Oral liquid formulations of lipid-lowering and blood pressure-lowering drugs
This application discloses oral liquid formulations of lipid/cholesterol-lowering drugs and blood pressure-lowering drugs, and combinations thereof, comprising surfactant(s) as stabilizer(s), which forms micelles with the drug molecules to enhance their solubility and stability.
1. An oral liquid formulation, comprising: (a) a combination of drugs wherein the drugs are selected from the group consisting of ezetimibe, statins, fenofibrate, amlodipine, valsartan, candesartan, telmisartan, losartan and salts thereof; (b) about 20% to about 90% w/w of one or more non-ionic surfactants that are liquids at ambient conditions; (c) about 0.05% to about 7.5% w/w of a co-solvent selected from the group consisting of an oil, glycerin, propylene glycol, polyethylene glycols that are liquids at ambient conditions, C1-C6 straight and branch monoalcohols and combinations thereof; (d) about 0.1% to about 5% w/w of a buffering agent, and (e) water wherein if present the ezetimibe is present in an amount of 0.05% to 10% w/w and if present the statins, fenofibrate, amlodipine, valsartan, candesartan, telmisartan, losartan and salts thereof are present in an amount of 0.05% to 20% w/w.
2. The oral liquid formulation of claim 1 , wherein the combination of drugs are selected from the group consisting of: (i) a combination of ezetimibe and a statin or salt thereof; (ii) a combination of ezetimibe and fenofibrate or salt thereof; (iii) a combination of ezetimibe and amlodipine or salt thereof; (iv) a combination of a statin or salt thereof and fenofibrate or salt thereof; (v) a combination of a statin or salt thereof and amlodipine or salt thereof; and (vii) a combination of fenofibrate or salt thereof and amlodipine or salt thereof.
3. The oral liquid formulation of claim 1 further comprising one or more excipients selected from an antioxidant, a preservative, an antimicrobial, a pH adjusting agent, a sweetening agent, a flavoring agent, a viscosity enhancing agent, a hydrophilic stabilizing agent and combinations thereof.
4. The oral liquid formulation of claim 3 , wherein the preservative is selected from the group consisting of methyl parahydroxybenzoate, ethylparahydroxybenzoate, propylparahydroxybenzoate, sorbic acid, potassium sorbate, and combinations thereof; the antioxidant is selected from the group consisting of butylated hydroxyanisole, butylated hydroxytoluene, ascorbic acid, and combinations thereof; the buffering agent is selected from the group consisting of citric acid, acetic acid, ascorbic acid, sodium citrate, sodium acetate, sodium ascorbate, disodium hydrogen phosphate, and combinations thereof; the sweetening agent is selected from the group consisting of sucrose, sorbitol, sodium saccharin, acesulfame potassium, xylitol, fructose, sucralose, and combinations thereof; and the flavoring agent is selected from the group consisting of citric acid, mint, spearmint, peppermint, wintergreen, anise, walnut, almond, menthol, lemon, lime, orange, grape, cherry, raspberry, bubblegum, chocolate extracts or oils, vanilla extracts or oils and combinations thereof.
5. The oral liquid formulation of claim 3 , comprising: 0.05% to 10% w/w of ezetimibe, polyoxyethylene 35 castor oil, caprylocaproyl polyoxylglycerides, one or more antioxidants, one or more preservatives, sodium citrate, citric acid, sucrose, and saccharin sodium.
6. The oral liquid formulation of claim 3 , comprising: 0.05% to 10% w/w of fenofibrate or salt thereof, polyoxyethylene 35 castor oil, caprylocaproyl polyoxylglycerides, one or more antioxidants, one or more preservatives, sodium citrate, citric acid, sucrose, and saccharin sodium.
7. The oral liquid formulation of claim 3 , comprising: 0.05% to 10% w/w of atorvastatin or salt thereof, polyoxyethylene 35 castor oil, caprylocaproyl polyoxylglycerides, one or more antioxidants, one or more preservatives, sodium citrate, citric acid, sucrose, and saccharin sodium.
8. The oral liquid formulation of claim 3 , comprising: 0.05% to 10% w/w of simvastatin, polyoxyethylene 35 castor oil, caprylocaproyl polyoxylglycerides, one or more antioxidants, one or more preservatives, sodium citrate, citric acid, sucrose, and saccharin sodium.
9. The oral liquid formulation of claim 3 , comprising: 0.05% to 10% w/w of ezetimibe, 0.05% to 10% w/w of simvastatin, caprylocaproyl polyoxylglycerides, one or more antioxidants, one or more preservatives, sodium citrate, citric acid, sucrose, and saccharin sodium.
10. The oral liquid formulation of claim 3 , comprising: 0.05% to 10% w/w of ezetimibe, 0.05% to 10% w/w of atorvastatin or salt thereof, caprylocaproyl polyoxylglycerides, one or more antioxidants, one or more preservatives, sodium citrate, citric acid, sucrose, and saccharin sodium.
11. The oral liquid formulation of claim 3 , comprising: 0.05% to 10% w/w of ezetimibe, 0.05% to 10% w/w of fenofibrate or salt thereof, caprylocaproyl polyoxylglycerides, one or more antioxidants, one or more preservatives, sodium citrate, citric acid, sucrose, and saccharin sodium.
12. The oral liquid formulation of claim 3 , comprising 0.05% to 10% w/w of fenofibrate or salt thereof, 0.05% to 10% w/w of simvastatin, caprylocaproyl polyoxylglycerides, one or more antioxidants, one or more preservatives, sodium citrate, citric acid, sucrose, and saccharin sodium.
13. The oral liquid formulation of claim 3 , comprising: 0.05% to 10% w/w of fenofibrate or salt thereof, 0.05% to 10% w/w of atorvastatin or salt thereof, polyoxyethylene 35 castor oil, caprylocaproyl polyoxylglycerides, one or more antioxidants, one or more preservatives, sodium citrate, citric acid, sucrose, and saccharin sodium.
14. The oral liquid formulation of claim 3 , comprising: 0.05% to 10% w/w of amlodipine or salt thereof, polyoxyethylene 35 castor oil, caprylocaproyl polyoxylglycerides, one or more antioxidants, one or more preservatives, sodium citrate, citric acid, sucrose, and saccharin sodium.
15. The oral liquid formulation of claim 3 , comprising: 0.05% to 10% w/w of ezetimibe, 0.05% to 10% w/w of amlodipine or salt thereof, polyoxyethylene 35 castor oil, caprylocaproyl polyoxylglycerides, one or more antioxidants, one or more preservatives, sodium citrate, citric acid, sucrose, and saccharin sodium.
16. The oral liquid formulation of claim 3 , comprising: 0.05% to 10% w/w of atorvastatin or salt thereof, 0.05% to 10% w/w of amlodipine or salt thereof, polyoxyethylene 35 castor oil, caprylocaproyl polyoxylglycerides, one or more antioxidants, one or more preservatives, sodium citrate, citric acid, sucrose, and saccharin sodium.
17. The oral liquid formulation of claim 3 , comprising: 0.05% to 10% w/w of simvastatin, 0.05% to 10% w/w of amlodipine or salt thereof, polyoxyethylene 35 castor oil, caprylocaproyl polyoxylglycerides, one or more antioxidants, one or more preservatives, sodium citrate, citric acid, sucrose, and saccharin sodium.
18. The oral liquid formulation of claim 3 , comprising: 0.05% to 10% w/w of fenofibrate or salt thereof, 0.05% to 10% w/w of amlodipine or salt thereof, polyoxyethylene 35 castor oil, caprylocaproyl polyoxylglycerides, one or more antioxidants, one or more preservatives, sodium citrate, citric acid, sucrose, and saccharin sodium.
19. A method of treating hyperlipidemia, mixed dyslipidemia, heterozygous familial hypercholesterolemia, atherosclerotic cardiovascular disease, hypertension, or coronary artery disease, comprising administering to a patient in need thereof a therapeutically effective amount of an oral liquid formulation according to claim 1 .
20. The oral liquid formulation of claim 1 wherein the one or more non-ionic surfactants that are liquids at ambient conditions comprises a combination of (i) one or more non-ionic surfactants with an HLB value of 10 or greater and (ii) one or more non-ionic surfactants with an HLB value of less than 10 and the weight ratio of (i) to (ii) is 0.2:1 to 1:0.2.
21. The oral liquid formulation of claim 1 wherein the one or more non-ionic surfactants that are liquids at ambient conditions comprises a combination of (i) one or more non-ionic surfactants with an HLB value of 10 or greater and (ii) one or more non-ionic surfactants with an HLB value of less than 10 and the weight ratio of (i) to (ii) is 0.5:1 to 1:0.5.
22. The oral liquid formulation of claim 1 wherein the co-solvent is present in an amount of about 0.5% to about 5% w/w.