Polymer compound and coated particle composition

• US 5,534,259 A
• Filed: 07/08/1993
• Issued: 07/09/1996
• Est. Priority Date: 07/08/1993
• Status: Expired due to Term

• Current Assignee: Liposome Technology, Inc.
• Original Assignee: Liposome Technology, Inc.
• Inventors: Martin, Francis J., Zalipsky, Samuel
• Primary Examiner(s): Nutter, Nathan M.
• Application Number:
  US08/089,086
• Time in Patent Office: 1,097 Days
• Field of Search: 264/4.1, 424/489, 424/490, 424/491, 424/497, 424/450, 424/417
• US Class Current: 424/450
• 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: A61K 9/1273 Polymersomes; Liposomes with polymerisable or polymerised bilayer-forming substances polymers grafted or coated on phosphatidyl liposomes A61K9/1271, on non-phosphatidyl liposomes A61K9/1272

Abstract

A composition of polymer-coated particles, and a polymer compound used in forming the particles are disclosed. The polymer compound is composed of a hydrophilic polymer attached to a lipophilic moiety through a linking segment which contains chemical groups through which the compound can be crosslinked to other such compounds. The particles in the composition are prepared by forming lipid structures containing ordered arrays of the polymer compounds, and crosslinking the compounds through their chemical groups. The particles are used for parenteral administration of a pharmaceutical compound which is entrapped in the particles.

Claims

1. A pharmaceutical composition for use in the parenteral delivery of a pharmaceutical compound, said composition comprising

particles having a selected uniform size in a size range between 0.03-1.0 microns,

each particle including (a) a single layer of linked polymer compounds composed of an outer hydrophilic polymer, an inner hydrophobic moiety, and a linking segment linking the polymer to the hydrophobic moiety and containing at least two chemical groups by which the compound can be crosslinked to at least two other compounds, (b) a crosslinked particle surface coated by said hydrophilic polymers, said crosslinked surface formed by a crosslinking structure created by crosslinks between said chemical groups, and (c) said pharmaceutical compound entrappod in said particle.

2. The composition of claim 1, wherein said hydrophobic moiety is a vesicle-forming lipid moiety.

3. The composition of claim 2, wherein said vesicle-forming lipid moiety is a phospholipid whose polar head group is covalently attached to said linking segment.

4. The composition of claim 1, wherein said hydrophilic polymer is polyethylene glycol.

5. The composition of claim 1, wherein the chemical groups in each linking segment include, in non-crosslinked form, sulfhydryl groups, and said crosslinking structure includes disulfide or thioether linkages with the chemical groups.

6. The composition of claim 1, wherein the chemical groups in each linking segment include, in non-crosslinked form, amine groups, and said crosslinking structure includes amide linkages with the chemical groups.

7. The composition of claim 1, wherein said linked polymers include first and second linked polymers having first and second different chemical groups, respectively, in non-crosslinked form, and the crosslinking structure crosslinks the different chemical groups on adjacent first and second linked polymers.

8. The composition of claim 7, wherein said first and second linked polymers have, as their chemical groups in non-crosslinked form, sulfhydryl and amine groups, respectively, and said crosslinking structure includes bridges linking the sulfhydryl groups, through disulfide or thioether linkages, to the amine groups, through amide linkages.

9. The composition of claim 1, wherein the particle further includes a radical initiator compound attached to the particle surface, and the chemical groups in each linking segment include, in non-crosslinked form, vinyl groups, and said crosslinking structure includes carbon-carbon bonds derived from vinyl group polymerization initiated from the initiator compound.

10. The composition of claim 1, wherein the chemical groups include first and second different chemical groups, in non-crosslinked form, and the crosslinking structure crosslinks similar chemical groups on adjacent linked polymers.

11. The composition of claim 10, wherein the chemical groups include, in non-crosslinked form, sulfhydryl and amine groups, and said crosslinking structure includes bridges linking the sulfhydryl groups, through disulfide or thioether linkages, to other sulfhydryl groups and linking the amine groups, through amide linkages, to other amine groups.

12. The composition of claim 1, wherein said particles are vesicular particles having an aqueous interior, and said pharmaceutical compound is a water-soluble compound entrapped in said interior volume.

13. The composition of claim 1, wherein the pharmaceutical compound is a polypeptide.

14. The composition of claim 1, wherein the particles are lipophilic-core particles having a lipophilic interior core, and said pharmaceutical compound is a lipophilic compound entrapped in said interior volume.

15. A method for preparing a pharmaceutical composition composed of particles having a selected uniform size between about 0.03-1.0 microns, for use in parentoral administration of a particle-entrapped pharmaceutical compound, said method comprising

(a) preparing, in an aqueous medium, lipid structures composed of a polymer compound having an outer hydrophilic polymer, an inner hydrophobic moiety, and a linking segment linking the polymer to the hydrophobic moiety and containing at least two chemical groups by which the compound can be crosslinked to at least two other compounds, and

(b) crosslinking the chemical groups in the linking segments of the polymer compounds.

16. The method of claim 15, wherein the structures are vesicular lipid structures formed by suspending in an aqueous medium, a mixture of 1-30 mole percent of the polymer compound and between 70-99 mole percent vesicle-forming lipids, and said forming further includes sizing the lipid structures to the selected particle size, and which further includes, after said crosslinking, removing said vesicle-forming lipids from the particles.

17. The method of claim 16, wherein said forming includes encapsulating such a pharmaceutical compound in the vesicular lipid structures.

18. The method of claim 15, wherein said structures are core lipid structures formed by suspending the polymer compound in an aqueous medium at a concentration above the critical micelle concentration of the compound.

19. The method of claim 15, wherein the chemical groups in the linking segment of each polymer compound are amine and sulfhydryl groups, and said crosslinking includes linking said sulfhydryl groups to one another through disulfide or thioether linkages, and linking the amine groups through amide linkages.

20. The method of claim 15, wherein the chemical groups in each linking segment include, in non-crosslinked form, amine groups, and said crosslinking includes reacting said groups with a bridging reagent having two or more activated carboxylic acid groups.

21. The method of claim 15, wherein the lipid structures are formed to include first and second polymer compounds having first and second different chemical groups, respectively, and said crosslinking includes reacting the vesicular structures with a bridging reagent having at least one reactive group which is reactive with said first chemical group, and at least one other reactive group which is reactive with said second chemical group.