2019 Samosir et al
e-mail : i.sopyan@unpad.ac.id (I. Sopyan)
Formulation and Evaluation of Ketoprofen Gel Preparations using Sesame
Oil, Soybean Oil and Oleic Acid as Enhancers
Rugun Clara Samosir
1
, Iyan Sopyan
1,2,*
, Dolih Gozali
1
1
Departemen of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Universitas
Padjadjaran, Bandung, Indonesia, +62227796200
2
Research Center of Drug Delivery and Disposition, Faculty of Pharmacy, Universitas Padjadjaran.
Bandung, +62227796200
Received : 18 Nov 2018/Revised : 26 Dec 2018/Accepted : 2 Jan 2019/Published 21 Jan 2019
ABSTRACT
Permeation is a measurable profile in drug penetration in the skin. Adding increasing permeation
substance (enhancer) in drug formulation is an important thing in pharmaceutical and toxicology in
nowadays. The purpose of this research was to evaluate the effect of sesame oil, soybean oil, and oleic
acid as an enhancer in ketoprofen gel permeation. Six formulas were prepared by varying concentration
of sesame oil, soybean oil, and oleic acid respectively 5% and 10% and one blank, without enhancer.
Permeation test was evaluated by in vitro permeation test using Franz diffusion cell method and shed
snake skin of reticulated python as a membrane. Permeation test was carried out for 6 hours. The result
showed that sesame oil, soybean oil, and oleic acid were able to increase ketoprofen permeation. B1
formula that contains 5% sesame oil had the greatest percent permeation after 6 hours is 5.913%, while
blank that contain no enhancer is 0.623%.
Keywords: Ketoprofen, permeation, enhancer, soybean oil, sesame oil, oleic acid
1.
Introduction
Permeation is a profile should be measured in the
penetration of the medication on the skin. The addition
of the substance (enhancer) permeation Enhancer at
medication dosage is crucial on the research of
pharmaceutics and Toxicology at the moment [1].
Permeation-enhancing compounds (enhancer) can
modify or impair the lipid composition of the stratum
cornea intercellular so that the transfer of drugs through
the skin can be improved. Penetration-enhancing
compounds that are widely used are dimethyl sulfoxide
(DMSO), dimethylacetamide (DMA),
dimethylformamide (DMF), propylene glycol, glycerol,
and others [2].
The use of organic solvents such as DMSO and
DMF are proven effective in increasing the penetration
of drug compounds like the barbiturates, steroids, and
griseofulvin, but has a weakness among them are
irritants, leaving only the morphological changes
significantly on the skin, can be denatured ceratin of
skin causing keratolysis, and toxic [3].
Therefore, sought relatively safe permeation
enhancers for the body. Based on United States Patent
by Sharma, et.al [4], it is said that the plant oils can
function as enhancers in transdermal preparation. In this
study, we used enhancers of sesame oil (sesame oil),
soybean oil (soybean oil), and oleic acid (oleic acid)
which are expected to enhance permeation of drugs
without causing toxic effects on the skin. In addition,
this plant is the excess oil that can be metabolized by the
body, the price is affordable and easy to obtain.
Active substances which are used in this research is
that ketoprofen is a propionic acid have activity as a
bitter taste with non-steroid analgesic and antipyretic
power working to inhibit the synthesis of
prostaglandins. The time of elimination ketoprofen
crusts quickly, i.e. 1.5–2 hours cause these drugs must
often be consumed when used per oral and on the use of
ketoprofen in high doses (300 mg >) can cause bleeding in
*Corresponding author, https://doi.org/10.24198/idjp.v1i1.19359
Vol 1, Issue 1, 2019 (26-32)
http://journal.unpad.ac.id/IdJP
R. C. Samosir et al / Indo J Pharm 1 (2019) 26-32
27
the stomach. One way of overcoming these weaknesses is
by giving ketoprofen topically so as to reduce the side
effects of the drug.
2.
Method
2.1. Tools
The tools used in this research are analytic scales
(Dragon 204), the Franz diffusion cell has been modified,
UV-spectrophotometer Visible (Analytic Jena Specord
200-222U179), pH meter (Metrohm Type 744), and
viscometer (Brookfield HBDV-II CP+P).
2.2. Materials
Ketoprofen (Hexpharm), carbopol 940 (Quadran),
sesami oil (Lansida), soybean oil (Lansida), oleic acid
(Brataco), ethanol (Brataco), triethanolamine (Quadran),
tween 80 (Quadran), span 60 (Quadran), n-octanol p.a.
(Brataco), aquabidest (IPHA), sodium hydroxide (Merck),
potassium phosphate (Merck), ketoprofen gel preparations
available on the market (® Profenid gel) (Sanbe), and
snake membranes swell (Reticulated Python Python)
(from the Bandung Zoo).
2.3. Organoleptic identification material observation
Examination materials are organoleptic, which
includes description and solubility are then compared with
the monograph listed in the Pharmacopoeia Indonesia
Edition IV and Handbook of Pharmaceutical Excipients.
2.4. Formulation of ketoprofen gel
Formulation of ketoprofen gel with sesame oil
enhancers, soybean oil, and oleic acid was designed based
on Table 1.
2.5. Evaluation of ketoprofen gel
Evaluation of ketoprofen gel includes organoleptic
observations, pH, the viscosity, determination of the levels
of ketoprofen in the gel, in-vitro testing and release of
ketoprofen from preparations gel using cell method Franz
diffusion and as well as the calculation of the partition
coefficient of ketoprofen from the gel.
2.6. Statistical analysis data
Statistically, data analysis using random complete block
design using the (α = 0.05, DBLA), with a confidence level
of 95%.
3.
Result
3.1. Results of material identification
The results of the examination of materials showing the
materials used comply with the standards contained in the
Indonesia Pharmacopoeia Edition IV and Handbook of
Pharmaceutical Excipients.
3.2. Results of gel ketoprofen formulation
Formulation of ketoprofen gel is made in three
variations with each enhancer comprising 2 variations in
concentration. Results formulation of ketoprofen gel
preparations can be seen in Figure 1 and the results of
observations of the organoleptic preparations can be seen
in Table 2.
Table 1. Gel formulation
Materials
Formulation (%w/w)
A1
A2
B1
B2
C1
C2
Carbopol 940
1
1
1
1
1
1
Ketoprofen
2.5
2.5
2.5
2.5
2.5
2.5
Triethanolamine
3
3
3
3
3
3
Soybean oil
5
10
-
-
-
-
Sesame oil
-
-
5
10
-
-
Oleic acid
-
-
-
-
5
10
Tween 80
0.1
0.2
0.1
0.2
0. 4
0.8
Span 60
0.4
0.8
0.4
0.8
0.1
0.2
Na
2
EDTA
0.1
0.1
0.1
0.1
0.1
0.1
Aquadest (ad)
100
100
100
100
100
100
R. C. Samosir et al / Indo J Pharm 1 (2019) 26-32
28
Figure 1. Ketoprofen gel formulation
Table 2. Observations of organoleptic ketoprofen gel
Formulation
Viscosity
Color
Smell
Blank
Viscous
Clear
-
A1
Viscous
White
Soybean oil
A2
Viscous
White
Soybean oil
B1
Viscous
White
Sesame oil
B2
Viscous
White
Sesame oil
C1
Viscous
White
Oleic acid
C2
Viscous
White
Oleic acid
Blank: ketoprofen gel with sesame oil without enhancers, soybean oil, and oleic acid
A1: ketoprofen gel with enhancer soy oil 5%
A2: ketoprofen gel with 10% soybean oil
B1: ketoprofen gel with sesame oil 5%
B2: ketoprofen gel with sesame oil 10%
C1: ketoprofen gel enhancer with oleic acid 5%
C2: ketoprofen gel enhancer with oleic acid 10%
3.3. The Evaluation Material of Ketoprofen Gel
The evaluation material of gel includes organoleptic
observations, measurements, measurement of pH,
viscosity determination of ketoprofen in inventory levels,
testing the release preparation of ketoprofen in in-vitro
using diffusion cell method of Franz, and results in partition
coefficient calculation of ketoprofen from preparations.
3.4. Observation organoleptic preparations
Ketoprofen gel with an enormous variety of enhancers
does not experience a change in organoleptic, good
consistency, color, and odor during the 56 days of storage.
3.5. Observation viscosity of preparations
The graph between the storage time and the viscosity
of the material at room temperature can be seen in Figure 2.
3.6. Observation pH preparations
The results of measurements of the pH of the
material can be seen in Figure 3.
3.7. Results of the determination of the levels of
ketoprofen in preparation
Determination of the levels of ketoprofen gel
preparations done in order to ensure that the resulting
preparations contain ketoprofen concentration
homogeneity. The results of the determination of the
levels of ketoprofen in preparations can be seen in
Table 3.
3.8. Determination of partition coefficient
The result of a determination partition
coefficient exhibited in Table 4.
R. C. Samosir et al / Indo J Pharm 1 (2019) 26-32
29
Day
s
Figure 2. The results of measurements of the viscosity during storage
Days
Figure 3. The results of pH measurements during storage
3.9. Evaluation of In vitro permeation
Preparation of ketoprofen permeation testing
using diffusion cells Franz in a way measure the
concentration of the active ingredients in the
liquid receiver on a specific time interval.
Permeation test in vitro preparations of ketoprofen
gel formula sixth blank and compared against existing
products in the market presented in Figure 4 and Table
5.
4.
Discussion
During the period of storage are happening
decreased viscosity preparations. It is thought to
be caused by the presence of the influence of air
from the outside causing material tends to absorb
water from the environment. However, the
viscosity of the material made it still meets the
standards of the viscosity of semisolid
preparations that are in the range of 500-5000
Poise [5].
Based on these images can be observed that an
increase in pH during storage preparation
compared to the initial pH of the preparations. An
increase in the pH of the material occurs in
amounts that are not too large. This show the
preparations relatively stable during storage and
an increase in pH that occurs likely caused by the
Day
s
Viscocit
y
p
H
R. C. Samosir et al / Indo J Pharm 1 (2019) 26-32
30
Table 3. Results of the determination of the levels of ketoprofen in preparation
Formulation
Theoretical
Concentration
(mg)
Concentration
(mg) (n=3)
Blank
25
2442.93± 22.54
1
25
2422.03±23.97
A2
25
2580.57±71.12
B1
25
2512.20± 80.83
B2
25
1797.99±10.90
C1
25
2442.94±13.65
C2
25
2569.83±52.80
Table 4. Partition coefficients of ketoprofen test results against a solvent of n-octanol and water
Samples
Partition coefficient
Ketoprofen
3.12
Blank
3.63
A1
3.59
A2
3.35
B1
3.28
B2
3.35
C1
3.46
C2
3.23
Days
Figure 4. Ketoprofen gel preparations permeation results
presence of an excipient which is alkaline in the
preparations. Based on the data obtained during
the storage preparations pH 58 days ranges from
6.40–6.77, and pH for topical preparations a pH
range between 5–8. Thus it can be concluded that the
preparations that have been made are quite safe to use.
Determination of coefficient of partition 1-
octanol/water, P o/w, is useful as relative
lipophilicity drug information. Although the 1-
octanol is not a biological molecule, the solvent is
better and more appropriate for drug partition
coefficient study between phospholipids and
water, P
membrane
, which can be calculated using the
membrane lipid bilayer. Optimum partition of the
drug on the lipid layer is one of the key
pharmaceuticals in product development [6].
Permeatio
n
R. C. Samosir et al / Indo J Pharm 1 (2019) 26-32
31
Table 5. Percent of dosage permeation for 6 hours
Time
(hours)
Permeation of ketoprofen (%)
Blank
A1
A2
B1
B2
C1
C2
Marketed product
0.25
0.164
2.329
0.657
3.135
2.535
2.383
0.156
0.108
0.5
0.303
2.656
0.771
3.347
2.790
2.520
0.249
0.532
0.75
0.339
2.945
0.943
3.517
2.877
2.667
0.250
0.739
1
0.354
3.106
1.085
3.716
3.134
2.849
0.257
1.163
2
0.404
3.346
1.365
3.935
3.389
3.098
0.330
1.345
3
0.379
3.930
1.456
4.413
3.668
3.265
0.451
1.451
4
0.513
4.744
1.707
5.058
4.180
3.669
0.459
1.910
5
0.580
5.246
1.957
5.614
4.690
3.902
0.672
2.219
6
0.623
6.358
2.182
5.913
4.985
4.418
0.844
2.824
Blank: gel with sesame oil without enhancers, soybean oil, and oleic acid
A1: ketoprofen gel with soybean oil 5% as an enhancer
A2: ketoprofen gel with 10% soybean oil as an enhancer
B1: ketoprofen gel with sesame oil 5% as enhancer
B2: ketoprofen gel with sesame oil 10% as enhancers
C1: ketoprofen gel with oleic acid 5% as an enhancer
C2: ketoprofen gel with oleic acid 10% as an enhancer
Active substances from stocks to rise compared
to the partition coefficient of active substances
without preparations. It is influenced by the effect
given by an excipient which is in preparation.
Partition coefficients of ketoprofen preparations
obtained are at 3.28 ranges up to 3.63. Based on
these data it can be concluded that such material is
eligible in ketoprofen for preparations
transdermal. The price of the partition coefficient
of the substance to be used as the material of
transdermal is the range between 2.5-4.
According to the analysis of the data are statistically
random complete block design using the (α= 0.05,
DBLA), with a confidence level of 95% oil addition
sesami oil, soybean oil, and oleic acid in ketoprofen gel
preparations will affect the increase in concentration of
ketoprofen the permeated of preparations (H
0
is
rejected). Therefore, a further test carried out using the
method of Duncan. Based on the results of further trials
Duncan retrieved that formula A1, A2, B1, B2, and C1
differs markedly with a blank. This shows that an
increase in ketoprofen permeation with the addition of
soybean oil, soybean oil, and oleic acid. Meanwhile, the
formula C2 revealed no different with a blank. This
shows that in the formula C2 with oleic acid 10% did
not provide a significant permeation enhancement
compared blank.
5.
Conclusion
It could be concluded that sesame oil, soybean
oil, and oleic acid can improve the profile of
ketoprofen gel permeation. The formula
containing 5% sesame oil gave a most excellent
permeation profile i.e. 5.913% during 6 hours
permeation.
Acknowledgements
We acknowledge to the director general of
Higher Education for providing all the materials
and funding in this study.
References
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http://www.ncbi.nlm.nih.gov/pubmed/1501974
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[3]
OECD, 1981, Test Guideline 107. Paris.
Decision of the Council C(81) 30 final.
[4]
Dinda, S.C., Vijay Ratna. 2006. Enhancement
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