J. DRUG DEL. SCI. TECH.

, 17 (6) 431-436 2007

Formulation and evaluation of quercetin

in certain dermatological preparations
E.-S. A. Ibrahim, M.A. Hassan*, M.M. El-Mahdy, A.S. Mohamed
Department of Pharmaceutics, Faculty of Pharmacy, Assiut University, Assiut, Egypt
*Correspondence: mahashawkat@yahoo.com
Quercetin is a bioactive flavonoid widely used as a health supplement. Quercetin was formulated in different dermatological preparations
as gel, emulgel and microemulsion gel. Different gel bases were used for the preparation of quercetin gel as sodium carboxymethylcellulose
(NaCMC), Carbopol 934 and Pluronic F-127. Also different formulae of both emulgel and microemulsion gel were prepared using different gel
bases and surfactants. These formulations were evaluated for their drug content, in vitro release of the drug from cellophane membrane and skin
permeability through hairless mouse skin. The antibacterial activity against Gram positive and Gram negative organisms was also studied. The
results of the drug release indicated that the highest release was obtained from the microemulsion gel followed by gel and emulgel, respectively.
The same results were obtained for drug penetration through hairless mouse skin. Analysis of the data according to different kinetic mechanisms
revealed that the release pattern of the drug from the tested bases followed zero-order and the Higuchi diffusion model. Results also indicated an
excellent activity against all tested organisms and the inhibition zone was dependent on the type of formulation used.
Key words: Quercetin Dermatological Formulation.

or bacterial invasion if given before an infection progresses [12, 13].

Quercetin is also indicated in diabetes for its ability to enhance insulin
secretion, protect the pancreatic beta-cells from the damaging effects
of free radicals and inhibit platelet aggregation [14, 15]. Quercetin
appears to have many beneficial effects on human health including
antiosteoporotic [16] and antiulcer effect [17].
The purpose of this study is the formulation of quercetin in different topical formulations as gel, emulgel and microemulsion gel,
and the evaluation of the in vitro release from cellophane membrane
and the effect of different polymers and formulae on drug release. The
penetration of quercetin through mouse skin from different formulae
was also studied. Moreover the microbiological activity of quercetin
in these topical formulations was studied using gram positive and
gram negative organisms.

Quercetin (3,3`,4`,5,7-pentahydroxyflavone, Figure 1) is a flavonoid that serves as the backbone for many other flavonoids. It is
consistently the most active of the flavonoids in experimental studies
and many medicinal plants owe much of their activity to their high
quercetin content. In nature it occurs in various fruits, vegetables,
nuts, seeds, leaves, flowers and barks. It is a part of our daily diet
with an average daily intake of 16 mg (expressed as aglycone). In
food, quercetin is usually glycosidated and mainly bound to glycose
and rutinose with high concentrations. It is found in onions, tea, and
apples [1, 2].
It is best known as an anti-inflammatory, anti-allergy agent. Because it stabilizes mast cell membranes and prevents the release of
histamine and other inflammatory agents [3, 4], it is often prescribed
for food and inhalant allergies, asthma, eczema, psoriasis, gout and
ulcerative colitis. Also, due to its antioxidant effect, quercetin can inhibit inflammatory process mediated by leukotrienes (inflammatory
effects a thousand times more powerful than histamines), hyaluronidase
(collagen-destroying enzymes), and lysosomal enzymes [3].
Its particular antioxidant activity has been found to help reduce
the risk of coronary heart disease [5, 6]. Quercetin helps to dilate and
relax blood vessels and has a protective effect against certain types of
arrhythmia [5, 6]. Quercetin has demonstrated its ability to reduce the
incidence of tumors, which attests to its ability to neutralize oxidants
within cellular material [7-11].
Its antiviral activity is particularly significant today; quercetin is a
remarkable bioflavonoid which can help protect the body against viral

I. EXPERIMENTAL
1. Materials

Sodium carboxymethylcellulose (BDH Chemical Ltd., Poole, UK),

Carbopol NF934 (C.P. Evans Co., UK), Pluronic F-127 (Sigma Chem.
Co., USA), methanol, isopropanol (Prolabo, France), liquid paraffin,
Tween 80 (El-Nasr Pharm. Chem. Co., Cairo, Egypt), propylene glycol
(C.P. Evans Co., UK), PEG400 (Merck Co., Germany) and standard
cellophane membrane (Sigma Chem. Co., USA). All the chemicals
used were of analytical grade.

2. Methods

2.1. Preparation of quercetin gels

NaCMC and Carbopol gel: the required amount of NaCMC or
Carbopol was dispersed in water and stirred by magnetic stirring
until a homogenous gel was obtained and left for 24h. The calculated
amount of quercetin was dissolved in PEG 400, then the drug solution
was added portionwise to the formed gel base to produce 1% w/w
quercetin concentration. The solution of the drug and the gel base was
mixed well using a magnetic stirrer (Witeg Electric, Germany).
Pluronic gel base: the required amount of Pluronic F-127 was dispersed in cold water (5-10C), under constant stirring with a magnetic
stirrer. Upon complete dissolution of the Pluronic F-127, the solution

OH
HO

OH
OH

Figure 1 - 3,3`,4`,5,7-pentahydroxyflavone (quercetin).

431

J. DRUG DEL. SCI. TECH., 17 (6) 431-436 2007

Formulation and evaluation of quercetin in certain dermatological preparations

E.-S.A. Ibrahim, M.A. Hassan, M.M. El-Mahdy, A.S. Mohamed

Table 1 - Percentage composition (% w/w) of quercetin gel, emulgel and microemulsion gel formulations.
Component

F1

F2

F3

F4

F5

F6

F7

F8

F9

Quercetin
NaCMC
Carbopol 934
Pluronic F127
PEG 400
Liquid paraffin
Tween 80
Ethanol
Isopropanol
Water qs

1
2
--30
----100

1
-1
-30
----100

1
--25
30
----100

1
2
---20
5
--100

1
-1
--20
5
--100

1
-2
--20
---100

1
-2
--20
20
-30
100

1
2
---20
20
30
-100

1
2
---20
20
-30
100

2.6. In vitro release of quercetin from the prepared

formulations
A one-gram sample of each formulation was weighed and placed
on cellophane membrane previously moistened with the receptor
phase. The loaded membrane was firmly stretched over one end of
a glass tube with diffusional area 1.77cm2. The tube was then immersed in a 100-mL beaker containing 50 of the release media (30%
v/v dimethylformamide in phosphate buffer pH 6.8) and placed in a
thermostatically controlled water bath (GFL, Germany) at 37 1C,
shaken at 25strokes/min. An aliquot of 5-mL sample was withdrawn
at different time intervals and then replaced with an equal volume of
the release medium maintained at the same temperature. The amount
of quercetin released at time intervals was determined spectrophotometrically at 255nm against a similarly treated blank.

of the drug in PEG 400 was added to the polymer solution to produce
1% w/w quercetin concentration. The dispersion was thoroughly mixed
with magnetic stirring while cold and left overnight in a refrigerator
to complete solubility. The gel formed when the solution was brought
back to room temperature. TableI showed the composition (% w/w)
of different gel formulae (F1, F2 and F3).
2.2. Preparation of quercetin emulgels
w/o emulsions or o/w emulsions were prepared at room temperature by the addition of water to the oil-surfactant mixture to form w/o
emulsions, or by the addition of oil to the water-surfactant mixture to
form o/w emulsion. Quercetin was added to the emulsion and stirred
continuously using a mechanical stirrer. The drug-loaded emulsion was
gelled using a preswollen gel, then it was treated with a homogenizer
for 5min until a homogenous emulgel was obtained. TableI showed
the composition (% w/w) of different emulgel formulae (F4, F5 and
F6).

2.7. In vitro skin permeation

In this study male mice (ICR) were used weighing from 25-30g.
Hairless mouse skin from the dorsal surface was excised. The skin
was mounted on diffusion cells with the epidermis facing the donor
compartment. The skin permeation studies were performed using the
same procedure as that described under the in vitro release study
using cellophane membrane.

2.3. Preparation of quercetin microemulsion gels

Microemulsions are thermodynamically stable, transparent dispersions of oil and water stabilized by an interfacial film of surfactant
molecules [18], while microemulsion gels are fluid microemulsions
which are thickened with a polymer to facilitate topical application
[18].
Firstly, the surfactant (Tween or Span) was combined with oil
phase or aqueous phase and the aqueous phase was added to the oily
phase. Then the specific volume of alcohol (ethanol or isopropanol)
was added gradually with magnetic stirring at room temperature, until
the system became transparent. The microemulsion was allowed to
equilibrate with gentle magnetic stirring for 30 min. Quercetin was
added to the preformed microemulsion and stirred continuously using
a magnetic stirrer. The polymer forming gel was slowly mixed with
microemulsion under stirring. After the gelling agent was entirely dissolved in the microemulsion, the clear microemulsion-based hydrogel
was then obtained. Table I shows the composition of the different
formulae (F7, F8 and F9).

2.8. Stability studies

Samples of the selected formulations were stored in stoppered glass
containers for six months at room temperature (25 1C) and at 4C.
The formulations were evaluated after preparation, and twice every
month for a period of six months. Evaluation of the samples stability was carried out using pH measurements and spectrophotometric
analysis of the drug content and release amount of the drug.
2.9. Kinetic studies
In order to determine the release model which describes the release
pattern of the drug, the selected formulations were analyzed according
to zero-order, first-order and the Higuchi diffusion model.
2.10. Microbiological study
The plate agar diffusion method was used. This method depends
on the diffusion of the drug formulation from holes made on seeded
agar. The agar plates were seeded with various Gram positive (G +ve)
organisms (Staphylococcus aureus and S. epidermidis) and others were
seeded with Gram negative (G -ve) organisms (K. pneumoniae, E. coli
and Cetrobacter). Using a sterile cork borer, four cups were aseptically
cut at equal distances from each other. A sterile applicator was used;
0.0005mg of each formulation was applied in the holes. The dishes
were incubated for 24h, and the diameter of each inhibition zone was
measured.

2.4. Determination of drug content

Drug content was determined by dissolving an accurately weighed
quantity of the formulation (100mg) in 5mL of dimethylformamide.
One milliliter was quantitatively transferred to a volumetric flask
(50mL) and appropriate dilutions were made with phosphate buffer
pH 6.8. The resulting solution was then filtered using a 0.45-m
membrane and measured spectrophotometrically at 255nm (Shimadzu,
UV-150-02, Japan).
2.5. pH measurements
The pH of each formulation was measured using a pH meter
(Jenway Ltd., UK) which was calibrated before each use with buffered
solutions at pH 4 and 7.

II. RESULTS AND DISCUSSION

Quercetin topical formulations have acceptable cosmetic and usage

criteria when prepared. All formulations have acceptable appearance
432

Formulation and evaluation of quercetin in certain dermatological preparations

E.-S.A. Ibrahim, M.A. Hassan, M.M. El-Mahdy, A.S. Mohamed

Cumulative amount released (g/cm2)

and odor. Quercetin semisolids were homogenous, exhibited suitable

consistency and spread easily when applied on the skin. The residual
impression after application varied according to the type of vehicle.
Quercetin content of the prepared formulations was determined. It
was 99.75 0.1%. The pH of all formulations prepared ranged from
5.95 to 6.6.

J. DRUG DEL. SCI. TECH., 17 (6) 431-436 2007

1. Release of quercetin from cellophane membrane

Quercetin release from different gel bases is illustrated in Figure2.

All gel bases contain 1% w/w of quercetin. From the figure it will be
observed that NaCMC gel gives the highest release rate, followed by
Carbopol gel, while Pluronic F127 gel give the lowest release rate.
The cumulative release was 1325.16, 1041.58 and 366.42 g/cm2
of quercetin from NaCMC, Carbopol and Pluronic F-127 gel bases
respectively. The decrease in the amount released from Pluronic F-127
may be attributed to the decrease in the availability of free drug as a
result of micellar complexation, i.e. the tendency of the drug to leave
the vehicle is strongly dependent on its microstructure [19]. The release
data indicated that the amount released increases with the time of the
release. NaCMC and Carbopol showed the highest release profile
while Pluronic F-127 gel base showed the lowest release rate.
Figure3 shows the release of quercetin from the microemulsion gel
and the emulgel. From the figure it will be observed that the emulgel
(F4, F5 and F6) which contain NaCMC as gelling agent gives the
highest release rate followed by Carbopol 934. The release rate from
Carbopol indicated that as the concentration of Carbopol increases,
the release rate decreases. This decrease is due to the difference in
the viscosity of the polymer (1 and 2% polymer concentration). The
cumulative amount released is 713.26, 624.82 and 469.97 g/cm2
from NaCMC, Carbopol 1% and Carbopol 2%, respectively. Also the
presence of Tween 80 in the formula which contained NaCMC, and
Carbopol 1% has an emulsifying effect, which led to an increase in
the release rate of quercetin.
On the other hand, Figure3 shows the release rate of the three
formulae (F7, F8 and F9) of the microemulsion gel. F7 contained
2% NaCMC, and the other two formulae (F8 and F9) contained 2%
of Carbopol as polymer. From the figure it will be observed that F7
containing NaCMC showed a higher release rate of quercetin than
the other two formulae containing 2% Carbopol, followed by F9 and
F8, respectively. The cumulative amounts released are 890.97, 700.24
and 821.28g/cm2 for F7, F8 and F9, respectively. The increase in the
release in F7 and F9 may be attributed to the presence of isopropanol,
which acts as solubilizing agent and increases the solubility of quercetin
which leads to a greater increase in the release of the drug than that
containing ethanol. Also the presence of Tween 80 at concentration
20% in microemulsion gel led to increased release of the drug.
The microemulsion gel formulations (F7, F8, F9) exhibit higher
quercetin releases than the emulgel formulations (F4, F5, F6) as shown
in Figure3. This observation can be explained by the fact that microemulsion gel formulations contain higher surfactant concentrations
and also contain cosurfactants (isopropanol and ethanol) which act
as solubilizers and release enhancers. It was therefore concluded that
the presence of cosurfactants and surfactants has the greatest effect
on quercetin release as deduced from the results.
The higher release rate of quercetin from the gel formulation may
be attributed to the lipophilicity of quercetin, hence the low attraction
between the drug and the gel base.
From the results obtained these topical formulations were arranged on the basis of quercetin release in the following order gel >
microemulsion gel > emulgel.

Time (h)

Cumulative amount released (g/cm2)

Figure 2 - Quercetin release from different gel bases. F1: NaCMC gel;
F2: Carbopol gel; F3: Pluronic F127 gel.

Time (h)

Cumulative amount permeated (g/cm2)

Figure 3 - Quercetin release from different emulgel (F4-F6) and micro

emulsion gel (F7-F9) formulations.

Time (h)

Figure 4 - Quercetin permeation across hairless mouse skin from the

selected formulations plotted according to zero-order kinetic. F1: NaCMC
gel; F4: emulgel; F7: microemulsion gel.

was determined by measuring the amount permeated as a function of

time. In the case of an infinite donor solution (drug concentration in
the vehicle, CV = constant), the cumulative drug permeated (g.cm-2)
was plotted against time (Figure4) and the steady state permeation
rate J (g.cm-2.h-1) was calculated from the slope of the linear portion
of the curve according to Ficks first law of diffusion.
J = (Dm K/L) . CV

Eq. 1

where Dm is the diffusion coefficient of the drug in the membrane, K

the drugs partition coefficient between the membrane and the vehicle
and L the diffusion path length in the membrane.
The permeability coefficient (P = Dm K/L) was then calculated by
dividing the slope by the concentration of the drug employed according to the Chow equation:

2. Release of quercetin from mouse skin

One formula from each topical formulation giving the highest

release of quercetin was selected for this study. The permeation rate of
the drug from the donor through the skin into the receptor compartment
433

P = J/CV

Formulation and evaluation of quercetin in certain dermatological preparations

E.-S.A. Ibrahim, M.A. Hassan, M.M. El-Mahdy, A.S. Mohamed

Eq. 2

Cumulative amount permeated (g/cm2)

J. DRUG DEL. SCI. TECH., 17 (6) 431-436 2007

The diffusion coefficient was calculated from the slope obtained

by plotting the cumulative amount of permeated drug (g/cm2) versus
the square root of time (Figure 5) according to Higuchi diffusion
equation. Equation3 was used to estimate the diffusion coefficient:
D = (slope/2CV)2

Eq. 3

The partition coefficient K was calculated from P and D using

the penetration barrier L with a known thickness of hairless rate skin
(0.2cm).
Many factors may influence the extent of percutaneous absorption
of a drug. Partitioning of the chemical between the vehicle and the
stratum corneum results in a concentration gradient developing across
the skin, which is influenced by chemical-vehicle-skin interactions
[20]. There is no doubt that the release of a drug from a topical pharmaceutical preparation can be effectively influenced by the vehicle
in which it is applied. An appropriate formulation of the topical agent
will ensure that it exerts its maximal activity on the skin [21]. The
primary requirement for topical therapy is that a drug incorporated
into a vehicle reaches the skin surface at an adequate rate and in sufficient amounts. The relative affinity of the drug for skin and vehicle
is represented by the partition coefficient K. TableII shows J, P, D
and K. A high K value indicates that the vehicle has poor affinity for
the drug. A low K value, which indicates a high degree of mutual
interaction, reflects the tendency of the drug to remain in the vehicle.
Hence the release of a substance will be favored by selecting vehicles
with low affinity for the penetrant [22]. TableII showed the difference
in K values according to the type of vehicle used.
Permeability is a function of the flux and concentration of the drug
in the donor recipient of the diffusion cell. In our case the concentration is constant; thus the difference is a consequence of flux. The flux
J is actually proportional to the gradient of thermodynamic activity
rather than to the concentration. This activity changes according to
different formulations [23].
Gel showed the highest flux followed by microemulsion gel and
emulgel respectively. Isopropanol acted as a permeability enhancer.
Generally the modes of action of skin penetration enhancers involve
increased drug diffusivity through the skin by affecting the intercellular lipids or the intercellular proteins or both, and/or increasing the
partitioning of the drug into stratum corneum, and consequent increase
in permeant diffusion coefficient [24]. Furthermore, the high concentration of the non-ionic polyoxyethylene surfactants could additionally intensify the skin permeation. All data for non-ionic surfactants
suggest that their mode of action on skin is related to their ability to
disperse into the intercellular lipid phase of the stratum corneum. This
increases fluidity in this region, which presumably reduces diffusional
resistance [25].
The diffusion coefficient D reflects the facility with which molecules move through the various membrane strata [26]. Diffusivities,
which are a function of the molecular structure of the diffusant, did
not change in our experiment. The diffusion coefficient is also a function of barrier material [27]. In our study the skin barrier seemed to
be affected by the vehicle, since significant differences in D values
were observed among the formulations used in the study.
The difference in quercetin permeation could be mainly attributed
to differences in diffusion through the skin barrier and to some extent
to the partitioning between the vehicle and the stratum corneum. The
results obtained in our study are in agreement with Bonina et al. [28],
which found that there is no relationship between skin permeation and
lipophilicity of the drugs tested, and the skin absorption of the drug
is determined not only by its partition coefficient, but also by other
physicochemical properties including water solubility, molecular size
and diffusivity [28].

Square root of time (h)

Figure 5 - Amount permeated per unit surface area versus square

root of time profile of quercetin from the selected formulations plotted
according to the Higuchi diffusion model. F1: NaCMC gel; F4: emulgel;
F7: microemulsion gel.
Table II - Percutanous penetration parameters of formulation containing
1% quercetin through full-thickness hairless mouse skin.
F1

F4

F7

Flux (J) (g/cm2 h)

166.3

119.0

131.6

Permeability coefficient (P) (cm/h) x 104

1.66

1.19

1.32

Diffusion coefficient
(D) (cm2/h) x 103

6.6

3.7

4.6

Partition coefficient
(K) x (10-3)

0.50

0.64

0.57

3. Kinetic study

TableIII shows the kinetic data obtained from zero order, first
order and the Higuchi diffusion model of the selected formulae through
cellophane membrane and hairless mouse skin. The results indicated
that the release rate of the gel was best fitted with zero-order, while
the release rate for emulgel and microemulsion gel was best fitted with
the Higuchi diffusion model, i.e. which give the highest correlation
coefficient (r).

4. Stability study

Visual inspection was performed for color change, odor, phase

change, texture and spreadability. Drug content, drug release and pH
of the stored samples were also determined and compared with the
fresh samples.
The results confirmed that no chemical degradation occurred, as
concluded from the close similarity in pH. On the other hand, some
formulations as microemulsion gels exhibited phase separation, and
so these formulations showed lower drug content and release.

5. Antibacterial activity

The antibacterial activity of quercetin in different topical formulations was tested against some Gram-positive organisms such as
S.aureus and S. epidermidis and some Gram-negative organisms such
as K.pneumoniae, E. coli and Cetrobacter using the agar diffusion
method. TableIV shows the inhibition zone (mm) of quercetin formulations. It was clear that all tested microorganisms were sensitive to
quercetin. The results also showed that the inhibition zone is greater
in emulgel and microemulsion gel than that of the gel formulae. This
may be attributed to the lower viscosity of emulgel and microemulsion gel than that of the gel which leads to easy diffusion of the drug
through the agar media. It was also clearly obvious that the inhibition
zone depends on the type of the formula used.

434

Formulation and evaluation of quercetin in certain dermatological preparations

E.-S.A. Ibrahim, M.A. Hassan, M.M. El-Mahdy, A.S. Mohamed

J. DRUG DEL. SCI. TECH., 17 (6) 431-436 2007

Table III - Kinetic data of percentage of quercetin permeated from certain dermatological formulations across cellulose dialysis membrane and hairless mouse skin.
Cellulose dialysis membrane

Mechanism of release
Zero-order
First-order
Higuchi
diffusion

Hairless mouse skin

F1

F4

F7

F1

F4

F7

0.996

0.978

0.971

0.998

0.985

0.982

Ko

8.269

4.325

5.335

5.887

4.216

4.66

0.574

0.596

0.592

0.586

0.596

0.594

0.891

0.940

0.928

0.922

0.942

0.936

0.966

0.994

0.996

0.958

0.988

0.991

Kh

14.578

7.99

0.941

10.275

7.690

8.542

zero

diffusion

diffusion

zero

diffusion

diffusion

Best fitted model

r: correlation coefficient. Ko: zero-order rate constant (% released/h). K: first-order rate constant (h-1). Kh: diffusion rate constant.
Table IV - Microbiological study of quercetin (1% w/w) in different topical formulations.
Formulations
F1
F4
F7

Inhibition zone (mm) for different micro-organisms

S. aureus

S. epidermidis

K. pneumoniae

E. coli

Cetobacter

7.0
10
11

7.5
10
11

7.0
10
10

8.0
10
10

7.0
10
10

6. Statistical evaluation

5.

Statistical analysis at P = 0.05 on the difference in the amount

released of quercetin from cellophane membrane for the different
formulae at different time intervals . The results obtained indicated
that there was significant difference at this level. The same results also
obtained for the amounts released from hairless mouse skin. T-test
was also applied at P = 0.05 on the inhibition zone of the selected
formulae (F1, F4 and F7) for different microorganisms. The results
showed significant differences between F1 and the other two formulae
F4 and F7 while there was no significant difference in inhibition zone
of the two formulae F4 and F7.

6.

7.
8.
9.

*
In this study quercetin was formulated in different dermatological
preparations as gel, emulgel and microemulsion gel. It was evaluated in
these different topical formulations. From the results it was concluded
that the release of quercetin from cellophane membrane and hairless
mouse skin depends on the type of formula which are ranked in the
following order: gel > microemulsion gel > emulgel. These results
depend on the type of polymer and the presence of some additives as
surfactants, and the cosurfactants which act as enhancers. The results
also indicated that gel and emulgel are more stable than microemulsion gel, and the release of the drug followed zero, and the Higuchi
diffusion mechanism. Moreover, the drug showed good antibacterial
activity against Gram positive and Gram negative organisms and the
inhibition zone depended on the type of formula.

10.
11.

12.
13.
14.
15.

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Manuscript
Received 12 July 2007, accepted for publication 10 October 2007.

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