ISSN: 2320 - 4230

Journal of Drug Discovery and Therapeutics

Available Online at www.jddt.in
RESEARCH ARTICLE
CODEN: - JDDTBP (Source: - American Chemical Society)
Volume 3, Issue 26, 2015, 07-14

Formulation & evaluation of voriconazole ointment for topical delivery

Rajesh Asija*, Prem Chand Dhaker, Nitin Nama
Department of pharmaceutics, Maharishi Arvind Institute of Pharmacy, Mansarovar, Jaipur. Rajasthan, 302020-India.

Received 18 February 2015; Accepted 03 March 2015

ABSTRACT
The studies were conducted with an object to develop a desired ointment for treatment of fungal infection like eczema
itching, purities’. Main objective of this study is to formulate the ointment with different ointment bases having good
consistency, diffusion, antifungal and antiseptic properties. To assess the efficacy of formulations assay, spread ability,
permeability, drug release, uniformity, viscosity, diffusivity, stability, and other physical characteristics were evaluated.
The ointment base was prepared and formulation of ointment was done by incorporating the active ingredients in most
effective ratio in the base by fusion method. The PEG ointments were prepared with changing the type of the liquid PEG
(low molecular weight). Then, the viscosity and the voriconazole release from the prepared formulations were studied.
Keywords: Voriconazole, Polyethylene glycols, Antifungal activity.

INTRODUCTION • Achieve of efficacy with decrease total daily dosage

Topical products for the treatment of dermatological of drug by continuous drug input.
diseases include a wide choice of vehicles ranging from to • Maintain in drug levels.
semisolids preparations are creams, gels, ointments, • Easily remove the medications, when needed.
pastes, aerosols and solutions. Ointments are topical • A large area of application in comparison with buccal
formulations that offer better patient compliance and or nasal cavity.
hence become more acceptable to patients. It is a • Selectively to a specific site.
semisolid dosage form that contains < 20% water and SKIN
volatiles and > 50% hydrocarbons, waxes or polyethylene Skin is one of the most readily accessible organs on
glycols as the vehicle for external application to the skin. human body for topical administration and is main route
The delivery of drug through the skin has long been a of topical drug delivery system. This research is concern
promising concept because of the ease of access, large with all detail information regarding rational approach to
surface area, wide exposure to the circulatory and topical formulation, aim of topical permeation and basic
lymphatic system, and noninvasive nature of the components of topical drug delivery systems. Absorption
treatment. This is true whether the bioavailability desired of ointment through the skin depends on a number of
is systemic or local. Ointments are homogeneous, factors, the important of which are concentration, time of
semisolid preparations intended for external application contact, solubility of drug, and physical condition of skin
to the skin or mucous membranes. Topically applied layer and part of the body exposed1.
dermal and transdermal delivery systems could replace FACTORS INFLUENCING ABSORPTION
needles required to administer many of the new Absorption of ointment through the skin depends on a
biologics-based drugs and vaccines, in addition to other number of factors:
advantages such as avoiding first-pass metabolism, • Concentration
gastric degradation and frequent dosing. • Duration of contact
ADVANTAGES OF TOPICAL DRUG DELIVERY SYSTEMS: • Solubility of medication
• Avoidance of first pass metabolism. • Physical condition of the skin
• Easy to apply. • The amount of hair on the skin.
• Avoid of the risks and inconveniences of intravenous MEDICAL USE OF SKIN ABSORPTION
therapy and of the varied conditions of absorption, like Dermal application of a medication or chemical allows
pH changes, presence of enzymes, gastric emptying time treatment to be localized, unlike injection. Some
etc. medications to be more effective (or are more efficient)

15
 Dr. Rajesh Asija, et al. / FORMULATION & EVALUATION OF VORICONAZOLE OINTMENT FOR TOPICAL DELIVERY

using the dermal route of administration. Some ingest Two type of method for preparation of ointments.
drug are heavily metabolized by the liver and may be 1. Mechanical method: This method also called
inactivated, but using a dermal application bypass this trituration method. The quantity of ointment is not more
metabolism step allowing more parent compound to than 50g, white porcelain or marble ointment should be
enter the peripheral circulation. The drug is absorbed used in conjunction with a flexible steel spatula. A steel
well through the skin it may be used as a means of spatula should not be used as medicament may react
systemic medication. Dermal dosage forms include: with the metal. the substance react with metal such as
lotions, ointments, creams, liniments, braces, dusting mercury compounds, tannic acid, salicylic acid and
powders, aerosols, and transdermal patches. iodine3.
OINTMENT 2. Fusion method: Ointment containing hard paraffin,
Ointment is a topical medication applied on the body beeswax, emulsified wax, wool alcohol are prepared by
surface. ointments is defines as a homogeneous, viscous, melting ingredients in a porcelain dish over a water bath.
semi-solid preparation with more viscosity, that is used In this process higher melting point substance should be
for external application. Ointment ingredient which serve melted first and add then other ingredients of the bases
a protective, antifungal or prophylactic purpose when in order of their melting point3.
applie on the skin or mucous membranes. Medicated MATERIALS AND METHOD FOR RESEARCH WORK
ointment are use for the treatment of infection, Materials
inflammation and antifungal activity. However, non- Voriconazole was procured from Jaipur pharmaceutical
medicated ointments are commonly used due to their works. PEG400 and PEG600 was procured from Maharishi
emollient/lubricating properties. Arvind Institute of Pharmacy, mansarovar, Jaipur. All
TYPES OF OINTMENTS BASES other chemicals were used of analytical grade and
The medicated stuff or the ingredients present inside the without any further chemical modification.
ointment is actually the main base of ointments. There Method
are ointment bases: The ointment containing voriconazole was prepared by a
1. Hydrocarbon bases. fusion method. The specified concentration of
e.g. hard paraffin and paraffin, microcrystalline wax and polyethylene glycol (PEG) 4000 was melted in a porcelain
ceresine. dish over a boiling water bath. PEG 400 or PEG 600 was
2. Absorption bases. heated to decrease order temperature and added to the
e.g. wool fat, beeswax. melted PEG 4000. The mixture was then removed from
3. Water soluble bases. heat and stirred. Then, voriconazole (5% w/w) dissolved
e.g. PEG 200, 300, 400. in 20% propylene glycol (which is slightly heated) was
4. Emulsifying bases. added to the PEGs mixture and stirred until congealing.
e.g. Emulsifying wax, Vegetable oils like as coconut oil, The excipients were taken according to drug weight. The
sesame oil, olive oil, almond oil and peanut oil2. different forms of ointment preparation together with
METHOD OF PREPARATION their compositions are given in following tables:

Table 1: Compositions of various ointment preparation of voriconazole

Formulation F1 F2 F3 F4 F5 F6 F7 F8
Drug 5 5 5 5 5 5 5 5
PEG 4000 20 20 20 20 20 20 20 20
PEG 400 10 20 30 40 - - - -
PEG 600 10 20 30 40
Methanol 2 2 2 2 2 2 2 2
Propylene glycol 20 20 20 20 20 20 20 20
Methyl paraben 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2
Propyl paraben 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2
Water q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s.

16
 Dr. Rajesh Asija, et al. / FORMULATION & EVALUATION OF VORICONAZOLE OINTMENT FOR TOPICAL DELIVERY

EVALUATION OF OINTMENT In-vitro Drug release study:

Fourier transforms infra red spectroscopy (FTIR): The in vitro release of voriconazole from the prepared
The primary objective of this investigation was to identify formulations was studied using dialysis method. 1 gram
a stable storage condition for drug in solid state and sample of each formulation was accurately weighed and
identification of compatible excipients for formulation. placed on a semi permeable cellophane membrane
The FTIR spectra of voriconazole was done and given in immersed in phosphate buffer pH 7.4 for 24 hours. The
Fig. 1 loaded membrane (donor compartment) was firmly
Physical Examination: stretched over the lower open end of a glass tube of 2.5
The Prepared ointment formulations were inspected cm internal diameter and made watertight by rubber
visually for their colour, homogeneity, consistency. band. The tube was then immersed in a beaker
Determination of pH: containing 25 ml of phosphate buffer pH 7.4 which is the
2.5gm Ointment sample was taken in 100 ml dry beaker, release medium (receptor compartment). The system
50 ml water was added to it. Beaker was heated on water was maintained for 3 hours at 37 ± 0.5ºC in a
bath maintained at about 60ºC to 70ºC for 10 minutes, thermostatic shaking water bath at 50 rpm. Samples of 5
cooled to room temperature, and then centrifuged at ml were withdrawn at intervals of 1, 2, 3, 4, 5, and 6
3000 rpm for 10 minutes. The pH of water extract was hours. The volume of each sample was replaced by the
measured by using pH meter. The pH measurements same volume of fresh buffer (kept at the same
were done by using a digital type pH meter by dipping the temperature) to maintain constant volume4.
glass electrode into the ointment formulation. In vitro antifungal activity:
Measurement of viscosity: Agar cup-plate method was adopted for this study. The in
The viscosity of the prepared ointment formulations was vitro antifungal activity of the selected voriconazole
determined using BrookField viscometer DV-III ULTRA formulations; PEG ointment against isolates of Candida
(Brookfield Engineering laboratories, USA) using spindle albicans (as a representative Yeast fungus) and isolates of
no. 64. The viscosity was measured in centipoises (cps) at Trichophyton Mentagrophyte (as a representative
10 rpm for 1 minute and temperature 25ºC using 20 gram Dermatophyte fungus) was studied. A single isolate of
sample4. each fungus was picked from the agar slab culture to
Spreadability: prepare spores suspensions in sterile water and was
The spreadability is expressed in terms of time in seconds adjusted to be 1×106 spores/ml. One ml of the spores'
taken by two slides to slip off from ointment, placed in suspension was mixed with Sabouraud agar (15-20 ml) in
between two slides under the direction of certain load. sterile Petri dish (9 cm in diameter) and the agar plates
Lesser the time taken for separation of two slides, better were allowed to solidify. After solidification, a single well
the spreadability of ointment. The spreadability was was made in each agar plate using a porer of size 1 cm
calculated by using the following formula. and filled with an accurately weighed 0.5 gm of each
formula (either medicated or plain). The plates were
Where, M = weight tied to upper slide incubated at 25± 1ºC for 3 days (for Candida isolates) and
L = length of glass slides 8 days (for Trichophyton isolates) and then they were
T = time taken to separate the slides examined for the inhibition zone diameter which is an
Extrudability: indicator for the antifungal activity. The mean value of
Extrudability test is the measure of the force required to the inhibition zone diameter from three plates was
extrude the material from a collapsible tube when certain calculated4.
amount of force has been applied on it in the form of Release kinetics of selected formulation:
weight. In the present study the quantity in percentage of To examine the drug release kinetics and mechanism, the
ointment extruded from the tube on application of cumulative release data were fitted to models represent
certain load was determined. The extruadibility of Zero order, First order, Higuchi model and Peppas model.
prepared ointment formulations was calculated by using RESULTS AND DISCUSSION
following formula. Fourier transforms infra red spectroscopy (FTIR):
Extrudability= Amount of ointment extruaded from the tube x 100
Total amount of ointment filled in the tube

17
 Dr. Rajesh Asija, et al. / FORMULATION & EVALUATION OF VORICONAZOLE OINTMENT FOR TOPICAL DELIVERY

Figure 1: IR spectra of Voriconazole

Physical Appearance:
Ointment formulations were white viscous preparation with a smooth homogeneous texture. Show Physical Appearance
discussed in Table 2.
Table 2: Physical Appearance

Formulation
S. No. Colour Homogeneity Consistency
Code
1 F1 White Good ++
2 F2 White Excellent +++
3 F3 White Excellent +++
4 F4 White Excellent +++
5 F5 White Poor +
6 F6 White Poor ++
7 F7 White Good ++
8 F8 White Good +++

Determination of pH:
The pH of the ointment solution was measured with the help of pH meter. 0.5g of ointment was dissolved in 50ml of
distilled water and stored for two hours. The measurement of pH each formulation was done in triplicate.
Table 7.3: pH of ointment

S. No. Formulation Code pH*

1 F1 6.36±0.3
2 F2 6.27±0.1
3 F3 7.09±0.6
4 F4 6.53±0.5
5 F5 6.09±0.18
6 F6 7.2±0.23
7 F7 7.12±0.4
8 F8 6.8±0.9

18
 Dr. Rajesh Asija, et al. / FORMULATION & EVALUATION OF VORICONAZOLE OINTMENT FOR TOPICAL DELIVERY

Rheological Study:
The viscosity is illustrated according to the change in type of fatty alcohol and concentration and the molecular weight
of the liquid polyethylene glycol (for PEG ointments). found that increasing the concentration of the emulsifying agent in
the ointments formulation led to increased viscosity of the formulation. In case of PEG ointment formulations, the
viscosity was increased with increasing the molecular weight of the liquid PEG used. So, F8 containing PEG 600 exhibited
higher viscosity over F4 containing PEG 400.

Table 7.4: viscosity of ointment

S. no. Formulation Code Viscosity (CP) *

1 F1 29,840±7.3

2 F2 32,646±16.4

3 F3 33,284±22.8

4 F4 34,028±17.7

5 F5 37,416±9.5

6 F6 37,996±11.3

7 F7 39,728±22.4

8 F8 41,176±18.5

Spreadability:
Pharmaceutical semisolid preparations include ointments, cream, emulsion, gel, and rigid foams. Their common
property is the ability to cling to the application surface for a reasonable period of time before they are washed off or
worn off. They usually serve as vehicles for topically applied drugs, as emollients, or as protective.

Table 7.4: spreadability of ointment

S. No. Formulation Code Spreadability*

1 F1 28.49±0.7
2 F2 36.31±0.58
3 F3 39.54±1.39
4 F4 42.38±0.75
5 F5 18.7±1.04
6 F6 22.15±1.39
7 F7 29.64±0.94
8 F8 32.87±1.8

Extrudability:
Ointments were filled into collapsible tubes after formulating them. The extrudability of the formulation has been
checked.

19
 Dr. Rajesh Asija, et al. / FORMULATION & EVALUATION OF VORICONAZOLE OINTMENT FOR TOPICAL DELIVERY

Table 7.5: Extrudability of ointment

S. No. Formulation Code Extrudability

1 F1 Easily Extrudable

2 F2 Easily Extrudable

3 F3 Easily Extrudable

4 F4 Easily Extrudable

5 F5 Easily Extrudable

6 F6 Easily Extrudable

7 F7 Easily Extrudable

8 F8 Easily Extrudable

In-vitro drug release study:

In-vitro drug release testing, a measure of release of the active pharmaceutical ingredient (API) from the drug product
matrix in controlled laboratory environment, is a key evaluation in drug development and quality control. It involves
subjecting the dosage form to a set of conditions that will induce drug release and quantitating the amount of drug
released under those conditions. In development, it is an essential test in assessing differences between prototypes,
predicting the timeframe of API release, and modeling in vivo behavior.

Table 7.6: In-vitro release of ointment

Formulation % CDR (6hr)* Drug content*

F1 72.38±1.14 96.1±0.46
F2 86.108±1.04 98.2±0.73
F3 89.722±0.75 98.7±0.39
F4 91.014±1.09 99.6±0.48
F5 63.079±0.95 95.3±0.35
F6 69.256±1.29 95.8±0.95
F7 78.871±1.26 96.3±0.57
F8 82.201±1.05 97.5±0.64

Release kinetics of optimized formulation (F4)

The data were treated according to zero order, first order, higuchi model and korsmeyer peppas pattern for kinetics of
drug release during dissolution process. The regression equation of optimized formulation F4 were find out according to
zero order equation 0.935 first order equation 0.034 and higuchi model 0.997 respectively. These value clearly indicate
that the formulation showed to be best expressed by higuchi kinetics. It was follow the higuchi release pattern.

Table 7.6: Data of release kinetics

Form. Zero order First order Higuchi Korsmeyer peppas

R2 K0(-) R2 K1(-) R2 KH R2 N
(1/S) M/L.S
F4 0.935 13.91 0.034 0.122 0.997 37.16 0.523 0.76

20
 Dr. Rajesh Asija, et al. / FORMULATION & EVALUATION OF VORICONAZOLE OINTMENT FOR TOPICAL DELIVERY

CONCLUSION: 11. Rajalakshmi G., Damodharan N., Formulation and

Voriconazole ointment were successfully formulated Evaluation of Clotrimazole and Ichthammol
using the mixture of PEG 4000, PEG 400, PEG 600 and Ointment, International Journal of Pharma and Bio
propylene glycol for delivery of drug to produce local Sciences, Vol.1, Issue-4, ( 2010), P.n. P7-P15
effect. Ointment could increase the drug permeability 12. Pawar P. L., Nabar B. M., Effect of Plant Extracts
across the skin and fast release of the drug could be Formulated in Different Ointment Bases on MDR
successfully achieved. The obtained results showed that Strains, Indian Journal of Pharmaceutical sciences,
the PEG ointment formulations exhibited better Vol.72, Issue 3, (2010), P.n. 397-401
voriconazole release formulation. For PEG ointments, the 13. Chhetri H.P., Yogol N.S., Formulation and Evaluation
nature of the base itself may be adjunctive to the efficacy of Antimicrobial Herbal Ointment, Kathmandu
of the used antifungal agent. So, PEG ointments could be University Journal of Science, Engineering and
a promising topical antifungal drug. Technology, Vol.6, Issue-1, (2010), P.n. 102-107
REFERENCES 14. Rao K. P., Venkateshwarlu P., Saran S.V., medicated
1. Upadhyay Mihir R., Design & Evaluation of derma sticks for skin disorders, Indian Journal of life
Aceclofenac Loaded Microsponge for Topical sciences biotechnology and pharma research, Vol. 1,
Delivery, thesis for Degree of Master of Pharmacy at Issue 1, (2012), P.n. 141-149
KLE University, Karnataka (2011), P.n.1-10 15. Rajasree P.H., Vishwanad V., Formulation and
2. Jain N.K., Sharma N.K., A text book of professional evaluation of antiseptic polyherbal ointment,
pharmacy fifth edition, vallabh prakashan, (2007) P.n. International Journal of Pharmacy & Life Sciences,
264-279 Vol.3, Issue 10, (2012), P.n. 2021-2031
3. Jain N.K., Pharmacrutical product development 16. Mhatre J., Nagaral S., Kulkarni S, Formulation and
second edition, CBH publishers, (2010) P.n. 269-286 Evaluation of Antibacterial Activity of a Herbal
4. Mekkawy I.A.A., Fathy M., Shanawany S., Study of Ointment Prepared from Crude Extracts of Aegle
Fluconazole Release from O/W Cream and Water Marmelos, (Bael), International Journal of Pharmacy
Soluble Ointment Bases, British Journal of and Pharmaceutical Sciences Vol.6, Issue-2, (2014),
Pharmaceutical Research, Vol.3, Issue-1, (2013) P.n. P.n. 575-579
1-12 17. Nimbekar T.P., Bhange P.G., Wanjari B.E., formulation
5. Yeu Chun Kim, Transdermal Drug Delivery Enhanced and evaluation of some framycetin sulphate
by Magainin Peptide, P.hd thesis at Georgia Institute ointment, International Journal of Pharma and Bio
of Technology (2007), P.n. 42-48. Sciences, Vol.3, Issue 2, (2012), P.n. 327-332
6. www.drugbank.com 18. Majumder P., Majumder S., Preparation and
7. Pandey A., Jagtap J.V., Formulation and evaluation of Characterization of Some Herbal Ointment
anti-bacterial and anti-fungal activity of a herbal Formulations with Evaluation of Antimicrobial
ointment containing Aloe-vera, Azadirachta indica Property, Indian Journal of Research in Pharmacy and
and Curcuma- longa, Journal of Chemical and Biotechnology, Vol.1, Issue-3, (2013), P.n. 385-390
Pharmaceutical Research, Vol.2, Issue-3, (2010), P.n. 19. Aukunuru J., Bonepally C., Preparation,
182-186 Characterization and Optimization of Ibuprofen
8. Ju M., Xu A., Duan Y., study of calcipotriol Ointment Intended for Topical and Systemic delivery,
betamethasone ointment in the treatment of Tropical Journal of Pharmaceutical Research, Vol.6,
patients with refractory chronic eczema, Asian Issue 4, (2007), P.n. 855-860
Journal of Pharmaceutical and Clinical Research, 20. Buhse L., Kolinsky R., Topical drug classification,
Vol.6, (2007), P.n. 34-40 International Journal of Pharmaceutics, Vol., 295
9. Nagai H., Teramachi H., Tuchiya T., Recent Advances (2005), P.n. 101-112
in the Development of Anti-allergic Drugs, 21. Mehta N. J., Patadiya N. D., Patel J., Development and
Department of Clinical Pharmacology, Gifu Evaluation of Antiarthritic Herbal Ointment,
Pharmaceutical University, Gifu, Japan, Vol.55, Issue Research Journal of Pharmaceutical, Biological and
1, (2006), P.n. 35-42 Chemical Sciences, Vol. 4 Issue 1, (2013) P.n, 221-228
10. Pasupathi A., Formulation, Development, Evaluation 22. Nayeem N., Kaevekar M. D., Stability studies and
Of Calcitriol And Clobetasol Propionate Ointment, evaluation of the semi solid dosage form of the rutin,
Indian Journal of Research in Pharmacy and quercitin, ellagic acid, gallic acid and sitosterol
Biotechnology, VoL.1, Issue-1, P.n. 95-105 isolated from the leaves of Tectona grandis for

21
 Dr. Rajesh Asija, et al. / FORMULATION & EVALUATION OF VORICONAZOLE OINTMENT FOR TOPICAL DELIVERY

wound healing activity, Archives of Applied Science cream formulations with respect to rubbing onto the
Research, Vol. 3 Isuue 1 (2011) P.n. 43-51 human body, Korea-Australia Rheology Journal, Vol.
23. Joseph P. M., Kalpana S.P., Robert A.L., Near Infrared 22 Isuue 4 (2010) P.n. 279-289
Spectrometry for the Quantification of Human 26. Gungor S., Erdal M.S., Aksu B., New Formulation
Dermal Absorption of Econazole Nitrate and Strategies in Topical Antifungal Therapy, Journal of
Estradiol, Pharmaceutical Research, (2006) P.n. 8-16 Cosmetics, Dermatological Sciences and Applications,
24. Kumar J. R., Muralidharan S., Parasuraman S., Vol.3 (2013) P.n. 56-65
Antifungal Agents: New Approach for Novel Delivery 27. Bruce S., Epinette W. W., Comparative study of
Systems, journal of pharmaceutical sciences and calcipotriene (MC 903) ointment and fluocinonide
Research, Vol. 1 Isuue 5 (2014) P.n. 229-235 ointment in the treatment of psoriasis, Journal of the
25. Park E. K., Song ki-won, Rheological evaluation of American Academy of Dermatology, Vol. 31 Isuue 5
petroleum jelly as a base material in ointment and (1994) P.n. 755-759

22