In addition to indometacin, the gel-like ointment for the topical treatment of inflammation contains a water-soluble cellulose ether or/and a polyacrylic acid, the carboxyl groups of which are neutralized by a water-soluble amine, plus water and ethanol or isopropanol; the components are present in the ratio of amounts suitable for forming a gel. Determination of the level of indometacin in the serum of humans has shown that the absorption through the skin of the active compound from the new ointment is significantly higher than that from the most closely related products.

Investigations have been carried out for some time with the object of 
producing a product based on indometacin for the topical treatment of 
inflammation. This is because the poor solubility of the active compound 
in water and customary media on the one hand, and a lack of its absorption 
through the human skin from the conventional ointment bases on the other 
hand, stand in the way of the necessary effectiveness of a product of this 
type. 
In order to overcome these difficulties, the use of methyl salicylate as 
vehicle and solubilizer has been proposed, first in German Patent 
Specification No. 2,103,833; it has said to increase the absorption at the 
same time. Such a product comprises, for example, the following: 
50% ethanol 
10% methyl salicylate 
15% polysorbate 80 
5% diisopropyl adipate and 
20% water 
and contains 2.0 mg of indometacin per milliliter of methyl salicylate. 
German Offenlegungsschriften No. 2,827,018 and 3,006,024 point in another 
direction, according to each of these glycol or a polyalkylene glycol 
being used as vehicle and solubilizer. In the second Offenlegungsschrift 
mentioned, the vehicle is composed of a preponderant amount of a 
polyalkylene glycol and a smaller amount of a polyethylene glycol C.sub.10 
-C.sub.14 -alkyl ether. A typical product of this type contains, in 
addition to indometacin, essentially polyethylene glycols, polyethylene 
glycol dodecyl ether and water in the weight ratio 75:5:7.4 for ointment 
and 20:2:73 for a gel; polyacrylic acid and triethanolamine are used for 
the formation of the gel. 
A gel is likewise described in German Offenlegungsschrift No. 2,827,018; 
the vehicle comprises a glycol, in particular propylene glycol, butylene 
glycol or polyethylene glycol, an alcohol and water. The gel-forming 
agents are cellulose and cellulose derivatives or the amine salt of a 
carboxyvinyl polymer (polyacrylic acid). A gel of this type is composed 
of, for example, the following: 
indometacin: 1.0 g 
carboxyvinyl polymer: 1.0 g 
hydroxyethylcellulose: 1.0 g 
polyethylene glycol 300: 10.0 g 
ethanol: 30.0 g 
diisopropyl adipate: 2.0 g 
diisopropylamine: 0.9 g 
water: 54.1 g 
Surprisingly, it has now been found that by omitting any glycol or 
polyalkylene glycol from the mixture described above, a gel-like ointment 
is obtained, and this not only has effectiveness on topical use but is 
even significantly superior to the most closely related product in this 
respect. 
The new product according to the invention contains indometacin, a 
water-soluble cellulose ether or/and a polyacrylic acid, the carboxyl 
groups of which are neutralized by a water-soluble amine, plus water and 
ethanol or isopropanol. The said components are present in a ratio of 
amounts suitable for the formation of a gel. 
The water-soluble cellulose ether and the polyacrylic acid in the product 
function as gel-forming agents, the intention being that the acid groups 
in the latter be neutralized by the basic group(s) of the water-soluble 
amine. Possible examples of an amine of this type are methylamine, 
dimethylamine, ethylamine, diethylamine, propylamine, isopropylamine, 
diisopropylamine, cyclohexylamine, benzylamine, guanidine, pyrrolidine, 
piperidine, morpholine, arginine, lysine, ethanolamine, diethanolamine, 
diisopropanolamine or triethanolamine. The lower aliphatic amines which 
are liquid at room temperature are preferred, for example 
diisopropanolamine or diethylamine. The amine is advantageously used in 
excess over the stoichiometric ratio to the carboxyl groups in the 
polyacrylic acid. 
The ointment should have a physiologically tolerated pH; it is 
advantageously adjusted to a pH in the range from 6.7 to 7.0, preferably 
to pH 6.8. It is possible to add the necessary amount of the 
abovementioned water-soluble amine to adjust the pH. 
Of the polyacrylic acids, also called carboxyvinyl polymers, it is possible 
to use, in particular, those which are obtainable under the tradename 
Carbopol, for example Carbopol 941, Carbopol 934 or Carbopol 940, which 
have a mean molecular weight of 1,250,000, 3,000,000 and 4,000,000 
respectively (manufactured by Goodrich Chemical Co., Cleveland, OH/USA). 
Examples of water-soluble cellulose ethers which may be mentioned are 
methylcellulose, ethylcellulose, carboxymethylcellulose (also called 
cellulose glycolate), hydroxyethylcellulose, hydroxypropylcellulose and 
celluloseethanesulfonic acid. In this context, see also Ullmanns 
Encyklopadie der technischen Chemie (Ullmann's Encyclopedia of Industrial 
Chemistry), 4th edition, volume 9, pages 192-212, Verlag Chemie, Weinheim, 
FRG, 1975. 
The ointment advantageously also contains a superfatting agent in order to 
make up for the possibility of the skin drying out under the action of 
ethanol or isopropanol. Examples of superfatting agents to be used are 
ethyl caproate, ethyl laurate, diethyl sebacate and diisopropyl adipate; 
the latter is preferred. 
The product preferably contains, for 1.0 part by weight of indometacin, the 
following: 
from 0.5 to 2.0 parts by weight of polyacrylic acid and/or water-soluble 
cellulose ether 
from 30 to 50 parts by weight of ethanol or isopropanol 
from 1.0 to 5.0 parts by weight of superfatting agent 
(from 1.0 to 2.0 parts by weight of water-soluble amine when a polyacrylic 
acid is used) 
and sufficient water to form 100 parts by weight. 
Where desired, the ointment can also contain an odor-improving agent 
(flavoring agent). Particularly suitable examples of this are ethereal 
oils, such as lavender oil, thyme oil, the citrus oils, for example 
bergamot oil, lemon oil, the conifer needle oils, such as cypress oil, 
pine-needle oil and dwarf-pine oil, also citronella oil, eucalyptus oil, 
camphor, thymol etc. It is possible to add, for example, 0.04% by weight 
of the conifer needle oils or, for example, 0.05% by weight of camphor or 
thymol. 
In as far as the composition of the ointment fits in with the invention, 
the product can additionally contain one or more other agents which are 
able to supplement or assist an antiphlogistic or antiinflammatory effect 
on topical use, and which in the form of a gel-like ointment are absorbed 
through the skin; examples of these which may be mentioned are analgesics 
and muscle relaxants. Of course, these types of new products likewise fall 
within the scope of the present patent. 
In order to test the effectiveness of the product, the bioavailability of 
indometacin was determined after external application of the ointment, ie. 
that amount of indometacin which appears in the blood after absorption 
through the skin. The investigations were carried out on 6 volunteer 
subjects using a 1% strength ointment according to the present Example 3; 
the reference or comparison product included in the investigation was a 1% 
strength commercial product according to German Offenlegungsschrift No. 
2,827,018. 
Before starting the trial, the nature, aims and extent of the trial were 
explained to the subjects and they all gave their consent to participate 
in the trial. They then underwent specialist examination (with 
comprehensive laboratory, drug and alcohol screening) and were classified 
as healthy. 
The single-dose crossover trial entailed the subjects having 3 g (which 
corresponds to a content of indometacin of 30 mg) of the new product or of 
the comparison product applied to an exactly defined site on the lower 
arm. 
After a period of 7 days without treatment, the subjects in the crossover 
trial received the other product in each case. 
Blood was sampled for the determination of the level of indometacin in the 
serum immediately before application of the products and 15', 30', 45', 
1h, 1h30', 2h, 3h, 4h, 5h, 8h, 12h and 24h thereafter. 
The levels in the serum, and the means, standard deviations and mean 
standard errors of these are indicated in Tables 1 and 2, and the 
pharmacokinetic parameters are to be found in Tables 3 and 4. 
TABLE 1 
__________________________________________________________________________ 
Levels in the serum of indometacin from the new product 
concentration in ng/ml 
Time 
Subject 
0 h 15' 
30' 
45' 
1 h 
1 h 30' 
2 h 
3 h 4 h 
5 h 
8 h 
12 h 
24 h 
__________________________________________________________________________ 
1 0 0 7.3 
6.9 
8.3 
3.5 7 2.7 5.1 
5.3 
3.2 
4.9 
2.5 
2 1.4 0 8.3 
4.02 
0 0 7.2 
3.8 16.2 
7.3 
5.7 
0 1.7 
3 1.2 2,7 
0 0 0 0 0 0 0 0 0 0 10.1 
4 (1.00.sup. 
5,4 
0 -- 7.2 
0 8.3 
11.1 
13.4 
11.5 
13 6 6.4 
5 5.2 5,3 
1.6 
4.9 
2.8 
1.9 4.1 
1.4 2.5 
3.4 
3.4 
5.6 
4.9 
6 2.6 4,5 
4.7 
1.5 
1.3 
2 3.7 
(1.00.sup. 
2.2 
4.4 
4 4.6 
1.5 
mean 
2.08 
2,98 
3.65 
3.46 
3.27 
1.23 
5.05 
3.8 6.57 
5.32 
4.88 
3.52 
4.52 
sdev 
1.97 
2.51 
3.66 
2.74 
3.64 
1.47 
3.07 
4.32 
6.64 
3.87 
4.39 
2.77 
3.35 
sem 0.88 
1.02 
1.49 
1.23 
1.49 
0.6 1.25 
1.93 
2.71 
1.58 
1.79 
1.13 
1.37 
__________________________________________________________________________ 
sdev: standard deviation 
sem: standard error of the mean 
( = value below the detection limit 
-- = sample lost or destroyed 
TABLE 2 
__________________________________________________________________________ 
Level in the serum of indometacin from the reference product 
concentration in ng/ml 
Time 
Subject 
0 h 
15' 
30' 45' 
1 h 
1 h 30' 
2 h 3 h 4 h 
5 h 8 h 
12 h 
24 h 
__________________________________________________________________________ 
1 0 2 2.6 6.2 
1.4 
-- 1.3 2.7 0 0 0 6.8 
-- 
2 -- 
0 (1.00.sup. 
5.9 
2.7 
2.3 
2.2 (1.00.sup. 
1.5 
0 0 0 6.3 
3 5.2 
8.5 
2.8 3.3 
2.3 
5.2 
2.2 (1.00.sup. 
3.1 
0 0 -- 0 
4 -- 
2.6 
(1.00.sup. 
0 2.5 
0 (1.00.sup. 
0 1.9 
(1.00.sup. 
2.8 
6 0 
5 0 7.8 
2.9 6.7 
7.1 
5 5 6.1 0 7.3 7.2 
8.9 
0 
6 0 1.7 
6 1.1 
0 1 1 (1.00.sup. 
1.9 
1 2.5 
4.3 
0 
mean 
1.3 
3.77 
3.58 
3.87 
2.67 
2.7 
2.34 
2.93 
1.4 
1.66 
2.08 
5.2 
1.26 
sdev 
2.6 
3.51 
1.62 
2.85 
2.39 
2.34 
1.58 
3.06 
1.21 
3.18 
2.82 
3.34 
2.82 
sem 1.3 
1.43 
0.81 
1.16 
0.98 
1.05 
0.71 
1.76 
0.49 
1.42 
1.15 
1.5 
1.26 
__________________________________________________________________________ 
sdev: standard deviation 
sem: standard error of the mean 
( = value below the detection limit 
-- = sample lost or destroyed 
TABLE 3 
______________________________________ 
Pharmacokinetic parameters of the new product, calculated 
from the levels in the serum (Table 1) 
Subject AUC Cmax Tmax 
______________________________________ 
1 97.46 8.3 1 
2 73.41 16.2 4 
3 61.43 10.1 24 
4 189.9 13.4 4 
5 105.5 5.6 12 
6 81.01 4.7 0,5 
mean 101.4 9.717 7.583 
stdev 46.18 4.469 9.036 
sem 18.85 1.825 3.689 
Unit: hxng/ml ng/ml h 
______________________________________ 
AUC: area under the curve 
Cmax: maximum concentration 
Tmax: time at which concentration is at maximum 
TABLE 4 
______________________________________ 
Pharmacokinetic parameters of the reference product, 
calculated from the levels in the serum (Table 2) 
Subject AUC Cmax Tmax 
______________________________________ 
1 21.18 6.8 12 
2 47.18 6.3 24 
3 15.16 8.5 0.25 
4 65.54 6 12 
5 130.4 8.9 12 
6 51.95 6 0.5 
mean 55.23 7.083 10.13 
stdev 41.45 1.292 8.868 
sem 16.92 0.5275 3.62 
Unit: hxng/ml ng/ml h 
______________________________________ 
AUC: area under the curve 
Cmax: maximum concentration 
Tmax: time at which concentration is at maximum 
As can be seen from Tables 3 and 4, the AUC for the new product was 101.4 
hxng/ml, and the figure for the reference product was 55.2 hxng/ml. The 
maximum concentration for the new product was 9.7 ng/ml and that for the 
reference product was 7.1 ng/ml. 
The relative bioavailability of the product according to the invention 
compared with the reference product is 183.6%, and it is thus a factor of 
1.8 better. 
Comparison of the compositions of the two products shows that this 
difference in effectiveness can only be due to the omission of the glycol 
or polyalkylene glycol. This result was all the more unexpected because 
propylene glycol, for example, is frequently employed as a solvent for 
active compounds in medicaments for external application and carries the 
dissolved active compound with it through the barrier of the horny layer 
of the skin (M. Gloor, Pharmakologie dermatologischer Externa (The 
Pharmacology of Topical Dermatological Products) published by Springer, 
Berlin, Heidelberg, New York, 1982, pages 7-8 and 42). Moreover, propylene 
glycol and polyethylene glycol are customarily used as water-soluble bases 
for ointments (L. S. Goodman and A. Gilman, The Pharmacological Basis of 
Therapeutics, 5th edition, Macmillan Publishing Co. Inc., New York 1975, 
page 947), and not only for ointments containing other active compounds 
but, in particular, even for ointments containing indometacin (European 
Patent Application No. 55,029). 
It is best to take advantage of the possibility of testing the therapeutic 
effect of the new product on human patients rather than by pharmacological 
tests in vitro or on living animals. Not until it has been used 
therapeutically in concrete cases in daily life, with assessment of the 
results by the treating physicians, will it be possible to draw final 
conclusions in respect of the effectiveness. 
For this reason, the effectiveness and the tolerance of the product 
according to Example 4 (under the protected tradename Bonidon Gel) have 
been investigated in a multicenter phase IV study, which has been running 
since January 1983, of the treatment in practice of inflammatory and 
degenerative rheumatic diseases and traumas of the joints and soft tissues 
in 153 patients. 
The intention in this trial was that Bonidon Gel should, in accordance with 
the information for use, be applied thinly to a large area over the 
affected part of the body 2-3 times daily. The intention was that therapy 
should not last longer than 3 weeks. The progress of the disease was to be 
checked after 1, 2 and, where appropriate, 3 weeks. The intensity of the 
symptoms was assessed by the physician and entered in the record sheet 
using the classes severe, moderate, slight and free of symptoms. 
It was necessary to exclude 24 patients because the conditions of the trial 
were not observed, insufficient data was collected for one other patient, 
and one discontinued treatment because of an undesired effect of the 
medicament; thus, the data for 127 patients were evaluated for the report. 
Of these, 39 suffered from degenerative joint diseases, 16 from 
non-articular rheumatism, 43 had suffered traumatic injuries and 29 
suffered from other complaints. 
The parameters which were assessed were pain, swelling and functional 
impairment. 19% of the patients were treated for one week, 33.2% for two 
weeks and 47.8% for three weeks. At the end of therapy, the symptoms had 
completely disappeared in 62.2% of the cases, and the symptoms had 
improved in 33.4%. 
The product was very well tolerated. Only 4.7% of the patients reported 
itching, reddening or burning of the treated areas of skin, the undesired 
effects being denoted mild and transient in the majority of cases.

Examples of the composition and the preparation of the product according to 
the invention are given in the following text; the amounts given relate to 
parts by weight. 
TABLE 5 
______________________________________ 
No. Substance 1 2 3 4 
______________________________________ 
1 indometacin 1.0 1.0 1.0 1.0 
2 Carbopol (R) 941 
-- 1.0 1.5 2.0 
3 hydroxypropylcellulose 
2.0 0.5 -- -- 
Klucel.sup.(R) * 
4 diisopropanolamine 
1.0 1.5 1.8 2.0 
5 95% ethanol 40.0 40.0 35.0 50.0 
6 diisopropyl adipate 
3.0 4.0 5.0 5.0 
7 purified water ad 
100.0 100.0 100.0 100.0 
______________________________________ 
*manufactured by Hercules Inc., Wilmington (DE/USA) 
______________________________________ 
Example 1 
(4) is dissolved in 10 parts of water (7) 
solution A 
(5) and (6) are mixed together, (1) is dis- 
solution B 
solved in this mixture with stirring and 
sufficient solution A is added slowly until 
a pH of 6.9 is reached 
(3) is mixed with 20 parts of water (7), 
gel C 
a homogeneous suspension is produced from 
this, solution B is added slowly, and the 
mixture is thoroughly stirred 
the gel is allowed to stand overnight and is 
gel D 
finally adjusted to the desired weight by 
adding water (7) 
Example 2 
(4) is dissolved in 10 parts of water (7) 
solution A 
(5) and (6) are mixed together, (1) is dis- 
solution B 
solved in this mixture with stirring, and 
sufficient solution A is added slowly until 
a pH of 6.8 is reached 
(3) is mixed with 20 parts of water (7), a 
gel C 
homogeneous suspension is produced from 
this, solution B is slowly added, and the 
mixture is thoroughly mixed and allowed to 
stand overnight 
(2) is dissolved in 20 parts of water (7) 
gel D 
by allowing it to swell for some time and 
stirring until a homogeneous composition is 
formed, and this is mixed slowly, with 
continuous stirring, into gel C in order 
to form a homogeneous gel, and the pH of 
the gel is adjusted to 6.8 by slowly 
adding solution A, and finally the mixture 
is adjusted to the desired weight by add- 
ing water (7) 
Examples 3 and 4 
(4) is dissolved in 10 parts of water (7) 
solution A 
(1) is dissolved in a mixture of (5) and 
solution B 
(6) with the formation of a clear solution, 
and sufficient solution A is slowly added 
until a pH of 6.8 is reached 
(2) is mixed with 20 parts of water (7), 
gel C 
allowed to swell for some time and stirred 
until a homogeneous composition is formed, 
and solution A is added, with stirring, 
until the pH is adjusted to 6.8 
solution B is mixed slowly, with continuous 
gel D 
stirring, into gel C in order to form a 
homogeneous gel, and the mixture is finally 
adjusted to the desired weight by adding 
water (7) 
Example 5 
2.0 g of diisopropanolamine are dissolved 
solution A 
in 10 ml of purified water 
1.0 g of indometacin is dissolved in a 
solution B 
mixture of 50 g of isopropanol and 5 g of 
diisopropyl adipate with the formation of 
a clear solution, and sufficient solution A 
is added slowly until a pH of 6.9 is 
reached 
2.0 g of carboxymethylcellulose are mixed 
gel C 
with 20 ml of purified water, allowed to 
swell for some time and stirred until a 
homogeneous composition is formed, and 
solution A is added, with stirring, until 
the pH is adjusted to 6.9 
solution B is mixed slowly, with continuous 
gel D 
stirring, into gel C in order to form a 
homogeneous gel, and finally the mixture is 
adjusted to a weight of 100 g by adding 
purified water 
Example 6 
2.0 g of diisopropanolamine are dissolved 
solution A 
in 10 ml of purified water 
1.0 g of indometacin is dissolved in a 
solution B 
mixture of 50 g of isopropanol, 5 g of 
diisopropyl adipate and 0.07 g of pine- 
needle oil with the formation of a clear 
solution, and sufficient solution A is 
added slowly until a pH of 6.9 is reached 
The further steps are carried out exactly as 
in Example 5 and they lead to 100 g of gel 
which correspond to that according to 
Example 5 apart from the odor and the con- 
tent of pine-needle oil (0.04% by weight). 
______________________________________