Kinase inhibitor salts and compositions thereof

Abstract

To provide compositions which improve kinase inhibitor absorption following oral administration, reduce the absorption variation when the kinase inhibitor is orally administered with or without food, and / or reduce the absorption variation when co-administered with other drugs such as gastric acid reducing agents.SOLUTION: The present invention relates to kinase inhibitor C8-C16 aliphatic sulfate salts, compositions comprising kinase inhibitor C8-C16 aliphatic sulfate salts, and their use.SELECTED DRAWING: Figure 1

Claims

1. Cabozantiniblauric sulfate.

2. An oral dosage form comprising a therapeutic dose of the salt described in claim 1, and one or more additives.

3. The aforementioned cabozantiniblaurill sulfate salt is (a) Amorphous, (b) Crystalline, or (c) A combination of amorphous and crystalline materials, The oral dosage form according to claim 2.

4. The oral dosage form according to claim 3, wherein the dosage form is a tablet.

5. The oral dosage form according to claim 3, wherein the dosage form is a capsule.

6. (i) 3% to 50% by weight of cabozantiniblauric sulfate, (ii) One or more wetting agents, emulsifiers, solubilizers, surfactants, or combinations thereof, in an amount of 1% to 90% by weight, each having an HLB value of 10 or more. The oral dosage form according to claim 5, including the above.

7. The oral dosage form according to claim 6, wherein the one or more wetting agents, emulsifiers, solubilizers, surfactants, or combinations thereof that exhibit an HLB value of 10 or more are selected from the group consisting of fatty alcoholic acids or amide ethoxylates, monoglyceride ethoxylates, sorbitan ester ethoxylate alkyl polyglycosides, polyoxyethylene castor oil, polyoxyethylene alkyl esters, polyglycerides, sorbitan fatty acid esters, glycerin fatty acid esters, fatty acid polyglycerides, fatty acid alcohol polyglycol ethers, acetylene glycol, acetylene alcohol, oxyalkylene block polymers, polyoxyethylene alkyl ethers, polyoxyethylene alkylaryl ethers, polyoxyethylene styrylaryl ethers, polyoxyethylene glycol alkyl ethers, polyoxyethylene fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene glycerin fatty acid esters, polyoxyethylene hydrogenated castor oil, polyoxypropylene fatty acid esters, polyoxylglycerides, polyoxylethylene stearate, or combinations thereof.

8. (i) 10% to 33% by weight of cabozantiniblaurill sulfate, (ii) 19% to 90% by weight of at least one pharmaceutically acceptable nonionic surfactant selected from the group consisting of vitamin E polyethylene glycol succinate, poloxamer, polyethoxylated castor oil, polyoxyethylene hydrogenated castor oil, polyoxylglycerides, polyoxyethylene stearate, and combinations thereof, having a hydrophilic-lipophilic balance (HLB) value of 10 or higher. The oral dosage form according to claim 5, including the above.

9. The oral dosage form according to claim 6, wherein the one or more wetting agents, emulsifiers, solubilizers, surfactants, or combinations thereof that exhibit an HLB value of 10 or more are solids with a melting point of 25°C to 120°C.

10. The oral dosage form according to any one of claims 2 to 9, further comprising at least one pharmaceutically acceptable additive having a hydrophilic-lipophilic balance (HLB) value of less than 10.

11. The oral dosage form according to claim 10, wherein at least one pharmaceutically acceptable additive having an HLB value of less than 10 is selected from the group consisting of wetting agents, emulsifiers, solubilizers, surfactants, or combinations thereof.

12. The oral dosage form according to claim 11, wherein at least one pharmaceutically acceptable additive having an HLB value of less than 10 is selected from medium-chain monoglycerides, medium-chain diglycerides, polyoxylglycerides, sorbitan esters, sorbitan fatty acid esters, phospholipids, and combinations thereof.

13. The oral dosage form according to any one of claims 2 to 12, further comprising one or more pharmaceutically acceptable additives selected from the group consisting of stabilizers, fillers, thickeners, binders, disintegrants, lubricants, flow promoters, fragrances, and combinations thereof.

14. The oral dosage form according to any one of claims 2 to 13, wherein when tested with USP Type II Apparatus (Paddle) (0.1N HCl, 75 rpm, with or without sinker, 37°C), (i) a solubility of 35% to 100% after 45 minutes, or (ii) a solubility of at least 70% after 60 minutes.

15. The dosage form is an oral dosage form according to any one of claims 2 to 14, comprising cabozantinib brauril sulfate equivalent to 5 mg to 200 mg of cabozantinib free base.

16. An oral dosage form according to any one of claims 2 to 15, which is used in an effective amount for the treatment of cancer.

17. The oral dosage form according to claim 16, wherein the cancer includes thyroid cancer, renal cell carcinoma and / or hepatocellular carcinoma.

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