WO1997031631A1 - Inhibiteurs selectifs de cox-2 destines a la maitrise de la periode de travail et des contractions uterines - Google Patents

Inhibiteurs selectifs de cox-2 destines a la maitrise de la periode de travail et des contractions uterines Download PDF

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Publication number
WO1997031631A1
WO1997031631A1 PCT/GB1997/000529 GB9700529W WO9731631A1 WO 1997031631 A1 WO1997031631 A1 WO 1997031631A1 GB 9700529 W GB9700529 W GB 9700529W WO 9731631 A1 WO9731631 A1 WO 9731631A1
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cox
compound
labour
female
selectively inhibits
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PCT/GB1997/000529
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English (en)
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Phillip Robert Bennett
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Rpms Technology Limited
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Priority claimed from GBGB9604143.9A external-priority patent/GB9604143D0/en
Application filed by Rpms Technology Limited filed Critical Rpms Technology Limited
Priority to EP97905274A priority Critical patent/EP0889724A1/fr
Publication of WO1997031631A1 publication Critical patent/WO1997031631A1/fr

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    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
    • A61K31/569—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone substituted in position 17 alpha, e.g. ethisterone
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • 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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
    • A61K31/5685—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone having an oxo group in position 17, e.g. androsterone
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • 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
    • A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide

Definitions

  • the present invention relates to compounds for use in managing labour, in particular compounds related to the management of pre-term contractions.
  • Prostaglandins are formed from the precursor arachidonic acid. Arachidonic acid is a substrate for at least tiiree enzyme groups. Metabolism via the cyclo- oxygenase pathway produces the classical prostaglandins, prostacyclin and thromboxane.
  • HETEs hydroxyeicosatetraenioc acids
  • the principle sources of the prostaglandins which initiate labour are the fetal membranes and decidua.
  • Amnion contains large stores of arachidonic acid.
  • arachidonic acid metabolism in amnion Prior to labour arachidonic acid metabolism in amnion is principally via the lipoxygenase enzyme pathways to produce 5- and 12- HETE and leukotriene B4 (Bennett et al (1993) "Changes in arachidonic acid metabolism in amnion cells associated with increased cyclo-oxygenase gene expression at parturition" Br. J. Obstet. Gynaecol. 100, 1037-42).
  • Prostaglandin E2 is known to mediate cervical ripening and to cause uterine contractions.
  • IL1 interleukin 1
  • Both of these are found in increased concentration in the amniotic fluid in association with labour, and both will stimulate prostaglandin production in amnion cells in vitro.
  • PAF is believed to be a particularly strong candidate since its secretion by the fetus into the amniotic fluid is related to fetal lung maturity.
  • COX-1 and COX-2 genes are on different chromosomes but have a similar intron/exon arrangement.
  • the COX-1 gene spans over 22 kb of genomic DNA whilst the COX-2 gene spans only 8 kb.
  • the long 3' untranslated portion of COX-2 mRNA contains multiple copies of the Shaw-Kamen sequence (AUUUA) which are a feature of early response genes with rapid mRNA degradation (Kosaska et al (1994) Eur. J Biochem. 221, 889-97).
  • the type 1 and type 2 proteins are of similar molecular size and show a high degree of homology.
  • COX-1 appears to be constitutively expressed in cells with constant prostaglandin synthesis.
  • COX-2 is an inducible, early response gene which mediates acute prostaglandin synthesis, for example in inflammation (Vane (1994) "Towards a better aspirin” Nature 367, 215).
  • cytokines such as interleukin I ⁇ (IL- 1/3) within the uterus (Romero et al (1989) Am. J. Obstet. Gynecol. 160, 1117-1123).
  • ⁇ - sympathomemetics such as Ritodrine, Salbutamol and Terbutaline
  • ⁇ - sympathomemetics cause significant maternal cardiovascular, respiratory and metabolic side effects and may lead to pulmonary oedema, cardiac failure and maternal death.
  • ⁇ - sympathomemetics such as Ritodrine, Salbutamol and Terbutaline
  • they are subject to tachyphylaxis and become ineffective after 24 to 48 hours. This tachyphylaxis is probably due to down regulation, by /3-sympathomemetics, of their own receptor.
  • Meta-analysis of randomised controlled trials has shown that the value of ⁇ - sympathomemetics is only in the temporary delay of labour to allow in utero transfer or administration of steroid to improve fetal lung surfactant production.
  • Indomethacin a cyclo-oxygenase inhibitor is effective in preventing the contractions of pre-term labour. It is more effective in short term prolongation of pregnancy than the j8-sympa ⁇ omimetics and, unlike ⁇ - sympathomemetics, it can reduce the risk of delivery pre-term (Keirse (1995) "Indomethacin tocolysis in preterm labour" in Pregnancy and Childbirth Module (Eds. Enkin, M.W., Keirse, M.J.N.C., Renfrew, M.J., Neilson, J.P.) Cochrane Database of Systematic Reviews, No 04383, Oxford). The use of Indomethacin is limited by fetal side effects.
  • Indomethacin reduces fetal urine output, both by reducing renal blood flow and by reducing prostaglandin E mediated inhibition of arginine vasopressin (AVP) in the collecting duct
  • AVP arginine vasopressin
  • indomethacin is limited in clinical practice to use ⁇ 32 weeks, and to short courses ( ⁇ 48 hours) after which any effects on the constriction of the ductus have been shown to be reversible (Tulzer et al (1991) "Doppler echocardiography of fetal ductus arteriosus constriction versus increased right ventricular output” JACC 18(2), 532-36; Moise et al (1993) "Effect of advancing gestational age on the frequency of fetal ductal constriction in association with maternal indomethacin use" Am. J. Obstet. Gynecol.
  • Sulindac produces a smaller reduction in fetal urine output and ntinimal effect on ductal patency (Carlon et al (1992) Obstet. Gynecol. 85(5), 169-11 ; Rasanen and Jouppila (1995) "Fetal cardiac function and ductus arteriosus during indomethacin and sulindac therapy for threatened preterm labour; A randomised study" Am. J. Obstet. Gynecol. 173(1), 20-25).
  • Nimesulide is a non-steroidal, anti-inflammatory drug (NSAID) which is widely prescribed in Europe for the management of connective tissue inflarnmatory disorders, post operative analgesia and febrile episodes in children. It is comparable in efficacy to other NSAID's but has fewer gastric side effects. Previous stodies of its mechanism of action have suggested that, unlike other NSAID's, it does not inhibit the action of prostaglandin endoperoxide synthase (PGHS, cyclo-oxygenase) or the synmesis of prostaglandins (Magni (1993) "The effect of Nimesulide on prostanoid formation" Drugs 46 (Suppl. 1), 10-14.
  • PGHS prostaglandin endoperoxide synthase
  • a first aspect of the invention provides a method of substantially preventing or reducing at least one of the changes in the female reproductive system associated with the onset or continuation of labour the method comprising administering to the female an effective amount of a compound which selectively inhibits cyclo-oxygenase-2 (COX-2) function.
  • COX-2 cyclo-oxygenase-2
  • Cyclo-oxygenase-2 (COX-2) is also called prostaglandin endoperoxide synthase-2 (PGHS-2).
  • PGHS-2 prostaglandin endoperoxide synthase-2
  • the COX-2 gene and the sequence of its polypeptide product are described in O'Banion et al (1991) /. Biol. Chem. 266, 23261-23267 incorporated herein by reference.
  • the female reproductive system (which includes the uterus, cervix and vagina) undergoes various biochemical changes which prepare the female for delivery.
  • the uterus increases in contractility and undergoes contractions.
  • the cervix also ripens in readiness for delivery.
  • Such changes are well known in the arts of obstetrics, gynaecology and midwifery and, for example, the Bishop's score indicates the degree of cervical ripening.
  • the method of the invention is particularly useful as a prophylactic method in those pregnant women at risk of pre-term labour.
  • the method of the invention allows for the interruption of labour by inhibiting uterine contractions. It is also useful to substantially prevent for a considerable duration pre- term labour using the method of the invention. In particular, it is useful to inhibit pre-term uterine contractions from the time when they first occur (or soon thereafter) until the normal time of delivery. Thus, typically, the woman is administered an effective amount of a compound which selectively inhibits COX-2 function from the time she presents with pre- term contractions to between 37 and 42 weeks following conception.
  • a particularly preferred embodiment of the invention therefore provides a method of substantially preventing or reducing uterine contractility or uterine contractions associated with pre-term labour the method comprising adininistering to the female an effective amount of a compound which selectively inhibits COX-2 function.
  • a compound which selectively inhibits COX-2 function substantially reduces or prevents uterine contractions.
  • Contractility is the rate or extent of contraction; the uterus has intrinsic contractility.
  • the compound which selectively inhibits COX-2 function acts as a tocolytic agent.
  • a further particularly preferred embodiment provides a method of substantially preventing or reducing ripening of the cervix the method comprising administering to the female an effective amount of a compound which selectively inhibits COX-2 function.
  • a second aspect of the invention provides a method of substantially preventing or reducing uterine contractility the method comprising administering to the female an effective amount of a compound which selectively inhibits COX-2 function.
  • the uterine contractility (or uterine contractions) may be associated with the onset or continuation of labour, especially the onset of pre-term labour.
  • the female is pregnant and the uterine contractility occurs during pregnancy.
  • the method substantially prevents or reduces pre-term labour.
  • the method of the second aspect of me invention is also useful in substantially preventing or reducing uterine contractility or contractions in non-pregnant women.
  • Such uterine contractions occur in some women during menorrhagia (excessive uterine bleeding occurring at regular intervals of menstruation).
  • the invention includes the substantial prevention or reduction in menorrhagia in women by administration of a compound which selectively inhibits COX-2 function.
  • the compound is administered following (a) signs of pre- term labour in the pregnant woman, or (b) an indication that the pregnant woman is at risk of pre-term labour, especially uterine contractions, or (c) symptoms of menorrhagia.
  • administration of the compound commences during the second or third trimester of pregnancy when the compound is administered prophylactically.
  • the compound is used to substantially inhibit contractions during pre- term labour it is preferred if the compound is administered for a period of between 24 and 72 hours, preferably 48 hours.
  • the compound, or a formulation thereof may be administered in any conventional way.
  • the compound, or a formulation thereof may be administered intravenously or via intraammotic or intravaginal administration but it is particularly preferred if the compound or formulation is administered orally or rectally to the mother.
  • the treatment may consist of a single dose or a plurality of dose over a period of time.
  • the compound may selectively inhibit COX-2 function at any level.
  • the compound selectively inhibits COX-2 enzyme activity.
  • COX-2 enzyme activity we mean that the compound preferably inhibits COX-2 in preference to other cyclo- oxygenase enzymes, in particular in preference to cyclo-oxygenase- 1 (COX-1).
  • COX-1 gene and the sequence of its polypeptide product are described in Yokoyama and Tanabe (1989) Biochem. Biophys. Res. Comm. 165, 888-894 incorporated herein by reference.
  • COX-2 is also called PGHS-1.
  • the compound which selectively inhibits COX-2 enzyme activity is at least ten times better at inhibiting COX-2 than COX-1; preferably it is at least fifty times better; preferably it is at least one hundred times better; still more preferably it is at least one thousand times better and in greater preference it is at least ten thousand times better.
  • the compound has substantially no inhibitory activity against the COX-1 enzyme.
  • the compound selectively inhibits COX-2 enzyme production.
  • the compound may, for example, selectively prevent transcription of the COX-2 or it may selectively prevent translation of the COX-2 message.
  • selectively inhibits COX-2 enzyme production we mean that the compound preferably inhibits the production of COX-2 in preference to other cyclo-oxygenases, in particular in preference to the production of COX-1.
  • the compound which selectively inhibits COX-2 enzyme production is at least ten times better at inhibiting COX-2 production than COX-1 production; preferably it is at least fifty times better; more preferably it is at least one hundred times better; more preferably still it is at least one thousand times better; and in greater preference it is at least ten thousand times better.
  • the compound has substantially no inhibitory activity against COX-1 enzyme production.
  • Methods for identifying whether a particular molecule is a compound which selectively inhibits COX-2 function include the following:
  • Activated macrophages are known to express COX-2 and thereby synthesise prostaglandin.
  • Seminal vesicle cells are known to express COX-1 and thereby synthesise prostaglandin.
  • Compounds which selectively inhibit prostaglandin synthesis in activated macrophages compared to prostaglandin synthesis in seminal vesicle cells are compounds which selectively inhibit COX-2 function.
  • the compounds identified by this screen may be COX-2 enzyme inhibitors or compounds which selectively inhibit COX-2 enzyme production, for example by inhibiting COX-2 gene transcription or COX-2 mRNA translation.
  • cells which produce COX-1 or COX-2, and can be used in a cell-based assay can be made by transfection with the relevant gene or cDNA.
  • the COX-1 and COX-2 cDNAs are known as disclosed above.
  • COX-1 and COX-2 enzyme can be produced using recombinant DNA techniques and the crystal structores of COX-1 and COX-2 are known. Biochemical screening of test compounds to select COX-2 selectively inhibitors can be carried out using purified COX-1 and COX-2 enzyme using methods that are known to the person skilled in the art.
  • Test compounds for screening by any suitable method may be from any library, or collection, of chemicals, including those made by combinatorial chemistry and derived from plant extracts.
  • chemicals we include molecules such as oligonucleotides and the like.
  • R x is an optionally halogenated alkyl radical
  • R is hydrogen, alkyl or a pharmaceutically acceptable cation
  • X is alkoxy, alkyl, halogen, acetamido, nitro, hydrogen, amino, alkoxycarbamoyl or dialkylarnino
  • Y is nitro, amino, alkoxycarbamoyl, dialkylamino or hydrogen, provided that one of X and Y is nitro, amino, alkoxycarbamoyl, or dialkylamino
  • Z is halogen, nitro or hydrogen
  • Z' is halogen, alkyl, alkoxy, nitro, amino, alkanamido, haloalkyl, hydroxy, dialkylamino, alkoxycarbamoyl, alkylthio, alkylsulfonyl, alkanoyl, or alkylsulfinyl and n is 0-2, provided that the individual aliphatic groups appearing
  • Ri represents a hydrogen atom, a methanesulphonyl group or an acetyl group
  • R 2 and R 3 together represent an oxo group or an oximino group
  • R 2 represents a hydrogen atom
  • R 3 represents a hydrogen atom, a hydroxyl group or an amino group, but excluding flosulide.
  • R is hydrogen, methyl or ethyl
  • R 2 is methyl, ethyl or n-propyl
  • Y is hydrogen, methyl, methoxy, fluorine or chlorine or a non-toxic, pharmacologically acceptable salt thereof formed with an inorganic or organic base, but excluding meloxicam.
  • Inclusion complexes of nimesulide alkali and alkaline earth salts may also be useful such as those described by WO 94/28031, incorporated herein by reference.
  • a particularly preferred embodiment is wherein the compound is any one of nimesulide, 4-hydroxynimesulide, flosulide, and meloxicam.
  • Nimesulide is N-(4-nitro-2-phenoxyphenyl) methanesulfonamide (also called 4-nitro-2-phenoxymethanesulfonanilide). Nimesulide is 100-fold more specific for COX-2 inhibition than for COX-1 inhibition. Nimesulide is manufactured by Boehringer.
  • Flosulide is 6-(2,4-difluorophenoxy)-5-methyl sulphonylamino-1-indanone (also known as N-6-(2,4-difluorophenoxy)-l-oxo-indan-5-yl methane- sulphonamide). Flosulide is 1000-fold more specific for COX-2 inhibition than for COX-1 inhibition. Flosulide is manufactured by Ciba Geigy. Meloxicam is 4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-l,2- benzotf ⁇ azine-3-carboxamide 1,1-dioxide. Meloxicam is 1000-fold more specific for COX-2 inhibition than for COX-1 inhibition. Meloxicam is manufactured by Boehringer.
  • Otiier COX-2-specific inhibitors which may be useful in the practice of the invention include:
  • L 475 L337 which is 500-fold more specific for COX-2 inhibition than for COX-1 inhibition. This is manufactured by Merck Frost.
  • Celecoxib which is 100-fold more specific for COX-2 inhibition than for COX-1 inhibition. Celecoxib is manufactured by Searle.
  • DuP 697 which is COX-2-selective and is manufactured by DuPont.
  • the female is adininistered between 0.1 and 40 mg/kg of nimesulide; more preferably between 1 and 20 mg/kg; still more preferably between 2 and 10 mg/kg; and most preferably between 3 and 6 mg/kg.
  • the female is administered between 0.1 and 40 mg/kg of flosulide; more preferably between 1 and 20 mg/kg; still more preferably between 2 and 10 mg/kg and most preferably between 3 and 6 mg/kg.
  • the amount of nimesulide, flosulide or meloxicam administered in the methods of the present invention may be the same as the amount administered in other indications for these drugs.
  • 200 mg of nimesulide may be administered to the woman every twelve hours for four doses, or it may be administered as a 200 mg suppository once daily.
  • Nimesulide, flosulide and meloxicam are COX-2 enzyme inhibitors, probably competitive inhibitors.
  • the female may be any female mammal such as human, horse, pig, cow, sheep, dog and cat.
  • the female is a human female.
  • a particular advantage of the present invention is that the COX-2 inhibitor reduces the possibility of harm being done to the foetos compared with other tocolytic agents. This is particularly the case when the COX-2 inhibitor is nimesulide, flosulide or meloxicam; more particularly when it is nimesulide.
  • a third aspect of the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound which selectively inhibits COX-2 function and a further component that is usefully administered to a female who has or is at risk of pre-term labour, or a female who has or is at risk of uterine contractions, or a female who suffers from menorrhagia.
  • the pharmaceutical composition is useful in the methods of the first or second aspects of the invention.
  • the said further compound that is usefully administered may be. any compound that is useful to administer with the compound which selectively inhibits COX-2 enzyme function in the first or second aspects of the invention.
  • the further compound is a progestogen, progestin or other progestational agent.
  • progesterone and its analogues such as allyloestrenol, dydrogesterone, hydroxyprogesterone and medroxyprogesterone.
  • Progestogens also include testosterone analogues such as norethisterone.
  • Progesterone is preferred.
  • the further compound may be a tocolytic and conveniently is any of beta- sympathomimetics, anti-oxytocins or calcium channel blockers as well as progesterone.
  • a fourth aspect of the invention provides a pharmaceutical composition comprising a compound which selectively inhibits COX-2 function wherein the composition is in a form adapted for delivery to the female reproductive system.
  • female reproductive system we include those parts that develop during pregnancy including the amnion.
  • the said composition is in a form adapted for delivery via or into the rectum, vagina or amnion of the mother; also preferably the composition is adapted for delivery to the cervix.
  • the composition is a pessary, sponge, ring, gel or other device adapted for delivery to the female reproductive system, particularly the vagina. Pessaries, gels, sponges, rings and other such devices are well known in the art, for example in various chemical contraceptive methods.
  • the pH of the vagina is usually acid due to the presence of Lactobacilli; it is preferred if the said compound is prepared in a composition in a form which is relatively stable to acidic conditions, especially those found in the vagina.
  • the composition is compatible with the amniotic fluid and that the composition is delivered into the amnion.
  • the amniotic fluid has a distinct pH and a distinct osmotic tension.
  • the composition comprises a compound which selectively inhibits COX-2 function and a further component, such as a liquid in which said compound is dispersed or dissolved, which has substantially the same pH or substantially the same osmotic tension as amniotic fluid.
  • the amniotic fluid pH and osmotic tension are well known to, or can be readily measured by, the person skilled in the art.
  • the compound selectively inhibits COX-2 enzyme activity .
  • the compound selectively inhibits COX-2 enzyme production.
  • the compound is any one of nimesulide, flosulide, 4-hydroxynimesulide, or meloxicam.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Such me ⁇ ods include the step of bringing into association the active ingredient (for example, COX-2-selective inhibitor) with the carrier which constitutes one or more accessory ingredients.
  • the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.
  • Formulations in accordance with the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets, each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
  • the active ingredient may also be presented as a bolus, electuary or paste.
  • a tablet may be made by compression or moulding, optionally widi one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder (eg povidone, gelatin, hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (eg sodium starch glycoiate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent.
  • Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened widi an inert liquid diluent.
  • the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmeurylcellulose in varying proportions to provide desired release profile.
  • Formulations suitable for topical administration in the mouth include lozenges comprising ⁇ e active ingredient in a flavoured basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouth-washes comprising the active ingredient in a suitable liquid carrier.
  • Formulations suitable for parenteral admimstration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render me formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
  • Preferred unit dosage formulations are those containing a daily dose or unit, daily sub-dose or an appropriate fraction thereof, of an active ingredient.
  • formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavouring agents.
  • a fifth aspect of the invention provides use of a compound which selectively inhibits COX-2 function in the manufacture of a medicament for substantially preventing or reducing uterine contractility, or for substantially preventing or reducing at least one of the changes in toe female reproductive system associated with the onset or continuation of labour.
  • a sixth aspect of the invention provides use of a compound which selectively inhibits COX-2 function as a tocolytic agent.
  • Figure 1 shows ethidium stained gel showing COX-2 RT-PCR products amplified from fetal membranes at various gestational ages.
  • Figure 2 shows the effect of IL-l ⁇ (top panel) and TPA (lower panel) upon expression of COX-2 (measured by qRT-PCR) in WISH cells.
  • Figure 3 shows the effect of LPS upon expression of COX-2 (measured by qRT-PCR) in intact fetal membranes.
  • Figure 4 shows etoidium stained gels showing expression of COX-1 (lower panel) and COX-2 (upper panel) in human fetal heart at between 20 and 24 weeks.
  • Figure 5 shows the action of nimesulide on prostanoid formation in human fetal membranes stimulated with interleukin- l ⁇ .
  • Figure 6 shows the effect of prophylactic Nimesulide upon amniotic fluid index in a single patient at very high risk of preterm labour.
  • Nimesulide was given from 17 to 34 weeks.
  • Preterm labour began 7 days after therapy was stopped.
  • Amniotic fluid index remained wi ⁇ in normal limits throughout treatment whereas treatment with the COX non-selective drug Indomethacin characteristically causes oligohydramnios wi ⁇ iin 7 days.
  • Figure 7 shows the effect of Nimesulide upon contractility in isolated human pregnant myometrial strip in an organ batti. Nimesulide significantly inhibits uterine contractions, suggesting an important role for COX-2 in uterine contractility.
  • Figure 8 shows COX-1 (top panel) and COX-2 (bottom panel) expression in myometrium at various gestational ages and before and after labour.
  • COX-2 expression increases near to term and with labour. This shows that increased prostaglandin synthesis in myometrium associated with labour is due to COX-2. It is likely that COX-1 mediates the synthesis of prostacyclin, a prostaglandin mat inhibits uterine contractility, whereas
  • COX-2 mediates synthesis of prostaglandin F2a which stimulates contractions.
  • Use of a COX-2 specific antiprostaglandin in preterm labour would inhibit prostaglandin F2a synthesis but not prostacyclin synthesis whereas a non-selective antiprostaglandin would inhibit synthesis of both compounds.
  • Figure 9 shows the effect of Nimesulide upon PG syn ⁇ esis in human fetal membranes compared with that of Indomethacin.
  • Membranes have been stimulated using ILlb to upregulate PG synthesis.
  • ILlb is thought to be an important mediator of preterm labour.
  • Nimesulide shows a 100 fold selectivity for COX-2 whereas Indomethacin is non-selective. Both have similar effects upon membrane prostaglandin synthesis suggesting that IL ⁇ lb stimulation of prostaglandin synthesis in fetal membranes is mediated via COX-2 and not COX-1.
  • Example 1 COX-2 expression in pregnancy
  • COX-1 expression exceeds diat of COX-2 (Fig 4). This strongly suggests that it is COX-2 whose increased expression mediates die onset of labour at term whilst COX-1 mediates normal fetal physiological function such as vascular tone, ductal patency, glomerular filtration rate and tubular reabsorbation.
  • Altoough tiiey are highly effective at inhibition of contractions and delaying of delivery (Keirse 1995)
  • anti-prostaglandins such as Indomethacin in pre-term labour is limited by fetal side effects. These include constriction of me ductus arteriosis, oligohydramnios, renal tobular dysfunction, intracranial haemorrhage and necrotising entercolitis . It is likely diat each of toese side effects is mediated by inhibition of constitotively syn iesised prostaglandins in fetal tissues. Since constitutive prostaglandin synmesis is likely to be mediated by COX-1, me use of at least some COX-2 specific anti-prostaglandins allows inhibition of pre- term contractions without fetal side effects.
  • Figure 7 shows the effect of Nimesulide upon contractility in isolated human pregnant myometrial strip in an organ bath. Nimesulide significandy inhibits uterine contractions, suggesting an important role for COX-2 in uterine contractility.
  • Figure 8 shows COX-1 (top panel) and COX-2 (bottom panel) expression in myometrium at various gestational ages and before and after labour. Expression of the two genes is at similar levels of mRNA abundance but COX-2 expression increases near to term and with labour. This shows mat increased prostaglandin synmesis in myometrium associated widi labour is due to COX-2.
  • COX-1 mediates the synmesis of prostacyclin
  • a prostaglandin mat inhibits uterine contractility
  • COX-2 mediates syndiesis of prostaglandin F2a which stimulates contractions.
  • Use of a COX-2 specific antiprostaglandin in preterm labour would inhibit prostaglandin F2a synthesis but not prostacyclin synmesis whereas a non-selective antiprostaglandin would inhibit syndiesis of bom compounds.
  • Figure 9 shows die effect of Nimesulide upon PG synmesis in human fetal membranes compared wi i mat of Indomethacin.
  • Membranes have been stimulated using ILlb to upregulate PG synthesis.
  • ILlb is thought to be an important mediator of preterm labour.
  • Nimesulide shows a 100 fold selectivity for COX-2 whereas Indomethacin is non-selective. Both have similar effects upon membrane prostaglandin synthesis suggesting mat IL- lb stimulation of prostaglandin synmesis in fetal membranes is mediated via COX-2 and not COX-1.
  • Example 3 Patient treated with Nimesulide
  • the patient was a 31 year old in her tenm pregnancy with no live children. Eight previous pregnancies, managed abroad, had ended in spontaneous preterm delivery at 27, 27, 26, 25, 29, 30, 27 and 32 weeks widi early neonatal death in every case. She had also had one spontaneous 18 week miscarriage. Vaginal cervical circlage was performed in die fourth and subsequent pregnancies. Prior to ⁇ is pregnancy, cervical circlage was performed abdominally as an interval procedure. Since we considered her at very high risk of preterm delivery she was treated witii Nimesulide, administered once daily as a 200 mg suppository from 16 weeks. Betameuiasone 12 mg i.m. was given twice at 12 hourly intervals once every week from the 24m week until delivery.
  • Ultrasound scans were performed at weekly intervals for measurement of amniotic fluid index (AFI) from 16 weeks and for ductal pulsatility index and peak velocity from 25 weeks.
  • AFI amniotic fluid index
  • Doppler flow indices for me ductus and for the umbilical and middle cerebral arteries remained normal.
  • Amniotic fluid index also remained normal throughout the pregnancy. There were no episodes of threatened preterm labour or contractions until Nimesulide was electively discontinued at 34 weeks. Seven days later she laboured and was delivered by caesarean section. The baby was ventilated for one day because of mild respiratory distress syndrome and men had an uncomplicated neonatal course.
  • Figure 6 shows the effect of prophylactic Nimesulide upon amniotic fluid index in a single patient at very high risk of preterm labour.
  • Nimesulide was given from 17 to 34 weeks.
  • Preterm labour began 7 days after therapy was stopped.
  • Amniotic fluid index remained widiin normal limits throughout treatment whereas treatment wim the COX non-selective drug Indomethacin characteristically causes oligohydramnios within 7 days.

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Abstract

La présente invention se rapporte à un procédé permettant d'éviter sensiblement ou de réduire au moins l'une des modifications se produisant dans l'appareil génital féminin au moment du démarrage du travail ou pendant la période de travail au cours d'un accouchement. Ledit procédé consiste à administrer à la patiente une quantité efficace d'un composé qui inhibe sélectivement la fonction de cyclo-oxygénase-2 (COX-2). L'invention se rapporte également à un procédé permettant d'éviter ou de réduire les contractions utérines se produisant soit au cours de la grossesse soit en raison d'une ménorragie. Le procédé consiste à administrer à la patiente une quantité efficace d'un composé qui inhibe sélectivement la fonction de cyclo-oxygénase-2 (COX-2). De préférence, le composé est nimésulide, flosulide ou méloxicame et il peut être combiné à un progestatif ou à une progestérone.
PCT/GB1997/000529 1996-02-27 1997-02-26 Inhibiteurs selectifs de cox-2 destines a la maitrise de la periode de travail et des contractions uterines WO1997031631A1 (fr)

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WO1999009988A1 (fr) * 1997-08-27 1999-03-04 Hexal Ag Nouvelles compositions pharmaceutiques de meloxicam presentant une solubilite et une biodisponibilite ameliorees
WO2002062391A2 (fr) * 2001-02-02 2002-08-15 Pharmacia Corporation Methode d'utilisation d'un inhibiteur de la cyclooxygenase-2 et de steroides sexuels dans une polytherapie pour traiter et prevenir la dysmenorrhee
WO2003017973A1 (fr) * 2001-08-31 2003-03-06 Pantarhei Bioscience B.V. Traitement de troubles gynecologiques benins et vecteur d'administration a cet effet
AU758566B2 (en) * 1997-10-31 2003-03-27 G.D. Searle & Co. Method of using cyclooxygenase-2 inhibitors in maintaining the fetal ductus ateriosus during treatment and prevention of preterm labor
EP1400242A1 (fr) * 1997-10-31 2004-03-24 G.D. Searle & Co. Procédé d'utilisation d'inhibiteurs de cyclooxygenase-2 dans le maintien du canal artériel foetal au cours du traitement et de la prévention du travail préterme
US8580294B2 (en) 2010-10-19 2013-11-12 International Partnership For Microbicides Platinum-catalyzed intravaginal rings
US8920820B2 (en) 2001-12-12 2014-12-30 Boehringer Ingelheim Vetmedica Gmbh Highly concentrated stable meloxicam solutions for needleless injection
US8992980B2 (en) 2002-10-25 2015-03-31 Boehringer Ingelheim Vetmedica Gmbh Water-soluble meloxicam granules
US9101529B2 (en) 2009-10-12 2015-08-11 Boehringer Ingelheim Vetmedica Gmbh Containers for compositions comprising meloxicam
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US9795568B2 (en) 2010-05-05 2017-10-24 Boehringer Ingelheim Vetmedica Gmbh Low concentration meloxicam tablets
US9907806B2 (en) 2009-06-23 2018-03-06 Bayer Intellectual Property, GmbH Pharmaceutical composition for emergency contraception
US9993557B2 (en) 2000-06-20 2018-06-12 Boehringer Ingelheim Vetmedica Gmbh Highly concentrated stable meloxicam solutions
US10137031B2 (en) 2013-11-14 2018-11-27 International Partnership For Microbicides, Inc. Combination therapy intravaginal rings
US10548901B2 (en) 2004-02-23 2020-02-04 Boehringer Ingelheim Vetmedica Gmbh Meloxicam for the treatment of respiratory diseases in pigs

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WO1999009988A1 (fr) * 1997-08-27 1999-03-04 Hexal Ag Nouvelles compositions pharmaceutiques de meloxicam presentant une solubilite et une biodisponibilite ameliorees
AU758566B2 (en) * 1997-10-31 2003-03-27 G.D. Searle & Co. Method of using cyclooxygenase-2 inhibitors in maintaining the fetal ductus ateriosus during treatment and prevention of preterm labor
EP1400242A1 (fr) * 1997-10-31 2004-03-24 G.D. Searle & Co. Procédé d'utilisation d'inhibiteurs de cyclooxygenase-2 dans le maintien du canal artériel foetal au cours du traitement et de la prévention du travail préterme
US9993557B2 (en) 2000-06-20 2018-06-12 Boehringer Ingelheim Vetmedica Gmbh Highly concentrated stable meloxicam solutions
WO2002062391A2 (fr) * 2001-02-02 2002-08-15 Pharmacia Corporation Methode d'utilisation d'un inhibiteur de la cyclooxygenase-2 et de steroides sexuels dans une polytherapie pour traiter et prevenir la dysmenorrhee
WO2002062391A3 (fr) * 2001-02-02 2003-09-18 Pharmacia Corp Methode d'utilisation d'un inhibiteur de la cyclooxygenase-2 et de steroides sexuels dans une polytherapie pour traiter et prevenir la dysmenorrhee
WO2003017973A1 (fr) * 2001-08-31 2003-03-06 Pantarhei Bioscience B.V. Traitement de troubles gynecologiques benins et vecteur d'administration a cet effet
US10098891B2 (en) 2001-12-12 2018-10-16 Boehringer Ingelheim Vetmedica Gmbh Highly concentrated stable meloxicam solutions for needleless injection
US8920820B2 (en) 2001-12-12 2014-12-30 Boehringer Ingelheim Vetmedica Gmbh Highly concentrated stable meloxicam solutions for needleless injection
US9066955B2 (en) 2002-10-25 2015-06-30 Boehringer Ingelheim Vetmedica Gmbh Water-soluble meloxicam granules
US8992980B2 (en) 2002-10-25 2015-03-31 Boehringer Ingelheim Vetmedica Gmbh Water-soluble meloxicam granules
US10548901B2 (en) 2004-02-23 2020-02-04 Boehringer Ingelheim Vetmedica Gmbh Meloxicam for the treatment of respiratory diseases in pigs
US11083731B2 (en) 2004-02-23 2021-08-10 Boehringer Ingelheim Vetmedica Gmbh Meloxicam for the treatment of respiratory diseases in pigs
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US9186296B2 (en) 2009-10-12 2015-11-17 Boehringer Ingelheim Vetmedica Gmbh Containers for compositions comprising meloxicam
US9101529B2 (en) 2009-10-12 2015-08-11 Boehringer Ingelheim Vetmedica Gmbh Containers for compositions comprising meloxicam
US9149480B2 (en) 2010-03-03 2015-10-06 Boehringer Ingeleheim Vetmedica GmbH Use of meloxicam for the long-term treatment of musculoskeletal disorders in cats
US9795568B2 (en) 2010-05-05 2017-10-24 Boehringer Ingelheim Vetmedica Gmbh Low concentration meloxicam tablets
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US9427400B2 (en) 2010-10-19 2016-08-30 International Partnership For Microbicides Platinum-catalyzed intravaginal rings
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