Pharmaceutical compositions of safingol and methods of using the same
Inventors
Gupta, Shanker • Reynolds, C. Patrick • Maurer, Barry J. • Vishnuvajjala, B. Rao
Assignees
Childrens Hospital Los Angeles • US Department of Health and Human Services
Publication Number
US-7476692-B2
Publication Date
2009-01-13
Expiration Date
2024-02-19
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Abstract
The present invention provides stable aqueous solutions consisting essentially of: (a) a sphingolipid; (b) lactic acid; and (c) optionally a stabilizing agent; wherein the solution has a molar ratio of lactic acid to sphingolipid of 1:1 to 10:1. The present invention further provides an emulsion formulation consisting essentially of: (a) lactic acid; (b) a sphingolipid, wherein the sphingolipid is present in an amount of about 0.1 to about 30 mg/ml of emulsion; (b) optionally an isotonic agent; and (c) a phospholipid present in an amount of about 0.2 to about 200 mg/ml of emulsion. Methods of making and using the compositions are also provided.
Core Innovation
The present invention provides stable aqueous solutions consisting essentially of a sphingolipid, lactic acid, and optionally a stabilizing agent, where the solution has a molar ratio of lactic acid to sphingolipid from 1:1 to 10:1. It additionally provides an emulsion formulation comprising lactic acid, a sphingolipid (0.1 to about 30 mg/ml), optionally an isotonic agent, and a phospholipid (0.2 to about 200 mg/ml). Methods of making and using these compositions are also described.
A significant problem addressed by this invention is the limited aqueous solubility and clinical formulation challenges of safingol, a synthetic sphingolipid with potential anti-cancer activity. Prior formulations, such as simple lactic acid solutions of safingol, caused thrombophlebitis and hemolysis when administered peripherally and had stability issues including precipitation. Existing vegetable oil-in-water emulsions were high in oil content, costly, and not currently manufactured, limiting safingol’s clinical use.
The invention overcomes these issues by providing improved lactic acid solutions of safingol with increased stability that can be lyophilized for storage and reconstituted for intravenous use. It further discloses novel phospholipid-based emulsions stable without requiring additional oils or surfactants, simplifying manufacturing and reducing costs. These formulations enable safer and more effective intravenous delivery of safingol and related sphingolipids, facilitating their use in treating cancers and hyperproliferative disorders.
Claims Coverage
The patent includes two independent claim groups covering stable aqueous sphingolipid solutions with stabilizing agents and phospholipid-based emulsion formulations containing sphingolipids.
Stable aqueous solution of sphingolipid with lactic acid and alcohol or mannitol
A stable aqueous solution comprising a sphingolipid, lactic acid, and either an alcohol or mannitol as a stabilizing agent, where the molar ratio of lactic acid to sphingolipid is from 1:1 to 10:1.
Reconstitutible lyophilized compositions of safingol in lactic acid
Reconstitutible composition produced by lyophilizing a stable aqueous solution of safingol stabilized in lactic acid with a molar ratio of lactic acid to safingol about 3.5:1 to 4:1, containing safingol around 2.5 to 5 mg/ml, and including ethanol (about 20 mg/ml) or mannitol (about 5 mg/ml).
Emulsion formulation comprising lactic acid, sphingolipid, optional isotonic agent, and phospholipid
An emulsion formulation consisting essentially of lactic acid; a sphingolipid at about 0.1 to 30 mg/ml; optionally an isotonic agent; and a phospholipid at about 0.2 to 200 mg/ml of emulsion.
Method of making phospholipid-based sphingolipid emulsion
A method of making a sphingolipid emulsion by dissolving sphingolipid in dilute lactic acid solution, optionally adding an isotonic agent, and adding phospholipid to form the emulsion.
Methods of treating cancer by administering sphingolipid solutions or emulsions
Methods of treating cancers such as leukemia, lymphoma, neuroblastoma, lung, skin, prostate, colon, breast, ovarian, cervical, brain, and pancreatic cancers by administering the claimed aqueous sphingolipid solutions or emulsions parenterally or intravenously to human or animal subjects.
The independent claims cover stable sphingolipid aqueous solutions with stabilizing agents allowing lyophilization and reconstitution, and phospholipid emulsions of sphingolipids stabilized in lactic acid, both useful for intravenous administration and cancer treatment. The inventive features include stable, simplified formulations with defined component ratios, methods for preparation, and therapeutic methods.
Stated Advantages
Increased stability of safingol aqueous solutions allowing lyophilization and long-term storage.
Simplified phospholipid-based emulsions without additional vegetable oils or surfactants, reducing manufacturing complexity and cost.
Improved intravenous delivery of safingol with reduced toxicity such as thrombophlebitis and hemolysis.
Stable emulsions with long shelf life at refrigerated temperatures (at least six to nine months).
Enhanced tolerability in animal models, including coadministration with other anticancer agents.
Documented Applications
Treatment of cancers and hyperproliferative disorders including leukemia, lymphoma, neuroblastoma, lung cancer, skin cancer, prostate cancer, colon cancer, breast cancer, ovarian cancer, cervical cancer, brain cancer, and pancreatic cancer by administration of sphingolipid solutions or emulsions.
Intravenous administration of safingol or related sphingolipid compositions for medicinal use in humans and animals.
Use of sphingolipid compositions in combination therapies, e.g., with fenretinide, for cancer treatment.
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