Skip to main content

TRANSDERMAL GEL OF MICONAZOLE NITRATE

 

Clinical courses

About Authors:
DHIRAJ YADAV
BABU BANARASI DAS UNIVERSITY,
LUCKNOW
dhirajyadav06@gmail.com

ABSTRACT
Miconazole is the antifungal drug, has been used in the treatment of fungal infection of skin and also in yeast infection. In order to decrease the skin rashes, skin irritation, and also for best effect on the skin, miconagol gels have been developed. This study was conducted to develop a gel formulation of miconazole using four types of gelling agents: carbopol, carboxymethylcellulose sodium (Na CMC) and sodium alginate. Effect of penetration enhancer (propylene glycol) on the release has been studied. The gels were evaluated for physical appearance, rheological behaviour, drug release and stability. The drug release from all gelling agents through a standard cellophane membrane was evaluated using Keshary-Chien diffusion cell. All batches of gels showed acceptable physical properties concerning colour, homogeneity, consistency, spreadability and pH value.
Among all the gel formulations, carbopol showed superior drug release than followed by Na CMC, and sodium alginate. Drug release decreased with increase in polymer concentration. Drug release was not linearly proportional with the concentration of penetration enhancer or co-solvents. Stability studies showed that the physical appearance, rheological properties, and drug release remained unchanged upon storage for two months at ambient condition.

Reference Id: PHARMATUTOR-ART-1404

Introduction:
Topicaldrug administration is a localized drug delivery system anywhere in the body through ophthalmic, rectal, vaginal and skin as topical routes. Skin is one of the most readily accessible organs on human body for topical administration and is main route of topical drug delivery system.
The skin of an average adult body covers a surface area approximately 2mand receives about one third of the blood circulating through the body. An average human skin surface is known to contain, on the average 40-70 hair follicles and 200-300 sweat ducts on every square cm of the skin. Although skin has been divided histologically into the stratum corneum, the living epidermis and the dermis, collectively it can be considered a laminate of barrier, permeation of this laminate can occur by diffusion via:
v  Transcellular penetration (across the cells)
v  Intracellular penetration (between the cells)
v  Transappendageal penetration (via hair follicles, sweat and sebum glands).


A myriad of medicated product are applied to the skin or readily accessible mucous membrane that in some way either augment or restore a fundamental function of a skin or pharmacologically modulate an action in the underlined tissues. Such products are referred as topical or dermatological product.

1.1 Rational Approach To Topical Formulations[3]:
Topical formulation can be used to manipulate the barrier function of the skin, for example, topical antibiotics and anti-bacterials help a damaged barrier to ward off infection, sun screening agents and the horny layer protect the viable tissues from U.V. radiation and emollient preparations restore pliability to a desiccated horny layer. Direct drugs to the viable skin tissues without using oral, systematic or other routes of therapy. For example, anaesthetic, anti-inflammatory, antipruritic and antihistaminics drugs are to be delivered to viable epidermis and dermis. For skin appendage treatment, for example, antiperspirants, exfolients and depilatories are to be delivered to the skin appendages. Deliver drugs for systematic treatment, for example, trans-dermal therapeutic systems provide systemic therapy for motion sickness, angina and hypertension.


1.2Classification of Medicated Application For The Skin[3]:
*  Liquid preparations

Liniment                            Lotions

Paints                                 Topical solution

Topical tinctures                Collodions

*  Semi-solid preparations
Ointments                             Creams

Pastes                                   Gels

*  Solid preparations
Topical powders (dusting powders)     Poultices

*  Miscellaneous preparations
Transdermal drug delivery systems          Tapes and Gauzes

Rubbing alcohols                                      Liquid cleanser

Topical solutions are of low viscosity and often use water or alcohol in the base. The solution can cause drying of the skin if alcohol is used in the base. These are usually a powder dissolved in water, alcohol, and sometimes oil. Alcohol in topical steroids can frequently cause drying if it is used as a base ingredient. There is significant variability between generic brands and name brands. There is a risk of irritation, depending on the preservative(s) and fragrances used in the base. Some examples of topical solutions are given below:
AluminiumAcetate topical solution: This is a colourless, with a faint acetous odour and sweetish taste. It is applied topically as an astringent after dilution with 10-40 parts of water. This is used in many types of dermatologic lotions, creams, and pastes. Commercial premeasured and packed tablets and powders are available for this preparation.

PovidoneIodine Topical solution: This is a chemical complex of iodine with polyvinylpyrrolidone, the agent being a polymer having an average molecular weight of 40,000. The povidone iodine contains 10% Available iodine, slowly released when applied to skin. This preparation is employed topically as a surgical scrub and non irritating antiseptic solution, with its effectiveness being directly attributed to the presence and release of iodine from the complex. Commercial Product: BETADINE SOLUTION

Lotion:  lotions are similar to solutions but are thicker and tend to be more emollientin nature than solution. They are usually an oil mixed with water, and more often than nothave less alcohol than solutions. Lotions can be drying if they contain a high amount of alcohol. There is a significant variability in the ingredients of base of generic lotions when compared to brand name lotions.

Shake lotion  A mixture that separates into two or three parts with time. Frequently an oil mixed with a water-based solution. Needs to be shaken into suspension before use. "Shake well before use".

Cream:  A cream is an emulsion of oil and water in approximately equal proportions. It penetrates the stratum corneum  outer layer of skin well. Cream is thicker than lotion, and maintains its shape when removed from its container. It tends to be moderate in moisturizing tendency. For topical steroid products, oil-in-water emulsions are common.

Ointment: An ointment is a homogeneous, viscous, semi-solid preparation, most commonly a greasy, thick oil (oil 80% - water 20%) with a high viscosity, that is intended for external application to the skin or mucous membranes. They are used as emollients or for the application of active ingredients to the skin for protective, therapeutic, or prophylactic purposes and where a degree of occlusion is desired.

Ointments are used topically on a variety of body surfaces. These include the skin and the mucus membrane  of the eye.

Ointments are usually very moisturizing, and good for dry skin. They have a low risk of sensitization due to having few ingredients beyond the base oil or fat, and low irritation risk. There is typically little variability between brands of generics and name brand drugs. They are often disliked by patients due to greasiness.

Gels: Gels are thicker than a solution. Often a semisolid emulsion in an alcohol base. Some will melt at body temperature. Tends to be cellulose cut with alcohol or acetone. Tends to be drying. Tends to have greatly variable ingredients between generic brands and trade names. Significant risk of inducing hypersensitivity due to fragrances and preservatives. Useful for the scalp and body folds. Avoid fissures and erosions due to drying and stinging effect of alcohol base. High rate of acceptance due to its cosmetic elegance.

Transdermal patch:  Transdermal patch can be a very precise time released method of delivering a drug. Cutting a patch in half might affect the dose delivered. The release of the active component from a transdermal delivery system (patch) may be controlled by diffusion through the adhesive which covers the whole patch, by diffusion through a membrane which may only have adhesive on the patch rim or drug release may be controlled by release from a polymer matrix. Cutting a patch might cause rapid dehydration of the base of the medicine and affect the rate of diffusion.

Powder:  powder is either the pure drug by itself (talcum powder), or is made of the drug mixed in a carrier such as corn starch or corn cob powder (Zeosorb AF - miconazole powder). Can be used as an inhaled topical (cocaine powder used in nasal surgery).

Solid Medication placed in a solid form. Such as deodorant, antiperspirants, astringents, and hemostatic agents. Some solids melts when they reach body temperature (e.g. rectal suppositories).

Sponge: Certain contraceptive methods relies on the sponge as a carrier of a liquid medicine. Lemon juice embedded in a sponge has been used as a primitive contraception in some cultures.

Tape: Cordran tape is an example of a topical steroid applied under occlusion  by tape. This greatly increase the potency and absorption of the topical steroid and is used to treat inflammatory skin diseases.

Paste: Paste combines three agents - oil, water, and powder. It is an ointment in which a powder is suspended.

1.3 Introduction To The Skin[2]:   
Human skin consistsof a stratified, cellular epidermis and an underlying dermis of connective tissue . The dermal–epidermal junction is undulating in section ridges of the epidermis, known as secrete ridges, project into the dermis. The junction provides mechanical support for the epidermis and acts as a partial barrier against exchange of cells and large molecules. Below the dermis is a fatty layer, the panniculus adiposus, usually designated as ‘subcutaneous’. This is separated from the rest of the body by a vestigial layer of striated muscle, the panniculus carnosus. There are two main kinds of human skin. Glabrous skin (non-hairy skin), found on the palms and soles, is grooved on its surface by continuously alternating ridges and sulci, in individually unique configurations known as dermato glyphics. It is characterized by a thick epidermis divided into several well-marked layers, including a compact stratum corneum, by the presence of encapsulated sense organs within the dermis, and by a lack of hair follicles and sebaceous glands. Hair-bearing skin on the other hand, has both hair follicles and sebaceous glands but lacks encapsulated sense organs. There is also wide variation between different body sites. For example, the scalp with its large hair follicles may be contrasted with the forehead, which has only small vellus-producing follicles, albeit associated with large sebaceous glands. The axilla is notable because it has apocrine glands in addition to the eccrine sweat glands, which are found throughout the body. Regional variation is further considered below

Skin Structure The skin can be considered to have four distinct layer
1. Non-viable epidermis (stratum corneum)
2. Viable epidermis
3. Viable dermis
4. Subcutaneous connective tissue (hypodermis)

Non-viable Epidermis: (stratum corneum) Stratum corneum is the outer most layer of skin, which is the actual physical barrier to Most substance that come in contact with the skin. The stratum corneum is 10 to 20 cell layer thick over most of the body. Each cell is a flat, plate-like structure - 34-44 μm long, 25 36 μm wide, 0.5 to 0.20 μm thick - with a surface area of 750 to 1200 μm2 stocked up to each other in brick like fashion. Stratum corneum consist of lipid (5-15%) including phospholipids, glycosphingolipid, cholesterol sulfate and neutral lipid, protein (75-85%) which is mainly keratin.

Viable epidermis:This layer of the skin resides between the stratum corneum and the dermis and has a thickness ranging from 50- 100 μm. The density of this region is not much different than water. The water content is about 90%.

Dermis: Just beneath the viable epidermis is the dermis. It is a structural fibrin and very few cells are like it can be found histologically in normal tissue. Dermis thickness range from 2000 to 3000 μm and consists of a matrix of loose connective tissue composed of fibrous.

Subcutaneous connective tissue:
The subcutaneous tissue or hypodermis is notactually considered a true part of thestructured connective tissue is composed ofloose textured, white, fibrous connective tissue containing blood and lymph vessels, secretory pores of the sweat gland and cutaneous nerves. Most investigators consider drug permeating through the skin enter the circulatory system before reaching the hypodermis, although the fatty tissue could serve as a depot of the drug.

1.4 Skin Barrier[2]:
The method employed for modifying the barrier properties of the stratum corneum to enhance drug penetration and absorption through skin may be classified into the following categories
1. Chemical enhancement  
2. Physical enhancement
3. Biochemical enhancemen 
4. Supersaturation enhancement
5. Bioconvertable prodrug

Fig1: Human skin structure

1.5 Gels[7,13,25]:
The term “Gel” was introduced in the late 1800 to name some semisolid material according to pharmacological, rather than molecular criteria.

The U.S.P. defines gels as a semisolid system consisting of dispersion made up of either small inorganic particle or large organic molecule enclosing and interpenetrated by liquid. The inorganic particles form a three-dimensional “house of cards” structure. Gels consist of two-phase system in which inorganic particles are not dissolved but merely dispersed throughout the continuous phase and large organic particles are dissolved in the continuous phase, randomly coiled in the flexible chains.

1.6 Classification of Gels:
Gels are classified  mainly by two methods based on:
a) Nature of colloid phase
i) Inorganic gels                                                         ii) Organic gels
b) Based on nature of solvent
i) Aqueous gels                                                      ii) Non aqueous gels

1.7 Gel forming substances:
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
Proteins:Collagen, Gelatin
* Polysaccharides:Agar, Alginate acid, Sodium or Potassium carageenan, Tragacanth, Pectin, Guar Gum, Cassia tora, Xanthan, Gellum Gum

2. Semisynthetic polymers
Cellulose derivatives: Carboxymethyl cellulose, Methylcellulose, Hydroxypropyl       cellulose, Hydroxy propyl (methyl cellulose), Hydroxyethyl cellulose.

3. Synthetic polymers
*  Carbomer: Carbopol 940, Carbopol 934                 
*  Polyacrylamide                                                       
*  Polyethylene and its co-polymer                              
*  Aluminium hydroxide                                                          

1.8 Advantages of Topical Drug Delivery Systems:
*  The topical administration of drug in order to achieve optimal cutaneous and percutaneous drug delivery has recently gain an importance because of various advantages:

* They can avoid gastrointestinal drug absorption difficulties caused by gastrointestinal pH and enzymatic activity and drug interaction with food and drinks.
*  They can substitute for oral administration of medication when that route is unsuitable.
*  To avoid the first pass effect, that is, the initial pass of drug substance through the systemic and portal circulation following gastrointestinal absorption.
*  The deactivation by digestive and liver enzyme.
*  They are non-invasive and have patient compliance.
*  They are less greasy and can be easily removed from the skin. Cost effective. Reduction of doses as compare to oral dosage forms.
*  Localized effect with minimum side effects.

1.9 Disadvantage of Topical Drug Delivery Systems:
Skin irritation of contact dermatitis may occur to the drug or/and  excipients.
Possibility of allergic reactions. Enzyme in epidermis may denature the drug
Drug of larger particle size not easy to absorb through the skin. Can be used only for drug which require very small plasma concentration for action.

1.10 Mechanism of Drug Absorption:
The rate of permeation across various layers of skin tissues in the course of topical application can be expressed mathematically as
dQ / dt = Ps (Cd – Cr)

where dQ / dt = rate of permeation across various layers.
Cd = concentration of drug in the donar phase.
Cr = concentration of drug in the receptor phase.
Ps = permeability coefficient of the skin tissues.

The concentration in the systemic circulation which is penetrating in the form of pharmacological active form such as :
Ps = KcDs / hs

where Kc = partition coefficient of the penetrant molecules.
hs  = overall thickness of the skin tissues. 
Ds = apparent diffusivity for the steady state diffusion of penetrate moles.
If Cd >>> Cr than the equation is written as dq / dt = PsCd

Ø  Physiological factors in percutaneous absorption
1. Skin integrity
2. Hydration
3. Temperature
4. Anatomic location
5. Age
6. Disease

1.11 Permeation Enhancer[3,12,23]:
The skin is a barrier to topically administered drugs. Although the outer layer also provide resistance to the global permeation process, in-vitro experiment have shown that the stratum corneum, with 10 – 15 micrometer thickness is the principal barrier. Penetration enhancement technology is a challenging development that would increase significantly the number of drugs available for topical administration. The permeation of drugs through skin can be enhanced by physical methods such as mechanical disruption, electrical disruption, chemical modification and by chemical penetration enhancers e.g. sulphoxides ( dimethyl sulphoxides), pyrrolidone, alcohols, glycols, surfactants and terpenes. These compounds increase skin permeability by increasing the partition coefficient of the drug into the skin and by increasing the thermodynamic activity of the drug in the vehicle.

1.12 Classification of permeation enhancers:

Ø  Drug vehicle based:

Drug selection                   Vesicles and particles i.e Liposomes, Ethosomes,

            Prodrug and ion pairs                 Chemical potential of drug

            Eutectic system                           Complexes

Ø  Chemical penetration enhancers:

Sulfoxides                                       Alchohols

              Polyols                                          Alkanes

              Fatty acid                                      Esters

              Amines and amides Terpenes      Surface active agent

Ø  Physical method:

              Radio frequency                            Thermophoresis

              Needleless injection                      Skin stretching

              Electroporation                              Ionotophoresis

              Ultrasound                                      Magnetophoresis

              Skin puncture and perforation

1.13 Pathway of Transdermal Permeation:
Permeation can occur by diffusion via
*  Transdermal permeation, through the stratum corneum.
*  Intercellular permeation, through the stratum corneum.
*  Transappendaged permeation, via the hair follicle, sebaceous and sweat Glands
*  Most molecules penetrate through skin via intercellular micro route and therefore many enhancing techniques aim to disrupt it elegant molecular architecture.
*  Ideal characteristics of chemical penetration enhancers Ideally, penetration enhancers         reversibly reduce the barrier resistance of the stratum corneum without damaging viable cells
*  They should be non-toxic, non-irritating and non-allergenic.
They would ideally work rapidly; the activity and duration of effect should be effective.
*  They should have no pharmacological activity within the body.
*  they should allow therapeutic agents into the body whilst preventing the loss of endogenous materials from the body.
*  When removed from the skin, barrier properties should return both rapidly and normal.They should be cosmetically acceptable with an appropriate skin feel.

NOW YOU CAN ALSO PUBLISH YOUR ARTICLE ONLINE.

SUBMIT YOUR ARTICLE/PROJECT AT articles@pharmatutor.org

Subscribe to PharmaTutor Alerts by Email

FIND OUT MORE ARTICLES AT OUR DATABASE

LITERATURE REVIEW:
1.Mohamed et al.(2012)
prepared celecoxib gels and evaluated the gel formulation on the oral bioavailability of the drug in human volunteers.Gels were prepared by sequential spraying method, which consist of cholesterol, span 60, and dicetyl phosphate in a molar ratio of 1:1:0.1, respectively. 

2.Srinivas et al. (2012) Prepared the topical gels by ether injection method using span 40 and 60. Its aim to improves the bioavailability. In evaluation study the effect of the varying composition of non ionic and cholesterol on the properties such as encapsulation efficiency, particle size and drug release were studied.

3.Ahmed et al .(2011) evaluated entrapment efficiency (EE%), particle size and microscopic examination of prepared topical gels. Gels prepared with Brij 72 and span 60 showed better formulation forming ability and higher EE% than those prepared with Brij 78 and Brij 92.

4.Murthy et al. (2011) formulated and evaluated of trans-dermal gels of diltiazem hydro chloride by using the polymer and penetration inhancers. Used polymer HPMC, carbopol, sodium alginate, which formed homogenicity,and clear solution.

5.Coviello et al.(2010) identified polysaccharide hydro-gels for modified release formulations with better release kinetics with application on the skin.

6. Gupta et al. (2009) designed  and developed  proniosomal tansdermal drug delivery system for captopril.

7.Ramana et al. (2008) proposed in vitroskin absorption and drug release a comparison of four commercial hydrophilic gel preparations for topical use.

8.Dykes  et al. (2007) proposed the Role of menthol in skin penetration fromtopical formulations of ibuprofen 5% in vivo.

9.Hornedo et al. (2006) proposed rheological characterization of topical carbomer gels neutralized to different pH.

10.Trottet  et al. (2005) identified the finite doses of propylene glycol on enhancement of in vitro percutaneous permeation of loperamide hydrochloride.

11.Ozkan  et al. (2004) proposed In vitro release studied of chlorpheniramine maleate from gels prepared by different method.

12.Agarwal . et al. (2003) described transdermal drug delivery system of ethinylestradiol and levonorgestrel for contraception and hormone replacement theraphy.

13.Faucci  et al. (2002) proposed evaluation of transcutol as a clonazepam transdermal penetration enhancer from hydrophilic gel formulations.

14. Lonsdale et al. (2001prepared developments in polymeric carriers and controlled release systems (some commercially available devices) have been described.

15.Arellano et al.(2000)Influenced the  propylene glycol and isopropyl myristate on the in vitro percutaneous penetration of diclofenac sodium from carbopol gels.

16.Williamset al.(1999) justified transdermal delivery from eutectic systems: enhanced permeation of a trans-dermal drug through skin with best absorption.

17.Chowdary et al. (1998)Formulated and evaluated of topical drug delivery systems of ciprofloxacin by using the different polymer and penetration enhacers.

18.Lucero et al. (1998)identified and studied  shear and compression deformations on hydrophilic gels of tretinoin.

19.Tsai et al. (1998)proposed hydro gel as a base for trans-dermal delivery of berberine and its evaluation in rat skin.

RESEARCH ENVISAGED
Miconazole is antifungal drug it also may used in case of yeast infection to the skin. Basically it used as the topical agent in case of fungal infection. It apply topically to the skin or mucus membranes to cure fungal infection.It work by inhibiting the ergosterol which is the component of fungal cell membrane.It also have some limited antibacterial activity.

Polymer like carbopol 934 fully soluble in water and form a clear gel. Carbomers are synthetic high-molecular-weight polymers of acrylicacid that are crosslinked with either allyl sucrose or allyl ethers of pentaerythritol.

Sodium Alginate is the purified carbohydrate product extracted from brown seaweeds by the use of dilute alkali.It consists chiefly of the sodium salt of Alginic Acid,a polyuronic acid composed of D-mannuronic acid residues linked so that the carboxyl group of each unit is free while the aldehyde group is shielded by a glycosidic linkage.It contains not less than 90.8percent and not more than 106.0percent of sodium alginate of average equivalent weight 222.00,calculated on the dried basis.

Propylene glycol has properties similar to those of highly toxic ethylene glycol (monoethylene glycol or MEG). (Note: infrequently, propylene glycol may also use the acronym MEG, but as an abbreviation of methyl ethyl glycol - the industry standard acronym for propylene glycol is PG or MPG (monopropylene glycol).) The industrial norm is to replace ethylene glycol with propylene glycol when safer properties are desired.

Our objectives are achieving the following characterstics in miconazole topical gel:

PLAN OF WORK
The proposed work proceeded following lines:

PREFORMULATION STUDIES

  • Identification and characterization

a)      physical appearance
b)      ultraviolet spectroscopy

  • Melting point
  • Solubility studies

QUANTITATIVE ESTIMATION OF DRUG
METHDOLOGY

Preparation of Topical Gel
Selection of polymers

CHARACTERIZATION
pH
Viscosity
Drug contents
In-vitro release study

DRUG AND EXCIPIENTS PROFILE
2.1DRUG PROFILE[15,24]

2.1.1 Drug Name:Miconazole

2.1.2 Chemical Name: 1-(2-(2,4-dichlorobenzyloxy)-2-(2,4-dichlorophenyl)ethyl)-1 H-imidazole.

2.1.3  Structure:

2.1.4 Molecular formula: C18H14Cl4N2O

2.1.5 Mol. Weight: 479.15

2.1.6 Appearance: White crystalline powder

2.1.7 Solubility: Soluble in methanol, slightly soluble in chloroform and Ethanol, very slightly soluble in Water and Ether.

2.1.8 Melting point: -179-1820C

2.1.9 Dose: 100 mg usual in miconazole pessaries and 150 mg in miconazole nitrate tablet, miconazole tablet.
0.6 to 3 gm daily by i.v. infusion 2% w/w in cream or gel                     

2.1.9 Pharmacology:  Miconazole is an imidazole antifungal agent, developed by Janssen Pharmaceutica, commonly applied topically to the skin or to mucus membranes to cure fungal infections. It works by inhibiting the synthesis of ergosterol, a critical component of fungal cell membranes. It can also be used against certain species of Leishmania protozoa which are a type of unicellular parasite that also contain ergosterol in their cell membranes.

2.1.11 Mode of action:
Acts by inhibiting the growth of the common dermatophytes: Trichophyton rubrum, mentagrophytes, and Epidermophyton floccosum ; the yeast - like fungus, Candida albicans ; and the organism responsible for tinea versicolor (Malassezia furfur).

Miconazole interacts with demythylase, a cytochrome p-450 enzyme necessary to convert lanosterol to ergosterol. Ergosterol is the essential component of the fungal cell membrane, inhibition of this synthesis result in increase cellular permeability causing lekage of cellular contents.

Miconazole also inhibit indogenous respiration, interact with membrane phospholipid, inhibit the transformation of yeast mycelia form, inhibit purine uptake, and impair triglyceride and/or phospholipid biosynthesis.

2.1.12 Pharmacokinetics[13,24]:

Peak plasma concentration

1µg/ml

Protein binding

90%

Absorption

Incompletely absorbed from gastrointestinal tract

Distribution

Widely distributed to body tissues, penetrate well into inflamed joints.

Metabolism

Hepatic, inhibit the metabolism of drug metabolised by cytochrome p450. Enhance the activity of oral anticoagulants.

Elimination

Eliminated via billiary excretion and renal excretion. Approximately 20% is excreted in urine and 50% in faeces

2.1.13 Therapeutics uses:
Miconazole is the antifungal drug. It is used in superficial candidiasis. It is highly efficacious drug for Tinea, Pityriasis versicolor, Otomycosis, Vulvovaginal candidiasis. Because of its good penetration power, it has been found effective, its singal application on skin acts for few days.

2.1.14 Adverse effects:
Infusion: 
Nausea, Vomiting, Diarrohoea, Drowsiness.

Topical:Allergic contact dermatitis, Burning, Maceration.

Vaginal: Abdominal cramps, Burning, Irritation, Itching.

2.1.15 Drug Interaction:
Miconazole may decrease the metabolism of Benzodiazepines(metabolised by oxidation), Alfentanil, Bosentan and calcium channel blocker(Nifedipine etc.).
Miconazole may increase the serum concentration of Eletripton.
Miconazole increase the anticoagulant effect of warfarin.

2.1.16 Toxicity:
Oral, mouse:LD50=3800mg/kg; Oral, rat:LD50=300mg/kg.

2.1.17 Dosage form:

Dosage form                       Route                                   Manufacturer

Aerosol                           opical                                    Insight pharmaceutical

Cream                             Intravaginal                          AL pharma

Cream                             Topical                                 Amazone pharmaceutical

Suppository                   Intravaginal                          Orthopharmceutical

2.1.18 Contraindications:
Hypersensitivity to miconazole or any component of the formulation.

2.1.19 Precautions:
Should a reaction suggesting chemical irritation or sensitivity develop, discontinueuse immediately. Avoid contact with eyes.potentializes the effects of coumarin-type anticoagulants and of hypoglycaemic sulfamides, the anticoagulant level should be carefully monitored and adapted.  may rise phenytoin-serum concentrations, it is advisable to monitor both levels if theyare used concomitantly. Pregnancy and lactation: no evidence of teratogenic effects in animals, prescription duringpregnancy should be outweighed with the expected benefits.

2.1.20 Storage: Store in well closed amber coloured glass container.

2.2 EXCIPIENTS PROFILE[17,19]
Excipients are indispensible component of medicinal product and in most cases comprises the gratest proportion of the dosage unit. It gose without saying that knowledge of the composition, function and behaviour of excipients is a prerequisiteto the successful design, development  and manufacture of pharmaceutical dosage forms. The requirements listed above can be considerd the prime resions to products performance. 

2.2.1CARBOPOL 934
Appearance:
Fluffy, white, mildly acidic polymer

Chemical name:Polyvinyl carboxy polymer crosslinked with ethers of pentaerythritol

Structure:

General Structure of Carbopol Polymers

Equivalent weight:     76 ± 4

Specific gravity:         1.41

Moisture content:       2.0% maximum

Glass transition temperature:100-1050C (212-2210F)

Melting point:Decomposition occurs within 30 min at 2600C

Solubility:Swellable in water and glycerine and after renutralization in ethanol(95%)

Density: (Bulk) 0.2gm/cm3(powder), 0.49gm/cm3(granular)

2.2.2 SODIUM ALGINATE[16,8]
Definition:                  
Sodium alginate is the sodium salt of alginic acid.
IUPAC Name :            sodium 3,4,5,6-tetrahydroxyoxane-2-carboxylate
Molar mass :               10,000 - 600,000
Chemical formula:    (C6H7NaO6)n
Molecular weight:        216.12

Structure:

Appearance:                      white to yellow, fibrous
Density                               1.601 g/cm3
Acidity (pKa):                     1.5-3.5
Functional uses:                 Stabilizer, thickener, gelling agent, emulsifier
Solubility:                           Dissolves slowly in water forming a viscous solution insoluble in ethanol

Packaging and storage:      Preserve in tight containers.

2.2.3 TRIETHANOLAMINE[7,23]
IUPAC Name:
                                      2,2',2"-Trihydroxy-triethylamine
Appearance:                                         Colourless,Transparent,Liquid
Odour:                                                  Amonical 
Molecular formula:                             C6H15NO3
Molar mass:                                         149.19 g/mol
Density:                                                 1.124 g/ml
Melting point:                                      220C
Boiling point:                                      3350C
Solubility in water:                             149dl-1 (at 200C)
Λmax:                                                     280 nm

Structure:

Flammability of the Product:      May be combustible at high temperature.
Flash Points:                                  CLOSED CUP: 179.44°C (355°F).
OPEN CUP: 190.5°C (374.9°F) (Cleveland).
Products of Combustion:          These products are carbon oxides (CO, CO2).
Colour:                                         Colourless to light yellow.
pH (1% sol./water):                     10 [Basic.]

Solubility:
Easily soluble in cold water, hot water. Soluble in methanol, acetone. Very slightly  soluble in diethyl ether, n-octanol.

Stability:  The product is stable.

Conditions of Instability:
Excess heat, light, exposure to air, exposure to moist air or water, incompatible materials  

Corrosivity:
Corrosive in presence of steel, of aluminum, of zinc, of copper. Non-corrosive in presence of glass.

Toxicity to Animals:
Acute oral toxicity (LD50): 2200 mg/kg [Rabbit].

2.2.4 PROPYLENE GLYCOL[19,24]
IUPAC Name:
Propane-1,2diol
Molecular formula:      C3H8O2
Molar mass:76.09 gm/mol
Melting point:-590C
Boiling point:188.20C
Solubility:Fully soluble in water, ethanol, diethylether, acetone, chloroform.
Density: 1.0369gm/cm3

METHODOLOGY
3.1 Preformulation Studies[13,20,25]:

Prior to the development of dosage form, it is essential that certain fundamental, physical and chemical propertyof the drug molecule and other derived property of the drug powder are determined and should be considerd in the formulation in relationto the proposed dosage form and route of administration.

These study should focus on those physiological properties of the drug that could affect drug performance and development of an efficacious dosage form.

3.1.1  Identification of Miconazole:
Physical Appearance:

The drug was found to be white crystalline powder with slight and characteristics odour. Drug  sample was studied for its organoleptic properties.

Melting Point:
The melting point of compound is the temperature at which it change from a solid to liquid. This is physical property to used to identified compound. It was done by capillary method.

Table 1:Melting Point Result of Miconazole

S.No.

Melting range

Melting point(0C)

 

179±1.52

    1

178-1810C

    2

177-1800C

    3

179-1820C

UV Identification:
The organic molecule in solution when exposed to light in the ultra-violet region of the spectrum absorbed light of particular wavelength depending on the type of electronic transition associated with absorption. For identification taken the drug sample of different concentration with different dilution and taken absorption of sample with help of UV spectroscopy.

The λ max determination of miconazole is done by UV/Vis-spectroscopy. Accurately weighed 10 mg of drug that is miconazole was dissolved in 10 ml of methanol to give  a solution of 0.1mg/ml(100µg/ml) concentration and this was served as standard  stock solution. From this solution 1ml was taken and diluted to 10 ml using methanol to get a solution were scanned in the range of 400-200 nm of using methanol as a blank with help of UV /Vis-spectrometer and  λ max were recorded.

3.1.2Solubility Study:
Solubility is defined as the concentration of the solute in the solution when equilibrium exist between the pure solute phase and the solute phase. The solubility of miconazole studied in various aqueous and non-aqueous solvent. Solubility is determined by exposing excess of powder drug to the solvent and assaying after equilibrium has established. Excess amount of miconazole was added to different solvent and agitated for 24 hr at room temperature.

Table 2:Solubility of Miconazole  in  Different Solvent

S.No.

Solvent

Description as per I.P.

1

Methanol

Freely Soluble

2

Chloroform

Slightly Soluble

3

Ether

Slightly Soluble

4

Water

Practically Insoluble

5

PBS pH 6.4

Very Slightly Soluble

3.1.3 Quantitative Estimation of Drug:
Accurately weighed 10mg of miconazole was dissolved in 10 ml of methanol to give a solution of 1000 µg/ml concentration. This solution served as standard stock solution ?. From this solution 1 ml was taken and diluted to 10 ml using distill water to get the concentration of 100µg/ml. This solution served as standard stock solution II. In to a series of 10 ml volumetric flask, aliquots of standard solution II {1 ml, 2 ml, 3 ml, 4ml, 5ml, 6ml, 7ml, 8ml, 9ml } were added and the volume was made up to 10 ml using methanol. The absorbance of this solution was measured against blank at 274 nm and the calibration curve was plotted.                                  

Fig.2 Regressed Curve of Miconazole in Methanol

3.2 Formulation Development:

Method of preparation:
3.2.1 By using carbopol 934:

v  Appropriate quantity of carbopol 934 was soaked in water for a period of 2 hours.

v  Then specified amount of drug was dissolved in appropriate and pre-weighted amounts of propylene glycol.

v  Solvent blend was transferred to carbopol container and agitated for additional 20 min. The dispersion was then allowed to hydrate and swell for 60 min.

v  Carbopol was then neutralized with tri-ethanolamine (TEA) with stirring &finally adjusted the pH with TEA until the desired pH value was approximately reached (6.8-7).  During pH adjustment, the mixture was stirred gently with a spatula until homogeneous gel was formed.

v  All the samples were allowed to equilibrate for at least 24 hours at room temperature prior to performing rheological measurements.

3.2.2 By Using 5% w/w Na CMC and  8% w/w Sodium Alginate:
v  5% w/w Na CMC  and  8% w/w sodium alginate in water  by continuous stirring for a period of 2 h.  Miconazole  was dissolved in  propylene glycol or methanol  and the solution was added gently to , Na CMC and sodium alginate dispersion under continuous stirring. The mixture was stirred gently with a spatula until homogeneous gel was formed.

v   All the samples were allowed to equilibrate for at least 24 h at room temperature prior to performing rheological measurements .

Table 3:Formulation of miconazole gels using different gelling agents:

S.No.

 

INGREDIENTS

C1

C2

N1

N2

S1

S2

1.

Miconazole

500 mg

500 mg

500 mg

500 mg

500 mg

500 mg

2.

Carbopol 934

1 gm

2 gm

-

-

-

-

3.

Na CMC

-

-

5 gm

5 gm

-

-

4.

Na alginate

-

-

-

-

8 gm

8 gm

5.

Propylene glycol

4.500

9.00

5

10

5

10

6.

Triethanolamine

q.s.

q.s.

-

-

-

-

7.

Distilled water

94

88.5

89.5

84.5

86.5

87.5

3.3 Evaluation And Characterization[23,24,25]:
3.3.1
Physical Examination:
The prepared miconazole gels of each batch (C1,C2, N1, N2, S1, S2) were inspected visually for their colour, homogeneity, consistency, spreadiability and phase separation.

3.3.2 pH Determination:
The pH was measured in each gel, using a pH meter, which was calibrated before each use with standard buffer solutions at pH 4, 7, 9.
pH of the each batch (C1, C2, N1, N2, S1, S2, ) of miconazole gel determined and it adjust between 6.8-7.

3.3.3Viscosity Measurement:
A viscometer (Brookfield digital viscometer DV II RVTDV-II USA) was used to measure the viscosities (in cPs) of the gels of each batch. The spindle (TF 96) was rotated at 5,10,20,50 rpm. Samples of the gels were to settle over 30 min at the assay temperature (25 ±/1oC) before the measurements were taken.

3.3.4Drug Content Studies:
To ensure uniform formulation of the gel, it was sampled from the different locations in the mixer and assayed for the drug content. Drug content of the gels was determined by dissolving an accurately weighed quantity of gel (about 1 gm) in about 10 ml of methanol solution. These solutions were quantitatively transferred to volumetric flasks and     appropriate dilutions were made with the same methanol solution. The resulting solutions were then filtered 0.45 mm membrane filters before subjecting the solution to spectro-photometric analysis for miconazole at 274 nm. Drug content was determined from the standard curve of miconazole.

Table 4: Physiological Evaluation of Topical Gel of Miconazole

Formulation

pH

Viscosity

(CPsX103)

%Drug contents

Spreadability(gm/cm3)

C1

6.72

152

98.04

32

C2

6.68

447

97.89

21.05

N1

6.67

320

96.98

20.05

N2

6.67

499

98.65

19.05

S1

6.74

58

95.64

14.28

S2

6.69

108

97.40

17.55

3.3.5 In Vitro Release Study of Miconazole:
Release of miconazole from various gel formulations was studies using a modified Keshary-Chien diffusion cell. A standard cellophane membrane (soaked in pH 6.8 for two hours before use) was fixed to one end of the cylinder with the aid of an adhesive to result in permeation cell. One gram of gel was taken in the cell (donor compartment) and the cell was immersed in beaker (100 ml) containing drug free phosphate buffer pH 6.8 (90 ml) as receptor compartment. The cell was immersed to a depth of 1 cm below the surface of phosphate buffer in the receptor compartment and was agitated using a magnetic stirrer and a temperature of 32 oC ± 1oC was maintained. Sample (5 ml) of the receptor compartment was taken at various interval of time (30, 60,  120,  180,  360 min) over a period of 6 hours and assayed for miconazole at 274 nm. The volume withdrawn at each time was replaced with drug free phosphate buffer. Amount of miconazole released at various intervals of time was calculated and plotted against time.

Table 5: In-Vitro Drug Release:

Formulation

  % drug (Miconazole)release

30 min

60 min

120min

180min

360min

    C1

3.45

7.05

12.42

14.27

23.53

   C2

3.03

6.12

8.98

12.98

20.94

     N1

3.22

6.88

9.65

14.54

24.03

   S1

2.45

4.99

9.01

12.08

18.08

 

Physical Examination:
The prepared miconazole gel formulations of different batches (C1, C2, N1, N2, S1, S2,) were transparent in carbopol 934, white viscous in  Na CMC and brownish gummy in sodium alginate with a smooth and homogeneous appearance. They were easily spreadable and form smooth layer to the skin with acceptable manner and easy to application.

Surface pH:
The pH values of all the prepared formulations ( C1,C2, N1, N2, S1, S2) ranged from 6.5 to 7.0. which is considered acceptable to avoid the risk of irritation upon application to the skin.

Effect of Polymer Concentration On Drug Release:
Ø  On The %Cumulative Drug Release:
In vitro dissolution profile of miconazole gelscontaining different concentration of carbopol (1%and 2%), Na CMC(5%w/w),Sodium alginate(8%w/w) are shown in Table1(C1,C2,N1,N2,S1, and S2). Theinitial concentration of miconazole in all of the gelswas kept as constant at 2%. It is clear from theTable 2 that drug release at 180 minute or 360minute decreased with increase in theconcentration of the polymer.

Ø  On The Viscosity:
Viscosity of miconazole gel formulation (C1, C2, N1, N2, S1, S2, ) increased  as polymer concentrationincreased. Viscosity is negatively related to therelease of active substance from formulations and itspenetration through the diffusion barriers. Thedecrease in the release could be attributed toincreased microviscosity of the gel by increasingpolymer concentration. Thus, both highconcentration of polymer and high viscosity competeeach other in decreasing the release of activesubstance from the formulation.

Effect of Penetration Enhancer:
One of the approaches for improving thetopical drug delivery uses the penetration enhancer. Among them, propylene glycol has beenthe most commonly used excipients in topicallyapplied dosage forms. In this study, effect of theconcentration of propylene glycol (5 and 10% v/v) onthe permeation of miconazole has been studied. Theconcentration of propylene glycol increased keepingthe concentration of polymer constant (carbopol 1% & 2%, Na-CMC 5% and sodium alginate 8%).It is believedthat increasing the concentration of an activecompound (miconazole) within the solvent(propylene glycol) can give rise to persistent solvatedcomplexes and evidence for that higher permeationof drug. In general, it is beveled that increase in theconcentration of propylene glycol in gels, increasespermeation of drug.

4.1 Summary:
The aim of present investigation was to formulate, evaluate and optimized transdermal gels for transdermal delivery of miconazole.

Miconazole is widely used antifungal agent, but it’s use in topical formulation is not efficacious deep seated fungal infectionare  defficult to treat with conventional topical formulation. The entrapment of drug in polymer facilitate the localized delivery of drug and improve availability by means of control controlled- release pattern can advance the treatment of deep fungal infections. This study examined critical parameters .

Miconazole  was identified and characterized as per the requirement of Indian pharmacopoeia and literature. The  λmax was obtained at 270.08 nm which is very near with official value 272 nm.

Standerd curve of miconazole was prepared in methanol in concentration range of 10- 90µg/ml by measuring absorbance at 274 nm.

Various type of polymer  were used like Carbopol 934, Na CMC, Sodium alginate and penetration enhancer like propylene glycol were used. Different- different concentration of polymer  were taken to formulate the  topical gels.

Polymer were used to form smooth gel, homogeneity, consistency, and as the vehicle for control  release . Penetration enhancer like propylene glycol were used, which causes the penetration of skin to  show the action of miconazole.

4.2 Conclusion:
From above results, we can conclude that miconazole gel formulations prepared with different gelling agents: carbopol934, Na CMC and sodium alginate showed acceptable physical properties and drug release study. All prepared gel showed acceptable physical properties concerning colour, homogeneity, consistency, spreadability and pH value. Among all gel formulations with polymer (carbopol, NaCMC, sodium alginate) carbopol gels shows superior drug release after that Na CMC and sodium alginate shows decreasing order of drug release. In carbopol gel formulations, the drug release was decrease with increase in carbopol concentration because polymer concentration increases, viscosity increases.

Viscosity is negatively related to the release of active substance (miconazole) from formulations. containing penetration enhancer (propylene glycol) were used at different concentrations (5 to 10%), among them formulations containing 5% propylene glycol showed higher flux (permeability and drug release) values.

Stability studies in all batches (C1, C2, N1, N2, S1, S2) gel formulations showed that, the physical appearance, drug content, pH, rheological properties, and drug release in all gel formulations remain unchanged upon storage for one months.

4.3 Future Scope:
The miconazole topical gels exhibited better antifungal activity and passive controlled delivery into the deeper layer of skin with extended duration of action, higher drug entrapment and controlled in vitro release through  topical route. Higher efficacy and minimizing undesirable side effect of the present study may be utilized alone or in combination of other biodegradable polymer to produce novel dosage form which make better product.

The high expectation  for better quality of life, and the ever-increasingly reported and potential application of the topical gel have offered unforeseen opportunities and certain challenges to the science and technology.

REFERENCES
1. Kofuji K, Akamine H, Qian CJ, Watanabe K, Togan Y, Nishimura M, Sugiyama I, Murata Y,Kawashima S. Therapeutic Efficacy of Sustained Drug Release from topical Gel on Local Inflammation. Int J Pharm 2004; 272: 65-78.
2. ASTM F719 - 81. Standard practice for testing biomaterials in rabbits for primary skin irritation. West Conshohocken, Philadelphia; 2007: 178-179.
3 .Sinha VR, Maninder PK. Permeation enhancers for trans-dermal drug delivery. Drug Dev Ind Pharm 2000; 26: 1131-1140.
4. Park E, Chang S, Hahn M, Chi S. Enhancing effect of propylene glycol on the skin permeation of topical gels. Int J Pharm 2000; 209: 109-119.
5. Brain KR, Green DM, Dykes PJ, Marks R, Bola TS. The Role of Menthol in Skin Penetration from Topical Formulations of antifungal gel 5% in vivo. Skin Pharmacology and Physiology 2005; 19: 17-21.
6. Chen H, Chang X, Du D, Li J, Xu H, Yang H. Microemulsion-based hydrogel formulation of antifungal gel for topical delivery. Int J Pharm 2006; 315: 52-58.
7. Chen H, Chang X, . Hydrogel formulation of antifungal and anti-inflammatory for topical delivery. Int J Pharm 2006; 315: 52-58.
8. Daniels R, Knie U. Galenics of dermal productsvehicles, properties and drug release. JDDG 2007; 5: 367-381.
9. Ankur Gupta, Sunil Kumar Prajapati, Balamurugan M, Mamta Singh, Daksh Bhatia. Design and development of  tansdermal drug delivery system for antifungal and antihypertensive(captripril). Tropical Journal of Pharmaceutical Research. 2007; 6(2): 687-693.
10. Chandra A and Sharma P.K. Proniosome based drug delivery system of Piroxicam. African journal of pharmacy and pharmacology. 2008; 2(9): 184-190.
11. Gopala Krishna Murthy T.E., Sai Kishore V. Formulation and evaluation of transdermal gels of diltiazem hydro chloride. Indian journal of pharmaceutical education an Kumar S.K, Jain S.K., Pancholi S.S., Agarwal S., Saraf D.K. and research. 2008; 42(3): 272-276.
12. Agarwal G.P. Provesicular transdermal drug delivery system of ethinylestradiol and levonorgestrel for contraception and hormone replacement therapy. Indian. J. pharma Sci. 2003; 65(6): 620-627.
13. circ.ahajournals.org/content/112/16/2436.full.pdf on line accessed on 15/08/2010.
14. Bonacucina G, Cespi M, Misici-Falzi M and Palmieri G (2006). Rheological, adhesive and release characterisation of semisolid carbopol/tetraglycol systems. Int. J. Pharm, 307: 129-140.
15. Bonina FP and Montenegro L (1994). Vehicle effects onin vitro heparin release and skin penetration from different gels. Int. J. Pharm., 102: 19-24.
16. Levin J and Maibach H (2005). The correlation between transepidermal water loss and percutaneous absorption: an overview. J. Cont. Release, 103(2): 291-299.
17. Muramatsu M, Ozeki T, Yuasa H and Kanaya Y (2000). Application of Carbopol to controlled release preparations 1. Carbopol ® as a novel coating material. Int. J. Pharm., 199: 77-83.
18. Sinha, V.R.; Kumria, R. Polysaccharides in colon-specific drug delivery. Int. J. Pharm. 2001, 224,19-38.
19. Gennaro AR. Remington’s Pharmaceutical Sciences. 18th ed. Philadelphia: Mack Publishing Co; 1990
20. Reynolds JEF, ed. Martindale: The Extra Pharmacopoeia. 29th ed. London: Pharmaceutical Press; 1989.
21. Ross DZ, Riley CM. Aqueous solubilities of some variously substituted quinolones antimicrobials. Int J Pharm. 1990;63:237–250.
22. Rathore YKS, Chatterjee PK, Mathur SC, Sunderlal K, Sethi PD. Studies on solubility of few quinolones. Indian Drugs. 1990;27:215–217.
23. googlescholar.org/content/192/34/2435.full.pdf online accessed on 08/04 2012.
24. drug.com/contents/365/.full.pdf online accessed on 09/04/2012.
25. sciencedirect.com/contents/657. Online accessed on 10/04/2012.

NOW YOU CAN ALSO PUBLISH YOUR ARTICLE ONLINE.

SUBMIT YOUR ARTICLE/PROJECT AT articles@pharmatutor.org

Subscribe to PharmaTutor Alerts by Email

FIND OUT MORE ARTICLES AT OUR DATABASE