for this process. This happens as the solvent enters the matrix. Gel solvent interactions take the role of gel-gel interactions. The amount of swelling is determined by the number of connections formed between individual gelling agent molecules and the strength of these bonds.

Many gels suddenly compress and release some fluid medium when left standing. This is known to as syneresis. As the concentration of gelling agent falls, the degree of syneresis increases. The presence of syneresis suggests that the initial gel was thermodynamically unstable. The contraction process has been linked to the release of elastic tension created during gel setting. As these tensions are eased, the available interstitial space for the solvent is reduced, driving the liquid out.

Slow spontaneous aggregation is common in colloidal systems. This is known as the ageing process. Ageing causes a denser network of the gelling ingredient to grow gradually in gels. Ageing causes a denser network of the gelling ingredient to grow gradually in gels.

According to this process is identical to the first gelling process and continues after the initial gelation since the fluid medium is lostfrom the freshly created gel.

The presence of a network generated by the interlinking of particles gelling agent causes the rigidity of a gel. The nature of the particles and the type of force responsible for the connections, which determines the network topology and gel characteristics. Individual hydrophilic colloid particles might be spherical or isometric collections of small molecules or single macromolecules.

Solutions containing gelling agents and flocculated solid dispersion are pseudo plastic, showing Non -Newtonian flow behavior defined by a decrease in viscosity with increasing shear rate. The fragile structure of inorganic particles scattered in water is disturbed by n gels, and ageing results in the eventual creation of a denser gelling agent network.

FUNGAL INFECTION

Mycoses are prevalent fungal infections, and a number of environmental and physiological circumstances can lead to the development of fungal illnesses. Inhalation of fungal spores or localized colonization on the skin can cause long-term infections; hence, mycoses frequently begin in the lungs or on the skin. Fungal infections of the skin were the fourth most frequent illness in 2010, affecting 984 million individuals. Individuals taking medications or with compromised immune systems are more likely to get fungal infections.¹ Fungi are eukaryotic organisms that can be unicellular or multicellular and can be found all over the planet. Fungi, like mushrooms, may be seen with the naked eye, as could yeast and moulds, which can be found in a variety of forms.  The illness caused by fungus kills about 1.5 million people and impacts billions more. Although it is still a neglected area for public health authorities, some deaths from fungus are still avoidable. Moderate fungal infection has been linked to health concerns such as cancer, organ transplantation, asthma, and corticosteroid use. Not all fungi are dangerous to humans, most do not cause any problems, and just a few are capable of causing disease under specific situations. Fungi cause infection by producing spores that can be collected directly, transmitted, or inhaled. Infectious disorders caused by fungus mostly affect the lungs, skin, and nails, but they can also penetrate the skin and harm organs, resulting in systemic infection. Fungal infections, often known as mycosis, are distinguished from most bacterial diseases. As a fungal infection that is chronic and kills the host on a regular basis, most intense mycoses necessitate a course of treatments that lasts a long period. Among both viral and bacterial diseases, fungal infections are seldom communicable, which leads to less interest in health monitoring, with the result that there is little information for fungal disease prevention and occurrence.¹⁰

ANTIFUNGAL DRUGS AVAILABLE IN GEL

These medications are used to treat mycoses. A topical or systemic treatment may be employed, depending on the type of the illness. Fluconazole, which is the basis of many over-the-counter antifungal medicines, is an example of an antifungal. Another example is amphotericin B, which is stronger and is used to treat the most severe fungal infections that have developed resistance to previous types of therapy. It is injected intravenously. Azole drugs, such as ketoconazole, itraconazole, and terbinafine, are used to treat skin infections. Candida albicans-caused vaginal yeast infections can be treated with medicated suppositories such as tioconazole and pessaries, whilst cutaneous yeast infections are treated with medicated ointments.¹¹

ANTIFUNGAL THERAPY DRUG DELIVERY VIA SKIN

The drug that will be delivered passively through the skin must be lipophilic and have a molecular weight of 500 Da. Only a few drugs achieve these percutaneous delivery requirements. The primary purpose of delivering such medications through the skin is to obtain improved systemic absorption or for local therapy. Although the intravenous approach avoids gastrointestinal side effects, it is invasive and cumbersome as compared to barrier layer-like topical preparations that have improved patient compliance and may be self-administered. After skin administration, antifungal medicines should achieve effective therapeutic levels in viable epidermis. Transdermal medicine distribution is most difficult because to stratum corneum and the various ways utilised to improve drug permeability. Various techniques are employed. Nano particulate carriers such as solid-lipid nanoparticles, nanostructured lipid carriers, vesicular carriers such as liposomes, ethosomes, niosomes, and transferosomes, and colloidal particulate carriers such as microemulsions, micelles, and Nanoemulsions are new carriers for antifungal transdermal administration.^{14, 15, 16}

PHYSIOCHEMICAL AND PHARMACOKINETIC PROPERTIES OF ANTIFUNGAL DRUGS

The physiochemical and pharmacokinetic properties of antifungal drugs and their inherent antifungal property determine their efficacy, so they are important issue for pre-development stage. Fluconazole is more polar than other azoles, slightly soluble in water (8 mg/ml). It is metabolically stable and low protein binding. Fluconazole is less active than ketoconazole in-vitro, its distribution throughout the body and high levels of free drug reached in blood contribute to its efficacy. Ketoconazole degrades by oxidation and hydrolysis and has poor water solubility. Fluconazole has a molecular weight of 306.3 Da and a pKa value of 3.7 (weak base), whereas ketoconazole has a molecular weight of 531.4 Da and pKa values of 6.51 and 2.94, making it a dibasic compound. Patients with impaired immune systems are also susceptible to oral infections caused by Candida species other than Candida albicans. Nystatin, an antimycotic medication from the polyene antifungal family, is used to treat or pharyngeal candidiasis. Nystatin causes leakage and permeability problems by binding to the sterols in cell membranes. It comes in ointment, powder, and cream form. It only works against candida.^{17, 18}

PREPARATION AVAILABLE IN MARKET¹⁹

These categories used to according its site of infection

These can be used to treat:

• Infections caused by dermatophytes such tinea corporis, tinea cruris, tineafaciei, tineamanuum, and tineapedis
• As an alternative to oral treatment for tinea barbae and tinea capitis.
• Yeast diseases like pityriasis versicolor and candida intertrigo.
• Infections of the nail plate and fungal skin conditions such tinea graeca.
• For two to four weeks, the creams are applied twice daily to the afflicted region, leaving a margin of several centimetres of healthy skin. Continue for one or two weeks following the disappearance of the final noticeable rash. Frequently, therapy must be repeated.

Example along with brand name

Additional antifungal medications available internationally include naftifine, the azoles bifonazole, tioconazole, sulconazole, efinaconazole, and luliconazole, as well as the benzoxaborole tavaborole.

In addition to being used to treat tinea capitis and scalp psoriasis, antifungal shampoos are mostly used to treat dandruff and seborrheic dermatitis.

Example along with brand name

To manage nail fold infections, a variety of antiseptic and antifungal medicines are available (paronychia). For several months, they should be used twice or three times every day.

Example along with brand name

It is capable of treating oral candidiasis with:

Example along with brand name

Vulvovaginal candidiasis can be treated with:

Example along with brand name

DRUG DELIVERY SYSTEM UNDER CURRENT DEVELOPMENT FOR IMPROVING TREATMENT OF FUNGAL DISEASES IN SKIN

The newest lipid nanoparticles, known as nanostructure lipid carriers (NLC), are gaining significant interest as cutting-edge topical colloidal drug carriers. To get around the restrictions SLN had, NLC were created. Solid lipids make up SLN, whereas liquid lipids (short chains) and properly mixed solid lipids (long chains) make up NLC, preferably in a ratio of 70:30 to 99.9:0.1. Although the resultant lipid particle matrix has a lower melting point than the initial solid lipid, it is still solid at body temperature. Limited drug loading capacity, drug ejection during storage, and relatively high water content in the dispersions (70-99.9%) are all often noted drawbacks of SLN. NLC have a greater drug-loading capacity than SLN for a variety of active compounds, and they prevent or reduce the possibility of active compounds being expelled during storage. Because liquid lipid is more soluble in a variety of medications than solid lipid is, drug loading is improved. Numerous characteristics of NLC are helpful for topical application. These carriers have minimal cytotoxicity and systemic toxicity due to their physiological and biodegradable lipid composition. Due to its solid lipid matrix and compact size, which ensures intimate contact with the stratum corneum, lipid particles can improve medication flow through the skin and allow for regulated release from carriers.

Figure 3: SLNs and NLCs.

1. Gelling Systems-polymeric Carriers
2. Nanosponges²¹

Targeting medication delivery systems has long been a goal in the effort to achieve desired results. Although the Nanosponge drug delivery method originally only had a surface use, it is now possible to inject Nanosponges orally as well as intravenously (IV).

A recent type of material known as a "nanosponge" is composed of tiny particles with a small, nanometer-wide cavity. Different kinds of materials can be used to fill these small cavities. These small particles have the potential to transport both hydrophilic and lipophilic medicinal substances which can boost the stability of molecules and drugs that are weakly water-soluble.

The nanosponges are a network or three-dimensional scaffold made of polyester that may break down organically. To create Nanosponges, these polyesters are dissolved in a solution together with a crosslinker. Here, the polyester degrades moderately in the body since it is typically biodegradable. When the nanosponges scaffold collapses, the drug molecules that were loaded are released in a damaging way.

Figure 4: Structure of a Nanosponge showing a cavity for drug.

Amphiphilic macromolecule-based self-assembly methods provide distinctive and unprecedented prospects for developing novel materials for cutting-edge applications in nanotechnology. Recent investigations have shown that the thermodynamic incompatibility between the various blocks results in a spatial organisation into ordered morphologies on the nanoscale with the generation of unique structural characteristics. The execution of extremely precise cellular tasks is possible in biosystems, where assemblies of various amphiphilic macromolecular components and their coordinated actions are leading examples. The essential characteristics of conventional, head/tail(s) type, amphiphiles, whose aggregation is fueled by soft contacts including hydrogen bonds and steric effects, as well as hydrophobic and electrostatic interaction. Steric influences, hydrophobic interaction, and electrostatic interaction. Additionally, we emphasise crucial instances where intricate processes, such as the modulation and regulation of morphology by other structure-directing interactions, might encourage expanded use in biological and pharmaceutical chemistry as well as materials research. The introduction of chirality, signal processing, and recognition processes are achieved by precisely tailoring chemical structures and the effective utilization of noncovalent forces. We conclude by providing insight into the unique structural characteristics.

Figure 5: Example of most common Nonionic (a), Anionic (b), Cationic (c), and Zwitterionic (d) Amphiphilic molecule.

Pharmaceutical semisolid dosage forms, especially emulgels, have drawn increased interest from academic and corporate researchers during the past ten years. For both systemic and local medication delivery, the skin is a crucial organ. Despite being a convenient method for drug delivery, certain medications may not permeate the skin. Simple solutions and ointments to multiphase nanotechnology-based treatments are all accessible as topical medicinal products. Topical medication delivery methods will be heavily utilised in the upcoming years to increase patient compliance. An emulsion and gel-based preparation is called emulgel. Oil-in-water (O/W) or water-in-oil (W/O) emulsions can be utilised, and both can be combined with a gelling agent to create an emulgel. These new formulations have been created recently for topical drug administration and have demonstrated their appropriateness for transporting hydrophobic medications. Additionally, it is anticipated that emulgel will emerge as a crucial method for incorporating hydrophobic pharmaceuticals into gel formulations. Emulgel functions as a dual-control medication release system because it combines the qualities of an emulsion and a gel. Many pharmaceutical companies have entered the commercial production of emulgels as a result of these advantages. These include the medications Diclofenac sodium (Voltaren Emulgel®), Miconaz-H (Miconazole Nitrate), Pernox® (Benzoyl Peroxide), and CLINAGEL® (Clindamycin phosphate).

Figure 6: Structure of Emulgels

1. Colloidal Carriers
2. Microemulsion

The term "micro emulsion" refers to a colloidal dispersion with a droplet diameter typically between 10 and 100 nm that is optically isotropic and thermodynamically stable. It is made up of an oil phase, an aqueous phase, a surfactant, and a co-surfactant in the proper proportions. The bioavailability of medications that are poorly soluble has been researched extensively in relation to microemulsions. In such circumstances, they provide a practical strategy. Microemulsions exhibit significant levels of absorption and penetration due to their extremely low surface tension and tiny droplet size. These adaptable carriers are becoming more popular, and in addition to the usual oral route, they are now being used in a variety of other administration methods as well. This can be ascribed to their distinctive solubilization capabilities and thermodynamic stability, which have attracted interest for their usage as new drug delivery systems.^{25, 26}

Microemulsions are superior to traditional emulsions, suspensions, and micellar solutions as well as the colloidal systems under research, and they might be used as alternative drug carriers. They are promising drug delivery systems that provide prolonged or regulated drug release for parenteral, topical, transdermal, ophthalmic, percutaneous, and oral medication administration. They have the benefits of spontaneous synthesis, simplicity in manufacturing and scaling up, thermodynamic stability, enhanced hydrophobic drug solubilization, and bioavailability. Additionally, inverted micellar structure microemulsions may be less comedogenic than creams or solutions. A quaternary system called a microemulsion consists of an oil phase, a water system, surfactants, and a cosurfactant. Specific physicochemical characteristics, including as transparency, optical isotropy, low viscosity, and thermodynamic stability, are present in these spontaneously generated systems. The greatest size of the dispersed phase droplets in these systems cannot be greater than 150 nm, which is one-fourth of the wavelength of visible light, which accounts for the transparency that has been seen in these systems. The name "micro emulsion" is deceptive because the droplet diameter in stable microemulsions is often in the range of 10-100 nm (100-1000 °A), indicating that these systems are truly nano-sized emulsions. Numerous investigations, largely in vitro but also some in vivo, have demonstrated that micro emulsion formulations have better transdermal and dermal distribution qualities. ²⁷

Figure 7: Microemulsion

Nanoemulsions, also referred to as submicron emulsions, ultrafine emulsions, and miniemulsions, are isotropic dispersions of two immiscible liquids, such as water and oil, stabilised by an interfacial film made of a suitable surfactant and co-surfactant to form a single phase. They are submicron sized colloidal particulate systems that are considered to be thermodynamically and kinetically Such nanoemulsions have been employed with a variety of surfactants, both ionic and non-ionic, with various properties. The most popular ones among them were cationic (quaternary ammonium halide), anionic (potassium laurate, sodium lauryl sulphate), nonionic (sorbitan esters, polysorbates), and zwitterions surfactants (quaternary ammonium halide). Early nanoemulsions were of the oil-in-water (O/W) type, with droplet sizes averaging between 50 and 1000 nm. More recently, nanoemulsions have been divided into three types: O/W type (oil is dispersed in the aqueous phase), water-in-oil (W/O) type (water is disseminated in the oil phase), and bi-continuous (water and oil microdomains are interdispersed within the system). By changing the components of the emulsions, it is possible to switch between these three forms. O/W and W/O emulsions coexist in one system concurrently in multiple emulsions, another form of nanoemulsion. Both hydrophilic and lipophilic surfactants are utilised simultaneously to stabilise these two emulsions. Comparing nanoemulsions to other dosage forms, some of these benefits include:

(1) Increased rate of absorption, 

(2) Decreased variability in absorption, 

(3) Protection from oxidation and hydrolysis in O/W nanoemulsions, 

(4) Delivery of lipophilic drugs after solubilization, 

(5) Aqueous dosage form for water-insoluble drugs, 

(6) Enhanced bioavailability for many drugs, 

(7) Ability to incorporate both lipophilic and hydrophilic drugs, 

(8) Delivery systems to enhance efficacy while reducing total dose,

(9) As safe, non-irritating delivery methods for skin and mucosal membranes,

(10) Drug permeation via a liquid film, whose hydrophilicity or lipophilicity as well as   thickness may be carefully regulated, to control drug release.

Figure 8: Nanoemulsion.

DIFFERENT TYPES OF POLYMERS USED TO PREPARE TOPICAL ANTIFUNGAL GEL:

These substances can also be employed as thickeners to improve the consistency of any dose form.

These are substances that enter the skin and interact with its components to enhance skin permeability temporarily and reversibly.

Emulsifying compounds are used to manage stability during a shelf life that can range from days for impromptu made emulsions to months or years for commercial preparations. They are also used to enhance emulsification at the time of creation.

Solvents are often made of purified water. Co-solvents, including alcohol, glycerol, PG, PEG 400, etc., can be employed to increase the therapeutic agent's solubility in the dosage form and/or to promote drug absorption through the skin.

Gels with aqueous and hydro alcoholic bases may use buffers to regulate the pH of the formulation. Buffer salt solubility is decreased in hydro alcoholic-based vehicles.

E.g., Phosphate, citrate, etc.

In order to reduce the concentration of free (antimicrobially active) preservative in the preparation, certain preservatives collaborate with the hydrophilic polymers used to make gels. Therefore, the initial concentration of these preservatives needs to be increased to make up for this.

EVALUATION OF GELS^{30, 31, 32}

The homogeneity of each generated gel was checked after it had been placed in the container using a visual inspection. They underwent inspections to check for aggregates and for outward signs of appearance.

All of the formulations were examined under a light microscope to determine whether any particles were present, but none were noticeable. Therefore, it is clear that the gel preparation satisfies the criteria for being free of specific materials and from grittiness as needed for any topical medication.

Digital pH meters were used to calculate the pH. 1g of gel should be dissolved in 100 ml of purified water and kept for two hours. Carry out the pH measurement in triplicate and determine the average readings.

100 ml of the suitable solvent were combined with 1g of the gel. Clean the stock solution. Then, using the appropriate dilutions, produce serial dilutions of various concentrations and measure the absorbance. The equation, which was obtained by a linear regression analysis of the calibration curve, was used to calculate the drug content.

A Brookfield Viscometer was used to measure the prepared gel's viscosity. Spindle number 64 was used to rotate the gels at 20 and 30 rpm. The corresponding dial reading for each speed was noted.

It shows the size of the region to which the gel spreads easily when applied to the affected area or skin. The spreading value affects the therapeutic effectiveness as well. Spreadability is measured as the amount of time, in seconds, it takes for two slides to separate from the gel that is sandwiched between them when a specific force is applied. Better spreadability is achieved with shorter gap times between two slides. The spreadability is calculated using the below formula.

Spreadability (S) = M × L / T

Where, 

M = weight tied to upper slide 

L = length of glass slides

T = time taken to separate the slides

The formulations are fill in the collapsible tubes, after it was set in the container. Extrudability is measured by the weight in gm required to extrude a 0.5 cm gel ribbon in 10 seconds.

For this test, albino mice of either sex weighing 20–22gms were used. The dorsal skin was used. Three days before to the trial, the mice's hair was removed. The animals were split into two batches, and then into two groups within each batch. The gel containing drug was used on test animal. As a control, a piece of cotton wool soaked in saturated medication solution was put on the back of albino mice. The animals were treated daily for seven days before being evaluated visually for erythema and edema.

The Malvern zeta sizer is used to choose globule size and course. The procedure includes dissolving a 1.0 gm test of gel game plan in refined water and vigorously stirring to get homogenous distributing. The resultant test diffusing is to be combined into the zeta sizer photocell.

In-vitro diffusion experiments of the produced gel were performed in a Keshary-Chien diffusion cell with a cellophane membrane. As the receptor compartment, one hundred millilitres of phosphate buffer were employed, and 500 mg of gel containing was evenly placed across the cellophane membrane. The donor compartment was kept in contact with the receptor compartment, and the temperature was kept at 37±0.5 0C. At specified time intervals, the solution on the receptor side was stirred by externally driven Teflon coated magnetic bars, and 5 ml of solution from the receptor compartment was pipette out and instantly replaced with fresh 5 ml phosphate buffer. The drug concentration in the receptor fluid was measured spectrophotometrically in comparison to an appropriate blank. The experiment was conducted out three times.

CONCLUSION

Gels are becoming incredibly common since they are more stable and can give controlled release than other semisolid preparations such as creams, ointments, pastes etc. The gel formulation may give improved absorption qualities, increasing the drug's bioavailability. A thorough investigation of the gel formulation stability qualities over a prolonged length of time may enable scope for its therapeutic usage in patients. Because the polymer is water soluble, it forms a water washable gel and has more potential for application as a topical medication delivery dosage form. The primary advantage of topical drug administration is that it allows for the development of high local drug concentrations inside the tissue and its surroundings for improved drug activity. This is especially useful when medicines with short biological half-lives and a limited therapeutic window are used. Clinical data indicates that topical gel is a safe and effective therapy option for the treatment of skin disorders.

CONFLICTS OF INTEREST

There are no conflicts of interest.

Acknowledgement

The author would like to thank all his mentors and our Principal, Dr V. V. P. Foundation's College of Pharmacy, Ahmednagar. The authors acknowledge the immense help they have received from researchers whose articles are cited and included in the references of this manuscript. The authors also thank the authors/editors/publishers of all articles, journals and books from which the literature for this article was reviewed and discussed.

REFERENCES:

1. Swarupanjali PA, Gauniya PS, Das PS and Rohit B, Evolutionary Aspect of Antifungal Topical Gel-A Review, 2018; 8(1):015-030.
2. Paye M, Barel AO And Maibach HI, Handbook of Cosmetic Science and Technology, 2005 (2^nd Edition). https://doi.org/10.1201/b14400
3. Bareggi SR, Pirola R, and De Benedittis G, Skin and Plasma Levels of Acetylsalicylic Acid: A Comparison between Topical Aspirin/Diethyl Ether Mixture and Oral Aspirin in Acute Herpes Zoster and Postherpetic Neuralgia, European Journal of Clinical Pharmacology, 1998; 54(3):231–235. https://doi.org/10.1007/s002280050451. 
4. Gisby J and Bryant J, Efficacy of A New Cream Formulation of Mupirocin: Comparison with Oral and Topical Agents In Experimental Skin Infections. Antimicrobial Agents and Chemotherapy, 2000; 44(2):255–260.  https://doi.org/10.1128/aac.44.2.255-260.2000. 
5. Salunkhe KN, Review On: Anti-Inflammatory Herbal Gel of Boswellia Serrata & Vitex Negundo, In International Journal of Pharmacy and Biological Sciences, 2013; 23(2):374-382.
6. Verma A, Singh S, Kaur R, Upendra KJ, Topical Gels as Drug Delivery Systems: A Review, International Journal of Pharmaceutical Sciences Review and Research, 2013; 23(2):374-382.
7. Ansel HC, Popovich NG, Loyd VA, Pharmaceutical Dosage Forms and Drug Delivery Systems, 9, B. I. Publications, New Delhi, 2005, 407-408.
8. Carter SJ, Disperse System In: Cooper and Gunn’s Tutorial Pharmacy, 6, CBS Publishers And Distributors, New Delhi, 2000, 68-72.
9. Lieberman HA, Rieger MM, Banker GS, Pharmaceutical Dosage Form: Disperse System, 2, Marcel Dekker, 2005, 399-421.
10. Saeeda W,Singh S, Sharique A, Fungal Diseases of Gynecological Aspect: A Review, Scholars International Journal of Obstetrics And Gynecology,2021; 4(9):360- 368. https://doi.org/10.36348/sijog.2021.v04i09.005.
11. Hay RJ, Johns NE, Williams HC, Bolliger IW, Dellavalle RP, Margolis DJ, Marks R, Naldi L, Weinstock MA, Wulf SK, Michaud CJ, Murray CV and Naghavi M. The Global Burden of Skin Disease In 2010: An Analysis of The Prevalence and Impact of Skin Conditions. Journal of Investigative Dermatology, 2014; 134(6):1527–1534.https://doi.org/10.1038/jid.2013.446. 
12. Article R, Glujoy M, Salerno C, Bregni C, Carlucci AM, Percutaneous Drug Delivery Systems for Improving Antifungal Therapy Effectiveness: A Review, International Journal of Pharmacy and Pharmaceutical Sciences, 2014; 6(6): 8-16.
13. Neubert AS, Reinhard HH, Potentials of New Nanocarriers for Dermal and Transdermal Drug Delivery, European Journal of Pharmaceutics and Biopharmaceutics, 2011; 77(1):1–2.https://doi.org/10.1016/j.ejpb.2010.11.003. 
14. Benson H, Elastic Liposomes for Topical and Transdermal Drug Delivery, Current Drug Delivery, 2012; 6(3):217–226. https://doi.org/10.2174/156720109788680813. 
15. Millikan LE, Current Concepts in Systemic and Topical Therapy for Superficial Mycoses. Clinics In Dermatology, 2010; 28(2):212–216. https://doi.org/10.1016/j.clindermatol.2009.12.016.  
16. King CT, Rogers P, David C, John D. And Chapman SW, Antifungal Therapy During Pregnancy Clinical Infectious Diseases , An Official Publication of The Infectious Diseases Society of America, 1998; 27(5):1151–1160. https://doi.org/10.1086/514977. 
17. Patel DD, Sandipan DS, Roja RY, Ray S and Mazumder B, Nanostructured Lipid Carriers (NLC)-Based Gel for The Topical Delivery of Aceclofenac: Preparation, Characterization, And In-vivo Evaluation, Scientia Pharmaceutica, 2012; 80(3):749.https://doi.org/10.3797/scipharm.1202-12. 
18. Bhowmik HG, Venkatesh D, Nagasamy K, Anuttam K, Kammari HH, Nanosponges: A Review, International Journal of Applied Pharmaceutics, 2018; 10(4):1–5. https://doi.org/10.22159/ijap.2018v10i4.25026.  
19. Hiremath SN, Godge GR, Sonawale BG, Shirsath RA, Pharmaceutical Advances In Cyclodextrin Inclusion Complexes For Improved Bioavailability Of Poorly-Soluble Drugs, International Journal of Pharmaceutical Sciences and Nanotechnology, 2015; 8(3):2894-2905. https://doi.org/10.37285/ijpsn.2015.8.3.2
20. Glotzer SC, Solomon MJ, Anisotropy of Building Blocks and Their Assembly Into Complex Structures, Nature Materials, 2007; 6(8):557–562. https://doi.org/10.1038/nmat1949.
21. Sriaandhal SL, Malitha AS, A Review on Emerging Applications of Emulgel As Topical Drug Delivery System, World Journal of Advanced Research and Reviews, 2022; 13(01):452–463. https://doi.org/10.30574/wjarr.2022.13.1.0048. 
22. Kovarik JM., Mueller EA, Van B, Johannes B, Tetzloff W,and Kutz K, Reduced Inter- and Intraindividual Variability in Cyclosporine Pharmacokinetics from A Microemulsion Formulation, Journal Of Pharmaceutical Sciences, 1994; 83(3):444–446. https://doi.org/10.1002/jps.2600830336.
23. Noble S, Markham A, Cyclosporin. A Review of The Pharmacokinetic Properties, Clinical Efficacy and Tolerability of a Microemulsion-Based Formulation (Neoral), Drugs, 1995; 50(5):924–941. https://doi.org/10.2165/00003495-199550050-00009. 
24. Sahu Gk, Sharma H, Gupta A and Kaur CD, Advancements In Microemulsion Based Drug Delivery Systems for Better Therapeutic Effects, International Journal of Pharmaceutical Sciences and Developmental Research, 2015;1(1):008–015. https://www.academia.edu/16902327/advancements_in_microemulsion_based_drug_delivery_systems_for_better_therapeutic_effects https://doi.org/10.17352/ijpsdr.000003
25. Gurpreet K And Singh SK, Review Of Nanoemulsion Formulation and Characterization Techniques, Indian Journal of Pharmaceutical Sciences, 2018;80(5):781–789. https://doi.org/10.4172/pharmaceutical-sciences.1000422.  
26. Yadav SK, Mishra MK, Tiwari A, and Shukla A, Emulgel: A New Approach for Enhanced Topical Drug Delivery, International Journal of Current Pharmaceutical Research, 2016; 9(1):15.  https://doi.org/10.22159/ijcpr.2017v9i1.16628. 
27. Hemendrasinh JR,Dhruti PM, A Review on Pharmaceutical Gel, International Journal of Pharmaceutical Sciences, 2015; 1(1):33-47.
28. Kaur L, Preet, Garg R, Gupta GD, Topical Gels: A Review, Research Journal of Pharmacy and Technology, 2010; 3(1):17-24.
29. Sanap D, Garje M, Godge G, Probiotics, their Health Benefits and Applications for development of Human Health: A Review, Journal of Drug Delivery and Therapeutics. 2019; 9(4-s):631-640.
30. Hiremath S, Godge G, Sonawale B and Shirsath R, Pharmaceutical Advances In Cyclodextrin Inclusion Complexes For Improved Bioavailability Of Poorly-Soluble Drugs, International Journal of Pharmaceutical Sciences and Nanotechnology, 2015; 8(3):2894-2905. https://doi.org/10.37285/ijpsn.2015.8.3.2
31. Godge GR, Garje MA, Dode AB, Tarkase KN. Nanosuspension Technology for Delivery of   Poorly Soluble Drugs and Its Applications: A Review, Int. J. Pharm. Sci. Nanotech, 2020; 13(4):4965-4978. https://doi.org/10.37285/ijpsn.2020.13.4.1
32. Godge GR, and Hiremath SN, An Investigation into the Characteristics of Natural Polysaccharide: Polymer Metoprolol Succinate Tablets for Colonic Drug Delivery, Mahidol University Journal of Pharmaceutical Sciences, 2014; 41(2):7-21.