US20170065556A1 - Oral formulations of pyrrolidine derivatives - Google Patents

Oral formulations of pyrrolidine derivatives Download PDF

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US20170065556A1
US20170065556A1 US15/104,683 US201415104683A US2017065556A1 US 20170065556 A1 US20170065556 A1 US 20170065556A1 US 201415104683 A US201415104683 A US 201415104683A US 2017065556 A1 US2017065556 A1 US 2017065556A1
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dispersible tablet
methyl
biphenyl
carbonyl
methyloxime
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Andre CHOLLET
Olivier Pohl
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Obseva SA
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/401—Proline; Derivatives thereof, e.g. captopril
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/40—Cyclodextrins; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/10—Drugs for disorders of the endocrine system of the posterior pituitary hormones, e.g. oxytocin, ADH

Definitions

  • the present invention relates to solid oral formulations comprising a compound of formula (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one-O-methyloxime, and/or an active metabolite thereof, and the use of said formulations in the treatment and/or prevention of preterm labor, premature birth, dysmenorrhea and embryo implantation failure due to uterine contractions.
  • the present invention is furthermore related to processes for their preparation.
  • Oxytocin is a cyclic nona-peptide that mediates its physiological actions through activation of the oxytocin receptor (OT-R), a cell membrane receptor belonging to the class of G protein-coupled receptors that is similar to arginine vasopressin receptors.
  • OOT-R oxytocin receptor
  • One important action of OT is to cause the contraction of the uterus of mammals during labor. Repeated, concerted and regular contraction of the uterus will cause the dilatation of the cervix, the rupture of foetal membranes and lead to expulsion of the foetus.
  • Premature labor is when these contractions occur before the normal term of pregnancy.
  • Preterm increase of uterine activity is the most common expression of preterm labor.
  • Premature labor leads to undesired premature birth, a serious health problem that remains the major cause of perinatal mortality and severe morbidity, especially respiratory distress syndrome, intraventricular haemorrhage, bronchopulmonary dysplasia and necrotising enterocolitis that are far more common in preterm than in term infants. Long-term impairments such as cerebral palsy, visual impairment and hearing loss are also more common in preterm infants.
  • preterm birth remains the leading cause of infant mortality and morbidity in industrialized nations, where, despite the significant improvements in obstetrical medicine, it is causing high costs for neonatal intensive care of premature babies.
  • preterm childbirth-related ailments such as respiratory distress syndrome, heart conditions, cerebral palsy, epilepsy, and severe learning disabilities.
  • the management of preterm labor represents a significant problem in the field of obstetrics.
  • the OT/OT-R system plays a vital role in initiating labor in mammals, in particular in humans.
  • the density of OT-R increases markedly in the myometrium before the onset and during labor.
  • the local OT peptide hormone concentration increases markedly before parturition in human.
  • the high circulating concentrations of progesterone induce uterine quiescence while the uterus acquires contractile ability.
  • plasma progesterone concentrations fall, OT-R expression in the uterus increases markedly, OT is released and uterine contractile activity increases. At term, the contractions rise to a crescendo, resulting in delivery as a result of two interacting positive feedback loops.
  • the first is a local uterine loop: within the uterus itself, contractile prostaglandins are produced and released in response to OT and uterine contractions. These prostaglandins may play a further role in cervical ripening and weakening of fetal membranes.
  • the second loop involves the hypothalamus: in response to uterine contractions and vaginal and cervical distension, magnocellular oxytocin neurons in the hypothalamus increase their activity resulting in the release of OT from their axon terminals in the posterior pituitary.
  • the released OT acts upon the uterus both to stimulate the further production of prostaglandins and to contribute further to the contractions of the uterus.
  • blocking the effect of OT by antagonizing OT-R might represent an attractive modality for the treatment of diseases related to the OT-R activity, in particular preterm labor, premature birth and dysmenorrhea.
  • Tocolytic i.e. uterus relaxing agents
  • Tocolytic i.e. uterus relaxing agents
  • Most of these agents are used off-label. They have shown very limited efficacy, if any, in prolonging gestation and without clear demonstration of improvement of neonate outcome.
  • Current tocolytics are very often associated with unwanted adverse effects on women, foetus or neonate.
  • Such tocolytics include beta-2-adrenergic agonists, prostaglandin synthesis inhibitors, magnesium sulfate, nitric acid donors and calcium channel blockers.
  • Beta-2-adrenergic agonists such as ritodrine or terbutaline cause a number of cardiovascular and metabolic side effects including maternal tachycardia, palpitations, hypotension, altered thyroid function and fetal and neonatal hypoglycaemia, tachycardia.
  • Ritodrine is no longer FDA approved.
  • the calcium channel blocker nifedipine is also a medicine that is used to try to stop contractions. Some of the side effects that may occur include facial flushing, headache, nausea, palpitations, and lightheadedness.
  • the total prostaglandin synthesis inhibitor (NSAID) indomethacin has been used.
  • a newborn that has been exposed to magnesium sulfate may show lethargy, hypotonia, respiratory depression, bone problems, osteopenia and fractures.
  • the FDA is advising healthcare professionals against using magnesium sulfate injection for longer than 5-7 days to stop preterm labor in women.
  • Atosiban a dual vasopressin V1a receptor and OT-R antagonist is marketed in EU and used to stop contractions and delay preterm delivery by a few days.
  • the principal drawback to the use of peptide antagonists like Atosiban is the problem of low oral bioavailability resulting from intestinal degradation. Hence, they must be administered parenterally.
  • the present invention provides a dispersible tablet comprising a compound of formula (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one-O-methyloxime, and at least one or more pharmaceutically acceptable excipients.
  • the invention also provides said dispersible tablet, for use in the treatment and/or prevention of disorders selected from the group comprising preterm labor, premature birth, embryo implantation failure due to uterine contractions, dysmenorrhea, premature ejaculation, sexual dysfunction, endometriosis, infertility, benign prostatic hyperplasia, neuro-psychiatric disorders, autism, social behavior disorders, psycho-social stress, and/or cardiovascular disorders.
  • disorders selected from the group comprising preterm labor, premature birth, embryo implantation failure due to uterine contractions, dysmenorrhea, premature ejaculation, sexual dysfunction, endometriosis, infertility, benign prostatic hyperplasia, neuro-psychiatric disorders, autism, social behavior disorders, psycho-social stress, and/or cardiovascular disorders.
  • the invention further provides a kit comprising said dispersible tablet, and information for use thereof.
  • FIG. 1 Plasma concentration profiles of solid oral formulations in the dog.
  • FIG. 1A shows the plasma concentration (ng/ml) vs. time profile of formulations 1 (10% granules), 2 (5.8% granules), 3 (dispersible tablets) and 4 (conventional tablets) over the time period from 0 to 72 h.
  • FIG. 1B shows an enlargement of FIG. 1A for the period from 0 to 12 h.
  • the present invention relates to a solid oral formulation
  • a solid oral formulation comprising a compound of formula 5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one-O-methyloxime, its geometrical isomers, its optically active forms as enantiomers, diastereoisomers, mixtures of these, its racemate forms as well as active metabolites thereof, and at least one or more pharmaceutically acceptable excipients.
  • the present invention relates to a solid oral formulation comprising a compound of formula (3Z/E,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one-O-methyloxime, and/or an active metabolite thereof, and at least one or more pharmaceutically acceptable excipients.
  • a compound of formula (3Z/E,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one-O-methyloxime and/or an active metabolite thereof, and at least one or more pharmaceutically acceptable excipients.
  • the present invention relates to a solid oral formulation comprising a compound of formula (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one-O-methyloxime, and/or an active metabolite thereof, and at least one or more pharmaceutically acceptable excipients.
  • said compound is synthesized and obtained in isomeric mixtures (3Z/E,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one-O-methyloxime comprising (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one-O-methyloxime and (3E,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one-O-methyloxime.
  • the purity of the compound (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one-O-methyloxime in said isomeric mixtures is at least 85% to 100%, preferably 85% to 99.9%, more preferably 90% to 99.9%, and even more preferably 95% to 99.9%.
  • the present invention relates to a solid oral formulation comprising a compound of formula (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one-O-methyloxime, and/or an active metabolite thereof, provided in substantially pure form, and at least one or more pharmaceutically acceptable excipients.
  • the term “substantially pure” refers to a compound provided in a form which is substantially free of other compounds.
  • said “other compounds” include (3E,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one-O-methyloxime, (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one, (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one oxime, (3R,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]-3-methoxyamino-pyrrolidine, (3S,5S)-5-(hydroxymethyl)-1-[(2
  • the compound of formula (3Z,5 S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one-O-methyloxime, and/or an active metabolite thereof is substantially free of the compound of formula (3E,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one-O-methyloxime.
  • the purity of a substantially pure form compound of formula (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one-O-methyloxime, and/or an active metabolite thereof is at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, at least 99.2%, at least 99.3%, at least 99.4%, at least 99.5%, at least 99.6%, at least 99.7%, at least 99.8%, at least 99.9% or at least 100% and is therefore substantially free of compound of formula (3E,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one-methyloxime.
  • the purity of the substantially pure form compound of formula (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one-O-methyloxime, and/or an active metabolite thereof is at least in the range of 85% to 100%, preferably 85% to 99.9%, more preferably 90% to 99.9%, and even more preferably in the range of 95% to 99.9%.
  • active metabolite thereof refers to a product produced through metabolism in the body, or in vitro, of a specified compound, i.e. in the present case (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one-O-methyloxime and which exhibits the same biological activity as (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one-O-methyloxime.
  • Active metabolites of (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one-O-methyloxime may be identified using routine techniques known in the art and their activities determined using tests such as those described herein. Such metabolites may result for example from the oxidation, glucuronidation or other conjugation, hydrolysis, reduction and the like, of the administered Z form.
  • the invention includes active metabolites of (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one-O-methyloxime, including compounds produced by a process comprising contacting a compound of this invention with a mammal for a period of time sufficient to yield a metabolic product thereof.
  • Such metabolite may also be produced in vitro by oxidation, reduction, hydrolysis, glucuronidation or other conjugation transformation of the corresponding (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one-O-methyloxime.
  • Examples of actives metabolites of (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one-O-methyloxime include compounds whose structures are shown below:
  • a compound which, upon administration to the recipient, is capable of being converted into a compound of (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one-O-methyloxime, and/or an active metabolite thereof as described above, is known as a “prodrug”.
  • a prodrug may, for example, be converted within the body, e.g. by hydrolysis in the blood, into its active form that has medical effects.
  • Pharmaceutical acceptable prodrugs are described in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of the A. C. S. Symposium Series (1976); “Design of Prodrugs” ed. H. Bundgaard, Elsevier, 1985; and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, which disclosures are incorporated herein by reference.
  • solid oral formulation refers to a tablet, a dispersible tablet, a fast dissolving tablet, a quick dissolving tablet, a fast melt tablet, a mouth-dissolving tablet, a melt-in mouth tablet, an orodispersible tablet, a lyophilised unit, a porous tablet, a conventional tablet, a coated tablet, an uncoated tablet, a gastro-resistant tablet, an effervescent tablet, a soluble tablet, a chewable tablet, an oral lyophilisate, a powder, an oral powder, a pellet, a capsule and/or a granule.
  • the solid oral formulation is a tablet, more preferably, a dispersible tablet.
  • disintegrating tablet includes a disintegrating tablet that is swallowed, or intended to be disintegrated rapidly in water and to be swallowed.
  • “pharmaceutically acceptable excipients” includes any carriers, diluents, adjuvants, vehicles, preserving agents, antioxidant agents, fillers, bulking agent, glidant, buffering agents, thickening agents, disintegrating agents, lubricants, binders, wetting agents, sweeteners, flavouring agent, taste-masking agents, emulsifying agents, suspending agents, solvents, dispersion media, coatings, antibacterial agents, anti-oxidants, antifungal agents, isotonic and absorption delaying agents and the like.
  • the use of such media and agents for pharmaceutical active substances is well-known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the solid oral formulation is contemplated. Supplementary active ingredients can also be incorporated into the solid oral formulation as suitable therapeutic combinations.
  • the dispersible tablet of the invention comprises a compound of formula (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one-O-methyloxime and at least one or more pharmaceutically acceptable excipients selected from the group comprising a disintegrant, a wetting agent, a carrier, a lubricant, a binder, a diluent, a sweetener, and/or a taste-masking agent.
  • the present invention relates to a dispersible tablet comprising a compound of formula (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one-O-methyloxime, and a disintegrant.
  • the “disintegrant” is selected from one of the group comprising sodium croscarmellose, crospovidone, sodium alginate, colloidal magnesium-aluminum silicate, calcium silicate, sodium starch glycolate, acrylic acid derivatives, microcrystalline cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, modified cellulose gum, cross-linked povidone, alginic acid and alginates, pregelatinised starch, modified corn starch and combination thereof.
  • the “disintegrant” is selected from the group comprising sodium croscarmellose, crospovidone and combination thereof. More preferably, the “disintegrant” is sodium croscarmellose.
  • the present invention alternatively relates to a dispersible tablet comprising a compound of formula (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one-O-methyloxime, and a wetting agent.
  • the “wetting agent” is selected from the group comprising poloxamer, sodium lauryl sulphate, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene stearate, sorbitan fatty acid esters and combination thereof.
  • the “wetting agent” is selected from the group comprising poloxamer, sodium lauryl sulfate and combination thereof. More preferably, the “wetting agent” is poloxamer 188.
  • the present invention relates to a dispersible tablet comprising a compound of formula (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one-O-methyloxime, and a carrier.
  • the “carrier” is selected from the group comprising calcium silicate, calcium carbonate, calcium phosphate, tribasic calcium phosphate, lactose, starch, modified starch, sugars, celluloses, cellulose derivatives, polymethacrylates, chitin, chitosan and combination thereof.
  • the “carrier” is selected from the group comprising calcium silicate, calcium carbonate, calcium phosphate and combination thereof. More preferably, the carrier is calcium silicate.
  • the present invention also relates to a dispersible tablet comprising a compound of formula (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one-O-methyloxime, and/or a disintegrant, and/or a wetting agent, and/or a carrier.
  • said dispersible tablet comprises a compound of formula (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one-O-methyloxime, and/or sodium croscarmellose, and/or poloxamer 188, and/or calcium silicate.
  • the present invention also relates to a dispersible tablet comprising a compound of formula (3Z,5 S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one-O-methyloxime and at least one or more pharmaceutically acceptable excipients in an amount effective to provide a tablet that releases between about 90 to 100% of (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one-O-methyloxime.
  • a classical Pharmacopeia compliant dissolution test was performed. As shown in the example, a rapid dissolution profile of the dispersible tablet of 200 mg is observed at 15 min wherein the concentration of (3Z,5S) in water is between 90% to 100% of the initial concentration value (Table 30).
  • the one or more pharmaceutical acceptable excipients includes at least one disintegrant.
  • the disintegrant is selected from the group consisting of sodium croscarmellose, crospovidone and a combination thereof. More preferably, the “disintegrant” is sodium croscarmellose.
  • the “binder” is selected from the group comprising polyvinylpyrrolidone, cross-linked PVP, cellulose or cellulose derivatives such as hydroxypropylmethyl cellulose (HPMC), carboxymethylcellulose sodium, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose, carboxyethylcellulose, calcium, guar gum, tragacanth, polyvinylacetates, gelatin, pregelatinised starch, starch, polyvinylalcohols, alginic acid, sodium alginate, sorbitol, glucose, magnesium aluminium silicate, dextrin, polyethylene glycol, polymethacrylates and combination thereof.
  • HPMC hydroxypropylmethyl cellulose
  • the “diluent” is selected from the group comprising microcrystalline cellulose, lactose monohydrate, lactose, compressible sugar, sugar, dextrose, mannitol, dextrin, maltodextrin, sorbitol, xylitol, sodium chloride, calcium carbonate, magnesium carbonate, calcium phosphate, calcium sulphate, magnesium oxide, kaolin, powdered cellulose, pregelatinized starch, starch, barium sulphate, magnesium trisilicate, aluminium hydroxide and combination thereof.
  • the “sweetener” is sodium saccharine, sucrose, sucralose, aspartame, sorbitol or combination thereof.
  • the “lubricant” is selected from the group comprising glycerol dibehenate, glycerol tribehenate, magnesium stearate, calcium stearate, talc, sodium stearyl fumarate, sodium behenate, stearic acid, cethyl alcohol, polyoxyethylene glycol, leucine, sodium benzoate, stearates, talc, polyethylene glycol, glyceryl monostearate, glyceryl palmitostearate, liquid paraffin, poloxamer, sodium lauryl sulphate, magnesium lauryl sulphate, hydrogenated castor oil, colloidal silicon dioxide, palmitostearate, stearic acid, zinc stearate, stearyl alcohol, hydrogenated vegetable oil and combination thereof.
  • the present invention also relates to a solid oral formulation comprising a compound of formula (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one-O-methyloxime, and/or an active metabolite thereof, and at least one or more pharmaceutically acceptable excipients, wherein the concentration of said compound and/or active metabolite thereof, is comprised between about 1% and 50% w/w.
  • the concentration of the compound of formula (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one-O-methyloxime, and/or an active metabolite thereof is 10-40% w/w, 20-30% w/w, about 20% w/w.
  • the term “about” applies to numeric values and refers to a range of numbers that one of skill in the art would consider equivalent to the recited values. For example, “about 20% w/w” refers to the range 15%-25% w/w.
  • the present invention also relates to a solid oral formulation comprising a compound of formula (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one-O-methyloxime, and/or an active metabolite thereof, and at least one or more pharmaceutically acceptable excipients, wherein said formulation comprises about 10 mg to about 500 mg of the compound of formula (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one-O-methyloxime, and/or an active metabolite thereof.
  • a solid oral formulation comprising a compound of formula (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one-O-methyloxime, and/or an active metabolite
  • said formulation comprises about 20-400 mg or 40-200 mg of the compound of formula (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one-O-methyloxime, and/or an active metabolite thereof.
  • said formulation in the form of a dispersible tablet comprises about 50 mg or 200 mg of a compound of formula (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one-O-methyloxime.
  • the present invention provides a solid oral formulation, which is i) convenient to administer, ii) suitable for providing a fast onset of action and which provides a good bioavailability of the compound of formula (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one-O-methyloxime, and/or active metabolite thereof.
  • Tmax refers to the time to reach the peak plasma concentration (Cmax) of a drug after administration wherein the concentration is the amount of the drug in a given volume of plasma, expressed in ng/ml in the examples.
  • onset of action refers to the time required after administration of a drug to become effective.
  • the solid oral formulations of the present invention in particular in the form of a dispersible tablet, have the advantage of being suitable for providing a rapid onset of action.
  • the maximum concentration in blood of the compound of formula (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one-O-methyloxime, and/or active metabolite thereof, is reached at a time Tmax less than 5 h, preferably less than 4 h, more preferably less than 3 h, less than 2 h, less than 1.5 h, even more preferably less than 1 h following administration of said solid oral formulation.
  • the maximum concentration in blood of the compound of formula (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one-O-methyloxime, and/or active metabolite thereof is reached at a time Tmax between 0.5 to 4 hours, 0.5 to 2 hours, preferably 0.5 to 1.5 hours, more preferably at a time between 0.5 to 1 hour following administration of said solid oral formulation.
  • said solid oral formulation is a dispersible tablet.
  • the concentration in blood of the compound of formula (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one-O-methyloxime, and/or active metabolite thereof is at least 25%, at least 35%, at least 40%, at least 45%, at least 55%, at least 65%, at least 75%, or at least 85% of Cmax.
  • said solid oral formulation is a dispersible tablet.
  • the concentration in blood of the compound of formula (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one-O-methyloxime, and/or active metabolite thereof is comprised between 35% to 100%, 45% to 100%, 55% to 100% of Cmax, preferentially 57% to 92% of Cmax indicating that the solid oral formulation is suitable for providing a rapid onset of action.
  • said solid oral formulation is a dispersible tablet.
  • the concentration in blood of the compound of formula (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one-O-methyloxime is comprised between 59% to 100% of Cmax in animal (Table 17), preferentially 57% to 92% of Cmax in human subjects (Table 22).
  • the present invention provides a solid oral formulation, preferably a dispersible tablet that is suitable for providing a rapid onset of action, which is crucial for the management of preterm labor and premature birth.
  • the maximum concentration of the active substance (3Z,5S) is detected rapidly at about 4 hours, 2 hours, 1.5 hours, or 1 hour following administration of the dispersible tablet of the present invention.
  • the solid oral formulation of the present invention is characterized by a bioavailability of the compound of formula (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one-O-methyloxime, and/or active metabolite thereof, comprised between 50-100%, and/or 50-99%.
  • said bioavailability is comprised between 75-100%, or 75-99%, more preferably, between 80-100%, or 80-99%.
  • bioavailability refers to the fraction of an administered dose of a product that reaches the systemic circulation. By definition, when the product is administered intravenously, its bioavailability is 100%. When the product is administered via other routes, its bioavailability generally decreases.
  • the bioavailability (F %) of the solid oral formulations of the present invention is comprised between 58% and 90% (Table 16).
  • the bioavailability of the solid oral formulation in the form of a dispersible tablet is comprised between 80% and 100% (Table 18, 102% in table 18 is indicated as 100% based on the standard deviation).
  • bioavailability of the active substance (3Z,5S) is about 89% following administration of the dispersible tablet of the present invention (Table 16).
  • patients administered with the solid oral formulation of the present invention will benefit from a fast onset of action and/or a good bioavailability.
  • the present invention provides a solid oral formulation comprising:
  • a compound of formula (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one-O-methyloxime, and/or an active metabolite thereof 1-20% by weight of calcium silicate; 0.1-20% by weight of PVP30K; 0.01-5% by weight of poloxamer 188; 0.5-20% by weight of sodium croscarmellose; 1-90% by weight of microcrystalline cellulose 112; 1-90% by weight of lactose monohydrate; 0.01-0.5% by weight of sodium saccharine; and 0.1-10% by weight of glycerol dibehenate.
  • the present invention provides a dispersible tablet comprising 20% by weight of a compound of formula (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one-O-methyloxime, and 0.5-20% by weight of a disintegrant.
  • a disintegrant is sodium croscarmellose.
  • a dispersible tablet comprising 20% by weight of a compound of formula (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one-O-methyloxime, and 1-20% by weight of a carrier.
  • said carrier is calcium silicate.
  • a dispersible tablet comprising 20% by weight of a compound of formula (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one-O-methyloxime, and 0.01-5% by weight of a wetting agent.
  • said wetting agent is poloxamer 188.
  • said solid oral formulation consists of:
  • the compound (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one-O-methyloxime and/or the active metabolite thereof may be used as the sole active ingredient of the solid oral formulation, it is also possible for the compound to be used in combination with at least one or more further active compounds.
  • Such further active compounds may be further compounds according to the invention, or other active compounds selected from the group comprising calcium channel blockers, magnesium sulfate, selective prostaglandin modulators, beta-2-adrenergic agonists, beta-3-adrenergic receptor agonists, and/or corticosteroids.
  • corticosteroids are selected from the group comprising Betamethasone and Dexamethasone, and/or salts thereof. These corticosteroids are given before birth to accelerate a preterm fetus' lung development and maturation to prevent respiratory distress syndrome (RDS) and other related complications following premature birth.
  • RDS respiratory distress syndrome
  • the solid oral formulation of the invention can be administered concomitantly or separately with at least one compound selected from the group comprising calcium channel blockers (such as nifedipine), magnesium sulfate, prostaglandin receptors modulators (such as agonists or antagonists of either EP1 or EP2 or EP3 or EP4 or FP receptors), prostaglandin synthesis inhibitors (such as indomethacin, nimesulide, sulindac, rofecoxib, celecoxib), beta-2-adrenergic agonists (such as ritodrine, terbutaline, salbutamol), beta-3-adrenergic receptor agonists, nitric acid donors (such as glyceryl trinitrate) and/or corticosteroids (such as dexamethasone, betamethasone).
  • calcium channel blockers such as nifedipine
  • magnesium sulfate such as agonists or antagonists of either EP1 or EP2 or EP
  • the term “concomitantly” refers to the administration of a solid oral formulation comprising a compound of formula (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one-O-methyloxime, and/or an active metabolite thereof, which is then immediately followed by the administration of at least one compound selected from the group disclosed supra.
  • the term “separately” encompasses sequential or subsequent administration and refers to the administration of a solid oral formulation of the invention comprising the compound of formula (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one-O-methyloxime, and/or an active metabolite thereof, followed by a time period of discontinuance, which is then followed by the administration of at least one compound disclosed supra.
  • the compound of formula (3Z,5 S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one-O-methyloxime, and/or an active metabolite thereof, is an oxytocin receptor antagonist.
  • oxytocin receptor antagonist refers to a compound that functions by inhibiting (partially or completely) or blocking the oxytocin receptor (OT-R), thereby preventing activation of the receptor by oxytocin.
  • the compound of formula (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one-O-methyloxime, and/or an active metabolite thereof, is a vasopressin V1a receptor antagonist.
  • vasopressin V1a receptor antagonist refers to a compound that functions by inhibiting (partially or completely) or blocking the vasopressin V1a receptor (also known as Arginine vasopressin receptor 1A), thereby preventing activation of the receptor by vasopressin.
  • Vasopressin V1a receptor is one of the three major receptor types for the peptide hormone arginine vasopressin, the others being V1b and V2 receptors.
  • the present invention relates to a solid oral formulation
  • a solid oral formulation comprising a compound of formula (3Z,5 S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one-O-methyloxime, and/or an active metabolite thereof, and at least one or more pharmaceutically acceptable excipients, wherein said compound is an oxytocin receptor antagonist and/or a vasopressin V1a receptor antagonist.
  • Disorders associated with the oxytocin receptor activity and/or vasopressin V1a receptor activity are selected from the non-limiting group comprising preterm labor, premature birth, embryo implantation failure due to uterine contractions, dysmenorrhea, premature ejaculation, sexual dysfunction, endometriosis, infertility, benign prostatic hyperplasia, neuro-psychiatric disorders, autism, social behavior disorders, psycho-social stress, and/or cardiovascular disorders.
  • preterm labor referring also to “premature labor”, shall mean expulsion from the uterus of a viable infant before the normal end of gestation, or more particularly, onset of labor with effacement and dilation of the cervix before the 37th week of gestation. It may or may not be associated with vaginal bleeding or rupture of the membranes.
  • dismenorrhea refers to a condition characterized by cyclic pain associated with menses during ovulatory cycles. The pain is thought to result from uterine contractions and ischemia.
  • sexual dysfunction refers to any disturbance or variation in the four phases—excitement phase, plateau phase, orgasmic phase and resolution phase characterizing the human sexual response.
  • neuro-psychiatric disorders refers to mental disorders attributable to diseases of the nervous system, e.g. depression, obsessive-compulsive disorder and others.
  • social behavior disorders refers to emotional disturbance, inappropriate types of behavior or feelings, pervasive mood of unhappiness or depression and a range of perceived difficulties to build or maintain satisfactory interpersonal relationships
  • psycho-social stress refers to a condition resulting from a perceived threat to the social status, social esteem, self-worth, respect or acceptance within a group, and that lead to development of a stress response in the body and physical symptoms.
  • Assisted reproduction technologies are methods applied in humans for the treatment of infertility and in animals for producing pregnancies.
  • Infertility which affects about 10% of human pairs worldwide, may be treated by in vitro fertilization and embryo transfer (IVF-ET) or in less complicated cases, by artificial insemination.
  • IVF-ET in vitro fertilization and embryo transfer
  • a success of an embryo transfer is dependent on uterine receptivity, an entity that is defined as an ability of uterus to provide optimal conditions mandating proper implantation and embryo development.
  • Basic components of uterine receptivity are uterine contractile activity and the condition of endometrium.
  • Uterine contractions occurring during the embryo transfer may expel embryos from the uterus towards vagina or oviducts, which may be a cause of unsuccessful treatment, or in latter case a cause of extra uterine pregnancy, a serious, potentially life-threatening complication.
  • the present invention provides a solid oral formulation, for use in the treatment and/or prevention of disorders selected from the group comprising preterm labor, premature birth, dysmenorrhea, premature ejaculation, sexual dysfunction, endometriosis, embryo implantation failure due to uterine contractions, infertility, benign prostatic hyperplasia, neuro-psychiatric disorders, autism, social behaviour disorders, psycho-social stress, and/or cardiovascular disorders.
  • said solid oral formulation is a dispersible tablet.
  • the present invention provides a solid oral formulation for use in the treatment and/or prevention of preterm labor, premature birth, dysmenorrhea and embryo implantation failure due to uterine contractions.
  • the present invention also provides a process for the preparation of a solid oral formulation comprising a compound of formula (3Z,5 S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one-O-methyloxime, and/or an active metabolite thereof, characterized by a step of wet granulation.
  • granules are formed by the addition on powder particles of a liquid such as water, ethanol and isopropanol, either alone or in combination.
  • the present invention provides a process for the preparation of a tablet comprising a compound of formula (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one-O-methyloxime, and/or an active metabolite thereof, characterized by a step of wet granulation. More preferably, said tablet is a dispersible tablet.
  • the present invention provides a process for the preparation of a solid oral formulation comprising a compound of formula (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one-O-methyloxime, and/or an active metabolite thereof, and at least one or more pharmaceutically acceptable excipients, characterized by the steps of: (i) mixing the compound of formula (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one-O-methyloxime, and/or an active metabolite thereof, and at least one or more pharmaceutically acceptable excipients;
  • step (ii) wet-granulating; (iii) sieving the granules (iv) blending with a lubricant such as glycerol dibehenate; and (v) compressing the mixture obtained in step (iv) to form a tablet.
  • a lubricant such as glycerol dibehenate
  • said tablet is a dispersible tablet.
  • the tablet cores may vary in shape and be, for example, round, oval, oblong, cylindrical or any other suitable shape.
  • the present invention also provides a kit comprising a solid oral formulation comprising a compound of formula (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one-O-methyloxime, and/or an active metabolite thereof, and at least one or more pharmaceutically acceptable excipients, and information for use thereof.
  • the information contains instructions to administer the oral formulation to a subject in need thereof.
  • the subject in need thereof is preferably a mammal, most preferably a human, more preferably a woman.
  • the solid oral formulation of the present invention can be packaged in a unit dose.
  • unit dose refers to a solid oral formulation that is dispensed in a package ready to administer to the patient.
  • Each unit dose contains a predetermined quantity of active product calculated to produce the desired therapeutic effect, in association with at least one or more suitable pharmaceutical excipients.
  • the compound of formula (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one-O-methyloxime was obtained as a crude isomeric mixture comprising (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one-O-methyloxime and (3E,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one-O-methyloxime.
  • Synthetic pathways of compounds used in the invention are for example those described in WO2004005249 and WO2005082848.
  • Toluene (4.41 L, 10.0 vol) and tetrahydrofuran (4.41 L, 10.0 vol) were added to the residue, the resulting mixture stirred vigorously and acidified to pH 1 with hydrochloric acid (6M, 2.00 L, 4.5 vol). The contents were stirred vigorously for 30 to 60 minutes and the layers separated. Toluene (2.20 L, 5.0 vol) and tetrahydrofuran (2.20 L, 5.0 vol) were added to the aqueous phase and the mixture stirred for 5 to 10 minutes. The layers were separated, the combined organic phases filtered and concentrated to 10.0 vol under vacuum at 35 to 40° C.
  • Toluene (4.41 L, 10.0 vol) was added to the residue and the resultant concentrated under vacuum at 35 to 40° C.
  • the tetrahydrofuran content of the resulting slurry was determined by ‘H NMR analysis (d6-DMSO) (Pass level: ⁇ 1.0% w/w tetrahydrofuran with respect to toluene).
  • the slurry was cooled to and aged at 0 to 5° C. for 30 to 60 minutes, the solid collected by filtration and the filter-cake washed with toluene (2.20 L, 5.0 val).
  • the solid was dried in a vacuum oven at 35 to 40° C. to give 4-(2-methylphenyl)benzoic acid [0.438 Kg, 94.1% th, 99.3% w/w, 1H NMR (d6-DMSO) concordant with structure] as a pale yellow solid.
  • Thionyl chloride (0.300 L, 4.11 mol, 0.685 vol) was added to a slurry of 4-(2-methylphenyl)benzoic acid (0.435 Kg, 2.05 mol, 1.0 wt) in toluene (4.35 L, 10.0 vol) at 10 to 25° C. and the mixture heated to and maintained at 75 to 80° C. 3 until complete by 1H NMR analysis (d6-benzene,), typically 4 to 5 hours. Reaction completion was accompanied by the formation of a hazy solution. The resultant was concentrated to 5.0 vol by removal of toluene under reduced pressure at 35 to 45° C.
  • Toluene (2.18 L, 5.0 vol) was added to the concentrate and the mixture concentrated to 4.0 vol by removal of toluene under reduced pressure at 35 to 45° C.
  • the resultant was filtered through glass microfibre paper and the filter-cake washed with toluene (0.44 L, 1.0 vol).
  • the toluene solution of 4-(2-methylphenyl)benzoic acid chloride [0.439 Kg, 92.8% th, 100.9% w/w, 1H NMR (d6-benzene) concordant with structure] was used directly in Stage 3.
  • a solution of potassium carbonate (0.526 Kg, 3.81 mol, 1.2 wt) in water (0.57 L, 1.3 vol) was charged to a solution of 4-hydroxy-L-proline (0.274 Kg, 2.09 mol, 0.625 wt) in tetrahydrofuran (2.20 L, 5.0 vol) and water (0.44 L, 1.0 vol) at 15 to 25° C. followed by a line rinse of water (0.44 L, 1.0 vol). The mixture was cooled to 0 to 5° C.
  • hydrochloric acid (2M, 0.88 L, 2.0 vol) at 15 to 25° C.
  • the mixture was cooled to and aged at 0 to 5° C. for 30 to 60 minutes, the precipitated solid collected by filtration, the filter-cake washed with water (2 ⁇ 1.75 L, 2 ⁇ 4.0 vol) and toluene (0.88 L, 2.0 vol) and pulled dry on the filter for 12 to 24 hours.
  • the collected solid was dried under vacuum at 40 to 45° C.
  • Triethylamine (1.80 L, 13.56 mol, 3.0 vol) was charged to a solution of (4R)-4-hydroxy-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]-L-proline (0.598 Kg, 1.84 mol, 1.0 wt) in dimethyl sulfoxide (4.42 L, 7.4 vol) at 15 to 20° C.
  • Pyridine-sulphur trioxide complex 0.879 Kg, 5.52 mol, 1.47 wt was charged portion-wise at 15 and 25° C. and the reaction mixture stirred at that temperature until reaction completion, as determined by TLC analysis (typically 1 to 3 hours). 7 The reaction was quenched with aq.
  • hydrochloric acid (3M, 4.80 L, 8.0 vol) at 0 to 30° C., tetrahydrofuran (3.00 L, 5.0 vol) and heptanes (0.60 L, 1.0 vol) charged, the layers separated and the aqueous phase extracted with tetrahydrofuran (2 ⁇ 3.00 L, 2 ⁇ 5.0 vol).
  • the combined organic phases were washed with aq. hydrochloric acid (1 M, 2 ⁇ 1 0.20 L, 2 ⁇ 2.0 vol) and saturated sodium chloride solution (2 ⁇ 1.20 L, 2 ⁇ 2.0 vol), the aqueous washes combined and back-extracted with tetrahydrofuran (2 ⁇ 0.60 L, 2 ⁇ 1.0 vol).
  • Crystallisation commenced during the concentration.
  • the concentrate was transferred to a suitable vessel with a line rinse of ethyl acetate (0.30 L, 0.5 vol) and heated to 70 to 80° C. Additional ethyl acetate (0.30 L, 0.5 vol) was added as necessary to achieve dissolution.
  • Heptanes (1.80 L, 3.0 vol) was added at 70 to 80° C. and the contents allowed to cool to between 15 and 25° C. over 1 to 2 hours.
  • the slurry was further cooled to and aged at 0 to 5° C. for 2 to 3 hours, filtered and the filtercake washed with ethyl acetate:heptanes (1:1, 0.60 L, 1.0 vol) at 0 to 5° C.
  • Triethylamine (0.40 L, 2.85 mol, 0.92 vol) was added to a solution of 1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]-4-oxo-L-proline (0.434 Kg, 1.34 mol, 1.0 wt) in dichloromethane (4.40 L, 10.0 vol) at 10 to 25° C. followed by a line rinse of dichloromethane (0.43 L, 1.0 vol). Methoxylamine hydrochloride (0.130 Kg, 1.56 mol, 0.30 wt) was added portionwise at 10 to 25° C.
  • Potassium carbonate (0.476 Kg, 3.44 mol, 1.0 wt) was added to a solution of 4-methoxyimino-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]-L-proline (0.475 Kg, 1.35 mol, 1.0 wt) in acetone (4.75 L, 10.0 vol) and the mixture cooled to 0 to 10° C.
  • Dimethyl sulfate (0.128 L, 1.35 mol, 0.27 vol) was added at 0 to 15° C. and the mixture stirred at 15 to 25° C. until reaction completion, as determined by TLC analysis, typically 3 to 16 hours. The solvent was removed under vacuum at 40 to 45° C.
  • Lithium borohydride (0.049 Kg, 2.26 mol, 0.1 wt) was added portionwise under nitrogen to a stirred solution of (4Z/E, 2S)-methyl-1-[(2′-methyl-1,1′-biphenyl-4-yl)-carbonyl]-4-methoxyimino pyrrolidine-2-carboxylate (0.492 Kg, 1.34 mol, 1.0 wt) in tetrahydrofuran (2.31 L, 4.7 vol) and methanol (2.31 L, 4.7 vol) at 0 to 30° C. The mixture was stirred at 15 to 25° C.
  • reaction completion as determined by TLC analysis (Eluent: ethyl acetate; Visualisation: ninhydrin), typically 2 to 6 hours.
  • the reaction mixture was quenched with water (0.40 L, 0.8 val) at 15 to 25° C. and stirred at 15 to 25° C. for 16 to 20 hours.
  • the resultant was concentrated under vacuum at 40 to 45° C. and the residue partitioned between water (2.46 L, 5.0 vol) and ethyl acetate (4.92 L, 10.0 vol).
  • the layers were separated, the organic phase washed sequentially with aq. hydrochloric acid (1M, 2.46 L, 5.0 vol), sat. aq. sodium hydrogen carbonate solution (2.46 L, 5.0 vol) and sat.
  • the dry-flash chromatography of the crude isomeric mixture does not allow the purification of (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one O-methyloxime.
  • the E/Z ratio pre and post dry-flash remain in the range of 30/70 to 40/60.
  • the initial solubility screen showed that pure (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one O-methyloxime isomer is soluble in a range of solvents.
  • crystallisation by addition of anti-solvent was examined and the results reported in Table 3.
  • the anti-solvent was added to a warm solution ca 40-50° C. and allowed to cool to room temperature.
  • the water (anti-solvent) was added to a warm (40-50° C.) solution of (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl) carbonyl]pyrrolidin-3-one O-methyloxime in IPA until cloudiness was reached and the mixture was allowed to cool to room temperature.
  • the IPA/water crystallisation conditions were applied to a crude isomeric mixture.
  • the toluene solution was first concentrated to dryness prior to dissolution in IPA (8 vol) and addition of water (18 vol). Unfortunately, this resulted in material de-mixing as oil.
  • the antisolvent was added to a solution of crude (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one O-methyloxime (90.4% area purity, contained 0.5% w/w toluene and 3.7% w/w THF) at room temperature until cloudiness was reached and the mixture was left to stand at room temperature (Table 4).
  • the level of residual solvent was determined by 1 H NMR analysis (CDCl 3 ) and when found to be ⁇ 1.0% w/w the solid was passed through a 500 nm aperture sieve. The solid was returned to the oven and dried at 40 to 42° C. until the solvent level was ⁇ 0.40% w/w to afford (3Z,5S)-1-[(biphenyl-4-yl-carbonyl)-5-hydroxy-methyl]-pyrrolidine-3-one-O-methyloxime (2.633 Kg, 97.1% w/w, 1H NMR (CDCl 3 ) concordant with structure, 98.65% area by HPLC.
  • Excipients were weighed directly into a beaker, which was transferred into a thermostatic water bath until all excipients were molten at 60° C. Then, always under controlled temperature, small aliquots of (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one-O-methyloxime were added until all the drug was dissolved or dispersed, under magnetic stirring, helix mixer or homogenizer.
  • the semi-solid bulk was maintained at 60° C. during the liquid filling of the capsule shells.
  • the filling step was performed at 60° C. (both dosing pump and feeder) with an automatic lab-scale capsule-filler machine. The machine was set to the correct dosage by weighing the filled capsules.
  • Hot melt granulation was conducted in a high shear granulator MiMiPro (Procept) using different set-ups depending on the batch size.
  • the general method of manufacture is characterized by the steps of:
  • the jacketed vessel was used at 65° C. when Gelucire 50/13 was used as binder.
  • Cover temperature was set at 5° C. lower than the jacketed vessel's. Duration of phases depend on the desired particle size distribution and on the batch size.
  • Hot melt granulation is an alternative technique of granulation: unlike the traditional use of aqueous or organic solvents as binders, in this process the agglomeration is obtained through the addition of a molten binder or a solid binder, which melts during the process and remains as a constituent of the formulation.
  • the spray-drying process produces porous/hollow particles and amorphous forms of the sprayed material. This approach is used when dissolution rate improvement is required.
  • the spray-drying process consists of four steps: atomisation of feed solution into a spray camera, spray-air contact involving flow and mixing, drying of sprayed droplets at elevated temperatures and separation of dried product from air.
  • the granules 5.8% were prepared by spray-drying of (3Z,5S), in presence of HP- ⁇ -CD (hydroxypropyl- ⁇ -cyclodextrin) in hydroethanolic solution.
  • (3Z,5S) is an amorphous material that forms clumps of particles in water, which reduces the drug dissolution rate. Therefore, a hydrophilic excipient, spray-dried together with (3Z,5S) was used to improve the dissolution rate of the drug by preventing the aggregation in water.
  • HP- ⁇ -CD was selected as hydrophilic excipients.
  • HP- ⁇ -CD spray dried product was obtained from the hydroalcoholic solution both using the Mini AirPro or Buchi equipment.
  • the feeding solution was prepared by mixing an equal volume of a HP- ⁇ -CD (100 g in 200 ml) aqueous solution and an (3Z,5S) (24 g in 200 ml) ethanolic solution that was left for 24 hours under agitation at room temperature.
  • the spray-drying conditions in the fluid bed Mini AirPro were: blower speed 1 m 3 /min, nozzle pressure 1 bar, liquid speed 3, inlet air temperature 70° C.
  • Spray-dried materials presented very poor flow properties precluding their use for sachet filling.
  • dry granulation and ethanolic wet granulation were the processes applied to the (3Z,5S)-HP- ⁇ -CD spray-dried material.
  • the dissolution rate of (3Z,5S) after spray-drying with HP- ⁇ -CD was almost instantaneous, in 15 minutes almost all drug was dissolved.
  • the granulation process by ethanolic wet granulation was performed on the (3Z,5S)-HP ⁇ CD spray-dried material. It did not modify the dissolution rate of the drug when compared to the (3Z,5S)-HP ⁇ CD spray-dried material.
  • a solution containing (3Z,5S) dissolved in Labrasol:Ethanol 3:1 v/v was prepared by heating at 45° C. and adding stepwise the required amount of drug.
  • Zeopharm 600 was dried for 2 hours into a vacuum oven at 50° C.
  • the addition of the solution on Zeopharm 600 bed was carried out into a 1900 ml bowl at 5 ml/min.
  • the granulator was set as follows: impeller at 900 rpm, chopper at 3500 rpm, and cover temperature at 80° C. To remove most of the solvent, the material was left overnight at room temperature, and 3.5 hours in a vacuum oven at 50° C.
  • the material was sieve-milled first through a 1.5 mm sieve and then through a 1 mm sieve.
  • the granule-adsorbate (87.5%) was then mixed with AcDiSol (4%), Compritol 888 ATO (3.5%), GL100 (0.2%) and Zeopharm 600 (4.8%) for 20 minutes at 22 r.p.m in the Turbula mixer.
  • the final blend for tabletting possessed a good (3Z,5S) content uniformity.
  • the conventional tablets were produced by compression of the granules using the eccentric tabletting machine EK-0.
  • a 850 g batch granulate was produced and then compressed into tablets.
  • a 5000 ml vessel set-up was used for this preparation.
  • Calcium silicate was vacuum dried prior to use.
  • the wet granulation was conducted with (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one-O-methyloxime and all excipients (with the exception of the lubricant) in a high shear granulator at room temperature with only the cover of the granulator heated (65° C.).
  • a total amount of 80 ml of ethanol was necessary to obtain suitable granules.
  • a final milling and/or sieving step was necessary to obtain a better granule size distribution.
  • the resulting granules were blended with the lubricant before compression.
  • the compound of formula (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one-O-methyloxime, and/or an active metabolite thereof, is in the form of dispersible tablets containing 50 or 200 mg of active drug substance (Table 13).
  • the shape and dimensions of the tablets are the following:
  • Formulation 1 Formulation 2
  • Formulation 3 Formulation 4
  • Formulation Solution Liquid Granules Granules Dispersible Conventional of (3Z,5S) filled 10% 5.8% tablet tablet capsules 200 mg 200 mg Dose mg/kg 15 mg/kg 300 mg/ 20 20 23.4 (3.4) 23.3 (3.2) dog (200 mg/dog) (200 mg/dog) Volume of 1 capsule 5 ml/kg 5 ml/kg 50 ml/dog 50 ml/dog administration size 00
  • FIG. 1A shows the plasma concentration vs. time profile of the different formulations over the time period from 0 to 72 h.
  • FIG. 1B shows an enlargement of FIG. 1A for the time period from 0 to 12 h.
  • the curve corresponding to formulation 3 shows that the maximum concentration of the active substance is detected rapidly at about 0.5-1 hour following its administration. In comparison, the maximum concentration of the active substance is detected at about 2-4 hours following administration of formulation 4 (conventional tablet).
  • FIG. 2 Treatment 3
  • FIG. 3 Treatment 4
  • the bioavailability is measured by calculating the area under the curve (AUC) of the product concentration vs. time profile.
  • AUC area under the curve
  • the absolute bioavailability compares the bioavailability of the product in systemic circulation following oral administration with the bioavailability of the product following intravenous administration.
  • D refers to the dose that is the amount of drug administered.
  • Cmax refers to the peak plasma concentration of a drug after administration wherein the concentration is the amount of drug in a given volume of plasma.
  • Tmax refers to the time to reach Cmax.
  • T 1/2 refers to the elimination half-life as the time required for the concentration of the drug to reach half of its original value.
  • AUC as used herein refers to the area under the curve that is the integral of the concentration-time curve (after a single dose or in steady state).
  • F % refers to the bioavailability that is the systemically available fraction of a drug.
  • the index of bioavailability after oral administration is calculated by the following equation using the AUC found after i.v. administration:
  • Formulations 1 and 2 showed equivalent responses and were characterized by a favorable fast compound absorption (Table 16). Their absolute bioavailability was good (about 60%), even though lower than the other formulations tested, but associated with a moderate variability between animals.
  • Dispersible tablets Formulation 3 showed a rate of absorption comparable to granules followed by a decay comparable to the Reference Capsule formulation. A very high compound exposure highlighted by the absolute bioavailability (higher than after administration of granules and comparable to the liquid filled capsule reference formulation) was observed.
  • Conventional tablets Formulation 4 gave a delayed absorption compared to Formulation 3 with a roughly similar bioavailability.
  • the concentration in blood of the compound of formula (3Z,5S) is comprised between 59% to 100% of Cmax indicating that said formulation is suitable for providing a rapid onset of action (Table 17).
  • Formulation 3 is characterized by a bioavailability of the compound of formula (3Z,5S) comprised between 80-100% (Table 18).
  • the concentration in blood of the compound of formula (3Z,5S) is comprised between 14% to 41% of Cmax (Table 19) a value markedly lower than for formulation 3 which is characterized by a higher concentration of the compound of formula (3Z,5S) comprised between 59% to 100% of Cmax (Table 17).
  • Formulation 2 (granule 5.8%) is characterized by a bioavailability of the compound of formula (3Z,5S) comprised between 41-76% (Table 20) markedly lower than for formulation 3 which is characterized by a very high bioavailability comprised between 80-100% (Table 18).
  • the dispersible tablet formulation 3 displays characteristics that are suitable for providing a fast onset of action and high bioavailability for the treatment of preterm labor.
  • conventional tablet (formulation 4) or granules (formulation 2) do not meet the pharmacokinetic requirements for treating preterm labor.
  • Betamethasone (Célèstene®, Schering-Plough, France) was administered by intramuscular injection of 12 mg/3 ml into the gluteus muscle, which is a recommended dose for antenatal betamethasone in preterm labor for the prevention of respiratory distress syndrome in neonates.
  • Subject S6 One subject (Subject S6) was withdrawn from the study after the first treatment period, due to high pre-dose blood pressure in the second treatment period. Therefore, pharmacokinetic parameters of the treatment with (3Z,5S) dispersible tablets were calculated for 12 subjects, whereas pharmacokinetic parameters of the combination treatment were assessed for 11 participants.
  • Pharmacokinetic parameters were estimated by non-compartmental methods using the Phoenix® WinNonLin® version 6.3 (Pharsight). The following pharmacokinetic parameters were calculated for (3Z,5 S) during each treatment period: measured maximum concentration (Cmax), time to Cmax (Tmax), and area under the plasma concentration-time curve (AUC).
  • Tables 21 to 23 show plasma concentration profiles of (3Z,5S) and pharmacokinetic parameters concerning (3Z,5S) which was administered to subjects using 3 dispersible tablets of 200 mg in 150 ml of water.
  • the maximum concentration Cmax in blood of the compound of formula (3Z,5S) is reached at a time Tmax between 0.5 to 4 hours.
  • Tmax is in the range of 0.5 to 2 hours for 9 subjects, and in the range of 0.5 to 1.5 hours for 5 subjects.
  • the concentration in blood of the compound of formula (3Z,5S) is comprised between 55% to 95% of Cmax for 10 subjects, preferentially between 57% to 92% of Cmax, indicating that the solid oral formulation is rapidly absorbed and suitable for providing a rapid onset of pharmacological action.
  • the plasma concentration of (3Z,5S) was below 55% at 0.5 h, respectively 35% and 28% of Cmax. However, it was respectively 71% and 51% of Cmax at 1 h following administration of the dispersible tablet which concentration is suitable for the management of preterm labor.
  • Tables 24 to 26 show plasma concentration profiles of (3Z,5S) and pharmacokinetic parameters concerning (3Z,5S) administered in combination with Betamethasone.
  • the maximum concentration Cmax in blood of the compound of formula (3Z,5S) is reached at a time Tmax between 1 to 6 hours.
  • Tmax is in the range of 2 to 4 hours for 9 subjects, and in the range of 2 to 3 hours for 6 subjects.
  • the concentration in blood of the compound of formula (3Z,5S) is comprised between 43% to 83% of Cmax for 10 subjects indicating that the solid oral formulation administered in combination with betamethasone is rapidly absorbed and suitable for providing a rapid onset of pharmacological action.
  • the plasma concentration of (3Z,5S) was below 43% at 0.5 h, respectively 10% and 28% of Cmax. However, it was respectively 51% and 62% of Cmax at 2 h following administration of the dispersible tablet.
  • the manufacturing process of the dispersible tablets of the present invention comprises the following steps:
  • the wet granulation is preferably conducted in a high shear granulator at room temperature with a minimal amount of ethanol equivalent to at least 7.4% (in weight based on the total weight of the tablet).
  • the vacuum drying is performed at room temperature
  • a sieving step is applied on the resulting granules.
  • Sieved glycerol dibehenate is blended with the granules.
  • the final blend is compressed with an eccentric or rotary tablet press and adapted punches for the targeted dispersible tablet strength.
  • Dissolution medium 0.5% Sodium Lauryl Sulfate in water
  • Dissolution medium volume 900 ml
  • Dissolution medium temperature 37° C.+/ ⁇ 0.5° C.
  • Rotation speed 50 rpm
  • Sampling time 15, 30, 45, 60 and 120 min
  • Sampling volume 3 ml
  • Separative technique PALL Acrodisc PSF GxF/Glass 1.0 ⁇ m
  • the paddle assembly is arranged so that the bottom of the paddle was 2.5 cm ⁇ 0.2 cm from the inside bottom of the flask.
  • the appropriate volume of dissolution medium is poured into each one of the six dissolution vessels.
  • the medium is equilibrated at 37.0 C ⁇ 0.5 C.
  • a (3Z,5S) dispersible tablet is inserted into each vessel.
  • the paddles rotation was controlled at 50 rpm.
  • 3 ml of medium is taken from a zone midway between the surface of the dissolution medium and the top of the blade of the paddle. Then, the sample is filtered through a PALL Acrodisc PSF GxF/Glass 1.0 ⁇ m directly into an HPLC vial for analysis.
  • Stability data are available at 1, 2 and 6 months storage time for (3Z,5S) dispersible tablets packaged in Alu/Alu blister packs. Parameters such as tablet appearance, (3Z,5S) content in % compared to the initial content value, disintegration time and dissolution were assessed (Tables 28 and 29).
  • the initial concentration value of (3Z,5S) measured by HPLC with a dispersible tablet is 90.0-110.0%.
  • a rapid disintegration of the tablet is observed following dissolution in the range of 20 to 40 sec at 25° C./60% RH.
  • the disintegration property of the dispersible tablet is likely due to its disintegrant component, for example, Sodium croscarmellose that promotes the breakup or disintegration of the tablet when placed in an aqueous environment and supports a fast dissolution profile.
  • the wetting agent for example, Poloxamer 188
  • the carrier agent selected with a large surface area for example Calcium silicate, was also identified as a potential benefit for the disintegration of the tablet.
  • a rapid dissolution profile of the tablet is observed for the different storage conditions.
  • the content of (3Z,5S) measured at 15 min is between 90 to 100% of the initial value.

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US10047048B2 (en) 2013-09-10 2018-08-14 ObsEva S.A. Pyrrolidine derivatives as oxytocin/vasopressin V1a receptors antagonists
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