Download Design and Evaluation of Niosomal Gel Delivery Systems for Topical

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