PRODRUG COMPOSITIONS AND METHODS OF TREATMENT
Systems and methods of delivering a drug product by inhalation can include a prodrug composition.
1 . A method of treating a medical condition in a human subject comprising:
administering by inhalation a composition including a prodrug, the prodrug passing through lung tissue to achieve an effective plasma concentration of a pharmaceutically active form of the prodrug in the human subject.
2 . The method of claim 1 , further comprising providing the composition in an inhaler.
3 . The method of claim 2 , wherein the composition is a powder having a mean median aerodynamic diameter of less than 5 microns.
4 . The method of claim 2 , wherein the composition is a liquid, gel or a suspension.
5 . The method of claim 2 , wherein the inhaler includes a propellant.
6 . The method of claim 1 , further comprising providing the composition in a nebulizer.
7 . The method of claim 1 , further comprising providing the composition in an aerosol.
8 . The method of claim 7 , wherein providing the composition in an aerosol includes rapidly heating the composition to vaporize or sublimate the composition.
9 . The method of claim 1 , wherein the composition consists essentially of the prodrug.
10 . The method of claim 1 , wherein the composition consists essentially of the prodrug and epinephrine.
11 . The method of claim 1 , wherein the composition consists essentially of the prodrug and a second prodrug.
12 . The method of claim 1 , wherein the prodrug includes an alkyl ester of a pharmaceutically active form of the prodrug.
13 . The method of claim 1 , wherein the prodrug includes a butyl ester of a pharmaceutically active form of the prodrug.
14 . The method of claim 1 , wherein the prodrug includes an isopropyl ester of a pharmaceutically active form of the prodrug.
15 . The method of claim 1 , wherein the prodrug includes an ethyl ester of a pharmaceutically active form of the prodrug.
16 . The method of claim 1 , wherein the prodrug includes an ester of epinephrine.
17 . The method of claim 1 , wherein the medical condition is in a spectrum of anaphylaxis.
18 . The method of claim 1 , wherein the medical condition is an allergic reaction.
19 . The method of claim 1 , wherein the medical condition is a cardiac abnormality.
20 . The method of claim 1 , wherein the medical condition is a pulmonary abnormality.
21 . The method of claim 1 , wherein the composition including a prodrug includes more than one prodrug with each prodrug being a derivative of a pharmaceutically active ingredient.
22 . The method of claim 21 , wherein the first prodrug is a first ester of epinephrine and the second prodrug is a second ester of epinephrine, the first ester of epinephrine and the second ester of epinephrine being different.
23 . The method of claim 1 , wherein the prodrug is a compound of formula (I), wherein
each of R 1a , R 1b , R 2 and R 3 , independently, can be H, C1-C16 acyl, alkyl aminocarbonyl, alkyloxycarbonyl, phenacyl, sulfate or phosphate, or R 1a and R 1b together, R 1a and R 2 together, R 1a and R 3 together, R 1b and R 2 together, R 1b and R 3 together, or R 2 and R 3 together form a cyclic structure including a dicarbonyl, disulfate or diphosphate moiety, provided that one of R 1 , R 2 and R 3 is not H, or a pharmaceutically acceptable salt thereof.
24 . The method of claim 23 , wherein R 2 and R 3 are H and each R 1a and R 1b , independently, is ethanoyl, n-propanoyl, isopropanoyl, n-butanoyl, isobutanoyl, sec-butanoyl, tert-butanoyl, n-pentanoyl, isopentanoyl, sec-pentanoyl, tert-pentanoyl, or neopentanoyl.
25 . An inhalation device comprising:
a housing and a composition within the housing, the composition including a prodrug.
26 . The device of claim 25 , wherein the composition consists essentially of the prodrug.
27 . The device of claim 25 , wherein the prodrug includes an alkyl ester of a pharmaceutically active compound.
28 . The device of claim 25 , wherein the prodrug includes a butyl ester of a pharmaceutically active compound.
29 . The device of claim 23 , wherein the prodrug includes an isopropyl ester of a pharmaceutically active compound.
30 . The device of claim 25 , wherein the prodrug includes an ethyl ester of a pharmaceutically active compound.
31 . The device of claim 25 , wherein the prodrug includes an ester of epinephrine.
32 . The device of claim 25 , wherein the composition including a prodrug includes more than one prodrug with each prodrug being a derivative of a pharmaceutically active ingredient.
33 . The device of claim 25 , wherein a first prodrug is a first ester of epinephrine and a second prodrug is a second ester of epinephrine, the first ester of epinephrine and the second ester of epinephrine being different.
34 . The device of claim 25 , wherein the prodrug is a compound of formula (I), wherein
each of R 1a , R 1b , R 2 and R 3 , independently, can be H, C1-C16 acyl, alkyl aminocarbonyl, alkyloxycarbonyl, phenacyl, sulfate or phosphate, or R 1a and R 1b together, R 1a and R 2 together, R 1a and R 3 together, R 1b and R 2 together, R 1b and R 3 together, or R 2 and R 3 together form a cyclic structure including a dicarbonyl, disulfate or diphosphate moiety, provided that one of R 1 , R 2 and R 3 is not H, or a pharmaceutically acceptable salt thereof.
35 . The device of claim 25 , wherein R 2 and R 3 are H and each R 1a and R 1b , independently, is ethanoyl, n-propanoyl, isopropanoyl, n-butanoyl, isobutanoyl, sec-butanoyl, tert-butanoyl, n-pentanoyl, isopentanoyl, sec-pentanoyl, tert-pentanoyl, or neopentanoyl.
36 . The inhalation device of claim 25 , wherein the housing is a blister-based housing and the composition is a preloaded dose of a powder.
37 . The inhalation device of claim 25 , wherein the housing includes a capsule comprising a unit dose of a powder of the composition.
38 . The composition of claim 25 , wherein the composition comprises the prodrug and epinephrine.
39 . The composition of claim 25 , wherein the composition comprises the prodrug and a second prodrug.
40 . A method of treating a medical condition in a mammal comprising administering a therapeutically effective amount of a composition comprising a prodrug and epinephrine, and delivering the composition both locally and systemically.
41 . A method of treating a medical condition in a mammal comprising administering a therapeutically effective amount of a composition comprising a first prodrug and a second prodrug and delivering the composition both locally and systemically.
42 . The method of claim 41 , wherein the therapeutically effective amount is a ratio of a presented dose to a deposited dose.
43 . The method of claim 42 , wherein the ratio is greater than 0.28.
44 . The method of claim 42 , wherein the ratio is about 0.3.
45 . The method of claim 41 , wherein the amount of the first prodrug deposited is greater than 0.09 mg/kg.
46 . The method of claim 41 wherein the second prodrug is deposited is greater than 0.13 mg/kg.
47 . The method of claim 41 , wherein the method of claim 41 , wherein the amount of the first prodrug deposited is greater than 0.3 mg/kg.
48 . The method of claim 41 wherein the second prodrug is deposited is greater than 0.25 mg/kg.
49 . The method of claim 12 wherein the pharmaceutically active form is epinephrine.
50 . The method of claim 13 wherein the pharmaceutically active form is epinephrine.
51 . The method of claim 14 wherein the pharmaceutically active form is epinephrine.
52 . The method of claim 15 wherein the pharmaceutically active form is epinephrine.
53 . The method of claim 1 , wherein the composition produces plasma levels of epinephrine greater than 0.5 mg/g and less than 450 mg/kg.
54 . The method of claim 1 , wherein the composition including a prodrug is administered in a dose of greater than 0.05 mg and less than 5 mg.
55 . The method of claim 54 wherein the dose is about 0.5 mg.
56 . The method of claim 54 wherein the dose is about 1.0 mg.
57 . The method of claim 54 wherein the dose is about 1.5 mg.
58 . The method of claim 54 wherein the dose is about 2.0 mg.
59 . The method of claim 1 , wherein the composition has a Cmax of greater than 5 and less than 300 mg/kg.
60 . The method of claim 1 , wherein the effective plasma concentration of a pharmaceutically active form of the prodrug has a Tmax of greater than 0.5 seconds and less than 40 seconds.