September - October 2013 Indian Journal of Pharmaceutical Sciences 569
Ketotifen Fumarate and Salbutamol Sulphate Combined
Transdermal Patch Formulations: In vitro release and
Ex vivo Permeation Studies
M. YOUSUF, M. AHMAD*, M. USMAN AND L. ALI
Department of Pharmacy, Faculty of Pharmacy and Alternative Medicine, The Islamia University of Bahawalpur,
Yousuf, et al.: Transdermal Patches of Ketotifen Fumarate and Salbutamol Sulphate
The present work was performed to develop and evaluate transdermal patches of combined antiasthmatic
drugs (salbutamol sulphate and ketotifen fumarate). Polyvinyl alcohol membrane was used as backing membrane
and eudragit RL‑100 was used as matrix material to suspend the drugs in the continuous thickness of the patch.
Methanol was solvent and propylene glycol was used as plasticizer. Tween 20, isopropyl myristate, eucalyptus oil,
castor oil and span‑20 were used as permeability enhancers. Thickness, weight variation and drug uniformity were
investigated. The patch formulations were also subjected to drug release in dissolution media and permeation through
rabbit skin. Effects of different enhancers were evaluated on release and permeation of drugs. F3 formulations having
isopropyl myristate as permeation enhancer, showed maximum amounts of drugs release (88.11% of salbutamol
sulphate and 88.33% of ketotifen fumarate) at the end of 24 h dissolution study. F3 also showed maximum
permeation of both drugs (4.235 mg salbutamol sulphate and 1.057 mg ketotifen fumarate) after 24 h permeation
study through rabbit skin mounted in Franz cell. The patches having no enhancer in the formulation also showed
some drug release and permeation due to the presence of plasticizer. The results of the study suggested that new
controlled release transdermal formulations of combined antiasthmatic drugs can be suitably developed as an
alternate to conventional dosage forms.
Key words: Ketotifen, permeability enhancers, transdermal patches, salbutamol
Transdermal patches are developed to deliver a
drug to blood stream across a multilayer system
of skin and keep therapeutically effective amount
of drug in the body. The drug from patch first
passes the stratum corneum (SC), then epidermis
and finally enters into the systemic circulation.
Transdermal delivery provides a leading edge over
injectable and oral routes. Transdermal patches can
deliver the drug from skin to systemic circulation
at controlled rate. It provides sustained effect of
drug for desired time period[2,3]. Avoidance of first
pass metabolism and gastrointestinal incompatibility
increase the bioavailability and reduce side effects.
Transdermal patch systems are suitable alternate for
drugs with short biological half‑lives and narrow
therapeutic window. Transdermal patches sustain the
constant level of drug for prolonged time period and
enhance pharmacological and physiological actions.
Termination of drug is possible at any point of time
in case of unwanted effects. Patient compliance
is enhanced due to reduced dose frequency and
self‑administration. Ketotifen fumarate (KF) has
been prophylactically used for chronic asthma. It is
an antihistaminergic and stabilizes the mast cells.
It is also being used in the treatment of rhinitis
and conjunctivitis. Dose size of KF is 1 mg (BD)
by oral route. After oral administration, drug is
completely absorbed from gastrointestinal tract (GIT).
But due to hepatic metabolism, 50% of drug is
destroyed reducing amount of drug one‑half at site of
action. Salbutamol sulphate (SS) is a β‑adrenergic
agonist. Mechanism of action of SS is more specific
than other drugs of the same class. It produces
pronounced bronchodilation which makes it a suitable
part of asthma therapy. The small doze size (2‑8 mg),
extensive first pass metabolism and shorter
half‑life (2‑3 h) of SS makes it a suitable agent to be
developed for transdermal drug delivery[6,7]. However,
low permeability of these drugs is the main barrier
*Address for correspondence
570 Indian Journal of Pharmaceutical Sciences September - October 2013
for delivering the drug through skin. Permeation
enhancers can be used to break the barrier of skin
and increase the permeation of drug through skin[8‑10].
Chemical penetration enhancers work by altering
reversibly the structure of stratum corneum. Drug
permeation may also be enhanced by increasing its
solubility in subject skin. Asthma is a chronic
inflammatory disorder of airways. Development of
asthma involves many cells and cellular elements
particularly mast cells, eosinophils, T‑lymphocytes,
macrophages, neutrophils and epithelial cells. They
lead to variable airway inflammation and airflow
obstruction causing difficulties in breathing[12,13]. The
management of chronic diseases like asthma depends
on long term compliance to the dosage regimen. More
than one pathological disorder may be involved in
asthma that usually requires multiple drugs therapy.
In such conditions, patient compliance found to be
low. To overcome these problems, drugs are to
be combined in single dosage regimen. Combination
of KF and SS used in allergic asthma is found to
enhance antiasthmatic action of SS. A combination of
KF (1 mg) and SS (2 mg) is available for treatment
of asthma in tablet dosage form (Mastifan‑s East West
In this work, novel strategy was applied to develop
new combined transdermal antiasthmatic formulations
of SS and KF. Different permeation enhancers were
used to enhance the drug dissolution and ex vivo
permeation through rabbit skin using Franz cell.
Physiochemical attributes like clarity, elasticity,
folding endurance, tensile strength, brittleness, weight
variation, moisture uptake, thickness uniformity and
drug content uniformity were also determined. F3
formulation showed superior behaviour in terms
of release and permeation of both drugs. Finally,
optimized patch formulation was subjected to skin
irritation study using human volunteers.
MATERIALS AND METHODS
Salbutamol sulphate (SS) was obtained as gift
sample from Glaxo Smithkline, Karachi, Pakistan.
Ketotifen fumarate (KF) was supplied as gift sample
from Barrett Hodgson, Karachi, Pakistan. Polyvinyl
alcohol (Mol. Wt. 72 000) and eudragit RL 100 were
purchased from Sigma‑Aldrich, UK. Eucalyptus oil
was obtained from George Rennie, France. Tween
20, isopropyl myristate (IPM), castor oil and span
20 were purchased from BDH, UK. Methanol and
propylene glycol (PG) were purchased from Merck,
Preparation of backing membrane:
Backing membrane of patch was prepared using poly
vinyl alcohol (PVA). Aqueous 4% w/v PVA solution
was prepared in conical flask with continuous stirring
on hot plate stirrer at 80°. After cooling, PVA solution
was deaerated for 2 min by sonicator. Finally, 15 ml
of the prepared solution was poured in glass petri
dishes of an area approximately 61 cm² and then
air dried for 24 h. Drying of films was carried
out at room temperature. However, temperature and
humidity of laboratory were maintained at favorable
conditions (25° and 75% RH) for fabrication of
transdermal patches. Sharma and Chandy developed
a series of membranes in ambient conditions by
air‑drying films of PVA. Chitosan blended films were
found to have excellent physicochemical properties.
PVA forms a water impermeable membrane.
PVA‑based membrane can protect transdermal system
from external environment. It provides occlusive
conditions leading to enhance the permeation of drug
through the skin. PVA is the most frequently used
polymer in manufacturing of backing membrane[19,20].
Preparation and casting of the matrix solution:
Table 1 describes the formulation variables per
100 ml of matrix dispersion. The patch formulation
solution was prepared by adding 5 g eudragit to
100 ml methanol in 250 ml conical flask. The flask
was sealed and solution was stirred at 500 rpm by
magnetic stirrer for 30 min. After thorough mixing,
relevant plasticizer and enhancers were added and
mixed well for 30 min. 2480 mg SS and 620 mg
KF were added and stirred for 30 min to obtain
a homogenous dispersion. Addition of the above
mentioned amounts of SS and KF in 100 ml of
TABLE 1: FORMULATION VARIABLES OF TRANSDERMAL
Eudragit RL 100 (g) 55
PG (g)1.75 ‑
Tween 20 (g)‑5
IPM (g) ‑‑
Eucalyptus oil (g) ‑‑
Castor oil (g) ‑‑
Span 20 (g) ‑‑
Methanol (ml) 100100
PG=propylene glycol, IPM=isopropyl myristate
September - October 2013 Indian Journal of Pharmaceutical Sciences 571
solvent gives 6 mg of SS and 1.5 mg of KF for each
patch of 1.5 cm² size. Then the matrix dispersion
was sonicated for 5 min to remove entrapped air.
Ten milliliter of above matrix dispersion was poured
in petri dishes containing PVA backing membranes.
The petri dishes were placed horizontally at room
temperature for 24 h covered with inverted funnels to
avoid rapid evaporation of solvent. The dried patches
containing multiple antiasthmatic drugs were carefully
removed from petri dishes, wrapped into aluminum
foil and stored at 25°.
Cutting of patches:
The dried films were cut into circular patches with
the help of specially designed stainless steel cutter
having diameter of 1.5 cm². Eighteen patches of 1.5
cm² were obtained from one petri dish.
Physical evaluation of transdermal patches:
Physical appearance, weight variation, thickness,
texture and colour of various transdermal patches
were evaluated. All transdermal patches were
visually inspected for the smoothness, clarity and
brittleness. Three patches were selected randomly
from each formulation and weight uniformity of
the dried and cut patches was checked on analytical
balance (Shimadzu AUX220, Germany). The
thickness of patches was determined by using digital
micrometer screw gauge (Sharpfine Type‑A, China).
For determining variation in thickness, each patch was
checked at three different places and finally mean of
three readings was taken.
To check the strength of patches, folding endurance
test was performed manually. The test was performed
by folding the transdermal film repeatedly at the same
place until patch break or crack. Values of folding
endurance were given from number of folding at same
place without breaking. Three patches were checked
and average was reported.
Moisture uptake of transdermal patches was evaluated
to determine the integrity and stability of the film
in humid conditions. In order to determine moisture
uptake capacity, 1.5 cm² of developed patches were
weighed and films were placed at room temperature
in a desiccator. After 24 h, films were taken and
exposed to 84% relative humidity in desiccator.
Humid condition was developed by saturated
solution of potassium chloride. Patches were weighed
repeatedly until a constant weight was achieved.
Moisture uptake (%) was calculated by the formula,
moisture content=[(final weight‑initial weight)/initial
Tensile strength of transdermal patches is measured to
determine the mechanical properties of the polymeric
films. Modified pulley system was used to determine
the tensile strength of fabricated transdermal
membranes. Three strips of transdermal patches
were cut in 2 cm length and 1 cm width and fixed
between two jaws of apparatus. Weight was gradually
increased until the film break. Three readings were
taken for each patch and average was calculated.
Tensile strength was measured in kg/cm².
Drug content uniformity was evaluated by the method
used by Gupta et al. and Dandagi et al.[24,25]. Patches
without drug were also prepared to be used as blank.
The films of each formulations containing drugs and
without drug were cut into small pieces of an area
of 1.5 cm². The cut pieces of both type of patches,
i.e. with drugs and without drug were put in 100 ml
of water in conical flask and stirred continuously on
magnetic stirrer for 36 h. Then solution was sonicated
for 30 min and filtered. After achieving suitable
dilutions, the solutions were analysed on double beam
UV/Vis Spectrophotometer (Shimadzu‑1601, Germany)
at wave length of 300 nm for KF and 276 nm for SS.
In vitro release studies:
In vitro drugs release experiments were carried
out in dissolution apparatus (PT‑DT7 Pharma Test,
Germany). The patch of an area of 1.5 cm² containing
6 mg of SS and 1.5 mg of KF was placed against the
watch glass and retained in position with stainless
steel mesh and clips. Both of antiasthmatic drugs (SS
and KF) are water soluble. SS is soluble in four parts
of water as per the United State Pharmacopoeia
and reported solubility for KF is 14.79 mg/ml. Hence,
water was used as dissolution medium at ambient
temperature. Solubilities of antiasthmatic drugs in sink
condition were observed as reported earlier. Vessels
were filled with 500 ml of distilled water maintained
at 32±0.5° (skin temperature) and paddles were fitted
so that the distance between the paddle blade and
the surface of disk assembly was 25 mm. The disk
assemblies holding the patch were placed at bottom
of the vessels with release surfaces facing upward
and were centred using a glass rod. The stirring
speed was set at 50 rpm and the vessels were covered
572 Indian Journal of Pharmaceutical Sciences September - October 2013
to minimize evaporation. Auto sampler (PTFC II,
Pharma Test, Germany) was used to withdraw 5 ml
of release media at 0, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8,
10, 12, 14, 16, 20 and 24 h after filtering through
Millipore filters. The drugs released were measured
by spectrophotometric analysis. Five patches of each
formulation were tested for in vitro release study and
average was calculated.
Permeation study through rabbit skin:
In the permeation study of combined antiasthmatic
patches, Franz diffusion cell (Permegear, Bethlehem
USA) with an area of 1.5 cm² and volume of receptor
compartment 12 ml was used. Due to the difficulty of
obtaining human skin samples, rabbit skin was used.
The receptor medium (distilled water) was filled in
the receptor compartment. The receptor was chosen
on the basis of compatibility with the membrane
formulation and on the basis of physicochemical
properties of drugs used. In Franz diffusion cell, the
temperature of outer jacket was set at 37±1° in order
to provide a temperature of 32±1° in the receptor
compartment. Actually, the loss of heat occurs in
plastic tubes that connect the Franz cell with the
thermostatic water bath (Brookfield, USA). The rabbit
skin membrane was carefully placed over the open
end of the receptor compartment. Patch of an area
of 1.5 cm² was placed over the membrane. The glass
disk of donor compartment was placed over receptor
compartment and both compartments were kept in
position with the help of the stainless steel clamp. To
avoid evaporation, the junction of two compartments
was wrapped with adhesive tape. To provide occlusive
conditions, the patches were covered with aluminium
foil and petroleum jelly. The whole assembly was
kept on magnetic stirrer and the receptor fluid was
kept stirring continuously during test by using
magnetic stirrer at a speed of 500 rpm. Sample of
1 ml was withdrawn at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8,
10, 12, 14, 16, 20 and 24 h from the sampling port
with the help of long needle syringe and replaced by
an equal volume of receptor fluid at each sampling
time. Dissolution medium (distilled water) was used
to take the blank reading. The collected samples were
suitably diluted and analysed spectrophotometrically at
a wave length of 300 nm for KF and 276 nm for SS
to measure permeated contents of antiasthmatic drugs.
Spectrophotometric method is being successfully used
for measuring the permeated concentration of drug in
receptor compartment, during the in vitro permeation
Skin irritation test:
Formulation showing best results during in vitro
studies was further evaluated for the presence
or absence of hazards of irritation. This test was
performed to ensure the safety of formulation for
the application on the intact skin. Irritation study
of formulated patches was performed on 10 healthy
human volunteers, weighing 60‑80 kg and in the age
of 21‑27 years. Before the application of patches,
erythema readings were taken from the inner arm of
volunteers by Mexameter™ (Courage and Khazaka,
Germany) and considered as control reading. Patches
were applied on the inner arm of the volunteer for
a period of 8 h. After specified time, patches were
removed and readings were taken again and compared
with control reading by statistical paired sample
RESULTS AND DISCUSSION
The aim of this study was to develop matrix type
patches of combined antiasthmatic drugs SS and KF
by solvent casting or plate casting method followed
by their in vitro and ex vivo permeation evaluation.
For this purpose, a series of matrix patches of
combined antiasthmatic drugs were prepared using
eudragit RL100 as polymer. Different enhancers,
tween 20, IPM, eucalyptus oil, castor oil and span
20 were employed. PG was applied as plasticizer.
Effects of different permeability enhancers on in vitro
dissolution and ex vivo permeation through rabbit skin
The results of visual inspection showed that the
patches containing tween 20, IPM, eucalyptus oil,
castor oil and span 20 as permeation enhancers were
smooth and transparent and do not need plasticizer
to be added (Table 2). This may be attributed to
plasticising effect of permeation enhancers. Results
of weight variation test are presented in Table 3. Low
TABLE 2: VISUAL APPEARANCE OF TRANSDERMAL
Formulation Smoothness Clarity Brittleness Overall appearance
+=level of satisfaction, ×=level of dissatisfaction
September - October 2013 Indian Journal of Pharmaceutical Sciences 573
values of standard deviations proved that the patches
containing combined antiasthmatic drugs possess
uniformity in weight. To ensure the uniformity in
thickness of transdermal patches, each patch was
checked at three places and averaged. Thickness values
of various patch formulations are shown in Table 3.
Thickness with low standard deviation values ensures
uniformity of thickness in films prepared by solvent
casting method. PG was primarily used as additive and
plasticizer in manufacturing of transdermal patches. It
reduces brittleness and rigidity of membrane leading
to improved smoothness, physical stability, plasticity
and appearance of films. Other formulations having
tween 20, isopropyl myristate, eucalyptus oil, castor
oil and span 20 as permeability enhancers, showed
satisfactory physical and mechanical properties without
plasticizer. Tween 20, isopropyl myristate, eucalyptus
oil, castor oil, and span 20 when used as enhancers
produce smooth, clear, transparent and flexible patch
membranes even without any addition of plasticizer.
These enhancers possess suitable physiochemical
properties to act as plasticizer.
Plasticizers act by interposing forces that holds the
polymer chains, causing softening and extending the
formulated matrix membrane. All prepared patches
possess suitable folding endurance. The results are
presented in Table 3. Moisture uptake study was
carried out at 84% relative humidity. Results of study
are shown in Table 3. Low values of moisture uptake
are attributed to hydrophobic nature of eudragit RL
100. Low moisture uptake favours formulation stability
for long term storage and reduces brittleness. Low
moisture uptake also keeps the product safe from
microbial contamination. Results of tensile strength
reveal that patches have suitable strength and elasticity.
Results are presented in Table 3.
All patches showed uniform distribution of both
drugs. Among different patches, difference in
percent uniformity of contents of both drugs was not
significant. The drug contents in different membrane
formulations are placed in Table 4. The results
showed that the plate casting method of producing
patches was capable of providing uniform drug
distribution in patches.
The percent cumulative release of both drugs
after 24 h dissolution experiments are presented
in Tables 5 and 6. Highest percent cumulative release
for both drugs was observed from F3 containing IPM
as permeation enhancer. This significant amount of
drug release form the patches within 24 h is due
to the presence of quaternary ammonium group
in eudragit RL 100, which make the polymer
hydrophilic to some extent. When formulation
comes in contact with dissolution medium, polymer
absorb fluid followed by hydration and swelling
of patches leading to the release of drug from
polymeric device. Further, addition of plasticizer
and enhancers increases the release rate of drug from
the patches during dissolution study (figs. 1 and 2).
High release rate of drugs is associated with the
presence of plasticizer and enhancer. The presence
of enhancer improves flexibility and smoothness of
eudragit RL 100 matrix of patches. Water molecules
permeate easily in formulated film and cause the film
to swell. This phenomenon ultimately increases the
amount of drug release from patches. The highest
release of F3 is due to solubilising effect of IPM.
Least amounts of percent cumulative release for both
drugs were observed from F1. This aspect of F1
can be associated with the absence of permeability
enhancer. Other formulations containing enhancers
showed relatively higher cumulative release of both
The in vitro permeation study gives prediction about
the in vivo performance of the formulation. The
permeation study was carried out on Franz Diffusion
TABLE 3: PHYSICOCHEMICAL PROPERTIES OF TRANSDERMAL PATCHES
The values are expressed as mean±SD, where SD is standard deviation
Folding endurance Thickness (μm) Moisture uptake (%)Tensile strength (kg/cm²)
574 Indian Journal of Pharmaceutical Sciences September - October 2013
TABLE 4: CONTENT UNIFORMITY OF SS AND KF IN
Formulation % Contents (mean±SD)
SD=Standard deviation, SS=salbutamol sulphate, KF=ketotifen fumarate
cell using rabbit skin membrane. Graphs representing
cumulative amounts of SS and KF permeated vs.
time were constructed (figs. 3 and 4). An increase
in concentration of both drugs was found in receptor
compartment with passage of time. Each formulated
patch contained 6 mg of SS and 1.5 mg of KF. The
amounts of both drugs permeated from transdermal
patches at the end of 24 h permeation study in
Franz Cell were (2.747 mg SS and 0.688 mg KF)
from formulation F1, (3.949 mg SS and 0.989 mg
KF) from F2, (4.235 mg SS and 1.057 mg KF)
from F3, (4.121 mg SS and 1.023 mg KF) from
F4, (2.787 mg SS and 0.697 mg KF) from F5
and (4.144 mg SS and 1.044 mg KF) from F6.
Formulation F1 having no permeability enhancer
showed minimum amount of drug permeation. Similar
effect has been reported for transdermal patches of
TABLE 5: AMOUNT OF SS RELEASED FROM TRANSDERMAL PATCHES
0.50 2.44±0.7 5.33±0.45
6.00 27.11±0.45 40.00±0.91
10.00 34.89±0.93 55.78±0.76
12.00 40.22±0.84 60.22±0.85
Values are presented as mean±SD. SD=Standard deviation, SS=salbutamol sulphate
Amount released (%)
F2F4 F5 F6
TABLE 6: AMOUNT OF KF RELEASED FROM TRANSDERMAL PATCHES
5 25±0.2 44.33±0.83
Values are presented as mean±SD. SD=Standard deviation, KF=ketotifen fumarate
Amount released (%)
September - October 2013 Indian Journal of Pharmaceutical Sciences 575
diclofenac sodium subjected to permeation study
through hairless rate skin. F2 has tween 20 as
permeability enhancer and showed sufficient amount
of drug permeated during ex vivo permeation study.
Tween 20 is nonionic surfactant used to enhance
the permeability of drug though stratum corneum.
The permeation promoting activity of nonionic
surfactant (tween) may be due to the reduction in
surface tension, improvement in wetting of skin and
enhanced distribution of the drug. F3 showed the
highest amounts of both drugs permeated through
rabbit skin. F3 patches have IPM as drug permeability
promoter. This can be explained on the fact that the
solubility parameter of IPM (16.40MPa1/2) is similar
to that of skin (20.01MPa1/2), which leads to high
affinity of IPM for SC. The high affinity of IPM for
SC results in the formation of a pool that drives the
drugs eventually into the SC, thereby reducing the
SC barrier function. Similarly, F3 also showed the
highest amounts of cumulative release for both drugs.
The results are in good agreement of expected results
as per dissolution study. Transdermal patches of F4
contain eucalyptus oil as enhancer. The permeation
enhancing effect of eucalyptus oil is primarily
believed to be due to the promotion of membrane
vehicle partitioning tendency of the drug with the
oils. It is believed that penetration of the vegetable
oil into the intracellular lipid phase of the membrane
may increase the degree of fluidity resulting in
decreased resistance to permeation. This mechanism
can increase flux of drugs. Formulation F6 contains
span 20 as permeability enhancer. The permeation
results of this formulation are comparable with
those reported by Vora et al.. Flux was calculated
Fig. 1: Release profile of salbutamol sulphate from transdermal
patches with various enhancers.
Drug release pattern of SS from patches F1-F6 F1=(
F3= () ; F4=(--x--); F5 (); F6 ( --●--).
Fig. 2: Release profile of ketotifen fumarate from transdermal patches
with various enhancers.
Drug release pattern of KF from patches F1-F6 F1=(
F3= () ; F4=(--x--); F5 ( ); F6 ( --●--).
Fig. 3: Cumulative amount of salbutamol sulphate permeated from
patches with various permeation enhancers.
Drug permeation pattern of SS from patches F1-F6 F1=(
F3= () ; F4=(--x--); F5 (); F6 ( --●--).
); F2=( );
Fig. 4: Cumulative amount of ketotifen fumarate from patches with
various permeation enhancers.
Drug permeation pattern of KF from patches F1-F6 F1=(
F3= () ; F4=(--x--); F5 (); F6 ( --●--).
576 Indian Journal of Pharmaceutical Sciences September - October 2013
to determine the quantity of drugs permeated per
centimeter square of patch per hour. Values of Flux
are presented in Table 7. Formulation F3 showed
maximum flux both for SS and KF through the
rabbit skin membrane. The formulation showed this
pronounced flux due to the presence of IPM as
permeation enhancer. The lag time of both drugs was
separately calculated from the intercept on the time
axis in the plot of cumulative amount permeated vs.
time and lag times for various formulations are given
in Table 7.
Formulation F3, which showed the best release rate
and permeation profile during in vitro and ex vivo
evaluations, was further subjected for skin irritation
test. Erythema values were taken before and 8 h after
the application of patches compared by t‑test in Graph
pad, keeping the confidence interval 95%. Results of
study give P value 0.37 and difference between the
readings before and after application of patches was
found insignificant (fig. 5). Results of irritation study
revealed that F3 transdermal patches possess high
compatibility and showed no sign of erythema or
irritation during the period of study.
In present study, KF and SS were combined and
evaluated successfully in transdermal patches.
Formulated patches were found to possess satisfactory
physicochemical properties and uniform dispersion of
drug. In vitro release and ex vivo permeation rates were
optimised by adding various permeation enhancers.
Formulation F3 having IPM as enhancer was superior
in performance and showed the highest amounts of both
drugs released from patches and permeated through
the rabbit skin membrane. Irritation study revealed
that formulation was free from the hazard of irritation
and safe for application on intact skin. Patches having
no enhancer showed very low permeability. The study
provides a comprehensive data to develop and optimize
transdermal patches of combined antiasthmatic drugs by
applying various chemical enhancers.
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Fig. 5: Skin erythema value.
Erythema value before and after application of the patches on
TABLE 7: FLUX AND LAG TIME OF SS AND KF FROM
F10.0851±0.023 0.0178±0.019 1.62±0.081
F20.1096±0.015 0.0272±0.027 0.85±0.095 0.87±0.074
F30.1423±0.020 0.0374±0.031 0.74±0.073 0.72±0.091
F40.0830±0.018 0.0263±0.016 1.46±0.120 1.50±0.063
F50.0920±0.021 0.0206±0.020 2.18±0.085 2.00±0.055
F60.1168±0.032 0.0325±0.015 0.75±0.061 0.69±0.100
Values are presented as mean±SD. SD=Standard deviation, KF=ketotifen
fumarate, SS=salbutamol sulphate
Lag time (h)
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Accepted 14 July 2013
Revised 11 July 2013
Received 18 February 2013
Indian J Pharm Sci 2013;75(5):569-577