Kinase inhibitor salts and compositions thereof
The present invention relates to kinase inhibitor C 8 -C 16 aliphatic sulfate salts, compositions containing kinase inhibitor C 8 -C 16 aliphatic sulfate salts and uses thereof.
1. A method for treating chronic myeloid leukemia comprising orally administering to a patient in need of such therapy a capsule comprising:
about 5 wt % to about 50 wt % of nilotinib lauryl sulfate salt; and
about 5 wt % to about 90 wt % of one or more excipients with a hydrophilic-lipophilic balance (HLB) value of less than 10 selected from a group consisting of a wetting agent, an emulsifying agent, a solubilizing agent, a surfactant or a combination thereof;
wherein the capsule exhibits:
a dissolution rate of about 10% to about 85% after 30 minutes of testing and about 40% to about 95% after 60 minutes of testing using a USP Type II Apparatus (Paddle) with a 0.1 N HCl and 0.1% Tween 80 media at 75 rpm, with or without a sinker at 37° C.;
and produces an AUC 0-48 of about 69.95 ng·hr/mL/mg to about 133.83 ng·hr/mL/mg when administered as a single dose of the capsule to one or more human patients or healthy human subjects under a fasted state;
a C max fed /C max fast ratio of about 0.80 to about 1.25 wherein the C max fed is a maximum nilotinib plasma concentration obtained by administering a single dose of the capsule to one or more human patients or healthy human subjects under a fed state and the C max fast is a maximum nilotinib plasma concentration obtained by administering a single dose of the capsule to the one or more patients or subjects under a fasted state;
an AUC 0-∞ fed /AUC 0-∞ fast ratio of about 0.80 to about 1.25 wherein the AUC 0-∞ fed is an AUC obtained from the time of administration of a single dose of the capsule to one or more human patients or healthy human subjects under a fed state to infinity and the AUC 0-∞ fast is an AUC obtained from the time of administration of a single dose of the capsule to the one or more patients or subjects under a fasted state to infinity; and
when administered as a single dose to one or more human patients or healthy human subjects under a fasted state at least a 25% greater AUC 0-48 compared to a similar dose of nilotinib free base administered by a capsule comprising nilotinib monohydrate monohydrochloride, colloidal silicon dioxide, crospovidone, lactose monohydrate, magnesium stearate and poloxamer 188.
2. The method of claim 1 wherein the one or more excipients with an HLB value of less than 10 comprises a medium chain monoglyceride, a medium chain diglyceride, a medium chain triglyceride, a vegetable oil, a hydrogenated vegetable oil, a fatty acid ester, a fatty acid alcohol, a polyoxylglyceride, a sorbitan ester, a sorbitan fatty acid ester, a phospholipid or a combination thereof.
3. The method of claim 1 wherein the one or more excipients with an HLB value of less than 10 comprises a medium chain monoglyceride, a medium chain diglyceride, a medium chain triglyceride, or a combination thereof.
4. The method of claim 1 wherein the one or more excipients with an HLB value of less than 10 comprise a glyceryl caprylate/caprate, a glyceryl caprylate, a glyceryl caprate, a glyceryl monocaprylocaprate or a mixture thereof.
5. The method of claim 1 wherein the capsule further comprises about 1 wt % to about 60 wt % of one or more excipients with an HLB value of 10 or greater selected from the group consisting of a wetting agent, an emulsifying agent, a solubilizing agent, a surfactant or a combination thereof.
6. The method of claim 5 wherein the one or more excipients with an HLB value of 10 or greater comprise a polyoxylethylene stearate, a fatty acid alcohol, a fatty alcohol acid or amide ethoxylate, a monoglyceride ethoxylate, a sorbitan ester ethoxylate, an alkyl polyglycoside, a polyoxyethylene castor oil, a polyoxyethylene hydrogenated castor oil, a poloxamer, a tyloxapol, a fatty acid ester or fatty acid alcohol of a polyglyceride and a combination thereof.
7. The method of claim 6 wherein the one or more excipients with an HLB value of 10 or greater comprises a polyoxylethylene stearate or a polyoxyethylene castor oil.
8. The method of claim 1 wherein the C max fed /C max fast ratio is a geometric mean ratio and the AUC 0-∞ fed /AUC 0-∞ fast ratio is a geometric mean ratio.
9. The method of claim 1 wherein the nilotinib lauryl sulfate capsule is not administered with a dosage form that decreases the pH of the patient's stomach.
10. The method of claim 1 wherein the nilotinib lauryl sulfate capsule is not administered with an amount of an acidifying agent to decrease the pH of the patient's stomach.