# US 7,608,687 B2 · Releasable linkage and compositions containing same

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- Number: US 7,608,687 B2
- Document ID: US7608687B2
- Status: Granted
- Kind: B2
- Application number: 11/903,199
- Filed: 2007-09-19
- Published: 2008-06-26
- Granted: 2009-10-27
- Earliest claimed: 1999-04-23
- Assignees: Alza Corporation
- Inventors: Samuel Zalipsky
- Web page: https://patentgrep.com/patent/US7608687B2

## CPC

- A61K 9/1271: Non-conventional liposomes, e.g. PEGylated liposomes or liposomes coated or grafted with polymers (liposomes as conjugates {A61K47/6911})
- A61K 9/0019: {Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00)}
- A61K 31/196: the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
- A61K 31/407: condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- A61K 31/56: Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K 38/14: Peptides containing saccharide radicals; Derivatives thereof {, e.g. bleomycin, phleomycin, muramylpeptides or vancomycin}
- A61K 47/54: the modifying agent being an organic compound
- A61K 47/542: {Carboxylic acids, e.g. a fatty acid or an amino acid}
- A61K 47/543: {Lipids, e.g. triglycerides; Polyamines, e.g. spermine or spermidine}
- A61K 47/544: {Phospholipids}
- A61K 47/554: {the modifying agent being a steroid plant sterol, glycyrrhetic acid, enoxolone or bile acid}
- A61K 47/60: the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
- A61K 47/6911: {the form being a liposome}
- A61P 35/00: Antineoplastic agents
- C07C 323/19: with singly-bound oxygen atoms bound to acyclic carbon atoms of the carbon skeleton
- C07D 239/553: with halogen atoms or nitro radicals directly attached to ring carbon atoms, e.g. fluorouracil
- C07D 487/14: Ortho-condensed systems
- C07H 17/08: Hetero rings containing eight or more ring members, e.g. erythromycins
- C07H 19/12: Triazine radicals
- C07H 19/16: Purine radicals
- Y10T 428/2984: Microcapsule with fluid core [includes liposome]
- 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
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C07H: SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS (derivatives of aldonic or saccharic acids C07C, C07D; aldonic acids, saccharic acids C07C59/105, C07C59/285; cyanohydrins C07C255/16; glycals C07D; compounds of unknown constitution C07G; polysaccharides, derivatives thereof C08B; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification C12N15/00; sugar industry C13)
- Y10T: TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION

## Abstract

A compound comprised of a hydrophilic polymer covalently yet reversibly linked to a amine-containing ligand through a dithiobenzyl linkage is described.

## Claims

### Claim 1

A polypeptide composition having the general structure:
wherein R1 is a hydrophilic polymer having a molecular weight of between 440-100,000 Daltons and comprising a linkage for attachment to the dithiobenzyl moiety; R2 is selected from the group consisting of H, alkyl, and aryl; R3 is selected from the group consisting of O(C═O), S(C═O), and O(C═S); R5 is selected from the group consisting of H, alkyl and aryl; where the polypeptide is between 10-30 kDa and where orientation of CH2—R3 is selected from the ortho position and the para position; and n is at least 1.

### Claim 2 (depends on 1)

The composition of claim 1, wherein said hydrophilic polymer R1 is selected from the group consisting of polyvinylpyrrolidone, polyvinylmethylether, polymethyloxazoline, polyethyloxazoline, polyhydroxypropyloxazoline, polyhydroxypropyl-methacrylamide, polymethacrylamide, polydimethyl-acrylamide, polyhydroxypropylmethacrylate, polyhydroxyethylacrylate, hydroxymethylcellulose, hydroxyethylcellulose, polyethyleneglycol, polyaspartamide, copolymers thereof, and polyethyleneoxide-polypropylene oxide.

### Claim 3 (depends on 1)

The composition of claim 1, wherein R1 is polyethyleneglycol.

### Claim 4 (depends on 1)

The composition of claim 1, wherein R5 is H and R2 is selected from the group consisting of H, OH3, C2H5, and C3H8.

### Claim 5 (depends on 1)

The composition of claim 1, wherein R2 and R5 are alkyls.

### Claim 6 (depends on 1)

The composition of claim 1, wherein n is between about 1 and about 6.

### Claim 7 (depends on 1)

The composition of claim 1, wherein the cytokine is a tumor necrosis factor.

### Claim 8

A polypeptide composition, comprising:
a polypeptide conjugated to at least one a hydrophilic polymer chain to form a modified polypeptide having the general structure:
wherein R1 is a hydrophilic polymer having a molecular weight of between 440-100,000 Daltons and comprising a linkage for attachment to the dithiobenzyl moiety; R2 is selected from the group consisting of H, alkyl, and aryl; R3 is selected from the group consisting of O(C═O), S(C═O), and O(C═S); R5 is selected from the group consisting of H, alkyl and aryl; where the polypeptide is between 10-30 kDa and where orientation of CH2—R3 is selected from the ortho position and the para position; and n is at least 1; and
a pharmaceutically-acceptable carrier.

### Claim 9 (depends on 8)

The composition of claim 8, wherein n is between about 1 and about 6.

### Claim 10 (depends on 8)

The composition of claim 8, wherein said hydrophilic polymer R1 is selected from the group consisting of polyvinylpyrrolidone, polyvinylmethylether, polymethyloxazoline, polyethyloxazoline, polyhydroxypropyloxazoline, polyhydroxypropyl-methacrylamide, polymethacrylamide, polydimethyl-acrylamide, polyhydroxypropylmethacrylate, polyhydroxyethylacrylate, hydroxymethylcellulose, hydroxyethylcellulose, polyethyleneglycol, polyaspartamide, copolymers thereof, and polyethyleneoxide-polypropylene oxide.

### Claim 11 (depends on 8)

The composition of claim 8, wherein R1 is polyethyleneglycol.

### Claim 12 (depends on 8)

The composition of claim 8, wherein R5 is H and R2 is selected from the group consisting of H, CH3, C2H5, and C3H8.

### Claim 13 (depends on 8)

The composition of claim 8, wherein R2 and R5 are alkyls.

### Claim 14 (depends on 8)

The composition of claim 8, wherein the cytokine is a tumor necrosis factor.