Poly(alkylene oxide) amino acid copolymers and drug carriers and charged copolymers based thereon

• US 5,219,564 A
• Filed: 07/05/1991
• Issued: 06/15/1993
• Est. Priority Date: 07/06/1990
• Status: Expired due to Term

• Current Assignee: Enzon Pharmaceuticals Inc. (Icahn Associates Holding LLC)
• Original Assignee: Enzon Pharmaceuticals Inc. (Icahn Associates Holding LLC)
• Inventors: Nathan, Aruna, Bolikal, Durgadas, Kohn, Joachim B., Zalipsky, Samuel
• Primary Examiner(s): Page, Thurman K.
• Assistant Examiner(s): Kulkosky, Peter F.
• Application Number:
  US07/726,301
• Time in Patent Office: 711 Days
• Field of Search: 424/78.08, 424/85.8, 424/85.5, 424/78.17, 530/390.1, 530/391.7, 528/310
• US Class Current: 424/78.17
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• CPC Class Codes: A61K 47/645 Polycationic or polyanionic oligopeptides, polypeptides or polyamino acids, e.g. polylysine, polyarginine, polyglutamic acid or peptide TAT
• CPC Class Codes: A61L 15/26 Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds; Derivatives thereof A61L15/225 takes precedence
• CPC Class Codes: A61L 27/18 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
• CPC Class Codes: C08G 63/6854 derived from polycarboxylic acids and polyhydroxy compounds
• CPC Class Codes: C08G 81/00 Macromolecular compounds obtained by interreacting polymers in the absence of monomers, e.g. block polymers involving only carbon-to-carbon unsaturated bond reactions C08F299/00 ; polyester-amides C08G69/44; polyester-imides C08G73/16; polyamides-imides C08G73/14; block- or graft polymers containing polysiloxane sequences C08G77/42
• CPC Class Codes: C08L 79/00 Compositions of macromolecular compounds obtained by reactions forming in the main chain of the macromolecule a linkage containing nitrogen with or without oxygen or carbon only, not provided for in groups C08L61/00 - C08L77/00
• CPC Class Codes: Y10S 530/81 Carrier - bound or immobilized peptides or proteins and the preparation thereof, e.g. biological cell or cell fragment as carrier

Abstract

Copolymers of poly(alkylene oxides) and amino acids or peptide sequences are disclosed, which amino acids or peptide sequences have pendant functional groups that are capable of being conjugated with pharmaceutically active compounds for drug delivery systems and cross-linked to form polymer matrices functional as hydrogel membranes. The copolymers can also be formed into conductive materials. Methods are also disclosed for preparing the polymers and forming the drug conjugates, hydrogel membranes and conductive materials.

Claims

1. A polymer comprised of one or more recurring structural units independently represented by the formula:

##STR30## wherein R₁ is a poly(alkylene oxide) copolymerized with R₂, which is an amino acid or peptide sequence containing two amino groups and at least one pendant carboxylic acid group.

2. The polymer of claim 1, wherein R₂ is an amino acid or peptide sequence represented by the formula:

##STR31## wherein R₃ and R₄ are independently selected from the group consisting of saturated and unsaturated, straight-chained and branched alkyl groups containing up to 6 carbon atoms and alkyl phenyl groups, the alkyl portions of which are covalently bonded to an amine and contain up to 6 carbon atoms; and

a and b are independently zero or one;

R₅ is --NH-- or --NH--AA--, wherein --AA-- is an amino acid or peptide sequence, with the proviso that --AA-- has a free N-terminus;

D is a pendant functional group selected from the group consisting of;

##STR32## wherein, when D is ##STR33## Y is selected from the group consisting of --OH, --NH--NH₂, '"'"'O--R₆ --NH₂, --O-- R₆ --OH, --NH--R₆ --NH₂, --NH--R₆ --OH, ##STR34## a C-terminus protecting group and a derivative of a pharmaceutically active compound covalently bonded to said pendant functional group by means of;

an amide bond in the case where in the underivatized pharmaceutically active compound a primary or secondary amine is present at the position of the amide bond in the derivative;

or

an ester bond in the case where in the underivatized pharmaceutically active compound a primary hydroxyl is present at the position of the ester bond in the derivative; and

when D is;

##STR35## Y is a derivative of a pharmaceutically active compound covalently bonded to said pendant functional group by means of X, wherein X is a linkage selected from the group consisting of;

(a) --NH--NH-- in the case where in the underivatized pharmaceutically active compound an aldehyde or ketone is present at the position linked to said pendant functional group by means of X;

(b) --NH--NH--, --NH--R₆ --NH--, --O--R₆ --NH--, --O--R₆ --O-- or --NH--R₆ --O-- in the case where in the underivatized pharmaceutically active compound a carboxylic acid is present at the position linked to said pendant functional group by means of X; and

##STR36## in the case where in the underivatized pharmaceutically active compound the primary or secondary amine or primary hydroxyl group is present in the position linked to said pendant functional group by means of X;

and R₆ is selected from the group consisting of alkyl groups containing from two to six carbon atoms, alpha-, beta-, gamma- and omega amino acids, and peptide sequences.

3. The polymer of claim 1, wherein said poly(alkylene oxide) is selected from the group consisting of polyethylene glycol, polypropylene glycol, poly(isopropylene glycol), polybutylene glycol, poly(isobutylene glycol) and copolymers thereof.

4. The polymer of claim 3, wherein said poly(alkylene oxide) has the structure:

space="preserve" listing-type="equation">--(O--R.sub.8).sub.c --(O--R.sub.9).sub.d --(O--R.sub.10).sub.e --

wherein R₈, R₉ and R₁₀ are independently selected from the group consisting of straight-chained and branched alkyl groups containing up to four carbon atoms; and

c is an integer between about 1 and about 100, inclusive, and d and e are independently integers between 0 and about 100, inclusive, with the proviso that the sum of c, d and e is between about 10 and about 100, inclusive.

5. The polymer of claim 3, wherein said poly(alkylene oxide) comprises polyethylene glycol.

6. The polymer of claim 2, wherein R₃ and R₄ are independently selected from the group consisting of alkyl groups containing between 1 and 6 carbon atoms.

7. The polymer of claim 2, wherein either a or b is zero.

8. The polymer of claim 2, wherein R₅ is --NH--.

9. The polymer of claim 2, wherein Y is --NH--NH₂.

10. The polymer of claim 2, wherein R₂ comprises a natural amino acid.

11. The polymer of claim 2, wherein Y is a C-terminus protecting group selected from the group consisting of alkyl, aryl and silicon protecting groups.

12. The polymer of claim 2, wherein Y comprises a derivative of a pharmaceutically active compound selected from the group consisting of acyclovir, cephradine, melphalan, procaine, ephedrine, adriamycin and daunomycin and linked to said pendant functional group by means of an amide bond at a position on said pharmaceutically active compound occupied in the underivatized form of said pharmaceutically active compound by a primary or secondary amine.

13. The polymer of claim 2, wherein Y comprises a derivative of a pharmaceutically active compound selected from the group consisting of acyclovir, plumbagin, atropine, quinine, digoxin and quinidine and linked to said pendant functional group by means of an ester bond at a position on said pharmaceutically active compound occupied in the underivatized form of said pharmaceutically active compound by a primary hydroxyl.

14. The polymer of claim 2, wherein Y comprises derivative of a pharmaceutically active compound selected from the group consisting of adriamycin, daunomycin and testosterone and linked to said pendant functional group by means of --X-- at a position on said pharmaceutically active compound occupied in the underivatized form of said pharmaceutically active compound by an aldehyde or ketone;

and --X-- comprises --NH--NH--.

15. The polymer of claim 2, wherein Y comprises a derivative of a pharmaceutically active compound selected from the group consisting of chlorin e₆, cephradine, cephalothin, melphalan, penicillin V, aspirin, nicotinic acid, chemodeoxycholic acid and chlorambucil and linked to said pendant functional group by means of --X-- at a position on said pharmaceutically active compound occupied in the underivatized form of said pharmaceutically active compound by a carboxylic acid;

and X is selected from the group consisting of --NH--NH--, --NH--R₆ --NH--, --O--R₆ --NH--, --O--R₆ --O-- and --NH--R₆ --O--.

16. The polymer of claim 2, wherein Y comprises a derivative of a pharmaceutically active compound selected from the group consisting of acyclovir, cephradine, malphalan, plumbagin, procaine, ephedrine, adriamycin, daunomycin, atropine, quinine, digoxin and quinidine and linked to said pendant functional group by means of --X-- at a position on said pharmaceutically active compound occupied in the underivatized form of said pharmaceutically active compound by a primary or secondary amine or primary hydroxyl, and --X-- is selected from the group consisting of:

##STR37##

17. The polymer of claim 2, wherein Y comprises a derivative of an oxidized monoclonal antibody covalently linked to said pendant functional group by means of --X-- at a position on said monoclonal antibody occupied in the underivatized form of said oxidized monoclonal antibody by a ketone or aldehyde, and X is selected from the group consisting of --NH--NH--, --NH₆ --NH-- and --O--R₆ --NH--.

18. The polymer of claim 17, wherein said polymer comprises said recurring structural units in which Y is a pharmaceutically active compound co-conjugated with said monoclonal antibody.

19. The polymer of claim 18, wherein the ratio of said pharmaceutically active compound conjugated on said polymer and said monoclonal antibody conjugated on said polymer is between about 4 and about 100.

20. The polymer of claim 19, wherein said pharmaceutically active compound comprises chlorin e₆ and said monoclonal antibody comprises an anti-T cell monoclonal antibody.