Pharmaceutical formulations employing short-chain sphingolipids and their use

• US 20070082855A1
• Filed: 11/11/2004
• Published: 04/12/2007
• Est. Priority Date: 11/14/2003
• Status: Active Grant

• Current Assignee: Het Nederlands Kanker Instituut
• Original Assignee: Het Nederlands Kanker Instituut
• Inventors: Verheij, Marcel, Veldman, Robert, Koning, Gerben, Van Blitterswijk, Wim
• Granted Patent: US 7,915,227 B2
• Time in Patent Office: Days
• US Class Current: 514/34
• CPC Class Codes: A61K 31/704 attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin digitoxin A61K31/7048
• CPC Class Codes: A61K 47/24 containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61K 9/127 Liposomes
• CPC Class Codes: A61P 35/00 Antineoplastic agents

Abstract

This invention pertains to pharmaceutical formulations which comprise (i) a drug (e.g., an amphiphilic drug) (e.g., an anthracycline) (e.g., doxorubicin) and (ii) a short-chain sphingolipid (e.g., a short-chain glycosphingolipid or a short-chain sphingomyelin) (e.g., N-octanoyl-glucosylceramide, referred to as C₈-GlcCer) (e.g., N-hexanoyl-sphingomyelin, referred to herein as C₆-SM), and which provide improved drug delivery and efficacy. The short-chain sphingolipidis selected from compounds of the following formula:
wherein: R¹ is independently: an O-linked saccharide group; or an O-linked polyhydric alcohol group; or: R¹ is independently: an O-linked (optionally N-(C_1-4alkyl)-substituted amino)-C_1-6alkyl-phosphate group; or an O-linked (polyhydric alcohol-substituted)-C_1-6alkyl-phosphate group; R² is independently C_3-9alkyl, and is independently unsubstituted or substituted; R³ is independently C_7-19alkyl, and is independently unsubstituted or substituted; R⁴ is independently —H, —OH, or —O—C_1-4alkyl; R^N is independently —H or C_1-4alkyl; the bond marked with an alpha (α) is independently a single bond or a double bond; if the bond marked with an alpha (α) is a double bond, then R⁵ is —H; if the bond marked with an alpha (α) is a single bond, then R⁵ is —H or —OH; the carbon atom marked (*) is independently in an R-configuration or an S-configuration; the carbon atom marked (**) is independently in an R-configuration or an S-configuration; and pharmaceutically acceptable salts, solvates, esters, ethers, chemically protected forms thereof. In one embodiment, the pharmaceutical formulation is a liposomal pharmaceutical formulation prepared using a mixture of lipids comprising, at least, vesicle-forming lipids (e.g., phospholipids) (e.g., phosphatidylcholines) (e.g., fully hydrogenated soy phosphatidylcholine (HSPC)) (e.g., dipalmitoyl-phosphatidylcholine (DPPC)) and said short-chain sphingolipid, and optionally cholesterol and optionally a vesicle-forming lipid which is derivatized with a polymer chain (e.g., a phosphatidylethanolamine (PE) which is derivatized with polyethyleneglycol (PEG)) (e.g., N-(carbonyl-methoxypolyethylene glycol 2000)-1,2-distearoyl-sn-glycero-3-phosphoethanolamine sodium salt (MPEG2000-DSPE). The present invention also pertains to methods for the preparation and use of such formulations.

Claims

1. A pharmaceutical formulation comprising:

(i) a drug; and

(ii) a short-chain sphingolipid selected from compounds of the following formula;

wherein;

R¹ is independently;

an O-linked saccharide group;

or

an O-linked polyhydric alcohol group;

or;

R¹ is independently;

an O-linked (optionally N—

(C_1-4alkyl)-substituted amino)-C_1-6alkyl-phosphate group;

or

an O-linked (polyhydric alcohol-substituted)-C_1-6alkyl-phosphate group;

R² is independently C_3-9alkyl,

and is independently unsubstituted or substituted;

R³ is independently C_7-19alkyl,

and is independently unsubstituted or substituted;

R⁴ is independently —

H, —

OH, or —

O—

C_1-4alkyl;

R^N is independently —

H or C_1-4alkyl;

the bond marked with an alpha (α

) is independently a single bond or a double bond;

if the bond marked with an alpha (α

) is a double bond, then R⁵ is —

H;

if the bond marked with an alpha (α

) is a single bond, then R⁵ is —

H or —

OH;

the carbon atom marked (*) is independently in an R-configuration or an S-configuration;

the carbon atom marked (**) is independently in an R-configuration or an S-configuration;

and pharmaceutically acceptable salts, solvates, esters, ethers, chemically protected forms thereof.

2-91. -91. (canceled)