Methods for treating inflammation

A non-steroidal anti-inflammatory composition comprising a therapeutically effective amount of active anti-inflammatory agent selected from the group consisting of 1-phenyl-1 cyclohexene, 4-phenylcyclohexanone, and mixtures thereof. The active agent may be formulated in a pharmaceutically acceptable carrier. These compositions are useful in the treatment in mammals of inflammation and other related symptoms, including pain.

The present invention relates to non-steroidal anti-inflammatory compounds 
useful as active agents in the treatment, in mammals, of inflammation and 
its related symptoms, including pain; pharmaceutically acceptable 
compositions containing these agents; and methods of treatment employing 
these agents. 
Non-steroidal anti-inflammatory compounds are well-known in the art. 
Examples of such compounds include aspirin, indomethacin, and 
phenylbutazone, to name a few. These compounds are known to cause 
side-effects, e.g., gastroenteric disorders and headaches. 
U.S. Pat. No. 4,145,444 to Hamazaki et al., discloses various 
non-carboxylic benzoyl derivatives as anti-inflammatory agents. In 
particular, the compounds disclosed have the formula 
##STR1## 
wherein R.sub.1 represents hydrogen, halogen, hydroxy, C.sub.1-8 alkyl or 
C.sub.1-8 alkoxy; R.sub.2 represents hydrogen, halogen, hydroxy, vinyl, 
C.sub.1-8 alkyl or C.sub.1-8 alkoxy; A represents carbonyl, methylene or a 
single bond; and n is an integer from 1 to 4. It is preferred that R.sub.2 
be C.sub.3-8 alkyl or C.sub.1-8 alkoxy substituted in the para position; n 
be 1; R.sub.1 be hydrogen or halogen substituted in the ortho position; 
and A, a single bond, e.g., 4-n-butylbenzophenone or 
4-n-butyl-2'-fluorobenzophenone. 
U.S. Pat. No. 4,244,970 to Dewhirst discloses a method of treating 
inflammation and inhibiting prostaglandin synthesis by administering an 
effective amount of 2-hydroxybenzophenone and certain substituted 
2-hydroxybenzophenones. 
The association between the production of prostaglandins in mammals and 
inflammation and related symptoms is well documented. For purposes of this 
application, the reference to inflammation shall be read to include 
reference to its related symptoms including pain. See Greaves and 
Sondergaard, Journal of Investigative Dermatology 54:365-367, 1970, where 
prostaglandin activity in tissue fluid taken from inflamed human skin was 
first reported. Other investigators have subsequently reported that 
PGE.sub.2 (prostaglandin E.sub.2) concentrations in skin increase after 
exposure to ultraviolet light and mediate a significant degree of redness 
particularly in the first 24 hours subsequent to exposure. The literature 
reveals that known non-steroidal anti-inflammatory agents, e.g., 
indomethacin, reduce ultraviolet-induced erythema by inhibiting the 
production of prostaglandin E.sub.2 within the first 24 hour period 
subsequent to UVB exposure. See "Prostaglandins in the Skin," by Neal S. 
Penneys, published by Upjohn Co., 1980. 
Without wishing to be bound by any one theory, it is believed that the 
inventive compositions of this application are effective prostaglandin 
synthesis inhibitors. It is theorized that the effective inhibition of 
prostaglandin synthesis is the mechanism by which the novel compounds 
reduce and control inflammation in mammals. 
It is apparent that there is a need for effective, non-steroidal 
anti-inflammatory compounds which can be formulated into compositions 
using pharmaceutically acceptable carriers for topical, oral, rectal, 
sublingual or parenteral administration. The compounds of this invention 
fulfill this need. 
The instant invention relates particularly to anti-inflammatory 
compositions containing a therapeutically effective amount of a compound 
having one of the following structural formulae: 
##STR2## 
and mixtures thereof. These compounds, not previously disclosed as having 
anti-inflammatory properties, have been found, when administered to 
mammals in therapeutically effective amounts, either alone or in a 
pharmaceutically acceptable carrier, to be effective against inflammation. 
They are intended for use in the treatment of a variety of inflammatory 
problems and diseases including systemic diseases such as arthritis and 
the like. 
When contained in a pharmaceutically acceptable carrier or composition, the 
compounds described above or mixtures thereof, (henceforth referred to as 
the "agent" in the composition), are generally present in therapeutically 
effective amounts of about 0.05% to about 25% by weight of the 
composition; preferably in amounts of about 0.05% to about 15% and most 
preferably about 0.1% to about 3% by weight of the composition. 
The inventive compounds are preferably used in compositions which can be 
easily and conveniently administered to a mammal experiencing 
inflammation. Pharmaceutically acceptable carriers may be varied to 
produce topical creams, pastes, ointments, gels, lotions and the like, for 
direct application to the inflamed area; capsules, tablets, solutions, 
syrups, powders and the like for oral administration; and compositions 
appropriate for rectal, sublingual and parenteral administration.

The preferred form of composition is a topical lotion. Useful 
pharmaceutically acceptable carriers for this embodiment include dimethyl 
sulfoxide; mono- and di-alcohols and polyols including lower alkyl 
alcohols such as ethanol, 1,2-propylene glycol, polyethylene glycol, and 
glycerol; mineral oils; vegetable oils; petrolatum; nonionic, cationic, 
and anionic surfactants; water and the like, as well as mixtures of these. 
Compositions comprising such carriers and the agent in amounts of from 
about 0.05% to about 25% by weight of the composition have been found 
particularly effective in the treatment of inflammation of the skin, 
commonly known in the art as erythema. 
The active anti-inflammatory compounds of the instant invention can be 
applied together with other anti-inflammatory agents, analgesics, thrombus 
dissolving agents, thrombus inhibiting agents, antibiotics and the like. 
In the case where the anti-inflammatory agent is incorporated in a 
pharmaceutically acceptable composition, other common materials such as 
occlusives, emulsifiers, emollients, humectants, surfactants, lubricants, 
preservatives, waxes, thickeners, demulcents, perfumes, coloring additives 
and the like may be added. These, of course, are not critical to the 
invention and their amounts, which can be varied and balanced to meet the 
desired properties of the overall composition, may be determined by 
routine experimentation by one skilled in the art. 
The instant compositions may include materials that serve as occlusives in 
that they hold moisture against the surface of the skin. Suitable 
occlusive compounds include cetyl alcohol, cetyl palmitate, petrolatum, 
mineral oil and the like. These materials are generally present in topical 
compositions, for example, in amounts of about 1% to about 25% by weight 
of the composition and preferably in amounts of about 2% to about 10%. 
A variety of materials may be utilized as emulsifiers, including high 
molecular weight polyethylene glycols, fatty alcohols such as stearyl 
alcohol and myristyl alcohol and the like. These materials are generally 
present in amounts of about 0.1% to about 15% by weight of the composition 
and preferably in amounts of about 1% to about 10%. 
Suitable emollients for use in the instant compositions containing the 
novel anti-inflammatory compounds include fatty acid esters such as cetyl 
palmitate, diisopropyl adipate, isopropyl isostearate, isostearyl 
isostearate and mixtures thereof, to name a few. Generally they are 
present in topical compositions in amounts of about 0.1% to about 20% by 
weight of the composition and preferably in amounts of about 1% to about 
10%. 
Suitable humectants may be any of those well known in the art. Examples of 
useful humectants include glycerin, propylene glycol, polyethylene glycol, 
polyhydric alcohols and mixtures thereof, to name a few. Preferably, 
glycerin is used. These materials may be incorporated in the inventive 
anti-inflammatory compositions in amounts of about 0.1% to about 30% by 
weight of the composition and preferably in amounts of about 3% to about 
20%. 
Numerous surfactants, and preferably non-ionic surfactants, may be added 
for their intended purpose. Among those preferred are polyalkanolamines 
such as triethanolamine, polyethylene glycol stearate, polyethylene glycol 
laurate, polyoxyethylene and polyoxypropylene compounds, e.g. derivatives 
of sorbitan and fatty alcohol esters, fatty acid esters of polyhydric 
alcohols and amine oxides; anionic surfactants, such as alkyl 
carboxylates, acyl lactylates, sulfuric acid esters (e.g. sodium lauryl 
sulfate), ester-linked sulfonates, and phosphated ethoxylated alcohols; 
cationic surfactants, such as monoalkyl and dialkyl quaternary ammonium 
salts, amidoamides and aminimides. These various surfactants, when 
compatible, can be added as mixtures to the instant compositions and are 
generally present in amounts of about 0.1% to about 15% by weight of the 
composition. 
Lubricating agents may be used when desired in the instant compositions. 
They include silicone oils or fluids such as substituted and unsubstituted 
polysiloxanes, e.g. dimethyl polysiloxane, also known as dimethicone, is 
particularly useful when the composition is to be used as a topical 
preparation. The lubricating agents, when incorporated in a topical 
composition, are generally present in amounts of about 0.1% to about 30% 
by weight of the composition and preferably in amounts of about 1% to 
about 10%. Other lubricating agents well known to the tableting and 
capsule art may be used when the composition takes the form of a tablet, 
pill or capsule. These lubricating agents are used primarily to aid in 
formation of tablets. 
Preservatives such as alkyl and aryl parabens and substituted phenols are 
also useful additives. Examples of the preferred parabens are the methyl, 
propyl and butyl parabens which may be employed in amounts of 0.1% to 
about 0.25% by weight of the composition. In a preferred embodiment, a 
combination of methyl, propyl and butyl paraben may be used in the 
respective amounts of about 0.1% to about 0.25%, 0.02% to about 0.2%, and 
0 to about 0.05%. Examples of suitable substituted phenols include 
chloro-substituted phenoxy phenols, such as 
5-chloro-2-(2,4-dichlorophenoxy)phenol, hexachlorophene, triclosan and 
dichlorophene, among others. 
Other useful preservatives include mercury derivatives, such as 
phenylmercuric acetate; quaternaries, such as benzethonium chloride, 
benzalkonium chlorides and cetyl trimethyl ammonium bromide; organic 
acids, such as sorbic acid; and a variety of other preservatives such as 
Kathon CG, a trademark of Rohm & Haas Co. which comprises a mixture of 
5-chloro-2-methyl-4isothiazolin-3-one and 2-methyl-4-isothiazolin-3-one. 
In addition, conventional additives such as waxes, thickeners, demulcents, 
fragrance oils, color additives, and other materials may be included. For 
example, in the case of a topical lotion, thickeners for viscosity 
adjustment would include xanthan gum, sodium stearyl sulfate, and 
materials of that type. 
The foregoing recitation of materials is presented for purposes of 
illustration and not limitation, it being understood that a variety of 
equivalent materials would all function in the capacities set forth above. 
The instant invention also includes a method of treatment for inflammation 
whereby a mammal is administered a therapeutically effective amount of 
1-phenyl-1-cyclohexene, 4-phenylcyclohexanone, or mixtures thereof. 
It should be recognized that the process for preparing the 
anti-inflammatory compositions of this invention which employ a 
pharmaceutically acceptable carrier are considered well known and not a 
part of this invention. Such routine procedures involving blending, 
molding, tableting and so forth are well within the scope of the ordinary 
artisan. 
The invention will be further appreciated by the following example which 
illustrates two embodiments of the instant invention. All percentages 
throughout the specification and claims are by weight of the total 
composition unless otherwise indicated. 
EXAMPLE 
This example is designed after the guinea pig model of Snyder, Journal of 
Investigative Dermatology, 64: 322-25, 1975, and demonstrates that skin 
inflamed by ultraviolet light (U.V.B.) can be therapeutically treated 
using compounds of the instant invention. Since it is known that U.V.B. 
irradiation-induced erythema is prostaglandin mediated, this example 
additionally demonstrates that the instant compounds when applied 
topically in a dermatological preparation are effective in inhibiting the 
production of prostaglandins. 
The dorsal surface of a male albino guinea pig was shaved with a standard 
animal clipper (#40 head), depilated with a commercially available 
thioglycolate based depilatory product, rinsed with tap water and dried. 
The animal was immobilized in a standard head stock and irradiated for 30 
minutes under a bank of Westinghouse FS-40 lamps. This period of 
irradiation was found to be equivalent to 3 MED's. An MED (minimum 
erythemal dose) is the minimum amount of U.V.B. radiation required to 
produce sunburn 24 hours subsequent to exposure. 
Immediately after irradiation, the animal's exposed dorsal surface was 
delineated with a black marking pen into treatment sites. Different sites 
were treated with ten (10) micro-liters of (A) a 3% by weight solution of 
1-phenyl-1-cyclohexane in 90% dimethyl sulfoxide (DMSO) (Compound A), (B) 
a 3% by weight solution of 4-phenylcyclohexanone in 90% DMSO (Compound B), 
and (C) a 3% by weight solution of 2-hydroxy-4-methoxybenzophenone in 90% 
DMSO as a control, this benzophenone compound being disclosed in U.S. Pat. 
No. 4,244,970 of Dewhirst. The sites were then visually evaluated for lack 
of erythema (blanching) at 1, 5 and 24 hours post-treatment. The results, 
as described below, were based on the following scale: 
0--No Blanching 
1--Barely Detectable Blanching 
2--Moderate Blanching 
3--Severe Blanching 
4--Complete Blanching (no erythema). 
The results are tabulated below: 
______________________________________ 
Blanching Score 
Agent Vehicle 1 hr. 5 hrs. 
24 hrs. 
______________________________________ 
1-phenyl- 90% DMSO* 1 0 0 
1-cyclo hexene 
(3%)** 
4-phenylcyclo- 
90% DMSO* 1 0 0 
hexanone 
(3%)** 
2-hydroxy-4 methoxy- 
90% DMSO* 1 0+ 0 
benzophenone 
______________________________________ 
*DMSO is the abbreviation for dimethyl sulfoxide, used in a ratio of 9:1, 
DMSO to water. 
**Percents on a weight/weight basis of total composition (vehicle and 
agent). 
These results indicate that post-irradiation application of a compound of 
the instant invention inhibits prostaglandin production as indicated by 
the reduction of inflammation evidenced by blanching. 
The invention being thus described, it will be obvious that the same may be 
varied in many ways. Such variations are not to be regarded as a departure 
from the spirit and scope of the invention and all such modifications are 
intended to be included within the scope of the claims.