INTRODUCTION:

The topical/transdermal (TT) delivery route for drug administration has many advantages over other pathways including avoiding the hepatic first pass effect, continuous drug delivery, fewer side effects and improved patient compliance¹. Topical drug products are intended for external use. They are intended for localization action on one or more layers of the skin (e.g., sun screens, keratolytic agents, local anesthetics, antiseptic and anti-inflammatory). Although some medication from these topical products may unintentionally reach systemic circulation, It is usually in subtherapeutic concentrations and does not produce effects of any major concern except possibly in special situations, such as pregnant or nursing patient².

1.1 Drug absorption from topical formulations³:

In topical applications the total quantity of active ingredient absorbed varies greatly based on many factors including application area size, the frequency and vigor of application and the viscosity or thickness of the applied vehicle. Other factors influencing drug absorption are application site, age and condition of the skin. Non-keratinized dermis is more easily penetrated by an active ingredient. In the optimum topical formulations, the drug diffusion through skin is controlled by ensuring that the drug is just soluble enough in the vehicle to encourage drug release at the desired rate. This is achieved by ensuring that the entire drug is in solution.

In addition, the vehicle components should increase the penetrability of the stratum corneum.Several considerations important in formulating topical preparations are:

i. stability of the active ingredient

ii. stability of the adjuvant

iii. visual appearance

iv. color

v. odor

vi. viscosity, extrudability, spreadability

vii. loss of water and other volatile vehicle components

viii. particle size distribution of dispersed phase

ix. pH

x. texture, feel upon application (stiffness, grittiness, greasiness, tackiness)

xi. microbial contamination

^xii.release/bioavailability

1.1.1 Topical vehicles⁴

In general, topical vehicles do not penetrate the skin and merely hold the active ingredient in place on the skin to enable drug absorption. The vehicle should be carefully selected, as it can influence the absorption of the drug through skin. The most critical factor to consider when selecting a topical delivery vehicle is the activity of the drug in that vehicle. For instance, the pH of the vehicle may be important if the drug is weakly acidic or weakly basic, as weakly acidic drugs have higher activity in the acidic vehicles and weakly basic drugs have higher activity in basic vehicles. In addition, the solubility of drug in the vehicle must be considered, as drug will diffuse out of a vehicle in which they are less soluble at faster rate than one in which they are highly soluble. A further factor to consider is the possibility of complexes forming between the active ingredient and the vehicle. Complexing may lower the activity coefficient, reducing drug diffusion.

1.1.2 Design of topical drug products⁵

Dermatological products applied to the skin are diverse in formulation and range in consistency from liquids to solid powder, but the most popular products are semisolid preparation.

Topical liquids: topical liquids include aqueous solution, hydroalcoholic solutions or tinctures (iodine tincture), organic solvent based collodions (salicylic acid collodion) etc.

Solid powders: Medicated and non-medicated powders are generally sprinkled o absorb skin over the skin for antisepsis or to absorb skin secretions.

Semisolid preparations include:

Ointments: Ointment form is mainly used for those products that have translucent appearance. Traditional ointment bases have been oleaginous in nature. These include, hydrocarbons (petrolatum, beeswax) or vegetable oils.

Creams: Creams are emulsions of oleaginous substance(s) and water and spread more easily over the skin than ointment. Oil-in water (o/w) type creams are easily water-washable, while the water-in-oil (w/o) ones are not. Cold cream and hydrous lanolin are w/o emulsions that can absorb limited amounts of water. The o/w emulsions bases, such as Dermabase^®, Unibase^® can absorb some water, but the consistency begins to thin as water is incorporated into the continuous phase of the emulsion.

Gels: Gels are relatively newer classes of dosage forms created by entrapment of large amount of aqueous or hydroalchoholic liquid in a network of colloidal solid particles. Gel formulation generally provides faster drug release compared with ointments and creams. These are superior in term of use and patient acceptability.

1.1.3 The rationale for gels versus patches⁶

To a very large extent, when the pharmaceutical industry must deliver drugs through the skin, it has shown a distinct preference for transdermal patches, rather than gels. However, patch design demand that all the medication contained within the device is delivered though a very limited area of skin. Delivery of such concentrated quantities of medication across a few square centimeters of skin can prove highly irritating to many individuals especially those who are sensitive to adhesives. This can traumatize the skin of sensitive individuals and the elderly. Patches also present a challenge to medicating elderly with altered mentation. Most patches must be kept in place for hours or even days, patients with psychiatric disorders frequently rip them off. Most patches depend upon a concentration gradient of drug within the matrix or reservoir to drive active drug through skin. As a result, a high percentage of the dose can remain when delivery slows or stops. Disposal of such patches can prove a real problem in institutional setting, especially if the undelivered drug is a narcotic. Finally, patches are costlier and require many steps for its development in comparison to gels. Therefore, the solution of many patch-related challenges in absorption-enhanced gels.

1.1.4 Transdermal versus topical⁷

For transdermal products, the goal of design is to maximize the flux through the skin into the systemic circulation and simultaneously minimize the retention and metabolism of the drug in the skin. In contrast, topical products are developed to minimize the flux of the drug through the skin while maximizing its retention in the skin. However for both transdermal and topical products drugs must penetrate across the stratum corneum, the outer most layer of the skin. Transdermal delivery involves the application of a drug to treat systemic disease and is aimed at achieving systemically active levels of drugs. Here, the percutaneous absorption with appreciable systemic drug delivery is absolutely essential. While ideally, there would be no local build up of drug, which is forced through the relatively small diffusional window, defined by contact area of patch. Topical delivery can be defined as the application of drug containing formulation to the skin to directly treat cutaneous disorders or the cutaneous manifestation of general disease, with the intent of confining the pharmacological or other effect of the drug to the surface of the skin or within the skin. Topical activities may or may not require intra-cutaneous penetration and deposition.

1.2 Topical Gels

The term ‘Gel’ was introduced in the late 1800 to name some semisolid material according to their physiological characteristics rather than molecular composition.

Gels are semisolid systems in which a liquid phase is constrained within a three dimensional polymeric matrix of natural or synthetic gums in which a high degree of physical or chemical cross linking has been established⁸.

Most topical gels are prepared with organic polymers, such as carbomers, that impart an aesthetically pleasing, clear, sparkling appearance to the products and are easily washed off from the skin with water. The type of base used in formulating a topical dermatological product greatly influences its effectiveness. Bases containing large amounts of oleaginous substances provide an emollient effect to dry irritated skin. More importantly, bases made up of non-volatile oleaginous substances (e.g. hydrocarbon bases) can form an occlusive barrier on the skin that prevents escape of moisture from the skin into the environment. As a result, moisture accumulates between the skin and the ointment layer that cause hydration of the stratum corneum. Hydration of stratum corneum all ‘opening up’ of intra and inter-cellular channels and pathway for easier passage of drug molecules. Additionally, the moisture layer provides a medium for dissolution of the drug that is otherwise dispersed as fine particles in the ointment base. Since only the dissolved drug presented to the skin, as an individual molecular entity is able to enter the stratum corneum, skin occlusion generally results in enhanced percutaneous drug absorption⁹.

Gels are the semi-rigid systems in which the movement of the dispersing medium is restricted by interlacing of three-dimensional network of the particles or solvated macromolecules of the dispersed phase. The increased viscosity caused by the interlacing and consequential internal function is responsible for the semi-solid state. When dispersed in an appropriate solvent, gelling agents merge or entangle to form a three dimensional colloidal network structures. This network structure is also responsible for a gels resistance to deformation and therefore its viscoelastic properties. The elasticity of certain gels may be due to the presence of double helix structure, similar to a water uptake capacity and to the rheological profile of each polymer tested¹⁰.

Integrity of the gel is determined by the nature of the polymer solvent affinity. Classical gel theory distinguishes between three categories of solvent:

i. free solvent that is very mobile.

ii. solvent bound as a salvation layer, usually through hydrogen bonding and

iii. solvent entrapped within the network structure.

The ratios of the three solvent types in a given gels are dependent on the polymer concentration and the solvent affinity for the polymer governs the extension of the random coil. The greater the solvent affinity, the more the coils expand and entangles with adjacent coils to form crosslinks¹¹.

Additionally, the moisture layer provides a medium for dissolution of the drug that is otherwise dispersed as fine particles in the ointment base. Since only the dissolved drug presented to the skin, as an individual molecular entity is able to enter the stratum corneum, skin occlusion generally results in enhanced percutaneous drug absorption^{11, 12}.

1.2.1. Classification of Topical Gels^12-16

A. On The Basis of the Nature of Colloidal Phase

i. Inorganic hydrogels are usually biphasic system such as aluminium hydroxide gels and bentonite magma. Bentonite magma has also been used as an ointment base in about 10-25 % concentrations.

ii. Organic gels are usually single-phase systems and may include such gelling agents as carbomer and tragacanth and those that contain an organic liquid such as Plastibase.

B. On the Basis of Solvent System

I. Hydrogels include the ingredients that are dispersible as colloids or are soluble in water and these include organic, hydrogels, natural and synthetic gums and inorganic hydrogels. Examples are hydrophilic colloids such as silica, bentonite, tragacanth, pectin, sodium alginate, methylcellulose, sodium CMC and alumina, which in high concentration, form semisolid gels. Applications of Hydrogels are given in Table 1.

II. Organogels include the hydrocarbon, animal/vegetable fats, soap base greases and the hydrophilic organogels. Included in the hydrocarbon type is Jelene, a Plastibase, a combination of mineral oils and heavy hydrocarbon waxes with a molecular weight of about 1300.

C. On the Basis of Gel Microstructure

Pharmaceutical gels may be categorized on the basis of their network microstructure by the scheme suggested by Flory.

1. Covalently Bonded Structures

Covalently cross-linked gels network are irreversible systems, which are prepared from synthetic hydrophilic polymer(s). In one of the methods of preparation, infinite gel networks arise from the nonlinear co-polymerization of two or more monomer species with the one being at least trifunctional. Both direction and position, by which each polymer chain grows during the reaction is random, resulting in final microstructure of this gel being completely disordered.

2. Physically Bonded Structure

Physically bonded gel networks are reversible systems. Factors such as temperature and ion additions can induce a transition between the sol and gel phases. These gels are primarily formed using natural organic polymers (protein and polysaccharides) and semi-synthetic cellulose derivatives. Polymer chains exist most often in the sol as random coil, which undergo conformational transition to gel. Such transition may involve large ordered sections of one or more chain, which fold into a single, double or triple helix.

3. Well-Ordered Gel Structure

Under suitable conditions, certain silica, alumina and clay sols form rigid gels or lyogels. When clay belonging to smectite class, such as bentonite, hectorite and loponite, come into contact with water, they undergo interlayer swelling spontaneously followed by osmotic swelling to produce a gel. The plate like clay particles associated into a “cubic cardhouse” ordered structure, which is stabilized by repulsive forces caused by interacting electrical double layer.

1.2.2. Gel Forming Substances¹⁷

Polymers are used to give the structural network, which is essential for the preparation of gels. Gel forming polymers are classified as follows:

1. Natural Polymer

a. Proteins- Collagen, Gelatin

b. Polysaccharides-Agar, Alginic acid, Sodium or Potassium carrageenan, Tragacanth, Pectin, Guar Gum, Cassia tora, Xanthin, Gellum Gum

2. Semisynthetic Polymers

Cellulose derivatives- Carboxymethyl cellulose, Methylcellulose, Hydroxypropyl cellulose, Hydroxypropyl methyl cellulose, Hydroxyethyl cellulose

3. Synthetic Polymers

Carbomer (Carbopol -940, Carbopol -934, Carbopol -941), Poloxamer, Polyacrylamide, Polyvinyl alcohol, Polyethylene and its co-polymers

4. Inorganic Substances

Aluminium hydroxide, Bentonite

5. Surfactants

Cetostearyl alcohol, Brij – 96

1.2.3. Advantages

The topical administration of drug in order to achieve optimal cutaneous and percutaneous drug delivery has recently gained an importance because of various advantages :

i. To avoid gastrointestinal drug absorption difficulties caused by gastrointestinal pH and enzymatic activity and drug interaction with food and drinks.

ii. To avoid the first pass effect, that is, the initial pass of drug substance through the systemic and portal circulation following gastrointestinal absorption, possibly avoiding the deactivation by digestive and liver enzymes.

iii. Non-invasive and have patient compliance.

iv. Less greasy and can be easily removed from the skin.

v. Economic.

vi. Reduction of doses as compare to oral dosage forms.

vii. Localized effect with minimum side effects.

1.2.4. Disadvantages

i. The entire drug is not suitable for such delivery system because of wide diversity of solubility in vehicle component and vast ranges of cutaneous fluxes.

ii. Limitation of this delivery route to a small drug population due to barrier properties of the skin and dose size.

iii. Various factors affecting the skin, such as age and physical condition, can change the reliability of the system’s ability to deliver medication.

1.2.5. Desirable Properties of Gels

i. It should be inert, compatible with other additives and non-toxic.

ii. It should be stable at storage condition.

iii. It should be free from microbial contamination.

iv. It should maintain all rheological properties of gel.

v. Economical.

vi. It should be washable with water and free from staining nature.

vii. It should not affect biological nature of drug.

viii. It should be convenient in handling and its application.

ix. It should possess properties such as thixotropic, greaseless, emollient, non-staining etc.

1.2.6. Desirable Properties of Gellants

i. It should be inert, compatible with addition and non-toxic.

ii. It should produce gels at low concentration.

iii. It should help gel formation.

iv. It should be economical.

v. It should be free from microbial contamination.

1.3 Principles of Topical Permeation¹⁸

Before a topically applied drug can act either locally or systemically, it must penetrate the stratum corneum - the skin permeation barrier. Percutaneous absorption involves passive diffusion of substances through the skin. The mechanism of permeation can involve passage through the epidermis itself (transepidermal absorption) or diffusion through shunts, particularly those offered by the relatively widely distributed hair follicles and eccrine glands (transfollicular or shunt pathway). In the initial transient diffusion stage, drug molecules may penetrate the skin along the hair follicles or sweat ducts and then absorbed through the follicular epithelium and the sebaceous glands. When a steady state has been reached the diffusion through the intact stratum corneum becomes the primary pathway for topical permeation¹³.

The release of a therapeutic agent from a formulation applied to the skin surface and its transport to the systemic circulation is a multistep process, which involves

Dissolution within and release from the formulation

i. Partitioning into the skin’s outermost layer, the stratum corneum (SC)

ii. Diffusion through the stratum corneum, principally via a lipidic intercellular pathway, (i.e., the rate-limiting step for most compounds)

iii. Partitioning from the stratum corneum into the aqueous viable epidermis, diffusion through the viable epidermis and into the upper dermis, and uptake into the papillary dermis and into the microcirculation.

1.3.1. Kinetics of Topical Permeation^18-20

Knowledge of skin permeation kinetics is vital to the successful development of topical systems. Topical permeation of a drug involves the following steps :

a. Sorption by stratum corneum

b. Penetration of drug through viable epidermis

c. Uptake of the drug by the capillary network in the dermal papillary layer

This permeation can be possible if the drug possesses certain physico-chemical properties. The rate of permeation across the skin (dQ/ dt) is given by:

dQ / dt = P_s (C_d – C_r) Eq. 1

Where,

C_d = Concentration of skin penetrant in the donar compartment (e.g., on the surface of stratum corneum)

C_r = Concentration in the receptor compartment (e.g., body) respectively

P_s = Overall permeability constant of the skin tissue to the penetrant

P_s= ( K_sD_ss) / h_s Eq. 2

Where,

K_sis the partition coefficient for the interfacial partitioning of the penetrant molecule from a solution medium

D_ss is the apparent diffusivity for the steady state diffusion of the penetrant molecule through a thickness of skin tissues

h_s is the overall thickness of skin tissues.

As K_s, D_ss and h_s are constant under given conditions, the permeability coefficient (P_s) for a skin penetrant can be considered to be constant.

From Eq.1 it is clear that a constant rate of drug permeation can be obtained only when C_d>>C_r i.e., the drug concentration at the surface of the stratum corneum (C_d) is consistently and substantially greater than the drug concentration in the body (C_r), then Eq. 1 becomes:

dQ / dt = P_sC_sEq. 3

Permeability coefficient = (KsDss) / hs = 1 / resistance

1.3.2. Physiological Factors in Percutaneous Absorption

Physiological factors are those that involve the properties of the barrier itself. Some important factors are: Skin integrity, Hydration, Temperature, Anatomic location, Age, Disease.

1.3.3. Drug Factors in Percutaneous Absorption

The drug factors affecting percutaneous absorption are given as follows: Molecular size, Chemical nature of drug, Partition coefficient, Binding to the skin, Metabolism, Thermodynamic activity of drug in donor.

1.3.4. Formulation Factors in Percutaneous Absorption

The nature of the dosage form is an extremely important factor in determination of skin penetration characteristics and various formulation factors such as: Occlusivity, Drug concentration, pH, Solubility, Surfactant, Penetration enhancer.

1.3.5. Basic Components of Topical Gel^20-21

Topical gel may include the following components:

Polymer

Polymer is an integral and foremost important component of Topical Gel. Different classes of polymeric materials have been used to achieve rate controlled drug delivery. The mechanism of drug release depends upon the physicochemical properties of the drug and polymer used in the manufacture of the device.

The following criteria should be satisfied for a polymer to be used in a topical system :

i. Molecular weight, glass transition temperature, chemical functionality of polymer must allow diffusion and release of the specific drug.The polymer should permit the incorporation of a large amount of drug.

ii. The polymer should not react, physically or chemically with the drug.

iii. The polymer should be easily manufactured and fabricated into the desired product and inexpensive.

iv. The polymer must be stable and must not decompose in the presence of drug and other excipients used in the formulation, at high humidity conditions, or at body temperature.

i. Polymers and its degradation products must be non-toxic¹⁷.

No single material may have all these attributes, certain excipients may be incorporated to alter some properties, e.g., Cosolvents such as ethanol, propylene glycol, PEG 400 could be added to increase drug solubility. Useful polymers for topical gel are given in table 2

Various techniques have been employed to modify the polymer properties and thus drug release rates.

a. Cross-linked polymers: The higher the degree of cross-linking, the more dense the polymer and slower the diffusion of drug molecules.

b. Polymer blends: Polymers have been blended on varying ratios to combine the advantages of the individual polymers. Advantages of polymer blends include easy fabrication of devices, manipulation of drug incorporating and other devices properties such as hydration, degradation rate and mechanical strength.

Drug Substance

Judicious choice of the drug plays an important role in the successful development of a topical product. The important drug properties that effect its diffusion through the device as well as through skin are as follows:

a. Physicochemical properties:

i. Drug should have a molecular weight of less than 500 Daltons.

ii. Drug must have adequate lipophilicity.

iii. A saturated aqueous solution of the drug should have a pH value between 5 and 9.

iv. Drugs highly acidic or alkaline in solution are not suitable for topical delivery.

b. Biological properties:

i. The drug should not be directly irritated to the skin.

ii. The drug should not stimulate an immune reaction in the skin.

iii. Drugs, which degrade in gastrointestinal tract or are inactivated by hepatic first pass effect, are suitable for topical delivery.

iv. Tolerance to the drug must not develop under the near zero order release profile of topical delivery.

v. Drugs which have to be administered for a long time or which cause adverse effects to non-target tissue can also be formulated for topical delivery.

Penetration Enhancers

These are the compounds, which promote skin permeability by altering the skin as a barrier to the flux of a desired penetrant and are considered as an integral part of most topical formulations. To achieve and maintain therapeutic concentration of drug in the blood, the resistance of skin (stratum corneum) to diffusion of drugs has to be reduced in order to allow drug molecules to cross skin and to maintain therapeutic levels in blood.They can modify the skin’s barrier to penetration either by interacting with the formulation that applied or with the skin itself.

Various criteria that ideal penetration enhancers must meet are:

i. Ability to act specifically, reversibly and for predictable duration.

ii. Pharmacological inertness.

iii. Non-toxic, non-allergenic, non-irritating.

iv. Controlled and reverse enhancing action.

v. Should not cause loss of body fluids, electrolytes or other endogeneous materials.

vi. Chemical and physical compatibility with drugs and other pharmaceutical excipients with which it is used.

vii. Following removal of the enhancer, the stratum corneum should immediately and fully recover its normal barrier property.

viii. Odourless, colorless and economical and cosmetically acceptable.

Enhancers increase the penetration of permeants by disrupting the structure of skin’s outer layer ‘stratum corneum’ and increasing penetrant solubility. Disruption either by chemical means, may affect both intracellular and extracellular structure. Disruption may be due to protein denaturation, fluidization and randomization of intercellular lipids or intercellular delamination and expansion. The accelerants cause keratin to swell and leach out essential structural material from the stratum corneum, thus reducing the diffusional resistance and increasing the permeation of drugs through skin. In hydrophilic topical penetration enhancer, the miscibility and solution properties of solvent are used for the enhanced topical permeation of a water-soluble drug.

Lipophilic enhancers assist the percutaneous absorption of both water soluble and oil soluble drugs. The enhancement in the absorption of oil soluble drugs is apparently due to the partial leaching of the epidermal lipids by the enhancer, resulting in the improvement of the skin condition for wetting and for topical and transfollicular penetration.

The effect of surfactant action upon the skin may change the physical stage of water in the skin in such a way as to permit greater freedom to the passage of charged hydrophilic substances. Their permeation promoting activity is due to the action to decrease the surface tension, to improve the wetting of the skin and to enhance the distribution of drugs. Furthermore it was observed that the more hydrophilic surfactants interact more strongly with keratin and alter permeation as compared to less hydrophilic surfactants (long chain alcohols).

Classification of permeation enhancers

Water, Sulphoxides (especially dimethylsulphoxide) and their analogues, Pyrrolidines, Fatty acid and alcohols, Azone and its derivatives, Surfactants – anionic, cationic and nonionic, Urea and its derivatives, Alcohols and glycols, Essential oils, Terpenes and derivatives, Synergistic mixture.

FORMULATION AND EVALUATION:

METHOD OF PREPARATION

i. Fusion method

ii. Cold Method

iii. Dispersion Method

Whether the scale of preparation is large or small, semisolid dosage forms are produced by one of two general methods. Either they are made at high temperature by blending the liquid or liquified components and dispersing the solids (fusion method) or the drug is incorporated in the already semisolid base (cold incorporation). Cold corporation is used with heat labile drugs, when a drug is to be added to an already prepared semisolid base or when the vehicle itself is heat labile as happens with plastibase.

The preparation of gels may involve a fusion process or may require a special procedure, depending on the gelling agent involved. Tragacanth system must be prepared at low temperature due to the extreme heat lability of this natural gum. On the other hand, it is easier to disperse methyl cellulose in hot than in cold water. The carbopols are prepared by a unique procedure. The polymer is dispersed in an acidic medium. When the dispersion is uniform, gellation is induced by neutralizing the system with an inorganic base (aqueous systems) or with an amine such as triethanolamine. This ionizes the acidic functional groups on the polymer, drawing the polymer into colloidal solution, in which state it forms the requisite structural matri

EVALUATION

Following parameters were used for the evaluation of gels:

Homogeneity

All developed gels were tested for homogeneity by visual inspection after the gels have been set in the container. They were tested for their appearance and presence of any aggregates.

Grittiness

All the formulations were evaluated microscopically for the presence of particles if any no appreciable particulate matter was seen under light microscope. Hence obviously the gel preparation fulfils the requirement of freedom from particular matter and from grittiness as desired for any topical preparation.

Extrudability Study^{22, 23}

A good gel extrude optimally from the gel with slight pressure applied. The extrudability of formulations from aluminium collapsible tubes, was determined using universal tube filling machine. Aluminium collapsible tubes filled with 10g gels were held between two clamps. A tube was compressed and extrudibility of the formulation was determined in terms of weight in grams required to extrude a 0.5 cm. ribbon of gel in 10 seconds.

Skin irritation studies:

The albino mice of either sex weighing 20-22gms were used for this test. The intact skin was used. The hair was removed from the mice 3 days before the experiment. The animals were divided into two batches and each batch was again divided into two groups. The gel containing drug were used on test animal. A piece of cotton wool soaked in saturated drug solution was placed on the back of albino mice taken as control. The animal were treated daily upto seven days and finally the treated skin was examined visually for erythema and edema.

Measurement of pH²⁴

The pH of gel formulations was determined by using digital pH meter. One gram of gel was dissolved in 100 ml of distilled water and stored for two hours. The measurement of pH of each formulation was done in triplicate and average values were calculated.

Drug content

The drug content was determined using spectrophotometric method by measuring the absorbance.

Viscosity study^25-27

The measurement of viscosity of the prepared gel was done with a Brookfield Viscometer. The gels were rotated at 20 and 30 rpm using spindle no. 64. At each speed, the corresponding dial reading was noted.

Spreadability^28,29

One of the criteria for a gel to meet the ideal quantities is that it should possess good Spreadability. It is the term expressed to denote the extent of area to which gel readily spreads on application to skin or affected part. The therapeutic efficacy of a formulation also depends upon its spreading value.

Spreadability is expressed in terms of time in seconds taken by two slides to slip off from gel and placed in between the slides under the direction of certain load, lesser the time taken for separation of two slides, better the spreadability. It is calculated by using the formula:

S = M. L / T

Where M = weight tied to upper slide

L = length of glass slides

T = time taken to separate the slide

Fig-4.2 Measurement of Viscosity By Using Brookefield Viscometer

In-vitro Diffusion studies^30-32

The in vitro diffusion studies of prepared gel were carried out in Keshary–Chien diffusion cell using through a cellophane membrane. One hundred milliliters of phosphate buffer was used as receptor compartment, then 500 mg of gel containing was spread uniformly on the cellophane membrane. The donor compartment was kept in contact with a receptor compartment and the temperature was maintained at 37±0.5 ⁰C. The solution on the receptor side were stirred by externally driven Teflon coated magnetic bars at predetermined time intervals, pipette out 5 ml of solution from the receptor compartment and immediately replaced with the fresh 5 ml phosphate buffer. The drug concentration on the receptor fluid was determined spectrophotometrically against appropriate blank. The experiment was carried out in triplicate.

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Received on 11.06.2009 Modified on 13.08.2009

Research J. Pharm. and Tech. 3(1): Jan.-Mar. 2010; Page 17-24

Pharmaceutical gels applications	Favorable properties
Dental	Highly thixotropic, optimal viscosity for filling fissure, adherent to enamel surface, optically clear, water soluble, orally digestible
Dermatological	Thixotropic, spreadability, greaseless, easily removable, emollient, demulcent, non-staining, compatible with number of excipients (water soluble or miscible)
Nasal	Adherent, odorless, non-irritant, water-soluble
Ophthalmic	Optically clear, sterile mucomimetic, lubricating or non-sterilizing, water soluble or miscible
Surgical & medical	Lubricating, adherent to instrument surface, maximal contact with mucous
Vaginal	Acid stable, adherent, does not liquefy at body temperature, slow dissolving, lubricating, greaseless