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/are 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. 
     
     
         3 . The dispersible tablet according to  claim 2 , wherein 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. 
     
     
         4 . The dispersible tablet according to  claim 2 , wherein 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. 
     
     
         5 . The dispersible tablet according to  claim 2 , wherein 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. 
     
     
         6 . The dispersible tablet according to  claim 2 , wherein the disintegrant is selected from 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. 
     
     
         7 . The dispersible tablet according to  claim 2 , wherein 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. 
     
     
         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 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. 
     
     
         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,5 S)-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 h after administration. 
     
     
         14 . The dispersible tablet according to  claim 1 , wherein said dispersible tablet is characterized by a bioavailability of the compound of formula (3Z,5 S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one-O-methyloxime comprised between 50-100%, preferably between 80-100%. 
     
     
         15 . The dispersible tablet according to  claim 1 , wherein said dispersible tablet is to be administered concomitantly or separately with at least one compound 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. 
     
     
         16 . The dispersible tablet according to  claim 14 , wherein corticosteroids are selected from the group comprising betamethasone, dexamethasone, and/or 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:
 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;   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.   
     
     
         19 . The dispersible tablet according to  claim 18 , consisting of:
 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,   5% by weight of calcium silicate,   1% by weight of PVP30K,   2% by weight of poloxamer 188,   5% by weight of sodium croscarmellose,   15% by weight of microcrystalline cellulose 112,   47.8% by weight of lactose monohydrate,   0.2% by weight of sodium saccharine and   4% by weight of glycerol dibehenate.   
     
     
         20 . The dispersible tablet according to  claim 1 , 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. 
     
     
         21 . A process for the preparation of a dispersible tablet according to  claim 1  characterized in that it comprises a step of wet granulation. 
     
     
         22 . A kit comprising a dispersible tablet according to  claim 1 , and information for use.