Water-soluble polymeric carriers for drug delivery

• US 5,648,506 A
• Filed: 06/05/1995
• Issued: 07/15/1997
• Est. Priority Date: 06/04/1992
• Status: Expired due to Term

• Current Assignee: ReNeuron Limited (ReNeuron Group Plc)
• Original Assignee: American Bioscience, Inc. (Bristol-Myers Squibb Company)
• Inventors: Soon-Shiong, P., Desai, Neil P., Sandford, Paul A.
• Primary Examiner(s): Trinh, Ba K.
• Application Number:
  US08/464,270
• Time in Patent Office: 771 Days
• Field of Search: 549/510, 549/511
• US Class Current: 549/510
• 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 47/61 the organic macromolecular compound being a polysaccharide or a derivative thereof
• CPC Class Codes: C07D 305/14 condensed with carbocyclic rings or ring systems

Abstract

In accordance with the present invention, there are provided polymeric drug delivery systems in which the drug is bound to a water-soluble polymer to provide a form of soluble drug delivery especially for those cases in which the drug by itself is water-insoluble. In particular, the drug taxol is covalently bound to water-soluble polyethylene glycols such as linear polyethylene glycols, branched polyethylene glycols, star polyethylene glycols, and branched copolymers of polyethylene glycols with other functional monomers to comprise a form of polymeric drug delivery. Also, crosslinked insoluble gels of these materials are prepared to serve as a form of implantable drug delivery.

Claims

1. A taxol derivative having the general formula R₁ --T--R₂ :

wherein R₁ =--X--P or --OH, and R₁ is located on the 2'"'"'-carbon of the taxol side chain;

wherein R₁ =--X--P or --OH, and R₂ is located on the 7-carbon atom of the ring structure;

but R₁ and R₂ are not simultaneously --OH;

and the drug taxol T, is covalently linked to a water-soluble polymer P, based on polyethylene glycol, through a covalent linking group X,

wherein P is selected from a branched chain polyethylene glycol, a star polyethylene glycol or a branched copolymer of a linear polyethylene glycol and a functional monomer, and

wherein X is selected from ester, diester, urethane, amide, secondary or tertiary amine or ether linking groups.

2. The composition of claim 1 in which the water-soluble polymer is a branched chain polyethylene glycol, and the taxol-polyethylene glycol derivative has the general formula:

##STR4## wherein A=R₁₂ (CH₂ CH₂ O)_n CH₂ CH₂ --Y-- and R₁₂ =HO--, or alkoxy, or aryloxy, or T--X--;

wherein B=T--X--(CH₂ CH₂ O)_p CH₂ CH₂ --Y--;

wherein R₆ =--H or --CH₃ ;

wherein X is located at either the 2'"'"' position of the taxol side chain or the 7 position of the taxol ring structure, but not both simultaneously;

wherein Y is a covalent linking group independently selected from the same groups as X;

and m, n, and p are numbers between, and including, 5 and 2500.

3. The composition of claim 1 in which the water-soluble polymer is a star polyethylene glycol, and the taxol-polyethylene glycol derivative has the general formula:

[T--X--(CH₂ CH₂ O)_n CH₂ CH₂ ]_q -(central core)

wherein X is located at either the 2'"'"' position of the taxol side chain or the 7 position of the taxol ring structure but not both simultaneously;

wherein q is the number of arms of a linear polyethylene glycol attached to a central core;

wherein n is a number between, and including, 5 and 2500;

and q is a number between, and including, 2 and 100.

4. The composition of claim 1 in which said water-soluble polymer is a branched copolymer of a linear polyethylene glycol and a functional monomer, the resultant copolymer-taxol derivative having the general formula:

##STR5## wherein A=R₁₂ (CH₂ CH₂ O)_n CH₂ CH₂ --Y-- and R₁₂ =HO--, or alkoxy, or aryloxy, or T--X--;

wherein R₆ =--H or --CH₃ ;

wherein Y is a covalent linking group independently selected from the same groups as X;

wherein R₇ is selected from H, or alkyl or aryl;

wherein E is selected from alkyl or aryl;

wherein G=--W--T, wherein W is a covalent linking group independently selected from the same groups as X, and T is linked to E through W;

wherein W is located at either the 2'"'"' position of the taxol side chain or the 7 position of the taxol ring structure but not both simultaneously;

and r is a number between, and including, 5 and 2500.

5. The composition of claim 2 in which a fraction of taxol substituents are replaced with unsaturated groups capable of undergoing free radical polymerization.

6. The composition of claim 3 in which a fraction of taxol substituents are replaced with unsaturated groups capable of undergoing free radical polymerization.

7. The composition of claim 4 in which a fraction of taxol substituents are replaced with unsaturated groups capable of undergoing free radical polymerization.

8. The composition of claim 2 in the form of a crosslinked insoluble gel containing covalently bound taxol.

9. The composition of claim 3 in the form of a crosslinked insoluble gel containing covalently bound taxol.

10. The composition of claim 4 in the form of a crosslinked insoluble gel containing covalently bound taxol.

11. A water-soluble drug-polymer conjugate having the general formula P--X--D:

wherein P is a water-soluble polymer based on polyethylene glycol, wherein P is selected from a branched chain polyethylene glycol, a star polyethylene glycol or a branched copolymer of a linear polyethylene glycol and a functional monomer;

wherein the drug D is taxol;

and the drug and polymer are linked by the covalent linkage X, wherein X is selected from ester, diester, urethane, amide, secondary or tertiary amine or ether linking groups.

12. The composition of claim 11 in which said water-soluble polymer is crosslinked to form an insoluble gel.

13. A method of solubilizing taxol by attaching taxol to a water-soluble polymeric carrier by a covalent linkage;

wherein said polymer carrier is based on polyethylene glycol, and wherein said polymeric carrier is selected from a branched chain polyethylene glycol, a star polyethylene glycol, or a branched copolymer of a linear polyethylene glycol and a functional monomer; and

wherein said covalent linkage is selected from ester, diester, urethane, amide, secondary or tertiary amine or ether linking groups.

15. A method of solubilizing water-insoluble or poorly water-soluble drugs in water according to claim 13, said method comprising attaching said drug, D, to a water-soluble polymeric carrier, P, by a covalent linkage, X or W;

wherein D is taxol;

wherein the resulting drug-polymer conjugates have the general formula;

##STR8## wherein A=R₅ (CH₂ CH₂ O)_n CH₂ CH₂ --Y-- and R₅ =HO--, or alkoxy, or aryloxy, or D--X--;

wherein B=D--X--(CH₂ CH₂ O)_p CH₂ CH₂ --Y--;

wherein R₆ =--H or --CH₃ ;

wherein X is a covalent linking group selected from ester, diester, urethane, amide, secondary or tertiary amine or ether linking groups;

wherein Y is independently selected from the same groups as X;

wherein m, n, and p are numbers between, and including, 5 and 2500;

or ##STR9## wherein A and R₆ are defined as above;

wherein R₇ is selected from --H, --CH₃, alkyl, or aryl;

wherein E is selected from alkyl or aryl;

and G=--W--D, wherein W is a covalent linking group independently selected from the same groups as X, and D is linked to E through W;

wherein r is a number between, and including, 5 and 2500;

or

space="preserve" listing-type="equation">(D--X--(CH.sub.2 CH.sub.2 O).sub.n CH.sub.2 CH.sub.2).sub.q -(central core)

wherein q is the number of arms of a linear polyethylene glycol attached to a central core and q is a number between, and including, 2 and 100;

and n is defined as above.

14. A water-soluble drug delivery system comprising water-soluble polymers of polyethylene glycol conjugated to a drug D by a covalent linking group, X or W,

wherein D is taxol;

wherein said polymers of polyethylene glycol are selected from branched polyethylene glycols, star polyethylene glycols, or branched copolymers of linear polyethylene glycol and a functional monomer, and

wherein said drug-polymer conjugates have the general formulas;

##STR6## wherein A=R₅ (CH₂ CH₂ O)_n CH₂ CH₂ --Y-- and R₅ =HO--, or alkoxy, or aryloxy, or D--X--;

wherein B=D--X--(CH₂ CH₂ O)_p CH₂ CH₂ --Y--;

wherein R₆ =--H or --CH₃ ;

wherein X is a covalent linking group selected from ester, diester, urethane, amide, secondary or tertiary amine or ether linking groups;

wherein Y is independently selected from the same groups as X;

wherein m, n, and p are numbers between, and including, 5 and 2500;

or ##STR7## wherein A and R₆ are defined as above;

wherein R₇ is selected from --H, --CH₃, alkyl, or aryl;

wherein E is selected from alkyl or aryl;

and G=--W--D, wherein W is a covalent linking group independently selected from the same groups as X, and D is linked to E through W;

wherein r is a number between, and including, 5 and 2500;

or

space="preserve" listing-type="equation">(D--X--(CH.sub.2 CH.sub.2 O).sub.n CH.sub.2 CH.sub.2).sub.q -(central core)

wherein q is the number of arms of a linear polyethylene glycol attached to a central core and q is a number between, and including, 2 and 100;

and n is defined as above.