An antiinflammatory analgesic ointment comprising: (a) an antiinflammatory amount of indomethacin; (b) a medium consisting of a hydroxy compound in the range of from 15 to 85% by weight, water in the range of 30 to 55% by weight and a gelating agent being present in an amount sufficient to effect gelation of said ointment and selected from the group consisting of a cellulose compound and a carboxyvinyl polymer which has been neutralized with aqueous ammonia or an amine; (c) an adjuvant being present in the range of from 0.5 to 5% by weight and selected from the group consisting of a C.sub.1 -C.sub.5 alcohol ester of a C.sub.4 -C.sub.14 monocarboxylic acid and a C.sub.1 -C.sub.3 alcohol diester of a C.sub.4 -C.sub.10 dicarboxylic acid; and (d) water in an amount sufficient to make up the balance of the ointment, said ointment being adjusted in its pH from an acidic to slightly basic level sufficient to solubilize said indomethacin in the composition but not too basic a pH level to cause decomposition of said indomethacin.

BACKGROUND OF THE INVENTION 
1. Field of the Invention 
This invention relates to an antiinflammatory analgesic ointment containing 
indomethacin as an active component. 
2. Description of the Prior Art 
Indomethacin is represented by the formula, 
##STR1## 
and is a known non-steroidal compound which possesses excellent 
antiinflammatory activity. 
Indomethacin was marketed in Japan in 1966 and has been widely used in 
capsule form for the treatment of chronic articular rheumatism, arthritis 
deformans, inflammatory diseases and inflammations which occur after 
operations. Indomethacin is a very effective antiinflammatory drug, and in 
fact, its effects are deemed to be the greatest among currently used 
nonsteroidal antiinflammatory agents. 
However, the administration of indomethacin induces adverse effects within 
the human body such as gastroenteric disorders resulting from the oral use 
of the drug. 
In order to overcome the difficulties of the oral administration, 
suppositories have been developed and employed in plastic surgery and 
other fields for the alleviation of inflammation, pain and fever in a 
patient to be treated. The adverse reactions such as gastroenteric 
disorders from the oral use of indomethacin are somewhat decreased by the 
administration of the drug in suppository form. It is impossible however 
to administer indomethacin even in suppository form to any patient 
suffering from peptic ulcer since the administration of indomethacin in 
suppository form would result in decreased appetite, nausea, vomiting, 
stomach ache, diarrhea and loose passage. There is therefore a continuing 
need for the development of an improved mode of administration of 
indomethacin. 
The present inventors have found upon extensive study that indomethacin, 
when administered topically, exhibits antiinflammatory analgesic activity 
to the same extent as attained by its internal use and that the adverse 
reactions attributable to the administration of indomethacin are 
completely eliminated. 
However, indomethacin ointments cannot be produced by conventional methods 
of preparing ointments because indomethacin is only slightly soluble in 
water and common media. For topical use, indomethacin suspended in 
conventional ointment bases is observed to remain unabsorbed by the skin 
of human beings and does not exhibit any therapeutic effect. 
In order to produce an ointment in which indomethacin is dissolved and 
which can be easily absorbed into the skin of human beings, the present 
inventors have conducted continuous research, and as a result, have 
discovered that indomethacin which is dissolvable in a medium consisting 
of glycol, an alcohol and water and which is gellable with a gelling agent 
can be administered topically without accompanying adverse side-effects 
which are experienced with the conventional forms of administration and 
that the absorption of indomethacin by the skin is substantially increased 
by combination with an adjuvant. 
SUMMARY OF THE INVENTION 
Accordingly, it is an object of the present invention to provide an 
antiinflammatory analgesic ointment which is devoid of the difficulties of 
the existing forms of administration of indomethacin and which is very 
stable and effectively useful for topical administration. 
Briefly, this object and other objects of the present invention as 
hereinafter will become more readily apparent can be attained in an 
antiinflammatory analgesic ointment, comprising: (a) an antiinflammatory 
amount of indomethacin; (b) a medium consisting of a hydroxy compound in 
the range of from 15 to 85% by weight, water in the range of 30 to 55% by 
weight and a gelating agent being present in an amount sufficient to 
effect gelation of said ointment and selected from the group consisting of 
a cellulose compound and a carboxyvinyl polymer which has been neutralized 
with aqueous ammonia or an amine; (c) an adjuvant being present in the 
range of from 0.5 to 5% by weight and selected from the group consisting 
of a C.sub.1 -C.sub.5 alcohol ester of a C.sub.4 -C.sub.14 monocarboxylic 
acid and a C.sub.1 -C.sub.3 alcohol diester of a C.sub.4 -C.sub.10 
dicarboxylic acid; and (d) water in an amount sufficient to make up the 
balance of the ointment, said ointment being adjusted in its pH from an 
acidic to slightly basic level sufficient to solublize said indomethacin 
in the composition but not too basic a pH level to cause decomposition of 
said indomethacin. 
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS 
Suitable hydroxy compounds useful in the invention include glycols such as 
propylene glycol, butylene glycol, polyethylene glycol and the like, and 
alcohols such as ethanol, isopropanol and the like. The hydroxy component 
of the present composition may be any hydroxy compound used alone or in 
combination with another hydroxy compound. When a combination is used, a 
preferred combination is glycol in an amount of 5 to 35% with any selected 
alcohol in the range of 10 to 50%. Particularly preferred is the 
combination range of 15 to 85% of hydroxy compound and 30 to 55% of water. 
(All percentages used herein are on a weight basis unless otherwise 
specifically indicated.) 
Suitable gelating agents useful in the invention include a carboxyvinyl 
polymer, a cellulose compound and the like. Suitable cellulose compounds 
include hydroxyethyl cellulose, methyl cellulose, carboxymethyl cellulose, 
hydroxypropyl cellulose, hydroxypropylmethyl cellulose and the like. 
The carboxyvinyl polymer previously neutralized with aqueous ammonia or an 
organic amine such as diisopropanol amine or triethanolamine is used as a 
gelating agent. This gelating agent is preferably present such that the 
concentration is 0.5 to 5%. 
Suitable adjuvants useful in the invention include a C.sub.1 -C.sub.5 
alcohol ester of C.sub.4 -C.sub.14 monocarboxylic acid and a C.sub.1 
-C.sub.3 alcohol diester of C.sub.4 -C.sub.10 dicarboxylic acid such as 
diisopropyl adipate, diethyl sebacate, ethyl caproate, ethyl laurate and 
the like. Any one selected adjuvant is preferably added in a concentration 
of 0.5 to 5%. Indomethacin is expected to exhibit a substantial 
therapeutic effect when utilized in an amount over the range of 0.5 to 
1.5%. 
The final pH of the ointment according to the invention should be adjusted 
from 4.8 to 7.5, preferably from 6.2 to 7.2. A pH level below 4.8 would 
induce crystallization of indomethacin during the ointment preparation. A 
pH level above 7.5 would result in decomposed indomethacin and hence in 
unstability and would adversely affect the human body. 
The ointment of the invention can be produced by (1) swelling a gelating 
agent in water, (2) dissolving indomethacin and an adjuvant in a mixture 
of a glycol and an alcohol and (3) adding (2) to (1), and further adding 
an amine to the resulting mixture to form a desired gel ointment. 
The ointment thus prepared can be stored in a stable state for a long 
period of time and hence exerts therapeutically excellent, 
antiinflammatory analgesic effects when applied to the human body by 
coating, as will be herinafter described.

The above disclosure generally describes the present invention. A more 
complete understanding will be obtained by the following specific examples 
which are presented for purposes of illustration only and are not 
construed as limiting to the invention. 
EXAMPLE 1 
______________________________________ 
1 Carboxyvinyl polymer 
1.0 g 
2 Indomethacin 1.0 g 
3 Propylene glycol 
10.0 g 
4 Ethanol 40.0 g 
5 Diisopropanolamine 
1.1 g 
6 Purified water An amount sufficient 
to bring the final 
weight to 100 g 
______________________________________ 
(A) Swell (1) in 20 g of (6). 
(B) Dissolve (2) in a mixture of (3) and (4). 
(C) Add (B) and (A) and mix until the mixture is completely hydrated. 
(D) Dissolve (5) in 10 g of (6). Add the mixture to (C) with mixing. Bring 
the resultant mixture to the final weight with the remainder of (6) and 
stir the composition until it becomes homogeneous. 
EXAMPLE 2 
______________________________________ 
1 Carboxyvinyl polymer 
1.0 g 
2 Indomethacin 1.0 g 
3 Propylene glycol 
20.0 g 
4 Ethanol 30.0 g 
5 Diisopropanolamine 
1.0 g 
6 Purified water An amount sufficient 
to bring the final 
weight to 100 g 
______________________________________ 
(A) Swell (1) in 20 g of (6). 
(B) Dissolve (2) in a mixture of (3) and (4). 
(C) Add (B) to (A) and mix until the mixture is completely hydrated. 
(D) Dissolve (5) in 10 g of (6). Add the mixture to (C) with mixing. Bring 
the resultant mixture to the final weight with the remainder of (6) and 
stir the composition until it becomes homogeneous. 
EXAMPLE 3 
______________________________________ 
1 Carboxyvinyl polymer 
1.0 g 
2 Indomethacin 1.0 g 
3 Propylene glycol 
12.0 g 
4 Ethanol 30.0 g 
5 Diisopropyl adipate 
2.0 g 
6 Diisopropanolamine 
1.1 g 
7 Purified water An amount sufficient 
to bring the final 
weight to 100 g 
______________________________________ 
(A) Swell (1) in 20 g of (7). 
(B) Dissolve (2) in a mixture of (3), (4) and (5). 
(C) Add (B) to (A) and mix until the mixture is completely hydrated. 
(D) Dissolve (6) in 10 g of (7). Add the mixture to (C) with mixing. Bring 
the resultant mixture to the final weight with the remainder of (7) and 
stir the composition until it becomes homogeneous. 
EXAMPLE 4 
______________________________________ 
1 Carboxyvinyl polymer 
1.0 g 
2 Hydroxyethyl cellulose 
1.0 g 
3 Indomethacin 1.0 g 
4 Polyethylene glycol 300 
10.0 g 
5 Ethanol 30.0 g 
6 Diisopropyl adipate 
2.0 g 
7 Diisopropanolamine 
0.9 g 
8 Purified water An amount sufficient 
to bring the final 
weight to 100 g 
______________________________________ 
(A) Swell (1) and (2) in 20 g of (8). 
(B) Dissolve (3) in a mixture of (4), (5) and (6). 
(C) Add (B) to (A) and mix until the mixture is completely hydrated. 
(D) Dissolve (7) in 10 g of (8). Add the mixture to (C) with mixing. Bring 
the resultant mixture to the final weight with the remainder of (8) and 
stir the composition until it becomes homogeneous. 
EXAMPLE 5 
______________________________________ 
1 Hydroxypropyl cellulose 
5.0 g 
2 Indomethacin 0.5 g 
3 Propylene glycol 20.0 g 
4 Triethanol amine 0.35 g 
5 Ethanol 30.0 g 
6 Purified water An amount sufficient 
to bring the final 
weight to 100 g 
______________________________________ 
(A) Swell (1) in 20 g of (6). 
(B) Dissolve (2) in a mixture of (3) and (5). 
(C) Dissolve (4) in the remainder of (6). 
(D) Add (A) and (C) to (B) and stir the resultant mixture until it becomes 
homogeneous. 
EXAMPLE 6 
Inhibitory Effect on Carrageenan-Induced Edema: 
Wister male rats each weighing about 200 g, each group consisting of six 
rats, were subcutaneously administered 0.05 ml of a 1% carrageenan 
solution on their hind right paws. Immediately thereafter, about 100 mg of 
the ointment prepared in Example 1 was coated over each injected area. 
Each coating was covered with a polyethylene film, which was fixed with 
gauze. Two hours later, both the polyethylene film and the gauze were 
removed. One hour after removal, the weight of edema was measured. The 
control group was coated only by the ointment base and thereafter treated 
in the same manner as in the test groups. The results are as shown in 
Table 1. 
TABLE 1 
______________________________________ 
Weight of edema (g) 
Inhibition ratio 
Test ointment 
Mean .+-. error 
(%) 
______________________________________ 
Control 0.50 .+-. 0.03 
-- 
Indomethacin 0.35 .+-. 0.04 
31.1* 
ointment (1%) 
______________________________________ 
*p &lt;0.05 
EXAMPLE 7 
Inhibitory Effect on Acceleration of Blood Vessel Permeability: 
Guinea pigs were coated twice with about 50 mg of the ointment prepared as 
in Example 1 on their hair-removed back skins at an interval of one hour. 
One hour after a second coating, a 1% Evans Blue solution was injected 
intravenously. Immediately thereafter, 10 .mu.g of a histamine 
hydrochloride solution was intradermally injected into each 
ointment-coated region. Thirty minutes later, the animals were depleted to 
death. Each skin dyed in blue was exfoliated, and the pigment was 
extracted with pyridine. The control group was coated only by the ointment 
base and thereafter treated in the same manner as in the test groups. 
The results obtained are as shown in Table 2. 
TABLE 2 
______________________________________ 
Evans' Blue (.mu.g/region) 
Inhibition 
Test ointment 
Mean .+-. error ratio (%) 
______________________________________ 
Control 246.2 .+-. 26.5 -- 
Indomethacin 
202.8 .+-. 28.1 17.6 
ointment (%) 
______________________________________ 
EXAMPLE 8 
Absorption from Skin: 
Guinea pigs were coated with about 1 g of each of the ointments prepared as 
described in Examples 1 and 3 and suspended with about 0.1 g of the 
ointment on the back skins each having a region of 2.times.2 cm from which 
the hair was removed one day after hair cutting. Five hours after coating, 
the preparation was recovered, and the absorption ratio was calculated 
from the amount recovered. The results obtained are as shown in Table 3. 
TABLE 3 
______________________________________ 
Test ointment 
Ointment Ointment 
Absorption ratio 
Cream* in Example 1 
in Example 3 
______________________________________ 
After 5 hours (%) 
6.0 .+-. 2.0 
13.4 .+-. 2.6 
25.5 .+-. 1.1 
______________________________________ 
*Prepared according to the method reported in Europ. J. Pharmacol., 3, 15 
(1968) 
EXAMPLE 9 
The results obtained for the clinical studies of 84 cases conducted by 
three establishments are as shown in Table 4 in which parenthesized are 
the percentage values. 
TABLE 4 
__________________________________________________________________________ 
Excell- Ineffec- 
Aggra- 
ent Good 
Fair 
tive vation 
Unknown 
Total 
__________________________________________________________________________ 
Distorsion 1 8 2 2 0 0 13 
Contusion 0 7 0 2 0 0 9 
Fracture, dislocation and 
0 2 4 1 0 0 7 
sequelae 
Traumatic arthritis 
0 1 2 1 0 0 4 
Total 1 18 8 6 0 0 33 
(3.0) 
(54.5) 
(24.2) 
(18.2) 
Arthritis deformans 
0 3 10 4 0 0 17 
Myositis 0 2 0 1 0 0 3 
Total 0 10 19 12 0 1 42 
(23.8) 
(45.2) 
(28.6) (2.4) 
Swelling post operative 
0 3 2 1 0 0 6 
Others 1 0 1 1 0 0 3 
Sum total 2 31 30 20 0 1 84 
(2.4) 
(36.9) 
(35.7) 
(23.8) (1.2) 
__________________________________________________________________________ 
EXAMPLE 10 
______________________________________ 
1 Carbopol 940 1.0 g 
(The B. F. Goodrich Company) 
2 Indomethacin 0.7 g 
3 Propylene glycol 8.0 g 
4 Ethanol 40.0 g 
5 Aqueous ammonia 10% 
0.6 g 
6 Distilled water An amount 
sufficient to 
bring the final 
weight to 100 g 
______________________________________ 
(A) Dissolve (2) in (3) and (4). 
(B) Disperse (1) in (A). 
(C) Add (6) to (B) and swell the resultant mixture. 
(D) Add (5) to (C) and stir the composition until it becomes homogeneous. 
EXAMPLE 11 
______________________________________ 
1 Indomethacin 1.0 g 
2 Isopropyl alcohol 45.0 g 
3 Hydroxypropylmethyl cellulose 
1.5 g 
4 Triethanolamine 0.4 g 
5 Distilled water An amount 
sufficient to 
bring the final 
weight to 100 g 
______________________________________ 
(A) Dissolve (1) in (2). 
(B) Swell (3) in 40 g of (5). 
(C) Add (B) to (A). Add the remainder of (5) and (4) to (C) and stir the 
composition until it becomes homogeneous. 
This invention now being fully described, it is apparent to those skilled 
in the art that many changes and modifications can be made to the 
invention without departing from the spirit or scope of the invention set 
forth herein.