RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES,

KARNATAKA, BANGALORE

M. PHARM SYNOPSIS

YEAR OF ADMISSION-AUGUST 2012

TITLE OF THE SYNOPSIS

PHARMACEUTICAL AND DIFFUSION KINETIC STUDIES OF FLUCONAZOLE

SEMISOLID DOSAGE FORMS

BY
S.G.S.KIRAN KUMAR BANDI
M. PHARM., PART-I
DEPARTMENT OF PHARMACEUTICS

UNDER THE GUIDANCE OF

DR. K. MANJUNATH, M. PHARM., Ph.D
PROFESSOR
DEPARTMENT OF PHARMACEUTICS

INSTITUTION
SREE SIDDAGANGA COLLEGE OF PHARMACY
B. H. ROAD, TUMKUR-572 102
KARNATAKA
 RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, KARNATAKA,
BANGALORE.

ANNEXURE-II

PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION

1. NAME OF THE S.G.S.KIRAN KUMAR BANDI

CANDIDATE I M. PHARM
AND ADDRESS DEPARTMENT OF PHARMACEUTICS,
SREE SIDDAGANGA COLLEGE OF PHARMACY,
B.H. ROAD,
TUMKUR-572102.
KARNATAKA

2. NAME OF THE SREE SIDDAGANGA COLLEGE OF PHARMACY

INSTITUTION B.H. ROAD, TUMKUR- 572 102
KARNATAKA

3. COURSE OF STUDY AND MASTER OF PHARMACY IN PHARMACEUTICS

SUBJECT

4. DATE OF ADMISSION
AUGUST-2012

5. TITLE OF THE TOPIC

“PHARMACEUTICAL AND DIFFUSION KINETIC STUDIES OF FLUCONAZOLE

SEMISOLID DOSAGE FORMS”

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6.0 BRIEF REVIEW OF THE INTENDED WORK

6.1. NEED FOR THE SYUDY

Fungal infections traditionally have been divided into two distinct classes namely systemic and
superficial. Consequently, the major antifungal agents are classified into systemic and topical
drugs. In another way antifungal drugs are classified according to their chemical structure as:
polyene antifungals, azole antifungals, allylamine antifungals, echinocandin antifungals and
others. Fluconazole is a synthetic antifungal agent belonging to the group of triazole. It is one of
the commonly used antifungal agents for most kinds of fungal infections including superficial
and invasive fungal infections. The presence of halogenated phenyl ring increases its antifungal
activity. The presence of two triazole rings (bis-triazole) makes this compound less lipophilic
and more hydrophilic when compared with other azoles antifungal agents.

The semi solid dosage forms have been recognized as one of the highly potential dosage forms
and provides the advantage of avoidance of the first-pass effect, ease of use and withdrawal (in
case of side effects), and better patient compliance because of their route of delivery i.e.
transdermal. However, the major limitation of this route is the difficulty of permeation of drug
through the skin. Studies have been carried out to find safe and suitable permeation enhancers to
promote the percutaneous absorption of a number of drugs1. Ideally, penetration enhancers
reversibly reduce the barrier resistance of the stratum corneum without damaging viable cells.

Mentha oil and clove oil were used as penetration enhancers in the preparation of emulgel of
mefenamic acid using Carbapol 940 as a gelling agent. The results indicated good release and
permeation of the drug2. The effect of penetration enhnacers (Urea, oleic acid, and d-limonene
on) the in vitro percutaneous absorption of diclofenac through horse skin. The results indicated
that limonene showed the highest enhancing effect at the lowest concentration (5%) applied3.

Nature of penetration enhancer plays a role in the penetration of particular drug, whether it
is hydrophilic or lipophilic. Cyclic monoterpenes generally showed stronger enhancement of
curcumin than other terpenes, flavanoids and cholestanol. From the above it is apparent that the
smaller terpenes tend to be more active permeation enhancers than the larger sequiterpenes.

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6.2. REVIEW OF LITERATURE:

Helal et al. formulated the gel by using different polymers Carbopol, Hydroxypropyl
methylcellulose, Methyl cellulose, Pectin and Pluronic at different concentration. The different
formulae prepared were characterized for syneresis, spreadability, pH, drug content and
rheological properties. The results of in vitro drug release and its permeation studies showed
that formulation released 91.3% of drug after 2 hr showed highest antifungal activity. The
rheological behavior of the prepared formulae showed shear-thinning flow indicating structural
breakdown of the existing intermolecular interactions between polymeric chains. Stability
studies revealed no significant difference in characteristics before and after storage period4.

Thakur et al., have formulated fluconazole gel by using gelling agents like carbopol, hydroxy
propyl methyl cellulose and xanthan gum for topical delivery. Different penetration enhancers
such as oleic acid, propylene glycol and tween 80 were used to enhance drug penetration from
the preparations. Gel formulations were characterized for drug content, pH determination,
viscosity measurement, in vitro diffusion and skin irritation. FT-IR studied to confirm the purity
of drug. They concluded that tween 80 in the maximum concentration (20% v/v) proved to be
the best release enhancer. In spite of presence of the penetration enhancers it was observed that
there was a negligible change in the pH of the formulations. Drug to skin application was found
to be highly beneficial in localizing the drug to desired site in the skin and reduced side effects
associated with conventional treatment5.

Yellanki et al. formulated metronidazole gel for local treatment of periodontitis and evaluated.
In their study six batches of metronidazole gels were prepared using natural biodegradable
polymers like chitosan, guar gum and locust bean gum in variable concentrations. The
formulated gels were characterized for surface pH, viscosity, syringeability, bioadhesion
strength, in vitro drug release studies and antimicrobial susceptibility test. They observed
surface pH was within the range of neutral pH. The bioadhesion strength was maximum for F3
formulation (3% Chitosan) the viscosity was within the range. Best formulation in terms of
cumulative percent drug release along with bioadhesion was formulation F3 with 78.23 % drug
release for 7 day. They conclude that metronidazole gels can be successfully prepared using
natural polymers which can be targeted in treatment of the periodontal disease and fulfilled
many requirements of once a week delivery system, easy to fabricate, cost effective, patient
compliance is also very high. Zone of inhibition was also found to be satisfactory for all the
formulations6.

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Rajalakshmi et al. formulated clotrimazole and ichthammol ointment with different ointment
bases having good consistency and better diffusion for treatment of fungal infection like eczema
itching, pruriti. Two Formulations formulation A and B have been prepared with same active
ingredients except different bases. Formulation A contains white soft paraffin and cetostearyl
alcohol while B contains hard paraffin, cetostearyl alcohol, Light liquid paraffin and
microcrystalline wax. They assess the efficacy of formulations by assay, drug release,
uniformity, viscosity, diffusivity, rheology, stability, spread ability, permeability and other
physical characteristics. Formulation B was observed to be better than formulation A in all
aspects like spreadability, viscosity, consistency, stability, diffusivity for the better therapy and
patient compliance can be attained7.

Rao et al. prepared and evaluated o/w cream for skin psoriasis. In their study salicylic acid
chosen as model drug which is the most effective keratolytic agent. Developed formulations
were subjected to various physiochemical parameters like drug content, pH, spread ability, tube
extrude ability, viscosity and IR studies. In vitro drug release studies were carried out in
phosphate buffer (pH 7.4) and compared with marketed formulation. The selected formulation
were subjected for primary skin irritation test using rabbits, guinea pigs, and healthy human
volunteers for 72 hours and observed for any skin rashes, inflammation, itching, or redness on
applied portions. Drug content, pH, Spread ability, tube extrudeability of the formulation was
found to be 95%, 6.1, 11.32 gm.cm/sec, 94.9% respectively. From rheogram they concluded that
formulation showed pseudo plastic flow property8.

Chakole et al. studied on formulation and evaluation of novel combined halobetasol propionate
and fusidic acid ointment for the treatment of Atopic Dermatitis. Atopic dermatitis is a
noncontiguous skin disease, which can be prevented by administration of drugs through topical
route. Combination of halobetasol propionate and fusidic acid is good rational and novel for the
treatment of atopic dermatitis. Assay, drug release, microbial activity, rheology, stability, spread
ability, permeability and other physical characteristics were satisfactory. Formulation containing
water miscible base was found better than other formulation9.

Ozcan et al. prepared topical gel formulation of terbinafine hydrochloride by using different
types of chitosan of different molecular weight. The antifungal inhibitory activity of prepared
topical formulations was evaluated to suggest an effective formulation for treatment of fungi
infection. The characteristics of gel formulation were determined with viscosity measurement
and texture profile analysis and found satisfactory. Stability studies were performed at different
temperature during 3 months. The antifungal inhibitory activity of formulation on candida
species and filamentous fungi was also examined with agar method. A higher drug release and
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the highest zone of inhibition were obtained from gels prepared with the lowest molecular
weight of chitosan10.

Chhetri et al. aimed to formulate and evaluate the antimicrobial herbal ointment from the local
medicinal plants. The ethanolic extracts of the selected plants were taken in different ratio
randomly and the antimicrobial tests of the combinations were carried out. The most effective
combination was then determined by comparing the results of the zone of inhibition given by
the 10 different extract ratios on Staphylococcus aureus, Escherichia coli and Klebsiella species.
The minimum inhibitory concentration of the effective combination was found out. The
ointment base was prepared and formulation of ointment was done by incorporating the active
ingredients in most effective ratio in the base by trituration. After the completion of the
formulation, quality of the ointment was assessed in terms of irritancy, spreadability, diffusion
and stability11.

Singh et al. studied skin permeation of miconazole using different novel carriers. They prepared
different novel carriers such as liposomes and ethosomes incorporated with miconazole and
compared their in vitro skin permeation with plane ointment using pig skin model. In vitro skin
permeation study results showed that the steady state fluxes of drug was higher in case of
ethosomal suspension incorporated ointment as compared to liposomal ointment. They
concluded that ethosomes showed better skin permeation as compared to liposomes12.

6.3. OBJECTIVE OF THE STUDY

Following are the objectives of the present study

 To formulate fluconazole creams, ointments and gels using different bases.

 To improve diffusivity of fluconazole across skin layers by using suitable penetration
enhancers in the formulation.
 To evaluate the formulated dosage forms for their pharmaceutical properties
 To evaluate stability of best dosage forms as per ICH guide lines.

MATERIALS AND METHODS

Materials:

Drug : Fluconazole
Gelling agent : Different grades of hydroxyl propyl methyl cellulose, carbopol,

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 guar gum, locast bean gum, etc.
Cream base : Soft white paraffin, liquid paraffin.
7.0
Ointment base : Emulsifying wax, soft white paraffin and liquid paraffin.
Penetration enhancers : Cineol, piperine, liquorice, tween 80, isopropyl myristate
Surfactants : SLS
Solvents : Ethanol, purified water
Co-solvents : Sorbitol, glycerine etc.
Antioxidants : Butylated hydroxy toluene, butylated hydroxy anisole,
ascorbic acid
Methods:

7.1. Source of Data

 Journals such as,

 Indian Journal of Pharmaceutical Sciences
 International Journal of Pharmaceuticals
 European Journal of Pharmaceutical Sciences
 American Association of Pharmaceutical Scientists Indian drugs
 Drug Bank (www.drugbank.ca)
 PubMed (www.ncbi.nlm.nih.gov/pumbed)

7.2. METHOD OF COLLECTION OF DATA

1. Evaluation of solubility of Fluconazole by co-solvency phenomena using sorbitol,

glycerine etc.
2. Formulation of different semisolid formulations of fluconazole like cream, ointment and
gel.
3. Evaluation of the various pharmaceutical properties of prepared cream, ointment and gel.
a) Physical examination
b) pH
c) Rheological properties (Viscosity, Spreadability, Performance in collapsible
tube, caking/hardening/softening at challenge temperature on storage)
d) Drug content
4. Best Formulation will be subjected for short term accelerated storage stability studies
(As per ICH guide lines)
a) Room Temperature
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 b) 15-25C ± 2C
c) 40C ± 2C and 75% RH ± 5%
After completion of storage period all the samples will be analysed for all pharmaceutical
properties mentioned above.

7.3 7.3. Does the study require any investigation or investigation to be conducted on patients or
other humans or animals?

“YES”

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

“ YES ”

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8.0 BIBILOGRAPHY

1. Shembale IA, Borole KD, Lohiya TR. Useful permeation enhancers for transdermal drug
delivery: A review. Int. J. Pharm. Res. Dev. 2010;2(5):1-6.

2. Khullar R, Kumar D, Seth N, Saini S. Formulation and evaluation of mefenamic acid

emulgel for topical delivery. Saudi Pharm. Journal 2012; 20: 63–67.

3. Ferrante M, Andreeta A, Landoni M F. Effect of different penetration enhancers on

diclofenac permeation across horse skin. The Veterinary Journal 2010;186:312–5.

4. Helal DA, El-rhman DA, Abdel-halim SA, El-nabarawi MA. Formulation and
evaluation of fluconazole topical gel. Int. J. Pharm. Sci. 2012;4(5):176-83.

5. Thakur V, Prashar B, Arora S. Formulation and in vitro evaluation of gel for topical
delivery of antifungal agent fluconazole using different penetration enhancers. Drug
Invention Today 2012; 4(8): 414-9.

6. Yellanki SK, Singh J, Manvi FV. Formulation, characterization and evaluation of

metronidazole gel for local treatment of periodontitis. Int. J. Pharm. Bio. Sci.
2010;1(2):19.

7. Rajalakshmi G, Damodharan N, Bhai CVKV, Janardhanreddy RP. Formulation and

evaluation of clotrimazole and ichthammol ointment. Int. J. Pharm. Bio. Sci.
2010;1(4):7-16.

8. Rao PKP, Khalia K, Kharat SS, Sagare P, Patil SK. Preparation and evaluation of o/w
cream for skin psoriasis. Int. J. Pharm. Bio. Sci. 2010;1(3):1-11.

9. Chakole CM, Shende MA, Khadatkar SN. Formulation and evaluation of novel
combined halobetasol propionate and fusidic acid ointment. Int. J. Chem. Tech. Res.
2009;1(1):103-16.

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 10. Özcan I, Abacı O, Uztan AH , Aksu B , Boyacıoglu H, Güneri T ,Özer O. Enhanced
topical delivery of terbinafine hydrochloride with chitosan hydrogels. AAPS PharmSci.
Tech. 2009;10(3):1024-31.

11. Chhetri HP, Yogol NS, Sherchan J, Anupa K.C, Mansoor S, Thapa P. Formulation and
evaluation of antimicrobial herbal ointment. Kathmandu Univ. J. Sci. Eng. Tech.
2010;6(1):102-107.

12. Singh A, Rathore P, Shukla M, Nayak S. Comparative studies on skin permeation of

miconazole using different novel carriers. Int. J. Pharm. Sci. Res. 2010;1(9):61-6.

9. SIGNATURE OF CANDIDATE

10. REMARKS OF GUIDE RECOMMENDED

11. NAME AND DESIGNATION

OF

11.1 GUIDE Dr. K. Manjunath, M. Pharm., Ph.D.

Professor
Department of Pharmaceutics

11.2 SIGNATURE

11.3 CO-GUIDE (If any) ------------------

11.4 SIGNATURE -----------------

11.5 HEAD OF Dr. Suresh V. Kulkarni,

DEPARTMENT M. Pharm., Ph.D.
Professor & Head, Department of Pharmaceutics

11.6 SIGNATURE

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12. 12.1 REMARKS OF THE Forwarded to university for approval.
CHAIRMAN AND
PRINCIPAL

12.2 SIGNATURE

(Dr. S. Badami)
Principal
Sree Siddaganga College of Pharmacy
Tumkur

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