CHEMICALLY MODIFIED SMALL MOLECULES
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.
1 . A method 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.
2 . The method according to claim 1 , wherein the hydrophilic polymer comprises a polymer chosen from polyethylene glycols and polyethylene oxides.
3 . The method according to claim 1 , wherein the weight average molecular weight of the polymer is from about 1000 to about 5000 Daltons.
4 . The method according to claim 1 , wherein the drug has a molecular weight of less than about 1500.
5 . The method according to claim 1 , wherein the hydrophilic polymer comprises a polyethylene glycol.
6 . The method according to claim 5 , wherein the polyethylene glycol is chosen from linear polyethylene glycols, branched polyethylene glycols, forked polyethylene glycols, and dumbbell polyethylene glycols.
7 . The method according to claim 1 , wherein the hydrophilic polymer comprises a polymer from a polydisperse population.
8 . The method according to claim 1 , wherein the hydrophilic polymer is a polymer chosen from monodisperse, bimodal, trimodal, or tetramodal polymer populations.
9 - 13 . (canceled)
14 . A method of controlling the rate of systemic absorption of a drug pulmonarily administered comprising covalently attaching to the drug a hydrophilic polymer having a weight average molecular weight of from about 50 to about 4000 Daltons, to form a drug-polymer conjugate.
15 . A pharmaceutical compound for pulmonary administration comprising a drug covalently attached to a hydrophilic polymer, wherein the pharmaceutical compound has a net hydrophilic character, and wherein the weight average molecular weight of the hydrophilic polymer is from about 50 to about 5000 Daltons
16 . A pharmaceutical composition comprising the pharmaceutical compound according to claim 15 , and at least one pharmaceutically acceptable excipient.
17 . The pharmaceutical composition according to claim 16 , in liquid form.
18 . The pharmaceutical composition according to claim 16 , in dry form.
19 . An aerosol comprising the pharmaceutical composition according to claim 16 .
20 . The pharmaceutical composition according to claim 17 , in an inhaler device.
21 . The pharmaceutical composition according to claim 16 , wherein the composition comprises particles having a mass median aerodynamic diameter (MMAD) of less than about 10 microns.
22 . The pharmaceutical composition according to claim 16 , wherein the composition comprises particles having a MMAD of less than about 5 microns.
23 . The pharmaceutical composition according to claim 18 , wherein said composition comprises a dry powder.
24 . The pharmaceutical composition according to claim 16 , characterized by an emitted dose of at least about 30 percent.
25 . A spray-dried pharmaceutical composition of claim 16 .
26 - 28 . (canceled)
29 . The pharmaceutical compound according to claim 15 , wherein the hydrophilic polymer is polyethylene glycol.
30 . The pharmaceutical composition according to claim 29 , wherein the polyethylene glycol is chosen from linear polyethylene glycols, branched polyethylene glycols, forked polyethylene glycols, and dumbbell polyethylene glycols.
31 . A unit dosage form comprising the pharmaceutical composition according to claim 16 .
32 . The pharmaceutical compound according to claim 15 , wherein the weight average molecular weight of the hydrophilic polymer is from about 50 to about 5000 Daltons and wherein pulmonary administration of the compound results in a half-life of elimination from the lung that can be described by the equation, t 1/2 -el=12.84*(1-e −kMW ), where k=0.000357, MW=molecular weight in Daltons, and t 1/2 =elimination half-life in hours.
33 . (canceled)
34 . The method according to claim 1 , wherein the half-life of elimination from the lung of the drug-polymer conjugate is at least about 2-fold greater than the half-life of elimination from the lung of the drug.
35 . The method according to claim 34 , wherein the half-life of elimination from the lung of the drug-polymer conjugate is at least about 4-fold greater than the half-life of elimination from the lung of the drug.
36 . The method according to claim 35 , wherein the half-life of elimination from the lung of the drug-polymer conjugate is at least about 10-fold greater than the half-life of elimination from the lung of the drug.
37 . (canceled)
38 . The pharmaceutical composition according to claim 18 in an inhaler device.