Chemically modified small molecules

• US 8,067,431 B2
• Filed: 02/22/2010
• Issued: 11/29/2011
• Est. Priority Date: 12/16/2003
• Status: Active Grant

• Current Assignee: Nektar Therapeutics
• Original Assignee: Nektar Therapeutics
• Inventors: Song, Yuan, Viegas, Tacey, Fishburn, C. Simone, Leach, Chester, Lechuga-Ballesteros, David, Gursahani, Hema, Kuo, Mei-Chang
• Primary Examiner(s): Landau; Sharmila G.
• Assistant Examiner(s): LOVE, TREVOR M
• Application Number:
  US12/710,167
• Publication Number:
  US 20100210676A1
• Time in Patent Office: 645 Days
• Field of Search: 514/282, 546/44
• US Class Current: 514/282
• CPC Class Codes: A61K 31/167 having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
• CPC Class Codes: A61K 31/485 Morphinan derivatives, e.g. morphine, codeine
• 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 9/007 Pulmonary tract; Aromatherapy
• CPC Class Codes: A61P 25/36 Opioid-abuse
• CPC Class Codes: C07C 41/24 by elimination of halogens, e.g. elimination of HCl

Abstract

Methods of modifying the rate of systemic absorption of a drug administered to a subject by a pulmonary route, the method comprising covalently conjugating a hydrophilic polymer to a drug, wherein the drug has a half-life of elimination from the lung of less than about 180 minutes, to form a drug-polymer conjugate, wherein the drug-polymer conjugate has a net hydrophilic character and a weight average molecular weight of from about 50 to about 20,000 Daltons, and wherein the half-life of elimination from the lung of the drug-polymer conjugate is at least about 1.5-fold greater than the half-life of elimination from the lung of the drug, wherein the half-life of elimination from the lung is measured by bronchoalveolar lavage followed by assaying residual lung material.

Claims

1. A method of treating a patient in need of an opioid antagonist, comprising:

administering to the patient an oral dosage form comprising a compound selected from the group consisting of

6-CH₃—

(OCH₂CH₂)₅—

O-naloxol;

6-CH₃—

(OCH₂CH₂)₆—

O-naloxol;

6-CH₃—

(OCH₂CH₂)₇—

O-naloxol;

6-CH₃—

(OCH₂CH₂)₈—

O-naloxol; and

6-CH₃—

(OCH₂CH₂)₉—

O-naloxol;

or a pharmaceutically acceptable salt thereof, wherein the compound is an α

-6 isomer, a β

-6 isomer or a mixture of α

-6 and β

-6 isomers.

2. The method of claim 1, wherein the compound comprises a mixture of α

-6 and β

-6 isomers.

3. The method of claim 2, wherein the compound is 6-CH₃—

(OCH₂CH₇)₇—

O-naloxol or a pharmaceutically acceptable salt thereof.

4. The method of claim 1, wherein the compound is selected from the group consisting of

α

-6-CH₃—

(OCH₂CH₂)₅—

O-naloxol;

α

-6-CH₃—

(OCH₂CH₂)₆—

O-naloxol;

α

-6-CH₃—

(OCH₂CH₂)₇—

O-naloxol;

α

-6-CH₃—

(OCH₂CH₂)₈—

O-naloxol; and

α

-6-CH₃—

(OCH₂CH₂)₉—

O-naloxol;

or a pharmaceutically acceptable salt thereof.

5. The method of claim 4, wherein the compound is α

-6-CH₃—

(OCH₂CH₂)₇—

O-naloxol or a pharmaceutically acceptable salt thereof.

6. The method of claim 1, wherein the compound is selected from the group consisting of

β

-6-CH₃—

(OCH₂CH₂)₅—

O-naloxol;

β

-6-CH₃—

(OCH₂CH₂)₆—

O-naloxol;

β

-6-CH₃—

(OCH₂CH₂)₇—

O-naloxol;

β

-6-CH₃—

(OCH₂CH₂)₈—

O-naloxol; and

β

-6-CH₃—

(OCH₂CH₂)₉—

O-naloxol;

or a pharmaceutically acceptable salt thereof.

7. The method of claim 1, wherein the compound is β

-6-CH₃—

(OCH₂CH₃)₇—

O-naloxol or a pharmaceutically acceptable salt thereof.