# US 7,744,861 B2 · Multi-arm polymer prodrugs

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- Number: US 7,744,861 B2
- Document ID: US7744861B2
- Status: Granted
- Kind: B2
- Application number: 10/943,799
- Filed: 2004-09-17
- Published: 2005-05-26
- Granted: 2010-06-29
- Earliest claimed: 2003-09-17
- Assignees: Nektar Therapeutics
- Inventors: Xuan Zhao; Michael D. Bentley; Zhongxu Ren; Tacey X. Viegas
- Web page: https://patentgrep.com/patent/US7744861B2

## CPC

- C08L 71/02: Polyalkylene oxides
- A61K 47/58: obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin
- A61K 47/59: obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
- A61K 47/595: {Polyamides, e.g. nylon (polyamino acids A61K47/62)}
- A61K 47/60: the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
- A61K 47/61: the organic macromolecular compound being a polysaccharide or a derivative thereof
- A61P 35/00: Antineoplastic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C08L: COMPOSITIONS OF MACROMOLECULAR COMPOUNDS (compositions based on polymerisable monomers C08F, C08G; artificial filaments or fibres D01F; textile treating compositions D06)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Provided herein are water-soluble prodrugs. The prodrugs of the invention comprise a water-soluble polymer having three or more arms, at least three of which are covalently attached to an active agent, e.g., a small molecule. The conjugates of the invention provide an optimal balance of polymer size and structure for achieving improved drug loading, since the conjugates of the invention possess three or more active agents releasably attached to a multi-armed water soluble polymer. The prodrugs of the invention are therapeutically effective, and exhibit improved properties in-vivo when compared to unmodified parent drug.

## Claims

### Claim 1

A multi-arm polymer prodrug having the structure:
wherein
R is an organic radical possessing from 3 to 150 carbon atoms,
Q is a linker, wherein R, when taken together with Q to form R(-Q-)q, is a residue of a polyol or a polythiol after removal of “q” hydroxyl or thiol protons, respectively, to form a point of attachment for POLY1,
POLY1, is a water-soluble polymer selected from the group consisting of poly(alkylene glycol), poly(olefinic alcohol), poly(vinylpyrrolidone), poly(hydroxylalkyl -methacrylamide), poly(hydroxyalkyl-methacrylate), poly(α-hydroxy acid), poly(acrylic acid), poly(vinyl alcohol), polyphosphazene, polyoxazoline, poly(N-acryloylmorpholine), and copolymers or terpolymers thereof,
D is a camptothecin attached at its 10-, 11- or 20- ring position, and
q has a value from 3 to 50.

### Claim 2 (depends on 1)

The multi-arm polymer prodrug of claim 1, wherein R possesses from 3 to 50 carbon atoms.

### Claim 3 (depends on 2)

The multi-arm polymer prodrug of claim 2, wherein R possesses from 3 to 25 carbon atoms.

### Claim 4 (depends on 3)

The multi-arm polymer prodrug of claim 3, wherein R possesses a number of carbon atoms selected from the group consisting of 3, 4, 5, 6, 7, 8, 9, and 10.

### Claim 5 (depends on 1)

The multi-arm polymer prodrug of claim 1, wherein R is linear or cyclic.

### Claim 6 (depends on 1)

The multi-armed polymer prodrug of claim 1, wherein R, taken together with Q to form R(-Q-)q, is a residue of glycerol, trimethylolpropane, pentaerythritol, sorbitol, or glycerol oligomers after removal of “q” hydroxyl protons.

### Claim 7 (depends on 6)

The multi-armed polymer prodrug of claim 6, wherein POLY1 is polyethylene glycol, the nominal average molecular weight of POLY1 ranges from about 500 to about 20,000 daltons, X has an atom length of from 5 atoms to 25 atoms, and q is 4.

### Claim 8 (depends on 1)

The multi-armed polymer prod rug of claim 1, wherein Q is a sulfur atom.

### Claim 9 (depends on 1)

The multi-armed polymer prodrug of claim 1, wherein Q comprises a heteroatom in addition to said polyol oxygen or said polythiol sulfur.

### Claim 10 (depends on 1)

The multi-armed polymer prodrug of claim 1, wherein Q contains from 1 to 10 atoms.

### Claim 11 (depends on 10)

The multi-armed polymer prodrug of claim 10, wherein Q is an oxygen atom.

### Claim 12 (depends on 1)

The multi-armed polymer prod rug of claim 1, wherein POLY1 is a polyethylene glycol.

### Claim 13 (depends on 12)

The multi-armed polymer prodrug of claim 12, wherein POLY1 is linear.

### Claim 14 (depends on 1)

The multi-armed polymer prodrug of claim 1, wherein the nominal average molecular weight of POLY1 ranges from 200 to 30,000 daltons.

### Claim 15 (depends on 1)

The multi-armed polymer prodrug of claim 1, wherein the nominal average molecular weight of POLY1 ranges from 500 to 20,000 daltons.

### Claim 16 (depends on 1)

The multi-armed polymer prodrug of claim 1, wherein the nominal average molecular weight of the prodrug is greater than 20,000 daltons.

### Claim 17 (depends on 1)

The multi-armed polymer prodrug of claim 1 wherein q ranges from 3 to 25.

### Claim 18 (depends on 17)

The multi-armed polymer prodrug of claim 17, wherein the value of q is selected from the group consisting of 3, 4, 5, 6, 7, 8, 9, and 10.

### Claim 19 (depends on 17)

The multi-armed polymer prodrug of claim 17, wherein each of said “q” polymer arms is
is the same.

### Claim 20 (depends on 1)

The multi-armed polymer prodrug of claim 1, wherein D is a camptothecin having a molecular weight of less than 800 daltons.

### Claim 21 (depends on 1)

The multi-armed polymer prodrug of claim 1, wherein D is a camptothecin compound having the structure:
wherein R1-R5 are each independently selected from the group consisting of hydrogen; halo; acyl; alkyl (e.g., C1-C6 alkyl); substituted alkyl; alkoxy; substituted alkoxy; alkenyl; alkynyl; cycloalkyl; hydroxyl; cyano; nitro; azido; amido; hydrazine; amino; substituted amino; hydroxcarbonyl; alkoxycarbonyl; alkylcarbonyloxy; alkylcarbonylamino; carbamoyloxy; arylsulfonyloxy; alkylsulfonyloxy; —C(R7)═N—(O)i—R8 wherein R7 is H, alkyl, alkenyl, cycloalkyl, or aryl, i is 0 or 1, and R8 is H, alkyl, alkenyl, cycloalkyl, or heterocycle; and R9C(O)O— wherein R9 is halogen, amino, substituted amino, heterocycle, substituted heterocycle, or R10—O—(CH2)m— where m is an integer of 1-10 and R10 is alkyl, phenyl, substituted phenyl, cycloalkyl, substituted cycloalkyl, heterocycle, or substituted heterocycle; or
R2 together with R3 or R3 together with R4 form substituted or unsubstituted methylenedioxy, ethylenedioxy, or ethyleneoxy;
R6 is H or OR′, wherein R′ is alkyl, alkenyl, cycloalkyl, haloalkyl, or hydroxyalkyl; and
L is the site of attachment.

### Claim 22 (depends on 21)

The multi-armed polymer prodrug of claim 21, wherein D has the structure:

### Claim 23 (depends on 22)

The multi-armed polymer prodrug of claim 22, having the structure:
where n ranges from 40 to 500.

### Claim 24 (depends on 23)

The multi-armed polymer prodrug of claim 23, wherein the overall nominal average molecular weight of the prodrug ranges from 20,000 to 80,000 daltons.

### Claim 25 (depends on 24)

A multi-armed polymer prodrug of claim 24, wherein said prodrug, when evaluated in a suitable animal model for solid tumor-type cancers and administered in a therapeutically effective amount, is effective to suppress tumor growth to an extent that is at least twice that observed for the unmodified anticancer agent when administered under the same conditions and at an equivalent dosage amount of anticancer agent over a time course of 30 days, based upon a comparison of tumor size.

### Claim 26 (depends on 24)

A multi-armed polymer prod rug of claim 24, wherein said prodrug, when evaluated in a suitable animal model for solid tumor-type cancers and administered in a therapeutically effective amount, is effective to suppress tumor growth to an extent that is at least 1.5 times that observed for the unmodified anticancer agent when administered under the same conditions and at an equivalent dosage amount of anticancer agent over a time course of 30 days, based upon a comparison of tumor size.

### Claim 27 (depends on 24)

A multi-armed polymer prodrug of claim 24, wherein said prodrug, when evaluated in a suitable animal model for solid tumor-type cancers and administered in a therapeutically effective amount, is effective to suppress tumor growth to an extent that is at least 1.5 times that observed for the unmodified anticancer agent when administered under the same conditions and at an equivalent dosage amount of anticancer agent over a time course of 60 days, based upon a comparison of tumor size.

### Claim 28 (depends on 24)

A multi-armed polymer prodrug of claim 24, wherein said prodrug, when evaluated in a suitable animal model for solid tumor-type cancers and administered in a therapeutically effective amount, is effective to suppress tumor growth to an extent that is at least 2 times that observed for the unmodified anticancer agent when administered under the same conditions and at an equivalent dosage amount of anticancer agent over a time course of 60 days, based upon a comparison of tumor size.

### Claim 29 (depends on 1)

The multi-armed polymer prodrug of claim 1, wherein D is SN-38.

### Claim 30 (depends on 29)

The multi-armed polymer prodrug of claim 29, wherein Q is oxygen and POLY1, is polyethylene glycol.

### Claim 31 (depends on 30)

The multi-armed polymer prodrug of claim 30, wherein R possesses a number of carbon atoms selected from the group consisting of 3, 4, 5, 6, 7, 8, 9, and 10.

### Claim 32 (depends on 1)

The multi-armed polymer prodrug of claim 1, wherein q is 4.

### Claim 33 (depends on 1)

The multi-armed polymer prodrug of claim 1.

### Claim 34 (depends on 1)

A pharmaceutical composition comprising a multi-arm polymer prodrug of claim 1.