Formulation and evaluation of topical gel

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“FORMULATION AND EVALUATION OF GEL CONTAINING ECONAZOLE NITRATE”:

“ FORMULATION AND EVALUATION OF GEL CONTAINING ECONAZOLE NITRATE ” GUIDED BY : Under the guidance of MR. ShRIPATHy.d , M.Pharm . ASST.PROFESSOR 1 PRESENTED BY : Saiesh Phaldesai Roll no : 11PU318 Department of Pharmaceutics Srinivas College of Pharmacy, Mangalore

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Introduction Objectives of The Study Review of literature Materials and method Results and discussion Summary and Conclusion References 2 CONTENTS

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“ 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 . 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 3 Introduction

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4 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

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Advantages of Topical Drug Delivery System Decreases the dose to be administered. Decreases side or unwanted effects. Decreases gastrointestinal side effects. Easy to discontinue in case of toxic effects. Increased patient compliance. Limitations of topical d rug d elivery : Drug with low molecular sizes are only suitable for formulation. It can be difficult for drugs to permeate through skin (this is so because the skin, in addition to being a physical barrier, also acts as a chemical barrier). Ionic drugs cannot be delivered transdermally . Drugs cannot be delivered in pulsatile fashion topicaly . 5

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To perform the preformulation studies of Econazole Nitrate. To perform Polymer -Drug Interaction Studies using F.T.I.R. To design and formulate topical gel containing antifungal agent ( Econazole Nitrate). To determine the drug content. To characterise the prepared gel. To study the release mechanism by suitable in-vitro method. To analyse the data with different kinetic models, to understand the mechanism of drug release. To conduct skin irritation test. To carry out zone of inhibition test. ( Anti-fungal activity ) To carry out stability studies as per ICH guidelines. 6 Objectives of the Study

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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 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 containing carbopol 934 was found to increase the skin permeation and deposition compared to control (marketed gel product) Lalit K, Ruchi V prepared sustained release bio-adhesive topical gel of nimesulide by cold mechanical method 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. 7 Review of literature

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Ravi PP, Raghavendra RNG et.al., formulated and evaluated anti-inflammatory activity etoricoxib gel, gel formulation was prepared using different polymers i.e. carbopol , HPMC K4M , HPC along with different permeation enhancers like DMSO , Lemongrass oil, Mentha oil, oleic acid. And evaluated for its physicochemical and drug release pattern. Based on the evaluation ( In-vivo evaluation) it was concluded that gel formulation containing polymer 2% HPMC and permeation enhancer as 2% lemon grass oil showed better topical activity compare to that of the others formulations containing different polymers and permeation enhancers Vivek KR and Satish K prepared and characterized the gel formulation containing different polymers as gelling agents in various concentrations. During the study different polymers such as carbopol 940(0.2‐1.0%w/v), carboxy methyl cellulose (3.5%w/v), HPMC (0.5‐1.0%w/v) used and evaluated for its anti-inflammatory activity using wistar rat model. It was inferred from the results that gel formulation prepared by carbopol 940 in the range 0.2‐0.6%w/w with drug concentration 1.5% w/w was found to be the best formulation compared to others . Bingham JS and Steele CE carried out the study on the treatment of vaginal candidosis with econazole nitrate and nystatin , where the comparison was done on the efficacy of econazole nitrate and nystatin in the treatment of vaginal candidosis over a period of three days course in the form of pessaries and evaluated for vaginal discharge, irritation, and redness. After the period of 14 days It was observed that nystatin pessaries was not as effective as econazole nitrate in treating vaginal infections caused by C. albicans . 8

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Gajanan D et al. , have reported Formulation and evaluation of transdermal drug delivery system of Clopodogrel bisulphate . Transdermal drug delivery system was prepared using various polymers such as, HPMC, PVP and Ethyl cellulose by solvent evaporation technique. The prepared formulations were evaluated for different physicochemical characteristics. The result of diffusion study shows that formulation, F2 ( HPMC and EC) showed maximum release of 90.06% in 4 hours. 9

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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 :- 164 - 166 ºC p ka : 3.35 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 10 Drug Profile: Econazole Nitrate

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Mechanism of action : Econazole Nitrate 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 . 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. 11

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12 Meterials and method Materials Sl No. Material Use Source 1. Econazole Nitrate API Yarrow Chemicals, Mumbai, India 2. HPMC K4M Gelling and viscosifying agent Yarrow Chemicals, Mumbai, India 3. Carbopol 934F Gelling agent Yarrow Chemicals, Mumbai, India 4. Sodium Alginte Gelling agent Loba Chemicals, Mumbai, India 6. Triethanolamine Neutralizing agent Hi-Media , Mumbai, India 7. DMSO Penetration Enhancer Hi-Media , Mumbai, India 8. Methyl Paraben. Preservative Hi-Media , Mumbai, India

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13 Instruments and Equipments Sl. No Name of the equipment Source 1. UV Spectrophotometer Shimadzu UV-1201 (Japan) 2. Single Pan Balance Dhona Instruments 3. Magnetic Stirrer Rotex (India) 5. Electrical Balance Afcoset ER-120A 6. Brookfield Viscometer Brookfield DV-II+Pro 7. F.T.I.R Jasco. 8. Diffusion cell Raghavenra Scientific Works, India 9. Stability chamber Rotex , 110L-45×45×60 RHC-4

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Determination of melting point Determination of solubility Determination of pH Identification of drug -Determination of λ max :- The standard stock solution of econazole nitrate having concentration of 10µg/ml in phosphate buffer pH 7.4 was scanned between 200-400nm in UV-visible Spectrometer ( Jasco V- 630).The maximum absorption (λ max ) of econazole nitrate peak was obtained at 220nm. -Calibration curve:- Econazole nitrate equivalent 100mg was accurately weighed and dissolved in small quantity of phosphate buffer pH 7.4 in 100ml volumetric flask, the volume was made up to the mark with phosphate buffer pH 7.4 to make concentration 1000µg/ml (stock solution “A”). From stock solution “A” 10ml was dissolved again in 100ml volumetric flask with phosphate buffer pH 7.4 to make concentration 100µg/ml (stock solution “B”). Aliquots 2ml, 4 ml, 6 ml, 8ml, 10ml and 12ml of stock solution “B” were pipette out and final volume was made to 100ml with phosphate buffer pH 7.4 to get concentration of 2µg/ml, 4 µg/ml, 6 µg/ml, 8 µg/ml, 10 µg/ml 12µg/ml respectively. The absorbance was measured at 220nm against blank. Drug and excipients compatibility study by FTIR 10 14 Preformulation studies of drug

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Constituents In terms of % w/w , in 100 gms of gel Econazole Nitrate ( EN ) ( API ) 1.5% Sodium alginate 0.25% - 1% HPMC K4M 0.25% - 1% Carbopol 934 0.25% - 1% DMSO ( Penetration Enhancer ) 0.002% METHYL PARABIN ( Preservative ) 0.015% 15

Formulation Chart :

Formulation Chart 16 Constituents   F1 F2 F3 F4 F5 F6 F7 F8 F9 F10 F11 F12 ECONAZOLE NITRATE ( gm ) 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 SODIUM ALGINATE ( gm ) 1 - - 0.5 0.25 0.75 - - - 0.5 0.25 0.75 HPMC K4M ( gm ) - 1 - 0.5 0.75 0.25 0.5 0.25 0.75 - - - CARBOPOL ( gm ) - - 1 - - - 0.5 0.75 0.25 0.5 0.75 0.25 TRIETHANOLAMINE ( ml) 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 ( ml ) 2.2 2.2 2.2 2.2 2.2 2.2 2.2 2.2 2.2 2.2 2.2 2.2 METHYL PARABIN ( mg ) 15 15 15 15 15 15 15 15 15 15 15 15 WATER UPTO 100GMS                        

Method Preparation of topical gels:-:

Method Preparation of topical gels :- 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 7 of the gel. Now the appropriate quantity of Econazole nitrate was dissolved first in DMSO (Dimethyl sulfoxide ) which was added to the gel, which behaves as the penetration enhancer . Step 3 - Finally Methyl Paraben was added to the gel with continuous stirring till it get dispersed in gel completely. 17

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18 Preparation of Topical Gel : Soaking of polymer: Step I Addition of Triethanolamine Step II Addition of E conazole nitrate With DMSO-Step III GEL Continues Stirring Vigorous Stirring Fig.No.1 Scheme of preparation of Econazole nitrate topical gel.

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Topical gels containing E conazole N itrate were evaluated for the following properties: Physical stability: 6 pH measurement: 7 Spreadability: 9 Extrudability study of the topical gel: 8 % drug content : 8 Viscosity measurement: 8 in-vitro evaluation of prepared gel: 7 Determination of zone of inhibition: 7 Skin irritation study: 8 Kinetic analysis of in-vitro release data : 10 Stability Study : 9 19 Evaluation of T opical G els

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20 Result and Discussion Preformulation studies of drug Parameter Result Reported Melting point 165 °C 164 - 166ºC pH 6.7 6.8 Solubility Freely soluble in methanol, chloroform, DMSO and slightly soluble in water. Freely soluble in methanol, chloroform, DMSO and very slightly soluble in water.

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21 UV spectrum Fig.No.2 UV spectrum of Econazole Nitrate in phosphate buffer pH 7.4

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22 Calibration curve for Econazole Nitrate SL. N0. Concentration (µg/ml) Absorbance 1. 0 0 2. 2 0.152 3. 4 0.268 4. 6 0.396 5. 8 0.526 6. 10 0.656 7. 12 0.802 Parameter Range Wavelength 220nm Coefficient of regression analysis 0.999 Slope 0.0663 Fig.No.3 Standard calibration curve.

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23 Drug and excipients compatibility studies Fig.No.3 F.T.I.R spectra of pure drug Econazole Nitrate Fig.No.4 F.T.I.R spectra of Econazole Nitrate + HPMC

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24 Fig.No.5 F.T.I.R spectra of Econazole Nitrate + Sodium alginate Fig.No.6 F.T.I.R spectra of Econazole Nitrate + Carbopol

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Formulation description Functional group Peak value     Econazole Nitrate     C=O 1718.26 cm -1 -O- 1226.65cm -1 -NO 2 1480.1 cm -1 C-N 2260.2 cm -1 - Cl 721.47 cm -1 25 Formulation description Functional group Peak value     Econazole nitrate + HPMC C=O 1718.37 cm -1 -O- 1232.89 cm -1 -NO 2 1473.35 cm -1 C-N 2258.21 cm -1 - Cl 719.31 cm -1 Formulation description Functional group Peak value     Econazole nitrate + Sodium Alginate C=O 1718.64 cm -1 -O- 1220.34 cm -1 -NO 2 1484.64 cm -1 C-N 2258.21 cm -1 - Cl 720.36 cm -1 Formulation description Functional group Peak value     Econazole nitrate + CARBOPOL C=O 1718.3 cm -1 -O- 1220.43 cm -1 -NO 2 1479.45 cm -1 C-N 2256.11 cm -1 - Cl 721.76 cm -1 Fig.No.7 Drug polymer interaction (F.T.I.R) study of pure drug EN Fig.No.8 Drug polymer interaction (F.T.I.R) study of EN + HPMC Fig.No.9 Drug polymer interaction (F.T.I.R) study of EN + SA Fig.No.10 Drug polymer interaction (F.T.I.R) study of EN + CARBOPOL

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Evaluation of Topical Gel FORMULATION CLARITY pH SPREADABILITY (gms.cm/sec) * VISCOSITY (cps) DRUG CONTENT % Extrudability               F1 + + 6.9 18.66 ± 0.0115 8954 98.7 ++ F2 +++ 6.4 25.01 ±0.0152 8 122 98.8 +++ F3 ++ 6.9 18.08 ±0.0152 8 632 98.4 ++ F4 + 6.8 25.86 ±0.0251 8 223 98 +++ F5 ++ 6.4 28.23 ±0.0057 9321 98.1 + F6 + 6.0 22.06 ±0.0305 8889 98.5 ++ F7 ++ 6.9 27.72 ±0.0264 8142 98.9 +++ F8 ++ 6.8 25.45 ±0.0152 8 826 98.2 ++ F9 + 6.7 18.07 ±0.0115 9116 98.3 + F10 ++ 6.1 23.08 ±0.0057 8874 98.4 ++ F11 ++ 6.6 22.34 ±0.0026 8954 98.1 +++ F12 + 6.3 18.75 ±0.0201 8765 98.2 ++ Note: clarity : turbid: +, clear ++, very clear (glassy): +++ Extrudability : + slow extruded, ++ easily Extruded, +++ Fast Extrudition * Average of three trials ( Average±S.D ) (n=3)

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27 Fig.No.11 Bar graph of pH measurement of different formulations Fig.No.12 Drug content (%) of gel formulations F1-F12

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Clarity The prepared formulation was evaluated by visual inspection under black background and it was graded as follows; + turbid, ++ clear, +++very clear (glassy). The clarity of different gels formulations were F1, F3, F5, F7, F8, F10 and F11 was clear. Formulation F4, F6, F9 and F12 was turbid and formulation F2 was found to be glassy pH Formulations F1 to F12 were checked for their pH using calibrated pH meter. pH of the formulations varied from 6 pH to 6.92 pH. Formulation F9 showed 6.9 pH whereas formulation F6 showed 6 pH . % Drug content The drug content was determined using single point standardization method. Content uniformity of the developed formulations F1 to F12 varied from 98% to 98.90%, which are within acceptable range as specified in Indian Pharmacopoeia (95%-105%). 28

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Viscosity study Formulations F1-F12 was evaluated for their rheological property using Brookfield viscometer at 37 0 C using spindle SC4-18 with increasing speed of 10rpm each time by 10 fold to 100rpm. Formulation F3 showed highest viscosity of 9632 cps and F10 showed 8874 cps. Results of the viscosity show that as the concentration of polymers increases the viscosity also increases, with aggregates formed are more closely packed which tend to form stiff gel like consistency 29

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Cumulative percent drug release from prepared gel containing EN + POLYMERS (HPMC + SA + CARBOPOL ) 30 Time ( mins ) F1 F2 F3 F4 F5 F6 F7 F8 F9 F10 F11 F12 0 0 0 0 0 0 0 0 0 0 0 0 0 5 17.94 20.06 16.89 15.83 19.00 16.89 22.17 21.11 20.06 17.94 24.28 16.89 15 23.02 26.29 21.92 19.75 24.13 22.97 31.67 30.56 28.40 23.02 31.77 20.86 30 38.86 41.22 35.59 34.38 36.85 32.47 36.29 35.14 32.88 29.36 35.34 23.93 45 44.84 55.75 47.76 47.56 49.06 37.10 49.52 46.20 39.61 33.83 40.07 30.26 60 57.36 62.44 57.26 57.06 56.51 46.10 63.29 54.55 45.55 37.40 47.05 34.74 90 65.10 71.49 62.89 61.6 65.25 51.23 77.62 63.19 51.68 45.29 52.18 39.36 120 73.10 77.57 70.78 67.37 75.36 63.90 85.11 75.3 58.01 51.38 58.52 48.36 150 81.34 85.97 79.98 77.47 82.65 73.95 89.63 86.82 66.66 59.77 69.28 53.49 180 88.78 93.56 90.58 87.93 90.14 81.06 95.27 91.35 76.67 68.47 79.38 61.94 210 91.80 95.57 91.55 89.94 92.15 86.12 97.28 93.36 80.69 74.50 87.43 67.97 240 93.81 97.586 92.55 90.95 93.16 90.14 99.29 96.38 89.74 78.53 88.43 75.01

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31 Fig.No.13 Cumulative percent drug release from prepared gel containing EN + POLYMERS (HPMC + SA + CARBOPOL )

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32 Fig.No.14 C omparative cumulative percent drug release from prepared gel formulations F1, F2 and F3 ( 1% w/v HPMC, 1% w/v Sodium Alginate and 1 % w/v Carbopol ) Fig.No.15 Comparative cumulative percent drug release from prepared gel formulations F4, F7 and F10 ( 0.5% w/v HPMC, 0.5% w/v Sodium Alginate and 0.5% w/v Carbopol )

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33 Fig.No.16 Comparative cumulative percent drug release from prepared gel formulations F5, F8 and F11 ( 0.25 % w/v HPMC, 0.25 % w/v Sodium Alginate and 0.25% w/v Carbopol ) Fig.No.17 Comparative cumulative percent drug release from prepared gel formulations F6, F9 and F12 ( 0.75 % w/v HPMC, 0.75 % w/v Sodium Alginate and 0.75 % w/v Carbopol )

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34 Fig.No.18 Comparative cumulative percent drug release to identify the best formulation from the selected formulations prepared gel formulations F2, F7, F8 and F9

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In-vitro diffusion study was carried out for 4 hours using franz diffusion cell . The cumulative % amount of the drug release from the gel at the end of 240 mins was found to be 99.29 % in formulation F7 containing 0.5%w/w of Carbopol and HPMC K4M each. The cumulative % amount of the drug release from the gel at the end of 240 mins was found to be 75.01 % in formulation F12 containing 0.75% w/w of Sodium alginate and Carbopol 0.25% w/w. Individual gel formulations F1, F2 and F3 prepared by using 1% w/w of Carbopol , HPMC K4M and Sodium alginate. Showing the release of 93.71%, 97.58 and 92.55. Amongst which F2 showed the best and highest release of 97.58% was selected. 35

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  In combination formulation F4, F7 and F10 ( 0.5% w/w of Carbopol , HPMC k4M and Sodium alginate) which showed the release of 90.95%, 99.29% and 78.53% out of which F7 was considered the best formulation for showing the release of 99.29%. Combination formulation F5, F8 and F11 (0.25% w/w of Carbopol , HPMC K4M and sodium alginate) which showed the release of 93.16%, 96.38 and 88.43%. out of which F8 showed the best release of 96.38 % Combination formulation F6, F9 and F12 (0.75% w/w of Carbopol , HPMC K4M and sodium alginate) which showed the release of 90.14%, 89.74% and 75.01%. out of which F6 showed the best release of 90.14%. 36

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37 Kinetic analysis of in-vitro release data   F o r m u l a tion c o d e   Zer o o r d e r   F i r st o r d e r   Hig hu c h i   B e st f it re l e ase m ec h a n ism n r 2 n r 2 n r 2 F2 0.3322   0.8877   1.502 0.775   0.34 0.9747     Highuchi models F7 0.3302   0.881   1.512   0.7446   0.14 0.9644     Highuchi models

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38 Fig.No.19 Zero Order Plots of selected gels containing Econazole Nitrate Fig.No.20 First Order Plots of selected gels containing Econazole Nitrate

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39 Fig.No.21 Higuchi’s plots of selected gels containing Econazole Nitrate

Skin irritation test data of best formulation of ( F2,F7 ):

Skin irritation test data of best formulation of ( F2,F7 ) 40 a b b a F2 Before Application F2 After 48 hrs of application \ F7 Before Application F7 After 48 hrs of application

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41 Gel Formulations   Before Application   After 24 hrs. of application   After 48 hrs. of application   I   R   E   I   R   E   I   R   E   F2 0 0 0 0 0 0 0 0 0 F7 0 0 0 0 0 0 0 0 0   Reaction   Score   Erythema   1   No erythema   0   Very slight erythema   2   Negligible irritation   0   Slight irritation   0.4 – 0.5   Moderate irritation   0.5 - 9   Severe irritation   1.9- 2   Redness   1   No redness   0 Classification system for skin irritation. NOTE :- I – Irritation R- Redness E- Erythema

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In skin irritation study 4 rats of either sex weighing between (400‐500g) was used. Animals were divided in to 2 groups of 2 animals each. Hairs were depleted from the abdomen of rats with the help of depilatories and area 4 cm 2 i.e 2cm 2 each was marked on both the sides . Both the sides were marked as A and B, where A represents as blank gel without the drug and B represents as gel containing drug Econazole Nitrate Formulation F2 and F7 showed no signs of the skin irritation, edema when observed after 24 and 48 hours. . 42

Microbial studies of Prepared gel formulations.:

Microbial studies of Prepared gel formulations.       Micro-organisms       Diameter of Zone of Inhibition (mm ) After 72 hrs   Pure Drug   F2   F7   Candida albicans 10mm   10mm   10.2mm 43

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44 Formulation F2 AND F7 Candida albicans Econazole Nitrate Candida albicans

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Anti-fungal activity was carried out using cup plate agar method. Formulation F2 and F7 was placed in liquefied molten sabouraud dextrose agar media containing Candida albican for the period of 72 hours. Similarly the econazole nitrate drug sample was tested. Results showed that F2 and F7 showed zone of inhibition 10mm and 10.2mm close to the observed pure drug, having 10mm . It was found that F2 and F7 showed better zone of inhibition as that of Econazole nitrate alone . 45

Stability study as per ICH guidelines:

Stability study as per ICH guidelines 46 Stability study of In-vitro diffusion studies of formulation F2 and F7 30±2 ° C and 65±5% RH ,   Time(h) %CDR   At 0 day After 30 Day After 60 day   - A* A* 5 20.06 16.360 15.5784 15 26.29 21.78 20.1017 30 41.22 36.66 35.3372 45 55.75 39.279 39.7005 60 62.44 54.377 53.781 90 71.49 63.611 61.843 120 77.57 71.149 70.242 150 85.97 79.855 76.159 180 93.56 87.614 85.620 210 95.57 94.377 93.847 240 97.58 96.291 95.745   Time(h) %CDR   At 0 day After 30 Day After 60 day   - A* A* 5 22.171 21.360 19.578 15 31.674 29.786 29.101 30 36.299 34.668 33.337 45 49.522 48.279 48.700 60 63.298 63.377 62.781 90 77.626 76.611 76.843 120 85.1181 83.149 82.242 150 89.643 87.855 87.159 180 95.274 94.614 93.620 210 97.285 96.377 95.847 240 99.2961 97.2919 97.745 In-vitro diffusion studies of formulation F2 In-vitro diffusion studies of formulation F7

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47 Fig.No.23 In-vitro diffusion study of F2 (A) Fig.No.24 In-vitro diffusion study of F7 [A: 30±2 ° C and 65±5% RH]

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48 Evaluation of physicochemical parameters of formulation F2 Physicochemical parameters Time (Days) 0 30 60   pH   A* 6.4 6.3 6.2 Drug Content (%) A* 98.8   97.34     97.17     Viscosity(cps)***   A* 8 122 8 128 8 129 Physicochemical parameters Time (Days) 0 30 60   pH   A* 6.9 6.8 6.6 Drug Content (%) A* 98.9   97.34     97.17     Viscosity(cps)***   A* 8 142 8148 8 149 * A: 30±2 ° C and 65±5% RH, *** Viscosity measured at 100 rpm Evaluation of physicochemical parameters of formulation F7

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Stability study Stability studies were carried out on selected formulations F2 and F7 as per ICH Guidelines Q1C. The most satisfactory formulations were stored in sealed aluminum tubes at 30 ± 2ºC, 65 ± 5% RH for 6 months.  Where viscosity of F2 was reported as 9128 and 9129 on 30 th and 60 th day. pH observed was 6.3 and 6.3 on 30 th and 60 th day. % drug content was noted as 97.34 and 97.17 on 30 th and 60 th day. Similarly F7 showed viscosity from 9148 and 9149. pH from 6.8 and 6.6 on 30 th and 60 th day. % drug content of 97.34% and 97.32% on 30 th and 60 th day. In-vitro drug release studied reveled readings from 96.29% and 95.74% in F2 and 97.29% and 96.74% in F7. Results were found promising without any changes in the parameters and gels were found stable Tab.no. 28–31 showed the results of in-vitro diffusion, viscosity, pH, drug content different temperature and humidity conditions. 49

summary:

summary In the present study an attempts were made to formulate and evaluate topical gels of Econazole Nitrate. In our preliminary study the standardization of Econazole Nitrate was carried out for purity and identity. Estimation of Econazole Nitrate was done in phosphate buffer pH 7.4 spectrophotometrically at 220nm. The formulation studies include identification, melting point, pH, solubility and In-vitro release studies were carried out. Results revealed that the F.T.I.R spectra of drug and excipients showed that there is no interaction between them. And the gels of all formulation have acceptable physical parameters. The gels prepared by cold mechanical method showed drug content in the range of 98 ±0.0147 %, 98.9 ±0.0146%, in-vitro diffusion release of 88.43% to 99.29 %, viscosity was found in between 8874 cps to 9856 cps, Spreadability was found to be between 18.08 ±0.0152 to 27.72 ±0.0264,pH ranging between 6 to 6.9. 50

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51 All the gels were evaluated for their appearance, pH, drug content, rheological properties, skin irritation test, in-vitro release, stability studies and anti-fungal activity. Visually Carbopol gels were sparkling & transparent, HPMC gels were translucent, sodium alginate gels were translucent . The pH range of Carbopol gels, HPMC gels and sodium alginate gels were found to be suitable for topical application. The drug content of formulated gels found in the range of 98.1% and 98.96% respectively. The viscosity measurement was done for selected gels using Brookfield viscometer at room temperature. Which was found between 8874 cps to 9856 cps Anti-fungal activity of selected best gels was compared with econazole nitrate using Candida albicans using cup plate method. The percentage of zone of inhibition observed for carbopol and HPMC in 0.5%w/w each and carbopol 1% w/w alone showed good results.

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52 The formulation F2 and F7 follows Higuchi’s Model equation which shows linear plot with their high regression co-efficient value between 0.97470 to 0.9644 indicating mechanism of drug release was through Higuchi’s model following zero order and diffusion control release. Stability study shows no significant changes in the post-formulation parameters and in-vitro drug release. This indicates that the gels are fairly stable at storage condition.

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Preformulation studies on EN comply with the reported literature limits. FTIR studies revealed no chemical interaction and indicating stability of drug in gel . The adopted method yielded uniform and reproducible release gel prepared using EN The Average drug content, spreadability , viscosity, extradurbality , washability and in-vitro release were uniform and reproducible . The release was directly proportional to concentration of polymers used . The adopted methods yielded uniform and reproducible gel formulations with all the polymers used. 53 Conclusion

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Gel formulations prepared with carbopol 934 and HPMC K4M showed good homogeneity, no skin irritation, good stability, and antifungal activity. However, the carbopol 934 and HPMC k4m based gel proved to be the formula of choice, since it showed the highest percentage of drug release and good rheological properties. In-vitro release rate studies showed that the drug release were maximum from formulations F2 (containing 1% w/w of HPMC polymer) that is 97.58% and F7 (containing combination of 0.5% w/w Carbopol + 0.5 % w/w HPMC K4M polymers) that is 99.29 %. It can be concluded from the present investigation that proper selection of polymers and drug is a prerequisite for designing and developing a topical drug delivery system. The IR and UV studies suggest that polymer selected i.e Carbopol 934, HPMC, sodium alginate were found to be compatible with the drug EN. The varying concentrations of the three polymers were found to affect the gel parameters like drug release, spreadability and its viscosity. 54

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Overall formulation F2 (containing 1% of HPMC polymer) and F7 (containing combination of 0.5% Carbopol + 0.5 % HPMC K4M polymers) based on diffusion release , viscosity and antifungal activity were found to be an excellent gels The Selected best formulations F2 and F7 were found to follow zero order release followed by non fickian diffusion control mechanism (Higuchi’s model). The combination of EN Carbopol 934, HPMC with DMSO provides results and no side effects such as skin irritation. All formulation containing trithanolamine , which act as a not only preservative but it also, acts as slight penetration enhancer didn’t show any kind of interaction . Anti-fungal effects of gels had been observed just in 72 hours after inoculation. The % zone of inhibition of selected formulation F2 and F7 tested in Candida albicans was found to be good when compared to econazole nitrate alone. All the formulations were found to be stable over the storage period. 55

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SCOPE FOR FURTHER STUDIES Further studies can be carried out by using different proportions and different combination of natural, synthetic and semisynthetic polymers with econazole nitrate by other methods method. The work can be extended to in-vivo studies by using Rabbit as animal model and carry out the in-vitro and in-vivo correlation studies. 56

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Sushil R, Vaibhav U, Avinash G, Santosh B, Shrishail P et.al., Development, Characterisation and Investigation of anti-inflammatory potential of valdecoxib topical gel. J sci ind res 2012;71:273-8. Nirmal HB, Bakliwal SR, Pawar SP. In-situ gel: new trends in controlled and sustained drug delivery system. Int journal of pharm tech res. 2010;2(1):1398-1408 . Ankur J, Piyusha D, Naveen V, Jitendra C, Hemant K et.al., Development of antifungal emulsion based gel for topical fungal infection(s). Int journal of pharm. res and dev 2003;2(12): 18-19. 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. South African med jou 1980; 23:314. Mitkari BV , Korde SA, Mahadik KR, Kokare CR . Formulation and evaluation of topical liposomal gel for fluconazole. In jour of pharm educ and res 2010;44(1)324-32. 57 References

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Swamy NG, Mazhar P, Zaheer A. Formulation and evaluation of diclofenac sodium gels using sodium carboxymethyl hydroxypropyl guar and hydroxypropyl methylcellulose. In jour of pharm ed and res2010;44(4)310-14 Abhijeet P, Jui V, Polshettiwar SA. Formulation and evaluation of in-vitro antimicrobial activity of gel containing essential oils and effect of polymer on their antimicrobial activity. Inter jour of pharm and pharmaceutical sci 2011:3(1): 235-6. Naresh A, Vipin S, Vijay KB, Atul G, Monika H et.al., Lalit S, Aakash SP, Gajanan D, Dinesh KJ. Formulation and evaluation of fluconazole amphiphilogel . . Schl res lib 2011;3(5)125-31 . Lalit S, Aakash SP, Gajanan D, Dinesh KJ. Formulation and evaluation of fluconazole amphiphilogel . Sch res library 2011;3(5)125-31 . Ravi P, Raghavendra NG, Chowdary S. Formulation, evaluation and antiinflammatory activity of topical etoricoxib gel. Asian J of pharm and clinical res 2010;3(1)126-8. 58

ANNEXURE :

ANNEXURE PAPERS PUBLISHED Review papers Phaldesai S*, Shabaraya AR, Shripathy D. Topical gel containing anti-fungal agent. Int J of U ni Pharm and Bio S ci . Review article 2013;2(5): 236-44 Phaldesai S*, Shabaraya AR, Shripathy D. Kinetic modeling of drug release from topical gel. Int J of Uni Pharm and Bio Sci . Review article ( under communication ) MANUSCRIPT ID IJUPBS-RP13140325/03-10-13 Research papers Phaldesai S*, Shabaraya AR, Shripathy D. Formulation and evaluation of topical gel containing econazole nitrate. Int J of Uni Pharm and Bio Sci . Research article. ( under communication ) MANUSCRIPT ID IJUPBS-RP12140362/19-10-13 59

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60 Thank You

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