Design and Evaluation of Miconazole Niosomal Gel Delivery Systems for Topical Application

DESIGN AND EVALUATION OF MICONAZOLE NIOSOMAL GEL DELIVERY SYSTEMS FOR TOPICAL APPLICATION

M.PHARM DISSERTATION PROTOCOL

SUBMITTED TO THE

RAJIVGANDHIUNIVERSITY OF HEALTH SCIENCES,

BANGALORE, KARNATAKA.

DANAM KEERTHY

Under the Guidance of

Dr.S.B.SHIRSAND M.Pharm., Ph.D.

DEPARTMENT OF PHARMACEUTICAL TECHNOLOGY

H.K.E.S’s, Matoshree Taradevi Rampure Institute of Pharmaceutical Sciences

GULBARGA-585105

2011-2012

RAJIVGANDHIUNIVERSITY OF HEALTH SCIENCES, KARNATAKA

BANGALORE

ANNEXURE-II

PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION

1. / Name of the candidate
(in block letters) /

DANAM KEERTHY

Permanent Address / D/O D.KISHORE
D.NO: 9/173,
MARIYANNA STREET,
GEORGEPET,
NELLORE,
ANDHRA PRADESH.
2. / Name of the Institution / HKES’s, Matoshree Taradevi Rampure Institute of Pharmaceutical Sciences, SEDAM ROAD, GULBARGA-585105
3. / Course of study and subjects / M.PHARM
(PHARMACEUTICAL TECHNOLOGY)
4. / Date of admission to the course / 18-12-2011
5. / Title of the Topic / DESIGN AND EVALUATION OF
MICONAZOLE NIOSOMAL GEL DELIVERY SYSTEMS FOR TOPICAL APPLICATION.
6. /

Brief Resume of the Intended work

6.1 /

Need for the study:

Miconazole 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 orophyaryngeal candidiasis, vaginal yeast infections; topical applications include fungal infections such as ring worm, athlete’s foot and jock itch. When applied topically Miconazole penetrates the epidermis but there is little if any systemic circulation, Absorption of 3-10% of a dose has been reported following vaginal administration.

Miconazole given orally is metabolized in liver to inactive compounds and extracted in the faeces and urine, after oral administration of Miconazole lozenges Nausea, Vomiting, unpleasant mouth sensation and pruritus have been reported1. Side effects of Miconazole on topical application include erythema, stringing, blistering, peeling, edema, pruritus, urticaria, burning, and general irritation of the skin, and cramps2.Because of poor dissolution and lack of absorption make it poor candidate for oral administration.

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 delivery3,4. 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 application5-8. 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 Miconazole 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.

Nataakalko et al(9) prepared metronidazole liposomes for topical application in the treatment of Rosacea with improved delivery of the drug to the skin.
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.
Katare et al(10) 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.
Jain et al(11) 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.
Behrooz Nasseri(12) studied the effect of cholesterol and temperature on the elastic properties of niosomal membrane.
Faddaet al(13) investigated in vitro cutaneous delivery of vesicle- incorporated Tretinoin. The work revealed that composition of niosomes is very important for improving cutaneous delivery or transdermal delivery ofa lipophilic drug like Tretinoin.
Payam Khazaeli et al(14) 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.
Muraet al(15) attempted an approach to design 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.
Donatella Paolinoet al(16) 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.
Manosroiet al(17) 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 oedema assay.
Panyosaket al(18) attempted an approach to assess safety of Azelaic acid and its derivatives entrapped in nano-vesicles. This study has demonstrated the safety of Azelaic Acid and its derivatives when entrapped in nano-vesicles because of no toxicity to normal cell lines and no allergy on rabbit skin.
Balakrishnan et al(19) prepared minoxidil niosomes for enhanced skin delivery. Niosomes formed from polyoxyethylene alkyl ethers or sorbitan with monoesters with cholesterol molar ratios of 0.1&1.5 were prepared with varying drug amount 20-50mg using thin film hydration method. The investigations further revealed the potential of niosomes in enhancing transdermal bioavailability of minodoxil in hairless mouse skin even at very low drug concentrations unlike control formulations.
Ataeiet al(20) investigated to study in vitro evaluation of itroconazole loaded vesicles prepared from non-ionic surfactant. The formulations prepared with span 60 resulted in the highest encapsulation efficiency, because the structure of span 60 has a long saturated alkyl chain /cholesterol with the molar ratio of 30:70. This vesicle system used for the delivery of fungal infections.
Coscoaet al(21) investigated effects of a lipid composition on the physico chemical and technological properties of a multidrug carrier(MDC)containing both gemcitabine (GEM) and tamoxifen (TMX) as well as its in-vitro anti-tumoral activity on different breast cancer cell by using three different liposomal formulations.a)DPPC/chol/DSPE, b)DPPC/chol/DOTAP,DPPC,c)DPPC/chol/DPPG.The liposomal MDC provided the best result with respect to the single drug tested in the free from or entrapped in the same liposomal formulation.
Maheshwari et al(22) approached to study ethosomes and ultrade formable lipospomes for transdermal delivery of clotrimazole: results of transdermal flux, bilayer fluidity measurement entrapment efficiency and invitro anti-candidal testing suggest better aptness of CLT with ethosomal formulation instead of UL formulation ,might be due to greater solubility, retentivity & adaptability in lipid bilayers consisting of ethanol.
Vimalet al(23) investigated that encapsulation of finasteride into niosomal and proniosomal gel formulation improves the skin permeation and permeation flux of finasteride and enhance the bioavailability of the drug. Phototrichogram analysis, clearly proved that there is a seven fold increase in hair growth on application of the gel.
6.3 /

Objectives of the study

In the proposed research work Miconazole niosomes will be prepared with the following objectives.

To bypass the hepatic metabolism of the drug.
To increase the residence time of drug at the target tissue.
Increased skin penetration of the drug.
To prepare more efficient drug delivery system.
1. To prepare the niosomes of miconazole using various surfactants by thin film hydration
/Ether injection method.
2. To evaluate for various parameters like Size, Shape, Entrapment Efficiency.
3. To incorporate the promising formulation in carbopol gel.
4. To evaluate the niosomal gel for its parameters like appearance, viscosity, pH and drug
content.
5. To evaluate for the skin irritation studies.
7 / Materials and Methods:
7.1 /

Materials:

Drug: Miconazole

Excipients :

Sorbitan Monoesters
Cholesterol
Diethyl Ether
Carbopol
Glycerin

Equipments :

UV-VIS spectrophotometer.
Optical microscope.
Rotary Flash Evaporator (superfit model).
Ultra sonicator.
IR spectrophotometer.
Stability Chamber.
Hot air oven.
Thermostatic hot plate with magnetic stirrer.
Digital over head stirrer.
Electronic Balance

11.Digital pH meter.
7.2 /

Method

Niosomes incorporated with Miconazole will be prepared by thin lipid evaporation method and ether injection method. The prepared Miconazole niosomes are incorporated in carbopol gel.

Evaluation of Miconazole Niosomes includes:

1.Size, Shape, Entrapment Efficiency10

2.In vitro drug release (exhaustive dialysis method)14

In vitro antifungal activity by cup-plate method.

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

…………………… Applied ……………………

7.4 /

Has ethical clearance have been obtained from your institution in case of 7.3?

……………………… Not applicable …………………………

8. /

List of Reference

1.Sweet man SC. The Complete Drug Reference. In: Martindale, editor.35 ed. P.488.
2.[Cited 2009 22/11/2009]; Available from:
3.Uchegbu IF, Double JA, Turton JA, Florence AT. Distribution, metabolism and tumoricidal activity of doxorubicin administered in sorbitanmonostearate (Span 60) niosomes in the mouse. Pham. Res. 1995;12(7):1019-24.
4.Varshosaz J, PardakhtyA,Hajhashemi VI, Najafabadi AR . Development and physical characterization of sorbitan monoester niosomes for insulin oral delivery.DrugDeliv. 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, SaettoneMF,Carafa M, Santucci E, AlhaiqueF. 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 Pham.Pham. Sci. 2002; 5(3):220-5.
8.VoraB, 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 system 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 vitrocutaneous 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 vitroreleasestudies.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 diethyl ammonium. Int. J Pharm.2008; 360(1-2):156-63.
18.Panyosak A, Manosroi J, Rojanasakul Y, Manosroi A. Safety assessment if Azelaic acid and its derivatives entrapped in nano-vesicles. Hum Exp Toxicol.2009; 28(6-7):387-92.
19. Balakrishnan P, Shanmugam S, Lee WS, Kim JO,Yong CS. Formulation and in vitro assessment of minoxidilniosomes for enhanced skin delivery. Int. J Pham. 2009; 377:1-8.
20.Ataei S, Moazeni E, Gilani k, Ghaffari A, Asgharian R, Najafabi AR. Invitro evaluation of Itraconazole loaded vesicles prepared from non-ionic surfactants. JPHS. 2011;1(1):50-52.
21.Coscoa D, Paolinoa D, Cilurzoa F, Casalea F, Frestaa M. Gemcitabine and tamoxifen-loaded liposomes as multidrug carriers for the treatment of breast cancer disease. Int. J Pham. 2012; 229-237.
22.Maheshwari GS, Tekade RK, Sharma PA, Tyagi A, Patel RP. Ethosomes and ultradeformable liposomes for transdermal delivery of clotrimazole: A comparative assessment. Saudi Pham. J. 2012; 20:161-170.
23.Vimal K.R., Sankar V.,Srinivas C.R. and kumaresan M. Enhancement of follicular delivery of Finasteride in Niosomes and Proniosomal Gel form for treating Androgenetic alopecia. Indian drugs. 2012;49(05):47-55.

Signature of the Candidate

/ DANAM KEERTHY

Remarks of the Guide

The proposed research topic is novel one, with the preparation of Niosomal Gel we can improve the efficiency of Miconazole for Fungal Infections

Name and Designation of Guide

Dr.S.B. SHIRSAND,

M.Pharm, Ph.D

ASST. PROFESSOR,
DEPT. OF PHARMACEUTICAL TECHNOLOGY,
HKES’s, Matoshree Taradevi Rampure Institute of Pharmaceutical Sciences,
GULBARGA-585105

11.1

Signature

11.2

Head of the Department

/ Dr. K. PURUSHOTHAM RAO
M.Pharm., Ph. D
PROFESSOR
DEPT.OF PHARMACEUTICAL TECHNOLOGY
H.K.E.S’s COLLEGE OF PHARMACY
GULBARGA-585105

11.3

Signature

11.4

Co-Guide

11.5

Signature

Remarks of the Chairman & Principal

12.1

Signature