Novel topically administrable pharmaceutical compositions

Novel topically administrable pharamceutical composition containing, as active ingredient, from approximately 0.1 to approximately 10% by weight of a non-steroidal, anti-inflammatorially active compound having at least one acidic group, from approximately 10 to approximately 50% by weight of a water-soluble, volatile lower alkanol having from 2 up to and including 4 carbon atoms, from approximately 3 to approximately 15% by weight of an optionally self-emulsifying lipid or a mixture of lipids, from approximately 0.5 to approximately 2% by weight of a gel structure former, from approximately 1 to approximately 20% by weight of a co-solvent, from approximately 40 to approximately 80% by weight of water, optionally from approximately 0.5 to approximately 5% by weight of an emulsifier if the lipid phase is not self-emulsifying and, if desired, non-essential constituents.

The therapeutic use of topically administrable pharmaceutical preparations 
is frequently indicated in those cases where oral or another form of 
parenteral administration leads to intolerability, risks or harmful side 
effects or where an undesired biotransformation of the active ingredient 
occurs. Application to the skin may, therefore, be advantageous if, for 
example, there is to be a continuous release of the active ingredient 
component, active ingredients are intended to act locally or act 
systemically with the gastro-intestinal tract being by-passed, or if 
active ingredients having a short biological half-life are to be used. A 
group of active ingredients suitable for topical administration is, for 
example, the non-steroidal, anti-inflammatory agents. 
The possibilities of using customary topically administrable pharmaceutical 
preparations are limited, for example, by inadequate solubility of the 
active ingredient or by the inability of such formulations to channel the 
active ingredient through the skin barrier and thereby enable a systemic 
action. 
Of the various kinds of medicinal formulations that are applied to the skin 
there may be mentioned, for example, suspensions, solutions, foams and 
emulsions, such as water/oil (W/O) and oil/water (O/W) emulsions, and also 
gels. 
Hitherto unknown are dermatics that are to be regarded at the same time as 
O/W emulsion and as gel. 
The present invention relates to the provision of a novel, almost neutral 
pharmaceutical preparation based on an oil/water emulsion and containing, 
as active ingredient, a non-steroidal, anti-inflammatorially active 
compound having at least one acidic group for topical use on intact 
epidermis, which preparation combines within it the properties of a gel 
with those of an oil/water emulsion, effects readier solubility of the 
active ingredient and which, if desired, is capable of transporting the 
active ingredient through the barrier of the stratum corneum, and to the 
use thereof and to the process for the manufacture of such formulations. 
The novel, almost neutral topically administrable pharmaceutical 
composition has a pH of from approximately 5 to approximately 7.5 and 
contains from approximately 10 to approximately 50% by weight of a 
water-soluble, volatile lower alkanol having from 2 up to and including 4 
carbon atoms, from approximately 1 to approximately 20% by weight of a 
co-solvent, from approximately 40 to approximately 80% by weight of water, 
from approximately 3 to approximately 15% by weight of an optionally 
self-emulsifying lipid or a mixture of lipids, optionally from 
approximately 0.5 to approximately 5% by weight of an emulsifier if the 
lipid phase is not self-emulsifying, from approximately 0.5 to 
approximately 2% by weight of a gel structure former, as active ingredient 
from approximately 0.1 to approximately 10% by weight of a non-steroidal, 
anti-inflammatorially active compound having at least one acidic group 
and, if desired, non-essential constituents. 
The base substance according to the invention does not have the 
disadvantages described above. The advantages of this novel formulation 
reside, for example, in the favourable cosmetic properties, in a 
distinctly readier solubility of active ingredients and the associated 
higher effective active ingredient concentration and also in a 
considerably improved chemical stability of the active ingredient in 
comparison with conventional topical formulations. 
As compared with a corresponding gel, the composition according to the 
invention is distinguished above all by the fact that the presence of the 
lipid phase and its fat-restoring properties enable the formulation to be 
massaged in whilst, at the same time, the direct absorption into the skin 
is experienced as a pleasant property. In addition, in comparison with 
hydrogels, there is an increased solubility for lipophilic active 
ingredients. 
The advantages over an O/W emulsion reside in the enhanced cooling effect 
which is brought about by the coldness due to evaporation of the 
additional alcohol component. In addition, as compared with O/W emulsions, 
there is an improved solubility of polar medicinal active ingredients. 
The interplay of alcohol component and co-solvent makes it possible to 
incorporate into a water-containing system, for example substances that 
are primarily sparingly soluble in water. For example, it is possible, by 
virtue of the fat component, successfully to incorporate lipophilic active 
substances into an aqueous system. 
In addition, the alcohol and co-solvent component promotes improved 
resorbability of an active ingredient, compared with gels and O/W 
emulsions. 
It is highly surprising that, for the first time, the manufacture of such a 
pharmaceutical preparation in a stable form has been successful although, 
according to the principles of general experience, the mixing of 
water-insoluble lower alkanols in the disclosed concentration with 
oil/water emulsions should result in their breakdown. As a result of the 
partial dissolution of the emulsifiers, a weakening of the emulsifier film 
stabilising the emulsion is what was to be expected. 
The invention is further based on the surprising discovery that besides the 
galenical base substance, also the particular active ingredient in the 
composition according to the invention is in stable form. For example, 
extensive investigations of stability have shown that the active 
ingredient proves to be extremely stable towards chemical reactions with 
the base substance of the formulation. Equally, after relatively long 
storage, almost no degradation products of the active ingredient are 
detected although it is known, for example, of many non-steroidal 
anti-inflammatorially active acids that these are subjected, for example 
in a cream base substance, to chemical changes, such as reduction or 
esterification as a result of which a certain portion of the active 
ingredient is chemically modified and hence the active ingredient 
concentration is reduced in an undesirable manner. These phenomena could 
not be observed in the composition on which the invention is based, as is 
demonstrated by reference to the following stability comparison of a cream 
with a formulation according to the invention having the composition given 
below: 
______________________________________ 
(B) composition according 
(A) cream composition 
to the invention 
______________________________________ 
diclofenac-sodium 
1% diclofenac-sodium 
1.0% 
polyethylene 7% isopropanol 20.0% 
glycol 300 diethanolamine 1.2% 
glycerine stearate 
10% acrylic acid polymerisate 
1.0% 
cetyl alcohol 1% (Carbopol 934 P) 
isopropyl myristate 
5% sodium sulphite 0.1% 
petroleum jelly, 
10% polyhydroxyethylene 
2.0% 
white, cetyl stearyl ether 
polyhydroxyethylene 
4% (Cetomacrogol 1000) 
(100)-stearate (Myrj 59) 
paraffin oil, viscous 
2.5% 
2-phenoxyethanol 
1% caprylic/capric acid 
2.5% 
water, demineralised 
61% ester (Cetiol LC) 
polyethylene glycol 300 
3.0% 
water, demineralised 
66.7% 
______________________________________ 
After each formulation had been stored for 6 months at 35.degree. C., 
chromatographic analysis, for example, showed for formulation A a content 
of approximately from 2 to 4% by weight of cetyl ester with the active 
ingredient and approximately from 2 to 4% by weight of reduction product, 
for example aldehyde and alcohol, formed from the active ingredient, 
whereas in formulation B according to the invention, despite the high 
proportion of lower alkanol, no esterification or reduction products of 
the active ingredient could be detected. This is highly surprising since, 
from a chemical standpoint, ester formation with a lower alkanol is 
favoured over esterification with a fatty alcohol (cetyl alcohol in this 
case). 
Accordingly, the present invention relates also to a process for the 
stabilisation of non-steroidal, anti-inflammatorially active compounds 
having at least one acidic group in pharmaceutical compositions for 
topical administration, characterised in that there is added to a suitable 
galenical base substance from approximately 10 to approximately 50% by 
weight of a water-soluble, volatile lower alkanol having from 2 up to and 
including 4 carbon atoms. 
The pharmaceutical compositions according to the invention can furthermore 
be used in a method for the treatment of painful conditions, inflammation 
and/or rheumatic diseases in warm-blooded animals. Corresponding 
formulations can be applied, for example, 2 or 3 times daily to the intact 
epidermis. When this novel pharmaceutical formulation is administered 
topically, the particular medicinal active ingredient can penetrate 
transcutaneously, in particular overcoming the skin barrier of the 
epidermis, for example into the corium or the subcutis and be taken up by 
the vascular system (resorption). 
In the case of an intact epidermis, the interface between the dead stratum 
corneum and the stratum granulosum represents the main obstacle to the 
penetration of active ingredient molecules into the region of the corium 
and the subcutis through which pass blood and lymph systems. 
The reason for the favourable resorption properties of the composition 
according to the invention lies, on the one hand, in the alteration of the 
stratum corneum structure which is contingent on the alcohol content, 
whereby, at the same time, the barrier function of the stratum corneum is 
to some extent removed and, on the other hand, in the carrier function of 
the co-solvent and finally in the readier solubility of the medicinal 
active ingredient. 
The alcohol component used in the composition according to the invention 
includes especially lower alkanols having preferably 2 or 3 carbon atoms, 
such as ethanol or especially isopropanol, and also mixtures thereof. The 
preferred alcohol proportion in the formulation according to the invention 
is at least 15% by weight, especially from approximately 20 to 
approximately 30% by weight. 
The function of the co-solvent is to maintain the active ingredient left 
behind on the skin in solution. In addition, the co-solvent must be 
miscible with the aqueous-alcoholic phase. Suitable for this purpose are, 
for example, polyhydric alcohols, such as glycerine, ethylene glycol or 
propylene glycol, especially poly-lower alkylene glycols, for example 
polyethylene glycol or polypropylene glycol, having a chain length of from 
approximately 200 to approximately 6000, preferably from approximately 300 
to approximately 1500, units. Preferably, from approximately 5 to 
approximately 10% by weight are co-solvent. 
The fatty phase constituents (lipids) that can be used for the novel 
formulation can be divided into those having non-emulsifying properties 
and those having self-emulsifying properties. The lipids can be of a 
vegetable or animal nature and also partly or completely synthetic. 
Accordingly, there come into consideration as fatty phase constituents, 
for example, lipids without ester linkages, such as hydrocarbons, fatty 
alcohols, sterols, fatty acids and salts thereof, and lipids having ester 
linkages, such as glycerides, waxes and phosphatides. The hydrocarbons 
include, for example, liquid, semi-solid or solid substances and mixtures, 
such as paraffins, petroleum jelly, solid paraffin and microcrystalline 
wax. Fatty alcohols can have, for example, 1 or 2 hydroxy functions and a 
carbon atom number of approximately from 6 to 34 and be saturated or 
unsaturated. Those having an even number of carbon atoms, especially those 
having from 12 to 18 carbon atoms, are preferred. Primary, linear and 
saturated fatty alcohols are, for example, decanol (capric alcohol), 
dodecanol (lauryl alcohol), tetradecanol (myristyl alcohol), hexadecanol 
(cetyl alcohol), octadecanol (stearyl alcohol), eicosanol (arachidyl 
alcohol), docosanol (behenyl alcohol). The 2-alkyl-fatty alcohols include, 
for example, 2-hexyl-decanol or 2-octyl-dodecanol. Examples of 
.alpha.-alkanediols that may be mentioned are, for example, 
1,12-octadecanediol or 9c-octadecen-1-ol. 
Sterols are, for example, naturally occurring steroids that have a 
3.beta.-hydroxy group and an aliphatic side chain in the 17.beta.-position 
and are derived, for example, from parent hydrocarbon cholestane, 
ergostane and stigmastane, such as cholesterol and lanolin. 
Fatty acids can be saturated or unsaturated and have, for example, from 6 
to 24 carbon atoms, 10 to 18 carbon atoms and an even number of carbon 
atoms being preferred. Examples of saturated fatty acids are: hexanoic 
acid (caproic acid), octanoic acid (caprylic acid), decanoic acid (capric 
acid), dodecanoic acid (lauric acid), tetradecanoic acid (myristic acid), 
hexadecanoic acid (palmitic acid), octadecanoic acid (stearic acid), 
eicosanoic acid (arachidic acid), docosanoic acid (behenic acid). Stearic 
acid is especially preferred. Mono-unsaturated fatty acids are, for 
example: 9-dodecenoic acid (lauroleic acid), 9-tetradecenoic acid 
(myristoleic acid), 9-hexadecenoic acid (palmitoleic acid), 9-octadecenoic 
acid (oleic acid), 6-octadecenoic acid (petroselic acid), 9-eicosanoic 
acid (gadoleic acid), 13-docosenoic acid (erucic acid), whilst as 
poly-unsaturated fatty acids there are suitable, for example, 
9,12-octadecadienoic acid (linoleic acid) and 9,12,15-octadecatrienoic 
acid (linolenic acid). As salts of such fatty acids there come into 
consideration, for example, alkali metal salts, such as sodium or 
potassium salts, ammonium salts or amine salts, such as mono-, di- or 
tri-substituted amines, for example corresponding lower alkylamines or 
lower alkanolamines, for example corresponding mono-, di- or 
tri-ethylamines or -ethanol-amines. 
Glycerides are understood to mean fatty acid esters of glycerine, it being 
possible for various fatty acid constituents, for example those mentioned 
above, to occur within the glyceride. In the case of an increased content 
of unsaturated fatty acids, the corresponding glycerides are liquid 
(oils). Glycerides and oils are, for example, groundnut oil (arachis oil), 
olive oil, castor oil, sesame oil, it being possible also for the oils to 
be hydrogenated, such as hydrogenated groundnut oil, hydrogenated cotton 
seed oil, for example Sterotex.RTM., hydrogenated castor oil, for example 
Cutina.RTM.HR. As semi-synthetic and completely synthetic glycerides there 
come into consideration, for example, caprylic/capric acid triglyceride, 
for example Miglyol.RTM.812 or Syndermin.RTM.GTC, or mono-, di- or 
tri-esters of palmitic and stearic acid, for example Precirol.RTM.. 
Waxes are likewise defined as fatty acid esters but, instead of glycerine, 
there are suitable as alcohol components alcohols of the sterine series 
and lower alcohols, for example having from 1 up to and including 12 
carbon atoms, such as ethanol, isopropanol or decanol, and also higher 
even-numbered aliphatic alcohols, for example having from 16 to 36 carbon 
atoms, especially those mentioned above. Solid and semi-synthetic waxes 
are, for example, beeswax, carnauba wax, cetyl palmitate, for example 
Cutina.RTM.CP, wool wax, and lanolin, and liquid waxes are, for example, 
isopropyl myristate, isopropyl stearate, oleic acid decyl ester, for 
example Cetiol.RTM.V, ethyl oleate, caprylic/capric acid esters of 
saturated fatty alcohols, especially having from 12 to 18 carbon atoms, 
for example Cetiol.RTM.LC. 
As phosphatides there come into consideration especially phosphoglycerides, 
preferably phosphatidyl cholines which are produced by esterification of 
sn-glycerine-3-phosphoric acid with a saturated and an unsaturated fatty 
acid, the phosphoric acid residue being for its part esterified by choline 
(also called lecithins). For example, egg lecithin or soya lecithin are 
used. 
If, for example, the fatty alcohol is etherified, for example by a lower 
alkanol or a lower alkoxy-lower alkanol, such as ethanol, a propanol, 
ethoxyethanol, a methoxy- or ethoxy-propanol, the fatty alcohol may be 
self-emulsifying, such as ethoxylated fatty alcohols, for example 
polyhydroxyethylene cetyl stearyl ether, such as Cetomacrogol1000.RTM.. 
The fat constituent of the composition according to the invention is 
preferably from approximately 5 to approximately 10% by weight and can 
also include mixtures of the compounds mentioned above. 
A further constituent of the pharmaceutical preparation according to the 
invention is emulsifiers the surface-active character of which is 
determined by the spatially separate lipophilic and hydrophilic centres in 
the same molecule. Preferably, anion-active surfactants having an acidic 
hydrophilic group and non-ionogenic surfactants are used. 
Corresponding anionic emulsifiers are especially carboxylates, such as 
readily or sparingly soluble fatty acid salts, salts of fluorinated fatty 
acids, of alkoxy-carboxylic acids, of sulphonamidocarboxylic acids, of 
fatty acid lactates, of alkylmalonic or alkylsuccinic acids, sulphonates, 
for example readily or sparingly soluble alkyl sulphonates, sulphonated 
fatty acid alkyl esters, fatty acid sulphonates, fatty acid ester 
sulphonates, perfluorinated alkyl sulphonates, readily or sparingly 
soluble alkylbenzene sulphonates, and sulphates, for example sulphated 
primary or secondary fatty alcohols, soaps, esters, amides, alkanolamides, 
mono- or poly-glycerides, polyglycol ethers, for example of fatty alcohols 
and alkylphenols. Of the great number of suitable anionic emulsifiers 
there may be mentioned: soluble soaps, such as sodium palmitate, stearate, 
oleate and triethanolammonium stearate, alkali metal salts, such as sodium 
salts, of fatty alcohol sulphates, for example sodium lauryl sulphate or 
sodium cetyl stearyl sulphate, and sulphosuccinates, such as sodium 
dioctyl sulphosuccinate. 
Non-ionic emulsifiers are, for example, fatty acid esters with mono- or 
poly-hydric alcohols, such as lower alkanols, ethylene glycol, propylene 
glycol, with oligohydroxy compounds, such as sorbitol, pentaerythritol or 
saccharose, or with polyhydroxy compounds, such as polyethylene glycol or 
polypropylene glycol. Especially suitable are partial glycerine fatty acid 
esters, glycerine monostearate, partial fatty acid esters of sorbitan, 
such as sorbitan monolaurate, stearate or sesquioleate, partial fatty acid 
esters of polyhydroxyethylene sorbitan, especially having from 
approximately 5 to approximately 20 oxyethylene units, such as 
polyethylene glycol (20)-sorbitan monostearate or monooleate. Other 
likewise preferred non-ionic emulsifiers are, for example, polyethylene 
and polypropylene glycol ethers, especially having approximately from 2 to 
23 ethylene glycol or ethylene oxide units, of alcohols, such as fatty 
alcohols, for example of the kind mentioned above, and also polyethers, of 
fatty acid esters, equally of the etherified and those of the glycerine 
and sorbitan type, or of fatty amines, such as the corresponding fatty 
amines derived from the fatty alcohols. Examples of such non-ionic 
emulsifiers that may be mentioned are: polyhydroxyethylene fatty alcohol 
ethers, especially having from approximately 12 to approximately 30 mole 
equivalents of oxyethylene, such as polyhydroxyethylene cetyl stearyl 
ether, for example Cetomacrogol 1000, polyhydroxyethylene (4)-lauryl 
ether, polyhydroxyethylene (23)-lauryl ether and others, 
polyhydroxyethylene fatty acid esters, such as polyhydroxyethylene 
stearates, especially having from 8 to 1000 oxyethylene groups, for 
example Myrj 59, and also polyhydroxyethylene glycerine fatty acid esters, 
for example Tagat S. Also suitable are ethylene oxide and propylene oxide 
block copolymers having hydrophilic polyhydroxyethylene groups and 
hydrophobic polyhydroxypropylene groups, for example 
polyoxyethylenepolyoxypropylene polymers, especially having a molecular 
weight of from approximately 1000 to approximately 11000, for example 
Pluronic.RTM.F 68. Preferred pharmaceutical formulations contain from 
approximately one to approximately two per cent by weight of emulsifier. 
As gel structure formers in the matrix of which is stored the water 
necessary for the formulation there are used inorganic and organic 
macromolecules. The base for high molecular weight inorganic components 
with gel-forming properties is predominantly water-containing silicates, 
such as aluminium silicate or magnesium aluminium silicates, such as 
Veegum, or colloidal silica, such as Aerosil. As high molecular weight 
organic substances there are used, for example, natural, semi-synthetic or 
synthetic macromolecules. Natural and semi-synthetic polymers are derived, 
for example, from polysaccharides having the most varied carbohydrate 
units, such as celluloses, starches, tragacanth, agar-agar, alginic acid 
and salts thereof, for example sodium alginate, and derivatives thereof, 
such as lower alkyl celluloses, for example methyl or ethyl celluloses, 
carboxy- or hydroxy-lower alkyl celluloses, such as carboxymethyl, 
hydroxyethyl, hydroxypropyl, hydroxypropylmethyl and ethylhydroxyethyl 
celluloses. Natural and semi-synthetic polymers include, for example, 
gelatine and gum arabic. The units of synthetic gel-forming macromolecules 
are, for example, vinyl alcohols, vinyl pyrrolidine, acrylic or 
methacrylic acid, and as examples of such polymers there may be mentioned 
polyvinyl alcohol derivatives, especially having a molecular weight of 
from approximately 28000 to approximately 40000, such as Polyviol.RTM. or 
Moviol.RTM., polyvinyl pyrrolidines, especially having a molecular weight 
of from approximately 10000 to approximately 1 million, such as 
Kollidon.RTM. or Plasdone.RTM., polyacrylates and polymethacrylates, 
especially having a molecular weight of from approximately 80000 to 
approximately 1 million, or salts thereof, such as Rohagit S.RTM., 
Eudispert.RTM. or Carbopol.RTM.. The preferred per cent by weight range 
when using a gel structure former or a mixture thereof is from 
approximately 1 to approximately 1.5 per cent by weight. 
As preferred categories of active ingredient there come into consideration 
especially those for systemic treatment that are to be applied to the 
intact skin, are to enter the skin layers, penetrate these and primarily 
pass into the circulation of the vascular system of the corium and the 
subcutis and possibly of the subcutaneous tissue lying beneath the latter 
and also of the muscle region. 
There come into consideration as non-steroidal, anti-inflammatorially 
active compounds having at least one acidic group for systemic treatment, 
for example, salicylic acid and derivatives thereof, such as diflunisal, 
flufenamic acid or tolfenamic acid, ketoalkanecarboxylic acids and 
derivatives thereof, such as fenbufen, aryl- and 
heteroaryl-alkylcarboxylic acids, such as phenylalkanecarboxylic acids and 
derivatives thereof, for example diclofenac, ketoprofen, pirprofen, 
fluoprofen, flurbiprofen, ibuprofen, suprofen, miprofen, and pyrrole-lower 
alkanecarboxylic acids and derivatives thereof, for example zomepirac, 
tolmetin or clopirac, lower alkanecarboxylic acids having di- or 
tri-cyclic aryl and heteroaryl groups, such as naproxen, sulindac, 
indomethacin, carprofen or pranoprofen, also pyrazole compounds, such as 
pyrazolealkanecarboxylic acids, such as lonazolac or pirazolac, or salts 
thereof. Especially preferred representatives are, for example, diclofenac 
and pirprofen and salts thereof. The preferred proportion of active 
ingredient is, for example, from approximately 1 to approximately 5% by 
weight. Salts of active ingredients having acidic groups, such as carboxyl 
groups, are derived primarily from bases. Corresponding salts are, for 
example, metal salts, such as alkali metal or alkaline earth metal salts, 
for example sodium, potassium, magnesium or calcium salts, aluminium salts 
or transition metal salts, such as zinc or copper salts, or corresponding 
salts with ammonia or organic amines. Organic amines that come into 
consideration are, for example, the following: alkylamines, such as mono-, 
di- or tri-lower alkylamines, alkylenediamines, such as lower 
alkylenediamines, alkylamines substituted by phenyl, such as mono- or 
di-phenyl-lower alkylamines, hydroxyalkylamines, such as mono-, di- or 
tri-hydroxy-lower alkylamines, an oligohydroxy-lower alkylamine or 
hydroxy-lower alkyl-di-lower alkylamines, amino sugars, for example those 
in which the amino group can optionally be substituted by at least one 
lower alkyl radical, cycloalkylamines, such as mono- or di-cyclo-lower 
alkylamines, basic amino acids, cyclic amines, such as lower 
alkyleneamines or lower alkenyleneamines having from 2 to 6 carbon atoms, 
it being possible for the carbon chain also to be interrupted by aza, 
N-lower alkylaza, oxa and/or thia. Mono-, di- or tri-lower alkylamines 
are, for example, ethylamine or tert.-butylamine, diethylamine or 
diisopropylamine, trimethylamine or triethylamine, and lower 
alkylenediamine is, for example, ethylenediamine. As phenyl-lower 
alkylamines there come into consideration, for example, benzylamine or 1- 
or 2-phenylethylamine. Mono-, di- or tri-hydroxy-lower alkylamines are, 
for example, mono-, di-, tri-ethanolamine or diisopropanolamine; an 
oligohydroxy-lower alkylamine is, for example, 
tris-(hydroxymethyl)-methylamine; and hydroxy-lower alkyl-di-lower 
alkylamines are, for example, N,N-dimethylamino- or 
N,N-diethylamino-ethanol. Amino sugars are derived, for example, from 
monosaccharides in which an alcoholic hydroxy group is replaced by an 
amino group, such as D-glucosamine, D-galactosamine or marmosamine. 
N-methyl-D-glucosamine may be mentioned as an example of an N-lower 
alkylated amino sugar. Mono- or di-cyclo-lower alkylamine is, for example, 
cyclohexylamine or dicyclohexylamine. Basic amino acids are, for example, 
arginine, histidine, lysine or ornithine. Lower alkyleneamines and lower 
alkenyleneamines are, for example, azirine, pyrrolidine, piperidine or 
pyrroline and as lower alkyleneamines and lower alkenyleneamines of which 
the carbon chain is interrupted by aza, N-lower alkylaza, oxa and/or thia 
there are suitable, for example, imidazoline, 3-methylimidazoline, 
piperazine, 4-methyl- or 4-ethylpiperazine, morpholine or thiomorpholine. 
As non-essential constituents of the base substance according to the 
invention there may be used, if desired, chemical stabilisers, 
moisture-retaining agents, if necessary bases for neutralising acidic 
groups, i.e. groups that yield protons, and/or perfumes. 
As chemical stabilisers there come into consideration, for example, 
anti-oxidants which prevent the oxidative decomposition of active 
ingredients and adjuncts. Suitable for this purpose are, for example, 
alkali metal sulphites, such as sodium or potassium sulphite, sodium or 
potassium bisulphite, alkali metal dithionites, such as sodium or 
potassium dithionite, or ascorbic acid, and also cysteine, cystine and 
hydrohalides, such as hydrochlorides, thereof. Suitable as anti-oxidants 
for fats, oils and emulsions are, for example, ascorbyl palmitate, 
tocopherols (vitamin E), phenols, for example propyl gallate, 
butylhydroxyanisole or butylhydroxytoluene. Additional protection against 
heavy metal anions, chiefly Cu.sup.2+ ions, is effected by the addition of 
complex formers, such as citric acid or, above all, 
ethylenediaminetetraacetic acid and salts thereof, such as alkali metal or 
alkaline earth metal salts, for example the corresponding disodium or 
calcium compounds. Preferably, an addition of approximately 0.1% by weight 
of sodium sulphite is used. 
The conditions that must be met by suitable moisture-retaining agents are a 
high affinity for water, it being necessary that the moisture range be 
narrow, a high viscosity and good tolerability. In addition, these 
substances should not have corrosive properties. There come into 
consideration, above all, polyhydric alcohols having at least two hydroxy 
functions, such as butanediols, glycerine, sorbitol, mannitol, glucose, 
ethylene glycol or propylene glycol. 
As bases for neutralising acidic groups, i.e. groups yielding protons, 
there are suitable, for example, those that result in the salts of active 
ingredients described above. Especially preferred bases are the mentioned 
organic amines. In addition to the active ingredients, especially gel 
structure formers having acidic groups are also neutralised. The addition 
of base serves especially to adjust the pH value. Consequently, the 
addition of base may be essential. 
The process for the manufacture of the pharmaceutical composition according 
to the invention is characterised in that the gel formed by dispersing the 
gel structure former in a portion of the water, the solution of the 
nonsteroidal, anti-inflammatorially active compound having at least one 
acidic group in the water-soluble, volatile lower alkanol having from 2 up 
to and including 4 carbon atoms, in the co-solvent and in a portion of the 
water, and the fatty phase formed by mixing the lipid constituents or, if 
these are not miscible when cold, by melting them together, are mixed 
optionally while heating and, if desired, the non-essential constituents 
are incorporated. 
The order of mixing the gel, active ingredient solution, fatty phase and 
neutralising agent is unimportant in the manufacture of the formulation. 
The novel, topically administrable pharmaceutical composition is prepared, 
for example, as follows: 
In a preferred procedure, in a first step the formation of a gel is 
effected by dispersing a gel structure former in a portion of the water. 
If the gel structure former has, for example, groups that yield protons, 
such as carboxy groups, these groups may, if desired, be neutralised with 
a neutralising agent. 
In the second step a solution of the active ingredient in the lower alkanol 
and a co-solvent and in a portion of the water is produced and is 
incorporated into the gel. In the next step there takes place, if 
necessary, the preparation of the fatty phase by mixing the fat 
constituents or, if these are not miscible when cold, by melting them 
together, for example while heating to from approximately 50.degree. to 
approximately 80.degree. C. 
In the following step the fatty phase is stirred into the gel, optionally 
while heating, for example in a boiling water bath. In the last step the 
non-essential constituents, such as anti-oxidants or perfumes, can 
optionally be incorporated into the base substance while stirring. 
In a variant of the manufacturing process the neutralisation of the gel 
structure former and of the active ingredient, if they contain groups that 
yield protons, and also for the purpose of setting the desired pH value 
can be effected after stirring the fatty phase into the gel. 
A modification of the described procedure comprises, for example, after 
swelling the gel structure former in water, after optional neutralisation 
of the same and/or adjustment of the pH value by means of a neutralising 
agent, first of all stirring the fatty phase into the gel and then 
incorporating the active ingredient solution and, if desired, the 
non-essential constituents. 
In a further variant for the formation of the novel formulation, to form 
the gel, the gel structure former is allowed to swell in a portion of the 
water, the active ingredient solution is stirred in, neutralised if 
desired, and then an emulsifier is added to the aqueous phase. 
Subsequently, the fatty phase and, if desired, the non-essential 
constituents are stirred in. 
The invention relates also to the formulations and their manufacturing 
processes described in the Examples.