IMPACT FACTOR 4.018* ICV 6.16* REVIEW ARTICLE AN …. RPA181925442019 .pdf · 2020-06-19 · extended period its bypasses the first pass metabolism avoids problems related to

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International Journal of Universal Pharmacy and Bio Sciences 9(3): May-June 2020

INTERNATIONAL JOURNAL OF UNIVERSAL

PHARMACY AND BIO SCIENCES IMPACT FACTOR 4.018***

ICV 6.16*** Pharmaceutical Sciences REVIEW ARTICLE……!!!

AN ADVANCED REVIEW ON KETOCONAZOLE GEL LOADED WITH

NATURAL SOURCE MENTHA ARVENSIS

N.G.RAGHAVENDRA RAO, YOGITA TYAGI KM. YAMINI CHAUHAN*

Department of Pharmacy GRD (PG) IMT, Rajpur Road Dehradun:-248001, Uttarakand, India.

KEYWORDS:

Gel, Ketoconazole, Antifungal

agent,Mentha arvensis,TDDS. FOR CORRESPONDENCE: KM. Yamini Chauhan

*

ADDRESS:

Department of Pharmacy

GRD (PG) IMT, Rajpur Road

Dehradun:-248001, Uttarakand,

India.

ABSTRACT

The objective of the present work aimed to formulate and

characterize (water insoluble antifungal agent) ketoconazole gel

using natural source mentha arvensis as bio retardant and bio

stabilizer for transhdermal drug delivery system. Ketoconazole

is an azole antifungal medication used to treat certain serious

fungal infections.it prevents growth of several types of fungi by

preventing production of the membranes that surround fungal

cells.



INTRODUCTION:

Fungal infection are caused by fungus ranges from superficial conditions of the skin and nails two the

deadly contagiousdiseasa a topical preparation of ketoconazole is used for treatment of the infection[3]

1. Ringworm also called dermatophytosis usually manifest as a series of rapidly expanding irritating

lesions which can occur in any area of this skin, chiefly attack stratum corneum and hair fibres resulting

in autolysis of the fiber stracture, braking off the hair and alopecia[3]

2. Ketoconazole is a antifungal agent with a broadspectrum of activity, ketoconazole is widely used

recent synthetic imidazole ring contening powerfull antifungal agent active against most of the species

of fungai and yeast. In bio-pharmaceutics classification system (BCS), ketoconazole is classified as a

class second drug based on its absorption and dissolution property, since it has a high permeability but

its solubility in aqueous media is insufficient for the whole dose to be dissolved in the GIT fluids under

normal condition.[3]

3. The poor aqueous solubility of ketoconazole is the limitation for topical delivery.[3]

TOPICAL DRUG DELIVERY SYSTEM[2,3]

Topical drug delivery system are extensively used for the treatment of local skin disorders, topical

application of drugs has potential advantages of delivery of the drug directly to the site of action for an

extended period its bypasses the first pass metabolism avoids problems related to absorption, changes

in PH and also avoids risk and IV therapy[2] how ever , stratum corneum the top layer of apidermis is

the mazor barrier of the drug penetration through the skin topical preparations like ointments , creams,

lotions are extensively used as the topical agent.[3]

2.1 Anatomy of Skin[1]

The Skin is composed of three main layers.

The epidermis

• Stratum Basale

• Stratum Spinosum

• Stratum Granumlosum

• Stratum Lucidum

• Stratum Corneum

The dermis

• Papilary Layer

• Reticular Layer

Hypodermis (The innermost subcutaneous fat layer)



FIG. 1: SCHEMATIC REPRESENTATION OF SKIN AND ITS APPENDAGES

THE EPIDERMIS:

The epidermis is composed of keratinized, stratified squamous epithelium. It is made of four or five

layers of epithelial cells, depending on its location in the body. It does not have any blood vessels

within it (i.e., it is avascular). Skin that has four layers of cells is referred to as “thin skin.” From deep

to superficial, these layers are the stratum basale, stratum spinosum, stratum granulosum, and stratum

corneum. Most of the skin can be classified as thin skin. “Thick skin” is found only on the palms of the

hands and the soles of the feet. It has a fifth layer, called the stratum lucidum, located between the

stratum corneum and the stratum granulosum.

The cells in all of the layers except the stratum basale are called keratinocytes. Akeratinocyte is a cell

that manufactures and stores the protein keratin. Keratin is an intracellular fibrous protein that gives

hair, nails, and skin their hardness and water-resistant properties. The keratinocytes in the stratum

corneum are dead and regularly slough away, being replaced by cells from the deeper layers.

STRATUM BASALE:

The stratum basale (also called the stratum germinativum) is the deepest epidermal layer and lattaches

the epidermis to the basal lamina, below which lie the layers of the dermis. The cells in the stratum

basale bond to the dermis via intertwining collagen fibers, referred to as the basement membrane. A

finger-like projection, or fold, known as the dermal papilla (plural = dermal papillae) is found in the

superficial portion of the dermis. Dermal papillae increase the strength of the connection between the

epidermis and dermis; the greater the folding, the stronger the connections made (Figure 2).



FIG 2. Layers of the Epidermis. The epidermis of thick skin has five layers: stratum basale,

stratum spinosum, stratum granulosum, stratum lucidum, and stratum corneum.

The stratum basale is a single layer of cells primarily made of basal cells. A basal cellis a cuboidal-

shaped stem cell that is a precursor of the keratinocytes of the epidermis. All of the keratinocytes are

produced from this single layer of cells, which are constantly going through mitosis to produce new

cells. As new cells are formed, the existing cells are pushed superficially away from the stratum basale.

Two other cell types are found dispersed among the basal cells in the stratum basale. The first is a

Merkel cell, which functions as a receptor and is responsible for stimulating sensory nerves that the

brain perceives as touch. These cells are especially abundant on the surfaces of the hands and feet. The

second is a melanocyte, a cell that produces the pigment melanin. Melanin gives hair and skin its

color, and also helps protect the living cells of the epidermis from ultraviolet (UV) radiation damage.

In a growing fetus, fingerprints form where the cells of the stratum basale meet the papillae of the

underlying dermal layer (papillary layer), resulting in the formation of the ridges on your fingers that

you recognize as fingerprints. Fingerprints are unique to each individual and are used for forensic

analyses because the patterns do not change with the growth and aging processes.

STRATUM SPINOSUM

As the name suggests, the stratum spinosum is spiny in appearance due to the protruding cell

processes that join the cells via a structure called a desmosome. The desmosomes interlock with each

other and strengthen the bond between the cells. It is interesting to note that the “spiny” nature of this

layer is an artifact of the staining process. Unstained epidermis samples do not exhibit this

characteristic appearance. The stratum spinosum is composed of eight to 10 layers of keratinocytes,



formed as a result of cell division in the stratum basale (Figure 2). Interspersed among the keratinocytes

of this layer is a type of dendritic cell called the Langerhans cell, which functions as a macrophage by

engulfing bacteria, foreign particles, and damaged cells that occur in this layer.

The keratinocytes in the stratum spinosum begin the synthesis of keratin and release a water-repelling

glycolipid that helps prevent water loss from the body, making the skin relatively waterproof. As new

keratinocytes are produced atop the stratum basale, the keratinocytes of the stratum spinosum are

pushed into the stratum granulosum.

STRATUM GRANULOSUM

The stratum granulosum has a grainy appearance due to further changes to the keratinocytes as they

are pushed from the stratum spinosum. The cells (three to five layers deep) become flatter, their cell

membranes thicken, and they generate large amounts of the proteins keratin, which is fibrous,

and keratohyalin, which accumulates as lamellar granules within the cells (see Figure 2. These two

proteins make up the bulk of the keratinocyte mass in the stratum granulosum and give the layer its

grainy appearance. The nuclei and other cell organelles disintegrate as the cells die, leaving behind the

keratin, keratohyalin, and cell membranes that will form the stratum lucidum, the stratum corneum, and

the accessory structures of hair and nails.

STRATUM LUCIDUM

The stratum lucidum is a smooth, seemingly translucent layer of the epidermis located just above the

stratum granulosum and below the stratum corneum. This thin layer of cells is found only in the thick

skin of the palms, soles, and digits. The keratinocytes that compose the stratum lucidum are dead and

flattened (see Figure 2). These cells are densely packed with eleiden, a clear protein rich in lipids,

derived from keratohyalin, which gives these cells their transparent (i.e., lucid) appearance and

provides a barrier to water.

STRATUM CORNEUM

The stratum corneum is the most superficial layer of the epidermis and is the layer exposed to the

outside environment (see Figure 2). The increased keratinization (also called cornification) of the cells

in this layer gives it its name. There are usually 15 to 30 layers of cells in the stratum corneum. This

dry, dead layer helps prevent the penetration of microbes and the dehydration of underlying tissues, and

provides a mechanical protection against abrasion for the more delicate, underlying layers. Cells in this

layer are shed periodically and are replaced by cells pushed up from the stratum granulosum (or stratum

lucidum in the case of the palms and soles of feet). The entire layer is replaced during a period of about



4 weeks. Cosmetic procedures, such as microdermabrasion, help remove some of the dry, upper layer

and aim to keep the skin looking “fresh” and healthy.

DERMIS

The dermis might be considered the “core” of the integumentary system (derma- = “skin”), as distinct

from the epidermis (epi- = “upon” or “over”) and hypodermis (hypo- = “below”). It contains blood and

lymph vessels, nerves, and other structures, such as hair follicles and sweat glands. The dermis is made

of two layers of connective tissue that compose an interconnected mesh of elastin and collagenous

fibers, produced by fibroblasts (Figure 5).

HYPODERMIS

The hypodermis (also called the subcutaneous layer or superficial fascia) is a layer directly below the

dermis and serves to connect the skin to the underlying fascia (fibrous tissue) of the bones and muscles.

It is not strictly a part of the skin, although the border between the hypodermis and dermis can be

difficult to distinguish. The hypodermis consists of well-vascularized, loose, areolar connective tissue

and adipose tissue, which functions as a mode of fat storage and provides insulation and cushioning for

the integument.

2.2 Rationale for topical preparation [3]

With the purpose to formulate an efficient and effective topical preparation, considerations are

mainly concerned with the site of action of the drugs and its effect. Topical preparations may be used

produce:

Effects on Surface Includes

1. The cleansing effect of removing germs and dirt.

2. Improves cosmetic appearance.

3. Protective action against moisture.

4. Produce an antimicrobial effect.

Effects on Stratum Corneum include

1. Protectives that penetrate this layer.

2. Keratolytic action.

3. Moisturizing effect.

4. Effects on Viable epidermis and dermis: Anesthetic, anti-inflammatory, antihistamine,

antipruritic, etc. are the major classes of drugs that penetrate these layers.

5. Systemic effects the drug responsible to produce systemic effects are nitroglycerin,

scopolamine,clonidine and estradiol.



6. Additional effects these effects include antimicrobial, antiperspirant.

2.3 Factors Affecting Topical drug absorption

1. Physiological factors

2. physicochemical

i. physiological factors

Hydration of skin

Blood flow

Lipid content

pH of skin

Thickness of skin

Temperature of skin

Density of sweat gland

Hydration of skin

Inflammation of skin.

2. Physiochemical factos

Molecular weight of drug

Partition coefficient

Degree of ionization

Vehicle effect

Concentration

Polymolrphysm

Particle size.

1. Introducton of Natural Resources[4,5]

The natural resources like Mentha arvensis (Mint), popularly know as Japanese mint or menthol mint,

is cultivated in india, china, brazil,japan, USA, france and Australia[5].



Figure 3: Mentha arvensis

Botanical name : Mentha arvensis.

English name : Mint (Japanese mint).

Indian name : Pudina (Hindi) , Putiha (Sanskrit) , Podina (Telugu).

Family : Lamiaceae.

Genus : Mentha.

Species : M.arvensis.

Botanical Source : The chemical composition of the essential oils obtained from the aerial parts of

mentha arvensis L.(corn mind).

Chemical Constituents Mentha arvensis : The major components identified in the oil of M. arvensis

were menthol (71.40%), p-menthone (8.04%), iso-menthone (5.42%) and neo-menthol (3.18%). The

main constituents found in the oil of C. flexuosus were citral (43.80%), z-citral (18.93%), geranyl

acetate (5.27%) and trans-geraniol (3.66%).[4]

Uses of Mentha arvensis : They are used as a carminative, stomachic, antispasmodic, stimulant,

sedative, sudorific, emmenagogue, astringent (externally) and refrigerant (externally) all over the

world. They are administered internally to treat indigestion, flatulence, gastro-intestinal atony, colic and

diarrhoea, or externally in the treatment of colds, influenza, fever, sinusitis, nose and throat complaints

(all e.g. as nasal drops), headache, facial neuralgia and insect stings (e.g. as rubefacient). In Indonesia,

pounded leaves are used externally against headache, and an infusion of the leaves as sudorific and

expectorant to treat cough, as a carminative, and as antispasmodic in gastro-enteritis. Although the

main use in the Philippines is reportedly as a culinary herb, an infusion of the leafy stems is also used

as carminative, and pounded leaves are used to treat insect stings. Mint leaves in the form of tea or

tablets are used in the Philippines as an analgesic, particularly in dental surgery. In Thailand, Mentha is

widely used as a culinary herb but also as a medicine for its carminative, stomachic and expectorant

properties.[4]



2. What is gel?

Gels are defined as subdstantially dilute cross linked system, Which exhibits no flow when in the

steady-state.

A Gel is a semi-solid that can have properties ranging from soft and weak to hard and tough.

By weight, gels are mostly liquid, yet they behave like solids due to are three dimensional cross linked

network with in the liquid, it is the cross linking with in the fluid that gives a gel its structure

(Hardness) and contributes to the adhesive stick (tack). In this way,gels are a dispersion of molecules of

a liquid with in a solid medium.

The word GEL was coined by 19th

century Scottish Chemist Thomas Graham by clipping from

gelatin.[6]

The word GEL is derived from GELATIN and both GEL and JELLY can be drawn back to the Latin

gelu FROST and gel are meaning FREEZE or CONGEAL.

The USP defines gels (sometime called jelly) as semi-solid systems containing either suspensions made

up of small inorganic particles, or large organic molecules interpenetrated by a liquid. Where the gel

mask contaions a network of small separate particles, the gel is classified as a two phase system. In a

two phases system “The particle size of the dispersed phases relatively large, the gel mass is sometimes

called as a magma”.[7]

Pharmaceutical gels are semi-solid system in which there is intraction (either physical of covalent)

between colloidal particles with in a liquid vehicle.

The vehicle may be…

AQUEOUS

HYDROALLCOHOLIC

ALCOHOL BASED

NON AQUEOUS.

Gels criteria…

HERMANS in 1949 suggested some crietria for gels.

They are colloidal systems of at least to components (THE GELLING AGENT AND THE

FLUID COMPONENT)

They exhibit the mechanical characteristics of the solid state.

Terminology related to gels: [8]

Imbibition: is the taking up of a certain amount of liquid without a measurable increase in volume.



Swelling: is the taking up of a liquid by a gel with an increase in volume, only liquids that solvate a

gel can cause swelling.

Synersis: occurs when the interaction between particles of the dispersed phase becomes so great that

on standing, the dispersion medium is squeezed out in droplets and the gel shrinks, it depends on the

conc. of gelling agent.

Aging: is the slow spontaneous aggregation which results in formation of denser network of gelling

agent.

Separation of solvent phase occur because of the elastic contraction of polymeric molecules, in the

swelling process during gel formation the macromolecules become stretched and the elastic forces

increase as a swelling proceeds. At equilibrium the restoring force of the macromolecules is balanced

by the swelling forces determined by osmotic pressure, if the osmotic pressure decreases as on

cooling, water may be squeezed out of the gel.

2 Classification and types of gels:

We have two classification:

Single phase gel: gels in which macromolecules are distributed so that no apparent boundaries exist

between them, it also called organic gels e.g carbopol, tragacanth.

Two phase gel: gels consist of floccules of small, distinct particles,and frequently called a magma

gels or inorganic gels e.g Aluminium hydroxide gel , bentonite magma.

Another classification is based on the type of continuous phase:

Hydrogels : includes ingredients that are dispersible as colloidals or soluble in water they include

organic hydrogels, natural and synthetic gums and inorganic hydrogels.

Organogels include hydroxylcarbons, animal and vegetable fats, and hydrophilic organogels.

Xerogels: gels in which vehicle has been removed leaving a polymer network.[8]

Structure of Gels [9,10]

The rigidity of a gel arises from the presence of a network formed by the interlinking of particles

gelling agent. The nature of the particles and the type of force that is responsible for the linkages, which

determines the structure of the network and the properties of the gel.



FIG : 4.(A) REPRESENTATION OF GEL STRUCTURE.

FIG: 4.(B) GEL STRUCTURE:- AGGREGATES OF SPHERICAL PARTICALES,

FRAMEWORK OF ROD-LIKE PARTICALES, PHYSICAL GEL WITH CRYSTALLINE

JUNCTIONS, CHEMICAL GEL-COVALENT JUNCTIONS.

Advantages.[13,14]

1. Hydrophobic drugs can be easily incorporated into gels using d/o/w emulsions. Most of the

hydrophobic drugs cannot be incorporated directly into gel base because solubility act as a

barrier and problem arises during the release of the drug. Emulgel helps in the incorporation of

hydrophobic drugs into the oil phase and then oily globules are dispersed in aqueous phase

resulting in o/w emulsion. And this emulsion can be mixed into gel base. This may be proving

better stability and release of drug than simply incorporating drugs into gel base.

2. Better stability: Other transdermal preparations are comparatively less stable than emulgels.

Like powders are hygroscopic, creams shows phase inversion or breaking and ointment

shows rancidity due to oily base.



3. Better loading capacity: Other novel approaches like niosomes and liposomes are of micro size

and due to vesicular structures may result in leakage and result in lesser entrapment efficiency.

But gels due to vast network have comparatively better loading capacity.

4. Production feasibility and low preparation cost: Preparation of emulgels comprises of simpler

and short steps which increases the feasibility of the production. There are no specialized

instruments needed for the production of emulgels. Moreover materials used are easily available

and cheaper. Hence, decreases the production cost of emulgels.

5. No intensive sonication: Production of vesicular molecules need intensive sonication which may

result in drug degradation and leakage. But this problem is not seen during the production of

emulgels as no sonication is needed.

6. Controlled release: Emulgels can be used to prolong the effect of drugs having shorter t1/2.

Limitation.

Expensive technique to completely remove the solvents and surfactants at the end of preparation

process.

Surfactant or monomer tracts may remain and can import adverse effects.

Difficulty in handling.

Difficulty in loading.

Properties of Gels[11,12]

Ideally, the gelling agent must be inert, safe and cannot react with other formulation

constituents.

The gelling agent should produce a sensible solid-like nature at the time of storage which is

easily broken when exposed to shear forces produced by squeezing the tube, trembling the

bottle or at the time of topical application.

It should have suitable anti-microbial agent.

The topical gel must not be sticky.

The ophthalmic gel must be sterile.

The apparent viscosity or gel strength increases with an increase in the effective crosslink

density of the gel. However, a rise in temperature may increase or decrease the apparent

viscosity, depending on the molecular interactions between the polymer and solvent.

They exhibit the mechanical characteristics of the solid state.

Each component is continuous throughout the system.



There is high degree of attraction amongst the dispersed phase and water medium so the gels

remain equally uniform upon standing and doesn’t freely settle.

Classification of Gels

Gels can be classified based on colloidal phases, nature of solvent used, physical nature and rheological

properties, etc.

Based on colloidal phases:- ,[11,15]

They are classified into:

a. Inorganic (Two phase system)

b. Organic (Single phase system)

Inorganic (Two phase system)

If the partition size of dispersed phase is relatively large and form the three-dimensional structure

throughout gel, such a system consists of floccules of small particles rather than larger molecules and

gel structure, in this, system is not always stable. They must be thixotropic-forming semisolid on

standing and become liquid on agitation.

Organic (Single phase system)

These consist of large organic molecules existing on the twisted strands dissolved in a continuous

phase. This larger organic molecule either natural or synthetic polymers are referred as gel formers,

they tend to entangle with each other their random motion or bound together by Vander walls forces.

Based on nature of solvent:- [11,15]

Hydrogels (Water based)

A hydrogel is a network of polymer chains that are hydrophilic, infrequently found as a colloidal gel in

which water is dispersion medium. They are highly absorbent natural or synthetic polymeric networks.

They also have a degree of flexibility likely to the natural tissue, due to their significant water content.

Uses for hydrogels

Sustained-release drug delivery systems

Rectal drug delivery and diagnosis

Hydrogel-coated wells have been used for cell culture

As scaffolds in tissue engineering

As environment sensitivity detector

Contact lenses (silicone hydrogels, polyacrylamides, polymacon)

ECG medical electrode

Dressing of healing



E.g., Bentonite magma, gelatin, cellulose derivatives, carpooler and poloxamer gel.

1.6. Organogels (With a non-aqueous solvent)

An organogel is a non-crystalline, non-glassy thermo reversible solid material composed of a liquid

organic phase trapped in a 3D cross-linked network. The liquid can be, E.g., vegetable oil, an organic

solvent or mineral oil. The solubility and particle sizes of the structurant are significant characteristics

for the elastic properties and firmness of the organogel. Frequently, these systems are based on self-

assembly of the structurant molecules.

Xerogels

It is a solid formed from a gel by drying with unrestricted shrinkage. It is frequently retains high

porosity (15-50%) and huge surface area (150-900 m2/g), along with very small pore size (1-10 nm).

When solvent removed under supercritical conditions, the network doesn’t shrink and a highly porous,

low-density material known as an aerogel is produced. Heat treatment of a xerogel at higher

temperature produces viscous sintering and efficiently transforms the porous gel into a thick glass. E.g.,

Tragacanth ribbons, β-cyclodextrin, dry cellulose and polystyrene, gelatin sheets and acacia tears.

Based on rheological properties:- [11,15,16]

Usually gels exhibit non-Newtonian flow properties. They are classified into:

a. Plastic gels

b. Pseudo plastic gels

c. Thixotropic gels

Plastic gels

E.g., Bingham bodies, flocculated suspensions of Aluminum hydroxide exhibit a plastic flow and the

plot of rheogram gives the yield value of the gels above which the elastic gel distorts and begins to

flow.

Pseudo-plastic gels

E.g., Liquid dispersion of tragacanth, sodium alginate, Na CMC, etc. exhibits pseudo-plastic flow. The

viscosity of these gels decreases with increasing rate of shear, with no yield value. The rheogram results

from a shearing action on the long chain molecules of the linear polymers. As the shearing stress is

increased the disarranged molecules begin to align their long axis in the direction of flow with the

release of solvent from gel matrix.[16]

Thixotropic gels

The bonds between particles in these gels are very weak and can be broken down by shaking. The

resulting solution will revert back to gel due to the particles colliding and linking together again (the



reversible isothermal gel-sol-gel transformation). This occurs in a colloidal system with non-spherical

particles to build up a scaffold like structure.

E.g., Kaolin, bentonite, agar, etc.

Based on physical nature:-

Elastic gels

Gels of agar, pectin, Guar gum and alginates exhibit an elastic behavior. The fibrous molecules being

linked at the point of junction by comparatively weak bonds like hydrogen bonds and dipole attraction.

If the molecule possesses free -COOH group then additional bonding takes place by a salt bridge of

type -COO-X-COO between two adjacent strand networks.

E.g., Alginate and Carbopol.

Rigid gels

This can be formed from macromolecule in which the framework linked by primary valence bonds.

E.g., In silica gel, silic acid molecules are held by Si-O-Si-O bond to give a polymer structure

possessing a network of pores.

Preparation of Gels

Gels are normally in the industrial scale prepared under room temperature. However, few of polymers

need special treatment before processing. Gels can be prepared by following methods:

1. Thermal changes

2. Flocculation

3. Chemical reaction

Thermal changes

Solvated polymers (lipophilic colloids) when subjected to thermal changes causes gelatin. Many

hydrogen formers are more soluble in hot than cold water. If the temperature is reduced, the degree of

hydration is decreased and gelation takes place. (Cooling of a concentrated hot solution will produce a

gel). E.g., Gelatin, agar sodium oleate, guar gummed, cellulose derivatives, etc. In contrast to this, some

materials like cellulose ether have their water solubility to hydrogen bonding with the water. Raising

the temperature of these solutions will disrupt the hydrogen bonding and reduced solubility, which will

cause gelation. Hence this method cannot be adopted to prepare gels as a general method.[16]

Flocculation

Here gelation is produced by adding just sufficient quantity of salt to precipitate to produce age state,

but inadequate to bring about complete precipitation. It is essential to ensure quick mixing to avoid

local high concentration of precipitant.



E.g., Solution of ethyl cellulose, polystyrene in benzene can be gelled by quick mixing with suitable

amounts of a non-solvent such as petroleum ether. The adding of salts to hydrophobic solution brings

about coagulation, gelation is infrequently observed. The gels formed by flocculation method are

Thixotropic in behavior. Hydrophilic colloids such as gelatin, proteins and acacia are only affected by

high concentration of electrolytes, when the effect is to “salt out”, the colloidal and gelation doesn’t

occur.[16]

Chemical reaction

In this method gel is produced by chemical interaction between the solute and solvent. E.g., Aluminium

hydroxide gel can be prepared by interaction in aqueous solution of an aluminium salt and sodium

carbonate an increased concentration of reactants will produce a gel structure. Few other examples that

involve chemical reaction between PVA, cyanoacrylates with glycidol ether (Glycidol), toluene

diisocyanates (TDI), methane diphenyl isocyanine (MDI) that cross-links the polymeric chain.[16]

Formulation Considerations for Pharmaceutical Gels [17,18]

The choice of vehicle/solvent:

1. Physical appearance

The prepared gel was examined for clarity, color , homogeneitv and the presence of foreign partycals.

2. Globule size and its distribution in emulgel

Globule size and distribution was determined by Malvern zetasizer. A 1.0 gm sample was dissolved in

purified water and agitated to get homogeneous dispersion. Sample was injected to photocell of

zetasizer. Mean globule diameter and distribution was obtained.[17]

3. Rheological Study

Viscosity measurement :

Viscosity was determined by Brookfield programmable DV III altra viscometer. In the present study,

spinble no CP 52 with an optimum speed of 0.01 rpm was used to measure the viscosity of the

prepration.[17]

Substance Gel-forming concentrations (wt%) Required additives

Gelatin 2-5

Alginates 0.5-1 Ca2+

Pectins(low methoxy) 0.8-2 Ca2+

Carboxymethylcellulose 4-6 Na2+

Cetostearly alcohol 10 Cetrimide



4. Swelling Index

To determine the swelling index of prepared topical gel, 1 gm of gel is taken on porous aluminum foil

and then placed separately in a 50 ml beaker containing 10 ml 0.1 N NaOH. Then samples were

removed from beakers at different time intervals and put it on dry place for some time after it

reweighed. Swelling index is calculated as follows:

Swelling Index (SW) % = [(Wt – Wo) / Wo] × 100.

Where, (SW) % = Equilibrium percent swelling,

Wo = Original weight of emulgel at zero time after time t,

Wt = Weight of swollen emulgel

5. Percentage Yield

The empty container was Weighed in which the gel formulation was stored then again the container

was weighed with gel formulation. Then subtracted the empty container weighed with the container

with gel formulation then it gives the practical yield. Then the percentage yield was calculated by the

formula.

Practical Yield

Percentage Yield =---------------------------------X 100

Theoretical Yield

6. Content uniformity

The druge content of the prepared gel was carried out by dissolving accurately weighed quantity of gel

equivalent to 10mg of the druge in 100ml volumetric flask and volume was made up to 100ml with

methanol.

The content was filtered through Whatman filter paper no 41.5ml of above solution was taken into a

25ml volumetric flask and volume was made up to mark with methanol.

The content of Ketoconazole was determined at 243nm against blank by using the UV/ visible

spectrophotometer. The drug content was determined from the calibration curve of Ketoconozole.[17]

7. Determination of pH

2.5gm of gel where accurately weighed and dispersed in 25ml of distilled water. The ph of dispersion

was measured by using a digital ph meter.[17]

8.Spreadability

It indicates the extent of the area to which gel readily spreads on application to the skin or affected part.

The therapeutic potency also depends upon spreading value. The time in sec taken by two slides to slip

off from gel which is placed in between the slides under the direction of certain load is expressed as



spreadability. [13], [20] Lesser the time taken for the separation of two slides, better the spreadability.

The following formula is used to calculate the spreadability:

Spreadability (S) = M × L / T

Where,

S = spreadabillity

M = weight tied to upper slide

L = length of glass slides

T= time taken to separate the slides completely from each other.

9. Extrudability :-

The gel formulations were filled into a collapsible metal tube or aluminium collapsible tube. The tube

was pressed to extrude the material and the extrudability of the formulation was checked. The

formulations are fill in the collapsible tubes, after it was set in the container. Extrudability is determine

in terms of weight in gm required to extrude a 0.5 cm ribbon of gel in 10 second.

10. In vitro diffusion study [13,19]

The abdominal skin of Albino mice, weighing 20–25 gm of 8–10 w old was shaved using hand razor

and clean the skin with hot water cotton swab. 5 gm of gel was applied uniformly to the skin.

The skin was mounted between the compartments of the Frantz diffusion cell with stratum corneum

facing the donor compartment.

Reservoir compartment was filled with 100 ml phosphate buffer of pH 6.8.

The study was carried out at 37±1 °C and the speed was adjusted until the vortex touches the skin and it

carried out for 4½ h. 5 ml of the sample was withdrawn from the reservoir compartment at 30 min

interval and absorbance was measured spectrophotometrically at 260 nm. Each time the reservoir

compartment was replenished with the 5 ml volume of phosphate buffer pH 6.8 solution to maintain a

constant volume.[13,19]

11.Skin irritation study

For skin irritation study, Guinea pigs (400-500g; either sex) were used.

The animals were maintained on the standard animal feed and had free access to water. The animals

were kept under standard conditions. Hair was shaved from the back.

5ml of each sample was withdrawn periodically at 1,2,3,4,5,6,7 and 8h and each sample was replaced

with an equal volume of fresh dissolution medium.

Then analyzed the samples for drug content by using phosphate buffer as guinea pigs and an area of 4

cm was marked blank on both the sides, one side served as control while the other side was test.



The gel was applied (500 mg/ guinea pig) twice a day for 7 days and the site was observed for any

sensitivity and the reaction if any.[13,19] It was graded as:

0 No reaction

1 Normal patchy erythema

2 Normal but confluent or modest but patchy erythema

3 Severe erythema with or without edema

12. Stability

It was carried out by freeze-thaw cycling. Here, the product to a temperature of 4°C for 1 month, then at

25°C for 1 month and then at 40°C for 1 month, syneresis was observed. Then the gel is exposed to

ambient room temperature.

Note the liquid exudate separated.

13. Homogeneity

Set the gel in container and then it were tested for homogeneity by visual inspection. They were tested

for their appearance and presence of any aggregates. [13,19]

Conclusion

The chemical composition of the essential oils obtained on hydrodistillation of M.arvensis. The major

constitents of the oil where menthol 71.40%, p-menthone 8.04%, iso-menthone 5.42% and neo menthol

3.18%. The menthol mint oil was found to be a complex mixture of monoterpenoids. Among tham ,

menthol, p-menthone, iso-menthone, and neo menthol were predominant and commercially valuable.

This constituents and menthol mint oil are reported to exhibit antifungal activity.

Mentha arvensis provided excellent stability for the formulating ketoconazole loaded nano dispersion

gel were found to be safe and compatible with the ophthalmic delivery for treatment of fungal

infection, and this is a novelistic approach significantly delivering the drug for a prolonged period, and

the biopolymer was served as a promising excipient for delivering dosage forms.The quality of mint oil

obtained by hydrodistillation methods can be determined by analyzing the physical and chemical

properties of the oil. Based on the analysis of the physical properties of the mint oil, it can be proposed

that the mint oil obtained by hydrodistillation has the same quality (refractive index and specific

gravity) with that obtained by hydrodistillation. Furthermore,based on the analysis of the chemical

properties of the mint oil, it can be proposed that mint oil obtained by hydrodistillation has better

quality the gel formulation can provide better absorption characteristics and hence increase the

bioavailability of the drug. A thorough investigation into the stability characteristics of the gel

formulation over an extended period of time may provide scope for its therapeutic use for patients. The



principal advantage of topical drug delivery lies in targeting the drug action directly to the site of

disorder by allowing accumulation of high local drug concentration within the tissue and around its

vicinity for enhanced drug action this is more effective when drugs with short biological half-life,

narrow therapeutic window are applied with topical route. The clinical evidence shows that topical gel

is a safe and effective treatment choice for use in the management of skin related diseases. Developed

formulations of ketoconazole were evaluated for the physiochemical parameters such as percentage

yield, drug content, pH, viscosity, spreadability, extrudability, in vitro drug diffusion. Viscosity studies

of various formulations revealed that some formulation was better to compare to others

REFERENCES:

1. Kim Ann Zimmermann, et all SKIN:The human body’s largest orgen.

2. Priya M, Sellakumar V, Natarajan RFormulation and in vitro evaluation of ciprofloxacin loaded

topical emulgel.int J Pharma Chem sci 2012.

3. Goel D, Gupta R.K, Warsi M.H, et all. Formulate and characterize nano dispersive gel for

topically delivery of water in solubule anti fungal agent ketoconazole. The International journal

of Pharmacy and P.S, 3-2,2018

4. Pandey A.K, Rai M.K, Acharya D, et all chemical composition of essential oils obtained from

the aerial part of mentha arvensis.

5. https://en.wikipedia.org/wiki/Mentha_arvensis.

6. https://en.wikipedia.org/wiki/Gels

7. Hemendarsinh J Rathod and Dhruti P Mehta “A review on pharmaceutical gel”. IJOPS

1.1(2015):33-47.

8. http://www.uobabylon.edu.iq/eprints/publication_3_31461_6264.pdf.

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NR_fig1_269946899

10. https://images.app.goo.gl/Fmetzg4GuKdj9JCe7

11. Loyd VA., et al. “Ansel’s pharmaceutical dosage forms and drug delivery systems. 9th ed.

Philadelphia: Lippincott Williams & Will- dns; (2011).

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Publishers and Distributors (2000): 68-72.

13. Pathan, I.B.; Setty, C.M. Chemical penetration enhancers for transdermal drug delivery

systems. Trop J Pharm Res. April 2009; 8:173-179.

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14. Rashmi, MS. Topical Gel: A Review, 2008. Available from:

http://www.pharmainfo.net/reviews/topic algel-review.

15. http://en.wikipedia.org [Internet]. Gel [updated 2014 December 13]. Available from:

http://en.wikipedia.org/wiki/Gel.

16. Niyaz BB., et al. “Formulation and evaluation of Gel containing Fluconazole-Antifungal

agent”. International Journal of Drug Devel- opment and Research 3.4 (2011): 109-128.

17. Patel RP,Patel H, Baria AH.Formulation and evaluation of carbopol gel containing liposome of

ketoconazole. Int J Drug Del Technol. 2009;1:42-5.

18. Staub I, Schapoval EE, Bergold AM. Microbiological assay of ketoconazole in shampoo.Int J

Pharm. 2005;292:195-9.

19. Mohamed MI. Optimization of Chlorphenesin emulgel formulation. Aaps, 6:1-7, 2004.

http://en.wikipedia.org/wiki/Gel

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