U.S. patent application number 12/692095 was filed with the patent office on 2010-05-13 for formoterol/steroid bronchodilating compositions and methods of use thereof.
This patent application is currently assigned to DEY, L.P.. Invention is credited to Partha S. Banerjee, Imtiaz A. Chaudry, Stephen Pham.
Application Number | 20100120734 12/692095 |
Document ID | / |
Family ID | 26962701 |
Filed Date | 2010-05-13 |
United States Patent
Application |
20100120734 |
Kind Code |
A1 |
Banerjee; Partha S. ; et
al. |
May 13, 2010 |
FORMOTEROL/STEROID BRONCHODILATING COMPOSITIONS AND METHODS OF USE
THEREOF
Abstract
Bronchodilating compositions and methods are provided. The
compositions are intended for administration as a nebulized
aerosol. In certain embodiments, the compositions contain
formoterol, or a derivative thereof, and a steroidal
anti-inflammatory agent. Methods for treatment, prevention, or
amelioration of one or more symptoms of bronchoconstrictive
disorders using the compositions provided herein are also
provided.
Inventors: |
Banerjee; Partha S.;
(Wynnewood, PA) ; Chaudry; Imtiaz A.; (American
Canyon, CA) ; Pham; Stephen; (Sacramento,
CA) |
Correspondence
Address: |
LUCAS & MERCANTI, LLP
475 PARK AVENUE SOUTH, 15TH FLOOR
NEW YORK
NY
10016
US
|
Assignee: |
DEY, L.P.
Napa
CA
|
Family ID: |
26962701 |
Appl. No.: |
12/692095 |
Filed: |
January 22, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09887496 |
Jun 22, 2001 |
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12692095 |
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60284607 |
Apr 17, 2001 |
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Current U.S.
Class: |
514/171 ;
514/291; 514/304; 514/653 |
Current CPC
Class: |
A61K 31/573 20130101;
A61P 11/08 20180101; A61K 31/191 20130101; A61P 11/00 20180101;
A61K 9/0078 20130101; A61K 31/167 20130101; A61K 47/10 20130101;
A61K 2300/00 20130101; A61K 31/58 20130101; A61K 2300/00 20130101;
A61K 2300/00 20130101; A61K 31/537 20130101; A61K 2300/00 20130101;
A61P 11/06 20180101; A61K 31/537 20130101; A61K 31/568 20130101;
A61K 31/167 20130101; A61K 31/573 20130101; A61K 45/06 20130101;
A61K 31/56 20130101; A61K 47/02 20130101; A61K 31/56 20130101 |
Class at
Publication: |
514/171 ;
514/291; 514/304; 514/653 |
International
Class: |
A61K 31/56 20060101
A61K031/56; A61K 31/439 20060101 A61K031/439; A61K 31/135 20060101
A61K031/135 |
Claims
1. A pharmaceutical composition, comprising: (i) formoterol, or a
pharmaceutically acceptable hydrate thereof in solution; and (ii) a
steroidal anti-inflammatory agent, or a pharmaceutically acceptable
salt or hydrate thereof in suspension; in a pharmacologically
suitable fluid comprising water that is propellant-free, wherein;
the composition is an aqueous composition formulated so that it is
stable during long term storage, whereby the composition has an
estimated shelf-life of greater than 1 month usage time at
25.degree. C. and greater than or equal to 1 year storage time at
5.degree. C., whereby greater than 90% of the initial amount of
formoterol in the composition remains at such time; the formoterol
free base concentration is about 5 .mu.g/mL to about 200 .mu.g/mL;
and the composition is formulated at a concentration for direct
administration to a human in need thereof.
2. The pharmaceutical composition of claim 1, wherein greater than
about 80% of the initial formoterol is present after 1 month usage
time at 25.degree. C. and 1 year storage time at 5.degree. C.
3. The pharmaceutical composition of claim 1 that has been
nebulized.
4. The pharmaceutical composition of claim 1, wherein the
pharmacologically suitable fluid further comprises a polar
solvent.
5. The pharmaceutical composition of claim 4, wherein the polar
solvent is a protic solvent.
6. The pharmaceutical composition of claim 5, further comprising a
tonicity adjusting agent.
7. The pharmaceutical composition of claim 6, wherein the tonicity
adjusting agent is ammonium carbonate, ammonium chloride, ammonium
lactate, ammonium nitrate, ammonium phosphate, ammonium sulfate,
ascorbic acid, bismuth sodium tartrate, boric acid, calcium
chloride, calcium disodium edetate, calcium gluconate, calcium
lactate, citric acid, dextrose, diethanolamine, dimethylsulfoxide,
edetate disodium, edetate trisodium monohydrate, fluorescein
sodium, fructose, galactose, glycerin, lactic acid, lactose,
magnesium chloride, magnesium sulfate, mannitol, polyethylene
glycol, potassium acetate, potassium chlorate, potassium chloride,
potassium iodide, potassium nitrate, potassium phosphate, potassium
sulfate, propylene glycol, silver nitrate, sodium acetate, sodium
bicarbonate, sodium biphosphate, sodium bisulfite, sodium borate,
sodium bromide, sodium cacodylate, sodium carbonate, sodium
chloride, sodium citrate, sodium iodide, sodium lactate, sodium
metabisulfite, sodium nitrate, sodium nitrite, sodium phosphate,
sodium propionate, sodium succinate, sodium sulfate, sodium
sulfite, sodium tartrate, sodium thiosulfate, sorbitol, sucrose,
tartaric acid, triethanolamine, urea, urethan, uridine or zinc
sulfate.
8. The pharmaceutical composition of claim 7, wherein the tonicity
adjusting agent is sodium chloride.
9. The pharmaceutical composition of claim 1, wherein the
pharmacologically suitable fluid comprises a buffer.
10. The pharmaceutical composition of claim 9, wherein the buffer
is citric acid/phosphate, acetate, barbital, borate, cacodylate,
citrate, collidine, formate, maleate, phosphate, succinate,
citrate-phosphate-borate (Teorell-Stanhagen), veronal acetate, MES
(2-(N-morpholino)ethanesulfonic acid), BIS-TRIS
(bis(2-hydroxyethyl)iminotris-(hydroxymethyl)methane), ADA
(N-(2-acetamido)-2-iminodiacetic acid), ACES
(N-(carbamoylmethyl)-2-amino-ethanesulfonic acid), PIPES
(piperazine-N,N'-bis(2-ethanesulfonic acid)), MOPSO
(3-(N-morpholino)-2-hydroxypropanesulfonic acid), BIS-TRIS PROPANE
(1,3-bis(tris(hydroxymethyl)methylamino)propane), BES
(N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonic acid), MOPS
(3-(N-morpholino)propanesulfonic acid), TES
(N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid), HEPES
(N-(2-hydroxyethyl)piperazine-N'-(2-ethanesulfonic acid), DIPSO
(3-(N,N-bis(2-hydroxyethyl)amino)-2-hydroxypropanesulfonic acid),
MOBS (4-(N-morpholino)butanesulfonic acid), TAPSO
(3-(N-tris(hydroxymethyl)methylamino)-2-hydroxy-propanesulfonic
acid), tris(hydroxymethylaminomethane,
HEPPSO(N-(2-hydroxyethyl)piperazine-N.sup.1-(2-hydroxypropanesulfonic
acid), POPSO (piperazine-N,N'-bis(2-hydroxypropane-sulfonic acid)),
TEA (triethanolamine),
EPPS(N-(2-hydroxyethyl)piperazine-1-N'-(3-propanesulfonic acid),
TRICINE (N-tris(hydroxymethyl)methylglycine)-, GLY-GLY
(glycylglycine), WINE (N,N-bis(2-hydroxyethyl)glycine), HEPBS
(N-(2-hydroxyethyl)piperazine-N'-(4-butanesulfonic acid)),
TAPS(N-tris(hydroxymethyl)methyl-3-aminopropanesulfonic acid), or
AMPD (2-amino-2-methyl-1,3-propanediol) buffer.
11. The pharmaceutical composition of claim 10, wherein the buffer
is citrate buffer.
12. The pharmaceutical composition of claim 11, wherein the buffer
concentration is from about 0.01 mM to about 150 mM.
13. The pharmaceutical composition of claim 12, wherein the buffer
concentration is from about 1 mM to about 20 mM.
14. The pharmaceutical composition of claim 13, wherein the buffer
concentration is about 5 mM.
15. The pharmaceutical composition of claim 7, wherein the ionic
strength of the composition is about 0 to about 0.4.
16. The pharmaceutical composition of claim 15, wherein the ionic
strength of the composition is about 0.05 to about 0.16.
17. The pharmaceutical composition of claim 1, wherein the pH of
the composition is about 2.0 to about 8.0.
18. The pharmaceutical composition of claim 17, wherein the pH of
the composition is about 4.0 to about 6.0.
19. The pharmaceutical composition of claim 18, wherein the pH of
the composition is about 4.5 to about 5.5.
20. The pharmaceutical composition of claim 19, wherein the pH of
the composition is about 5.0.
21. The pharmaceutical composition of claim 1, wherein the
formoterol free base concentration is about 10 .mu.g/mL to about
200 .mu.g/mL.
22. The pharmaceutical composition of claim 21, wherein the
formoterol free base concentration is about 50 g/mL to about 200
.mu.g/mL.
23. The pharmaceutical composition of claim 22, wherein the
formoterol free base concentration is about 59 .mu.g/mL.
24. The pharmaceutical composition of claim 22, wherein the
formoterol free base concentration is about 118 .mu.g/mL.
25. The pharmaceutical composition of claim 7, further comprising a
buffer.
26. The pharmaceutical composition of claim 25, wherein the buffer
is citric acid/phosphate, acetate, barbital, borate, cacodylate,
citrate, collidine, formate, maleate, phosphate, succinate,
citrate-phosphate-borate (Teorell-Stanhagen), veronal acetate, MES
(2-(N-morpholino)ethanesulfonic acid), BIS-TRIS
(bis(2-hydroxyethyl)iminotris-(hydroxymethyl)methane), ADA
(N-(2-acetamido)-2-iminodiacetic acid), ACES
(N-(carbamoylmethyl)-2-amino-ethanesulfonic acid), PIPES
(piperazine-N,N'-bis(2-ethanesulfonic acid)), MOPSO
(3-(N-morpholino)-2-hydroxypropanesulfonic acid), BIS-TRIS PROPANE
(1,3-bis(tris(hydroxymethyl)methylamino)propane), BES
(N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonic acid), MOPS
(3-(N-morpholino)propanesulfonic acid), TES
(N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid), HEPES
(N-(2-hydroxyethyl)piperazine-N-(2-ethanesulfonic acid), DIPSO
(3-(N,N-bis(2-hydroxyethyl)amino)-2-hydroxypropanesulfonic acid),
MOBS (4-(N-morpholino)butanesulfonic acid), TAPSO
(3-(N-tris(hydroxymethyl)methylamino)-2-hydroxy-propanesulfonic
acid), tris(hydroxymethylaminomethane,
HEPPSO(N-(2-hydroxyethyl)piperazine-N'-(2-hydroxypropanesulfonic
acid), POPSO (piperazine-N,N'-bis(2-hydroxypropane-sulfonic acid)),
TEA (triethanolamine),
EPPS(N-(2-hydroxyethyl)piperazine-N'-(3-propanesulfonic acid),
TRICINE (N-tris(hydroxymethyl)methylglycine-), GLY-GLY
(glycylglycine), BICINE (N,N-bis(2-hydroxyethyl)glycine), HEPBS
(N-(2-hydroxyethyl)piperazine-N'-(4-butanesulfonic acid)),
TAPS(N-tris(hydroxyl-methyl)methyl-3-aminopropanesulfonic acid), or
AMPD (2-amino-2-methyl-1,3-propanediol) buffer.
27. The pharmaceutical composition of claim 26, wherein the buffer
is citrate buffer.
28. The pharmaceutical composition of claim 27, wherein the buffer
concentration is from about 0.01 mM to about 150 mM.
29. The pharmaceutical composition of claim 28, wherein the buffer
concentration is from about 1 mM to about 20 mM.
30. The pharmaceutical composition of claim 29, wherein the buffer
concentration is about 5 mM.
31. The pharmaceutical composition of claim 25, wherein the ionic
strength of the composition is about 0 to about 0.4.
32. The pharmaceutical composition of claim 31, wherein the ionic
strength of the composition is about 0.05 to about 0.16.
33. The pharmaceutical composition of claim 25, wherein the pH of
the composition is about 2.0 to about 8.0.
34. The pharmaceutical composition of claim 33, wherein the pH of
the composition is about 4.0 to about 6.0.
35. The pharmaceutical composition of claim 34, wherein the pH of
the composition is about 4.5 to about 5.5.
36. The pharmaceutical composition of claim 35, wherein the pH of
the composition is about 5.0.
37. The pharmaceutical composition of claim 25, wherein the
formoterol free base concentration is about 10 .mu.g/mL to about
200 .mu.g/mL.
38. The pharmaceutical composition of claim 37, wherein the
formoterol free base concentration is about 50 .mu.g/mL to about
200 .mu.g/mL.
39. The pharmaceutical composition of claim 38, wherein the
formoterol free base concentration is about 59 .mu.g/mL.
40. The pharmaceutical composition of claim 38, wherein the
formoterol free base concentration is about 118 .mu.g/mL.
41. The pharmaceutical composition of claim 23 that has been
nebulized.
42. The pharmaceutical composition of claim 24 that has been
nebulized.
43. The pharmaceutical composition of claim 39 that has been
nebulized.
44. The pharmaceutical composition of claim 40 that has been
nebulized.
45. The pharmaceutical composition of claim 25 that has been
nebulized.
46. The pharmaceutical composition of claim 39, wherein the buffer
is citrate buffer.
47. The pharmaceutical composition of claim 39, wherein the buffer
concentration is about 5 mM.
48. The pharmaceutical composition of claim 39, wherein the ionic
strength of the composition is about 0.05 to about 0.16.
49. The pharmaceutical composition of claim 39, wherein the pH of
the composition is about 5.0.
50. The pharmaceutical composition of claim 39, wherein the buffer
is citrate buffer; the buffer concentration is about 5 mM; the
ionic strength of the composition is about 0.05 to about 0.16; and
the pH of the composition is about 5.0.
51. The pharmaceutical composition of claim 40, wherein the buffer
is citrate buffer.
52. The pharmaceutical composition of claim 40, wherein the buffer
concentration is about 5 mM.
53. The pharmaceutical composition of claim 40, wherein the ionic
strength of the composition is about 0.05 to about 0.16.
54. The pharmaceutical composition of claim 40, wherein the pH of
the composition is about 5.0.
55. The pharmaceutical composition of claim 40, wherein the buffer
is citrate buffer; the buffer concentration is about 5 mM; the
ionic strength of the composition is about 0.05 to about 0.16; and
the pH of the composition is about 5.0.
56. The pharmaceutical composition of claim 50 that has been
nebulized.
57. The pharmaceutical composition of claim 55 that has been
nebulized.
58. The pharmaceutical composition of claim 10, wherein the buffer
comprises citric acid/phosphate buffer, acetate buffer, citrate
buffer or phosphate buffer.
59. The pharmaceutical composition of claim 25, wherein the buffer
comprises citric acid/phosphate buffer, acetate buffer, citrate
buffer or phosphate buffer.
60. The pharmaceutical composition of claim 1, wherein the
steroidal anti-inflammatory agent is beclomethasone dipropionate,
beclomethasone monopropionate, flunisolide, triamcinolone
acetonide, dexamethasone, tipredane, ciclesonid, rofleponide,
mometasone, mometasone furoate, RPR 106541 having the formula
##STR00002## fluticasone or fluticasone propionate or budesonide,
or a pharmaceutically acceptable salt or hydrate thereof.
61. The pharmaceutical composition of claim 60, wherein the
steroidal anti-inflammatory agent is budesonide or fluticasone
propionate, or a pharmaceutically acceptable salt or hydrate
thereof.
62. The pharmaceutical composition of claim 61, wherein the
steroidal anti-inflammatory agent is budesonide, or a derivative
thereof.
63. The pharmaceutical composition of claim 62, wherein the
budesonide concentration is about 5 .mu.g/mL to about 2 mg/mL.
64. The pharmaceutical composition of claim 62, wherein the
budesonide concentration is about 75 .mu.g/mL to about 500
.mu.g/mL.
65. The pharmaceutical composition of claim 62, wherein the
budesonide concentration is about 125 .mu.g/mL or about 250
.mu.g/mL.
66. The pharmaceutical composition of claim 61, wherein the
steroidal anti-inflammatory agent is fluticasone propionate.
67. The pharmaceutical composition of claim 66, wherein the
concentration of fluticasone propionate is about 5 .mu.g/mL to
about 2 mg/mL.
68. The pharmaceutical composition of claim 67, wherein the
concentration of fluticasone propionate is about 75 .mu.g/mL to
about 1000 .mu.g/mL.
69. The pharmaceutical composition of claim 68, wherein the
concentration of fluticasone propionate is about 125 .mu.g/mL or
about 250 .mu.g/mL.
70. The pharmaceutical composition of claim 50, wherein the
steroidal anti-inflammatory agent is budesonide or fluticasone
propionate.
71. The pharmaceutical composition of claim 55, wherein the
steroidal anti-inflammatory agent is budesonide or fluticasone
propionate.
72. A kit, comprising: (a) an aqueous composition comprising (i)
formoterol or a pharmaceutically acceptable salt or hydrate thereof
in solution, wherein the formoterol is present at a concentration
of 5 .mu.g/mL to about 200 .mu.g/mL; and (ii) a steroidal
anti-inflammatory agent or a pharmaceutically acceptable salt or
hydrate thereof in suspension, formulated for single dosage
administration, wherein the aqueous composition is propellant-free
and has an estimated shelf-life of greater than 1 month usage time
at 25.degree. C. and greater than or equal to 1 year storage time
at 5.degree. C.; and (b) a nebulizer.
73. The kit of claim 72, wherein the aqueous composition comprises
(a) formoterol free base at a concentration of about 59 .mu.g/mL;
(b) aqueous saline comprising sodium chloride; and (c) citrate
buffer at a concentration of about 5 mM; wherein the ionic strength
of the composition is about 0.05 to about 0.16; and the pH of the
composition is about 5.0.
74. The kit of claim 72, wherein the aqueous composition comprises
(a) formoterol free base at a concentration of about 118 .mu.g/mL;
(b) aqueous saline comprising sodium chloride; and (c) citrate
buffer at a concentration of about 5 mM; wherein the ionic strength
of the composition is about 0.05 to about 0.16; and the pH of the
composition is about 5.0.
75. A combination, comprising: (a) the pharmaceutical composition
of claim 1 formulated for single dosage administration; and (b) a
vial.
76. The combination of claim 75, wherein the aqueous composition
comprises (a) formoterol free base at a concentration of about 59
.mu.g/mL; (b) aqueous saline comprising sodium chloride; and (c)
citrate buffer at a concentration of about 5 mM; wherein the ionic
strength of the composition is about 0.05 to about 0.16; and the pH
of the composition is about 5.0.
77. The combination of claim 75, wherein the aqueous composition
comprises (a) formoterol free base at a concentration of about 118
.mu.g/mL; (b) aqueous saline comprising sodium chloride; and (c)
citrate buffer at a concentration of about 5 mM; wherein the ionic
strength of the composition is about 0.05 to about 0.16; and the pH
of the composition is about 5.0.
78. An article of manufacture, comprising packaging material, an
aqueous composition comprising the composition of claim 1
formulated for single dosage administration, which is useful for
treatment or amelioration of one or more symptoms of diseases or
disorders associated with undesired and/or uncontrolled
bronchoconstriction, and a label that indicates that the
composition is used for treatment, amelioration of one or more
symptoms of diseases or disorders associated with undesired and/or
uncontrolled bronchoconstriction.
79. An article of manufacture, comprising packaging material, the
composition of claim 70 formulated for single dosage
administration, which is useful for treatment or amelioration of
one or more symptoms of diseases or disorders associated with
undesired and/or uncontrolled bronchoconstriction, and a label that
indicates that the composition is used for treatment or
amelioration of one or more symptoms of diseases or disorders
associated with undesired and/or uncontrolled
bronchoconstriction.
80. An article of manufacture, comprising packaging material, the
composition of claim 71 formulated for single dosage
administration, which is useful for treatment or amelioration of
one or more symptoms of diseases or disorders associated with
undesired and/or uncontrolled bronchoconstriction, and a label that
indicates that the composition is used for treatment or
amelioration of one or more symptoms of diseases or disorders
associated with undesired and/or uncontrolled
bronchoconstriction.
81. The pharmaceutical composition of claim 1, further comprising
one or more of (a) to (j) as follows: (a) a
.beta..sub.2-adrenoreceptor agonist; (b) a dopamine (D.sub.2)
receptor agonist; (c) an IL-5 inhibitor; (d) an antisense modulator
of IL-5; (e) a tryptase inhibitor; (f) a tachykinin receptor
antagonist; (g) milrinone or milrinone lactate; (h) a leukotriene
receptor antagonist; (i) a 5-lypoxygenase inhibitor; or (j) an
anti-IgE antibody.
82. The pharmaceutical composition of claim 12, wherein the buffer
concentration is from about 1 mM to about 50 mM.
83. The pharmaceutical composition of claim 82, wherein the buffer
concentration is about 20 mM.
84. The pharmaceutical composition of claim 28, wherein the buffer
concentration is from about 1 mM to about 50 mM.
85. The pharmaceutical composition of claim 84, wherein the buffer
concentration is about 20 mM.
86. The pharmaceutical composition of claim 39, wherein the buffer
concentration is about 20 mM.
87. The pharmaceutical composition of claim 39, wherein the buffer
is citrate buffer; the buffer concentration is about 20 mM; the
ionic strength of the composition is about 0.05 to about 0.16; and
the pH of the composition is about 5.0.
88. The pharmaceutical composition of claim 40, wherein the buffer
concentration is about 20 mM.
89. The pharmaceutical composition of claim 40, wherein the buffer
is citrate buffer; the buffer concentration is about 20 mM; the
ionic strength of the composition is about 0.05 to about 0.16; and
the pH of the composition is about 5.0.
90. The pharmaceutical composition of claim 87 that has been
nebulized.
91. The pharmaceutical composition of claim 89 that has been
nebulized.
92. The kit of claim 72, wherein the aqueous composition comprises
(a) formoterol free base at a concentration of about 59 .mu.g/mL;
(b) aqueous saline comprising sodium chloride; and (c) citrate
buffer at a concentration of about 20 mM; wherein the ionic
strength of the composition is about 0.05 to about 0.16; and the pH
of the composition is about 5.0.
93. The kit of claim 72, wherein the aqueous composition comprises
(a) formoterol free base at a concentration of about 118 .mu.g/mL;
(b) aqueous saline comprising sodium chloride; and (c) citrate
buffer at a concentration of about 20 mM; wherein the ionic
strength of the composition is about 0.05 to about 0.16; and the pH
of the composition is about 5.0.
94. The combination of claim 75, wherein the aqueous composition
comprises (a) formoterol free base at a concentration of about 59
.mu.g/mL; (b) aqueous saline comprising sodium chloride; and (c)
citrate buffer at a concentration of about 20 mM; wherein the ionic
strength of the composition is about 0.05 to about 0.16; and the pH
of the composition is about 5.0.
95. The combination of claim 75, wherein the aqueous composition
comprises (a) formoterol free base at a concentration of about 118
.mu.g/mL; (b) aqueous saline comprising sodium chloride; and (c)
citrate buffer at a concentration of about 20 mM; wherein the ionic
strength of the composition is about 0.05 to about 0.16; and the pH
of the composition is about 5.0.
96. The pharmaceutical composition of claim 1, further comprising
an anticholinergic agent.
97. The pharmaceutical composition of claim 96, wherein the
anticholinergic agent is ipratropium bromide, oxitropium bromide,
atropine methyl nitrate, tiotropium bromide or glycopyrronium
bromide.
98. The pharmaceutical composition of claim 97, wherein the
anticholinergic agent is ipratropium bromide.
99. The pharmaceutical composition of claim 98, wherein the
ipratropium bromide is present at a concentration of about 5
.mu.g/mL to about 5 mg/mL.
100. A combination, comprising: (a) a composition comprising
formoterol, or a pharmaceutically acceptable salt or hydrate
thereof in solution, the composition being in a pharmacologically
suitable fluid comprising water that is propellant-free, and the
composition having an estimated shelf-life of greater than 1 month
usage time at 25.degree. C. and greater than or equal to 1 year
storage time when stored at 5.degree. C. whereby greater than 90%
of the initial amount of formoterol in the compositions remains at
such time; the formoterol free base concentration is about 5
.mu.g/mL to about 200 .mu.g/mL, and the composition is formulated
at a concentration for direct administration to a human in need
thereof; and (b) a composition comprising a bronchodilating
steroid, or a pharmaceutically acceptable salt or hydrate thereof
in suspension.
101. The combination of claim 100, further comprising a
nebulizer.
102. The combination of claim 101 that is packaged as a kit;
optionally comprising instructions for use of the nebulizer; and
optionally comprising instructions for mixing the compositions.
103. The pharmaceutical composition of claim 97, wherein the
anticholinergic agent is tiotropium bromide.
104. The pharmaceutical composition of claim 98, wherein the
tiotropium bromide is present at a concentration of about 5
.mu.g/mL to about 5 mg/mL.
105. A pharmaceutical composition, comprising: (i) formoterol, or a
pharmaceutically acceptable salt or hydrate thereof in solution, at
a concentration with reference to the free base of about 5 .mu.g/mL
to about 200 .mu.g/mL; and (ii) a steroid anti-inflammatory agent,
or a pharmaceutically acceptable salt or hydrate thereof in
suspension; in a pharmacologically suitable fluid comprising water,
which is propellant-free, wherein: the composition is an aqueous
composition that contains buffer at a concentration of 1-20 mM, has
a pH of 4 to 6, an ionic strength of 0.05-0.16, selected so that
the composition has an estimated shelf-life of greater than 1 month
usage time at 25.degree. C. and greater than or equal to 1 year
storage time at 5.degree. C.
106. The pharmaceutical composition of claim 1, wherein the
formoterol is formoterol fumarate dihydrate; and the steroidal
anti-inflammatory agent is fluticasone propionate.
107. The pharmaceutical composition of claim 106, wherein the
concentration of fluticasone propionate in the composition is about
75 .mu.g/mL to about 1000 .mu.g/mL.
108. The pharmaceutical composition of claim 107, wherein the
concentration of fluticasone propionate in the composition is about
250 .mu.g/mL to about 1000 .mu.g/mL.
109. The pharmaceutical composition of claim 107, wherein the
concentration of fluticasone propionate in the composition is about
125 .mu.g/mL to about 250 .mu.g/mL
110. The pharmaceutical composition of claim 106, wherein the
composition further comprises a tonicity adjusting agent, a
suspension stabilizer, and the pharmaceutically suitable fluid
comprises a buffer.
111. The pharmaceutical composition of claim 110, wherein the
tonicity adjusting agent comprises sodium chloride and sodium
edetate, the suspension stabilizer is Polysorbate 80, and the
buffer is a sodium citrate buffer.
112. A sterile unit dose, comprising: (a) a pharmaceutical
composition comprising formoterol or a salt thereof at a
concentration of from about 5 .mu.g/mL to about 200 .mu.g/mL based
on formoterol free base, in a pharmacologically suitable solution,
wherein the composition further comprises water and a buffer having
a concentration of from about 1 mM to about 50 mM, said composition
having a pH of about 4.0 to about 6.0, and having an estimated
shelf life of greater than 90% after 3 months storage at 25.degree.
C. and after 3 years storage at 5.degree. C.; (b) packaged in a
pharmaceutical packaging material.
113. The sterile unit dose as in any one of claims 112 wherein said
buffer is selected from the group consisting of a citric
acid/phosphate buffer, acetate buffer, citrate buffer or phosphate
buffer.
114. The sterile unit dose of claim 113 wherein said buffer is
present at a concentration of between about 1 mM and about 20
mM.
115. The sterile unit dose as in any one of claims 112 wherein said
pharmaceutical packaging material is selected from the group
consisting of blister packs, bottles, tubes, inhalers, pumps, bags,
vials, containers and syringes.
116. The sterile unit dose of claim 115 wherein said pharmaceutical
packaging material is a vial.
117. The sterile unit dose as in any one of claims 112, wherein
said buffer has a concentration of from about 1 mM to about 20
mM.
118. The sterile unit dose as in any one of claims 112, wherein
said composition has a pH of about 5.
119. The sterile unit dose of claim 117, wherein said buffer has a
pH of about 5.
120. The sterile unit dose as in any one of claims 112, wherein
said formoterol or a salt thereof is formoterol tartrate.
121. The sterile unit dose of claim 117, wherein said formoterol or
a salt thereof is formoterol tartrate.
122. A sterile unit dose, comprising: (a) a pharmaceutical
composition comprising formoterol or a salt thereof at a
concentration of from about 5 .mu.g/mL to about 200 .mu.g/mL based
on formoterol free base, in a pharmacologically suitable solution,
wherein the composition further comprises water and a buffer
selected from the group consisting of citric acid/phosphate buffer,
acetate buffer, citrate buffer or phosphate buffer at a
concentration of from about 1 mM to about 50 mM, said composition
having a pH of about 4.5 to about 5.5; (b) packaged in a
pharmaceutical packaging material.
123. The sterile unit dose of claim 122, wherein said
pharmaceutical packaging material is a vial.
124. The sterile unit dose of claim 122, wherein said buffer has a
concentration of from about 1 mM to about 20 mM.
125. The sterile unit dose of claim 122, wherein said composition
has a pH of about 5.
126. The sterile unit dose of claim 124, wherein said buffer has a
pH of about 5.
127. The sterile unit dose of claim 122, wherein said formoterol or
a salt thereof is formoterol tartrate.
128. The sterile unit dose of claim 124, wherein said formoterol or
a salt thereof is formoterol tartrate.
129. The sterile unit dose of claim 126, wherein said formoterol or
a salt thereof is formoterol tartrate.
Description
RELATED APPLICATIONS
[0001] Benefit of priority under 35 U.S.C. .sctn.119(e) is claimed
to U.S. provisional patent application Ser. No. 60/284,607, filed
Apr. 17, 2001, to Banerjee et al. The disclosure of the
above-referenced application is incorporated herein by reference in
its entirety.
FIELD OF THE INVENTION
[0002] Compositions and methods are provided relating to treatment,
prevention, or amelioration of one or more symptoms of
bronchoconstrictive disorders. In particular, the compositions and
methods herein include formoterol, and/or a derivative thereof, and
a steroid, and/or a derivative thereof. The compositions are
propellant-free, sterile unit dose or multidose inhalation
solutions intended for administration via nebulization.
BACKGROUND OF THE INVENTION
[0003] Bronchoconstrictive disorders affect millions worldwide.
Such disorders include asthma (including bronchial asthma, allergic
asthma and intrinsic asthma, e.g., late asthma and airway
hyper-responsiveness), chronic bronchitis and other chronic
obstructive pulmonary diseases. Compounds having
.beta..sub.2-adrenoreceptor agonist activity have been developed to
treat these conditions. Such compounds include, but are not limited
to, Albuterol
(.alpha..sup.1-(((1,1-dimethylethyl)amino)methyl)-4-hydroxy-1,3-benzenedi-
methanol); Bambuterol (dimethylcarbamic acid
5-(2-((1,1-dimethylethyl)amino)-1-hydroxyethyl)-1,3-phenylene
ester); Bitolterol (4-methylbenzoic acid
4-(2-((1,1-dimethylethyl)amino)-1-hydroxyethyl)-1,2-phenylene
ester); Broxaterol
(3-bromo-.alpha.-(((1,1-dimethylethyl)amino)-methyl)-5-isoxazolemethanol)-
; Isoproterenol
(4-(1-hydroxy-2-((1-methylethyl)amino)ethyl)-1,2-benzenediol);
Trimetoquinol
(1,2,3,4-tetrahydro-1-((3,4,5-trimethoxyphenyl)methyl)-6,7-isoquinolinedi-
ol); Clenbuterol
(4-amino-3,5-dichloro-.alpha.-(((1,1-dimethylethyl)amino)methyl)benzeneme-
thanol; Fenoterol
(5-(1-hydroxy-2-((2-(4-hydroxyphenyl)-1-methylethyl)-amino)ethyl)-1,3-ben-
zenediol); Formoterol
(2-hydroxy-5-((1RS)-1-hydroxy-2-(((1RS)-2-(p-methoxyphenyl)-1-methylethyl-
)amino)ethyl)formanilide); (R,R)-Formoterol; Desformoterol ((R,R)
or
(S,S)-3-amino-4-hydroxy-.alpha.-(((2-(4-methoxyphenyl)-1-methylethyl)amin-
o)methyl)benzenemethanol); Hexoprenaline
(4,4'-(1,6-nexanediyl)-bis(imino(1-hydroxy-2,1-ethanediyl)))bis-1,2-benze-
nediol); Isoetharine
(4-(1-hydroxy-2-((1-methylethyl)amino)-butyl)-1,2-benzenediol);
Isoprenaline
(4-(1-hydroxy-2-((1-methylethyl)-amino)ethyl)-1,2-benzenediol);
Metaproterenol
(5-(1-hydroxy-2-((1-methylethyl)amino)ethyl)-1,3-benzenediol);
Picumeterol
(4-amino-3,5-dichloro-.alpha.-(((6-(2-(2-pyridinyl)ethoxy)hexyl)amino)met-
hyl)benzenemethanol); Pirbuterol
(.alpha..sup.6-(((1,1-dimethylethyl)amino)methyl)-3-hydroxy-2,6-pyridinem-
ethanol); Procaterol
(((R*,S*)-(.+-.)-8-hydroxy-5-(1-hydroxy-2-((1-methylethyl)amino)butyl)-2(-
1H)-quinolinone); Reproterol
((.about.7-(3-((2-(3,5-dihydroxyphenyl)-2-hydroxyethyl)amino)propyl)-3,7--
dihydro-1,3-dimethyl-1H-purine-2,6-dione); Rimiterol
(4-(hydroxy-2-piperidinylmethyl)-1,2-benzenediol); Salbutamol
((.+-.)-.alpha..sup.1-(((1,1-dimethylethyl)amino)methyl)-4-hydroxy-1,3-be-
nzenedimethanol); (R)-Salbutamol; Salmeterol
((.+-.)-4-hydroxy-.alpha..sup.1-(((6-(4-phenylbutoxy)hexyl)amino)methyl)--
1,3-benzenedimethanol); (R)-Salmeterol; Terbutaline
(5-(2-((1,1-dimethylethyl)amino)-1-hydroxyethyl)-1,3-benzenediol);
Tulobuterol
(2-chloro-.beta.-(((1,1-dimethylethyl)amino)methyl)benzenemethanol);
and TA-2005
(8-hydroxy-5-((1R)-1-hydroxy-2-(N-((1R)-2-(4-methoxyphenyl)-1-met-
hylethyl)amino)ethyl)-carbostyril hydrochloride).
[0004] These compounds are typically formulated for inhalation
therapy. Aqueous or liquid formulations are preferred over
formulations of solids. Powdered formulations are more difficult to
administer, particularly to the young and elderly who are most
often the patients in need of such therapy. Compounds, such as
formoterol, which has many desirable properties, are not adequately
stable in aqueous solutions to be formulated as liquids. Hence
there is a need for formulations of compounds, such as formoterol,
in a form that can be conveniently administered.
[0005] Other prophylactic therapeutics for use in treatment of
bronchoconstrictive disorders include steroidal anti-inflammatory
agents such as beclomethasone dipropionate (BDP), beclomethasone
monopropionate (BMP), flunisolide, triamcinolone acetonide,
dexamethasone, tipredane, ciclesonide, mometasone, mometasone
furoate (Asmanex.RTM. Twisthaler.TM., Shering-Plough Corporation,
Kenilworth, N.J.), RPR 106541, fluticasone, fluticasone propionate
and budesonide. These agents can be formulated for inhalation
therapy.
[0006] Effective treatment of asthma and other bronchoconstrictive
disorders often requires combination therapy. It is advantageous to
administer combinations of bronchodilators and other agents, such
as anti-steroidal agents. Since some the
.beta..sub.2-adrenoreceptor agonist compounds are not available as
aqueous or liquid formulations, combinations thereof with other
agents, are not available as aqueous or liquid formulations. Since
aqueous or liquid formulations are preferred, there is need to
develop liquid formulations. Therefore, it is an object herein to
provide stable liquid formulations of .beta..sub.2-adrenoreceptor
agonist compounds. It is a further object herein to improve the
stability of existing liquid formulations.
SUMMARY OF THE INVENTION
[0007] Compositions and methods for treatment, prevention, or
amelioration of one or more symptoms of bronchoconstrictive
disorders are provided. The compositions provided herein are stable
solutions of a bronchodilating agent, and/or a derivative thereof,
and a prophylactic therapeutic agent, including, but not limited
to, a steroid and/or a derivative thereof. The compositions are
formulated in a pharmacologically suitable fluid that contains
water and that are stable during long term storage. The
compositions are suitable for direct administration to a subject in
need thereof. Pharmacologically suitable fluids include, but are
not limited to, polar fluids, including protic fluids. In certain
embodiments herein, the compositions are aqueous solutions.
[0008] Compositions provided herein possess an estimated shelf-life
of greater than 1, 2 or 3 months usage time at 25.degree. C. and
greater than or equal to 1, 2 or 3 years storage time at 5.degree.
C. In certain of these embodiments, using Arrhenius kinetics,
>80% or >85% or >90% or >95% estimated bronchodilating
agent remains after such storage. These compositions are
particularly useful for administration via nebulization. In certain
embodiments herein, the subject is a mammal. In other embodiments,
the subject is a human.
[0009] The compositions provided herein are formulated to remain
stable over a relatively long period of time. For example, the
compositions provided herein are stored between -15.degree. C. and
25.degree. C., or between 2.degree. C. and 8.degree. C. In one
embodiment, the compositions are stored at 5.degree. C.
[0010] Among the bronchodilating agents for use herein are
Albuterol
(.beta..sup.1-(((1,1-dimethylethyl)amino)methyl)-4-hydroxy-1,3-benzenedim-
ethanol); Bambuterol (dimethylcarbamic acid
5-(2-((1,1-dimethylethyl)amino)-1-hydroxyethyl)-1,3-phenylene
ester); Bitolterol (4-methylbenzoic acid
4-(2-((1,1-dimethylethyl)amino)-1-hydroxyethyl)-1,2-phenylene
ester); Broxaterol
(3-bromo-.alpha.-(((1,1-dimethylethyl)amino)methyl)-5-isoxazolemethanol);
Isoproterenol
(4-(1-hydroxy-2-((1-methylethyl)amino)ethyl)-1,2-benzenediol);
Trimetoquinol
(1,2,3,4-tetrahydro-1-((3,4,5-trimethoxyphenyl)-methyl)-6,7-isoquinolined-
iol); Clenbuterol
(4-amino-3,5-dichloro-.alpha.-(((1,1-dimethylethyl)amino)methyl)benzeneme-
thanol); Fenoterol
(5-(1-hydroxy-2-((2-(4-hydroxyphenyl)-1-methylethyl)amino)ethyl)-1,3-benz-
enediol); Formoterol
(2-hydroxy-5-((1RS)-1-hydroxy-2-(((1RS)-2-(p-methoxyphenyl)-1-methylethyl-
)amino)ethyl)formanilide); (R,R)-Formoterol; Desformoterol ((R,R)
or
(S,S)-3-amino-4-hydroxy-.alpha.-(((2-(4-methoxyphenyl)-1-methylethyl)amin-
o)methyl)benzenemethanol); Hexoprenaline
(4,4'-(1,6-hexanediyl)-bis(imino(1-hydroxy-2,1-ethanediyl)))bis-1,2-benze-
nediol); Isoetharine
(4-O-hydroxy-2-((1-methylethyl)amino)butyl)-1,2-benzenediol);
Isoprenaline
(4-(1-hydroxy-2-((1-methylethyl)amino)ethyl)-1,2-benzenediol);
Metaproterenol
(5-(1-hydroxy-2-((1-methylethyl)amino)ethyl)-1,3-benzenediol);
Picumeterol
(4-amino-3,5-dichloro-.alpha.-(((6-(2-(2-pyridinyl)ethoxy)hexyl)-amino)me-
thyl)benzenemethanol); Pirbuterol
(.alpha..sup.6-(((1,1-dimethylethyl)-amino)methyl)-3-hydroxy-2,6-pyridine-
methanol); Procaterol
(R*,S*)-(.+-.)-8-hydroxy-5-(1-hydroxy-2-((1-methylethyl)amino)butyl)-2(1H-
)-quinolinone); Reproterol
((7-(3-((2-(3,5-dihydroxyphenyl)-2-hydroxyethyl)amino)-propyl)-3,7-dihydr-
o-1,3-dimethyl-1H-purine-2,6-dione); Rimiterol
(4-(hydroxy-2-piperidinylmethyl)-1,2-benzenediol); Salbutamol
((.+-.)-.alpha..sup.1-(((1,1-dimethylethyl)amino)methyl)-4-hydroxy-1,3-be-
nzenedimethanol); (R)-Salbutamol; Salmeterol
((.+-.)-4-hydroxy-.alpha..sup.1-(((6-(4-phenylbutoxy)hexyl)-amino)methyl)-
-1,3-benzenedimethanol); (R)-Salmeterol; Terbutaline
(5-(2-((1,1-dimethylethyl)amino)-1-hydroxyethyl)-1,3-benzenediol);
Tulobuterol
(2-chloro-.alpha.-(((1,1-dimethylethyl)amino)methyl)benzenemethanol);
and TA-2005
(8-hydroxy-5-((1R)-1-hydroxy-2-(N-((1R)-2-(4-methoxyphenyl)-1-met-
hylethyl)amino)ethyl)carbostyril hydrochloride).
[0011] Of particular interest herein is formoterol, having the
formula:
##STR00001##
[0012] Formoterol for use in the compositions and methods provided
herein includes
2-hydroxy-5-((1RS)-1-hydroxy-2-(((1RS)-2-(p-methoxyphenyl)-1-met-
hylethyl)amino)ethyl)formanilide; or a stereoisomer thereof; and
also includes the single enantiomers
2-hydroxy-5-((1S)-1-hydroxy-2-(((1S)-2-(p-methoxyphenyl)-1-methylethyl)am-
ino)ethyl)formanilide and
2-hydroxy-5-((1R)-1-hydroxy-2-(((1R)-2-(p-methoxyphenyl)-1-methylethyl)-a-
mino)ethyl)formanilide.
[0013] Prophylactic therapeutics for use in the compositions and
methods herein include steroidal anti-inflammatory agents,
including, but not limited to, beclomethasone dipropionate (BDP),
beclomethasone monopropionate (BMP), flunisolide, triamcinolone
acetonide, dexamethasone, tipredane, ciclesonid, rofleponide,
mometasone, mometasone furoate (Asmanex.RTM. Twisthaler.TM.,
Shering-Plough Corporation, Kenilworth, N.J.), RPR 106541,
fluticasone or fluticasone propionate and budesonide, or
derivatives thereof. In one embodiment, the steroidal
anti-inflammatory is fluticasone, fluticasone propionate,
budesonide, or a derivative thereof.
[0014] In certain embodiments, the compositions are administered
via nebulization. Administration of a nebulized aerosol is
preferred over the use of dry powders for inhalation in certain
subject populations, including pediatric and geriatric groups.
[0015] In one embodiment, the compositions for use in the methods
provided herein contain a pharmaceutically acceptable derivative of
formoterol. In another embodiment, the compositions for use in the
methods provided herein contain a pharmaceutically acceptable salt
of formoterol. Pharmaceutically acceptable salts include, but are
not limited to, salts of mineral acids, such as but not limited to
hydrochlorides and sulfates; and salts of organic acids, such as
but not limited to acetates, lactates, malates, tartrates,
citrates, ascorbates, succinates, butyrates, valerates and
fumarates. In one embodiment, the compositions for use in the
methods provided herein contain formoterol fumarate or formoterol
fumarate dihydrate. In another embodiment, the compositions for use
in the methods provided herein contain formoterol tartrate.
[0016] In another embodiment, the compositions for use in the
methods provided herein contain budesonide or fluticasone
propionate. Compositions containing formoterol, budesonide and a
fluoroalkane propellant are disclosed in U.S. Pat. No. 6,004,537.
Compositions containing formoterol and budesonide for dry powder
inhalation or metered dose inhalation are disclosed in U.S. Pat.
Nos. 5,674,860 and 5,972,919. These references do not disclose the
compositions provided herein that are formulated in a
pharmacologically suitable fluid, as defined herein, that contains
water and that are stable during long term storage.
[0017] Also provided herein are combinations containing
compositions provided herein. The compositions may be formulated
separately or mixed in a single composition. The compositions
contained in the combinations may be administered sequentially or
intermittently. The compositions contained in the combinations can
be mixed prior to use or can be formulated as a single composition.
The combinations may further include a nebulizer. The combinations
can be packaged as kits, which optionally contain other components,
including instructions for use of the nebulizer and/or instructions
for mixing the compositions if provided separately.
[0018] Any nebulizer is contemplated for use in the kits and
methods provided herein. In particular, the nebulizers for use
herein nebulize liquid formulations, including the compositions
provided herein, containing no propellant. The nebulizer may
produce the nebulized mist by any method known to those of skill in
the art, including, but not limited to, compressed air, ultrasonic
waves, or vibration. The nebulizer may further have an internal
baffle. The internal baffle, together with the housing of the
nebulizer, selectively removes large droplets from the mist by
impaction and allows the droplets to return to the reservoir. The
fine aerosol droplets thus produced are entrained into the lung by
the inhaling air/oxygen.
[0019] Methods for the treatment, prevention, or amelioration of
one or more symptoms of bronchoconstrictive disorders, including,
but not limited to, asthma, including, but not limited to,
bronchial asthma, allergic asthma and intrinsic asthma, e.g., late
asthma and airway hyper-responsiveness; chronic bronchitis; and
other chronic obstructive pulmonary diseases are provided. The
methods involve administering an effective amount of a
pharmaceutical composition provided herein to a subject in need of
such treatment.
[0020] Articles of manufacture, containing packaging material, a
composition provided herein, which is useful for treatment,
prevention or amelioration of one or more symptoms of diseases or
disorders associated with undesired and/or uncontrolled
bronchoconstriction, and a label that indicates that the
composition is used for treatment, prevention or amelioration of
one or more symptoms of diseases or disorders associated with
undesired and/or uncontrolled bronchoconstriction, are also
provided.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
Definitions
[0021] Unless defined otherwise, all technical and scientific terms
used herein have the same meaning as is commonly understood by one
of ordinary skill in the art to which this invention belongs. All
patents, applications, published applications and other
publications are incorporated by reference in their entirety. In
the event that there are a plurality of definitions for a term
herein, those in this section prevail unless stated otherwise.
[0022] As used herein, formoterol refers to
2-hydroxy-5-((1RS)-1-hydroxy-2-(((1RS)-2-(p-methoxyphenyl)-1-methylethyl)-
amino)ethyl)formanilide; or a stereoisomer thereof. The term
formoterol also refers to the single enantiomers
2-hydroxy-5-((1S)-1-hydroxy-2-(((1S)-2-(p-methoxyphenyl)-1-methylethyl)am-
ino)ethyl)formanilide and
2-hydroxy-5-((1R)-1-hydroxy-2-(((1R)-2-(p-methoxyphenyl)-1-methylethyl)am-
ino)ethyl)formanilide.
[0023] As used herein, formoterol fumarate refers to a salt of
formoterol having the formula (formoterol)1/2fumarate. Formoterol
fumarate dihydrate refers to the dihydrate of formoterol
fumarate.
[0024] As used herein, formoterol free base refers to the neutral,
anhydrous form of formoterol. Thus, a recitation that a composition
contains, e.g., 59 .mu.g/mL of formoterol free base means that the
composition contains 59 .mu.g/mL of neutral, anhydrous formoterol.
Such compositions may be prepared using a derivative of
formoterol.
[0025] As used herein, budesonide refers to
(RS)-11.beta.,16.alpha.,17,21-tetrahydroxypregna-1,4-diene-3,20-dione
cyclic 16,17-acetal with butyraldehyde. The term budesonide refers
to the (R) isomer, the (S) isomer, and mixtures thereof.
[0026] As used herein, fluticasone refers to
(6.alpha.,9.alpha.,11.beta.,16.alpha.,17.alpha.)-6,9-difluoro-11-hydroxy--
16-methyl-3-oxo-17-hydroxyandrosta-1,4-diene-17-carbothioic acid,
S-fluoromethyl ester. Fluticasone propionate refers to
(6.alpha.,9.alpha.,11.beta.,16.alpha.,17.alpha.)-6,9-difluoro-11-hydroxy--
16-methyl-3-oxo-17-(1-oxo-propoxy)androsta-1,4-diene-17-carbothioic
acid, S-fluoromethyl ester.
[0027] As used herein, an aerosol is liquid or particulate matter
dispersed in air. Aerosols include dispersions of liquids,
including aqueous and other solutions, and solids, including
powders, in air.
[0028] As used herein, a nebulized solution refers to a solution
that is dispersed in air to form an aerosol. Thus, a nebulized
solution is a particular form of an aerosol.
[0029] As used herein, a nebulizer is an instrument that is capable
of generating very fine liquid droplets for inhalation into the
lung. Within this instrument, the nebulizing liquid or solution is
atomized into a mist of droplets with a broad size distribution by
methods known to those of skill in the art, including, but not
limited to, compressed air, ultrasonic waves, or a vibrating
orifice. Nebulizers may father contain, e.g., a baffle which, along
with the housing of the instrument, selectively removes large
droplets from the mist by impaction. Thus, the mist inhaled into
the lung contains fine aerosol droplets.
[0030] As used herein, a pharmacologically suitable fluid is a
solvent suitable for pharmaceutical use which is not a liquified
propellant gas. Exemplary pharmacologically suitable fluids include
polar fluids, including protic fluids such as water.
[0031] As used herein, a combination refers to any association
between two or among more items.
[0032] As used herein, fluid refers to any composition that can
flow. Fluids thus encompass compositions that are in the form of
semi-solids, pastes, solutions, aqueous mixtures, gels, lotions,
creams and other such compositions.
[0033] As used herein, a mixture is a mutual incorporation of two
or more substances, without chemical union, the physical
characteristics of each of the components being retained.
[0034] As used herein, the stability of a composition provided
herein refers to the length of time at a given temperature that
greater than 80%, 85%, 90% or 95% of the initial amount of active
ingredient, e.g., formoterol, is present in the composition. Thus,
for example, a composition that is stable for 30 days at 25.degree.
C. would have greater than 80%, 85%, 90% or 95% of the initial
amount of active ingredient present in the composition at 30 days
following storage at 25.degree. C.
[0035] As used herein, pharmaceutically acceptable derivatives of a
compound include salts, esters, enol ethers, enol esters, acids,
bases, solvates, hydrates or prodrugs thereof. Such derivatives may
be readily prepared by those of skill in this art using known
methods for such derivatization. The compounds produced may be
administered to animals or humans without substantial toxic effects
and either are pharmaceutically active or are prodrugs.
Pharmaceutically acceptable salts include, but are not limited to,
amine salts, such as but not limited to
N,N'-dibenzylethylenediamine, chloroprocaine, choline, ammonia,
diethanolamine and other hydroxyalkylamines, ethylenediamine,
N-methylglucamine, procaine, N-benzylphenethylamine,
1-para-chlorobenzyl-2-pyrrolidin-1'-ylmethyl-benzimidazole,
diethylamine and other alkylamines, piperazine and
tris(hydroxymethyl)aminomethane; alkali metal salts, such as but
not limited to lithium, potassium and sodium; alkali earth metal
salts, such as but not limited to barium, calcium and magnesium;
transition metal salts, such as but not limited to zinc; and other
metal salts, such as but not limited to sodium hydrogen phosphate
and disodium phosphate; and also including, but not limited to,
salts of mineral acids, such as but not limited to hydrochlorides
and sulfates; and salts of organic acids, such as but not limited
to acetates, lactates, malates, tartrates, citrates, ascorbates,
succinates, butyrates, valerates and fumarates. Pharmaceutically
acceptable esters include, but are not limited to, alkyl, alkenyl,
alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl and
heterocyclyl esters of acidic groups, including, but not limited
to, carboxylic acids, phosphoric acids, phosphinic acids, sulfonic
acids, sulfinic acids and boronic acids. Pharmaceutically
acceptable enol ethers include, but are not limited to, derivatives
of formula C.dbd.C(OR) where R is hydrogen, alkyl, alkenyl,
alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl and
heterocyclyl. Pharmaceutically acceptable enol esters include, but
are not limited to, derivatives of formula C.dbd.C(OC(O)R) where R
is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl,
heteroaralkyl, cycloalkyl and heterocyclyl. Pharmaceutically
acceptable solvates and hydrates are complexes of a compound with
one or more solvent or water molecule, preferably 1 to about 100,
more preferably 1 to about 10, most preferably one to about 2, 3 or
4, solvent or water molecules. Formoterol salts and hydrates are
used in certain embodiments herein.
[0036] As used herein, treatment means any manner in which one or
more of the symptoms of a condition, disorder or disease are
ameliorated or otherwise beneficially altered. Treatment also
encompasses any pharmaceutical use of the compositions herein, such
as use for treating cancer.
[0037] As used herein, amelioration of the symptoms of a particular
disorder by administration of a particular pharmaceutical
composition refers to any lessening, whether permanent or
temporary, lasting or transient that can be attributed to or
associated with administration of the composition.
[0038] As used herein, a prodrug is a compound that, upon in vivo
administration, is metabolized or otherwise converted to the
biologically, pharmaceutically or therapeutically active form of
the compound. To produce a prodrug, the pharmaceutically active
compound is modified such that the active compound will be
regenerated by metabolic processes. The prodrug may be designed to
alter the metabolic stability or the transport characteristics of a
drug, to mask side effects or toxicity, to improve the flavor of a
drug or to alter other characteristics or properties of a drug. By
virtue of knowledge of pharmacodynamic processes and drug
metabolism in vivo, those of skill in this art, once a
pharmaceutically active compound is known, can design prodrugs of
the compound (see, e.g., Nogrady (1985) Medicinal Chemistry A
Biochemical Approach, Oxford University Press, New York, pages
388-392).
[0039] It is to be understood that the compounds for use in the
compositions and methods provided herein may contain chiral
centers. Such chiral centers may be of either the (R) or (S)
configuration, or may be a mixture thereof. Thus, the compounds for
use in the compositions provided herein may be enantiomerically
pure, or be stereoisomeric or diastereomeric mixtures. It is to be
understood that the chiral centers of the compounds provided herein
may undergo epimerization in vivo. Thus, one of skill in the art
will recognize that administration of a compound in its (R) form is
equivalent, for compounds that undergo epimerization in vivo, to
administration of the compound in its (S) form.
[0040] As used herein, bronchoconstriction refers to a reduction in
the caliber of a bronchus or bronchi.
[0041] As used herein, undesired and/or uncontrolled
bronchoconstriction refers to bronchoconstriction that results in
or from a pathological symptom or condition. Pathological
conditions include, but are not limited to, asthma and chronic
obstructive pulmonary disease (COPD). Pathological symptoms
include, but are not limited to, asthma and COPD.
[0042] As used herein, the statement that a composition is stable
during "long term storage" means that the composition is suitable
for administration to a subject in need thereof when it has an
estimated shelf-life of greater than 1, 2 or 3 months usage time at
25.degree. C. and greater than or equal to 1, 2 or 3 years storage
time at 5.degree. C. In certain embodiments herein, using Arrhenius
kinetics, >80% or >85% or >90% or >95% estimated
bronchodilating agent remains after such storage.
A. Formoterol, Budesonide and Fluticasone Propionate
[0043] 1. Formoterol
[0044] Formoterol
(2-hydroxy-5-((1RS)-1-hydroxy-2-(((1RS)-2-(p-methoxyphenyl)-1-methylethyl-
)amino)ethyl)formanilide) is derived from adrenaline and, as noted
above, is used as a .beta..sub.2-stimulator in inhalation therapy
of respiratory diseases, particularly for the treatment of
bronchial asthma. It has been reported that in patients with
reversible obstructive respiratory diseases, formoterol has a
bronchodilatory effect. This effect has a relatively rapid onset
(approximately 1-3 minutes) and a relatively long duration (greater
than 12 hours). Formoterol inhibits the release of leukotrienes and
other messenger substances involved with inflammation, such as
histamines. In addition, formoterol may bring about a hyperglycemic
activity.
[0045] To date, formoterol has been formulated as a dry powder and
administered via devices such as the Turbuhaler.RTM. and the
Aerolizer.RTM.. See, e.g., Seberova et al. (2000) Respir. Med.
94(6):607-611; Lotvall at al. (1999) Can. Respir. J. 6(5):412-416;
Campbell et al. (1999) Respir. Med. 93(4):236-244; Nightingale et
al. (1999) Am. J. Respir. Crit. Care Med. 159(6):1786-1790;
Lecaillon et al. (1999) Eur. J. Clin. Pharmacol. 55(2):131-138;
Bartow et al. (1998) Drugs 55(2):303-322; Ekstrom et al. (1998)
Respir. Med. 92(8):1040-1045; Ringdal et al. (1998) Respir. Med.
92(8):1017-1021; Totterman et al. (1998) Eur. Respir. J.
12(3):573-579; Palmqvist et al. (1997) Eur. Respir. J.
10(11):2484-2489; Nielsen et al. (1997) Eur. Respir. J.
10(9):2105-2109; Ullman et al. (1996) Allergy 51(10):745-748;
Selroos et al. (1996) Clin. Immunother. 6:273-299; and Schreurs et
al. (1996) Eur. Respir. J. 9(8):1678-1683.
[0046] Formoterol is also available as a tablet and a dry syrup in
certain areas of the world (e.g., Atock.RTM., marketed by
Yamanouchi Pharmaceutical Co. Ltd., Japan). Formoterol formulations
are also available in other areas (e.g., Europe and U.S.) for
propellant-based metered dose inhalers and dry powder inhalers
(e.g., Turbuhaler.RTM., Aerolizer.RTM. and Foradil
Aerolizer.degree.. None of these formulations are water based.
Sterile, stable, aqueous based inhalation solutions of formoterol
for nebulization are not available, nor have they been reported.
Compositions containing formoterol in combination with other active
ingredients have been disclosed. See, e.g., U.S. Pat. No.
5,668,110, U.S. Pat. No. 5,683,983, U.S. Pat. No. 5,677,280 and
U.S. Pat. No. 5,654,276 (formoterol and IL-5 inhibitors), U.S. Pat.
No. 6,136,603 (formoterol and antisense modulators of IL-5), U.S.
Pat. No. 5,602,110 (formoterol and milrinone), U.S. Pat. No.
5,525,623 (formoterol and a tryptase inhibitor), U.S. Pat. No.
5,691,336, U.S. Pat. No. 5,877,191, U.S. Pat. No. 5,929,094, U.S.
Pat. No. 5,750,549 and U.S. Pat. No. 5,780,467 (formoterol and a
tachykinin receptor antagonist); and International Patent
Application Publication Nos. WO 99/00134 (formoterol and
rofleponide) and WO 99/36095 (formoterol and a dopamine D.sub.2
receptor agonist).
[0047] Other compositions containing formoterol have been disclosed
in U.S. Pat. Nos. 5,677,809, 6,126,919, 5,733,526, 6,071,971,
6,068,833, 5,795,564, 6,040,344, 6,041,777, 5,874,481, 5,965,622
and 6,161,536.
[0048] U.S. Pat. No. 6,150,418 discloses a "liquid active substance
concentrate" containing formoterol in the form of its free base or
in the form of one of the pharmacologically acceptable salts or
addition products (adducts) thereof as active substance. This
"liquid active substance concentrate" is reported to be a
concentrated (i.e., greater than 10 mg/mL, preferably 75 to 500
mg/mL) solution or suspension that is stable for a period of
several months possibly up to several years without any
deterioration in the pharmaceutical quality. This patent teaches
that it is the high concentration that allows for the stability of
the concentrate. The "liquid active substance concentrate" is not
suitable for direct administration to a subject.
[0049] U.S. Pat. No. 6,040,344 discloses an aqueous aerosol
formulation of formoterol tartrate for use in a nebulizer. This
patent states that the formulation disclosed therein is not
attractive for long term storage.
[0050] 2. Budenoside and Fluticasone Propionate
[0051] Budesonide,
(RS)-11.beta.,16.alpha.,17,21-tetrahydroxypregna-1,4-diene-3,20-dione
cyclic 16,17-acetal with butyraldehyde, is an anti-inflammatory,
synthetic corticosteroid. Fluticasone propionate,
(6.alpha.,11.beta.,16.alpha.,17.alpha.)-6,9,-difluoro-11-hydroxy-16-methy-
l-3-oxo-17-(1-oxopropoxy)androsta-1,4-diene-17-carbothioic acid,
S-fluoromethyl ester, is a synthetic fluorinated corticosteroid,
and is known for topical dermatologic use. Topical corticosteroids
constitute a class of primarily synthetic steroids used as
anti-inflammatory and antipruritic agents. The mechanism of the
anti-inflammatory activity of topical steroids, in general, is
unclear. However, corticosteroids are thought to act by the
induction of phospholipase A2 inhibitory proteins (lipocortins). It
is postulated that these proteins control the biosynthesis of
prostaglandins and leukotrienes by inhibiting the release of
arachidonic acid.
B. Compositions for Use in Treatment, Prevention, or Amelioration
of One or More Symptoms of Bronchoconstrictive Disorders
[0052] Pharmaceutical compositions containing a
.beta..sub.2-adrenoreceptor agonist and a steroid for
administration via nebulization are provided. The compositions are
sterile filtered and filled in vials, including unit dose vials
providing sterile unit dose formulations which are used in a
nebulizer and suitably nebulized. Each unit dose vial is sterile
and is suitably nebulized without contaminating other vials or the
next dose. The bulk sterile formulation is sterilized by steam,
gamma radiation or is prepared using sterile steroidal powder.
[0053] The unit dose vials are formed in a form-fill-seal machine
or by any other suitable method known to those of skill in the art.
The vials may be made of plastic materials that are suitably used
in these processes. For example, plastic materials for preparing
the unit dose vials include, but are not limited to, low density
polyethylene, high density polyethylene, polypropylene and
polyesters. In one embodiment, the plastic material is low density
polyethylene.
[0054] In one embodiment, the .beta..sub.2-adrenoreceptor agonist
is formoterol, or a pharmaceutically acceptable derivative thereof.
In other embodiments, the formoterol for use in the compositions
provided herein is formoterol fumarate. Formoterol refers to
2-hydroxy-5-(1RS)-1-hydroxy-2-(((1RS)-2-(p-methoxyphenyl)-1-methylethyl)a-
mino)ethyl)formanilide; or a stereoisomer thereof. The term
formoterol also refers herein to the single enantiomers
2-hydroxy-5-(((1S)-1-hydroxy-2-(((1S)-2-(p-methoxyphenyl)-1-methylethyl)a-
mino)ethyl)formanilide and
2-hydroxy-5-((1R)-1-hydroxy-2-(((1R)-2-(p-methoxyphenyl)-1-methylethyl)am-
ino)ethyl)formanilide.
[0055] In one embodiment, the compositions contain, in addition to
a steroidal anti-inflammatory agent, including, but not limited to,
budesonide and fluticasone propionate, formoterol free base at a
concentration of about 5 .mu.g/mL to about 2 mg/mL. In other
embodiments, the maximum concentration of formoterol free base in
the compositions is 1.5 mg/mL. In further embodiments, the
concentration of formoterol free base in the compositions is about
10 .mu.g/mL to about 1 mg/mL, or about 50 .mu.g/mL to about 200
.mu.g/mL. In other embodiments, the compositions contain formoterol
fumarate at a concentration of about 80 .mu.g/mL up to about 175 to
200 .mu.g/mL. In further embodiments, the compositions contain
formoterol fumarate at a concentration of about 90 .mu.g/mL up to
about 125 to 150 .mu.g/mL. The formoterol fumarate is formulated,
in certain compositions provided herein, at a concentration of
about 100 .mu.g/mL, The formoterol fumarate is formulated, in other
compositions provided herein, at a concentration of about 85
.mu.g/mL or about 170 .mu.g/mL. In one embodiment, the formoterol
fumarate is formulated for single dosage administration via
nebulization at a concentration of about 100 .mu.g/mL. In another
embodiment, the compositions contain formoterol free base at a
concentration of about 40 to about 150 .mu.g/mL, particularly about
59 or about 118 .mu.g/mL.
[0056] The compositions provided herein further contain, in
addition to a .beta..sub.2 adrenoreceptor agonist, including
formoterol, a steroidal anti-inflammatory agent, including, but not
limited to, budesonide or fluticasone propionate. Budesonide is
RS)-11.beta.,16.alpha.,17,21-tetrahydroxypregna-1,4-diene-3,20-d
lone cyclic 16,17-acetal with butyraldehyde. Budesonide also refers
to the (Ft) isomer, the (S) isomer, and mixtures thereof.
Fluticasone propionate refers to
(6.alpha.,11.beta.,16.alpha.,17.alpha.)-6,9-difluoro-11-hydroxy-
-16-methyl-3-oxo-17-(1-oxo-propoxy)androsta-1,4-diene-17-carbothioic
acid, S-fluoromethyl ester.
[0057] In one embodiment, the compositions contain budesonide or
fluticasone propionate at a concentration of about 5 .mu.g/mL to
about 2 mg/mL. In another embodiment, the compositions contain
budesonide at a concentration of about 75 .mu.g/mL to about 500
.mu.g/mL, or about 125 .mu.g/mL to about 500 .mu.g/mL. In certain
embodiments, the compositions contain budesonide at a concentration
of about 125 .mu.g/mL or 250 .mu.g/mL. In another embodiment, the
compositions contain fluticasone propionate at a concentration of
about 75 .mu.g/mL to about 1000 .mu.g/mL, or about 250 .mu.g/mL to
about 1000 .mu.g/mL. In further embodiments, the compositions
contain fluticasone propionate at a concentration of about 125
.mu.g/mL or about 250 .mu.g/mL.
[0058] The compositions are formulated as solutions or suspensions
with a pharmacologically suitable fluid. Pharmacologically suitable
fluids include, but are not limited to, polar solvents, including,
but not limited to, compounds that contain hydroxyl groups or other
polar groups. Such solvents include, but are not limited to, water
or alcohols, such as ethanol, isopropanol, and glycols including
propylene glycol, polyethylene glycol, polypropylene glycol, glycol
ether, glycerol and polyoxyethylene alcohols.
[0059] Polar solvents also include protic solvents, including, but
not limited to, water, aqueous saline solutions with one or more
pharmaceutically acceptable salt(s), alcohols, glycols or a mixture
thereof. For a saline solution as the solvent or as a component
thereof, particularly suitable salts are those which display no or
only negligible pharmacological activity after administration.
[0060] In the embodiments herein, the compositions have a pH of
about 2.0 to about 8.0. The particular pH of a given composition
for long term storage provided herein may be determined empirically
using standard stability assays well known to those of skill in the
art (see, e.g., the Examples). For example, in certain embodiments,
the compositions have a pH of about 4.0 to about 6.0, or about 4.5
to about 5.5. In certain of the above embodiments, the compositions
are formulated at a pH of about 4, 4.4 or 4.6 up to about 5.5, 5.7
or 6. In other embodiments, the pH is about 5.0. It has been found
herein that the rate constant for decomposition of an aqueous
solution of formoterol is dependent on pH. The rate constant
(k.sub.obs) at 60.degree. C. at a pH of 3, 4, 5 and 7 is
approximately 0.62, 0.11, 0.044 and 0.55 day.sup.-1, respectively.
Therefore, the decomposition of formoterol in aqueous solution at
60.degree. C. at a buffer concentration of 5 mM and an ionic
strength of 0.05 is slowest at a pH of about 5.0.
[0061] The solubility of formoterol in aqueous solution has been
found herein to be dependent on pH. Thus, at a pH of between about
5 and about 7, the aqueous solubility of formoterol at ambient
temperature is approximately 2.2 mg/mL. At a pH of about 4, the
aqueous solubility of formoterol at ambient temperature is
approximately 3 mg/mL, while at a pH of about 3, the aqueous
solubility of formoterol at ambient temperature is about 4.8 mg/mL.
The solubility of formoterol in pure water, for example, high
performance liquid chromatography (HPLC) water, at ambient
temperature is approximately 2 mg/mL.
[0062] In other of the above embodiments, the compositions further
contain a buffer, including, but not limited to, citric
acid/phosphate, acetate, barbital, borate, Britton-Robinson,
cacodylate, citrate, collidine, formate, maleate, McIlvaine,
phosphate, Prideaux-Ward, succinate, citrate-phosphate-borate
(Teorell-Stanhagen), veronal acetate, MES
(2-(N-morpholino)ethanesulfonic acid), BIS-TRIS
(bis(2-hydroxyethyl)iminotris(hydroxymethyl)methane), ADA
(N-(2-acetamido)-2-iminodiacetic acid), ACES
(N-(carbamoylmethyl)-2-aminoethanesulfonic acid), PIPES
(piperazine-N,N'-bis(2-ethanesulfonic acid)), MOPSO
(3-(N-morpholino)-2-hydroxypropanesulfonic acid), BIS-TRIS PROPANE
(1,3-bis(tris(hydroxymethyl)methylamino)propane), BES
(N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonic acid), MOPS
(3-(N-morpholino)propanesulfonic acid), TES
(N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid), HEPES
(N-(2-hydroxyethyl)piperazine-N'-(2-ethanesulfonic acid), DIPSO
(3-(N,N-bis(2-hydroxyethyl)amino)-2-hydroxypropanesulfonic acid),
MOBS (4-(N-morpholino)butanesulfonic acid), TAPSO
(3-(N-tris(hydroxymethyl)methylamino)-2-hydroxypropanesulfonic
acid), TRIZMA.RTM. (tris(hydroxymethylaminomethane),
HEPPSO(N-(2-hydroxyethyl)piperazine-N'-(2-hydroxypropanesulfonic
acid), POPSO (piperazine-N,N'-bis(2-hydroxypropanesulfonic acid)),
TEA (triethanolamine),
EPPS(N-(2-hydroxyethyl)piperazine-N'-(3-propanesulfonic acid),
TRICINE (N-tris(hydroxymethyl)methylglycine), GLY-GLY
(glycylglycine), BICINE (N,N-bis(2-hydroxyethyl)glycine), HEPBS
(N-(2-hydroxyethyl)piperazine-N'-(4-butanesulfonic acid)),
TAPS(N-tris(hydroxymethyl)methyl-3-aminopropanesulfonic acid), AMPD
(2-amino-2-methyl-1,3-propanediol), and/or any other buffers known
to those of skill in the art. In one embodiment, the buffer is
citric acid/phosphate buffer, acetate buffer, citrate buffer or
phosphate buffer. In another embodiment, the buffer is a citrate
buffer (citric acid/sodium citrate). The buffer concentration has
been found herein to affect the stability of the composition.
Buffer concentrations for use herein include from about 0 or 0.01
mM to about 150 mM, or about 1 mM to about 20 mM. In one
embodiment, the buffer concentration is about 5 mM. In another
embodiment, the buffer concentration is about 1 mM to about 50 mM,
or about 20 mM. The kinetic-pH profile of formoterol is dependent
on buffer concentration. At low and approximately neutral
conditions, increasing the buffer concentration from 5 mM to 20 mM
increased the rate constant of decomposition significantly.
However, no noticeable differences in rate constant were observed
in the pH region of about 4.5 to about 5.5 with increasing buffer
concentration from 5 mM to 20 mM. The particular buffer and buffer
concentration of a given composition for long term storage provided
herein may be determined empirically using standard stability
assays well known to those of skill in the art (see, e.g., the
Examples).
[0063] The ionic strength of the compositions provided herein also
has been found herein to affect the stability of the composition.
Ionic strengths of the compositions provided herein are from about
0 to about 0.4, or from about 0.05 to about 0.16. Compositions
having a lower ionic strength exhibit improved stability over
formulations having higher ionic strength. The rate constant of
decomposition was essentially the same at ionic strength 0.05 to
0.1, but increased to some extent at ionic strength of 0.2. The
particular ionic strength of a given composition for long term
storage provided herein may be determined empirically using
standard stability assays well known to those of skill in the art
(see, e.g., the Examples).
[0064] In embodiments where the pharmacologically suitable fluid is
a saline solution, tonicity adjusting agents may be added to
provide the desired ionic strength. Tonicity adjusting agents for
use herein include those which display no or only negligible
pharmacological activity after administration. Both inorganic and
organic tonicity adjusting agents may be used in the compositions
provided herein. Tonicity adjusting agents include, but are not
limited to, ammonium carbonate, ammonium chloride, ammonium
lactate, ammonium nitrate, ammonium phosphate, ammonium sulfate,
ascorbic acid, bismuth sodium tartrate, boric acid, calcium
chloride, calcium disodium edetate, calcium gluconate, calcium
lactate, citric acid, dextrose, diethanolamine, dimethylsulfoxide,
edetate disodium, edetate trisodium monohydrate, fluorescein
sodium, fructose, galactose, glycerin, lactic acid, lactose,
magnesium chloride, magnesium sulfate, mannitol, polyethylene
glycol, potassium acetate, potassium chlorate, potassium chloride,
potassium iodide, potassium nitrate, potassium phosphate, potassium
sulfate, propylene glycol, silver nitrate, sodium acetate, sodium
bicarbonate, sodium biphosphate, sodium bisulfite, sodium borate,
sodium bromide, sodium cacodylate, sodium carbonate, sodium
chloride, sodium citrate, sodium iodide, sodium lactate, sodium
metabisulfite, sodium nitrate, sodium nitrite, sodium phosphate,
sodium propionate, sodium succinate, sodium sulfate, sodium
sulfite, sodium tartrate, sodium thiosulfate, sorbitol, sucrose,
tartaric acid, triethanolamine, urea, urethan, uridine and zinc
sulfate. In certain embodiments, the tonicity adjusting agent is
sodium chloride, which is present at a concentration of from about
0 mg/mL to about 10, 15 or 20 mg/mL. In further embodiments, the
compositions contain sodium chloride at a concentration of from
about 0 mg/mL to about 7.5 mg/mL. In another embodiment, the
compositions contain sodium chloride at a concentration of 0 mg/mL,
1.5 mg/mL, 6.8 mg/mL or 7.5 mg/mL. In these embodiments, the
pharmacologically suitable fluid is aqueous saline.
[0065] The storage temperature of the compositions provided herein
also has been found herein to affect the stability of the
composition. Compositions stored at a lower temperature-exhibit
improved stability over formulations stored at higher temperatures.
The effect of temperature on the rate constant of decomposition at
pH 5, a buffer concentration of 5 mM, and an ionic strength of
0.05, was linear according to Arrhenius kinetics, i.e., when Ln
k.sub.abs was plotted against 1/T, where T is the temperature in
degree Kelvin.
[0066] The estimated shelf-life of formoterol in the compositions
provided herein is significantly greater than that reported for
known formoterol compositions. The estimated shelf-life of
formoterol in the compositions provided herein is about 6.2 years
at 5.degree. C. and about 7.5 months at 25.degree. C. The estimated
formoterol concentrations in the compositions provided herein as a
function of storage time at 5.degree. C. and usage time at
25.degree. C. was determined. It is estimated that greater than 90%
of the initial formoterol present in the composition remains after
3 months of usage time at 25.degree. C. and 3 years of storage time
at 5.degree. C. as well as after 0.5 months of usage time at
25.degree. C. and 1 year of storage time at 5.degree. C.
[0067] In certain embodiments, the compositions provided herein are
prepared containing formoterol fumarate at a nominal concentration
of 0.1 mg/mL at the indicated pH and citric acid/phosphate buffer
concentrations. The solutions were stored at 60.degree. C. In these
compositions, formoterol is relatively more stable at a pH from
about 4 to about 5, and is also more stable at lower buffer
concentration.
[0068] The compositions provided herein also may include excipients
and additives. The particular excipient or additive for use in the
compositions for long term storage provided herein may be
determined empirically using methods well known to those of skill
in the art (see, e.g., the Examples). Excipients and additives are
any pharmacologically suitable and therapeutically useful substance
which is not an active substance. Excipients and additives
generally have no pharmacological activity, or at least no
undesirable pharmacological activity. The excipients and additives
include, but are not limited to, surfactants, stabilizers,
complexing agents, antioxidants, or preservatives which prolong the
duration of use of the finished pharmaceutical formulation,
flavorings, vitamins, or other additives known in the art.
Complexing agents include, but are not limited to,
ethylenediaminetetraacetic acid (EDTA) or a salt thereof, such as
the disodium salt, citric acid, nitrilotriacetic acid and the salts
thereof. In one embodiment, the complexing agent is EDTA. In
another embodiment, particularly in the suspension formulations
provided herein, the complexing agent is sodium edetate. In these
embodiments, the compositions contain sodium edetate at a
concentration of about 0.05 mg/mL to about 0.5 mg/mL, or about 0.1
mg/mL to about 0.2 mg/mL.
[0069] Preservatives include, but are not limited to, those that
protect the solution from contamination with pathogenic particles,
including benzalkonium chloride or benzoic acid, or benzoates such
as sodium benzoate. Antioxidants include, but are not limited to,
vitamins, provitamins, ascorbic acid, vitamin E or salts or esters
thereof.
[0070] In certain embodiments herein, particularly in the solution
formulations provided herein, the compositions contain vitamin E
TPGS (d-.alpha.-tocopheryl polyethylene glycol 1000 succinate). In
these embodiments, vitamin E TPGS is present at a concentration of
about 0 mg/mL to about 100 mg/mL, or about 5 mg/mL to about 50
mg/mL. In certain embodiments herein, the compositions contain
vitamin E TPGS at a concentration of 10 mg/mL, 20 mg/mL, 30 mg/mL
or 50 mg/mL.
[0071] The compositions provided herein also may include a
cosolvent, which increases the solubility of additives or the
active ingredient(s). The particular cosolvent for use in the
compositions for long term storage provided herein may be
determined empirically using methods well known to those of skill
in the art (see, e.g., the Examples). Cosolvents for use herein
include, but are not limited to, hydroxylated solvents or other
polar solvents, such as alcohols such as isopropyl alcohol, glycols
such as propylene glycol, polyethylene glycol, polypropylene
glycol, glycol ether, glycerol, and polyoxyethylene alcohols. In
certain embodiments herein, particularly in the solution
formulations provided herein, the compositions contain a glycol. In
other embodiments, the compositions contain propylene glycol and/or
polyethylene glycol, including polyethylene glycol 400. In these
embodiments, the glycol is present at a concentration of about 0
mg/mL to about 100 mg/mL, or about 5 mg/mL to about 50 mg/mL. In
further embodiments, the compositions contain propylene glycol at a
concentration of 17 mg/mL or 20 mg/mL. In other embodiments, the
compositions contain polyethylene glycol 400 at a concentration of
10 mg/mL, 20 mg/mL, 30 mg/mL or 50 mg/mL.
[0072] The compositions provided herein, particularly the
suspension formulations provided herein, may also contain one or
more emulsifiers. The particular emulsifier for use in the
compositions for long term storage provided herein may be
determined empirically using methods well known to those of skill
in the art (see, e.g., the Examples). Emulsifiers for use herein
include, but are not limited to, polyoxyethylene sorbitan fatty
esters or polysorbates, including, but not limited to, polyethylene
sorbitan monooleate (Polysorbate 80), polysorbate 20
(polyoxyethylene (20) sorbitan monolaurate), polysorbate 65
(polyoxyethylene (20) sorbitan tristearate), polyoxyethylene (20)
sorbitan mono-oleate, polyoxyethylene (20) sorbitan monopalmitate,
polyoxyethylene (20) sorbitan monostearate; lecithins; alginic
acid; sodium alginate; potassium alginate; ammonium alginate;
calcium alginate; propane-1,2-diol alginate; agar; carrageenan;
locust bean gum; guar gum; tragacanth; acacia; xanthan gum; karaya
gum; pectin; amidated pectin; ammonium phosphatides;
microcrystalline cellulose; methylcellulose;
hydroxypropylcellulose; hydroxypropylmethylcellulose;
ethylmethylcellulose; carboxymethylcellulose; sodium, potassium and
calcium salts of fatty acids; mono- and di-glycerides of fatty
acids; acetic acid esters of mono- and di-glycerides of fatty
acids; lactic acid esters of mono- and di-glycerides of fatty
acids; citric acid esters of mono- and di-glycerides of fatty
acids; tartaric acid esters of mono- and di-glycerides of fatty
acids; mono- and diacetyltartaric acid esters of mono- and
di-glycerides of fatty acids; mixed acetic and tartaric acid esters
of mono- and di-glycerides of fatty acids; sucrose esters of fatty
acids; sucroglycerides; polyglycerol esters of fatty acids;
polyglycerol esters of polycondensed fatty acids of castor oil;
propane-1,2-diol esters of fatty acids; sodium
stearoyl-2-lactylate; calcium stearoyl-2-lactylate; stearoyl
tartrate; sorbitan monostearate; sorbitan tristearate; sorbitan
monolaurate; sorbitan mono-oleate; sorbitan monopalmitate; extract
of quillaia; polyglycerol esters of dimerised fatty acids of soya
bean oil; oxidatively polymerised soya bean oil; and pectin
extract.
[0073] In certain embodiments herein, the emulsifier(s) is (are) a
polyoxyethylene sorbitan fatty ester or polysorbate, including, but
not limited to, polyethylene sorbitan monooleate (Polysorbate 80),
polysorbate 20 (polyoxyethylene (20) sorbitan monolaurate),
polysorbate 65 (polyoxyethylene (20) sorbitan tristearate),
polyoxyethylene (20) sorbitan mono-oleate, polyoxyethylene (20)
sorbitan monopalmitate, polyoxyethylene (20) sorbitan monostearate;
sorbitan monostearate; sorbitan tristearate; sorbitan monolaurate;
sorbitan mono-oleate; or sorbitan monopalmitate. In further
embodiments, the emulsifier(s) is (are) polysorbate 80, sorbitan
monolaruate or polyoxyethylene (20) sorbitan monolaurate.
C. Preparation of Compounds for Use in the Compositions
[0074] The preparation of the compounds used in the compositions
provided herein is described below. Any such compound or similar
compound may be synthesized according to a method discussed in
general below or by only minor modification of the methods by
selecting appropriate starting materials.
[0075] Formoterol may be prepared according to the method disclosed
in U.S. Pat. No. 3,994,974. Briefly,
4-benzyloxy-3-nitro-.alpha.-bromoacetophenone is reacted with
N-benzyl-N-(1-methyl-2-p-methoxyphenylethyl)amine to form the
.alpha.-aminoacetophenone. This compound was subjected to the
following series of reactions: (i) reduction of the ketone with
sodium borohydride; (ii) reduction of the nitro group with aqueous
hydrochloric acid and iron powder; (iii) amine formylation with
acetic anhydride and formic acid; and (iv) catalytic reduction over
10% palladium on carbon to afford formoterol free base.
Crystallization of the 1/2 fumarate salt from ethanol provides
(formoterol)1/2fumarate.
[0076] The individual enantiomers of formoterol,
2-hydroxy-5-((1S)-1-hydroxy-2-(((1S)-2-(p-methoxyphenyl)-1-methylethyl)am-
ino)ethyl)-formanilide and
2-hydroxy-5-((1R)-1-hydroxy-2-(((1R)-2-(p-methoxyphenyl)-1-methylethyl)am-
ino)ethyl)formanilide, may be prepared by the method disclosed in
U.S. Pat. No. 6,040,344. Briefly, reaction of optically pure
4-benzyloxy-3-formamidostyrene oxide with an optically pure
4-methoxy-.alpha.-methyl-N-(phenylmethyl)benzeneethanamine,
followed by debenzylation, affords the desired enantiomer of
formoterol. Debenzylation may be accomplished by reduction with
hydrogen gas in the presence of a noble metal catalyst, such as
palladium on carbon.
[0077] The required optically pure 4-benzyloxy-3-formamidostyrene
oxide may be prepared from
4-benzyloxy-3-nitro-.alpha.-bromoacetophenone by (i) reduction with
vorane in the presence of an optically pure aminoindanol, (ii)
hydrogenation over platinum oxide catalyst, (iii) formylation with
formic acid and acetic anhydride, and (iv) epoxide formation in the
presence of potassium carbonate.
[0078] The required optically pure
4-methoxy-.alpha.-methyl-N-(phenylmethyl)-benzeneethanamine may be
prepared from 4-methoxyphenylacetone by (i) reductive amination
with benzylamine in the presence of hydrogen and a platinum
catalyst, and (ii) crystallization of the desired optically pure
amine from the resulting racemic mixture as its mandelic acid
salt.
[0079] Budesonide may be synthesized by the procedure disclosed in
U.S. Pat. No. 3,929,768. Briefly, reaction of triamcinolon with
propionaldehyde and catalytic perchloric acid in dry dioxane at
ambient temperature provides, following chromatography on
hydroxy-propylated, cross-linked dextran gel, budesonide.
[0080] Fluticasone propionate may be synthesized by the procedure
disclosed in U.S. Pat. No. 4,335,121. Briefly, the corresponding
carbothioic acid is prepared from the carboxylic acid precursor by
reaction with dimethylthiocarbamoyl chloride in the presence of
triethylamine. Reaction with bromochloromethane and sodium hydrogen
carbonate in dimethylacetamide affords the corresponding
S-chloromethyl carbothioate. This compound is treated with sodium
iodide in acetone to give the corresponding S-iodomethyl
carbothioate. Fluoride substitution of the iodo group is
accomplished by reaction with silver fluoride in acetonitrile to
afford the desired compound.
D. Formulation of Pharmaceutical Compositions
[0081] The compositions provided herein are prepared by procedures
well known to those of skill in the art. For example, a solution
formulations may be prepared by the procedure of EXAMPLE 1.
Briefly, polyethylene glycol 400 and/or propylene glycol, and a
preservative, such as vitamin E TPGS, are mixed at about 42.degree.
C. until a homogeneous solution forms. The temperature is lowered
and the steroidal anti-inflammatory agent is added. In a second
vessel, formoterol fumarate dihydrate and the remaining ingredients
are dissolved in approximately 70% water. The two solutions are
mixed and the resulting solution is diluted with water to the
desired volume.
[0082] Suspension formulations are prepared by the procedure of
EXAMPLE 2. Briefly, all ingredients other than the steroidal
anti-inflammatory agent and formoterol fumarate dihydrate are
dissolved in about 40% water with mixing. The steroidal
anti-inflammatory agent, which is micronized, is dispersed in the
above mixture with high speed homogenization. Formoterol fumarate
dihydrate is dissolved in 50% water and added to the steroidal
suspension with mixing until a uniform suspension forms.
E. Evaluation of the Activity of the Compositions
[0083] Standard physiological, pharmacological and biochemical
procedures are available for testing the compositions provided
herein to identify those that possess bronchodilatory activity.
[0084] In vitro and in vivo assays that may be used to evaluate
bronchodilatory activity are well known to those of skill in the
art. See also, e.g., U.S. Pat. Nos. 3,994,974, and 6,068,833;
German Patent No. 2,305,092; Kaumann et al. (1985) Naunyn-Schmied
Arch. Pharmacol. 331:27-39; Lemoine et al. (1985) Naunyn-Schmied
Arch. Pharmacol. 331:40-51; Tomioka et al. (1981) Arch. Int.
Pharmacodyn. 250:279-292; Dellamary et al. (2000) Pharm. Res.
17(2):168-174; Rico-Mendez et al. (1999) Rev. Alerg. Mex.
46(5):130-135; Seberova et al. (2000) Respir. Med. 94(6):607-611;
Lotvall et al. (1999) Can. Respir. J. 6(5):412-416; Campbell et al.
(1999) Respir. Med. 93(4):236-244; Nightingale et al. (1999) Am. J.
Respir. Crit. Care Med. 159(6):1786-1790; Lecaillon et al. (1999)
Eur. J. Clin. Pharmacol. 55(2):131-138; Bartow et al. (1998) Drugs
55(2):303-322; Ekstrom et al. (1998) Respir. Med. 92(8):1040-1045;
Ringdal et al. (1998) Respir. Med. 92(8):1017-1021; Totterman et
al. (1998) Eur. Respir. J. 12(3):573-579; Palmqvist et al. (1997)
Eur. Respir. J. 10(11):2484-2489; Nielsen et al. (1997) Eur.
Respir. J. 10(9):2105-2109; Ullman et al. (1996) Allergy
51(10):745-748; Selroos et al. (1996) Clin. Immunother. 6:273-299;
and Schreurs et al. (1996) Eur. Respir. J. 9(8):1678-1683.
F. Methods of Treatment of Bronchoconstrictive Disorders
[0085] The compositions provided herein are used for treating,
preventing, or ameliorating one or more symptoms of a
bronchoconstrictive disorders in a subject. In one embodiment, the
method includes administering to a subject an effective amount of a
composition containing a .beta..sub.2-adrenoreceptor agonist,
including, but not limited to, formoterol, and a steroidal
anti-inflammatory agent, including, but not limited to, budesonide
and fluticasone propionate, whereby the disease or disorder is
treated or prevented, or one or more symptoms are ameliorated. The
subject treated is, in certain embodiments, a mammal. In certain of
these embodiments, the mammal is a human.
[0086] In another embodiment, the method provided herein includes
oral administration of a composition provided herein. In certain
embodiments herein, the composition is directly administered to a
subject in need of such treatment via nebulization without dilution
or other modification of the composition prior to
administration.
[0087] The methods for treatment, prevention, or amelioration of
one or more symptoms of bronchoconstrictive disorders, in another
embodiment, further include administering one or more of (a), (b)
or (c) as follows: (a) a .beta..sub.2-adrenoreceptor agonist; (b) a
dopamine (D.sub.2) receptor agonist; or (c) an anti-cholinergic
agent; simultaneously with, prior to or subsequent to the
composition provided herein.
[0088] .beta..sub.2-Adrenoreceptor agonists for use in combination
with the compositions provided herein include, but are not limited
to, Albuterol
(.alpha..sup.1-(((1,1-dimethylethyl)amino)methyl)-4-hydroxy-1,3-
-benzenedimethanol); Bambuterol (dimethylcarbamic acid
5-(2-((1,1-dimethylethyl)amino)-1-hydroxyethyl)-1,3-phenylene
ester); Bitolterol (4-methylbenzoic acid
4-(2-((1,1-dimethylethyl)amino)-1-hydroxyethyl)-1,2-phenylene
ester); Broxaterol
(3-bromo-.alpha.-(((1,1-dimethylethyl)amino)methyl)-5-isoxazolemethanol);
Isoproterenol
(4-(1-hydroxy-2-((1-methylethyl)amino)ethyl)-1,2-benzenediol);
Trimetoquinol
(1,2,3,4-tetrahydro-1-((3,4,5-trimethoxyphenyl)-methyl)-6,7-isoquinolined-
iol); Clenbuterol
(4-amino-3,5-dichloro-.alpha.-(((1,1-dimethylethyl)amino)methyl)benzeneme-
thanol); Fenoterol
(5-(1-hydroxy-2-((2-(4-hydroxyphenyl)-1-methylethyl)amino)ethyl)-1,3-benz-
enediol); Formoterol
(2-hydroxy-5-((1RS)-1-hydroxy-2-(((1RS)-2-(p-methoxyphenyl)-1-methylethyl-
)amino)ethyl)formanilide); (R,R)-Formoterol; Desformoterol ((R,R)
or
(S,S)-3-amino-4-hydroxy-.alpha.-(((2-(4-methoxyphenyl)-1-methylethyl)amin-
o)methyl)benzenemethanol); Hexoprenaline
(4,4'-(1,6-hexanediyl)-bis(imino(1-hydroxy-2,1-ethanediyl)))bis-1,2-benze-
nediol); Isoetharine
(4-(1-hydroxy-2-((1-methylethyl)amino)butyl)-1,2-benzenediol);
Isoprenaline
(4-(1-hydroxy-2-((1-methylethyl)amino)ethyl)-1,2-benzenediol);
Metaproterenol
(5-(1-hydroxy-2-((1-methylethyl)amino)ethyl)-1,3-benzenediol);
Picumeterol
(4-amino-3,5-dichloro-.alpha.-(((6-(2-(2-pyridinyl)ethoxy)hexyl)-amino)me-
thyl)benzenemethanol); Pirbuterol
(.alpha..sup.6-(((1,1-dimethylethyl)-amino)methyl)-3-hydroxy-2,6-pyridine-
methanol); Procaterol
(((R*,S*)-(.+-.)-8-hydroxy-5-(1-hydroxy-2-((1-methylethyl)amino)butyl)-2(-
1H)-quinolinone); Reproterol
((7-(3-((2-(3,5-dihydroxyphenyl)-2-hydroxyethyl)amino)-propyl)-3,7-dihydr-
o-1,3-dimethyl-1H-purine-2,6-dione); Rimiterol
(4-(hydroxy-2-piperidinylmethyl)-1,2-benzenediol); Salbutamol
((.+-.)-.alpha..sup.1-(((1,1-dimethylethyl)amino)methyl)-4-hydroxy-1,3-be-
nzenedimethanol); (R)-Salbutamol; Salmeterol
((.+-.)-4-hydroxy-.alpha..sup.1-(((6-(4-phenylbutoxy)hexyl)-amino)methyl)-
-1,3-benzenedimethanol); (R)-Salmeterol; Terbutaline
(5-(2-((1,1-dimethylethyl)amino)-1-hydroxyethyl)-1,3-benzenediol);
Tulobuterol
(2-chloro-.alpha.-(((1,1-dimethylethyl)amino)methyl)benzenemethanol);
and TA-2005
(8-hydroxy-5-((1R)-1-hydroxy-2-(N-((1R)-2-(4-methoxyphenyl)-1-met-
hylethyl)amino)ethyl)carbostyril hydrochloride).
[0089] Dopamine (D.sub.2) receptor agonists include, but are not
limited to, Apomorphine
((r)-5,6,6a,7-tetrahydro-6-methyl-4H-dibenzo[de,g]quinoline-10,11-diol);
Bromocriptine ((5'
.alpha.)-2-bromo-12'-hydroxy-2'-(1-methylethyl)-5'-(2-methylpropyl)ergota-
man-3',6',18-trione); Cabergoline
((8.beta.)-N-(3-(dimethylamino)propyl)-N-((ethylamino)carbonyl)-6-(2-prop-
enyl)ergoline-8-carboxamide); Lisuride
(N'-((8.alpha.)-9,10-didehydro-6-methylergolin-8-yl)-N,N-diethylurea);
Pergolide ((8.beta.)-8-((methylthio)methyl)-6-propylergoline);
Levodopa (3-hydroxy-L-tryrosine); Pramipexole
((s)-4,5,6,7-tetrahydro-N.sup.6-propyl-2,6-benzothiazolediamine);
Quinpirole hydrochloride
(trans-(-)-4aR-4,4-a,5,6,7,8,8a,9-octahydro-5-propyl-1H-pyrazolo[3,4-g]qu-
inoline hydrochloride); Ropinirole
(4-(2-(dipropylamino)ethyl)-1,3-dihydro-2H-indol-2-one); and
Talipexole
(5,6,7,8-tetrahydro-6-(2-propenyl)-4H-thiazolo[4,5-d]azepin-2-amine).
Other dopamine D.sub.2 receptor agonists for use herein are
disclosed in International Patent Application Publication No. WO
99/36095.
[0090] Anticholinergic agents for use herein include, but are not
limited to, ipratropium bromide, oxitropium bromide, atropine
methyl nitrate, atropine sulfate, ipratropium, belladonna extract,
scopolamine, scopolamine methobromide, homatropine methobromide,
hyoscyamine, isopriopramide, orphenadrine, benzalkonium chloride,
tiotropium bromide and glycopyrronium bromide. In certain
embodiments, the compositions contain an anticholinergic agent,
such as ipratropium bromide or tiotropium bromide, at a
concentration of about 5 .mu.g/mL to about 5 mg/mL, or about 50
.mu.g/mL to about 200 .mu.g/mL. In other embodiments, the
compositions for use in the methods herein contain an
anticholinergic agent, including ipratropium bromide and tiotropium
bromide, at a concentration of about 83 .mu.g/mL or about 167
.mu.g/mL.
[0091] Other active ingredients for use herein in combination
therapy, include, but are not limited to, IL-5 inhibitors such as
those disclosed in U.S. Pat. Nos. 5,668,110, 5,683,983, 5,677,280
and 5,654,276; antisense modulators of IL-5 such as those disclosed
in U.S. Pat. No. 6,136,603; milrinone
(1,6-dihydro-2-methyl-6-oxo[3,4'-bipyridine]-5-carbonitrile);
milrinone lactate; tryptase inhibitors such as those disclosed in
U.S. Pat. No. 5,525,623; tachykinin receptor antagonists such as
those disclosed in U.S. Pat. Nos. 5,691,336, 5,877,191, 5,929,094,
5,750,549 and 5,780,467; leukotriene receptor antagonists such as
montelukast sodium (Singular.RTM.,
R-(E)]-1-[[[1-[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydrox-
y-1-methylethyl)phenyl]-propyl]thio]methyl]cyclopropaneacetic acid,
monosodium salt), 5-lypoxygenase inhibitors such as zileuton
(Zyflo.RTM., Abbott Laboratories, Abbott Park, Ill.), and anti-IgE
antibodies such as Xolair.RTM. (recombinant humanized anti-IgE
monoclonal antibody (CGP 51901; IGE 025A; rhuMAb-E25), Genentech,
Inc.).
[0092] The bronchoconstrictive disorder to be treated, prevented,
or whose one or more symptoms are to be ameliorated is associated
with asthma, including, but not limited to, bronchial asthma,
allergic asthma and intrinsic asthma, e.g., late asthma and airway
hyper-responsiveness; and, particularly in embodiments where an
anticholinergic agent is used, other chronic obstructive pulmonary
diseases (COPDs), including, but not limited to, chronic
bronchitis, emphysema, and associated cor pulmonale (heart disease
secondary to disease of the lungs and respiratory system) with
pulmonary hypertension, right ventricular hypertrophy and right
heart failure. COPD is frequently associated with cigarette
smoking, infections, environmental pollution and occupational dust
exposure.
G. Nebulizers
[0093] The compositions provided herein are intended for
administration to a subject in need of such treatment via
nebulization. Nebulizers that nebulize liquid formulations
containing no propellant are suitable for use with the compositions
provided herein. Nebulizers are available from, e.g., Pari GmbH
(Sternberg, Germany), DeVilbiss Healthcare (Heston, Middlesex, UK),
Healthdyne, Vital Signs, Baxter, Allied Health Care, Invacare,
Hudson, Siemens, Aerogen, Omron, Bremed, AirSep, Luminscope,
Medisana, Mountain Medical, Aerosol Medical Ltd. (Colchester,
Essex, UK), AFP Medical (Rugby, Warwickshire, UK), Bard Ltd.
(Sunderland, UK), Carri-Med Ltd. (Dorking, UK), Plaem Nuiva
(Brescia, Italy), Henleys Medical Supplies (London, UK),
Intersurgical (Berkshire, UK), Lifecare Hospital Supplies (Leies,
UK), Medic-Aid Ltd. (West Sussex, UK), Medix Ltd. (Essex, UK),
Sinclair Medical Ltd. (Surrey, UK), and many others.
[0094] Nebulizers for use herein include, but are not limited to,
jet nebulizers (optionally sold with compressors), ultrasonic
nebulizers, and others. Exemplary jet nebulizers for use herein
include Pari LC plus/ProNeb, Pari LC plus/ProNeb Turbo, Pari LC
plus/Dura Neb 1000 & 2000, Pari LC plus/Walkhaler, Peri LC
plus/Pari Master, Peri LC star, Omron CompAir XL Portable Nebulizer
System (NE-C18 and JETAir Disposable nebulizer), Omron CompAir
Elite Compressor Nebulizer System (NE-C21 and Elite Air Reusable
Nebulizer), Pari LC Plus or Pari LC Star nebulizer with Proneb
Ultra compressor, Pulmo-aide, Pulmo-aide LT, Pulmo-aide traveler,
Invacare Passport, Inspiration Healthdyne 626, Pulmo-Neb Traveler,
DeVilbiss 646, Whisper Jet, Acorn II, Misty-Neb, Allied aerosol,
Schuco Home Care, Lexan Plastic Pocet Neb, SideStream Hand Held
Neb, Mobil Mist, Up-Draft, Up-Draft II, T Up-Draft, ISO-NEB,
AVA-NEB, Micro Mist, and PulmoMate. Exemplary ultrasonic nebulizers
for use herein include MicroAir, UltraAir, CompAir, Pulmosonic,
Scout, 5003 Ultrasonic Neb, 5110 Ultrasonic Neb, 5004 Desk
Ultrasonic Nebulizer, Mystique Ultrasonic, Siemens Ultra Nebulizer
145, Luminscope's Ultrasonic Nebulizer, Medisana Ultrasonic
Nebulizer, Microstat Ultrasonic Nebulizer, and MABISMist Hand Held
Ultrasonic Nebulizer. Other nebulizers for use herein include 5000
Electromagnetic Neb, Aeroneb.TM. Partable Nebulizer System,
Aerodose.TM. Inhaler, 5001 Electromagnetic Neb 5002, Rotary Piston
Neb, Lumineb 1 Piston Nebulizer 5500, and AeroEclipse Breath
Actuated Nebulizer.
H. Articles of Manufacture
[0095] The compositions provided herein may be packaged as articles
of manufacture containing packaging material, a composition
provided herein, which is useful for treatment, prevention or
amelioration of one or more symptoms of diseases or disorders
associated with undesired and/or uncontrolled bronchoconstriction,
and a label that indicates that the composition is used for
treatment, prevention or amelioration of one or more symptoms of
diseases or disorders associated with undesired and/or uncontrolled
bronchoconstriction.
[0096] The articles of manufacture provided herein contain
packaging materials. Packaging materials for use in packaging
pharmaceutical products are well known to those of skill in the
art. See, e.g., U.S. Pat. Nos. 5,323,907, 5,052,558 and 5,033,252.
Examples of pharmaceutical packaging materials include, but are not
limited to, blister packs, bottles, tubes, inhalers, pumps, bags,
vials, containers, syringes, bottles, and any packaging material
suitable for a selected formulation and intended mode of
administration and treatment.
[0097] In one embodiment herein, the compositions are packaged with
a nebulizer for direct administration of the composition to a
subject in need thereof.
[0098] The following examples are included for illustrative
purposes only and are not intended to limit the scope of the
invention.
Example 1
Preparation of Solution Formulations
[0099] Polyethylene glycol 400 and/or propylene glycol and vitamin
E TPGS were mixed in a stainless steel container with heating at
about 42.degree. C. until a homogeneous liquid formed. While
maintaining the liquid phase, the temperature was lowered and the
steroid active ingredient, e.g., budesonide or fluticasone
propionate, was added. The mixing was continued until all of the
drug substance had dissolved. In another container all other
ingredients, including formoterol fumarate dihydrate, were mixed
with about 70% water until a clear solution formed. The two
solutions were mixed together until a homogeneous clear solution
formed. The volume Was made up with water and the solution was
mixed to give the desired composition.
[0100] Using the above procedure, the following solution
compositions containing the indicated ingredients in the indicated
amounts were prepared. For each steroidal anti-inflammatory agent,
a low strength and a high strength formulation was prepared.
TABLE-US-00001 Budesonide/Formoterol solution formulations
Concentration Ingredient Low strength High strength Formoterol
fumarate 85 .mu.g/mL 170 .mu.g/mL dihydrate Budesonide 125 .mu.g/mL
250 .mu.g/mL Vitamin E TPGS 10 mg/mL 20 mg/mL Either: Propylene
glycol or 17 mg/mL 20 mg/mL Polyethylene glycol 400 10 mg/mL 20
mg/mL Citrate buffer 5 mM 5 mM Sodium Chloride 7.5 mg/mL 6.8 mg/mL
Water q.s. q.s.
TABLE-US-00002 Fluticasone propionate/Formoterol solution
formulations Concentration Ingredient Low strength High strength
Formoterol fumarate 85 .mu.g/mL 170 .mu.g/mL dihydrate Fluticasone
125 .mu.g/mL 250 .mu.g/mL propionate Vitamin E TPGS 30 mg/mL 50
mg/mL Either: Propylene glycol or 17 mg/mL 20 mg/mL Polyethylene
glycol 400 30 mg/mL 50 mg/mL Citrate buffer 5 mM 5 mM Sodium
Chloride 1.5 mg/mL 0 mg/mL Water q.s. q.s.
Example 2
Preparation of Suspension Formulations
[0101] All ingredients, with the exception of formoterol fumarate
dihydrate and the steroidal anti-inflammatory agent, e.g.,
budesonide or fluticasone propionate, were dissolved in about 40%
water in a container with mixing. The steroidal active ingredient
was added and the mixture was dispersed with high speed
homogenization. Formoterol fumarate dihydrate was dissolved in
about 50% water with mixing and the resulting solution was added to
the steroidal suspension with mixing until a uniform suspension
formed.
[0102] Using the above procedure, the following suspension
formulations containing the indicated ingredients in the indicated
amounts were prepared.
TABLE-US-00003 Budesonide/Formoterol suspension formulations
Ingredient Concentration Formoterol fumarate dihydrate 5-2000
.mu.g/mL or 50-200 .mu.g/mL Budesonide 125-500 .mu.g/mL Disodium
edetate 0.1-0.2 mg/mL Polysorbate 80 0.2-0.3 mg/mL Sodium chloride
5-10 mg/mL Citrate buffer 1-20 mM Water q.s.
TABLE-US-00004 Fluticasone propionate/Formoterol suspension
formulations Ingredient Concentration Formoterol fumarate dihydrate
5-2000 .mu.g/mL or 50-200 .mu.g/mL Fluticasone propionate
micronized 250-1000 .mu.g/mL Sorbitan monolaurate 0.05-0.2 mg/mL
Polyoxyethylene 20 sorbitan 0.1-0.3 mg/mL monolaurate Sodium
chloride 5-10 mg/mL Citrate buffer 1-20 mM Water q.s.
[0103] Since modifications will be apparent to those of skill in
this art, it is intended that this invention be limited only by the
scope of the appended claims.
* * * * *