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DESIGN AND EVALUATION OF NIOSOMAL GEL DELIVERY SYSTEMS FOR TOPICAL APPLICATION OF CLOTRIMAZOLE M.PHARM DISSERTATION PROTOCOL SUBMITTED TO THE RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, BANGALORE, KARNATAKA. By RATHAN KUMAR G Under the guidance of S.B SHIRSAND M. Pharm, (Ph.D) DEPARTMENT OF PHARMACEUTICAL TECHNOLOGY H.K.E.S’s COLLEGE OF PHARMACY GULBARGA-585105 2009-10 1 RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, KARNATAKA BANGALORE ANNEXURE – II PROFORMA FOR REGISTRATION OF SUBJECT FOR DISSERTATION 1. Name of the candidate (In block letters) Permanent Address 2. Name of the Institution 3. Course of study and subjects 4. Date of admission to the course 5. Title of the Topic 6. Brief Resume of the Intended work 6.1 RATHAN KUMAR G HNO- 3288 “VENKATESHWARA NILAYA” RAGHAVENDRA COLONY NEAR St. ALPHONSA CHURCH SHAKTINAGAR 584 170 H.K.E. SOCIETY’S COLLEGE OF PHARMACY, SEDAM ROAD, GULBARGA - 585105 M.PHARM (PHARMACEUTICAL TECHNOLOGY) 20.06.2009 DESIGN AND EVALUATION OF NIOSOMAL GEL DELIVERY SYSTEMS FOR TOPICAL APPLICATION OF CLOTRIMAZOLE Need for the study: Clotrimazole is an imidazole derivative with a broad spectrum antimycotic activity. It acts by inhibiting biosynthesis of sterol ergosterol, an important component of fungal cell membranes. It is widely used for the treatment of local oropharyngeal candidiasis, vaginal yeast infections; topical applications include fungal infections such as ring worm, athlete’s foot and jock itch. When applied topically clotrimazole penetrates the epidermis but there is little if any systemic circulation, Absorption of 3 to 10% of a dose has been reported following vaginal administration1. 2 Clotrimazole given orally is metabolized in liver to inactive compounds and excreted in the faeces and urine, after oral administration of Clotrimazole lozenges Nausea, Vomiting, unpleasant mouth sensation and pruritus have been reported1. Side effects of clotrimazole on topical application include erythema, stinging, blistering, peeling, edema, pruritus, urticaria, burning, and general irritation of the skin, and cramps2. Nowadays, niosomes play an increasingly important role in drug delivery as they can reduce toxicity and modify drug pharmacokinetics and bioavailability. Niosomes seem an interesting drug delivery system in the treatment of dermatological disorders. In fact, topically applied niosomes can increase the residence time of drugs in the stratum corneum and epidermis, while reducing the systemic absorption of the drug. Niosomes have also been widely studied as drug carriers for controlled and targeted delivery 3, 4. Preliminary studies indicate that niosomes behave in vivo like liposomes, prolonging the circulation of entrapped drug to alter its organ distribution and metabolic stability, or prolonging contact time of drug with the applied tissues in topical application 5-8. Niosomes are unilamellar or multilamellar vesicles formed from synthetic non-ionic surfactants, offering an alternative to liposomes as drug carriers. The proposed work investigates the feasibility of niosomes of clotrimazole for topical application. To enhance the stability and increase the viscosity of this system, carbapol gel will be prepared. 6.2 Review of Literature Exhaustive literature survey was carried out on the proposed topic using Internet, RGUHS (Helinet Consortium) and referring journals. The survey reveals that no work has been carried out on the proposed topic and some related work is quoted below. 1. Nataa kalko et al.9 have prepared metronidazole liposomes for topical application in the treatment of Rosacea with improved delivery of the drug to the skin. 3 2. Yi-Hung Tsai et al.5 Investigated in vitro skin permeation of Estradiol from various proniosomes with various types and contents of non ionic surfactant. The study revealed Estradiol included in proniosomes was entrapped within the lipid bilayers formed by this technique with high efficiency. A significant amount of non-ionic surfactant (span 40) in the proniosomal formulation was needed to enhance estradiol permeation across skin. The findings suggest that inclusion of surfactants and lecithin in vesicles may play an important role than inclusion of cholesterol in determining Estradiol permeation. 3. O.P Katare et al10 have prepared and evaluated (in vitro) Dithranol liposomal/niosomal delivery system. The amount of drug loaded into these vesicles was in the range of 0.97mg/70mg to 3.51mg/180mg of total lipid. These systems have been found to reasonably well in their size and stability characteristics and exhibited improved permeation properties. The results reveal the merits of developed drug-loaded liposomes and niosomes and justify their potential in strengthening the efficacy and safety of the drug. 4. N.K Jain et al11 have prepared a transdermal delivery system of an analgesic agent using elastic liposomes. Common anti inflammatory non-steroidal drug Diclofenac was choosen to provide sustained and targeted delivery. Elastic liposomes were prepared and characterized in vitro and in vivo 5. Behrooz Nasseri12 has studied the effect of cholesterol and temperature on the elastic properties of niosomal membrane. 6. Anna M. Fadda et al13 made a study into the in vitro cutaneous delivery of vesicle- incorporated Tretinoin. The work reveald that composition of niosomes is very important for improving cutaneous delivery or transdermal delivery of a lipophilic drug like Tretinoin. 7. Payam Khazaeli et al14 characterized and studied in vitro release of Caffeine loaded niosomes. The in vitro permeation of caffeine from niosomes of various compositions reveals that neutral vesicles prepared with span60 and cholesterol, entrap a higher caffeine amount, at pH 7.4, niosomes may be a promising carrier for caffeine, especially to their simple production and facile scale up. 4 8. Mura S et al15 made an approach to study liposomes and niosomes as potential carriers for dermal delivery of Minoxidil. liposomes were found to enhance Minoxidil bioavailability in human skin more than propylene glycol-ethanol-water solution. The work suggests that liposomes have great potential for cutaneous targeting and could be used as a feasible therapeutic approach to various skin diseases. 9. Donatella Paolino et al16 have Prepared bola-surfactant niosomes as topical delivery systems of 5-fluorouracil for the treatment of cancer. Studies reveal that inclusion of the active compound inside the vesicles does not modify the physicochemical properties of the carriers. Confocal laser scanning microscopy (CLSM) studies demonstrated that bola-niosomes were able to promote the intra cellular delivery thus improving the anticancer activity of the entrapped 5-fluorouracil. 10. A.Manosroi et al17 have prepared gel containing novel elastic niosomes entrapped with Diclofenac Diethylammonium. The gel showed physical and chemical stability for 3 months and also high fluxes through the rat skin and high anti inflammatory activity in rat ear edema assay. 11. A.Panyosak et al18 made an approach to asses safety of Azelaic acid and its derivatives entrapped in nanovesicles. This study has demonstrated the safety of Azelaic Acid and its derivatives when entrapped in nanovesicles because of no toxicity to normal cell lines and no allergy on rabbit skin. 6.3 Objectives of the study In the proposed research work Clotrimazole Niosomes will be prepared with the following objectives. 1. To bypass the hepatic metabolism of the drug. 2. To increase the residence time of drug at the target tissue. 3. Increased skin penetration of the drug. 4. To prepare more efficient drug delivery system. 5 7. Materials and Methods 7.1 Materials: Drug: Clotrimazole Excipients: 1. Sorbitan Monoesters 2. Cholesterol 3. Diethyl Ether 4. Carbopol 5. Glycerin Equipments: 1. UV-VIS spectrophotometer. 2. Optical microscope. 3. Rotary Flash Evaporator (superfit model). 4. Ultra sonicator. 5. IR spectrophotometer. 6. Stability Chamber. 7. Hot air oven. 8. Thermostatic hot plate with magnetic stirrer. 9. Digital over head stirrer. 10. Electronic Balance. 11. Digital pH meter 7.2 Method Niosomes incorporated with Clotrimazole will be prepared by thin lipid evaporation method; the prepared clotrimazole niosomes are incorporated in carbopol gel17 Evaluation of Clotrimazole Niosomes includes: 1. Size, Shape, Entrapment Efficiency10 2. In vitro drug release (exhaustive dialysis method)14 3. In vitro antifungal activity by cup-plate method 4. Drug leakage on storage and stability10 6 7.3 Does the study require any investigation or intervention to be conducted on patients or other humans or animals? If so please describe briefly Not under the plan of work 7.4 Has ethical clearance have been obtained from your institution in case of 7.3? Not applicable 8. List of Reference 1. Sweetman SC. In: Martindale, editor. The Complete Drug Reference. 35 ed. London: Pharmaceutical Press; 2007. p. 477. 2. [cited 2009 22/11/2009]; Available from: http://www.drugbank.ca/drugs/DB00257. 3. Uchegbu IF, Double JA, Turton JA, Florence AT. Distribution, metabolism and tumoricidal activity of doxorubicin administered in sorbitan monostearate (Span 60) niosomes in the mouse. Pharm Res. 1995;12(7):1019-24. 4. Varshosaz J, Pardakhty A, Hajhashemi VI, Najafabadi AR. Development and physical characterization of sorbitan monoester niosomes for insulin oral delivery. Drug Deliv. 2003;10(4):251-62. 5. Fang JY, Hong CT, Chiu WT, Wang YY. Effect of liposomes and niosomes on skin permeation of enoxacin. Int J Pharm. 2001;219(1-2):61-72. 6. Perini G, Saettone MF, Carafa M, Santucci E, Alhaique F. Niosomes as carriers for ophthalmic drugs: in vitro/in vivo evaluation. Boll Chim Farm. 1996;135(2):145-6. 7. Shahiwala A, Misra A. Studies in topical application of niosomally entrapped Nimesulide. J Pharm Pharm Sci. 2002;5(3):220-5. 8. Vora B, Khopade AJ, Jain NK. Proniosome based transdermal delivery of levonorgestrel for effective contraception. J Control Release. 1998;54(2):149-65. 9. Kalko. Nataa., ajkovac., Jalenjak. Ma, Ivan. Liposomes with Metronidazole for Topical Use: The Choice of Preparation Method and Vehicle. Journal of Liposome Research. 1998;8(2):283-93. 7 10. Agarwal R, Katare OP, Vyas SP. Preparation and in vitro evaluation of liposomal/niosomal delivery systems for antipsoriatic drug dithranol. Int J Pharm. 2001;228(1-2):43-52. 11. Jain S, Jain N, Bhadra D, Tiwary AK, Jain NK. Transdermal delivery of an analgesic agent using elastic liposomes: preparation, characterization and performance evaluation. Curr Drug Deliv. 2005;2(3):223-33. 12. Nasseri B. Effect of cholesterol and temperature on the elastic properties of niosomal membranes. Int J Pharm. 2005;300(1-2):95-101. 13. Manconi M, Sinico C, Valenti D, Lai F, Fadda AM. Niosomes as carriers for tretinoin. III. A study into the in vitro cutaneous delivery of vesicle-incorporated tretinoin. Int J Pharm. 2006;311(1-2):11-9. 14. Khazaeli P, Pardakhty A, Shoorabi H. Caffeine-loaded niosomes: characterization and in vitro release studies. Drug Deliv. 2007;14(7):447-52. 15. Mura S, Pirot F, Manconi M, Falson F, Fadda AM. Liposomes and niosomes as potential carriers for dermal delivery of minoxidil. J Drug Target. 2007;15(2):101-8. 16. Paolino D, Cosco D, Muzzalupo R, Trapasso E, Picci N, Fresta M. Innovative bola-surfactant niosomes as topical delivery systems of 5-fluorouracil for the treatment of skin cancer. Int J Pharm. 2008;353(1-2):233-42. 17. Manosroi A, Jantrawut P, Manosroi J. Anti-inflammatory activity of gel containing novel elastic niosomes entrapped with diclofenac diethylammonium. Int J Pharm. 2008;360(1-2):156-63. 18. Panyosak A, Manosroi J, Rojanasakul Y, Manosroi A. Safety assessment of azelaic acid and its derivatives entrapped in nanovesicles. Hum Exp Toxicol. 2009;28(6-7):387-92. 8 9 Signature of the Candidate Rathan Kumar G 10 Remarks of the Guide 11 Name and Designation of The proposed research topic is novel one, with the preparation of Niosomal Gel we can improve the efficiency of Clotrimazole for Fungal Infections S.B ShirsandM.Pharm (Ph.D) Assistant Professor 11.1 Guide Department of Pharmaceutical Technology H.K.E.S’s College of Pharmacy GULBARGA- 585105 11.2 Signature Dr. S.S BushettiM.Pharm, Ph.D Professor 11.3 Co-Guide Department of Pharmaceutical Technology H.K.E.S’s College of Pharmacy Gulbarga 11.4 12 12.1 Signature Remarks of the Chairman & Principal Signature 9 1. Sweetman SC. In: Martindale, editor. The Complete Drug Reference. 35 ed. London: Pharmaceutical Press; 2007. p. 477. 2. ; [cited 2009 22/11/2009]; Available from: http://www.drugbank.ca/drugs/DB00257. 3. Uchegbu IF, Double JA, Turton JA, Florence AT. Distribution, metabolism and tumoricidal activity of doxorubicin administered in sorbitan monostearate (Span 60) niosomes in the mouse. Pharm Res. 1995;12(7):1019-24. 4. Varshosaz J, Pardakhty A, Hajhashemi VI, Najafabadi AR. Development and physical characterization of sorbitan monoester niosomes for insulin oral delivery. Drug Deliv. 2003;10(4):251-62. 5. Fang JY, Hong CT, Chiu WT, Wang YY. Effect of liposomes and niosomes on skin permeation of enoxacin. Int J Pharm. 2001;219(1-2):61-72. 6. Perini G, Saettone MF, Carafa M, Santucci E, Alhaique F. Niosomes as carriers for ophthalmic drugs: in vitro/in vivo evaluation. Boll Chim Farm. 1996;135(2):145-6. 7. Shahiwala A, Misra A. Studies in topical application of niosomally entrapped Nimesulide. J Pharm Pharm Sci. 2002;5(3):220-5. 8. Vora B, Khopade AJ, Jain NK. Proniosome based transdermal delivery of levonorgestrel for effective contraception. J Control Release. 1998;54(2):149-65. 9. Kalko., Nataa., ajkovac., Jalenjak. Ma, Ivan. Liposomes with Metronidazole for Topical Use: The Choice of Preparation Method and Vehicle. Journal of Liposome Research. 1998;8(2):283-93. 10. Agarwal R, Katare OP, Vyas SP. Preparation and in vitro evaluation of liposomal/niosomal delivery systems for antipsoriatic drug dithranol. Int J Pharm. 2001;228(1-2):43-52. 11. Jain S, Jain N, Bhadra D, Tiwary AK, Jain NK. Transdermal delivery of an analgesic agent using elastic liposomes: preparation, characterization and performance evaluation. Curr Drug Deliv. 2005;2(3):223-33. 12. Nasseri B. Effect of cholesterol and temperature on the elastic properties of niosomal membranes. Int J Pharm. 2005;300(1-2):95-101. 13. Manconi M, Sinico C, Valenti D, Lai F, Fadda AM. Niosomes as carriers for tretinoin. III. A study into the in vitro cutaneous delivery of vesicle-incorporated tretinoin. Int J Pharm. 2006;311(1-2):11-9. 14. Khazaeli P, Pardakhty A, Shoorabi H. Caffeine-loaded niosomes: characterization and in vitro release studies. Drug Deliv. 2007;14(7):447-52. 15. Mura S, Pirot F, Manconi M, Falson F, Fadda AM. Liposomes and niosomes as potential carriers for dermal delivery of minoxidil. J Drug Target. 2007;15(2):101-8. 16. Paolino D, Cosco D, Muzzalupo R, Trapasso E, Picci N, Fresta M. Innovative bolasurfactant niosomes as topical delivery systems of 5-fluorouracil for the treatment of skin cancer. Int J Pharm. 2008;353(1-2):233-42. 17. Manosroi A, Jantrawut P, Manosroi J. Anti-inflammatory activity of gel containing novel elastic niosomes entrapped with diclofenac diethylammonium. Int J Pharm. 2008;360(1-2):156-63. 18. Panyosak A, Manosroi J, Rojanasakul Y, Manosroi A. Safety assessment of azelaic acid and its derivatives entrapped in nanovesicles. Hum Exp Toxicol. 2009;28(6-7):387-92. 10