PHARMACEUTICAL COMBINATION OF A CYCLOOXYGENASE-2 INHIBITOR
The object of the present invention is a novel pharmaceutical combination having application notably in the treatment of pain and inflammatory phenomena. More specifically, the invention relates to a pharmaceutical composition comprising a combination of a cyclooxygenase-2 inhibitor and an NMDA antagonist as active principle.
Selective cyctooxygenasc-2 (COX-2) inhibitors constitute a novel class of non-steroid analgesic and anti-inflammatory agents. Such compounds have been described for example in the documents WO
94/15932, WO 96/03388 by GD Searle, WO 95/00501 by Merck & Frosst Canada Inc., WO 95/18799, WO 96/08482 by Merck & Co. or even in FR 2747123, FR 2747124 by the Applicant.
Amongst the particularly preferred compounds which have been descπbed m the state of the art,
- 5-bromo-2-[4-fluorophenyl]-3 [4-methanesulphonylphenyljthiophen known under the code name of DuP 697,
- 4-[5-(4-methylphenyl)-3-(trifluoromethyl)pyrazol- l-yl]benzene- sulphonamide known under the designation Celecoxib, - (Z)-3-[l-(4-chlorophenyl)-l-(4-methanesulphonylphenyl)methylene]- dihydrofuran-2-one known under the code name UP 454-21, may notably be cited.
Generally, these compounds possess anti-inflammatory and analgesic activities, the latter being demonstrated in various experimental inflammatory pain models. However, it is known that the selective cyclooxygenase-2 inhibitors are inactive or not very active in the non-inflammatory acute pain tests. Ilus, Gans et aτ_, 1. Phann. Exp. Ther. 1990 ; (254) : 180-187 have demonstrated that the DuP 697 product mentioned above is inactive in the phenylbenzoquinone test m the mouse. Furthermore, it is known that the activation of N-methyl D aspartate (NMDA) receptors by neuroexcitatory ammo acids (aspartate, glutamate) is implicated in certain pain processes; NMDA antagonists possess an analgesic activity demonstrated in numerous tests, including chronic pain tests.
It has been discovered, and this constitutes the basis of the present invention, that the combination of a cyclooxygenase-2 inhibitor and an NMDA antagonist compound possesses a significant analgesic effect at doses at which each one of the products constituting this combination is inactive or not very active.
The beneficial effect of the combination in accordance with the present invention has been demonstrated both in inflammatory pain models and in noninflammatory acute pain models.
The results obtained have shown that this combination possesses an analgesic activity greater than that of each one of its constituent products used alone at the same dose.
The potentiation effect thus demonstrated renders the use of low doses of each one of the constituent products of the combination possible thereby limiting their possible side effects. Moreover, this combination enables treating pain of very varied origin in a larger number of patients.
Advantageously, the pharmaceutical combination in accordance with the present invention will be in a form suitable for an administration :
- via the oral route, such as simple or coated tablets, capsules or granules, for example;
- via the rectal route, such as suppositories for example
- via the parenteral route, such as injectable preparations for example
- via the ocular route, such as eye lotions or ophthalmic solutions for example; - via the transdermal route
- via the nasal route, such as aerosols and sprays for example; or
- via the auricular route, such as drops for example.
Such a composition can be prepared, according to the methods known per se, by incoφorating the active principle, consisting of the above-mentioned combination, with excipients usually used such as talc, gum arabic, lactose, starch, magnesium stearate, polyvidone, cellulose derivatives, cocoa butter, semisynthetic glycerides, aqueous or non-aqueous vehicles, fats of animal or vegetable origin, glycols, wetting agents, dispersing agents or emulsifiers, silicone gels, certain polymers or co- polymers, preservatives, flavors and coloring agents.
In general, any compound having a cyclooxygenase-2 inhibiting activity can be used within the context of the present invention. Preferably, diaryl methylidene tetrahydrofuran derivatives will be used such as those described in the applications FR 2747123 and FR 2747124 of the Applicant which are incoφorated herein by reference. A particularly preferred compound is (Z)-3-[l-(4-chlorophenyl)-l-(4- methanesulphonylphenyl)methylene]dihydrofuran-2-one known under the code name of UP 454-21.
Dextromethoφhan, ketamine, dizocilpine or even phencyclidine will in particular be cited amongst the NMDA antagonist compounds which can be used within the context of the present invention.
Dextromethoφhan, a non toxic compound which has been known for a long time, will most particularly be preferred.
Advantageously, the pharmaceutical compositions according to the invention will be in the form of a unit dose.
In the pharmaceutical combination in accordance with the present invention, the weight ratio of the cyclooxygenase-2 inhibiting compound to the NMDA antagonist compound will be that which possesses the greater synergy between the two combined compounds, it will be between 0.01 and 10 for the majority of the examples and will be preferably from 0.1 to 3.5.
The daily dose which can be used of the various compounds constituting the pharmaceutical combination in accordance with the present invention will of course depend upon the state of the patient to be treated.
A suitable daily dose of cyclooxygenase-2 inhibitor will generally be between about 50 mg and about 500 mg.
The pharmaceutical compositions in accordance with the present invention are suitable in the treatment of inflammatory phenomena as well as in the treatment of pain.
Their use may be cited for example in the treatment of arthritis, especially rheumatoid arthritis, spondylitis, gouty arthritis, osteoarthritis, juvenile arthritis, autoimmune diseases and lupus erythematosus.
These compositions can also be used within the context of the treatment of bronchial asthma, dysmenorrhea, tendinitis, bursitis, dermatological inflammations such as psoriasis, eczema, burns and dermatitis.
These compositions can also be used within the context of the treatment of gastrointestinal inflammations, Crohn's disease, gastritis and ulcerative colitis, in the prevention of cancer, especially adenocarcinoma of the colon, in the prevention of neurodegenerative diseases, particularly Alzheimer's disease, in the prevention of cerebral ischaemia and epilepsy, and in the prevention of premature labor.
Finally, these compositions can be used within the context of the treatment of pain symptoms, especially in the treatment of myalgia, articular pain or neuralgia, dental pain, heφes zoster and migraine, in the treatment of rheumatic complaints and pain of cancerous origin, and also as complementary treatments for infectious and febrile states.
The invention further covers a method of therapeutic treatment of mammals, characterized in that it consists in administering a therapeutically effective amount to this
mammal of a combination of a cyclooxygenase-2 inhibiting compound and an NMDA antagonist such as described previously.
This method especially enables treating inflammatory phenomena and pain.
Demonstration of the analgesic properties of the pharmaceutical combination in accordance with the invention.
In order to demonstrate the specific analgesic properties of the pharmaceutical combination in accordance with the present invention, several pharmacological tests have been performed whose experimental protocols and results obtained are given below.
In these tests, the compound used as an example of a selective cyclooxygenase-2 inhibitor is the compound known under the code name of UP 454-21 of the following general formula
while the compound used as the NMDA antagonist is dextromethoφhan.
The results obtained for these tests are expressed in percentage inhibition of the pain reaction with respect to a control group.
Test No. 1 : Kaolin arthritis test in the rat
An inflammation is induced by the administration of a 10% aqueous kaolin suspension into the tibio-femoral joint in the rat. The compounds and the combination studied are administered orally 30 minutes after the injection of kaolin.
The spontaneous painful behavior (discomfort in walking) is then quoted 5 and 6 hours after the injection of kaolin.
The results obtained are represented in Figure I which shows the effect of potentiation exerted by dextromethoφhan upon the cyclooxygenase-2 inhibiting compound (UP 454-21).
Test No. 2: Paw pressure test in the carrageenin hyperalgesia model
The inflammation is induced in the rat by plantar administration of a 2% carrageenin solution.
3 hours after this injection, an increasing pressure is exerted upon the animal's paw.
The pain threshold, expressed in grams, is then noted down.
The compounds and the combination studied are administered orally one hour before the paw pressure test.
The results obtained are represented in Figure 2 which shows respectively the effect of potentiation exerted by dextromethoφhan upon the cyclooxygenase-2 inhibiting compound (UP 454-21).
Several examples of pharmaceutical compositions according to the invention will now be given:
EXAMPLES OF UP 454-21/DEXTROMETHORPHAN COMBINATIONS
Example 1 : capsule (size no. 1)
UP 454-21 50 mg
Dextromethoφhan 20 mg
Microcrystallinc cellulose 100 mg
Hydroxypropyl methyl cellulose 10 mg Magnesium stearate 5 mg for a capsule
Example 2: Tablet
UP 454-21 50 mg
Dextromethoφhan 20 mg Microcrystalline cellulose 100 mg
Lactose 100 mg
Hydroxypropyl methyl cellulose 10 mg
Magnesium stearate 5 mg
Hydroxypropyl cellulose 50 mg for a tablet
Example 3 : Suppository
UP 454-21 100 mg
Dextromethoφhan 40 mg
Semi-synthetic glyceride (suppocire) 1900 mg for a suppository
Example 4 : Ophthalmic solution UP 454-21 0.1%
Dextromethoφhan 0.06%
Castor oil (Cremophor EL) 5. %
Polysorbate 80 1%
Water preparation for injections q.s.p. 100 %
Example 5 : Injectable preparation
UP 454-21 0.1%
Dextromethoφhan 0.06% PEG 400 30.%
Ethyl alcohol .' 10.%
Water preparation for injections q.s.p. 100 %