COMPOSITION CONTAINING MEFENAMIC ACID IN ASSOCIATION WITH CODEINE

Abstract: The invention relates to a composition exempt of paracetamol containing fenamic acid derivative in association with codeine. The invention also covers the use thereof in the manufacture of a medicament having central analgesic activity.

Description: COMPOSITION CONTAINING MEFENAMIC ACID IN ASSOCIATION WITH CODEINE The present invention relates to a composition exempt of paracetamol containing fenamic acid derivative in as¬ sociation with codeine, this composition having analgesic activity. Numerous analgesic - or antalgic - medicaments have already been developed. They are generally classified as a function of the pain to be treated. This classifica¬ tion, which originates from the World Health Organization is as follows: level 1 is that of antalgics having peripheral action, such as paracetomol and non-steroidal anti- inflammatory drugs (NSAID) , which are effective for slight to moderate pain; level 2 is that of associations of antalgics having level 1 peripheral action, of the paracetomol type, with weak morphinic drugs such as dextropropoxyphene or codeine, intended for treating moderate to severe pain; level 3 is that of analgesics having central action, strong morphinic drugs intended for treating severe to very severe pain. Associations are already known for obtaining level 2 type medicaments; the association paracetamol/codeine can be given as an example feramic acid derivatives are on. Moreover, fenamic acid derivatives are known and dis¬ closed for example in "The Pharmacological Basis of Therapeutics", 8eme edition, Goodman and Gilman pages 662-663, Pergamon press 1990. Mefenamic acid, which is an analgesic having essentially peripheral activity, but also central activity, is already known. Mefenamic acid is employed for treating slight to moderate pain, being taken in the form of 1 to 3 daily doses of 250 to 500 mg each. A pharmaceutical composition comprising meferamic acid as the sole active ingredient is available under the trade mark PONSTAN from Warner-Lambert. The composition possesses anti-inflammatory, analgesic and anti-pyretic activity and is of value in mitigating the symptoms asso¬ ciated with fever, rheumatic, arthritic and other inflam- matory or painful conditions. Codeine is also known; this is a weak morphinic medicament having central analgesic activity, taken in 20 to 60 mg doses. Codeine is already employed in associa¬ tion, with paracetomol, as stated above. The use of a composition containing a combination of analgesic agents for the treatment of pain caused by ex¬ cessive prostaglandin activity is disclosed from South African patent application no 893274. This application discloses more particularly a tertiary composition con- taining paracetamol, codeine and naproxen or mefenamic acid. Pharmaceutical composition comprising non-steroidal anti-inflammatory drugs in combination with at least one other component selected from an anti-histamine, de- congestant, cough suppressant or expectorant and their use for the relief of cough, cold and cold-like symptoms are disclosed in PCT 85/00596. The sole example given describes a composition comprising ibuprofen and di- phenhydramine . None of the prior art documents discloses or suggests the surprising effects obtained with the binary com¬ position according to the present invention and its use for the manufacture of a medicament having central anal¬ gesic activity. Thus, this invention provides a composition exempt of paracetamol containing: (a) a fenamic acid derivative (b) codeine in a fenamic acid derivative/codeine weight ratio com- prised between 3/1 and 30/1. In a preferred embodiment, the fenamic acid deriva¬ tive is mefenamic acid. In one preferred embodiment, the fenamic acid deriva¬ tive/codeine weight ratio is comprised between 5/1 and 20/1; the ratio being preferably comprised between 8/1 and 12.5/1. The fenamic acid derivative/codeine weight ratio is advantageously about 10/1. In a preferred embodiment, the fenamic acid deriva¬ tive is present in an amount of from 50 to 1000 mg. In a preferred embodiment, the codeine is present in an amount of from 10 to 100 mg. According to a preferred feature, the composition ad¬ ditionally contains pharmaceutically acceptable addi¬ tives . The invention also relates to the present composition used as a medicament, and notably a medicament having central analgesic activity. The invention also relates to the use of the present composition for manufacturing a medicament having central analgesic activity. The invention will now be described in more detail below. As used in the present specification, the expression "fenamic acid derivative" covers fenamic, mefenamic, meclofenamic, flufenamic, tolfenamic and etofenamic acids and should be taken to mean both the acid form as well as pharmaceutically acceptable salts thereof, such as the hydrochloride, etc. All weight data refer to the acid form; all data rae given with respect to mefenamic acid. As used in this present specification, the term "codeine" means both the free base form as well as phar- maceutically acceptable salts, such as the phosphate, camsilate, hydrochloride, hydrobromide, etc. All weight data given are based on the free base form. The present composition, which is the association of an antalgic having peripheral action and an antalgic having central action, exhibits antalgic synergy, in other words a surprising improvement in central activity. This has been shown from pharmacological analgesic tests carried out on the composition. The pharmaceutical composition of the invention may be used to treat inflammation in mammals and produces an enhanced analgesic effect in addition to a good anti-in¬ flammatory and anti-pyretic effect. Compositions according to the invention take the form of a pharmaceutical composition, designed for administra¬ tion in various ways, notably by the oral route. The pharmaceutical composition contains conventional addi¬ tives and is prepared in a way known by the person skilled in the art. For greater clarity, the following description con- cers only the mefenamic acid, but it is clear that any other fenamic acid derivative mentioned-above may be used. The pharmaceutical composition of the invention typi¬ cally comprises a non-toxic pharmaceutical carrier or diluent. The composition can be in the form of tablets, lozenges, capsules (either liquid or dry filled) , dragees, pills, powders and aqueous and non-aqueous solu- tions or suspensions. Some examples of the substances which can serve as non-toxic pharmaceutical carriers or as ingredients of the non-toxic pharmaceutical carriers in the compositions of the invention are gelatin cap¬ sules,- sugars such as lactose and sucrose; starches, such as corn starch and potato starch; cellulose derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, methyl cellulose, cellulose acetate phthalate; gelatin; talc; stearic acid; magnesium stearate; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, and oil of theobroma; propylene glycol; glycerine; sorbitol; polyethylene glycol; ethanol; water; agar; alginic acid; isotonic saline; and phosphate buffer solutions, as well as other non-toxic compatible subs¬ tances used in pharmaceutical formulations. In addition to said active ingredients and a non¬ toxic pharmaceutical carrier, the composition of the in¬ vention can contain colouring agents, flavouring agents and/or preservatives. These materials are used in rela- tively small amounts which do not add materially to the toxicity of the final composition. The relative amounts of the active ingredients in the compositions of the invention may be varied. However, the active ingredients should be present in a concentration sufficient to ensure that a suitable dosage will be ob¬ tained. Typical dosages per day will fall within the range of about 10-30 mg/kg body weight for mefenamic acid and about 0,2-1,5 mg/kg body weight for codeine. The co - positions may be administered orally, however, several various dosage forms may be administered by different routes at about the same time. It is clear that the ac¬ tual dose depends on the individual, his weight and age, seriousness of symptoms etc. Generally speaking, the com- position is taken one or several times, the respective amounts of mefenamic acid and codeine absorbed being, re¬ spectively, 50 to 1000 mg and 10 to 100 mg. For the purposes of oral administration, solid compo¬ sitions such as capsules or tablets and liquid composi- tions such as suspensions, which contain appropriate amounts of said two active ingredients per dosage unit, are preferred. The solid compositions for oral administration can contain from 200 mg-500 mg of mefenamic acid and 8 mg to 25 mg of codeine phosphate per dosage unit. The liquid preparations for oral use are prepared in such a manner that each dosage unit, such as one teaspoon or a given number of millilitres, eg 5 ml, contains between 25 mg to 100 mg mefenamic acid and 1,25 mg to 5 mg codeine phos- phate. The daily dosage of the compositions of the inven¬ tion naturally varies somewhat with the nature and seve¬ rity of the inflammatory condition being treated and the size of the patient. Single or divided doses will ge¬ nerally be administered per day in a unit dosage form, such as capsules or tablets, each dosage containing 250 mg of mefenamic acid and 25 mg of codeine phosphate, or suspensions, each dosage containing 50 mg mefenamic acid and 2,5 mg of codeine phosphate. In preparing the compositions of the invention, con¬ ventional pharmaceutical pratices and precautions are used. Ordinary care should be exercised that non incom¬ patible condition exists between the active ingredients and the carrier, preservative, flavouring agent, colou¬ ring agent or any other constituents in the compositions as well as in the conditions employed in the preparation of the compositions. The invention will now be illustrated, by way of non¬ limiting examples, with reference to the following Exam¬ ples . EXAMPLE 1 Capsules containing mefenamic acid and codeine phos¬ phate. Each capsule contains the ingredients set out be¬ low: INGREDIENT QUANTITY PER CAPSULE Mefenamic acid 200 - 500 mg Codeine phosphate 8 - 25 mg Binders/Di luents 0,1 - 15% by mass Lubricant 0,1 - 2% by mass The ingredients are mixed together by conventional procedures and filled into size 1 or 0 capsules. The capsules are suitable for the treatment of pain associated with inflammation at a dose of one capsule 3 - 4 times a day. EXAMPLE 2 Tablets containing mefenamic acid and codeine phos- phate. Each tablet contains the ingredients set out be¬ low: INGREDIENT QUANTITY PER TABLET Mefenamic acid 200 - 500 mg Codeine phosphate 8 - 25 mg Binders 1 - 10% of core mass Di luents 5 - 30% of core mass Disintegrants 0,5 - 10% of core mass Lubricants 0,1 - 2% of core mass Core mass 225 - 800 mg The tablets are formulated by conventional procedures and can be coated using standard sugar-coating or film¬ coating ingredients. The tablets are suitable for the treatment of pain associated with inflammation at a dose of one tablet 3 - 4 times a day. EXAMPLE 3 A suspension containing mefenamic acid and codeine phosphate. Each 5 ml contains the ingredients set out be¬ low. INGREDIENT QUANTITY PER 5 ml Mefenamic acid 25 - 100 mg Codeine phosphate 1,25 - 5 mg Suspending agents 1 - 5% mass/volume Preservati es 0,1 - 2% mass/volume Sweeteners 0,05 - 25% mass/volume Flavourants 0,05 - 1% mass/volume Colourants 0 - 1% mass/volume Stabi I izing agents 0,05 - 1% mass/volume Water to 100% The suspension is formulated by conventional proce¬ dures . The suspension is suitable for the treatment of pain associated with pyrexia and/or inflammation, at a dose of 2 , 5 ml - 10 ml (dependent on body mass) 3- 4 times a day. Below, the main characteristics of the compositions according to the invention are discussed. ANALGESIC ACTIVITY Mefenamic acid is available commercially; the form employed is the free acid form. Codeine is available com¬ mercially; the form employed is the phosphate form. Two series of experimental trials were conducted to confirm analgesic activity in animals (ED = effective dose) : peripheral analgesic activity was determined by measuring hind motor contractions induced in mice by an algogenic agent consisting of phenylbenzoquinone. Mefenamic acid is able to decrease the number of painful contortion measured in the control; ED50 is 16 mg/kg. central analgesic activity was determined by the hot plate test, in which codeine is particularly active. Mefenamic acid remains weakly effective; its ED50 is 108 mg/kg. After determining the ED50 of mefenamic acid, various compositions according to the invention were tested. The amount of mefenamic acid was fixed at 500 mg while the amount of codeine was varied. Then, the analgesic activity tests were repeated. Table 1 below gives the results, the ED50 doses being ex¬ pressed in mg/kg. TABLE I COMPOSITION PERIPHERAL ANALGESIC CENTRAL ANALGESIC ACTIVITY ACTIVITY (MG/KG) (MG/KG) Mefenamic acid alone 16 108 Codeine alone 10 63 Mefenamic acid + codeine, 22 53 ratio of 10/1.2 Mefenamic acid + codeine, 20 58 ratio of 10/1 From the results given in the table, the ED50 of the composition according to the invention, in a 10/1 ratio, is 20 mg/kg for peripheral analgesia, bearing witness to the absence of synergy as regards mefenamic acid. As against this, for central analgesia, the results are completely surprising. Considering, for example, the composition according to the invention in a 10/1 ratio, the ED50 for central analgesia is 58 mg/kg, which can be compared with the value of 108 mg/kg obtained with mefe¬ namic acid by itself. The synergy obtained is of the or¬ der of 50%; the fact of adding codeine thus makes it pos¬ sible to observe central analgesic activity at doses for which neither mefenamic acid alone, nor codeine alone, has analgesic properties. By way of comparison, a composition of paracetomol and codeine in a weight ratio 10/0.6 was tested. The ED50 for this composition according to the prior art was, for central analgesia, 367 mg/kg, in other words a dose more than 10 times higher than that needed with the com¬ position according to the invention, in a ratio of 10/1. TOXICOLOGY OF THE COMPOSITION ACCORDING TO THE INVENTION Acute and sub-chronic toxicity was measured for the composition according to the invention in a mefenamic acid/codeine ratio of 10/1. The composition was administered orally to 2 rodent species, the rat and the mouse, and acute toxicity was determined (LD = lethal dose) : LD50 in the rat: 896 to 1339 mg/kg; LD50 in the mouse: 600 to 814 mg/kg. Moreover, sub-chronic toxicity was determined by ad- ministering the composition according to the invention to rats over a 4 week period. The composition had a mefe¬ namic acid/codeine ratio of 10/1. Three types of dose were administered to three sets of rats. The low dose was equal to 3 HTD (Human Therapeutic Dose) , the medium dose was 9 HTD and the strong dose was equal to 18 HTD. The HTD is the therapeutic dose proposed for man, in other words 20 to 25 mg/kg/day of mefenamic acid and 2-2.5 mg/kg/day of codeine. No sign of major intolerance appeared in animals treated with the two first doses, and weight changes were comparable to those of the controls. In stronger doses, high toxicity appeared, with mortality from the 6th day. At the end of the trials, and taking account of his¬ tological data, the low dose (70 mg/kg of mefenamic acid and 7 mg/kg codeine) constituted the dose without any toxic effect. Beyond this, at the medium dose, patholo¬ gies can be observed consecutive to loss of renal func¬ tions with reduction of diuresis. All these symptoms are considerably aggravated at the strongest dose and consti- tute the well known dose-dependent aggressiveness of non¬ steroidal anti-inflammatory drugs on the digestive and renal apparatus. Bearing in mind the above results, a clearly suffi¬ cient gradient of safety margin is left for therapeutic use of the compositions according to the invention. BIO-AVAILABILITY The bio-availability of the mefenamic acid and the codeine starting from a capsule form of 250 mg mefenamic acid and 25 mg codeine was compared to those of mefenamic acid alone, and codeine alone. The statistical comparisons carried out showed no significant difference in any of the bio-availability pa¬ rameters studied: areas under the curves for plasma con¬ centration as a function of time (ASC) , maximum plasma concentration (Cmax) , time needed to reach these concen¬ trations (Tmax) , mean residence time (MRT) and elimina- tion half-life (Tl/2) . The relative bio-availability of mefenamic acid, evaluated by the areas under the curves (ASC) was 1.00 +/- 0.027 (see table II) . TABLE II MEFENAMIC ACID T max Cmax ASC MRT h mcg/ml mcg/ml x h h Alone 1.35 4.38 18.57 5.3 + Codeine 1.71 4.96 19.19 4.17 The relative bio-availability for codeine, evaluated by the areas under the curves was 1.18 +/- 0.36 (see table III) . TABLE III CODEINE Tmax Cmax Asc MRT h mcg/ml mcg/ml x h h Alone 1.15 155.08 543.32 4.16 + mefenamic acid 0.98 141.08 481.06 4.00 Thus, in the present compositions, comprising mefe¬ namic acid and codeine, the bio-availability is equiva- lent to the respective bio-availability of each one of the two products administered alone. CLINICAL TRIALS 1- Randomized double-blind cross-over study of cen¬ tral analgesic effects of mefenamic acid and codeine phosphate, alone or in association, compared to those for a placebo, using the flexion nociceptive reflex in healthy volunteer subjects. The test was carried out on healthy volunteers who had received no medication in the 15 days preceding the test. The medicament studied: (mefenamic acid 500 mg, codeine phosphate 50 mg) ; mefe- namic acid 500mg; codeine phosphate 50mg; or placebo (corresponding to a capsule of identical weight but only consisting of pharmaceutically acceptable excipients) was administered orally in a single dose. Analgesic activity was evaluated by monitoring the evolution of the RIII re- flex threshold and the value of the RIII reflex (% varia¬ tion) using statistical analysis of variance for repeated measurements with one factor (treatment) and for repeated measurements using two factors (treatment and time) . Variance analysis showed a time effect in the sense of an increase in the RIII reflex threshold. The extent of increase in the threshold was greater for the present medicament than for the other treatments. The nociceptive reflex evoked by constant supraliminal stimulation pro¬ gressively dropped as a function of time, regardless of the treatment administered. Just like the case of threshold values, the biggest decrease was observed with the present medicament: in 80-90 minutes an inhibition of about 40% of the nociceptive reflex was observed whereas for the other products, decrease of 6% (mefenamic acid) , 23% (codeine) , and 19% (placebo) were encountered. This depressive effect of the present medicament is comparable to that caused by administering 0.1 mg/kg morphine hydrochloride . Regression analysis showed no significant difference between the 4 treatments. The only result suggesting a difference between the treatments related to the slope of the regression line which is significantly different from 0 for the present medicament, whereas it is not for the other 3 treatments tested. 2- Randomised double blind test on 3 parallel groups of ambulatory patients having pain after extraction of an included 3rd lower molar, of antalgic effectiveness and tolerance of single oral doses of the present medicament, of mefenamic acid and of placebo. Additionally, the frequency, nature and intensity of possible side effects were noted. The test was carried out using a randomised double blind monocentric method of 3 parallel groups of pa¬ tients, one group (the present medicament) of 55 pa¬ tients, another group (mefenamic acid) of 55 patients, and a placebo group of 53 patients. The patients studied had undergone local anaesthetic less than 22 hours ear¬ lier for extraction of an included lower third molar ne¬ cessitating gingival incision and bone resection. The medicament studied, consisting of 500 mg mefe¬ namic acid + 50 mg codeine phosphate; 500 mg mefenamic acid; or a placebo was administered orally in a single dose . The intensity of pain, the degree of relief, the use or non-use of supplementary antalgics, the patient's evaluation of pain relief and judgement of tolerance were employed as evaluation criteria. The medicament's effec¬ tiveness was evaluated by descriptive analysis, differ¬ ence variance analysis at different times, multiple com¬ parisons of mean values, and by Chi2 testing of the pa¬ tients' and investigator's evaluations. Tolerance was evaluated by determining the frequency of side effects between the comparative groups using Chi2 testing. Considering the patients as a whole, the activity of the present medicament on pain intensity or pain relief was not significantly different from that of mefenamic acid at the various times, these two products differing significantly from the placebo except for the value of pain intensity at 30 minutes where only the activity of the present medicament differed from that of the placebo. The proportion of patients using a supplementary antalgic was not significantly different in the groups taking the present medicament and mefenamic acid alone, but differed significantly for the placebo group. Tolerance was satis- factory and no difference in the incidence of side ef¬ fects between the treatment groups came to light. 3- Randomized double blind study of 3 parallel groups of hospitalized patients experiencing pain consecutive to an episiotomy, for antalgic effectiveness and tolerance of single oral doses of the present medicament, of mefe¬ namic acid alone and placebo. Additionally, frequency, nature and intensity of pos¬ sible side effects were compared. The effects of the medicaments were studied on three groups of patients: 55 patients (present medicament) , 48 patients (mefenamic acid) , and 53 patients (placebo) having just given birth and having received medio-lateral episiotomy less than 24 h previously, hospitalized with moderate to sever pain. Posology, evaluation criteria and methods of statis¬ tically analysing the results were as described under item 2) above. Of 156 patients studied, 6 were excluded from analy¬ sis of effectiveness through taking an antalgic before the 2nd hour. Considering the complete set of patients, the activ¬ ity of the present medicament on pain intensity or pain relief was not significantly different from that for mefenamic acid alone at the various times, these two products differing significantly from the placebo except for the value of pain intensity at 30 min and 1 h, where only the activity of the present medicament was different from that of the placebo. The proportion of patients using a supplementary antalgic was not significantly different in the present medicament and mefenamic acid alone groups, but differed significantly from the placebo group. If only patients presenting intense pain are considered, the time needed to obtain significant or complete relief, and the time needed to obtain complete relief differ significantly between the groups, with an advantage to the present medicament . Tolerance was overall satisfactory and no difference in the incidence of undesirable side effects between the treatment groups came to light. 4- Randomized double blind study on 3 parallel groups of hospitalized patients experiencing post-operative pain after cesarean section or hemorroidectomy, of antalgic effectiveness and tolerance for single oral doses of the present medicament, of mefenamic acid, and of placebo. The frequency, nature and intensity of possible unde¬ sirable side effects were also compared. The effects of the medicaments were studied on three groups of patients: 46 patients (present medicament) , 49 patients (mefenamic acid) and 51 patients (placebo) having undergone cesarean section or hemorroidectomy less than 24 h previously and hospitalized with moderate to sever pain. Posology, evaluation criteria and methods for statis¬ tical analysis of the results were as described under item 2) above. Of the 146 patients studied, 11 were excluded from analysis of effectiveness, 10 for having taken an antalgic before the 2nd hour and one through vomiting after taking treatment. Considering the patients overall, the activity of the three products on intensity of pain did not significantly differ except for the sum of the differences in the value of pain intensity, regardless of the period, where only the activity of the present medicament differed from that of the placebo. For pain relief alone, the activity of the present medicament differed from that of the placebo for the period HO to H2. For the period HO to H6 , the activity of the present medicament and of the mefenamic acid differed significantly from that of the placebo. The proportion of patients having used a supplementary antalgic did not significantly differ from one group to the other. The time needed to obtain significant or com¬ plete relief differed significantly between groups. Tolerance was satisfactory overall and no difference in the incidence of undesirable side effects between the treatment groups came to light. 5- Randomized double blind study on 2 groups of pa¬ tients hospitalized having sever pain after stomato¬ logical or maxillo-facial surgery, for antalgic effec- tiveness and tolerance of the present medicament versus paracetamol/codeine, for repeated doses. The antalgic activity and tolerance of the present medicament were compared with those of a paraceta¬ mol/codeine association. The test employed randomized double blind monocentric analysis on two parallel groups of patients : 43 patients (present medicament) and 44 patients (paracetamol/ codeine) . The hospitalized patients studied had under¬ gone, less than 24h previously and under general ana- esthetic, surgery for dental inclusion or cancerologic or post-traumatic intervention and experiencing sever acute pain on the day following surgery. The medicament studied (500 mg mefenamic acid + 50 mg codeine phosphate; 1000 mg paracetamol + 60 mg codeine phosphate) was administered 3 times per day for 3 days by oral route. Analgesic activity and tolerance were eva¬ luated by pain intensity, use or non-use of a supplemen¬ tary antalgic, occurrence of undesirable side effects, patient appreciation of pain relief and overall judgement of tolerance. Descriptive analysis was carried out on the demographic and surgical data and for the treatments em¬ ployed together with comparison of these data before treatment, to check homogeneity of the two groups of pa¬ tients. The principle criteria was expressed in a fre- quency table per randomization group. A Chi2 test was ap¬ plied (or exact Fischer test if conditionε justified it) . Supplementary analysis after success-failure regrouping . 16 was carried out . Secondary criteria were evaluated by Chi2 testing. In this study, the association mefenamic acid plus codeine phosphate (present medicament) showed higher an- talgic effectiveness than that of a paracetamol/codeine phosphate association, by the percentage of patients having a mean value for pain intensity less than 50% of base value, and by the percentage of full or partial suc¬ cesses. The two products were comparable as regards all the other parameters studied. Biological and clinical tolerance of the present medicament was satisfactory overall. Tolerance was judged to be satisfactory by 95.3% of patients treated by the present medicament and 93.2% of the patients treated with paracetamol/codeine. 11.6% of the patients receiving the present medicament and 18.2% of those receiving the paracetamol-codeine association reported undesirable clinical side effects. No significant difference was found. 6- Randomized double blind study on 2 groups of pa¬ tients hospitalized and presenting sever pain after gynaecological surgery, for antalgic effectiveness and tolerance of the present medicament compared with para¬ cetamol/dextropropoxyphene, at repeated doses. The antalgic activity and tolerance of the present medicament were compared with those of a paraceta- mol/dextropropoxyphene association. The test was carried out using a randomized double blind bicentric analysis method on two parallel groups of patients: 52 patients (present medicament) and 52 pa¬ tients (paracetamol/dextropropoxyphene) . The hospitalized patients studied had, within the previous 24h, undergone surgery under general anaesthetic for dental inclusion or gynaecological, pelvic cancerological or breast surgery, and were experiencing sever acute pain on the day following surgery. The medicament studied (500mg mefenamic acid + 50mg codeine phosphate; or 800mg paracetomol + 60mg dextro- propoxyphene) was administered 3 times per day for 3 days, by oral route. Analgesic activity and tolerance were studied on the basis of pain intensity, the use or non-use of a supplementary antalgic, occurrence of unde- sirable clinical side effects, the patient's appreciation of pain relief and the overall judgement of tolerance. Descriptive analysis was carried out on the demographic and surgical data and for the treatments employed together with comparison of these data before treatment, to check homogeneity of the two groups of patients. The principle criteria was expressed in a frequency table per randomization group. A Chi2 test was applied (or exact Fischer test if conditions justified it) . Supplementary analysis after success-failure regrouping was carried out. Secondary criteria were evaluated by Chi2 testing. In this study, the mefenamic acid/codeine phosphate association (present medicament) showed higher antalgic effectiveness than that of the paracetamol/dextro- propoxyphene association for the mean of pain intensi- ties. The two products did not differ statistically for the reminder of the parameters studied, but the results were overall favourable to the present medicament. Biological and clinical tolerance of the present medicament was satisfactory overall. Tolerance was judged satisfactory by 86.5% of patients treated with the pre¬ sent medicament and 82.7 of the patients treated with paracetamol-dextropropoxyphene. 26.9% of the patients re¬ ceiving the present medicament and 23.1 of those re¬ ceiving the paracetamol-dextropropoxyphene association reported undesirable clinical side effects. No signifi¬ cant difference was found. 7- Randomized double blind study of 2 groups of hos¬ pitalized patients having sever pain after orthopedic or traumatologic surgery, for antalgic effectiveness and tolerance of the present medicament compared to paraceta¬ mol/codeine, at repeated doses. The antalgic activity and tolerance of the present medicament were compared with those of a paraceta¬ mol/codeine association. The test was carried out using a randomized mono- centric double blind analysis method on two parallel groups of hospitalized patients: 44 patients (present medicament) and 46 patients (paracetamol/codeine)) having undergone, within the previous 24h and under general anaesthetic, orthopedic or traumatological surgery and experiencing sever acute pain on the day following surgery. The medicament studied (500mg mefenamic acid + 50mg codeine phosphate; or lOOOmg paracetomol + codeine 60mg) was administered 3 times a day for 3 days by oral route. Analgesic activity and tolerance were evaluated on the basis of intensity of pain, use or non-use of supplemen¬ tary antalgic, occurrence of undesirable clinical side effects, patient's appreciation of pain relief and over¬ all judgement of tolerance. Descriptive analysis was car- ried out on the demographic and surgical data and for the treatments employed together with comparison of these data before treatment, to check homogeneity of the two groups of patients. The principle criteria was expressed in a frequency table per randomization group. A Chi2 test was applied (or exact Fischer test if conditions justi¬ fied it) . Supplementary analysis after success-failure regrouping was carried out . Secondary criteria were eva¬ luated by Chi2 testing. In this study the mefenamic acid/codeine phosphate association (present medicament) showed higher antalgic effectiveness than that of the paracetamol/codeine phos¬ phate association for the mean of pain intensities, for evaluation of pain intensity on the analog visual scale, for the number of patients having complete disappearance, or significants or complete disappearance of pain and for the time needed for significant or complete pain relief to occur in patients, and for patient evaluation of pain relief at the end of the study. Biological and clinical tolerance of the present medicament was satisfactory overall. Tolerance was judged satisfactory by 97.7% of patients treated by the present medicament and 100.0% of the patients treated with para¬ cetamol/codeine phosphate. 18.2% of patients receiving the present medicament and 10.9% of those receiving the paracetamol/codeine phosphate association reported unde¬ sirable clinical side effects. No significant difference was found.

Claims: CLAIMS 1.- A composition exempt of paracetamol containing (a) fenamic acid derivative (b) codeine in a fenamic acid derivative/codeine weight ratio com¬ prised between 3/1 and 30/1. 2. - The composition according to claim 1 in which the fenamic acid derivative is mefenamic acid. 3. - The composition according to claim 1 or 2 in which the fenamic acid derivative/codeine weight ratio is comprised between 5/1 and 20/1. 4. - The composition according to claim 3 in which the fenamic acid derivative/codeine weight ratio is comprised between 8/1 and 12.5/1. 5. - The composition according to claim 4 in which the fenamic acid derivative/codeine weight ratio is about 10/1. 6. - The composition according to any one of claims 1 to 5, in which the fenamic acid derivative is present in an amount of from 50 to 1000 mg. 7.- The composition according to any one of claims 1 to 6 , in which the codeine is present in an amount of from 10 to 100 mg. 8. - The composition according to any one of claims 1 to 7, additionally containing pharmaceutically acceptable additives . 9.- The composition according to any one of claim 1 to 8 , for use as a medicament . 10.- The composition according to claim 9, for use as a medicament having a central analgesic activity. 11.- The use of the composition according to any one of claims 1 to 8, for the manufacture of a medicament having central analgesic activity.

Inventors: COURTEILLE FREDERIC, LARGIER TIMOTHY WALTER, NOUALHAC HENRI, COURTEILLE, FREDERIC, LARGIER, TIMOTHY, WALTER, NOUALHAC, HENRI
Applicants: COURTEILLE FREDERIC, LARGIER TIMOTHY WALTER, NOUALHAC HENRI, PARKE DAVIS, COURTEILLE, FREDERIC, LARGIER, TIMOTHY, WALTER, NOUALHAC, HENRI
Application year: 1996
Main classification: A61K31
IPC codes: A61K31