Oral formulations of pyrrolidine derivatives

Abstract

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.

1 . 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. 
     
     
         2 . The dispersible tablet according to  claim 1 , wherein the at least one or more pharmaceutically acceptable excipients is selected from the group consisting of a disintegrant, a wetting agent, a carrier, a lubricant, a binder, a diluent, a sweetener, and a taste-masking agent. 
     
     
         3 . The dispersible tablet according to  claim 2 , wherein the carrier is selected from the group consisting of calcium silicate, calcium carbonate, calcium phosphate, tribasic calcium phosphate, lactose, starch, modified starch, sugars, celluloses, cellulose derivatives, polymethacrylates, chitin, chitosan and combinations thereof. 
     
     
         4 . The dispersible tablet according to  claim 2 , wherein the binder is selected from the group consisting of polyvinylpyrrolidone, cross-linked PVP, cellulose or cellulose derivatives such as hydroxypropylmethylcellulose (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 combinations thereof. 
     
     
         5 . The dispersible tablet according to  claim 2 , wherein the wetting agent is selected from the group consisting of poloxamer, sodium lauryl sulphate, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene stearate, sorbitan fatty acid esters and combinations thereof. 
     
     
         6 . The dispersible tablet according to  claim 2 , wherein the disintegrant is selected from the group consisting of 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 combinations thereof. 
     
     
         7 . The dispersible tablet according to  claim 2 , wherein the diluent is selected from the group consisting of 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 combinations thereof. 
     
     
         8 . The dispersible tablet according to  claim 2 , wherein the sweetener is sodium saccharine. 
     
     
         9 . The dispersible tablet according to  claim 2 , wherein the lubricant is selected from the group consisting of 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. 
     
     
         10 . The dispersible tablet according to  claim 1 , wherein 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 is comprised between about 1% and 50% w/w. 
     
     
         11 . The dispersible tablet according to  claim 1 , wherein said dispersible tablet comprises about 10 mg to 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 
     
     
         12 . The dispersible tablet according to  claim 1 , wherein 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 is reached at a time between 0.5 to 2 hours after administration. 
     
     
         13 . The dispersible tablet according to  claim 1 , wherein 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 at least 40% of Cmax at 0.5 after administration. 
     
     
         14 . The dispersible tablet according to  claim 1 , wherein said dispersible tablet provides 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 between 50-100%. 
     
     
         15 . A method of administering the dispersible tablet according to  claim 1 , the method comprising the step of administering to a patient said dispersible tablet concomitantly or separately with at least one compound selected from the group consisting of calcium channel blockers, magnesium sulfate, selective prostaglandin modulators, beta-2-adrenergic agonists, beta-3-adrenergic receptor agonists, corticosteroids and combinations thereof. 
     
     
         16 . The method according to  claim 15 , wherein corticosteroids are selected from the group consisting of betamethasone, dexamethasone, and salts thereof. 
     
     
         17 . The dispersible tablet according to  claim 1 , wherein said dispersible tablet is in a unit dose. 
     
     
         18 . The dispersible tablet according to  claim 1 , comprising:
 about 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;   about 1-20% by weight of calcium silicate;   about 0.1-20% by weight of PVP30K;   about 0.01-5% by weight of poloxamer 188;   about 0.5-20% by weight of sodium croscarmellose;   about 1-90% by weight of microcrystalline cellulose 112;   about 1-90% by weight of lactose monohydrate;   about 0.01-0.5% by weight of sodium saccharine; and   about 0.1-10% by weight of glycerol dibehenate.   
     
     
         19 . The dispersible tablet according to  claim 18 , consisting essentially of: about 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,
 about 5% by weight of calcium silicate, 
 about 1% by weight of PVP30K, 
 about 2% by weight of poloxamer 188, 
 about 5% by weight of sodium croscarmellose, 
 about 15% by weight of microcrystalline cellulose 112, 
 about 47.8% by weight of lactose monohydate, 
 about 0.2% by weight of sodium saccharine and 
 about 4% by weight of glycerol dibehenate. 
 
     
     
         20 . A method or treating and/or preventing of disorders selected from the group consisting of 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 cardiovascular disorders, the method comprising the step of administering the disperisible tablet according to  claim 1  to a patient in need thereof. 
     
     
         21 . A process for the preparation of a dispersible tablet according to  claim 1 , wherein the process comprises a step of wet granulation. 
     
     
         22 . A kit comprising a dispersible tablet according to  claims 1  and information for use.