GB2117238A - Morniflumate pharmaceutical compositions having antiinflammatory, analgesic, antipyretic and gastroprotective activity - Google Patents

Abstract

Morniflumate having formula (I), <IMAGE> can be used for oral administration as antiinflammatory, analgesic and antipyretic agent, particularly in combination with other non steroidal antiinflammatory agents such as aspirin, indomethacine, niflumic acid, sodium diclofenac and ketoprofen. It also possesses gastroprotective properties.

Description

SPECIFICATION Pharmaceutical compositions having antiinflammatory, analgesic, antipyretic and gastroprotective activity The present invention refers to new pharmaceutical formulations containing morniflumate, i.e.

beta-morpholinoethyl ester of niflumic acid, having formula I

Both niflumic acid and morniflumate are known compounds, used in therapy as antiinflammatory, analgesic and antipyretic agents, but they are used by different administration routes: the former exclusively by oral or topical route, morniflumate exclusively by rectal route. It has now been found that morniflumate can be advantageously used by the oral route, in the form of capsules, tablets or similar compositions. By this administration route, in fact, the product turns out to be well adsorbed and rapidly distributed in the organism, substantially maintaining the pharmacological properties of the acidic parent compound, without producing its side effects.In fact, morniflumate is completely devoid of ulcerogenic effects at gastric level and exhibits an intestinal lesivity and an acute toxicity remarkably lower than niflumic acid.

It has also surprisingly been found that morniflumate exerts a gastroprotective activity, because it counteracts the effects of other ulcerogenic or gastrolesive agents.

According to the present invention there are provided pharmaceutical formulations endowed with antiinflammatory and gastroprotective activity comprising moniflumate or one of its pharmaceutically acceptable salts in combination with at least one other non steroidal antiinflammatory agent.

It is known that the damage to the gastro-intestinal mucosa constitutes the most important problem connected with the use of non steroidal antiinflammatory drugs. Morniflumate, in the oral formulations, because of its unforeseeable properties, is an antiinflammatory agent endowed with quite particular characteristics because it releases in the organism the active principle responsible for the antiinflammatory activity exerting contemporaneously a protective action on the potential gastrolesivity of its own precursor, proving therefore to be an effective and safe drug.

The tests carried out to point out the absorption and activity characteristics of morniflumate when administered by the oral route, using niflumic acid as reference compound, as well as the protective effect from gastrolesive agents, exerted by morniflumate, are hereinunder reported.

Bioavailability and pharmacokinetics in the rat.

Male rats weighing 250-300 g, fasted for 1 8 hours but with water ad libitum, have been used.

The oral administration of niflumic acid or of morniflumate has been carried out by gastric tube using 5% maize starch suspensions (10 ml/kg); the compounds have been administered at the equimolar dose of 253 ssmol/kg.

The detection of the compounds under examination has been performed by high performance liquid chromatography (HPLC). The results obtained are represented in the figure's diagrams reporting in ordinate the plasma levels (expressed in 4g/mí) respectively of niflumic acid ( ) and of morniflumate (--------) as such, plotted against time (expressed in hours), following the oral administration of niflumic acid (left diagram) and of morniflumate (right diagram).

The oral administration of niflumic acid produces plasma levels with a peak of 1 77 Mg/ml at the 3rd hour and with a disappearance half-life of about 5 hours.

The oral administration of morniflumate produces plasma levels of niflumic acid with a peak of 50 yg/ml at the first hour and a half-life of 5 hours, as well as very low and rapidly decreasing plasma levels of morniflumate.

These results and the analogies noticed with plasma a half-life values found after intravenous morniflumate administration, as well as the fast appearing of niflumic acid in the plasma after intravenous morniflumate administration, lead one to believe that the ester is adsorbed as such from the gastrointestinal tract and is then rapidly hydrolysed in the plasma to the biologically active niflumic acid.

On the other hand, the fact that morniflumate after oral administration substantially keeps the pharmacological activity of niflumic acid, in spite of the differences of plasma levels in free acid, leads one to suppose that the amount of unchanged ester initially present ir the plasma reaches more rapidly the extraplasmatic spaces thanks to its higher lipophilia and then the inflammation sites.

'Antiinilammatory activity in the carrageenin edema test Male Charles River CD(SD) rats, weighing 140-1 80 g, housed in normal conditions, fasted for 1 8 hours and with free access to water, have been used.

The activity of the compounds under examination, administered by the oral route at different doses by means of a gastric tube, in the form of a suspension in 5% maize starch and in a constant volume of 20 ml/kg, has been assessed by measuring the protection against the development of the edema induced in the rat's paw by injecting (after one hour from the administration of the active principle) 0.1 ml of 1% carrageenin in physiological saline in the subplantar aponeurosis of the right hind paw, according to the method of Winter (Winter C.A. et al., Proc. Soc. Exp. Biol. Med. 111, 544, 1962).

The controls were treated only with the vehicle. The volume of the treated paw has been measured by means of a water-mercury pletismograph according to Lence (Lence P., Arch. Int. Pharmacodyn. 16, 237, 1 967) just before and at different times after the phlogogenic agent injection. The ED50 values, determined for the areas under the curve expressing the paw volume plotted against time, are shown in Table I.

TABLE I

Activity determined from the areas under the curve (paw's volume-time): ED50 P.R.

Compound jumoilkg (potency ratio) Morniflumate 303 0.79 (676-136) Niflumic acid 239 1 (475-i21) Antiinflammatory activity in the U.V. induced erythema test.

Male guinea-pigs fasted for 1 8 hours but with free access to water, weighing 340 400 g, previously subjected to depilation on one side and then to ultraviolet irradiation using a 500 w U.V.

source, water screened and water cooled, manufactured on Kromayer's principle by Helios Italquartz (Milan), have been used.

The drugs were administered as suspension by gastric tube one hour before exposure to U.V., while giving to the controls only an equal volume of vehicle (5% maize starch, 5 ml/kg). The intensity of erythema was scored one hour after U.V. exposure by an observer unaware of the treatment, according to the non-parametric scoring scale of Awouters et al. (Arzneim. Forsch. 25, 1509, 1975).

The animals whose erythema rated less than 1 were considered "protected"; from the incidences thus obtained the ED > o values were calculated by the method of Litchfield and Wilcoxon (J. Pharmacol.

Exp. Ther. 96, 99, 1949) (see Table II).

TABLE II

ED50 P.R.

Compound (pmol/kg) (potency ratio) Morniflumate 51 0.93 (109-24) Niflumic acid 55 1 (91-33) Analgesic activity in the "writhing" test by phenylquinone.

Male mice, weighing 1 9-22 g, housed in normal conditions, fasted for 1 8 hours with free access to water, have been used.

The activity of the compounds under examination, administered by oral route at different doses, by means of a gastric tube, suspended in 5% maize starch and in a constant volume of 10 ml/kg, has been evaluated by measuring the protection against a typical syndrone (writhing) induced by endoperitoneal injection of a 0.1 mIll 0 g body weight phenylquinone aqueous solution (0.02% in 5% ethanol) according to a modified experimental model (Arzneim. Forsch. 31 (1), 87, 1981) in comparison with the one reported by Siegmund (J. Pharmacol. Exp. Ther. 119, 184, 1957). The controls were treated only with the vehicle. The EDso values determined from the dose-response curve are reported in Table Ill.

TABLE Ill

ED50 P.R.

Compound /,umof/kg) (potency ratio) Morniflumate 118 1.05 (190--73) Niflumic acid 124 1 (156-99) Antipyretic acitivity Male rats weighing 130-140 g, fasted for 1 8 hours but with free access to water, have been used.

Fever was induced by subcutaneous injection, of 10 ml/kg of a 15% suspension of brewer's yeast in 1% arabic gum into the skin of the back.

The drugs under study were given, 4 hours after the pyrogen, by gastric tube as a suspension in 5% maize starch in the amount of 10 ml/kg; the controls received the vehicle only. The increases of the rectal temperature from the baseline value were measured at different times from administration by means of an Ellab multichannel electric thermometer. A significant (T-test) reduction of the temperature rise versus the controls was considered evidence of an antipyretic effect. The EDso values (shown in Table IV) were graphically interpolated on the ground of the percent inhibitions in comparison with the controls observed one hour after drug administration.

TABLE IV

ED50 P.R.

Compounds (,umol/kg) {potency ratio) Morniflumate 67 0.73 (157-29) Niflumic acid 49 1 (117-20) Gastrolesive activity Male rats weighing 220-320 g housed in standard conditions and fasted for 24 hours before the test and with free access to water, have been used. The drugs were given by gastric tube, suspended in 5% maize starch, in a constant volume of 10 ml/kg; the controls received the vehicle only. 5 hours after drug administration the rats were sacrificed. The stomach was slit along the lesser curvature, washed under running water and examined by the naked eye, by an observer unaware of the treatment, for ulcers in the glandular part of the mucosa.

The following were recorded: (a) the sum of the maximum diameters of all the ulcerated spots; (b) the number of ulcerated spots.

The UDso (reported in Table V) was calculated by the method of Litchfield and Wilcoxon (J.

Pharmacol. Exp. Ther. 96, 99, 1949) with the "all or none" criterion, all animals with gastric lesions whose sum was 2 mm or more being rated as "ulcerated".

TABLE V

Compound UD50 (,umoí/kg) Morniflumate inactive Niflumic acid 117 (184--71) Intestinal perforating effect The test has been carried out in male rats weighing 250-300 g, normally fed, because the damages of the bowel are more marked in fed animals.

The drugs were given daily in a 5% maize suspension, constant volume 10 ml/kg, for 12 consecutive days, the controls receiving the equivalent volume of vehicle. Animals dying in the course of the treatments and surviving animals were necropsied, and when perforated intestinal ulcers or exudative peritonitis was observed the test was rated positive.

The daily dose inducing intestinal perforations in 50% of the animals (PDso) was calculated by the method of Litchfield and Wilcoxon from the number of deaths during the 12 days of treatment.

The results are reported in the Table VI.

TABLE Vi

- - Compound ( mol/kg/die) P.R.

Morniflumate 970 0.19 (1248-755) Niflumic acid 184 1 (212-163) Acute toxicity The toxicity after single administration has been determined by oral route in two animal species, fasted with water ad libitum 18 hours before the experiment.

--Male mice, weighing 26-31 g and female, weighing 20-25 g; male rats, weighing 155-190 g and female, weighing 140-1 65 g.

There were obtained the results shown in the Table VII expressed as LD50 values, calculated according to the method of Litchfield-Wilcoxon: TABLE VII

Animal Animal LD50 P.R.

Compound species Sex (mmol/kg) male 9.96 0.10 (12.46-7.96) rat female 11.46 (14.89-8.82) Morniflumate ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ --- --- male 11.23 0.12 (18.10-6.96) mouse female 12.50 (19.63-7.96) rat male 0.99 (1.20--0.82) Niflumic acid ------------------------- mouse male 1.33 (1.60-1.10) The above described results show therefore that morniflumate (I) in formulations for oral administration is an effective and safe compound endowed with antiinflammatory, analgesic and antipyretic activity, unforeseeably quite devoid of ulcerogenic activity even at very high doses.

Even more surprisingly, it has been shown that morniflumate is not only devoid of ulcerogenic effects, but it counteracts significantly the gastrolesive effects induced by other agents, in some models of experimental modeis, as pointed out from the experiments summarised hereinbelow.

Cytoprotective activity on the gastric necrosis by ethanol.

The study of this activity has been carried out using an experimental model described by Derelanko M.J. and Long J.F. (Proc. Soc. Exp. Biol. Med. 166, 394, 1981). Morniflumate was given at different doses by oral route to male Charles River CD(SD) rats fasted for 1 8 hours, in 5% maize starch suspension, in constant volume of 2.5 ml/kg.

After 20 minutes the animals were treated by gastric tube with 1 ml of absolute ethanol. 60 minutes after administration the animals were sacrificed, the stomachs were removed and slit along the lesser curvature and microscopically examined for necrotic lesions in the glandular part of the gastric mucosa, according to a 9 scores (0--8) conventional scale.

A control group of animals was treated with the vehicle only and with the lesive agent in the same conditions. The statistical difference of the values between treated animals and controls has been evaluated by the "U" test of Mann and Whitney.

The ED50 value for morniflumate, calculated from the percent inhibitions versus respective controls, turned out to be 12 mg/kg (28 ymol/kg).

Antiulcer activity on lesions induced by non-steroidal antiinflammatory drugs.

The test has been carried out on male Charles River CD(SD) rats, weighing 200-270 g, fasted for 1 8 hours. The damaging agent (niflumic acid 100 mg/kg; acetylsalicylic acid 1 50 mg/kg; indomethacin 20 mg/kg; sodium diclofenac 50 mg/kg; ketoprofen 30 mg/kg) and morniflumate having been contemporaneously administered by oral route, in a 5% maize starch suspension, in the constant volume of 10 ml/kg. After respectively 2 hours from acetylsalicylic acid treatment and 5 hours for the other lesive agents mentioned above (intervals constituting the peak of the ulcerogenic activity of the used agents), the animals have been sacrificed and the stomach withdrawn and examined for ulcers according to the above described criteria. A control group in each test has been treated with the vehicle only.

The ED50 values, determined from the percent inhibitions in comparison with respective controls, turned out to be the followings: ED50 morniflumate Lesive agent mg/kg FLmollkg Acetylsalicylic acid 36 83 Indomethacine 74 171 Niflumicacd 199 461 Sodium diclofenac 98 227 In comparison with ketoprofen, morniflumate exhibited a significant gastroprotective activity at the dose of 100 mg/kg.

On the ground of these results, morniflumate showed to exert a gastroprotective activity on different experimental modeis of induced ulcer.

Such an activity has been also confirmed after administration of the compound by the parenteral route.

The administration of morniflumate in combination with other non steroid antiinflammatory drugs (NSAID's) proves to be particularly advantageous because morniflumate, besides exerting a gastroprotective effect in respect of the above cited compounds, does not modify their antiinflammatory activity, which is on the contrary in some instances significantly enhanced as can be seen from the data expressed in Table VIII below. This sets out the results obtained from the carrageenin edema test in rats using the method of Winter as described above. These results are expressed as percent inhibition of increase in the area under the curve obtained by plotting paw volume against time using non-steroidal antiinflammatory drugs alone and in combination with morniflumate.

TABLE VIII

Dose of Respective Doses NSAID Inhibition NSAID + Morniflumate Inhibition NSAID (mg/kg) % (mg/kg) Acetylsalicyclic acid 50 11 50 + 75 38 Indomethacine 5 16 5 + 25 19 Niflumic acid 20 21 20 + 20 33 Sodium diclofenac 2 16 2 + 4 15 Ketoprofen 5 39 5 + 16.7 37 The present invention relates also to all the industrially applicable aspects connected with the oral use of morniflumate -- as such or in form of addition salts with pharmaceutically acceptable acids - as an antiinflammatory, analgesic and antipyretic agent. The invention therefore provides orally administrable pharmaceutical formulations, containing predetermined and therapeutically effective amounts of morniflumate or its salts, in the form of capsules, tablets, sachets or similar formulations, mixed with suitable excipients chosen between the ones commonly used for this kind of composition.

The composition of a tablet of the unitary weight of 0.6 g, dosed at 0.5 g of active principle, is reported by way of example, without limiting in any way the scope of the invention: morniflumate HCI 0.5 g polyvinylpyrroldone 0.015 g Avicel 0.078 g Magnesium stearate 0.007 g.

Because of its gastroprotective action, morniflumate can be moreover advantageously used in pharmaceutical compositions for oral administration, in combination with other non stereoidal antiinflammatory drugs, such as indomethacine, niflumic acid, salicylates, ketoprofen, sodium diclofenac, and the like, of which it counteracts the ulcerogenic effects. In these formulations the weight ratio of the active principles may vary from about 30:1 to about 1:30 according to the specific activity of each compound. Such formulations may take the form of capsules, tablets, sachets, or similar orally administrable formulations, wherein the active principles may be mixed with suitable excipients chosen from amongst those conventionally used for such types of formulation. Typically such formulations contain from about 0.2 to about 0.8 g of the mixture of active principles.

The composition of some pharmaceutical formulations, suitable for oral administration, such as tablets and sachets, are described hereunder by way of example.

1. Formulations containing morniflumate and indomethacine.

Preferably such formulations contain morniflumate and indomethacine in a weight ratio of from about 10:1 to about 5:1. A typical formulation of a tablet of unitary weight 0.5 g, wherein the active principles are present in the weight ratio 6.66:1, is the following: Morniflumate HCI 0.2 g Indomethacine 0.03 g Avicel 0.078 g Lactose 0.172 9 Polyvinylpyrrolidone 0.01 5 g Magnesium stearate 0.005 g.

2. Formulations containing morniflumate in combination with sodium diclofenac.

Preferably such formulations contain morniflumate and sodium diclofenac in a weight ratio of from about 5:1 to about 2:1. A typical formulation of a tablet of unitary weight 0.5 g, wherein the active principles are present in a weight ratio of 4:1 is the following: Morniflumate 0.2 g Sodium diclofenac 0.05 g Polyvinylpyrrolidone 0.01 5 g Avicel 0.05 g Encompress 0.180 g Magnesium stearate 0.005 g.

3. Formulations containing morniflumate in combination with niflumic acid.

Preferably such formulations contain morniflumate and niflumic acid in a weight ratio of from about 2:1 to about 1:2. A typical formulation of a tablet of unitary weight 0.6 g, wherein the active principles are present in a weight ratio of 1:1 is the following:- Morniflumate HCI 0.250 g Niflumic acid 0.250 g Polyvinylpyrrolidone 0.015 g Avicel 0.078 g Magnesium stearate 0.007 g 4. Formulations containing morniflumate in combination with acetylsalicylic acid.

Preferably such formulations contain morniflumate and acetylsalicylic acid in a weight ratio of from about 0.5:1 to about 1:1.

(a) A typical formulation for a sachet of unitary weight 5 g, wherein the active principles are present in a weight ratio of 0.5:1 is the following.

Morniflumate HCI 0.250 g Acetylsalicylic acid 0.5 g Saccharose 2.225 g Saccharin 0.010g Orange flavour 2g Aerosil 0.005 g Citric acid 0.010g (b) A typical formulation for an effervescent tablet of unitary weight 4 g, wherein the active principles are present in a weight ratio of 0.5:1 is the following Morniflumate HCI 0.250 g Acetylsalicylic acid 0.5 g Granular anhydrous citric acid 1.325 g Granular sodium bicarbonate 1.7 g Sodium bicarbonate powder 0.175 g Natural flavours 0.05 g

Claims (12)

1. Pharmaceutical formulations endowed with antiinflammatory and gastroprotective activity, comprising morniflumate having formula I:

or one of its pharmaceutically acceptable salts, in combination with at least one other non steroidal antiinflammatory agent.

2. Pharmaceutical formulations according to claim 1, in which morniflumate and said at least one other non steroidal anfiinflammatory agent are present in a weight ratio of from about 30:1 to about 1:30.

3. Pharmaceutical formulations according to claim 1 or claim 2, in the form of capsules, tablets, sachets or similar formulations containing from about 0.2 to about 0.8 g of the mixture of morniflumate and said at least one other non steroidal antiinflammatory agent per dose unit.

4. Pharmaceutical formulations according to any one of claims 1 to 3, in which said at least one other non steroidal antiinflammatory agent is selected from acetylsalicylic acid, indomethacine, niflumic acid, sodium diclofenac, and ketoprofen.

5. Pharmaceutical formulations according to any one of claims 1 to 4, containing morniflumate and indomethacine in a weight ratio of from about 10:1 to about 5:1.

6. Pharmaceutical formulations according to any one of claims 1 to 4, containing morniflumate and sodium diclofenac in a weight ratio of from about 5:1 to about 2:1.

7. Pharmaceutical formulations according to any one of claims 1 to 4, containing morniflumate and niflumic acid in a weight ratio of from about 2:1 to about 1:2.

8. Pharmaceutical formulations according to any one of claims 1 to 4, containing morniflumate and acetylsalicylic acid in a weight ratio of from about 0.5:1 to about 1:1.

9. Pharmaceutical formulations according to claim 1 substantially as herein described and exemplified.

10. Orally administrable pharmaceutical formulations endowed with antiinflammatory, analgesic, antipyretic and gastroprotective activity, containing as the active principle morniflumate having formula

or one of its pharmaceutically acceptable salts.

11. Pharmaceutical formulations according to claim 10, in the form of capsules, tablets or similar formulations containing from 0.3 to 0.8 g of active principle per dose unit.

12. Pharmaceutical formulations according to claim 1 substantially as herein described and exemplified.

1 3. Each and every novel feature, and combination of features, herein described and their obvious equivalents.