Chemically Modified Small Molecules

• US 20100210676A1
• Filed: 02/22/2010
• Published: 08/19/2010
• Est. Priority Date: 12/16/2003
• Status: Active Grant

• Current Assignee: Nektar Therapeutics
• Original Assignee: Nektar Therapeutics
• Inventors: Lechuga-Ballesteros, David, Song, Yuan, Viegas, Tacey, Gursahani, Hema, Fishburn, C. Simone, Leach, Chester, Kuo, Mei-Chang
• Granted Patent: US 8,067,431 B2
• Time in Patent Office: Days
• 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

1-38. -38. (canceled)

39. A method of treating a condition responsive to naloxone in a patient in need thereof, 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 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.

40. The method of claim 39, wherein the compound comprises a mixture of α

-6 and β

-6 isomers.

41. The method of claim 40, wherein the compound is 6-CH₃—

(OCH₂CH₂)₇—

O-naloxol or pharmaceutically acceptable salt thereof.

42. The method of claim 39, 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 pharmaceutically acceptable salt thereof.

43. The method of claim 42, wherein the compound is α

-6-CH₃—

(OCH₂CH₂)₇—

O-naloxol or pharmaceutically acceptable salt thereof.

44. The method of claim 39, 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 pharmaceutically acceptable salt thereof.

45. The method of claim 39, wherein the compound is β

-6-CH₃—

(OCH₂CH₂)₇—

O-naloxol or pharmaceutically acceptable salt thereof.