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WO1997006801A1 - Composition contenant de l'acide mefenamique en association avec de la codeine - Google Patents

Composition contenant de l'acide mefenamique en association avec de la codeine Download PDF

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Publication number
WO1997006801A1
WO1997006801A1 PCT/EP1996/003592 EP9603592W WO9706801A1 WO 1997006801 A1 WO1997006801 A1 WO 1997006801A1 EP 9603592 W EP9603592 W EP 9603592W WO 9706801 A1 WO9706801 A1 WO 9706801A1
Authority
WO
WIPO (PCT)
Prior art keywords
codeine
mefenamic acid
medicament
patients
pain
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/EP1996/003592
Other languages
English (en)
Inventor
Henri Noualhac
Frédéric Courteille
Timothy Walter Largier
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Parke Davis and Co
Original Assignee
Parke Davis and Co
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from FR9513613A external-priority patent/FR2741264B1/fr
Application filed by Parke Davis and Co filed Critical Parke Davis and Co
Priority to EP96928463A priority Critical patent/EP0863758A1/fr
Priority to BR9609937-2A priority patent/BR9609937A/pt
Priority to AU68214/96A priority patent/AU6821496A/en
Publication of WO1997006801A1 publication Critical patent/WO1997006801A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine

Definitions

  • the present invention relates to a composition exempt of paracetamol containing fenamic acid derivative in as ⁇ sociation with codeine, this composition having analgesic activity.
  • 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.
  • NSAID non-steroidal anti- inflammatory drugs
  • 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.
  • compositions 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.
  • this invention provides a composition exempt of paracetamol containing:
  • the fenamic acid deriva ⁇ tive is mefenamic acid.
  • 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.
  • the fenamic acid deriva ⁇ tive is present in an amount of from 50 to 1000 mg.
  • the codeine is present in an amount of from 10 to 100 mg.
  • 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 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 are used 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 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.
  • 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.
  • a suspension containing mefenamic acid and codeine phosphate contains the ingredients set out be ⁇ low.
  • 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
  • ANALGESIC ACTIVITY Mefenamic acid is available commercially; the form employed is the free acid form. Codeine is available com ⁇ flashally; the form employed is the phosphate form.
  • 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
  • central analgesic activity was determined by the hot plate test, in which codeine is particularly active.
  • Mefenamic acid remains weakly effective; its ED50 is
  • 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.
  • the results are completely surprising.
  • 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.
  • Acute and sub-chronic toxicity was measured for the composition according to the invention in a mefenamic acid/codeine ratio of 10/1.
  • LD50 in the rat 896 to 1339 mg/kg
  • LD50 in the mouse 600 to 814 mg/kg.
  • 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 low dose was equal to 3 HTD (Human Therapeutic Dose)
  • the medium dose was 9 HTD
  • the strong dose was equal to 18 HTD.
  • 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.
  • the low dose 70 mg/kg of mefenamic acid and 7 mg/kg codeine
  • the low dose 70 mg/kg of mefenamic acid and 7 mg/kg codeine
  • 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.
  • 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 relative bio-availability of mefenamic acid, evaluated by the areas under the curves (ASC) was 1.00 +/- 0.027 (see table II) .
  • 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.
  • 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.
  • 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 .
  • 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.
  • 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.
  • 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 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.
  • the activity of the present medicament differed from that of the placebo for the period HO to H2.
  • 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.
  • 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 condition ⁇ justified it) . Supplementary analysis after success-failure regrouping .
  • association mefenamic acid plus codeine phosphate 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 ⁇ Founds.
  • the two products were comparable as regards all the other parameters studied.
  • 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.
  • 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.
  • 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.
  • 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.

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  • Health & Medical Sciences (AREA)
  • Emergency Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne une composition exempte de paracétamol contenant un dérivé de l'acide fénamique en association avec de la codéine. L'invention traite également de l'utilisation de ladite composition dans la fabrication d'un médicament présentant une activité analgésique centrale.
PCT/EP1996/003592 1995-08-18 1996-08-14 Composition contenant de l'acide mefenamique en association avec de la codeine Ceased WO1997006801A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP96928463A EP0863758A1 (fr) 1995-08-18 1996-08-14 Composition contenant de l'acide mefenamique en association avec de la codeine
BR9609937-2A BR9609937A (pt) 1995-08-18 1996-08-14 Composição contendo ácido mefenâmico em associação com codeìna
AU68214/96A AU6821496A (en) 1995-08-18 1996-08-14 Composition containing mefenamic acid in association with codeine

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
ZA95/6923 1995-08-18
ZA956923 1995-08-18
FR9513613A FR2741264B1 (fr) 1995-11-16 1995-11-16 Composition contenant de l'acide mefenamique en association avec de la codeine
FR95/13613 1995-11-16

Publications (1)

Publication Number Publication Date
WO1997006801A1 true WO1997006801A1 (fr) 1997-02-27

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1996/003592 Ceased WO1997006801A1 (fr) 1995-08-18 1996-08-14 Composition contenant de l'acide mefenamique en association avec de la codeine

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EP (1) EP0863758A1 (fr)
AU (1) AU6821496A (fr)
BR (1) BR9609937A (fr)
WO (1) WO1997006801A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1985004589A1 (fr) * 1984-04-09 1985-10-24 Abraham Sunshine Melanges contre la toux et le rhume comprenant des medicaments anti-inflammatoires non steraniques
ZA893274B (en) * 1988-05-27 1990-02-28 Harold Restein Pharmaceutical composition containing a combination of analgesic agents

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1985004589A1 (fr) * 1984-04-09 1985-10-24 Abraham Sunshine Melanges contre la toux et le rhume comprenant des medicaments anti-inflammatoires non steraniques
ZA893274B (en) * 1988-05-27 1990-02-28 Harold Restein Pharmaceutical composition containing a combination of analgesic agents

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DATABASE WPI Section Ch Week 9026, Derwent World Patents Index; Class B05, AN 90-201269, XP002004041 *
GLEASON J.A. ET AL: "Comparison of meclofenamate sodium with codeine and placebo for the treatment of episiotomy pain", CLIN. THER., 1987, 9/6 (585-593), USA, XP000613075 *

Also Published As

Publication number Publication date
MX9801222A (es) 1998-10-31
EP0863758A1 (fr) 1998-09-16
AU6821496A (en) 1997-03-12
BR9609937A (pt) 1999-12-21

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