Lipophilic drug derivatives for use in liposomes

• US 5,534,499 A
• Filed: 05/19/1994
• Issued: 07/09/1996
• Est. Priority Date: 05/19/1994
• Status: Expired due to Fees

• Current Assignee: University of British Columbia
• Original Assignee: University of British Columbia
• Inventors: Ansell, Steve
• Primary Examiner(s): Kunz, Gary L.
• Assistant Examiner(s): Fonda, Kathleen Kahler
• Application Number:
  US08/246,010
• Time in Patent Office: 782 Days
• Field of Search: 514/2, 514/25, 514/34, 514/449, 514/463, 424/1.21, 424/450, 536/4.1, 536/6.4, 536/17.2, 536/18.1, 549/510, 549/432
• US Class Current: 514/25
• CPC Class Codes: A61K 9/1075 Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers A61K9/0026 takes precedence
• CPC Class Codes: A61K 9/1271 Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers liposome as conjugate A61K47/6911
• CPC Class Codes: Y10S 977/801 Drug
• CPC Class Codes: Y10S 977/905 Specially adapted for travel through blood circulatory system
• CPC Class Codes: Y10S 977/907 Liposome
• CPC Class Codes: Y10S 977/926 Topical chemical, e.g. cosmetic or sunscreen

Abstract

The present invention provides novel lipophilic drug derivatives which are capable of being formulated in liposomes or micelles. These drug derivatives are known therapeutic agents which are covalently attached to a fatty acid chain of a phospholipid, glyceride, ceramide or 1,2-diacyloxypropane-3-amine. The linkage between the therapeutic agent and the lipid is one which can be cleaved in vivo, allowing the therapeutic agent to be separated from the micellar or liposomal formulation.

Claims

1. A pharmaceutical compound for use in liposome and micellar formulations, said compound being a member selected from the group consisting of compounds of formula I and compounds of formula II:

##STR21## wherein, A is a member selected from the group consisting of a serine radical, an ethanolamine radical, a choline radical, a phosphocholine radical, a phosphoserine radical, a phosphoethanolamine radical, a glycerol radical, a phosphoglycerol radical, an inositol radical, a phosphoinositol radical, --NR¹ R², --OCOR³, --OH, --O--glucose, --O--galactose and --O--oligosaccharide;

wherein,

R¹ and R² are each members independently selected from the group consisting of H and lower alkyl; and

R³ is a member selected from the group consisting of alkyl radicals and unsaturated alkyl radicals;

X¹ and X² are each members independently selected from the group consisting of alkyl, unsaturated alkyl, alkyl linking group, and unsaturated alkyl linking group;

Y¹ and Y² are each members independently selected from the group consisting of --S--, --NH--, --NHCO--, --CO(CH₂)_p CO₂ --, --O--, ═

NNHCO--, --CO-- and --CO(CH₂)_p CONH--, wherein p is an integer of from 0 to 8;

Z¹ and Z² are each independently a therapeutic agent; and

m and n are each independently an integer of from 0 to 1, with the proviso that n+m is at least 1; and

with the further provisos that when m is 0, X¹ is not a linking group, and when n is 0 that X² is not a linking group.

2. A pharmaceutical compound of claim 1 wherein said compound is of formula I, and A is a member selected from the group consisting of a phosphocholine radical, a phosphoserine radical, a phosphoethanolamine radical, a phosphoglycerol radical, and a phosphoinositol radical.

3. A pharmaceutical compound of claim 1 wherein said compound is of formula I and A is a member selected from the group consisting of --OCOR³, --O--glucose, --O--galaclose and --O--oligosaccharide.

4. A pharmaceutical compound of claim 1 wherein said compound is of formula I and A is --NR¹ R².

5. A pharmaceutical compound of claim 2 wherein m is 0, X¹ is alkyl and Z² is a therapeutic agent selected from the group consisting of paclitaxel, doxorubicin and podophyllotoxin.

6. A pharmaceutical compound of claim 2 wherein n is 0, X² is alkyl and Z¹ is a therapeutic agent selected from the group consisting of paclitaxel, doxorubicin and podophyllotoxin.

7. A pharmaceutical compound of claim 3 wherein m is 0, X¹ is alkyl and Z² is a therapeutic agent selected from the group consisting of paclitaxel, doxorubicin and podophyllotoxin.

8. A pharmaceutical compound of claim 3 wherein n is 0, X² is alkyl and Z¹ is a therapeutic agent selected from the group consisting of paclitaxel, doxorubicin and podophyllotoxin.

9. A pharmaceutical compound of claim 4 wherein m is 0, X¹ is alkyl and Z² is a therapeutic agent selected from the group consisting of paclitaxel, doxorubicin and podophyllotoxin.

10. A pharmaceutical compound of claim 4 wherein n is 0, X² is alkyl and Z¹ is a therapeutic agent selected from the group consisting of paclitaxel, doxorubicin and podophyllotoxin.

11. A pharmaceutical composition comprising a compound selected from the group consisting of compounds of formula I and compounds of formula II:

##STR22## wherein, A is a member selected from the group consisting of a serine radical, an ethanolamine radical, a choline radical, a phosphocholine radical, a phosphoserine radical, a phosphoethanolamine radical, a glycerol radical, a phosphoglycerol radical, an inositol radical, a phosphoinsitol radical, --NR¹ R², --OCOR³, --OH, --O--glucose, --O--galactose and --O--oligosaccharide;

wherein,

R¹ and R² are each members independently selected from the group consisting of H and lower alkyl; and

R³ is a member selected from the group consisting of alkyl radicals and unsaturated alkyl radicals;

X¹ and X² are each members independently selected from the group consisting of alkyl, unsaturated alkyl, alkyl linking group, and unsaturated alkyl linking group;

Y¹ and Y² are each members independently selected from the group consisting of --S--, --NH--, --NHCO--, --CO(CH₂)_p CO₂ --, --O--, ═

NNHCO--, --CO-- and --CO(CH₂)_p CONH--, wherein p is an integer of from 0 to 8;

Z¹ and Z² are each independently a therapeutic agent; and

m and n are each independently an integer of from 0 to 1, with the proviso that n+m is at least 1, and with the further provisos that when m is 0 that X¹ is not a linking group, and when n is 0 that X² is not a linking group, in a micellar formulation.

12. A pharmaceutical composition of claim 11 wherein said micellar formulation comprises a member selected from the group consisting of lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylserine, lysophosphatidylglycerol, acyl-polyoxyethylene esters, alkyl-polyoxyethylene ethers, phosphatidylethanolamine-polyoxyethylene conjugates, phosphatidic acid-polyoxyethylene conjugates and octyl glucopyranoside.

13. A pharmaceutical composition of claim 11 wherein said micellar formulation comprises 1-stearoyl-L-α

-phosphatidylcholine.

14. A pharmaceutical composition of claim 11 wherein said compound is 1-oleoyl-2-(N-(4 '"'"'-O-(2"-taxyl)-succinoyl)- 11-aminoundecanoyl)-L-α

-phosphatidylcholine and said micellar formulation comprises 1-stearoyl-L-60 -phosphatidylcholine.

15. A pharmaceutical composition comprising a compound selected from the group consisting of compounds of formula I and compounds of formula II:

##STR23## wherein, A is a member selected from the group consisting of a serine radical, an ethanolamine radical, a choline radical, a phosphocholine radical, a phosphoserine radical, a phosphoethanolamine radical, a glycerol radical, a phosphoglycerol radical, an inositol radical, a phosphoinositol radical and --NR¹ R², --OCOR³, hydrogen, --O--glucose, --O--galactose and --O--oligosaccharide;

wherein,

R¹ and R² are each members independently selected from the group consisting of H and lower alkyl; and

R³ is a member selected from the group consisting of alkyl radicals and unsaturated alkyl radicals;

X¹ and X² are each members independently selected from the group consisting of alkyl, unsaturated alkyl, alkyl linking group, and unsaturated alkyl linking group;

Y¹ and Y² are each members independently selected from the group consisting of --S--, --NH--, --NHCO--, --CO(CH₂)_p CO₂ --, --O--, ═

NNHCO--, --CO-- and --CO(CH₂)_p CONH--, wherein p is an integer of from 0 to 8;

Z¹ and Z² are each independently a therapeutic agent; and

m and n are each independently an integer of from 0 to 1, with the proviso that n+m is at least 1, and with the further provisos that when m is 0 that X¹ is not a linking group, and when n is 0 that X² is not a linking group, in a liposomal formulation.

16. A pharmaceutical composition of claim 15 wherein said liposomal formulation comprises a member selected from the group consisting of phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerol, phosphatidylinositol, cholesterol, diglycerides, ceramides, phosphatidylethanolamine-polyoxyethylene conjugates and phosphatidic acid-polyoxyethylene conjugates.

17. A pharmaceutical composition of claim 15 wherein said liposomal formulation comprises egg phosphatidylcholine.

18. A pharmaceutical composition of claim 15 wherein said liposomal formulation comprises egg phosphatidylcholine and 1-stearoyl-L-α

-phosphatidylcholine.

19. A pharmaceutical composition of claim 15 wherein said compound is 1-oleoyl-2-(N-(4'"'"'-O-(2"-paclitaxyl)-succinoyl)- 11-aminoundecanoyl)-L-α

-phosphatidylcholine and said liposomal formulation comprises egg phosphatidylcholine and 1-stearoyl-L-α

-phosphatidylcholine.