Anti-inflammatory and analgesic gel composition

An anti-inflammatory analgesic gel composition comprising (1) ketoprofen and/or flurbiprofen as the effective ingredient, as well as (2) a glycol, lower alcohol, water and/or a mixture of a lower alcohol with water, (3) a gel-forming agent and, if desired, (4) a solubilizing agent and/or non-ionic surface-active agent as the ingredients of a gel base for the gel composition.

This invention relates to an anti-inflammatory and analgesic gel 
composition comprising ketoprofen and/or flurbiprofen as the effective 
ingredient. 
Ketoprofen and flurbiprofen are phenylpropionic acid derivatives 
represented respectively by the formulae (I) and (II) 
##STR1## 
These compounds of the formulae (I) and (II) are a non-steroid type 
medicine having anti-inflammatory and analgesic activities and are 
generally used particularly for the remedy of chronic rheumatoid arthritis 
deformable arthritis and trauma, for relieving the pain and inflammation 
caused after having undergone an operation and for the cure of 
inflammatory diseases in various departments. 
Conventional non-steroid type anti-inflammatory, analgesic medicines have 
been usually used in the form of capsules and tablets by oral 
administration and have clinically exhibited excellent results, while 
repeated oral administration of said medicines has raised problems as to 
the side reactions, such as gastrointestinal, hepatic and nephric 
troubles. Thus, in attempts to reduce such side reactions, suppositories 
and other preparations were tried to be produced with the result that 
satisfactory ones are not obtained yet. 
Particularly the conventional non-steroid type, anti-inflammatory and 
analgesic medicines have generally been known to be extremely inferior in 
percutaneous absorption. So, most of these medicines were externally used 
in some cases but they did not exhibit satisfactory percutaneous 
absorption in these cases. In addition, there are very few medicines for 
external application which are useful enough from the view-point of 
topical effectiveness and safety. 
In Japanese Laid-Open Patent application No. 53-81616 for example, there is 
disclosed an anti-inflammatory and analgesic ointment containing 
indomethacin, which ointment is the one developed as a medicine for the 
cure of inflammatory diseases in order to reduce the side reactions such 
as gastrointestinal troubles by the external and local use of the 
ointment. However, this ointment is also inferior in percutaneous 
absorption because of unsatisfactory discharge of the effective ingredient 
from the gel base of the ointment, has side effects such as cutaneous 
irritation, is not so developed as to cause no gastrointestinal troubles 
and, therefore, clinically raises many problems as to success of 
treatment; thus, the ointment is not such that has overcome the 
conventional drawbacks. 
For the reasons mentioned above, there are now sought the development of 
anti-inflammatory, analgesic medicines for external use which have 
excellent percutaneous absorbability, medicinal efficacy and higher 
safety. 
Indomethacin contained as the effective ingredient in the 
indomethacin-containing gel composition which has been compared with the 
gel composition of the present invention, and heretofore been widely used 
as an oral medicine and is equal or somewhat superior in anti-inflammatory 
analgesic action as an oral medicine to the effective ingredient of the 
composition of the present invention. 
As indicated in, for example, "Japanese Journal of Pharmacology, 70(4) 
543-569 (1974)", "Pharmacology and Remedy, 3(5) 828-835 (1975)", 
"Rheumatism 14(3) 279-286 (1974)" and "Diagnosis and New Medicines 17(3) 
531-541 (1980)", indomethacin and ketoprofen (which is one of the 
effective ingredients of the gel composition of the present invention) 
were respectively orally administered to make a comparative test for 
anti-inflammatory action, analgesic and antipyretic action, central 
action, medicinal efficacy for chronic articular rheumatism, results of 
clinical study of chronic lumbaginous disease, and the like. 
All these publications indicate that indomethacin is equal or slightly 
superior in medicinal efficacy to the effective ingredient of the 
composition of this invention when orally administered. 
The present inventors, on the other hand, found that indomethacin which 
exhibits a satisfactory medicinal efficacy when orally administered as 
mentioned above will surprisingly not exhibit a satisfactory medicinal 
efficacy as compared with the effective ingredient according to this 
invention when used as an indomethacin-containing gel composition for 
external application to integument. 
In contrast, the effective ingredient according to this invention which has 
been chosen by the present inventors after their intensive studies, will 
exhibit a marked medicinal efficacy and effect as compared with 
indomethacin when used as the effective ingredient-containing gel 
composition for external application to integument although said effective 
ingredient is equal or slightly inferior in efficacy to indomethacin when 
orally administered. It was found that particularly the effective 
ingredient according to this invention has excellent percutaneous 
absorbability, anti-inflammatory analgesic effect and higher safety. 
It is seen from the foregoing that, in general, medicinal ingredients which 
are effective when orally administered are not necessarily effective when 
used as a gel composition for external application to integument and, 
therefore, they must be intensively studied to find their uses, especially 
their best uses, and solve pharmaceutical problems. Further, indomethacin 
is pharmaceutically disadvantageous in that it is unstable to alkalies, 
inferior in solubility in the gel base and apt to crystallize out, while 
the present inventors found that ketoprofen and flurbiprofen are each 
excellent in stability to and solubility in the gel base according to this 
invention and also found that the gel composition of this invention is 
excellent in feeling when in use. Thus, the present invention are based on 
these findings. 
The gel compositions of this invention may be obtained by mixing together 
(1) ketoprofen and/or flurbiprofen, (2) a glycol, a lower alcohol, water 
or a lower alcohol-water mixture, (3) a gel-forming agent and, if desired, 
(4) a solubilizing agent and/or a non-ionic surface-active agent and then 
allowing the whole to gel. In addition, a neutralizing agent may be 
suitably incorporated depending on the kind of a gel-forming agent used. 
More particularly, preferable glycols used in this invention include 
propylene glycol, butylene glycol, polyethylene glycol, polypropylene 
glycol, polyethylene glycol dodecyl ether and glycerine; and preferable 
lower alcohols used herein include ethanol, denatured ethanol, propanol 
and isopropanol. The lower alcohols are usually used with water in 
admixture or they are not used at all in some cases where other certain 
ingredients are used although water is used alone in these cases. In this 
invention, the glycol, the lower alcohol and water may be used in amounts 
by weight of 20-40%, preferably 5-35%, 0-60%, preferably 20-45%; and 
20-55%, preferably 25-45%, respectively. 
The gel-forming agents used herein include carboxyvinyl polymers, 
hydroxyethylcellulose, methylcellulose, carboxymethylcellulose, 
hydroxypropylcellulose and alginic acid-propylene glycol ester. They may 
preferably be used in such an amount that their final concentration is in 
the range of 0.5-5%, preferably 1-3%, by weight. 
Further, organic amines usable for neutralizing the carboxyvinyl polymers 
preferably include triethanolamine, diethylamine, triethylamine, 
diisopropylamine and diisopropanolamine. These neutralizing agents may 
preferably be used in an amount by weight of 0.1-3%, preferably 0.4-2%. 
The amount thereof used may be controlled so that the gel composition of 
this invention is kept nearly neutral (preferably pH 4.5-7), more 
preferably at a pH of 5.0-6.5. 
The solubilizing agents may preferably include propylene carbonate, diethyl 
sebacate, benzyl alcohol and diisopropyl adipate. They are preferably be 
used in amounts by weight of 0-20%, preferably 0-10% to solubilize 
ketoprofen and/or flurbiprofen. 
The non-ionic surface-active agents used herein may preferably include 
sesquioleic acid sorbitan, trioleic acid sorbitan, monooleic acid 
sorbitan, monostearic acid sorbitan, monolauric acid sorbitan, monostearic 
acid polyethylene glycol, monooleic acid polyoxyethylenesorbitan, 
monolauric acid polyoxyethylenesorbitan, polyoxyethylenenonylphenyl ether, 
polyoxyethylenecetyl ether, polyoxyethylenelauryl ether and mixtures 
thereof. The surface-active agents may be used in amounts by weight of 
0-15%. 
Ketoprofen and flurbiprofen which is the effective ingredients of the gel 
composition of this invention may be used in an amount by weight of 
0.5-10%, preferably 1-7%. 
The ketoprofen- or flurbiprofen-containing gel compositions of this 
invention may be obtained, for example, by (A) swelling a gelling agent 
with water, (B) dissolving ketoprofen and/or flurbiprofen with a 
solubilizing agent, further dissolving the material (B) in a mixture of a 
glycol and a lower alcohol, adding the material (B) so further dissolved 
to the material (A) to form a mixture, incorporating the mixture with an 
amine and then allowing the whole to gel. In addition, the gel composition 
of this invention may also be obtained even in cases where the 
aforementioned procedure such as the order of incorporation of the 
ingredients, is somewhat changed. 
The gel compositions of this invention so obtained will be stable when 
stored for a long time and will exhibit excellent anti-inflammatory and 
analgesic effects with high safety when applied to skins as evidenced by 
the following experiments.

This invention will be better understood by the non-limitative examples 
wherein all parts are by weight unless otherwise specified. 
EXAMPLE 1 
One and a half (1.5) parts of carboxyvinyl polymer (Carbopol 940 produced 
by Goodrich Chemical Co.) were swollen in 20 parts of water. Separately, 
10 parts of propylene carbonate were mixed with 35 parts of propylene 
glycol to form a mixture in which 1 part of ketoprofen was dissolved. 
Then, 2 parts of hydroxypropylcellulose were dissolved in 20 parts of 
ethanol to form a solution which was added to the swollen carboxyvinyl 
polymer and agitated until the swollen polymer had been thoroughly 
hydrated. The polymer so hydrated was mixed with said solution of 
ketoprofen in the mixture of propylene carbonate and propylene glycol, 
incorporated with an aqueous solution of 0.2 parts of triethanolamine in 
10.3 parts of water and then thoroughly agitated until the whole was made 
homogeneous, thereby to obtain an anti-inflammatory and analgesic gel 
composition. 
EXAMPLE 2 
Two parts of carboxyvinyl polymer (Hiviswako 104 produced by Wako Junyaku 
Kogyo Co., Ltd.) were swollen in 20 parts of water. Separately, 15 parts 
of propylene carbonate were mixed with 20 parts of propylene glycol to 
form a mixture in which 3 parts of ketoprofen were dissolved. Then, 2 
parts of hydroxypropylcellulose were dissolved in 30 parts of ethanol and 
the resulting solution was added to said swollen carboxyvinyl polymer and 
agitated until the polymer had been entirely hydrated. The whole so 
agitated was incorporated with said solution of ketoprofen in the mixture 
of propylene carbonate and propylene glycol, further incorporated with a 
solution of 0.2 parts of triethanolamine in 7.8 parts of water and 
thoroughly agitated until the whole was made homogeneous thereby to obtain 
an anti-inflammatory and analgesic gel composition. 
EXAMPLE 3 
One and a half (1.5) parts of carboxyvinyl polymer (the same as that used 
in Example 1) were swollen in 20 parts of water. Separately, 10 parts of 
propylene carbonate and 35 parts of propylene glycol were mixed together 
to form a mixture in which 0.5 parts of ketoprofen were dissolved. Then, 
1.5 parts of hydroxypropylcellulose were dissolved in 25 parts of water, 
and the resulting solution was added to said swollen carboxyvinyl polymer 
and agitated until the polymer had been entirely hydrated. The whole so 
agitated was mixed with said solution of ketoprofen in the mixture of 
propylene carbonate and propylene glycol, incorporated with an aqueous 
solution of 0.5 parts of diisopropanolamine in 6.0 parts of water and then 
thoroughly agitated until the whole had been made homogeneous, thereby to 
obtain an anti-inflammatory and analgesic gel composition. 
EXAMPLE 4 
Two and a half (2.5) parts of carboxyvinyl polymer (the same as that used 
in Example 1) were swollen in 20 parts of water. Separately, 15 parts of 
propylene carbonate, 10 parts of propylene glycol and 20 parts of ethanol 
were mixed together to form a mixture in which 5 parts of ketoprofen were 
dissolved. Then, 2 parts of hydroxypropylcellulose were dissolved in 20 
parts of ethanol, and the resulting solution was added to said swollen 
carboxyvinyl polymer and then agitated until the polymer had been entirely 
hydrated. The whole so agitated was incorporated with said solution of 
ketoprofen in the mixture of propylene carbonate, propylene glycol and 
ethanol, further incorporated with an aqueous solution of 0.3 parts of 
triethanolamine in 5.2 parts of water and then agitated until the whole 
had been made homogeneous, thereby to obtain an anti-inflammatory and 
analgesic gel composition. 
EXAMPLE 5 
One and a half (1.5) parts of carboxyvinyl polymer (Carbopol 940 produced 
by Goodrich Chemical Co.) were swollen in 20 parts of water. Separately, 
10 parts of propylene carbonate and 35 parts of propylene glycol were 
mixed together to form a mixture in which 1 part of flurbiprofen was 
dissolved. Then, 2 parts of hydroxypropylcellulose were dissolved in 20 
parts of ethanol, and the resulting solution was added to said swollen 
carboxyvinyl polymer and then agitated until the polymer had been entirely 
hydrated. The whole so agitated was incorporated with said solution of 
flurbiprofen in the mixture of propylene carbonate and propylene glycol, 
further incorporated with an aqueous solution of 0.2 parts of 
triethaolamine in 10.3 parts of water and then thoroughly agitated until 
the whole had been made homogeneous, thereby obtaining an 
anti-inflammatory and analgesic gel composition. 
EXAMPLE 6 
Two parts of carboxyvinyl polymer (Hiviswako 104 produced by Wako Junyaku 
Kogyo Co., Ltd.) were swollen in 20 parts of water. Separately, 15 parts 
of propylene carbonate and 20 parts of propylene glycol were mixed 
together to form a mixture in which 3 parts of flurbiprofen were 
dissolved. Then, 2 parts of hydroxypropylcellulose were dissolved in 30 
parts of ethanol, and the resulting solution was added to said swollen 
carboxyvinyl polymer and agitated until the polymer had been entirely 
hydrated. The whole so agitated was incorporated with said solution of 
flurbiprofen in the mixture of propylene carbonate and propylene glycol, 
further incorporated with an aqueous solution of 0.2 parts of 
triethanolamine in 7.8 parts of water and then thoroughly agitated until 
the whole had been made homogeneous, thereby obtaining an 
anti-inflammatory and analgesic gel composition. 
EXAMPLE 7 
One and a half (1.5) parts of carboxyvinyl polymer (the same as that used 
in Example 1) were swollen in 20 parts of water. Separately, 10 parts of 
propylene carbonate and 35 parts of propylene glycol were mixed together 
to form a mixture in which 0.5 parts of flurbiprofen were dissolved. Then, 
1.5 parts of hydroxypropylcellulose were dissolved in 25 parts of water to 
form a solution which was added to said swollen carboxyvinyl polymer and 
agitated until the polymer had been entirely hydrated. The whole so 
agitated was incorporated with said solution of flurbiprofen in the 
mixture of propylene carbonate and propylene glycol, further incorporated 
with an aqueous solution of 0.5 parts of diisopropanolamine in 6.0 parts 
of water and then thoroughly agitated until the whole had been made 
homogeneous, thereby to obtain an anti-inflammatory and analgesic gel 
composition. 
EXAMPLE 8 
Two and a half (2.5 ) parts of carboxyvinyl polymer (the same as that used 
in Example 1) were swollen in 20 parts of water. Separately, 15 parts of 
propylene carbonate, 10 parts of propylene glycol and 20 parts of ethanol 
were mixed together to form a mixture wherein 5 parts of flurbiprofen were 
dissolved. Then, 2 parts of hydroxypropylcellulose were dissolved in 20 
parts of ethanol, and the resulting solution was added to said swollen 
carboxyvinyl polymer and agitated until the polymer had been entirely 
hydrated. The whole so agitated was incorporated with said solution of 
flurbiprofen in the mixture of propylene carbonate, propylene glycol and 
ethanol, further incorporated with an aqueous solution of 0.3 parts of 
triethanolamine in 5.2 parts of water and then thoroughly agitated until 
the whole had been made homogeneous, thereby obtaining an 
anti-inflammatory and analgesic gel composition. 
EXAMPLE 9 
One and a half (1.5) grams of a carboxyvinyl polymer (produced under the 
trademark of Carbopol 940 by Goodrich Chemical Corp.) were swollen in 300 
g of water. Separately, 10 g of propylene carbonate and 5 g of propylene 
glycol were mixed together to form a mixture in which 1 g of ketoprofen 
was dissolved. Then, 2 g of hydroxypropylcellulose were dissolved in 44 g 
of ethanol, added to said swollen carboxyvinyl polymer and agitated to an 
extent that the polymer had been entirely hydrated. The whole so agitated 
was mixed with said solution of ketoprofen in the mixture of the propylene 
carbonate and propylene glycol, incorporated with a solution of 0.2 g 
triethanolamine in 6.3 g water and thoroughly agitated until the resulting 
mixture had been made homogeneous, thereby to obtain an anti-inflammatory 
analgesic gel composition. 
EXAMPLE 10 
Two (2.0) grams of carboxyvinyl polymer (produced under the trademark of 
Hiviswako 104 by Wako Junyaku Kogyo Co., Ltd.) were swollen in 25 g of 
water. Separately, 10 g of propylene carbonate and 5 g of propylene glycol 
were mixed together to form a mixture in which 3 g of ketoprofen were 
dissolved. Then, a solution of 2 g hydroxypropylcellulose in 44 g ethanol 
was added to said carboxyvinyl polymer so swollen and agitated until the 
polymer had been entirely hydrated. The whole so agitated was mixed with 
said ketoprofen dissolved in the propylene carbonate-propylene glycol 
mixture, incorporated with a solution of 0.2 g ethanolamine in 8.8 g water 
and then thoroughly agitated until the resulting mixture had wholly been 
made homogeneous, thereby to obtain an anti-inflammatory analgesic gel 
composition. 
EXAMPLE 11 
Five (5) grams of ketoprofen were dissolved in a mixture of 44 g ethanol, 5 
g propylene glycol and 10 g propylene carbonate and then incorporated with 
2.3 g of hydroxypropylcellulose. The whole was incorporated with 2.2 g of 
a carboxyvinyl polymer (same as used in Example 10) swollen in 25 g of 
water and agitated until the polymer had been entirely hydrated. The whole 
so agitated was incorporated with a solution of 0.3 g triethanolamine in 
6.2 g water and then thoroughly agitated until the resulting mixture had 
wholly been made homogeneous, thereby to obtain an anti-inflammatory 
analgesic gel composition. 
EXAMPLE 12 
Three (3) grams of ketoprofen were dissolved in a mixture of 40 g ethanol 
and 20 g propylene glycol to form a ketoprofen solution which was 
incorporated with 2.0 g of a carboxyvinyl polymer (same as used in Example 
10) swollen in 23.9 g of water and agitated until the polymer had wholly 
been made homogeneous. The ketoprofen solution so incorporated and 
agitated was incorporated with a solution of 1.1 g diisopropanolamine in 
10 g water and then thoroughly agitated until the whole had wholly been 
made homogeneous, thereby to obtain an anti-inflammatory analgesic gel 
composition. 
EXAMPLE 13 
Three (3) grams of ketoprofen were dissolved in a mixture of 40 g ethanol, 
15 g propylene glycol and 10 g propylene carbonate to form a ketoprofen 
solution which was incorporated under agitation with 1.0 g of 
hydroxypropylcellulose. The whole was incorporated with 2 g of a 
carboxyvinyl polymer (same as used in Example 10) swollen in 18 g of water 
and agitated until the polymer had been entirely hydrated. The whole so 
incorporated and agitated was thoroughly agitated until the whole had been 
made homogeneous, thereby to obtain an anti-inflammatory analgesic gel 
composition. 
EXAMPLE 14 
Three (3) grams of ketoprofen were dissolved in a mixture of 40 g ethanol, 
5 g polyoxyethylene (10) monolaurate, 10 g propylene glycol and 10 g 
propylene carbonate, incorporated with 2.2 g of a carboxyvinyl polymer 
(same as used in Example 10) swollen in 18.6 g of water and agitated until 
the polymer had been entirely hydrated. The whole was added to a solution 
of 1.2 g diisopropanolamine in 10 g of water and then thoroughly agitated 
until the resulting whole mass had been made homogeneous, thereby to 
obtain an anti-inflammatory analgesic gel composition. 
EXAMPLE 15 
Three (3) grams of ketoprofen were dissolved in a mixture of 20 g ethanol, 
35 g propylene glycol and 10 g propylene carbonate and incorporated under 
agitation with 1.5 g of hydroxypropylcellulose. The whole was incorporated 
with 2.0 g of a carboxyvinyl polymer (same as used in Example 10) swollen 
in 18.1 g of water, agitated until the polymer had been entirely hydrated, 
incorporated with a solution of 0.4 g diisopropanolamine in 100 g of water 
and then thoroughly agitated until a homogeneous mass had been formed, 
thereby to obtain an anti-inflammatory analgesic composition. 
EXAMPLE 16 
Three (3) grams of ketoprofen were dissolved in a mixture of 40 g ethanol, 
10 g polyoxyethylene (10) monolaurate, 6 g propylene glycol and 2 g 
diisopropyl adipate to form a ketoprofen solution which was incorporated 
with 2.3 g of a carboxyvinyl polymer (same as used in Example 10) swollen 
in 25.7 g of water and agitated until the polymer had been entirely 
hydrated. The whole was incorporated with 1.0 g of diisopropanolamine 
dissolved in 10 g of water and then thoroughly agitated until the 
resulting mixture had wholly been made homogeneous, thereby to obtain an 
anti-inflammatory analgesic gel composition. 
EXAMPLE 17 
Seven (7) grams of ketoprofen were dissolved in a mixture of 44 g ethanol, 
10 g propylene glycol and 10 g propylene carbonate, incorporated under 
agitation with 2.4 g of hydroxypropylcellulose, further incorporated with 
2.5 g of a carboxyvinyl polymer (same as used in Example 10) swollen in 
18 g of water and agitated until the polymer had been entirely hydrated. 
The whole was incorporated with 0.4 g of triethanolamine dissolved in 5.7 
g of water and then thoroughly agitated until the resulting mixture had 
wholly been mad homogeneous, thereby to obtain an anti-inflammatory 
analgesic gel composition. 
Furthermore, the following reference example indicates a conventional gel 
composition for comparison with the gel composition of this invention in 
the following percutaneous absorption and pharmacological experiments. 
REFERENCE EXAMPLE 
One and a half (1.5) parts of carboxyvinyl polymer (the same as that used 
in Example 1) were swollen in 20 parts of water. Separately, 10 parts of 
propylene carbonate and 35 parts of propylene glycol were mixed together 
to form a mixture in which 1 part of indomethacin was dissolved. After 
this, the same procedure as in Example 1 was followed thereby to obtain an 
anti-inflammatory and analgesic gel composition. 
The percutaneous absorption effects, anti-inflammatory effects and safety 
of the gel compositions of this invention will be substantiated by the 
following pharmacological experiments. 
EXPERIMENT 1 
Percutaneous absorption test 
Five healthy male adults were used as subjects. In each adult, the skin of 
inner side of his forearm was defined by applying an adhesive tape on the 
skin to obtain 8 skin portions, each 1.4 cm.times.1.4 cm in area, 
respectively defined by the adhesive tape. Then, microsyringes were filled 
with gels compositions containing 1% of ketoprofen, flurbiprofen and 
indomethacin in the same gel base, respectively, in accordance with the 
method of Lindsay C. et al. Twenty .mu.l (190 .mu.g as the medicine or 
effective ingredient) of each of the gel compositions were applied 
externally to said skin portion and then fixed directly by an adhesive 
tape. The adhesive tapes were peeled zero and 4 hours after the 
application and then inserted into 25-ml measuring flasks, respectively, 
while the gel compositions remaining on the skin portions were recovered, 
respectively, by pressing a funnel against the skin portions, pouring a 
small amount of methanol from the foot of the funnel to the skin portions 
to wash the remaining gel composition and repeating this washing procedure 
several times to recover the whole of the remaining composition in 
solution in methanol. In this case, methanol was used in such an amount 
that the methanol solution so recovered amounted to 25 ml. For the 
ketoprofen and flurbiprofen, 2 ml of their respective methanol solutions 
were diluted with 2 ml of methanol and then measured for absorbancy at a 
wavelength of 225 nm and 246 nm by the use of a double beam 
spectrophotometer produced by Shimadzu Seisakusho Co., Ltd. On the other 
hand, for the indomethacin, 25 ml of its methanol solution recovered were 
measured, without dilution, for absorbancy at a wavelength of 320 nm. 
Quantitative determination was made from a quantity inspection curve 
prepared from absorbancies for solution of the medicines having various 
known concentrations. 
The percutaneous absorption ratio was calculated from the following 
formula: 
##EQU1## 
The test results are as shown in the following Table 1. 
TABLE 1 
______________________________________ 
Amount of medicine 
absorbed 4 hours after 
Gel composition tested 
administration 
______________________________________ 
Gel composition of Example 1 
(containing 1% of ketoprofen) 
48.3 .+-. 3.4 
Gel composition of Example 5 
(containing 1% of flurbiprofen) 
49.2 .+-. 5.5 
Gel composition of Reference 
Example 
(containing 1% of indomethacin) 
11.5 .+-. 3.6 
______________________________________ 
The above values are the mean values and standard errors for the five 
subjects. 
EXPERIMENT 2 
Topical anti-inflammatory activity on carrageenin-induced dorsal cutaneous 
edema in rats 
Male rats of Wister strain, weighing 90-110 g (four weeks old), were 
depilated with Eba Cream (tradename, a depilatory produced by Tokyo Tanabe 
Pharmaceutical Co., Ltd.) and allowed to stand overnight for use in the 
experiment. Then, 0.1 ml/site of a physiological salt solution containing 
1% of carrageenin (Picnin A produced by Pasco International Co.) was 
hypodermally injected into one side of the dorsal skin of the rats, while 
0.1 ml/site of a physiological salt solution (containing no carrageenin) 
was intradermally injected into the other dorsal side thereof, these sides 
being positioned symmetrically to each other with respect to the backbone 
of the rats. Soon after the injection of the carrageenin-containing 
solution, an adhesive plaster (for patch tests) containing 100 mg of the 
medicine to be tested was applied to each of the sites at which the 
carrageenin-containing solution was injected. The adhesive plaster used 
was the "Small size" one produced by Torii Pharmaceutical Co., Ltd. Two 
and a half (2.5) hours later, 0.5 ml/100 g (body weight) of a 
physiological salt solution containing 1% of pontamine sky blue (PSB) was 
intravenously injected to the tail of the rats, 30 minutes after which the 
rats so injected were allowed to die by bloodletting. The skin of the dead 
rats was peeled therefrom and immediately measured for thickness at the 
carrageenin injected site with a dial thickness gauge (pressure 40 g, 
manufactured by Ozaki Seisakusho Co., Ltd.). The swelling ratios (%) at 
the edema portion of the skin were calculated as follows: 
##EQU2## 
Further, the dye extravasating area was calculated by multiplying the 
longer diameter by the shorter diameter in the dye extravasating portion 
of the skin. Still further, the pontamine sky blue was extracted by the 
use of the Harada et al.'s method (Harada, M., Takeuchi, M., Fukao, T. and 
Katagiri, K.; J. Pharm. Pharmacol. 23, 218, 1971) and then measured for 
the amount of the extravasating dye by the use of a spectrophotometer. 
The test results are as indicated in Table 2. 
TABLE 2 
__________________________________________________________________________ 
No. of Amount of dye 
animals 
Swelling 
Dye extravasating 
extravasated 
Gel composition tested 
tested 
(%) area (cm.sup.2) 
(.mu.g) 
__________________________________________________________________________ 
Control group 7 73.9 .+-. 4.4 
0.60 .+-. 0.06 
10.5 .+-. 1.9 
(Gel base) 
Gel composition of Ex. 1 
8 51.8 .+-. 2.6** 
0.16 .+-. 0.04** 
5.1 .+-. 0.8* 
(containing 1% of Ketoprofen) 
[30.0] [73.3] [51.9] 
Gel composition of Ex. 2 
7 42.5 .+-. 2.4** 
0.14 .+-. 0.03** 
5.2 .+-. 0.7* 
(containing 3% of Ketoprofen) 
[42.6] [76.7] [50.5] 
Gel composition of Ex. 5 
7 52.9 .+-. 4.0** 
0.20 .+-. 0.05** 
5.3 .+-. 1.2* 
(containing 1% of flurbiprofen) 
[28.4] [66.7] [49.5] 
Gel composition of Ex. 6 
7 49.5 .+-. 2.9** 
0.15 .+-. 0.05** 
5.3 .+-. 0.7* 
(containing 3% of flurbiprofen) 
[33.0] [75.0] [49.5] 
Gel composition of Ref. Ex. 
8 57.1 .+-. 3.2** 
0.26 .+-. 0.04** 
5.5 .+-. 0.6* 
(containing 1% of indomethacin) 
[22.8] [56.7] [47.2] 
__________________________________________________________________________ 
Notes: 
(1) Each of the gel compositions to be tested was applied in an amount of 
100 mg for 3 hours immediately after the intradermal injection of the 
solution containing 1% of carrageenin. 
(2) Asterisks * and ** indicate P &lt; 0.05 and P &lt; 0.01 respectively, 
thereby to mean that there is a significant difference. 
(3) Ex. = Example, Ref. Ex. = Reference Example 
(4) The values in the parentheses indicate inhibition ratios with respect 
to the Control group (gel base). 
TABLE 3 
______________________________________ 
Inhibi- 
No. of tion 
animals Swelling ratio 
Gel composition tested 
used ratio (%) (%) 
______________________________________ 
Control group 8 60.4 .+-. 2.1 
-- 
(Gel base) 
Gel composition of Ex. 1 
8 45.3 .+-. 2.8** 
25.0 
(containing 1% of Ketoprofen) 
Gel composition of Ex. 2 
8 39.8 .+-. 2.8** 
34.1 
(containing 3% Ketoprofen) 
Gel composition of Ex. 5 
8 47.9 .+-. 3.3** 
20.7 
(containing 1% of flurbiprofen) 
Gel composition of Ex. 6 
8 46.4 .+-. 3.0** 
23.2 
(containing 3% of flurbiprofen) 
Gel composition of Ref. Ex. 
8 51.0 .+-. 2.3** 
15.6 
(containing 1% of indomethacin) 
______________________________________ 
Notes: 
(1) One hundred (100) mg of each of the gel compositions to be tested wer 
applied one time for 3 hours just before the fracture and another one tim 
for 3 hours just after the fracture. 
(2) Asterisks ** indicate P &lt; 0.01 thereby to mean that there is a 
significant difference. 
(3) Ex. = Example, Ref. Ex. = Reference Example 
(4) Inhibition ratio was expressed with respect to control group (gel 
base). 
EXPERIMENT 3 
Topical anti-inflammatory activity on fracture edema at the hind leg 
portions of rats 
Male rats of Wister strain, weighing about 130 g (five weeks old), were 
used as the test animals. 
One hundred (100) mg of the gel compositions shown in Table 3 were 
thoroughly rubbed into the left legs of the rats, and the leg skin 
portions to which the composition was applied were wrapped with a Saran 
wrap (Polyvinylidene type synthetic resin film produced by Asahi Dow 
Chemical Co.) to prevent the rats from licking the gel composition so 
applied. In addition, a disposable beaker was put on the head of the rats 
and fixed with a rubber tape to enclose the head in the beaker, for 
prevention from licking the applied medicine. Three hours later, the rats 
were anesthetized lightly with ether and then the test medicine-applied 
leg portions were held between Kocher forceps and subjected to cross 
linear fracture at the metatarsal bone, soon after which 100 mg of the gel 
composition were again applied to said leg portions and then treated in 
the same manner as above. Three hours after the fracture, the measurements 
were made as follows. 
The volumes of the leg portions before the fracture and 3 hours thereafter 
were measured by the Fujihira's method (Fujihira, E: Applied Pharmacol. 5, 
119, 1971), and the swelling ratios (%) were calculated as follows. 
##EQU3## 
The test results are as shown in Table 3. 
EXPERIMENT 4 
Anti-inflammatory activity on gastric mucous membrane troubles in rats 
Male rats of Wister strain, each weighing about 200 g, were fasted except 
for unlimited feeding of water for a time period of 24 hours, after which 
each of the test compounds shown in Table 4 was administered to the rats 
so fasted. The test compound in the form of a gel composition was 
administered by applying a plaster for patch test (the plaster being 
coated with 0.1 ml of said gel composition) to the rat's back the hair of 
which had been shaved with an electric razor. The ketoprofen and 
indomethacin each in the powder form were suspended in an 0.5% tragacanth 
rubber-containing physiological saline solution and then orally 
administered to the test animals, respectively. Six hours after said 
administration, the test animals were slaughtered to remove their stomachs 
which were incised along the greater curvature thereof to visually observe 
whether or not an ulcer was formed at the gastric mucous membrane of their 
stomachs. The ulceration ratio (%) was calculated from the following 
equation: 
##EQU4## 
The test results are as shown in Table 4. 
TABLE 4 
______________________________________ 
No. of 
Method of animals Ulceration 
Test compound administration 
tested ratio (%) 
______________________________________ 
Control -- 6 0 
Gel composition of 
Percutaneous 
6 0 
Example 2 
(ketoprofen content: 3%) 
Indomethacin ointment 
Percutaneous 
6 33.3 
(indomethacin content: 1%) 
Ketoprofen powder 
Oral 6 100.0 
(5 mg/Kg) 
Indomethacin powder 
Oral 6 100.0 
(1 mg/Kg) 
______________________________________ 
It is seen from the above test results that the ulceration ratios for the 
ketoprofen and indomethacin powders orally administered were 100% 
respectively and that the ulceration ratio for the indomethacin ointment 
percutaneously administered was 33.3%. 
On the other hand, Table 4 indicates that the ulceration ratio for the 
ketoprofen gel composition of the present invention was zero, that is, the 
formation of ulcers was not appreciated at all. This is an unexpected fact 
which will be helpful in eliminating side effects (gastrointestinal 
troubles) caused by non-steroid preparations, the side effects being now 
taken up very often as a problem to be solved. In addition, this fact also 
proved the safety and usefulness of the ketoprofen gel composition as well 
as high superiority thereof to the indomethacin ointment. 
EXPERIMENT 5 
Test for toxicity 
A group of 10 mice consisting of male and female ones of ddy strain, each 
weighing 19-26 g, and a group of 10 rats consisting of male and female 
ones of Wister strain, each weighing 102-130 g, were used as the test 
animals. Test compounds (in the forms of gel compositions containing 3% 
ketoprofen and 3% flurbiprofen, respectively) shown in Table 5 were coated 
on the test animals' backs the hair of which had been shaved with an 
electric razor, in amounts of 15,000 mg/Kg which was the maximum coatable 
amount for the test compounds in the forms of gel compositions, 
respectively, to find how many of the test animals died during 14 days 
after the coating of the test compounds. The results are as shown in Table 
5. 
TABLE 5 
______________________________________ 
No. of 
dead 
animals/ 
No. of 
Test animals 
Percutaneous 
Test compound 
animal Sex tested LD.sub.50 (mg/Kg) 
______________________________________ 
Ketoprofen Mice .male. 0/10 &gt;15000 
(in the form of a gel 
.female. 
0/10 &gt;15000 
composition containing 
Rats .male. 0/10 &gt;15000 
3% ketoprofen) .female. 
0/10 &gt;15000 
Flurbiprofen Mice .male. 0/10 &gt;15000 
(in the form of a gel 
.female. 
0/10 &gt;15000 
composition containing 
Rats .male. 0/10 &gt;15000 
3% flurbiprofen) .female. 
0/10 &gt;15000 
______________________________________ 
It is seen from Table 5 that none of the test animals died during the test 
even in cases where they were coated on the hair-shaved back with the test 
compound in an amount of 15,000 mg/Kg which was the maximum coatable 
amount. This proves that ketoprofen and flurbioprofen in the gel 
composition form are harmless and safe to animals when externally applied. 
EXPERIMENT 6 
Patch test on healthy human beings 
Twenty-five (25) male people were subjected to patch test in accordance 
with the test method proposed by Kawamura et al. [Taro Kawamura et al.: 
Nippi Kaishi (Journal of Japanese Dermatology), 80, 301, 1969]. More 
particularly, plasters for the patch test which were coated with 0.1 ml of 
the test compounds respectively as shown in Table 7, were applied to the 
male subjects in the inner side of their upper arm and maintained there 
for 24 hours respectively. The plasters so applied were peeled to visually 
observe the conditions of the upper arm portion (from which the patch had 
been peeled) 30 minutes and 24 hours after the peeling in accordance with 
the criteria as shown in Table 6. The results are as shown in Table 7. 
TABLE 6 
______________________________________ 
Score 
______________________________________ 
- No extraordinary reaction 
.+-. Slight erythema 
+ Erythema or Papule 
++ Erythema and Swelling; or Erythema and Papule 
+++ Erythema, Swelling and small vesicle; 
or Erythema, Swelling and Papule 
++++ Vesicle and Erosion 
______________________________________ 
TABLE 7 
______________________________________ 
Observations 
Positivity (%), determined on 
the basis of the score .+-. 
or higher being assumed 
positive. 
Test compound 30 minutes later 
24 hours later 
______________________________________ 
Gel composition of Example 2 
4.5 (1/22) 4.5 (1/22) 
(ketoprofen content: 3%) 
Gel composition of Example 6 
4.0 (1/25) 4.0 (1/25) 
(flurbiprofen content: 3%) 
Indomethacin ointment 
56.0** (14/25) 
44.0** (11/25) 
(indomethacin content: 1%) 
______________________________________ 
The double asterisk ** indicates that a significant difference exists at 
&lt; 0.01 between the two. 
As is seen from the results in Table 7, the indomethacin ointment caused a 
considerable amount of erythema, papule, swelling, etc., while the 
ketoprofen or flurbiprofen gel composition caused a very small amount of 
slight erythema and erythema only. This proves that the ketoprofen and 
flurbiprofen gel compositions are excellently safe to human bodies. 
It has been found from the aforementioned pharmacological experiments that 
the gel compositions of this invention are very excellent in percutaneous 
absorption and medicinal efficacy as well as in safety.