FORMULATION AND EVALUATION OF GEL CONTAINING ECONAZOLE NITRATE

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“FORMULATION AND EVALUATION OF GEL CONTAINING ECONAZOLE NITRATE” :

“FORMULATION AND EVALUATION OF GEL CONTAINING ECONAZOLE NITRATE” Saiesh P urushottam Phaldesai Under The Guidance of MR. ShRIPATHy.d M.Pharm ASST.PROFESSOR DEPARTMENT OF PHARMACEUTICS

Contents :

Contents Introduction Need for the study Review Of Literature Objective Material And Methods Evaluation Parameters References

Need for the study:-:

Need for the study :- The topical gel formulation offers an interesting alternative for achieving systemic drug effects of parental routes, which can be inconvenient for oral route, which can result in nausea, vomiting, low bioavailability and passes the hepatic first-pass metabolism. This novel drug delivery system promotes the importantly ease and convenience of administration, deliverance of accurate dose as well as to prolong residence time of drug in contact with skin membrane. Smart polymeric system represents promising means of delivering the drug. Various synthetic and natural polymers are been used in the formulation of topical gels .

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Superficial fungal infections are among the most widespread diseases known to man. They target the parts of the body as diverse in form and function as the skin, the nail, the buccal cavity, the eye and the vagina. Fungistatic azole drugs, that is, imidazole and triazole -containing compounds, have been the mainstay of antifungal therapy for many years. The imidazole derivative econazole nitrate is effective in treating Candida albicans infections. Other new agents include the echinocandins (e.g. caspofungin ) that are primarily intended for systemic administration but which may have a role in topical therapy . Topical drug delivery systems have been used for centuries for the treatment of local skin disorders, one side the topical applications of the drug offer the potential advantages of delivering the drug directly to the site of action and delivering the drug for extended period of time at the affected site that mainly acts at the related regions.

List Of Skin Infections :

List Of Skin Infections Candida Albicans Fungal Infactions Tinea Infections Ring Worm

ABOUT THE DISEASE:

ABOUT THE DISEASE Ring Worm :- Ringworm of the skin usually causes a very itchy rash. It often makes a pattern in the shape of a ring, but not always. Sometimes it is just a red, itchy rash. Jock itch is a rash in the skin folds of the groin. It may also spread to the inner thighs or buttocks. Ringworm of the hand looks like athlete's foot. The skin on the palm of the hand gets thick, dry, and scaly. And skin between the fingers may be moist and have open sores . Candida  Albicans is a normally harmless yeast infection found in the mouth, intestinal tract, and vagina. Candidiasis is an infection caused by a fungus called Candida; most commonly the Candida albicans variety. The Candida infection (also known as a yeast infection) usually affects the skin and/or the mucous membranes of the mouth, intestines, or the vagina.

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Tinea capitis is a skin infection or ringworm of the scalp caused by a fungus called dermatophytes ( capitis comes from the Latin word for head). It mostly affects children. Tinea corporis is ringworm of the body ( corporis means body in Latin). In wrestlers this is often called tinea gladiatorum . Tinea pedis or athlete’s foot is an infection that occurs on the feet, particularly between the toes ( pedis is the Latin word for foot ). Tinea cruris or jock itch tends to create a rash in the moist, warm areas of the groin ( cruris means leg in Latin). It most often occurs in boys when they wear athletic gear. Tinea versicolor or pityriasis versicolor is a common skin infection caused by a slow-growing fungus ( Pityrosporum orbiculare ) that is a type of yeast. It is a mild infection that can occur on many parts of the body.

Signs and symptoms :

Signs and symptoms In many cases of ringworm and other tinea infections, circular, ring-shaped sores are formed, which is why the term ringworm is used. On the body, these lesions or patches may be slightly red and often have a scaly border. They may grow to about 1 inch in diameter. While some children have just one patch, others may have several of them. They tend to be itchy and uncomfortable . In ringworm of the scalp, itching may develop on the head, along with round and raised lesions. Hair loss can occur in patches. Some cases of scalp ringworm do not produce obvious rings and can be confused with dandruff or cradle cap. In a few cases, the child will have a reaction to the fungus and develop a large boggy area called a kerion . This looks like a pus-filled sore (abscess), but it is really an allergic reaction to the fungus. The infected area will heal once the fungus is treated. Steroids are often given to speed healing. Sometimes, bacteria can infect the area later. If this occurs, your pediatrician may advise the use of antibacterials .

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Treatment Antifungal medications applied directly on the head are ineffective for treating ringworm of the scalp. Instea ddoctors may recommend giving child antifungal medications by mouth, most often a medicine called griseofulvin , that should be taken for an average of 4 to 6 weeks . A variety of other medicines can be used. Washing hair with selenium sulfide shampoo can decrease shedding that could spread the infection to others . Over-the-counter antifungal or drying powders and creams are effective for other types of tinea infections, including athlete’s foot and tinea corporis . Your pediatrician may prescribe a cream for treating the rash associated with jock itch. Topical medications including clotrimazole,ketoconazole and Econazole Nitrate are used to treat ringworm of the body as well as tinea versicolor .

REVIEW OF LITERATURE::

REVIEW OF LITERATURE: Naresh A, Vipin S, Vijay KB, Atul G, Monika H, Joyati S et al., formulated and evaluated diclofenac sodium gel by using natural polymer, like sodium algenate as natural polymer in different concentrations i.e. 3, 4, 5 gms and assessed for various parameters like clarity, viscosity, pH, extrudability , sterility and In –vitro drug release using dialysis membrane and depending on the base of study it was found that polymer having concentration 5gm showed release upto 9, 8, 6 hours respectively. Showing better release profile than others. Mitkari BV, Korde SA, Mahadik KR, Kokare CR formulated and evaluated topical liposomal gel for fluconazole. The gel was prepared using film hydration technique, using phospholipid (PL 90H), cholesterol (CH) and carbopol 934 NF at different concentrations i.e. 1%, 1.5%, and 2% w/w as gelling agent. The prepared formulation was compared with the marketed gels. And it was concluded that the Liposomal gel was found to increase the skin permeation and deposition compared to control (marketed gel product)

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Lalit K, Ruchi V prepared sustained release bio-adhesive topical gel of nimesulide using natural polymer aegel marmelos (plant Bale). The prepared bio-adhesive topical gel was evaluated with the help of different parameters like drug content, spreadability , extrudability , swelling index study, in–vitro drug diffusion study, in-vitro drug release kinetic study and ex–vivo bioadhesive measurement. On the basis of in–vitro drug diffusion study and ex–vivo bio-adhesive measurement property of gel, it was concluded that natural polymer aegel marmelos is the best polymer for the preparation of sustained release bio-adhesive topical gel.

OBJECTIVES OF THE STUDY::

OBJECTIVES OF THE STUDY: The objective of the study is to prepare polymeric gel containing the antifungal agent for topical skin infections .   Specific objectives of the present investigation are as follows : To design and formulate topical gel containing antifungal agent ( Econazole Nitrate ). To perform Polymer -Drug Interaction Studies using FTIR. To determine the drug content. To characterise the prepared gel. To study the release mechanism by suitable in-vitro method. To carry out stability studies as per ICH guidelines. To carry out zone of inhibition test. ( Anti-fungal activity ) To conduct skin irritation test.

Material And Methods:

Material And Methods USES Drug Econazole Nitrate API Carbopol Polymer ( Gelling Agent) HPMC Polymer ( Gelling Agent) Excipients Sodium alginate Polymer ( Gelling Agent) DMSO ( Dimethyl sulfoxide ) Permeation Enhancer Methyl Paraben Preservative Triethalonamine Neutralising Agent Water etc.

DRUG PROFILE:

DRUG PROFILE Physiological properties: Structural Formula : IUPAC Name : 1-(2-[(4-chlorophenyl) methoxy ]-2-[ 2,4-dichlorophenyl]ethyl )-1H-imidazole nitrate; 1-[2,4- dichloro - β-[( p- chlorobenzyl )oxy] phenethyl ]imidazole Molecular Formula :- C18H15Cl3N2O • HNO3 Molecular Weight (g/mol) : 444.7 Category: Imidazole-derivative azole antifungal. Melting Point :- 162 ºC Solubility : Sparingly soluble in aqueous media. Completely soluble in methanol, DMSO. Storage: Preserve in well-closed, light resistant containers. Pharmacokinetic data: Metabolism : Hepatic. Systemically absorbed drug excreted in urine 39% to 40% and feces (<1% of topical Dose) Plasma Protien Binding :- 98% Half life ( hrs ) : 4 to 6 hours

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Mechanism of action : Econazole interacts with 14-α demethylase , a cytochrome P-450 enzyme necessary to convert lanosterol to ergosterol . As ergosterol is an essential component of the fungal cell membrane, inhibition of its synthesis results in increased cellular permeability causing leakage of cellular contents. Econazole may also inhibit endogenous respiration, interact with membrane phospholipids, inhibit the transformation of yeasts to mycelial forms, inhibit purine uptake, and impair triglyceride and/or phospholipid biosynthesis . Dose: : 150 mg Topicaly once a day. Contraindications: For external use only Use only for topical application to the skin; not for ophthalmic  or intravaginal use . Adverse effects: During clinical trials, approximately 3% of patients treated with econazole nitrate 1% cream reported side effects thought possibly to be due to the drug, consisting mainly of burning, itching, stinging and erythema. One case of pruritic rash has also been reported.

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Constituents F1 F2 F3 F4 F5 F6 F7 F8 F9 F10 F11 F12 Econazole Nitrate (mg) 150 150 150 150 150 150 150 150 150 150 150 150 Sodium Alginate(g) 1 - - 0.5 0.25 0.75 - - 0.5 0.25 0.75 HPMC K4M (g) - 1 - 0.5 0.75 0.25 0.5 0.25 0.75 - - - Carbopol (g) - - 1 - - - 0.5 0.75 0.25 0.5 0.75 0.25 Triethanolamine (mg) 0.23 0.23 0.23 0.23 0.23 0.23 0.23 0.23 0.23 0.23 0.23 0.23 DMSO( gms ) 2.20 2.20 2.20 2.20 2.20 2.20 2.20 2.20 2.20 2.20 2.20 0.23 MP (mg) 15 15 15 15 15 15 15 15 15 15 15 15 water

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Methods:   Gels were prepared by cold mechanical method described by Kumar et al. 15   Step 1 - Required quantity of polymer was weighed and it was sprinkled slowly on surface of purified water for 2 hrs. After which it was continuously stirred by mechanical stirrer, till the polymer soaked in the water.   Step 2 - With continuous stirring, triethanolamine was added to neutralize the gel and it maintains the pH of the gel. Now the appropriate quantity of DMSO (Dimethyl sulfoxide ) was added to the gel, which behaves as the penetration enhancer, followed by the required quantity of Econazole Nitrate.   Step 3 - Finally Methyl Paraben Was added was added to the gel with continuous stirring till drug get dispersed in gel completely.  

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Preparation of Topical Gel : Soaking of polymer: Step I Addition of Triethanolamine Step II Addition of econazole nitrate With DMSO-Step III GEL Continues Stirring

Evaluation Parameters::

Evaluation Parameters: Physical stability: 6 Inspected visually for its colour, homogeneity, consistency, spread ability, and phase separation . pH measurement: 7 pH values of 1% aqueous solutions of the prepared gels were measured by a pH meter Spreadability: 9 For the determination of spread ability, excess of sample was applied in between two glass slides and was compressed to uniform thickness by placing 1kg weight for 5 min. weight (50 g) was added to the pan. The time in which the upper glass slide moves over to the lower plate was taken as measure of spread ability . S= ML/T M- Weight tied to hte upper slide L- Length moved on the glass. T- Time Taken

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Extrudability study of the topical gel: 8 Measure the force required to extrude the material from tube. Extrudability was based upon the quantity in percentage of gel and gel extruded from lacquered aluminium collapsible tube on application of weight in grams required to extrude at least 0.5 cm ribbon of gel in 10 seconds Content uniformity: 8 Drug content of gel was determined by dissolving accurately weighed 1gm of gels in Methanol. After suitable dilution absorbance was recorded by using UV- visible spectrophotometer (UV – 1700, Shimadzu, Japan) at 222 nm. Drug content was determined using slope of standard curve . Viscosity measurement: 8 The viscosity of the different gel formulations was determined at 25°C using a cone and plate viscometer.

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Evaluation of containers for gel: 10 The collapsible aluminium tubes were tested for freedom from leakage by placing filled tubes in a horizontal position on a sheet of absorbent blotting paper in an oven maintained at 60 ± 3 °C for 8 h and observing for leakage. The tubes were tested for freedom from metal particles by observing the smears of gels under light microscope. in-vitro evaluation of prepared gel. 7 The diffusion medium used was Phosphate buffer Ph 7.4, carried out using franz diffusion cell. The diffusion cell was placed on the magnetic stirrer.; the outlet of the resorvior was maiuntained at 37 c. The receptor compartment was filled with fluid ( Phosphate buffer 7.4Ph), the cellophane paper was used as the membrane / Rat skin. The speed of the stirrer was kept constant . With the help of micropipette sample was taken for specified period of time.

List of References: :

List of References: Mitkari BV, Korde SA, Mahadik KR and Kokare CR. Formulation and evaluation of topical liposomal gel for fluconazole. Indian J Pharm Educ Res 2010;44(1):324-32 . Naresh A, Vipin S, Vijay KB, Atul G, Monika H, Joyati S et.al . Formulation and Evaluation of diclofenac sodium gel by using natural polymer. Rasayan J Chem 2008;1(3):554-6. Ankur J, Piyusha D, Naveen V, Jitendra C, Hemant K, Sanjay J. Development of antifungal emulsion based gel for topical fungal infection(s). Int J Pharm Res Dev 2003;2(12):18-9. Pfaller MA, Sutton DA. In-vitro activity of sertaconazole nitrate in the treatment of superficial fungal infections. Diagnostic microbiology and infectious disease 2006; 56:147-52. Bloch B, kretzel A. Econazole nitrate in the treatment of candidal vaginitis. S A medical journal 1980; 23:314. Magdy IM. Optimization of Chlorphenesin Emulgel Formulation. The AAPS Journal 2004 ;6(3):1-7 .

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Jayaraj KK, Jayachandran . E, Sreenivas GM. Formulation and Evaluation of in situ gels containing ciclopriox olamine for oral thrush. Int J Pharm 2010; 1(5):204-15 Lalit K, Ruchi V. In vitro evaluation of topical gel prepared using natural polymer. Int J Drug Del 2010;2:58-63 Sanju D, Bikash M, Sunny C. Formulation and evaluation of diltiazem Hydrochloride Gels for the Treatment of Anal Fissures. Scientia Pharmaceutica 2009;77: 465–82.

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