INTRODUCTION:

Topical drug delivery system is generally used in where other systems of drug administration fail or it is mainly used in local skin infection like fungal infection.

Topical drug delivery can be defined as the application of a drug containing formulation to the skin to directly treat cutaneous disorder. A unique feature of topical drug delivery is the direct accessibility of the skin as a target organ on human body for diagnosis and treatment. Topical preparation was used for the localized effect at the site of their application by virtue of drug penetration in to the underlying layer of skin or mucous membrane.

Nowadays scenario pharmaceutical researches work is focused to fulfil the therapeutic needs of patients and the attention on pharmaceutical researches gradually shifting to the development of drug delivery systems rather than finding newer chemical entities for an around improve drug therapy.

Novel drug delivery systems are designed to achieve a continuous delivery of drugs at predictable and reproducible kinetics over an extended period of time in the circulation. The potential advantages of this concept include minimization of drug related side effects due to controlled therapeutic blood levels instead of oscillating blood levels, improved patient compliance due to reduced frequency of dosing and the reduction of the total dose of drug administered.

Advantages⁶

· Avoidance of first pass metabolism.

· Simple and easy to apply.

· Avoids drug deactivation by liver enzymes and first –pass metabolism.

· Ability to easily terminate the medications, when needed.

· Targeted the drug to a specific site.

· Avoidance of gastrointestinal inconsistency.

· Providing use of drugs with short biological half-life and narrow therapeutic window.

· Enhance patient compliance.

· Provide suitability for self-medication.

Drawbacks⁷

· Chance to occur allergenic reaction.

· Skin irritation may occur because of drugs and excipients interaction.

· Enzyme in epidermis may denature the drugs.

Factors Affecting Topical Absorption of Drug⁸

· Skin thickness

· Lipid content

· Density of hair follicles

· Density of sweat glands

· Skin pH

· Blood flow

· Hydration of skin

· Inflammation of skin

Anatomy of Human Skin⁹

The human skin is the outer covering of the body and is the largest organ of the integumentary system. The skin has up to seven layers of ectodermal tissue and guards the underlying muscles, bones, ligaments and internal organs. Human skin is similar to most of the other mammals' skin, and it is very similar to pig skin. Though nearly all human skin is covered with hair follicles, it can appear hairless. There are two general types of skin, hairy and glabrous skin (hairless). The adjective cutaneous literally means "of the skin" (from Latin cutis, skin).

Routes of Drug Administration through Skin

Introduction to microemulsion¹⁰

The term microemulsion was first introduced by Schulman et al. Their droplet size varies from 100 Å to 100 nm. Microemulsions generally contain both a surfactant and co-surfactant that induce spontaneous formation of the system. Microemulsions are often transparent to the eye with low viscosity and are thermodynamically stable. This stability is due to their very low interfacial tension (enthalpy), typically [10-1 to 10-2] mN/m 33, and small droplet size (entropy).

Advantages of microemulsion¹¹

Advantages:

a. Thermodynamically steadiness and require minimum energy for formation.

b. Compatibility in manufacturing.

c. Improved drug solubilization and improved bioavailability.

d. Micro emulsion are having extensive applications in colloidal drug delivery systems for the purpose of drug targeting and controlled release.

Disadvantages of microemulsion ¹²

Disadvantage of Microemulsions

1. The main problem in a microemulsions application is a high concentration and a narrow range of physiologically acceptable surfactants and cosurfactants.

2. It has limit potential topical application due to their toxic and irritant properties of component.

3. Large surfactant concentration (10-40%) determines their stability.

4. It is poor palatability due to the lipid content leading to the poor patient compliance. Moreover, due to their water content, Microemulsions cannot be encapsulated in soft gelatin or hard gelatin capsules.

Limitations:

· The concentration of surfactants and co-surfactants used must be kept low for toxicological reasons.

· Suffers from limitations of phase separation.

· For intravenous use, the demand of toxicity on the formulation is rigorous and very few studies have been reported so far.

Characterization of Microemulsion:¹³

The systems is observed for visual clarity and flow. The MEs is placed between two polarized plates (Cross polarized light microscopy) in series and is then observed for light transmittance. After this, one of the plates is rotated relative to the other through 90^o and is examined. ME systems are subjected to centrifugation at 4000rpm for 30 minutes and then are examined for any phase separation.

Introduction to Gel¹⁴

The term ‘GEL’ represents a physical state with properties intermediate between those of solids and liquids. Gels are defined as semisolid system consisting of dispersion made up of either small inorganic particle or large organic particle enclosing or inter penetrated by liquid.A gel consists of a polymer which swells in the presence of fluid perhaps within its structure. Gels are either translucent or transparent semisolid formulations which containing the solubilised ingredients.

Structure of Gel

These systems form a 3-D, polymeric matrix in which a high degree of physical resticulation has been comprised. In gel structure individual particles of hydrophilic colloid may consist of either spherical or an isometric aggregate of small molecules, or single macromolecules. These possible arrangements of such particles in a gel network. Gel formulation provides faster drug release and stability in compared with conventional cream and ointment. Topical gels are intended for skin application for local action or penetration of medicament or for their emollient or for protective action.

Ideal properties of microemulsion based gel:¹⁵

1. Should be inert, compatible with other additives

2. Should be free from microbial contamination

3. Should be non-toxic

4. Should be economical

5. Should be maintained all rheological properties of the gel

6. Should be washed with water and free from staining nature

7. Should be convenient in handling and its application

8. Should be stable at storage condition

Advantages of Topical Gel¹⁶

· Avoid gastrointestinal drug absorption difficulties caused by gastrointestinal pH and enzymatic activity.

· To avoid the first pass effect that is the initial pass of the drug substance through the systemic and partial circulation following gastrointestinal absorption.

· Avoiding the deactivation by digestive and liver enzymes.

· They are less greasy in nature and can be easily removed from the skin.

· Cost effective

· Reduction of dose as compare to the oral dosage form.

· Localized effect with minimum side effects.

Limitations of Gel¹⁷

· Poor permeability of some drugs through the skin.

· Difficult in delivery of hydrophobic drug.

· Enzyme in epidermis may denature the drugs.

Introduction of Emulgel as A Topical Drug Delivery System¹⁸

As the name suggest they are the combination of emulsion and gel. Emulgel is the one of the recent technologies in NDDS used for Dual action of emulsion and gel for topical drug delivery system. Emulgel is emulsions, either of the oil-in-water or water-in-oil type, which are gelled by mixing with a gelling agent. Emulgel is one such a unique feature of topical system for drug makes the localized administration and direct acceptability of the drug anywhere in the body through ophthalmic, vaginal, skin & rectal routes. The main objective behind emulgel is delivery of hydro phobic drug via skin so that hydrophobic moiety can enjoy the unique properties of gels. The clinical evidence indicates that topical emulgel is a safe and effective treatment.

Types of Emulgels¹⁹

A. Macroemulsions gel:

Most common type of emulgels where the particle size of droplets of emulsion is more than 400nm. They are visually opaque but the individual droplets can be easily observed under microscope. Macroemulsion are thermodynamically unstable, but can be stabilized using surface active agents.

B. Microemulsion gel:

Microemulsions are transparent and thermodynamically stable as their droplet size range from 10 to 100nm and they do not coalesce. Microemulsions are composed of oil, surfactant, co surfactant and water in specific proportions. The ingredients of microemulsion could facilitate the permeation rate of the drug by reducing the diffusion barrier of the stratum corneum. Microemulsion has low viscosity so it’s overcome by incorporate in gel for forming microemulsion based gel.

Formulation Considerations:

Challenges in formulating topical emulgels are:

· Determining systems that are non-toxic, non-irritating, non-comedogenic and no sensitizing.

· Formulating cosmetically elegant emulgel.

· The emulgel have low allergic potential, good physiological compatibility and high biocompatibility.

Advantages of Emulgel¹⁹

· Hydrophobic drug can be easily incorporated into gel using o/w emulsion.

· Control released.

· Better drug loading capacity.

· Production feasibility and low preparation cost

· Increases the stability of formulation.

· Increases contact time and mean residence time of the drug.

· Dual release of drug from emulsion and gel.

· Emulgels used even for cosmetic purposes.

Preparation of Microemulgel

A weighed amount of polymer is soaked in the microemulsion system, stirred to disperse the polymer in the ME and left overnight for gelling. To this the required quantity of triethanolamine is added for neutralizing the carboxylic acid groups in carbopol. Then the measured quantity of dimethlyformamide/benzyl alcohol is added.¹³

Drug Release Mechanisms:

A number of mechanisms have been anticipated to explain the microemulsion based emulgel for topical delivery of drugs:

· Dermally applied microemulsion is expected to penetrate the stratum corneum and to exist intact in the whole horny layer, alter both lipid and polar pathways. The drug dissolved in the lipid domain of the microemulsion can directly penetrate the lipid of the stratum corneum, thereby destabilising its bilayer structure. These interactions will increase the lipid pathway permeability to drugs.

· Ingredients of microemulsion may reduce the diffusion barrier of stratum corneum and increase the permeation rate of drug via skin by acting as permeation enhancers.

· The hydration effects of microemulsion on the stratum corneum may influence the permeation ability of formulations.

Characterization of Emulgel ^20-27

· Physical appearance

· Viscosity:

The viscosity of a formulation is used to determine its rheological properties. Brookfield Viscometer The viscosity is measured using the rotational r form.

· pH measurement:

The pH is calculated using a digital pH metre, the measurements are duplicated seven times, and the average of the results is used. The pH of the Micro-emulsion must also be measured because changes in pH will affect the zeta potential and, as a result, the product's stability.

· Spreadability measurement:

To test its Spreadability of a micro-emulsion-based emulgel, 0.5 g of emulgel is put in a 1 cm diameter circle pre-marked on a glass plate, which is then placed on a second plate. For 5 minutes, a weight of 500 g is allowed to rest on the upper glass plate. The emulgel causes the diameter to increase, and the spreading is noticeable.

· Rheological study:

A Brookfield viscometer is used to calculate the main viscosity at 37°C.

· Drug content determination:

The amount of drug is determined using a UV visible spectroscopic process.

· Flux and permeability Co-efficient study

· Extrudability test: -

It's a common empirical test to determine how much force is needed to extrude material from a tube. The method used to assess the extrudability of microemulsion-based emulgel formulations is based on the percentage of gel and gel extruded from an aluminium collapsible tube, as well as the weight in grammes needed to extrude at least a 0.5 cm ribbon of emulgel in 10 seconds. The more quantity extruded better the quality.

· Homogeneity and grittiness

· In vitro diffusion study:

The drug release experiments are conducted using a Franz diffusion cell (effective diffusion area 3.14 cm2 and cell volume 15.5 mL). Microemulgel (1 g) is uniformly distributed to the egg membrane's surface. Between the donor and the receptor chamber of the diffusion cell, the egg membrane is clamped. A freshly formulated phosphate buffer solution is poured into the receptor chamber (pH 6.8). The samples are taken at appropriate intervals. After sufficient dilutions, samples are analysed for drug content using a UV visible spectrophotometer at max (nm). The amount of drug released cumulatively through the egg membrane is calculated as a function of time.

· Drug release kinetic study

· Skin irritation study:

In the formulation, 0.5g of each is uniformly distributed over a 4 cm2 region on the hairless skin of rabbits. After 24, 48, and 72 hours of application of the formulation, the skin surface is examined for any visible changes such as erythema (redness). Depending on the degree of erythema, the following mean erythemal scores are recorded: No erythema=0, mild erythema=1, moderate erythema (dark pink) =2, moderate to severe erythema (light red) =3, and severe erythema (extreme redness) =4.

· Accelerated Stability study:

Samples of drug-loaded microemulgel formulations are sealed in ampoules and stored in stability chambers for two months at various temperatures, including room temperature [(25)°C, 60% relative humidity] and accelerated temperature [(40)°C, 75% relative humidity]. At the 0th, 1st, and 2nd month, duplicate samples are taken to assess their physical and chemical stability. Visual monitoring for physical changes such as phase separation and drug precipitation is used to assess physical stability. Chemical stability is defined as the amount of drug detected using a UV visible spectroscopic method at a maximum concentration (nm).

Centrifuge test: Samples were applied to 9000 rpm for 20 min and assessed for phase separation.

· Syneresis measurement test:

When the gel system is left to stand for a while, it shrinks slightly and a small amount of liquid is pressed out. Syneresis is the term for this phenomenon. Microemulgel is placed in a cylindrical plastic tube with a perforated bottom that is coated with filter paper for this examination (Whatman No. 41). After that, the tubes are put in centrifuge tubes and spun for 15 minutes. Weigh the cylindrical plastic tube and the liquid that had separated from the microemulgel. The liquid removed from the microemulgel is weighed. The percentage of syneresis is determined by multiplying the weight of liquid removed from the microemulgel by the total weight of the microemulgel before centrifugation. The information was presented as a five-point average.

· Swelling index

Ideal Properties of Drug Candidate to Formulate as Emulgel:²⁸

· Drug dose should be low i.e., less than 10mg.

· Molecular weight of drug should be 400 Dalton or less.

· Partition coefficient i.e., Log p (Octanol-water) between 0.4-0.8.

· Half life of drug 10 hr or less.

· Oral bioavailability and therapeutic index should be low.

· Drug should be non irritating and non-sensitizer having a less polarity.

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Received on 27.04.2021 Modified on 22.11.2021

Res. J. Pharma. Dosage Forms and Tech.2022; 14(2):171-176.

DOI: 10.52711/0975-4377.2022.00027