Drug carriers comprising amphilphilic block copolymers

Patent metadata

Field	Value
Publication number	US-9765213-B2
Application number	US-201213355910-A
Country	US
Kind code	B2
Filing date	Jan 23, 2012
Priority date	Mar 7, 2002
Publication date	Sep 19, 2017
Grant date	Sep 19, 2017

Abstract

An aqueous composition comprises an amphiphilic block copolymer, having a hydrophilic block comprising pendant zwitterionic groups and a hydrophobic block, and a biologically active compound associated with the polymer. The polymer is preferably in the form of micelles, and preferably the biological active is a hydrophobic drug. The hydrophilic block is preferably formed from acrylic monomer including phosphorylcholine groups. The hydrophobic group is suitably formed from monomer which has groups which can be ionised at useful pH's, especially tertiary amine groups. Micelles may be formed by dissolving the block copolymer in aqueous solvent at a pH at which the amine groups are protonated then raising the pH to a value at which the amine groups are substantially deprotonated, whereupon micelles spontaneously form. The preformed micelles are then contacted with active, under conditions such that solubilisation of the active occurs. The active may be for tumour treatment.

First claim

What is claimed is:

1. An aqueous composition comprising an amphiphilic block copolymer having a hydrophilic block and a hydrophobic block, dispersed in a solution, and a biologically active compound associated with the copolymer, wherein the hydrophilic block has pendant zwitterionic groups, a log concentration (μg/ml) of the amphiphilic block copolymer in the aqueous composition is from 0.1 to 100, the copolymer comprising a hydrophilic block formed by radical polymerisation of an ethylenically unsaturated zwitterionic monomer, which is 2-methacryloyloxyethyl-2′-trimethylammonium ethyl phosphate inner salt, and a hydrophobic block formed from (diisopropyl-amino)ethyl methacrylate, the aqueous composition comprising micelles of the copolymer and the biologically active compound associated with the copolymer in the micelles, the pH of the aqueous composition being 6.5 to 7.4 whereby the copolymer is above the critical micelle concentration in the aqueous composition.

2. A composition according to claim 1 in which the biologically active molecule is associated by hydrophobic interactions with the copolymer.

3. A composition according to claim 2 in which the biologically active compound has a measured and/or calculated partition coefficient between octanol and water of at least 1.0.

4. A composition according to claim 1 in which the hydrophobic block comprises pendant groups which are ionisable, having a pK A or pK B in the range 4 to 10.

5. A composition according to claim 1 in which the hydrophillic block is formed by radical polymerization of the 2-methacryloyloxyethyl-2′-trimethylammonium ethyl phosphate inner salt and comonomer.

6. A composition according to claim 5 in which the comonomer has the general formula VIII

in which R 18 is selected from the group consisting of hydrogen, halogen, C 1-4 alky and groups COOR 22 in which R 22 is hydrogen and C 1-4 alkyl;
R 19 is selected from the group consisting of hydrogen, halogen and C 1-4 alkyl;
R 20 is selected from the group consisting of hydrogen, halogen, C 1-4 alkyl and groups COOR 22 provided that R 18 and R 20 are not both COOR 22 ; and
R 21 is selected from the group consisting of C 1-10 alkyl, C 1-20 alkoxycarbonyl, mono- or di-(C 1-20 alkyl) amino carbonyl, C 6-20 aryl (including alkaryl) C 7-20 aralkyl, C 6-20 aryloxycarbonyl, C 1-20 -aralkyloxycarbonyl, C 6-20 arylamino carbonyl, C 7-20 aralkyl-amino, hydroxyl and C 2-10 acyloxy groups, any of which may have one or more substituents selected from the group consisting of halogen atoms, and alkoxy, oligo-alkoxy, aryloxy, acyloxy, acylamino, amine, carboxyl, sulphonyl, phosphoryl, phosphino, zwitterionic, hydroxyl, vinyloxycarbonyl, and reactive silyl and silyloxy groups;
or R 21 and R 20 or R 21 and R 19 may together form —CONR 23 CO in which R 23 is a C 1-20 alkyl group.

7. A composition according to claim 6 in which the comonomer is selected from the group consisting of C 1-24 alkyl(alk)-acrylates, C 1-24 -alkyl(alk)-acrylamides, mono- and di- hydroxy-C 1-6 -alkyl(alk)-acrylates, mono- and di-hydroxy-C 1-6 -alkyl(alk)acrylamides, oligo(C 2-3 alkoxy) C 2-18 alkyl(alk)-acrylates, C 2-18 alkyl(alk)acrylamides, styrene, vinylacetate and N-vinyllactam.

8. A composition according to claim 1 in which the polydispersity of molecular weight of each of the blocks is less than 2.0.

9. A composition according to claim 1 in which the degree of polymerisation of the hydrophilic block is in the range 2 to 1000.

10. A composition according to claim 1 in which the degree of polymerisation of the hydrophobic block is in the range 5 to 2000.

11. A composition according to claim 9 in which the ratio of the degrees of polymerisation of the hydrophobic to hydrophilic blocks is in the range 1:5 to 10:1.

12. A composition according to claim 1 in which the radical polymerisation is a controlled radical polymerisation.

13. A composition according to claim 12 in which the polymerisation is an atom transfer radical polymerisation or group transfer polymerisation.

14. A composition according to claim 13 in which the initiator for the radical transfer polymerisation process is a polymer compound in which the polymeric moiety is hydrophobic which forms the hydrophobic block of the copolymer.

15. A composition according to claim 13 in which the hydrophobic block is also formed from ethylenically unsaturated monomers by a radical transfer polymerisation process.

16. A composition according to claim 1 in which the biologically active molecule is a cytotoxic compound.

17. A method of forming an aqueous composition comprising an amphiphilic block copolymer and a biologically active compound, in which the copolymer comprises a hydrophilic block formed by radical polymerisation of an ethylenically unsaturated zwitterionic monomer, which is 2-methacryloyloxyethyl-2′-trimethylammonium ethyl phosphate inner salt and a hydrophobic block formed from (diisopropyl-amino)ethyl methacrylate in which process an aqueous dispersion of empty copolymer micelles is formed and the micellar dispersion is contacted with biologically active compound under conditions such that the biologically active compound becomes associated with the copolymer in the micelles, wherein the hydrophilic block has pendant zwitterionic groups, in which the biologically active compound has a partition coefficient between octanol and water of at least 1.0, and in which the hydrophobic block of the copolymer comprises ionisable groups which are primary, secondary or tertiary amine groups, and in which the empty copolymer micelles are formed by a process comprising:
a) a first copolymer dissolution step in which the block copolymer, with the groups of hydrophobic block in at least partially ionised form, is dissolved in an aqueous liquid, and
b) a second micelle forming step in which the conditions in the solution are adjusted by raising the pH to a pH of 6.5 to 7.4 so that the ionised groups are converted at least partially to their deprotonated form, whereby the copolymer is above the critical micelle concentration in the aqueous liquid and micelles are formed, wherein a log concentration (μg/ml) of the amphiphilic block copolymer in the aqueous composition is from 0.1 to 100.

18. A method according to claim 17 in which the conditions which are adjusted are of temperature and pH.

19. A method according to claim 17 in which the biologically active compound is in solid form when it is contacted with the aqueous dispersion of empty micelles.

20. A method according to claim 17 in which the biologically active compound is in solution in an organic solvent when it is contacted with the aqueous dispersion of empty micelles.

21. A composition according to claim 3 in which the partition coefficient is at least 1.5.

22. A composition according to claim 1 in which the hydrophillic block is formed from (diisopropyl-amino)ethyl methacrylate and comonomer.

23. A composition according to claim 22 in which the comonomer has the general formula VIII

in which R 18 is selected from the group consisting of hydrogen, halogen, C 1-4 alkyl and groups COOR 22 in which R 22 is hydrogen or C 1-4 alkyl;
R 19 is selected from the group consisting

Assignees

• Lewis Andrew Leonard
• Armes Steven Peter
• Lloyd Andrew W
• Salvage Jonathan P
• Biocompatibles Uk Ltd

Inventors

• Lewis Andrew Leonard
• Armes Steven Peter
• Lloyd Andrew W
• Salvage Jonathan P

Classifications

• C08L53/00 Primary

  Compositions of block copolymers containing at least one sequence of a polymer obtained by reactions only involving carbon-to-carbon unsaturated bonds; Compositions of derivatives of such polymers · CPC title

• A61K9/1075

  Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers (A61K9/0026 takes precedence) · CPC title

• C08F293/005

  using free radical "living" or "controlled" polymerisation, e.g. using a complexing agent · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C08L2666/02

  Organic macromolecular compounds, natural resins, waxes or and bituminous materials · CPC title