PHARMACEUTICAL FORMULATIONS
The present invention relates to oral formulations comprising an active agent comprising at least one of 2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-propanoic acid, salts of 2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-propanoic acid or buffered 2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-propanoic acid.
1 . A modified release pharmaceutical composition suitable for oral administration, comprising:
(i) a choline salt of 2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-propanoic acid; and
(ii) at least one rate-controlling mechanism,
wherein a percentage of the composition dissolved in an in vitro dissolution at a single pH at about one-half (0.5) hours is at least about 15.0% but not greater than about 71.0%, at about one (1) hour is at least about 40.0% but not greater than about 81.0%; or at about one-half (0.5) hours is at least about 15.0% but not greater than about 71.0% and at about one (1) hour is at least about 40.0% but not greater than about 81.0%.
2 . The composition of claim 1 , wherein the percent of the composition dissolved in an in vitro dissolution at a single pH at about one-half (0.5) hours is at least about 15.0% and is less than or equal to about 57.0%; at about one (1) hour is at least about 40.0% and less than or equal to about 70.0%; or at 0.5 hours is at least about 15.0% and is less than or equal to about 57.0% and at about one (1) hour is at least about 40.0% and less than or equal to about 70.0%.
3 . The composition of claim 1 , wherein the choline salt of 2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-propanoic acid is present in an amount of about 35% to about 71.5%.
4 . The composition of claim 1 , wherein the rate controlling mechanism is selected from a group consisting of: a hydrophilic agent, a hydrophobic agent, or combinations of the foregoing.
5 . The composition of claim 4 , wherein the hydrophilic agent is selected from a group consisting of: a cellulose, a polyethylene oxide, a polyethylene glycol, a xanthum gum, an alginate, a polyvinyl pyrrolidone, a starch, a cross-linked homopolymer, a copolymer of acrylic acid, or combinations of the foregoing.
6 . The composition of claim 5 , wherein the cellulose is selected from a group consisting of: hydroxylpropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, or combinations of the foregoing.
7 . The composition of claim 4 , wherein the hydrophobic agent is selected from a group consisting of: a wax or a water-insoluble agent.
8 . The composition of claim 7 , wherein the wax is selection from a group consisting of: a natural wax, a synthetic wax, or combinations of the foregoing.
9 . The composition of claim 7 , wherein the water-insoluble agent is selected from a group consisting of: an amminomethacrylate copolymer, a cellulose, an ethylcellulose, a cellulose acetate, a cellulose acetate butyrate, a cellulose acetate proprionate, a methacrylic ester copolymer, a microcrystalline cellulose, a dibasic calcium phosphate, or combinations of the foregoing.
10 . The composition of claim 1 , further comprises an enteric coating.
11 . The composition of claim 10 , wherein the enteric coating is selected from a group consisting of: a methylacrylic acid and methacrylic ester copolymer, a cellulose acetate phthalate, a hydroxylpropylmethylcellulose phthalate, a hydroxylpropylmethylcellulose acetate succinate, a polyvinyl acetate phthalate, a ethylacrylate/methylacrylic acid copolymer, a cellulose acetate trimellitate, a shellac, or combinations of the foregoing.
12 . The composition of claim 1 , wherein upon oral administration of the composition to a human subject, an AUC in a fed state does not differ substantially compared to an AUC in a fasting state.
13 . The composition of claim 12 , wherein the AUC in the fed state over the AUC in the fasting state is about 0.70 to about 1.43.
14 . The composition of claim 12 , wherein the AUC in the fed state over the AUC in the fasting state is about 0.80 to about 1.25.
15 . The composition of claim 1 , further comprising a therapeutic agent is selected from the group consisting of: an anti-hypertensive or a lipid-regulating agent.
16 . The composition of claim 15 , wherein the anti-hypertensive is selected from the group consisting of: amlodipine, benazepril, benidipine, candesartan, captopril, carvedilol, darodipine, dilitazem, diazoxide, doxazosin, enalapril, epleronone, eprosartan, felodipine, fenoldopam, fosinopril, guanabenz, iloprost, irbesartan, isradipine, lercardinipine, lisinopril, losartan, minoxidil, nebivolol, nicardipine, nifedipine, nimodipine, nisoldipine, omapatrilat, phenoxybenzamine, prazosin, quinapril, reserpine, semotiadil, sitaxsentan, terazosin, telmisartan, labetolol, valsartan, triamterene, metoprolol, methyldopa, ramipril, olmesartan, timolol, verapamil, clonidine, nadolol, bendromethiazide, torsemide, hydrochlorothiazide, spinronolactone, perindopril, hydralazine, betaxolol, furosimide, penbutolol, acebutolol, atenolol, bisoprolol, nadolol, penbutolol, pindolol, propranolol, timolol, indapamide, trandolopril, amiloride, moexipril, metolozone, or valsartan.
17 . The composition of claim 15 , wherein the lipid-regulating agent is selected from the group consisting of: atorvastatin, simvastatin, fluvastatin, pravastatin, lovastatin, cerivastatin, rosuvastatin, pitavastatin, clofibric acid, niacin/nicotinic acid, torcetrapib, colestipol, omega-3 acid ethyl esters, colesevelam, cholestyramine, ezetimibe, MD-0727, gemfibrozil or probucol.
18 . A method of treating a medical condition in a human subject in need thereof, comprising orally administering a pharmaceutical composition comprising:
(i) a choline salt of 2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-propanoic acid; and
(ii) at least one rate-controlling mechanism,
wherein a percentage of the composition dissolved in an in vitro dissolution at a single pH at about one-half (0.5) hours is at least about 15.0% but not greater than about 71.0%, at about one (1) hour is at least about 40.0% but not greater than about 81.0%; or at about one-half (0.5) hours is at least about 15.0% but not greater than about 71.0% and at about one (1) hour is at least about 40.0% but not greater than about 81.0%; and
wherein the medical condition is selected from a group consisting of: hypercholesterolemia, hypertriglyceridemia, cardiovascular disorders, coronary heart disease, peripheral vascular disease, and metabolic disorders.
19 . The method of claim 18 , wherein the pharmaceutical composition further comprises an enteric coating.
20 . The method of claim 18 , wherein upon oral administration of the composition to a human subject, an AUC in a fed state does not differ substantially compared to an AUC in a fasting state.
21 . The method of claim 20 , wherein the AUC in the fed state over the AUC in the fasting state is about 0.70 to about 1.43.
22 . The method of claim 20 , wherein the AUC in the fed state over the AUC in the fasting state is about 0.80 to about 1.25.
23 . The method of claim 18 , wherein the percent of the composition dissolved in an in vitro dissolution at a single pH at about one-half (0.5) hours is at least about 15.0% and is less than or equal to about 57.0%; at about one (1) hour is at least about 40.0% and less than or equal to about 70.0%; or at 0.5 hours is at least about 15.0% and is less than or equal to about 57.0% and at about one (1) hour is at least about 40.0% and less than or equal to about 70.0%.