# US 8,771,662 B2 · Multi-arm polymer prodrugs

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- Number: US 8,771,662 B2
- Document ID: US8771662B2
- Status: Granted
- Kind: B2
- Application number: 13/765,433
- Filed: 2013-02-12
- Published: 2013-06-20
- Granted: 2014-07-08
- Earliest claimed: 2003-09-17
- Assignees: Nektar Therapeutics
- Applicants: Nektar Therapeutics
- Inventors: Xuan Zhao; Michael David Bentley; Zhongxu Ren; Tacey X. Viegas
- Web page: https://patentgrep.com/patent/US8771662B2

## CPC

- A61K 31/4745: condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines (yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48)
- A61K 31/4709: Non-condensed quinolines and containing further heterocyclic rings
- 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
- A61K 47/64: Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent (peptidic linkers A61K47/65)
- A61P 35/04: specific for metastasis
- C08G 65/3314: {cyclic}
- C08G 65/3324: {cyclic}
- C08G 65/33317: {heterocyclic}
- C08G 65/3348: {containing nitrogen in addition to sulfur}
- C08L 2203/02: for biomedical use
- 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
- C08G: MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08L: COMPOSITIONS OF MACROMOLECULAR COMPOUNDS (compositions based on polymerisable monomers C08F, C08G; artificial filaments or fibres D01F; textile treating compositions D06)

## Abstract

Provided herein are water-soluble prodrugs, compositions comprising such prodrugs, and related methods of making and administering the same. The prodrugs of the invention comprise a water-soluble polymer having three or more arms, at least three of which are typically 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 method of treating cancer in a mammalian subject, said method comprising:
administering a therapeutically effective amount of a composition comprising a prodrug having the structure:
or a pharmaceutically acceptable salt form thereof,
where n ranges from 40 to 500, to a subject having one or more cancerous solid tumors, over a duration of time effective to produce an inhibition of growth of said one or more cancerous solid tumors in said subject.

### Claim 2 (depends on 1)

The method of claim 1, wherein said cancerous solid tumor type is selected from the group consisting of colorectal, ovarian, breast, non-small cell lung and prostate.

### Claim 3 (depends on 2)

The method of claim 2, wherein the cancer is breast cancer.

### Claim 4 (depends on 2)

The method of claim 2, wherein the cancer is colorectal cancer.

### Claim 5 (depends on 2)

The method of claim 2, wherein the cancer is non-small cell lung cancer.

### Claim 6 (depends on 2)

The method of claim 2, wherein the cancer is prostate cancer.

### Claim 7 (depends on 2)

The method of claim 2, wherein the cancer is ovarian cancer.

### Claim 8 (depends on 1)

The method of claim 1, wherein the mammalian subject is human.

### Claim 9 (depends on 1)

The method of claim 1, wherein the overall nominal average molecular weight of the prodrug ranges from about 20,000 to about 80,000 daltons.

### Claim 10 (depends on 1)

The method of claim 1, wherein the composition further comprises one or more additional prodrugs having a structure selected from the group consisting of:
or a pharmaceutically acceptable salt form thereof,
wherein O-Irinotecan is
L is the site of attachment, and
n ranges from 40 to 500.

### Claim 11 (depends on 1)

The method of claim 1, wherein the composition further comprises a pharmaceutically acceptable carrier.

### Claim 12 (depends on 1)

The method of claim 1, wherein said administering is parenteral.

### Claim 13 (depends on 12)

The method of claim 12, wherein said parenteral administering is via a route selected from intraperitoneal, intravenous, subcutaneous, and intramuscular injection.

### Claim 14 (depends on 13)

The method of claim 13, wherein said administering is by intravenous infusion.

### Claim 15 (depends on 14)

The method of claim 14, wherein the composition comprises a sterile aqueous preparation of the prodrug.

### Claim 16 (depends on 7)

The method of claim 7, wherein the dosage administered comprises from about 10.0 to about 60 mg irinotecan/kg body weight of the subject.