U.S. patent application number 11/613187 was filed with the patent office on 2007-08-30 for inhalant formulation containing sulfoalkyl ether cyclodextrin and corticosteroid.
Invention is credited to GEROLD L. MOSHER, JAMES D. PIPKIN, DIANEO THOMPSON, RUPERT O. ZIMMERER.
Application Number | 20070202054 11/613187 |
Document ID | / |
Family ID | 38894876 |
Filed Date | 2007-08-30 |
United States Patent
Application |
20070202054 |
Kind Code |
A1 |
PIPKIN; JAMES D. ; et
al. |
August 30, 2007 |
Inhalant Formulation Containing Sulfoalkyl Ether Cyclodextrin and
Corticosteroid
Abstract
An inhalable formulation containing SAE-CD and corticosteroid is
provided. The formulation is adapted for administration to a
subject by nebulization with any known nebulizer. The formulation
can be included in a kit. The formulation is administered as an
aqueous solution, however, it can be stored as a dry powder,
ready-to-use solution, or concentrated composition. The formulation
is employed in an improved nebulization system for administering
corticosteroid by inhalation. SAE-CD present in the formulation
significantly enhances the chemical stability of budesonide. A
method of administering the formulation by inhalation is provided.
The formulation can also be administered by conventional nasal
delivery apparatus.
Inventors: |
PIPKIN; JAMES D.; (LAWRENCE,
KS) ; ZIMMERER; RUPERT O.; (LAWRENCE, KS) ;
THOMPSON; DIANEO; (KANSAS CITY, MO) ; MOSHER; GEROLD
L.; (KANSAS CITY, MO) |
Correspondence
Address: |
INNOVAR, LLC
P O BOX 250647
PLANO
TX
75025
US
|
Family ID: |
38894876 |
Appl. No.: |
11/613187 |
Filed: |
December 19, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11479979 |
Jun 30, 2006 |
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11613187 |
Dec 19, 2006 |
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PCT/US05/00082 |
Dec 31, 2004 |
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11479979 |
Jun 30, 2006 |
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60533628 |
Dec 31, 2003 |
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Current U.S.
Class: |
424/46 ; 514/171;
514/263.31; 514/288; 514/292; 514/357; 514/58; 514/649;
514/651 |
Current CPC
Class: |
A61P 37/08 20180101;
A61K 47/6851 20170801; C08B 37/0015 20130101; A61K 47/6951
20170801; A61K 47/61 20170801; A61P 11/00 20180101; A61P 27/16
20180101; A61K 45/06 20130101; B82Y 5/00 20130101; A61P 11/02
20180101; A61K 31/58 20130101; A61K 47/40 20130101; A61K 9/0078
20130101; A61K 31/573 20130101; A61P 27/14 20180101; A61P 43/00
20180101; C08L 5/16 20130101; A61K 31/724 20130101; A61P 11/06
20180101; A61P 27/02 20180101; A61K 31/573 20130101; A61K 2300/00
20130101; A61K 31/724 20130101; A61K 2300/00 20130101 |
Class at
Publication: |
424/046 ;
514/171; 514/649; 514/651; 514/263.31; 514/357; 514/292; 514/288;
514/058 |
International
Class: |
A61K 31/724 20060101
A61K031/724; A61K 31/573 20060101 A61K031/573; A61K 9/14 20060101
A61K009/14; A61K 31/522 20060101 A61K031/522; A61K 31/48 20060101
A61K031/48; A61K 31/4745 20060101 A61K031/4745; A61K 31/138
20060101 A61K031/138 |
Claims
1-42. (canceled)
43. The invention according to any one of claims 71, 72, 101, 104,
105, 106, or 107, wherein the cyclodextrin is a compound of the
Formula 1: ##STR3## wherein: n is 4, 5 or 6; R.sub.1, R.sub.2,
R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8 and R.sub.9
are each, independently, --O-- or a --O--(C.sub.2-C.sub.6
alkylene)-SO.sub.3.sup.- group, wherein at least one of
R.sub.1-R.sub.9 is independently a --O--(C.sub.2-C.sub.6
alkylene)-SO.sub.3.sup.- group, a
--O--(CH.sub.2).sub.mSO.sub.3.sup.- group wherein m is 2 to 6,
--OCH.sub.2CH.sub.2CH.sub.2SO.sub.3.sup.-, or
--OCH.sub.2CH.sub.2CH.sub.2CH.sub.2SO.sub.3.sup.-); and S.sub.1,
S.sub.2, S.sub.3, S.sub.4, S.sub.5, S.sub.6, S.sub.7, S.sub.8 and
S.sub.9 are each, independently, a pharmaceutically acceptable
cation.
44. The invention according to any one of claims 71, 72, 101, 104,
105, 106, or 107, wherein the cyclodextrin is a compound of the
Formula II (SAEx-.alpha.-CD), wherein "x" ranges from 1 to 18; of
the Formula III (SAEy-.beta.-CD), wherein "y" ranges from 1 to 21;
or of the Formula IV (SAEz-.gamma.-CD), wherein "z" ranges from 1
to 24, and wherein "SAE" represents a sulfoalkyl ether substituent,
and the values "x", "y" and "z" represent the average degree of
substitution in terms of the number of sulfoalkyl ether groups per
CD molecule.
45. The invention according to claim 44, wherein the cyclodextrin
is selected from the group consisting of: SAEx-.alpha.-CD
SAEy-.beta.-CD SAEz-.gamma.-CD SEEx-.alpha.-CD SEEy-.beta.-CD
SEEz-.gamma.-CD SPEx-.alpha.-CD SPEy-.beta.-CD SPEz-.gamma.-CD
SBEx-.alpha.-CD SBEy-.beta.-CD SBEz-.gamma.-CD SPtEx-.alpha.-CD
SPtEy-.beta.-CD SPtEz-.gamma.-CD SHEx-.alpha.-CD SHEy-.beta.-CD
SHEz-.gamma.-CD.
46-70. (canceled)
71. A method of treating a disease or disorder of the airways, in a
subject in need thereof, comprising administering or delivering,
via inhalation, to the subject an aqueous liquid formulation
comprising an aqueous liquid carrier, a sulfoalkyl ether
cyclodextrin, and a dose of corticosteroid dissolved therein,
wherein the formulation provides an enhanced pharmacokinetic
profile over a suspension based formulation administered under
similar conditions.
72. A method of administering or delivering a dose of
corticosteroid to the air passageways of a subject in need thereof,
the method comprising administering or delivering the
corticosteroid with a nebulizer comprising a charge of an aqueous
liquid formulation, the formulation comprising an aqueous liquid
carrier, sulfoalkyl ether cyclodextrin, and the corticosteroid
dissolved therein, wherein, during operation, the system provides
enhanced drug delivery, increased rate of drug administration,
reduced treatment time, reduced toxicity, improved stability,
enhanced bioabsorption, increased output rate, increased total
output, enhanced pharmacokinetic profile, reduced
corticosteroid-related side effects, enhanced pulmonary deposition,
reduced oropharyngeal deposition, and/or improved nebulization
performance over another system comprising the nebulizer and a
suspension based formulation of the corticosteroid.
73. The method of claim 71, wherein the formulation provides
enhanced drug delivery, increased rate of drug administration,
reduced treatment time, reduced toxicity, improved stability,
enhanced bioabsorption, increased output rate, increased total
output, enhanced pharmacokinetic profile, reduced
corticosteroid-related side effects, enhanced pulmonary deposition,
reduced oropharyngeal deposition, and/or improved nebulization
performance over a suspension based formulation administered under
similar conditions.
74. The method of claim 71, wherein the dose of corticosteroid is
at least 25 .mu.g, 40 .mu.g, at least 45 .mu.g, at least 48 .mu.g,
45-1000 .mu.g, about 1 .mu.g to 20 mg, or 1 .mu.g to 10 mg, 0.01 mg
to 10 mg, 0.025 mg to 10 mg, 0.05 mg to 5 mg, 0.1 mg to 5 mg, 0.125
mg to 5 mg, 0.25 mg to 5 mg, 0.5 mg to 5 mg, 0.05 mg to 2 mg, 0.1
mg to 2 mg, 0.125 mg to 2 mg, 0.25 mg to 2 mg, 0.5 mg to 2 mg, 1
.mu.g, 10 .mu.g, 25 .mu.g, 50 .mu.g, 100 .mu.g, 125 .mu.g, 200
.mu.g, 250 .mu.g, 25 to 66 .mu.g, 48 to 81 .mu.g, 73 to 125 .mu.g,
40 .mu.g, 64 .mu.g, 95 .mu.g, 35 to 95 .mu.g, 25 to 125 .mu.g, 60
to 170 .mu.g, 110 .mu.g, 170 .mu.g, 45 to 220 .mu.g, 45 to 85
.mu.g, 48 to 82 .mu.g, 85 to 160 .mu.g, 140 to 220 .mu.g, 120 to
325 .mu.g, 205 .mu.g, 320 .mu.g, 325 .mu.g, 90 to 400 .mu.g, 95 to
170 .mu.g, 165 to 275 .mu.g, 275 to 400 .mu.g.
75. The method of claim 71, wherein the liquid has a volume of 10
.mu.l to 100 ml, 50 .mu.l to 50 ml, 50 .mu.l to 10 ml, 0.1 to 10
ml, 0.1 ml to less than 10 ml, 0.1 ml to 7.5 ml, 0.1 ml to 5 ml,
0.1 ml to 3 ml, 0.1 ml to 2 ml, 0.1 ml to 1 ml, 0.05 ml to 7.5 ml,
0.05 ml to 5 ml, 0.05 ml to 3 ml, 0.05 ml to 2 ml, or 0.05 ml to 1
ml.
76. The method of claim 71, wherein the step of delivering or
administering is conducted over a period of less than 30 min, less
than 20 min, less than 10 min, less than 7 min, less than 5 min,
less than 3 min, or less than 2 min, or the time is about 0.05 to
10 min, about 0.1 to 5 min, about 0.1 to 3 min, about 0.1 to 2 min,
about 0.1 to 1.5 min, about 0.5 min to about 1.5 min, or about 1
min, or the time is about the time it takes for a subject to take a
single breath (about 1 to 3 or 1 to 5 sec).
77. The method of claim 71, wherein the enhanced pharmacokinetic
profile is an enhancement of 1.5 to 8 fold higher, 1.5 to 6 fold
higher, 1.5 to 4 fold higher, 1.5 to 2 fold higher, 1.64 to 3.55
fold higher for Cmax, 1.48 to 6.25 fold higher for Cmax, 1.59 to
3.55 or 1.19 to 6.11 fold higher for AUC.sub.inf, 1.69-3.67 or 1.21
to 7.66 fold higher for AUC.sub.last as compared to administration
of the suspension formulation.
78. The method of claim 71, wherein 20% to 85%, or 30% to 80%, or
at least 30%, at least 40%, at least 56%, at least 59%, at least
62% of the dose of corticosteroid is delivered to the lungs of the
subject.
79. The method of claim 71, wherein the method provides in the
subject a C.sub.max (pg of corticosteroid/ml) of 90 to 900, 200 to
600, 200 to 550, 200 to 250, 400 to 450, 500 to 600, 225, 437, or
545 on a dose non-normalized basis.
80. The method of claim 71, wherein the method provides in the
subject a dose normalized C.sub.max (pg/ml/.mu.g) of: 1) 0.3 to 2,
0.35 to 2, 0.6 to 1.5, 0.5 to 1.2, 0.8 to 1, 0.8 to 0.9, 0.7 to
0.8, 0.4, 1.9, 0.6, 1.5, 0.5, 1.2, 0.35, 2, 0.7, 0.8, or 0.9 on a
nominal available dose normalized basis; 2) 3.4 to 9.2, 3.5 to 8.5,
5.5 to 9.2, 4.5 to 7.5, 5.8 to 7, 3.4, 3.5, 4.5, 5.5, 9.2, 8.5,
7.5, 5.8, 5.9, 6, or 7 on a dose to lung normalized basis; 3) 1.7
to 7.5, 3.2 to 4.1, 1.9 to 6, 3.2 to 7.5, 1.7 to 5.2, 3.6, 4.1,
3.2, 1.9, 6, 3.2, 7.4, 7.5, 1.7, 5.2 or 5.3 on a dose to subject
normalized basis; 4) 0.9 to 3.3, 1.7 to 2.2, 0.9 to 3, 1 to 3, 1.7
to 3.3, 1 to 2.7, 1.9, 2.1, 2.2, 1.7, 0.9, 1, 2, 3, 2.9, 3.2, 3.3,
or 2.7 on an emitted dose normalized basis.
81. The method of claim 71, wherein the, on the basis of the
non-normalized dose of corticosteroid, the Cmax provided by the
formulation is 1.6 to 2, 1.5 to 3, 1.5 to 2.5, 1.5 to 2, 1.5, 1.6,
2, 2.5, or 3 fold higher than the Cmax provided by the
suspension-based formulation when the dose of corticosteroid in the
formulation and the suspension is approximately the same amount
loaded.
82. The method of claim 71, wherein, on the basis of normalization
to the nominal available dose of corticosteroid, the Cmax provided
by the corticosteroid formulation is 1.8 to 6.2, 1.5 to 6.5, 2 to
6.5, 1.5 to 5.5, 2 to 4, 1.5 to 4, 1.5 to 3, 2.7, 3.3, 3.4, 1.5,
6.5, 2, 5.5, 4, or 3 fold higher than the Cmax provided by the
suspension-based formulation.
83. The method of claim 71, wherein, on the basis of normalization
to the dose of corticosteroid to lung, the Cmax provided by the
corticosteroid formulation is 1.4 to 4.3, 1.4 to 4.5, 1.5 to 4.5,
1.5 to 3.5, 1.5 to 3, 1.4 to 3, 1.5 to 2.5, 1.5 to 2, 2, 2.3, 1.4,
4/5, 3.5, 3, 1.5 or 2.5 fold higher than the Cmax provided by the
suspension-based formulation.
84. The method of claim 71, wherein, on the basis of normalization
to the dose of corticosteroid to subject, the Cmax provided by the
corticosteroid formulation is 2 to 3.5, 2 to 5, 1.7 to 3.8, 1.7 to
5, 2.7, 3, 2.4, 2, 3.5, 5, 1.7, or 3.8 fold higher than the Cmax
provided by the suspension-based formulation.
85. The method of claim 71, wherein, on the basis of normalization
to the emitted dose of corticosteroid, the Cmax provided by the
corticosteroid formulation is 1.9 to 6.3, 1.75 to 6.5, 2.2 to 4.2,
2.2 to 6.3, 1.9 to 4.2, 3.2, 3.5, 3.6, 2.8, 1.75, 6.5, 2.2, 4.2, or
6.3 fold higher than the Cmax provided by the suspension-based
formulation.
86. The method of claim 71, wherein the Cmax provided by the
corticosteroid formulation is at least 1.5, 1.6, 2, 2.6, and 3 fold
higher than the Cmax provided by the suspension-based formulation
when the dose of corticosteroid in the formulation is about 2 fold
lower than the dose in the suspension.
87. The method of claim 71, wherein the method provides a C.sub.max
(pg/ml) of 1600 to 1800, 1650 to 1750, or 1700 on a dose
non-normalized basis.
88. The method of claim 71, wherein the method provides a dose
normalized C.sub.max (pg/ml/.mu.g) of: 1) 1 to 2, 1.6 to 1.8, or
1.7 on a loaded dose nominal normalized basis; 2) 2 to 2.5, or 2.2
on an emitted dose normalized basis.
89. The method of claim 71, wherein, on the basis of the normalized
nominal dose of corticosteroid, the C.sub.max provided by the
corticosteroid formulation is at least 1.7, 1.8, 1.9, or 2 fold
higher than the C.sub.max provided by the suspension-based
formulation when the dose of corticosteroid in the formulation and
the suspension is approximately the same.
90. The method of claim 71, wherein, on the basis of normalization
to the emitted dose of corticosteroid, the C.sub.max provided by
the corticosteroid formulation is at least 1.5, 1.6, to 2 fold
higher than the C.sub.max provided by the suspension-based
formulation.
91. The method of claim 71, wherein the method provides in the
subject an AUC.sub.inf (pg*h/ml) of 500 to 1700, 530 to 1650, 250
to 2500, 280 to 1300, 780 to 1300, 980 to 2450, 275, 775, 980,
2400, 2500, 1300, 1290, 530, 1650, 250, 280 or 780 on a dose
non-normalized basis.
92. The method of claim 71, wherein the method provides in the
subject a dose normalized AUC.sub.inf (pg/ml/.mu.g) of: 1) 1 to
5.5, 2 to 2.2, 1 to 5.3, 1.1 to 5.2, 1.5 to 2.6, 1.3 to 3.3, 2,
2.1, 2.2, 1, 5.5, 5.3, 5.2, 1.5, 2.6, 1.3 or 3.3 on a nominal
available dose normalized basis; 2) 10 to 25, 14 to 18, 10.2 to 20,
13.6 to 18.8, 11.2 to 24.7, 10.2, 20, 13.6, 14, 19, 18.8, 11, 11.2,
25, 24.7, 14.2, 16.2, 17.3 on a dose to lung normalized basis; 3) 4
to 16, 4.2 to 16.1, 8 to 12.2, 5.4 to 16, 5.4 to 17, 8.5 to 9.6,
8.5, 9.5, 9.6, 4.2, 16.1, 8, 12.2, 12, 5.4, 16, 17, or 16.5 on a
dose to subject normalized basis; 4) 2.5 to 9, 2.6 to 8.5, 4.5 to
5.1, 2.5 to 8, 2.6 to 7.9, 4.2 to 6.7, 3.1 to 8.5, 3.2 to 8.5, 4.5,
4.6, 5, 5.1, 2.5, 2.6, 4.2, 3.1, 9, 8.5, 5.1, 8, 7.9, or 6.7 to on
an emitted dose normalized basis.
93. The method of claim 71, wherein, on the basis of the
non-normalized dose of corticosteroid, the AUC.sub.inf provided by
the corticosteroid formulation is 1.6 to 2.5, 1.6 to 3.1, 1.5 to
3.5, 1.5 to 3.3, 2.5 to 3.3, 3.1, 1.5, 3.3, 1.6, or 2.5 fold higher
than the AUC.sub.inf provided by the suspension-based formulation
when the dose of corticosteroid in the formulation and the
suspension is approximately the same.
94. The method of claim 71, wherein, on the basis of normalization
to the nominal available dose of corticosteroid, the AUC.sub.inf
provided by the corticosteroid formulation is 1.75 to 6.5, 1.75 to
6.1, 2 to 6.5, 2 to 6.1, 2 to 4.5, 2 to 4.4, 3.3, 3.2, 3.5, 3.4,
1.75, 6.5, 6.1, 2, 4.5, or 4.4 fold higher than the AUC.sub.inf
provided by the suspension-based formulation.
95. The method of claim 71, wherein, on the basis of normalization
to the dose of corticosteroid to lung, the AUC.sub.inf provided by
the corticosteroid formulation is 1.2 to 3.5, 1.2 to 4, 1.2 to 3,
1.2 to 2.85, 1.5 to 3.5, 1.4 to 3.5, 2, 2.2, 2.3, 2.4, 1.2, 3, 4,
2.85, 1.5, 3.5, or 1.4 fold higher than the AUC.sub.inf provided by
the suspension-based formulation.
96. The method of claim 71, wherein, on the basis of normalization
to the dose of corticosteroid to subject, the AUC.sub.inf provided
by the corticosteroid formulation is 1.6 to 4.9, 1.5 to 5, 1.6 to
5, 1.6 to 3.7, 1.6 to 3.6, 2 to 4.9, 1.9 to 4, 2.6, 1.5, 5, 1.6,
3.7, 3.6, 2, 4.9, 1.9, or 4 fold higher than the AUC.sub.inf
provided by the suspension-based formulation.
97. The method of claim 71, wherein, on the basis of normalization
to the emitted dose of corticosteroid, the AUC.sub.inf provided by
the corticosteroid formulation is 1.5 to 6, 1.7 to 6, 1.9 to 6, 1.9
to 5.4, 2.3 to 5.8, 1.9 to 5.5, 1.9 to 5.8, 1.5, 6, 1.7, 1.9, 5.4,
2.3, 5.8, 5.8, 3.2, 3.5, or 3.6 fold higher than the AUC.sub.inf
provided by the suspension-based formulation.
98. The method of claim 71, wherein the AUC.sub.inf provided by the
corticosteroid formulation is at least 1.5, 1.6, 2, 2.5, 3 and 3.1
fold higher than the AUC.sub.inf provided by the suspension-based
formulation when the dose of corticosteroid in the formulation is
about 2 fold lower than the dose in the suspension.
99. The method of claim 71, wherein the method provides in the
subject an AUC.sub.0-8 hr (pg*h/ml) of 2000 to 3000, 2500 to 2700,
2000, 3000, or 2600 on a dose non-normalized basis for the
corticosteroid.
100. The method of claim 71, wherein the method provides in the
subject a dose normalized AUC.sub.inf (pg/ml/.mu.g) of: 1) 2 to 3,
2.5 to 2.7, or 2.6 on a loaded dose nominal normalized basis;
and/or 2) 3 to 4, 3.4 to 3.5, or 3.4 on an emitted dose normalized
basis.
101. A system comprising: a nebulizer equipped with a reservoir;
and an aqueous liquid formulation comprising an aqueous liquid
carrier, solubility enhancer, and a dose of corticosteroid,
wherein, during nebulization of the formulation, the nebulizer
provides a percentage decrease in the rate of increasing
concentration of corticosteroid in the formulation in the reservoir
as compared to the rate of increasing concentration of a
suspension-based formulation nebulized with the nebulizer under
similar conditions.
102. The system of claim 101, wherein the percentage decrease in
the rate of increasing concentration is 10% to 60%, 15% to 60%, 20%
to 60%, 30% to 60%, or 40% to 60%.
103. The system of claim 101, wherein the system provide a rate of
increasing concentration of 0 to 40, 1 to 40, 5 to 30, or 10 to 30
mcg of corticosteroid/mL of formulation volume per min of
nebulization.
104. A method of treating a disease or disorder of the airways, in
a subject in need thereof, comprising administering via inhalation
to the subject a liquid formulation comprising an aqueous liquid
carrier, a sulfoalkyl ether cyclodextrin, and a dose of
corticosteroid dissolved therein, wherein the dose of
corticosteroid is present in an amount sufficient to provide a mean
plasma AUC.sub.t of 160-1600 pg*h/ml, and wherein the molar ratio
of SAE-CD to corticosteroid is greater than 10:1.
105. A method of providing a corticosteroid to a subject, the
method comprising: administering to the subject, via nebulization,
25-400 .mu.g of a corticosteroid dissolved in an aqueous liquid
carrier comprising sulfoalkyl ether cyclodextrin to provide a
plasma AUC.sub.t of 150-1600 pg*h/ml for the corticosteroid.
106. A method of providing in a subject a plasma AUC.sub.t,
normalized for dose of corticosteroid, of at least 6
(pg*h/ml)/.mu.g of corticosteroid, comprising: administering to the
subject, via nebulization, a dose of at least 25 .mu.g of
corticosteroid dissolved in an aqueous liquid carrier comprising
sulfoalkyl ether cyclodextrin.
107. A method of providing in a subject an AUC.sub.i, normalized
for dose of corticosteroid, of at least 8 (pg*h/ml)/.mu.g of
corticosteroid, comprising: administering to the subject, via
nebulization, a dose of at least 25 .mu.g of corticosteroid
dissolved in an aqueous liquid carrier comprising sulfoalkyl ether
cyclodextrin.
108. The invention according to any one of claims 71, 72, 101, 104,
105, 106, or 107, wherein the corticosteroid is budesonide.
109. The invention according to any one of claims 71, 72, 101, 104,
105, 106, or 107, wherein the corticosteroid has a lipophilicity
approximating or exceeding that of flunisolide.
110. The invention according to claim 109, wherein the
corticosteroid is selected from the group consisting of
beclomethasone dipropionate, beclomethasone monopropionate,
budesonide, ciclesonide, desisobutyryl-ciclesonide, flunisolide,
fluticasone propionate, fluticasone furoate, mometasone furoate,
icomethasone enbutate, tixocortol 21-pivalate, and triamcinolone
acetonide.
111. The invention according to any one of claims 71, 72, 101, 104,
105, 106, or 107, wherein the step of administering or delivering
is conducted with a nebulizer selected from the group consisting of
an air jet nebulizer, ultrasonic nebulizer, electronic nebulizer,
vibrating membrane nebulizer, vibrating mesh nebulizer, vibrating
plate nebulizer, a nebulizer comprising a vibration generator and
an aqueous chamber, and a nebulizer comprising a nozzle array.
Description
CROSS-REFERENCE TO EARLIER FILED APPLICATIONS
[0001] The present application is a continuation-in-part of and
claims the priority of U.S. application Ser. No. 11/479,979 filed
Jun. 30, 2006, which is a continuation-in-part of PCT International
Application No. PCT/US05/00082 filed Dec. 31, 2004, which claims
benefit of the filing date of provisional application No.
60/533,628 filed Dec. 31, 2003, the disclosures of which are hereby
incorporated by reference in their entirety.
FIELD OF THE INVENTION
[0002] The present invention relates to methods of and systems for
administering formulations of sulfoalkyl ether cyclodextrin and
corticosteroid, such as budesonide, by nebulization and inhalation.
The invention also relates to methods of treating respiratory
diseases or disorders of the air passageways.
BACKGROUND OF THE INVENTION
[0003] The delivery of a drug by inhalation allows deposition of
the drug in different sections of the respiratory tract, e.g.,
throat, trachea, bronchi and alveoli. Generally, the smaller the
particle size, the longer the particle will remain suspended in air
and the farther down the respiratory tract the drug can be
delivered. Corticosteroids are delivered by inhalation using
nebulizers, metered dose inhalers, or dry powder inhalers. The
principle advantages of nebulizers over other methods of pulmonary
installation are that patient cooperation is not required and the
delivery of higher doses of medication is easier. The main concerns
about nebulizers, however, are their increased cost, reduced
portability and the inconvenience of needing to prepare medication
beforehand and the increased time requirement for administering a
treatment. A method of improving the administration of drugs, such
as corticosteroids by nebulization would be desired.
[0004] Budesonide
((R,S)-11.beta.,16.alpha.,17,21-tetrahydroxypregna-1,4-diene-3,20-dione
cyclic 16,17-acetal with butyraldehyde; C.sub.25H.sub.34O.sub.6;
Mw: 430.5) is well known. It is provided commercially as a mixture
of two isomers (22R and 22S). Budesonide is an anti-inflammatory
corticosteroid that exhibits potent glucocorticoid activity.
Administration of budesonide is indicated for maintenance treatment
of asthma and as prophylactic therapy in children.
[0005] Commercial formulations of budesonide are sold by
AstraZeneca LP (Wilmington, Del.) under the trademarks ENTOCORT.TM.
EC, PULMICORT RESPULES.RTM., Rhinocort Aqua.RTM., Rhinocort.RTM.
Nasal Inhaler and Pulmicort Turbuhaler.RTM., and under its generic
name. PULMICORT RESPULES.RTM. suspension, which is a sterile
aqueous suspension of micronized budesonide, is administered by
inhalation using a nebulizer, in particular a compressed air driven
jet nebulizer that delivers from 2 to 18% of the drug mass
contained in the nominal charge. The general formulation for a unit
dose of the PULMICORT RESPULES is set forth in U.S. Pat. No.
6,598,603, and it is an aqueous suspension in which budesonide is
suspended in an aqueous medium comprising about 0.05 to 1.0 mg of
budesonide, 0.05 to 0.15 mg of NaEDTA, 8.0 to 9.0 mg of NaCl, 0.15
to 0.25 mg of polysorbate, 0.25 to 0.30 mg of anhydrous citric
acid, and 0.45 to 0.55 mg of sodium citrate per one ml of water.
RHINOCORT.RTM. NASAL INHALER.TM. is a metered-dose pressurized
aerosol unit containing a suspension of micronized budesonide in a
mixture of propellants. RHINOCORT.RTM. AQUA.TM. is an unscented
metered-dose manual-pump spray formulation containing a suspension
of micronized budesonide in an aqueous medium. The suspensions
should not be administered with an ultrasonic nebulizer.
[0006] A wide variety of nebulizers differing in mode of operation
are available, e.g. jet nebulizers (optionally sold with
compressors), ultrasonic nebulizers, vibrating membrane, vibrating
mesh nebulizers, vibrating plate nebulizers, vibrating cone
nebulizers, and others. The vibrating mesh, vibrating cone or
vibrating plate nebulizers are of particular interest since they do
not require the use of an air compressor for delivery, have a
minimal residual volume in the reservoir after delivery of a unit
dose, and can be used to deliver low volumes of inhalable
solutions. Exemplary vibrating membrane, mesh or plate nebulizers
are described by R. Dhand (Respiratory Care, (December 2002),
47(12), p. 1406-1418). Keller et al. (ATS 99.sup.th International
Conference, Seattle, May 16-21, 2003; poster 2727) disclose the
results of a study on the administration of AZTREONAM with a PARI
eFlow nebulizer and report low oropharyngeal deposition,
nebulization efficiency unaffected by fill volume, a respirable
fraction of 82.+-.1.7%, constant dose administration per inhalation
cycle time, and an excellent correlation between delivered dose,
fill volume and nebulization time, and expected high lung
deposition.
[0007] The desired properties of a liquid for nebulization
generally include: 1) reduced viscosity; 2) sterile medium; 3)
reduced surface tension; 4) stability toward the mechanism of the
nebulizer; 5) moderate pH of about 4-10; 6) ability to form
droplets with an MMAD of <5 .mu.m or preferably <3 .mu.m; 7)
absence of irritating preservatives and stabilizing agents; 8)
suitable tonicity. On the one hand, suspensions possess some
advantages but on the other hand solutions possess other
advantages.
[0008] Smaldone et al. (J. Aerosol Med. (1998), 11, 113-125)
disclose the results of a study on the in vitro determination of
inhaled mass and particle distribution of a budesonide suspension.
They conclude that 2%-18% of the nebulizer's charge of budesonide
was delivered from the suspension, meaning that budesonide delivery
was incomplete resulting in a significant waste of drug. In the
thirteen most efficient systems, the suspension can be nebulized
sufficiently well for lower respiratory tract delivery.
[0009] Another study further demonstrated the highly variable
efficiency of nebulization from one nebulizer to another. Barry et
al. (J. Allergy Clin. Immunol. (1998), 320-321) state that this
variability should be taken into account when treating patients
with nebulized budesonide. Berg et al. (J. Aerosol Sci. (1998),
19(7), 1101-1104) also report the highly variable efficiency of
nebulization of PULMICORT.TM. suspension from one nebulizer to the
next. Moreover, the mass mean aerodynamic diameter (MMAD) of the
nebulized droplets is highly variable from one nebulizer to the
next. In general, suspensions are less efficiently nebulized than
solutions, O'Riordan (Respiratory Care, (2002), 1305-1313). Inhaled
corticosteroids are utilized in the treatment of asthma and are of
significant benefit because they are delivered directly to the site
of action, the lung. The goal of an inhaled corticosteroid is to
provide localized therapy with immediate drug activity in the
lungs. Inhaled corticosteroids are well absorbed from the lungs. In
fact, it can be assumed that all of the drug available at the
receptor site in the lungs will be absorbed systemically. However,
it is well known that using current methods and formulations the
greater part of an inhaled corticosteroid dose is swallowed and
becomes available for oral absorption, resulting in unwanted
systemic effects. For inhaled corticosteroids, high pulmonary
availability is more important than high oral bioavailability
because the lung is the target organ. A product with high pulmonary
availability has greater potential to exert positive effects in the
lung. The ideal inhaled corticosteroid formulation would provide
minimum oral delivery thereby reducing the likelihood of systemic
adverse effects.
[0010] The majority of the corticosteroid dose delivered to the
lung is absorbed and available systemically. For the portion of the
inhaled corticosteroid dose delivered orally, bioavailability
depends upon absorption from the GI tract and the extent of first
pass metabolism in the liver. Since this oral component of
corticosteroid drug delivery does not provide any beneficial
therapeutic effect but can increase systemic side effects, it is
desirable for the oral bioavailability of inhaled corticosteroid to
be relatively low.
[0011] Both particle size and formulation influence the efficacy of
an inhaled corticosteroid. The formulation of a drug has a
significant impact on the delivery of that drug to the lungs, and
therefore its efficacy. Most important in the delivery of drug to
the lung are the aerosol vehicle and the size of the particles
delivered. Additionally, a reduced degree of pulmonary deposition
suggests a greater degree of oropharyngeal deposition. Due to a
particular formulation employed, some corticosteroids are more
likely to be deposited in the mouth and throat and may cause local
adverse effects.
[0012] While receptor distribution is the major determinant of
bronchodilator efficacy, particle size appears to be more important
in determining the efficacy of an inhaled corticodsteroid. The
smallest airways have an internal diameter of 2 micrometers (mcm)
or less. Thus, an inhaler with particles having a mean aerodynamic
diameter of 1 mcm should have a greater respirable fraction than an
inhaler with particles that have an average diameter of 3.5 to 4
mcm. For patients with obstructive lung disease, all particles
should ideally be no greater than 2 to 3 mcm. A particle that is
small (less than 5 mcm) is more likely to be inhaled into the
smaller airways of the lungs, thus improving efficacy. In contrast,
particles that are larger than 5 mcm can be deposited in the mouth
and throat, both reducing the proportion of particles that reach
the lungs and potentially causing local adverse effects such as
oral candidiasis and hoarseness (dysphonia). Particles having a
mass median aerodynamic diameter (MMAD) of close to 1 mcm are
considered to have a greater respirable fraction per dose than
those with a diameter of 3.5 mcm or greater.
[0013] A further disadvantage to the nebulization of budesonide
suspensions is the need to generate very small droplets, MMAD of
about <3 .mu.m. Since the nebulized droplets are so small, then
the micronized budesonide must be even smaller or in the range of
0.5-2.0 .mu.m and the particles should have a narrow particle size
distribution. Generation of such particles is difficult.
[0014] Even so, efforts have been made to improve the nebulization
of budesonide suspensions with ultrasonic nebulizers by using
submicron-sized particles (Keller et al. in Respiratory Drug
Delivery VIII (2002), 197-206). A suspension of nanoparticles
(0.1-1.0 .mu.m) of the corticosteroid might be used to increase the
proportion of respirable particles as compared to a coarser
suspension as in the PULMICORT.TM. suspension. No improvement over
PULMICORT.TM. suspension (about 4.4 .mu.m budesonide particle size
in suspension) was observed. Moreover, concerns exist regarding the
use of nanosuspensions in that the small particles (<0.05 .mu.m)
may induce an allergic response in a subject. Sheffield
Pharmaceuticals, Inc. (St. Louis, Mo.; "The Pharmacokinetics of
Nebulized Nanocrystal Budesonide Suspension in Healthy Volunteers",
Kraft, et al. in J. Clin. Pharmacol., (2004), 44:67-72) has
disclosed the preparation and evaluation of UDB (unit dose
budesonide), which is a suspension-based formulation containing
nanoparticles of budesonide dispersed in a liquid medium. This
product is being developed by MAP Pharmaceuticals, Inc. (Mountain
View, Calif.). Seeman et al. (ATS 99.sup.th International
Conference, Seattle, May 16-21, 2003; poster 2727) disclose the
results of a study evaluating the performance of the PARI eFlow
nebulizer with a budesonide suspension (PULMICORT RESPULES, 500
.mu.g/ml, in a 2 ml ampoule) and report achieving a MMAD of 3.6-4.2
.mu.m and a respirable fraction of greater than 67%.
[0015] The inhalation of drug particles as opposed to dissolved
drug is known to be disadvantageous. Brain et al. (Bronchial
Asthma, 2.sup.nd Ed. (Ed. E. B. Weis et al., Little Brown & Co.
(1985), pp. 594-603) report that less soluble particles that
deposit on the mucous blanket covering pulmonary airways and the
nasal passages are moved toward the pharynx by the cilia. Such
particles would include the larger drug particles deposited in the
upper respiratory tract. Mucus, cells and debris coming from the
nasal cavities and the lungs meet at the pharynx, mix with saliva,
and enter the gastrointestinal tract upon being swallowed.
Reportedly, by this mechanism, particles are removed from the lungs
with half-times of minutes to hours. Accordingly, there is little
time for solubilization of slowly dissolving drugs, such as
budesonide. In contrast, particles deposited in the nonciliated
compartments, such as the alveoli, have much longer residence
times. Since it is difficult to generate very small particles of
budesonide for deep lung deposition, much of the inhaled suspension
would likely be found in the upper to middle respiratory tract.
However, it is much easier to generate small droplets from a
solution than it is from a suspension of solids. For these reasons,
nebulization of a budesonide-containing solution should be
preferred over that of a suspension.
[0016] O'Riordan (Respiratory Care (November 2002), 47(11),
1305-1313) states that drugs can be delivered by nebulization of
either solutions or suspensions, but that in general, nebulization
of a solution is preferred over that of a suspension. He states
that ultrasonic nebulizers should not be used on suspensions and
should be used only on solutions.
[0017] O'Callaghan (Thorax, (1990), 45, 109-111), Storr et al.
(Arch. Dis. Child (1986), 61, 270-273), and Webb et al. (Arch. Dis.
Child (1986), 61, 1108-1110) suggest that nebulization of
corticosteroid (in particular beclomethasone) solutions may be
preferred over that of suspensions because the latter may be
inefficient if the nebulized particles are too large to enter the
lung in therapeutically effective amounts. However, data presented
by O'Callaghan (J. Pharm. Pharmacol. (2002), 54, 565-569) on the
nebulization of flunisolide solution versus suspension showed that
the two performed similarly. Therefore, it cannot be generalized
that nebulization of a solution is preferred over that of a
suspension.
[0018] Accordingly, there is a widely recognized need for a
non-suspension formulation comprising a corticosteroid for
administration via nebulization. However, the PULMICORT.RTM.
suspension unit dose formulation is widely available and accepted
in the field of inhalation therapy. It would be of great benefit to
this field of therapy to provide a method of improving the
administration of the PULMICORT.RTM. suspension unit dose
formulation, or more generally, of a suspension unit dose
formulation containing a corticosteroid.
[0019] However, the current focus in nebulizer therapy is to
administer higher concentrations of drug, use solution, preferably
predominantly aqueous-based solutions in preference to non-aqueous
or alcoholic or non-aqueous alcoholic solutions or suspensions if
possible, minimize treatment time, synchronize nebulization with
inhalation, and administer smaller droplets for deeper lung
deposition of drug.
[0020] Corticosteroid-containing solutions for nebulization are
known. There are a number of different ways to prepare solutions
for nebulization. These generally have been prepared by the
addition of a cosolvent, surfactant, or buffer. However,
cosolvents, such as ethanol, polyethylene glycol and propylene
glycol are only tolerated in low amounts when administered by
inhalation due to irritation of the respiratory tract. There are
limits to acceptable levels of these cosolvents in inhaled
products. Typically, the cosolvents make up less than about 35% by
weight of the nebulized composition, although it is the total dose
of cosolvent as well as its concentration that determines these
limits. The limits are set by the propensity of these solvents
either to cause local irritation of lung tissue, to form
hyperosmotic solutions that would draw fluid into the lungs, and/or
to intoxicate the patient. In addition, most potential hydrophobic
therapeutic agents are not sufficiently soluble in these cosolvent
mixtures.
[0021] Saidi et al. (U.S. Pat. No. 6,241,969) disclose the
preparation of corticosteroid-containing solutions for nasal and
pulmonary delivery. The dissolved corticosteroids are present in a
concentrated, essentially non-aqueous form for storage or in a
diluted, aqueous-based form for administration.
[0022] Keller et al. (in Respiratory Drug Delivery IX (2004)
221-231) disclose the deposition of solution formulations
containing budesonide and surfactants to children.
[0023] Lintz et al. (AAPS Annual Meeting and Exposition, Baltimore,
Nov. 8, 2004; Poster M1128) disclose the preparation and aerosol
characterization of liquid formulations containing budesonide,
water, citrate salt, sodium chloride and alcohol, propylene glycol
and/or surfactant, such as Tween, Pluronic, or phospholipids with
HLB-values between 10 and 20. The aerosol characterization of such
a combination surfactant solution in a vibrating membrane/mesh
nebulizer (the Pari eFlow) compared to a suspension was studied
using adult and child breath simulation. They reported a respirable
fraction of 83.3% for the PARI eFlow with the solution and 61% for
the PULMICORT RESPULES with the PARI LC+. They also reported the
results regarding the respirable drug delivery rate (% drug<5
.mu.m/min), delivered dose (% of drug charged to device), drug
delivery rate (% drug/min), and respirable dose (%<5 .mu.m).
[0024] Schueepp et al. (ATS 99.sup.th International Conference,
Seattle, May 16-21, 2003; poster 1607) disclose assessment of the
aerosol performance of a customized eFlow Baby Functional Model
with an experimental budesonide solution (100 .mu.g in 0.5 ml)
utilizing a baby cast model and applying different breathing
patterns.
[0025] An alternative approach to administration of the
PULMICORT.TM. suspension is administration of a liposome
formulation. Waldrep et al. (J. Aerosol Med. (1994), 7(2), 135-145)
reportedly succeeded in preparing a liposome formulation of
budesonide and phosphatidylcholine derivatives.
[0026] None of the above-identified formulations has provided a
method of improving the administration of a suspension-based unit
dose formulation containing a corticosteroid. Instead, the general
focus of the art has been to completely circumvent formulating a
suspension by first preparing a liquid formulation that is then
divided into multiple unit doses that are packaged for marketing
and then sold for use.
[0027] Solubilization of drugs by cyclodextrins and their
derivatives is well known. Cyclodextrins are cyclic carbohydrates
derived from starch. The unmodified cyclodextrins differ by the
number of glucopyranose units joined together in the cylindrical
structure. The parent cyclodextrins contain 6, 7, or 8
glucopyranose units and are referred to as .alpha.-, .beta.-, and
.gamma.-cyclodextrin respectively. Each cyclodextrin subunit has
secondary hydroxyl groups at the 2 and 3 positions and a primary
hydroxyl group at the 6-position. The cyclodextrins may be pictured
as hollow truncated cones with hydrophilic exterior surfaces and
hydrophobic interior cavities. In aqueous solutions, these
hydrophobic cavities provide a haven for hydrophobic organic
compounds that can fit all or part of their structure into these
cavities. This process, known as inclusion complexation, may result
in increased apparent aqueous solubility and stability for the
complexed drug. The complex is stabilized by hydrophobic
interactions and does not involve the formation of any covalent
bonds.
[0028] This dynamic and reversible equilibrium process can be
described by Equations 1 and 2, where the amount in the complexed
form is a function of the concentrations of the drug and
cyclodextrin, and the equilibrium or binding constant, K.sub.b.
When cyclodextrin formulations are administered by injection into
the blood stream, the complex rapidly dissociates due to the
effects of dilution and non-specific binding of the drug to blood
and tissue components. Drug + Cyclodextrin .times. K b .times.
Complex Equation .times. .times. 1 K b = Complex Drug .times.
Cyclodextrin Equation .times. .times. 2 ##EQU1##
[0029] Binding constants of cyclodextrin and an active agent can be
determined by the equilibrium solubility technique (T. Higuchi et
al. in "Advances in Analytical Chemistry and Instrumentation Vol.
4"; C. N. Reilly ed.; John Wiley & Sons, Inc, 1965, pp.
117-212). Generally, the higher the concentration of cyclodextrin,
the more the equilibrium process of Equations 1 and 2 is shifted to
the formation of more complex, meaning that the concentration of
free drug is generally decreased by increasing the concentration of
cyclodextrin in solution.
[0030] The underivatized parent cyclodextrins are known to interact
with human tissues and extract cholesterol and other membrane
components, particularly upon accumulation in the kidney tubule
cells, leading to toxic and sometimes fatal renal effects.
[0031] The parent cyclodextrins often exhibit a differing affinity
for any given substrate. For example, .gamma.-cyclodextrin often
forms complexes with limited solubility, resulting in solubility
curves of the type Bs. This behavior is known for a large number of
steroids which imposes serious limitations towards the use of
.gamma.-CD in liquid preparations. .beta.-CD, however, does not
complex well with a host of different classes of compounds. It has
been shown for .beta.-CD and .gamma.-CD that derivatization, e.g.
alkylation, results in not only better aqueous solubility of the
derivatives compared to the parent CD, but also changes the type of
solubility curves from the limiting Bs-type to the more linear
A-type curve (Bernd W. Muller and Ulrich Brauns, "Change of
Phase-Solubility Behavior by Gamma-Cyclodextrin Derivatization",
Pharmaceutical Research (1985) p 309-310).
[0032] Chemical modification of the parent cyclodextrins (usually
at the hydroxyls) has resulted in derivatives with improved safety
while retaining or improving the complexation ability. Of the
numerous derivatized cyclodextrins prepared to date, only two
appear to be commercially viable: the 2-hydroxypropyl derivatives
(HP-CD; neutral ##STR1##
Sulfobutyl Ether-.beta.-Cyclodextrin (Captisol.RTM.)
[0033] cyclodextrins being commercially developed by Janssen and
others), and the sulfoalkyl ether derivatives, such as sulfobutyl
ether, (SBE-CD; anionic cyclodextrins being developed by CyDex,
Inc.) However, the HP-.beta.-CD still possesses toxicity that the
SBE-CD does not.
[0034] U.S. Pat. No. 5,376,645 and No. 5,134,127 to Stella et al.,
U.S. Pat. No. 3,426,011 to Parmerter et al., Lammers et al. (Recl.
Trav. Chim. Pays-Bas (1972), 91(6), 733-742); Staerke (1971),
23(5), 167-171) and Qu et al. (J. Inclusion Phenom. Macro. Chem.,
(2002), 43, 213-221) disclose sulfoalkyl ether derivatized
cyclodextrins. The references suggest that SAE-CD should be
suitable for solubilizing a range of different compounds. However,
Stella discloses that the molar ratio of sulfoalkyl ether
derivatized cyclodextrin to active ingredient suitable for
solubilization of the active ingredient, even a corticosteroid, in
water ranges from 10:1 to 1:10.
[0035] A sulfobutyl ether derivative of beta cyclodextrin
(SBE-.beta.-CD), in particular the derivative with an average of
about 7 substituents per cyclodextrin molecule (SBE7-.beta.-CD),
has been commercialized by CyDex, Inc. as CAPTISOL.RTM.. The
anionic sulfobutyl ether substituent dramatically improves the
aqueous solubility of the parent cyclodextrin. In addition, the
presence of the charges decreases the ability of the molecule to
complex with cholesterol as compared to the hydroxypropyl
derivative. Reversible, non-covalent, complexation of drugs with
CAPTISOL.RTM. cyclodextrin generally allows for increased
solubility and stability of drugs in aqueous solutions. While
CAPTISOL.RTM. is a relatively new but known cyclodextrin, its use
in the preparation of corticosteroid-containing solutions for
nebulization has not previously been evaluated.
[0036] Hemolytic assays are generally used in the field of
parenteral formulations to predict whether or not a particular
formulation is likely to be unsuitable for injection into the
bloodstream of a subject. If the formulation being tested induces a
significant amount of hemolysis, that formulation will generally be
considered unsuitable for administration to a subject. It is
generally expected that a higher osmolality is associated with a
higher hemolytic potential. As depicted in FIG. 1 (Thompson, D. O.,
Critical Reviews in Therapeutic Drug Carrier Systems, (1997),
14(1), 1-104), the hemolytic behavior of the CAPTISOL.RTM. is
compared to the same for the parent .beta.-cyclodextrin, the
commercially available hydroxypropyl derivatives, ENCAPSIN.TM.
cyclodextrin (degree of substitution.about.3-4) and MOLECUSOL.RTM.
cyclodextrin (degree of substitution.about.7-8), and two other
sulfobutyl ether derivatives, SBEL-.beta.-CD and SBE4-.beta.-CD.
Unlike the other cyclodextrin derivatives, sulfoalkyl ether
(SAE-CD) derivatives, in particular those such as the CAPTISOL.RTM.
(degree of substitution.about.7) and SBE4-.beta.-CD (degree of
substitution.about.4), show essentially no hemolytic behavior and
exhibit substantially lower membrane damaging potential than the
commercially available hydroxypropyl derivatives at concentrations
typically used to solubilize pharmaceutical formulations. The range
of concentrations depicted in the figure includes the
concentrations typically used to solubilize pharmaceutical
formulations when initially diluted in the blood stream after
injection. After oral administration, SAE-CD does not undergo
significant systemic absorption.
[0037] The osmolality of a formulation is generally associated with
its hemolytic potential: the higher the osmolality (or the more
hypertonic), the greater the hemolytic potential. Zannou et al.
("Osmotic properties of sulfobutyl ether and hydroxypropyl
cyclodextrins", Pharma. Res. (2001), 18(8), 1226-1231) compared the
osmolality of solutions containing SBE-CD and HP-CD. As depicted in
FIG. 2, the SBE-CD containing solutions have a greater osmolality
than HP-CD containing solutions comprising similar concentrations
of cyclodextrin derivative. Thus, it is surprising that SAE-CD
exhibits lower hemolysis than does HP-CD at equivalent
concentrations, even though HP-CD has a lower osmolality.
[0038] Methylated cyclodextrins have been prepared and their
hemolytic effect on human erythrocytes has been evaluated. These
cyclodextrins were found to cause moderate to severe hemolysis
(Jodal et al., Proc. 4.sup.th Int. Symp. Cyclodextrins, (1988),
421-425; Yoshida et al., Int. J. Pharm., (1988), 46(3),
217-222).
[0039] Administration of cyclodextrins into the lungs of a mammal
may not be acceptable. In fact, literature exists on the potential
or observed toxicity of native cyclodextrins and cyclodextrin
derivatives. The NTP Chemical Repository indicates that
.alpha.-cyclodextrin may be harmful by inhalation. Nimbalkar et al.
(Biotechnol. Appl. Biochem. (2001), 33, 123-125) cautions on the
pulmonary use of an HP-.beta.-CD/diacetyldapsone complex due to its
initial effect of delaying cell growth of lung cells.
[0040] Even so, a number of studies regarding the use of
cyclodextrins for inhalation have been reported although none have
been commercialized. The studies suggest that different
drug-cyclodextrin combinations will be required for specific
optimal or even useful inhaled or intra-nasal formulations.
Attempts have been made to develop cyclodextrin-containing powders
and solutions for buccal, pulmonary and/or nasal delivery.
[0041] U.S. Pat. No. 5,914,122 to Otterbeck et al. discloses the
preparation of stable budesonide-containing solutions for rectal
administration as a foam. They demonstrate the use of cyclodextrin,
such as .beta.-CD, .gamma.-CD or HP-.beta.-CD, and/or EDTA as a
stabilizer. Cyclodextrin is also suggested as a solubilizer for
increasing the concentration of budesonide in solution. In each
case, the greatest shelf-life they report for any of their
formulations is, in terms of acceptable retention of the active
ingredient, only three to six months.
[0042] U.S. Pregrant Patent Publication No. 20020055496 to McCoy et
al. discloses essentially non-aqueous intra-oral formulations
containing HP-.beta.-CD. The formulations may be administered with
an aerosol, spray pump or propellant.
[0043] Russian Patent No. 2180217 to Chuchalin discloses a stable
budesonide-containing solution for inhalation. The solution
comprises budesonide, propylene glycol, poly(ethylene oxide),
succinic acid, Trilon B, nipazole, thiourea, water, and optionally
HP-.beta.-CD.
[0044] Muller et al. (Proceed. Int'l. Symp. Control. Rel. Bioact.
Mater. (1997), 24, 69-70) discloses the results of a study on the
preparation of budesonide microparticles by an ASES (Aerosol
Solvent Extraction System) supercritical carbon dioxide process for
use in a dry powder inhaler. HP-.beta.-CD is suggested as a carrier
for a powder.
[0045] Muller et al. (U.S. Pat. No. 6,407,079) discloses
pharmaceutical compositions containing HP-.beta.-CD. They suggest
that nasal administration of a solution containing the cyclodextrin
is possible.
[0046] The art recognizes that it may be necessary to evaluate
structurally related variations of a particular type of
cyclodextrin derivative in order to optimize the binding of a
particular compound with that type of cyclodextrin derivative.
However, it is often the case that there are not extreme
differences in the binding of a particular compound with a first
embodiment versus a second embodiment of a particular cyclodextrin
derivative. For example, cases where there are extreme differences
in the binding of a particular therapeutic agent for a first
cyclodextrin derivative versus a structurally related second
cyclodextrin derivative are uncommon. When such situations do
exist, they are unexpected. Worth et al. (24.sup.th International
Symposium on Controlled Release of Bioactive Materials (1997))
disclose the results of a study evaluating the utility of
steroid/cyclodextrin complexes for pulmonary delivery. In
side-by-side comparisons, .beta.-CD, SBE7-.beta.-CD, and
HP-.beta.-CD were evaluated according to their ability to form
inclusion complexes with beclomethasone dipropionate (BDP) and its
active metabolite beclomethasone monopropionate (BMP). BMP was more
easily solubilized with a cyclodextrin, and the observed order of
solubilizing power was: HP-.beta.-CD
(highest)>.beta.-CD>SBE7-.beta.-CD. Thus, the artisan would
expect that SAE-CD derivatives would not be as suitable for use in
solubilizing corticosteroids such as BMP or BDP. Although no
results regarding actual utility in an inhaled formulation were
disclosed, they suggest that BMP rather than BDP would be a better
alternative for development of a nebulizer solution.
[0047] Kinnarinen et al. (11.sup.th International Cyclodextrin
Symposium CD, (2002)) disclose the results of a study of the in
vitro pulmonary deposition of a budesonide/.gamma.-CD inclusion
complex for dry powder inhalation. No advantage was observed by
complexation with .gamma.-CD. Vozone et al. (11.sup.th
International Cyclodextrin Symposium CD, (2002)) disclose the
results of a study on the complexation of budesonide with
.gamma.-cyclodextrin for use in dry powder inhalation. No
difference was observed within emitted doses of the cyclodextrin
complex or a physical mixture of budesonide and the CD. But, a
difference observed in the fine particle fraction of both
formulations suggested that use of a cyclodextrin complex for
pulmonary drug delivery might increase the respirable fraction of
the dry powder.
[0048] Pinto et al. (S.T.P. Pharma. Sciences (1999), 9(3), 253-256)
disclose the results of a study on the use of HP-.beta.-CD in an
inhalable dry powder formulation for beclomethasone. The
HP-.beta.-CD was evaluated as a complex or physical mixture with
the drug in a study of in vitro deposition of the emitted dose from
a MICRO-HALER.TM. inhalation device. The amount of respirable drug
fraction was reportedly highest with the complex and lowest with
the micronized drug alone.
[0049] Rajewski et al. (J. Pharm. Sci. (1996), 85(11), 1142-1169)
provide a review of the pharmaceutical applications of
cyclodextrins. In that review, they cite studies evaluating the use
of cyclodextrin complexes in dry powder inhalation systems.
[0050] Shao et al (Eur. J. Pharm. Biopharm. (1994), 40, 283-288)
reported on the effectiveness of cyclodextrins as pulmonary
absorption promoters. The relative effectiveness of cyclodextrins
in enhancing pulmonary insulin absorption, as measured by
pharmacodynamics, and relative efficiency was ranked as follows:
dimethyl-.beta.-cyclodextrin>.alpha.-cyclodextrin>.beta.-cyclodextr-
in>.gamma.-cyclodextrin>hydroxypropyl-.beta.-cyclodextrin. In
view of this report, the artisan would expect the water soluble
derivative of .gamma.-CD to be less suitable for delivering
compounds via inhalation than the respective derivative of
.beta.-CD because the underivatized .beta.-CD is more suitable than
the underivatized .gamma.-CD.
[0051] Williams et al. (Eur. J. Pharm. Biopharm. (March 1999),
47(2), 145-52) reported the results of a study to determine the
influence of the formulation technique for
2-hydroxypropyl-beta-cyclodextrin (HP-.beta.-CD) on the stability
of aspirin in a suspension-based pressurized metered-dose inhaler
(pMDI) formulation containing a hydrofluoroalkane (HFA) propellant.
HP-.beta.-CD was formulated in a pMDI as a lyophilized inclusion
complex or a physical mixture with aspirin. Aspirin in the
lyophilized inclusion complex exhibited the most significant degree
of degradation during the 6-months storage, while aspirin alone in
the pMDI demonstrated a moderate degree of degradation. Aspirin
formulated in the physical mixture displayed the least degree of
degradation. Reportedly, HP-.beta.-CD may be used to enhance the
stability of a chemically labile drug, but the drug stability may
be affected by the method of preparation of the formulation.
[0052] Gudmundsdottir et al. (Pharmazie (December 2001), 56(12),
963-6) disclose the results of a study in which midazolam was
formulated in aqueous sulfobutylether-beta-cyclodextrin buffer
solution. The nasal spray was tested in healthy volunteers and
compared to intravenous midazolam in an open crossover trial. The
nasal formulation reportedly approaches the intravenous form in
speed of absorption, serum concentration and clinical sedation
effect. No serious side effects were observed.
[0053] Srichana et al. (Respir. Med. (June 2001), 95(6), 513-9)
report the results of a study to develop a new carrier in dry
powder aerosols. Two types of cyclodextrin were chosen; gamma
cyclodextrin (.gamma.-CD) and dimethyl-beta-cyclodextrin (DMCD) as
carriers in dry powder formulations. Salbutamol was used as a model
drug and a control formulation containing lactose and the drug was
included. A twin-stage impinger (TSI) was used to evaluate in
delivery efficiency of those dry powder formulations. From the
results obtained, it was found that the formulation containing
.gamma.-CD-enhanced drug delivery to the lower stage of the TSI
(deposition=65%) much greater than that of both formulations
containing DMCD (50%) and the control formulation (40%)
(P<0.05). The haemolysis of red blood cells incubated with the
DMCD complex was higher than that obtained in the .gamma.-CD
complex. The drug release in both formulations containing
.gamma.-CD and DMCD was fast (over 70% was released in 5 min) and
nearly all the drug was released within 30 min.
[0054] van der Kuy et al. (Eur. J. Clin. Pharmacol. (November
1999), 55(9), 677-80) report the results of the pharmacokinetic
properties of two intranasal preparations of dihydroergotamine
mesylate (DHEM)-containing formulation using a commercially
available intranasal preparation. The formulations also contained
randomly methylated .beta.-cyclodextrin (RAMEB). No statistically
significant differences were found in maximum plasma concentration
(Cmax), time to reach Cmax (tmax), area under plasma
concentration-time curve (AUC0-8 h), Fre1(t=8 h) and Cmax/AUC(t=8
h) for the three intranasal preparations. The results indicate that
the pharmacokinetic properties of the intranasal preparations are
not significantly different from the commercially available nasal
spray.
[0055] U.S. Pat. Nos. 5,942,251 and 5,756,483 to Merkus cover
pharmaceutical compositions for the intranasal administration of
dihydroergotamine, apomorphine and morphine comprising one of these
pharmacologically active ingredients in combination with a
cyclodextrin and/or a disaccharide and/or a polysaccharide and/or a
sugar alcohol.
[0056] U.S. Pat. No. 5,955,454 discloses a pharmaceutical
preparation suitable for nasal administration containing a
progestogen and a methylated .beta.-cyclodextrin having a degree of
substitution of between 0.5 and 3.0.
[0057] U.S. Pat. No. 5,977,070 to Piazza et al. discloses a
pharmaceutical composition for the nasal delivery of compounds
useful for treating osteoporosis, comprising an effective amount of
a physiologically active truncated analog of PTH or PTHrp, or salt
thereof and an absorption enhancer selected from the group
consisting of dimethyl-.beta.-cyclodextrin.
[0058] U.S. Pat. No. 6,436,902 to Backstrom et al. discloses
compositions and methods for the pulmonary administration of a
parathyroid hormone in the form of a dry powder suitable for
inhalation in which at least 50% of the dry powder consists of (a)
particles having a diameter of up to 10 microns; or (b)
agglomerates of such particles. A dry powder inhaler device
contains a preparation consisting of a dry powder comprising (i) a
parathyroid hormone (PTH), and (ii) a substance that enhances the
absorption of PTH in the lower respiratory tract, wherein at least
50% of (i) and (ii) consists of primary particles having a diameter
of up to 10 microns, and wherein the substance is selected from the
group consisting of a salt of a fatty acid, a bile salt or
derivative thereof, a phospholipid, and a cyclodextrin or
derivative thereof.
[0059] U.S. Pat. No. 6,518,239 to Kuo et al. discloses a
dispersible aerosol formulation comprising an active agent and a
dipeptide or tripeptide for aerosolized administration to the lung.
The compositions reportedly may also include polymeric
excipients/additives, e.g., polyvinylpyrrolidones, derivatized
celluloses such as hydroxymethylcellulose, hydroxyethylcellulose,
and hydroxypropyl methylcellulose, Ficolls (a polymeric sugar),
hydroxyethylstarch, dextrates (e.g., cyclodextrins, such as
2-hydroxypropyl-.beta.-cyclodextrin and
sulfobutylether-.beta.-cyclodextrin), polyethylene glycols, and
pectin.
[0060] Nakate et al. (Eur. J. Pharm. Biopharm. (March 2003), 55(2),
147-54) disclose the results of a study to determine the
improvement of pulmonary absorption of the cyclopeptide FK224 (low
aqueous solubility) in rats by co-formulating it with
beta-cyclodextrin. The purpose of the study was to investigate the
effect of pulmonary delivery on the systemic absorption of FK224 in
comparison with other administration routes, and to determine the
bioavailability (BA) of FK224 following pulmonary administration in
rats using various dosage forms. After administration of an aqueous
suspension, the bioavailability was reduced to 2.7% compared with
16.8% for the solution. However, .beta.-cyclodextrin (.beta.-CD)
was found to be an effective additive as far as improving the
solubility of FK224 was concerned. The bioavailability of the
aqueous suspension containing .beta.-CD was increased to 19.2%. It
was observed that both the C(max) and AUC of FK224 were increased
as the amount of .beta.-CD increased. The plasma profiles showed
sustained absorption. They suggest that .beta.-CD is an extremely
effective additive as far as improving the pulmonary absorption of
FK224 is concerned. They also suggest that .beta.-CD or derivatives
with various degrees of aqueous solubility are potential drug
carriers for controlling pulmonary absorption.
[0061] Kobayashi et al. (Pharm. Res. (January 1996), 13(1), 80-3)
disclose the results of a study on pulmonary delivery of salmon
calcitonin (sCT) dry powders containing absorption enhancers in
rats. After intratracheal administration of sCT dry powder and
liquid (solution) preparations to rats, plasma sCT levels and
calcium levels were measured. Reportedly, sCT in the dry powder and
in the liquid were absorbed nearly to the same degree. Absorption
enhancers (oleic acid, lecithin, citric acid, taurocholic acid,
dimethyl-.beta.-cyclodextrin, octyl-.beta.-D-glucoside) were much
more effective in the dry powder than in the solution.
[0062] Adjei et al. (Pharm. Res. (February 1992), 9(2), 244-9)
disclose the results of a study on the bioavailability of
leuprolide acetate following nasal and inhalation delivery to rats
and healthy humans. Systemic delivery of leuprolide acetate, a
luteinizing hormone releasing hormone (LHRH) agonist, was compared
after inhalation (i.h.) and intranasal (i.n.) administration. The
i.n. bioavailability in rats was significantly increased by
.alpha.-cyclodextrin (CD), EDTA, and solution volume. Absorption
ranged from 8 to 46% compared to i.v. controls. Studies in healthy
human males were conducted with leuprolide acetate i.n. by spray,
or inhalation aerosol (i.h.), and subcutaneous (s.c.) and
intravenous (i.v.) injection. The s.c. injection was 94%
bioavailable compared with i.v. The i.n. bioavailability averaged
2.4%, with significant subject-to-subject variability. Inhalation
delivery gave a slightly lower intersubject variability. Mean Cmax
with a 1-mg dose of solution aerosol was 0.97 ng/ml, compared with
4.4 and 11.4 ng/ml for suspension aerosols given at 1- and 2-mg
bolus dosages, respectively. The mean bioavailability of the
suspension aerosols (28% relative to s.c. administration) was
fourfold greater than that of the solution aerosol (6.6%).
[0063] CyDex (Cyclopedia (2002), 5(1), 3) discloses that SBE-CD is
non-toxic to rats in an inhaled aerosol composition when present
alone. They do not disclose a nebulizable composition comprising a
drug, in particular a corticosteroid, and SBE-CD. Studies comparing
the nebulization of PULMICORT RESPULES and an aqueous inhalable
solution of budesonide and SAE-CD in various nebulizers have been
disclosed (Zimmerer et al. Respiratory Drug Delivery IX (2004)
461-464).
[0064] In deciding whether to administer a suspension versus
solution, one must also consider the type of nebulizer to be used.
The two most common types of nebulizers are the ultrasonic
nebulizer and the air driven jet nebulizer. There are significant
differences between the two. For example, jet nebulizers cool
rather than heat the liquid in the reservoir, whereas ultrasonic
nebulizers heat the liquid. While heating of the solution in
reservoir can reduce the viscosity of the solution and enhance
formation of droplets, excessive heating could lead to drug
degradation. The ultrasonic nebulizer is quieter and provides
faster delivery than the jet nebulizer, but ultrasonic nebulizers
are more expensive and are not advised for the administration of
the currently available steroid for nebulization. Most importantly,
however, ultrasonic nebulizers generally provide a significantly
higher rate of administration than do jet nebulizers.
[0065] Patients with asthma are often treated with inhaled short
acting or long acting .beta.2-agonists, inhaled anticholinergics,
and inhaled corticosteroids alone, sequentially or in combination.
Combinations of inhaled corticosteroids and long acting
.beta.2-agonists are known, for example budesonide plus formoterol
or fluticasone plus salmeterol are available in a dry powder
inhaler. However, there is no example of such combinations that are
available as a solution for nebulization. Combining the medications
into one solution would reduce the time required to administer the
medications separately.
[0066] For inhaled corticosteroids, high pulmonary availability is
more important than high oral bioavailability because the lung is
the target organ. A product with high pulmonary availability has
greater potential to exert positive effects in the lung. The ideal
ICS would have minimum oral bioavailability, reducing the
likelihood of systemic adverse effects.
[0067] Although extremely effective in the treatment of asthma,
inhaled corticosteroids can have a number of adverse side effects
such as oral candidiasis, hoarseness (dysphonia), and pharyngitis.
Therefore, inhaled corticosteroids are best delivered by a method
that minimizes the oral and/or pharyngeal deposition of the
corticosteroid and instead maximizes pulmonary delivery.
[0068] Some corticosteroids posses a hydroxyl group at position 21
of the corticosteroid. Those compounds include budesonide,
flunisolide, triamcinolone acetonide, beclomethasone
monopropionate, and the active form of ciclesonide
(desisobutyryl-ciclesonide). It is known that ciclesonide is
inhaled as an inactive compound and converted by esterases in the
lung to its active form, desisobutyryl-ciclesonide (des-CIC).
Budesonide conjugates to form intracellular fatty acid esters,
which are highly lipophilic. Budesonide forms conjugates with 5
fatty acids: oleate, palmitate, linoleate, palmitoleate, and
arachidonate.
[0069] In summary, the art suggests that, in some cases,
nebulization of solutions may be preferred over that of suspensions
and that, in some cases, an ultrasonic nebulizer, vibrating mesh,
electronic or other mechanism of aerosolization may be preferred
over an air driven jet nebulizer depending upon the nebulization
liquid formulations being compared. Even though the art discloses
inhalable solution formulations containing a corticosteroid and
cyclodextrin, the results of the art are unpredictable. In other
words, the combination of one cyclodextrin with one drug does not
suggest that another cyclodextrin may be suitable. Neither does the
art suggest that one cyclodextrin-corticosteroid inhalable
formulation will possess advantages over another
cyclodextrin-corticosteroid inhalable formulation.
[0070] A need remains in the art for a stabilized aqueous solution
budesonide-containing inhalable formulation that does not require
the addition of preservatives and that provides significant
advantages over other stabilized aqueous solution
budesonide-containing inhalable formulations. A need also remains
for a method of improving the administration of
budesonide-containing suspension formulations by nebulization by
converting the suspension to a solution.
[0071] There is also a need to develop improved systems that can
solubilize water-insoluble drugs for nebulization, and to minimize
the levels of cosolvent necessary to accomplish this. The ideal
system would consist of non-toxic ingredients and be stable for
long periods of storage at room temperature. When nebulized, it
would produce respirable droplets in the less than 10 micron or
less than 5 micron or less than 3 micron and a substantial portion
of extra-fine aerosol in the less than about 1 micron size
range.
[0072] The need continues to remain for a method of improving the
administration, by nebulization, of a suspension-based unit dose
formulation. Such a method would reduce the overall time of
administration, increase the overall amount of drug administered,
reduce the amount of drug left in the reservoir of the nebulizer,
increase the portion of pulmonary deposition relative to
oropharyngeal deposition of corticosteroid, and/or enhance deep
lung penetration of the corticosteroid as compared to such
administration, absent the improvement, of the suspension-based
unit dose formulation.
SUMMARY OF THE INVENTION
[0073] The present invention seeks to overcome the disadvantages
present in known formulations. As such, a derivatized
cyclodextrin-based, e.g., sulfoalkyl ether cyclodextrin
(SAE-CD)-based, inhalable formulation is provided. The present
formulation includes a corticosteroid as a principle active agent.
The present formulation may provide enhanced solubility and/or
enhanced chemical, thermochemical, hydrolytic and/or photochemical
stability of the active agent or other ingredients in the
formulation. Moreover, the present formulation may possess other
advantages, e.g. enhanced drug delivery, increased rate of drug
administration, reduced treatment time, reduced toxicity, ease of
manufacture, assurance of sterility, improved stability, enhanced
bioabsorption, no requirement of particle size control, increased
output rate, increased total output, no concern for solid particle
growth, enhanced pharmacokinetic profile, reduced
corticosteroid-related side effects, enhanced pulmonary deposition,
reduced oropharyngeal deposition, improved nebulization
performance, and/or no need to confirm formation of a suspension,
over other inhalable solution or suspension formulations containing
a corticosteroid, such as budesonide.
[0074] The invention provides a formulation, system and method for
treating a respiratory disease or disorder that is therapeutically
responsive to corticosteroid therapy. The system of the invention
comprises a nebulizer, and a liquid formulation of the invention.
The liquid formulation of the invention comprises a dose of
corticosteroid, an aqueous liquid carrier and a solubility
enhancer.
[0075] The invention provides a method of treating, preventing or
ameliorating in a subject a corticosteroid-responsive disease or
disorder, meaning a disease or disorder in a subject that can be
treated with a therapeutically effective amount of corticosteroid
to provide a clinical or therapeutic benefit to the subject. The
method comprises: providing an aqueous inhalable formulation
comprising a corticosteroid, an aqueous liquid carrier, and
solubility enhancer; and delivering or administering via
nebulization to a subject in need thereof a dose of about at least
25 .mu.g, 40 .mu.g, at least 45 .mu.g, at least 48 .mu.g, 45-1000
.mu.g, about 1 .mu.g to 20 mg, or 1 .mu.g to 10 mg, 0.01 mg to 10
mg, 0.025 mg to 10 mg, 0.05 mg to 5 mg, 0.1 mg to 5 mg, 0.125 mg to
5 mg, 0.25 mg to 5 mg, 0.5 mg to 5 mg, 0.05 mg to 2 mg, 0.1 mg to 2
mg, 0.125 mg to 2 mg, 0.25 mg to 2 mg, 0.5 mg to 2 mg, 1 .mu.g, 10
.mu.g, 25 .mu.g, 50 .mu.g, 100 .mu.g, 125 .mu.g, 200 .mu.g, 250
.mu.g, 25 to 66 .mu.g, 48 to 81 .mu.g, 73 to 125 .mu.g, 40 .mu.g,
64 .mu.g, 95 .mu.g, 35 to 95 .mu.g, 25 to 125 .mu.g, 60 to 170
.mu.g, 110 .mu.g, 170 .mu.g, 45 to 220 .mu.g, 45 to 85 .mu.g, 48 to
82 .mu.g, 85 to 160 .mu.g, 140 to 220 .mu.g, 120 to 325 .mu.g, 205
.mu.g, 320 .mu.g, 325 .mu.g, 90 to 400 .mu.g, 95 to 170 .mu.g, 165
to 275 .mu.g, or 275 to 400 .mu.g of the corticosteroid. In some
embodiments, the corticosteroid is budesonide.
[0076] In some embodiments: 1) the inhalable formulation has a
volume of about 10 .mu.l to 100 ml, 50 .mu.l to 50 ml, 50 .mu.l to
10 ml, 0.1 to 10 ml, 0.1 ml to less than 10 ml, 0.1 ml to 7.5 ml,
0.1 ml to 5 ml, 0.1 ml to 3 ml, 0.1 ml to 2 ml, 0.1 ml to 1 ml,
0.05 ml to 7.5 ml, 0.05 ml to 5 ml, 0.05 ml to 3 ml, 0.05 ml to 2
ml, or 0.05 ml to 1 ml; 2) the step of delivering or administering
is conducted over a period of less than 30 min, less than 20 min,
less than 10 min, less than 7 min, less than 5 min, less than 3
min, or less than 2 min, or the time is about 0.05 to 10 min, about
0.1 to 5 min, about 0.1 to 3 min, about 0.1 to 2 min, about 0.1 to
1.5 min, about 0.5 min to about 1.5 min, or about 1 min, or the
time is about the time it takes for a subject to take a single
breath (about 1 to 3 or 1 to 5 sec); 3) 20% to 85%, or 30% to 80%,
or at least 30%, at least 40%, at least 56%, at least 59%, at least
62% of the dose of corticosteroid is delivered to the lungs of the
subject; 4) the formulation, system or method provides an enhanced
pharmacokinetic profile of 1.5 to 8 fold, 1.5 to 6 fold, 1.5 to 4
fold, 1.5 to 2 fold, 1.64 to 3.55 fold for Cmax, 1.48 to 6.25 fold
for Cmax, 1.59 to 3.55 or 1.19 to 6.11 fold for AUC.sub.inf,
1.69-3.67 or 1.21 to 7.66 fold for AUC.sub.last, on normalized
dose, as compared to administration of a suspension formulation
comprising approximately the same amount of corticosteroid and
delivered under substantially the same conditions; 5) no more than,
15% to 85%, 15% to 70%, no more than 20% to 70%, no more than 50%,
no more than 40%, or no more than 60% of the dose of corticosteroid
is delivered to the subject outside the lung.
[0077] The present inventors have unexpectedly discovered that
SAE-CD is systemically absorbed following administration via
inhalation. It is also eliminated from the lungs. SAE-CD also
complexes with corticosteroids in aqueous inhalable liquid
formulations. Coadministration of the corticosteroid with SAE-CD
may result in increased output rate and total drug delivery as
compared to a control excluding SAE-CD. Moreover, an inhalable
solution of the invention administered by nebulization provides
other advantages set forth herein as compared to a
control/reference sample of a suspension comprising substantially
the same amount of corticosteroid in substantially the same volume
of liquid when administered under substantially the same
conditions.
[0078] The inhalable solution can be used in more types of
nebulizers as suspensions can clog vibrating mesh nebulizers and do
not perform well in ultrasonic nebulizers. The nebulizers would be
more easily cleaned of residual corticosteroid resulting in less
contamination. As drug in solution will be distributed equally in
the large and small droplets leaving the nebulizer, the fine
particle fraction will contain more corticosteroid resulting in a
greater respirable dose that can reach the peripheral lung and
smaller airways. This may result in less of the total drug
depositing in the oropharyngeal cavity and being swallowed, thus
reducing the potential for undesired side effects while enhancing
bioavailability and maximizing the desired effect. The inhalable
solution will also allow reducing the amount of drug in the unit
dose and/or reducing the time of nebulization to achieve the
desired amount of drug in the lung. The inhalable solution is more
easily manufactured and filled into unit doses and product
performance does not depend on very tight control of the particle
size of ingoing corticosteroid and maintenance of a homogeneous
suspension during filling. However, smaller particle size will, in
general, facilitate more rapid dissolution during manufacturing. It
is not necessary to maintain tight control as described above. It
may be terminally sterilized without risk of changing the
corticosteroid's particle size of the suspended corticosteroid. The
inhalable solution is not subject to change due to particle growth
via Ostwald ripening or agglomeration thus the amount of drug in
the respirable fraction will not change over time. It does not need
to be resuspended prior to administration with carefully scripted
procedures to reduce foaming so as not to create large variation is
dose. It may be more accurately diluted to achieve the desired
amount of drug in the volume placed in the nebulizer.
Alternatively, dose adjustment may be controlled more easily by
adjusting the time of nebulization as the concentration of the
inhalable solution does not change as fast in the nebulizer as does
concentration of the suspension, especially in air-jet
nebulizers.
[0079] An SAE-CD-containing formulation can be prepared with
sufficient active agent solubility and stability for a commercial
product. If needed, the SAE-CD-containing formulation can be
prepared as a clear aqueous solution that can be sterile filtered
through a filter having a pore size of 0.45 .mu.m or less and that
is stable and preserved under a variety of storage conditions. The
invention thus provides a filtration-sterilized liquid formulation
comprising a solution of the invention and a method of sterilizing
a solution of the invention by sterile filtration through a filter.
Sterile filtration can be done without substantial mass loss of
solubilized corticosteroid, meaning less than 5% mass loss.
[0080] Any corticosteroid suitable for administration via
inhalation can be used according to the invention. Exemplary
suitable corticosteroids are listed herein. Some embodiments of the
invention comprise a corticosteroid having a lipophilicity
approximating or exceeding that of flunisolide. Some embodiments of
the invention exclude a corticosteroid having a lipophilicity less
than flunisolide, i.e, embodiments excluding hydrocortisone,
prednisolone, prednisone, dexamethasone, betamethasone,
methylprednisolone, triamcinolone, fluocortolone.
[0081] One aspect of the invention provides a liquid formulation
comprising an effective amount of corticosteroid, such as
budesonide, and an SAE-CD, wherein the SAE-CD is present in an
amount sufficient to dissolve and stabilize the corticosteroid
during storage.
[0082] Another aspect of the invention provides a method of
improving the administration of corticosteroid to a subject by
nebulization, the method comprising the steps of:
[0083] providing in a unit dose an aqueous suspension formulation
comprising water and corticosteroid suspended therein;
[0084] combining the suspension with an amount of SAE-CD sufficient
to and for a period of time sufficient to solubilize the
corticosteroid and form a solution; and
[0085] administering the solution to the subject, wherein the
amount of time required to administer a therapeutic dose of
corticosteroid with the solution is less than the amount of time
required to administer the same therapeutic dose of corticosteroid
with the suspension under similar, or otherwise comparable,
nebulization conditions.
[0086] When administered with a nebulizer, a suspension for
nebulization will provide a first corticosteroid output rate under
a first set of nebulization conditions. However, when SAE-CD is
added to the suspension and mixed therein, a sufficient amount of
the corticosteroid is dissolved to form a liquid formulation for
nebulization that provides a greater corticosteroid output rate as
compared to the formulation excluding the SAE-CD when administered
under substantially the same conditions. In one embodiment, the
drug output rate of the formulation is increased over that of the
suspension even though the total volume of nebulized composition,
i.e., the total volume of solution emitted by the nebulizer, has
not increased. In another embodiment, SAE-CD is present in an
amount sufficient to solubilize at least 50%, at least 75%, at
least 90%, at least 95% or substantially all of the corticosteroid.
Some embodiments of the invention include those wherein at least
50% wt., at least 75% wt., at least 90% wt., at least 95% wt., at
least 98% wt., or all of the corticosteroid is dissolved in the
inhalable liquid formulation.
[0087] In some embodiments, SAE-CD is present in an amount
sufficient to decrease the amount of unsolubilized corticosteroid
in the suspension formulation and to improve the administration of
the suspension formulation via nebulization. In some embodiments,
SAE-CD is present in an amount sufficient to solubilize enough
corticosteroid such that the suspension formulation to which the
SAE-CD was added is converted to a solution, substantially clear
solution (containing less than 5% precipitate or solid), or a clear
solution. It is possible that other components of the suspension
formulation will not completely dissolve in, or may separate out
from, the solution formulation containing SAE-CD.
[0088] According to some embodiments, a nebulizer charged with a
corticosteroid/ SAE-CD-containing solution generates smaller
droplets than does the same nebulizer charged with a
corticosteroid/HP-.beta.-CD-containing solution operated under
otherwise similar conditions. As a result of generating smaller
droplets, the system comprising SAE-CD is improved over an
otherwise similar system comprising HP-.beta.-CD, since the SAE-CD
based system will generate a greater proportion of respirable
droplets and permit deeper lung penetration.
[0089] Some aspects of the invention provides for the use of SAE-CD
in a nebulizable unit dose liquid formulation. In one embodiment,
the invention provides use of SAE-CD for converting a nebulizable
corticosteroid-containing suspension-based unit dose formulation to
a nebulizable corticosteroid-containing liquid unit dose
formulation.
[0090] Some embodiments of the invention include those wherein: 1)
the corticosteroid to SAE-CD molar ratio is 0.5 to 0.0001 (1:2 to
1:10,000), 1:1 to 1:100, 1:1 to 1:10,000, or 0.1 (1:10) to 0.03
(1:33.33). The molar ratio of SAE-CD to corticosteroid in the
formulation or system is generally greater than 10:1, greater than
about 11:1, greater than 13:1, or greater than 14:1. Depending upon
the corticosteroid used in the formulation, the molar ratio of
corticosteroid to SAE-CD can vary in order to obtain a solution
suitable for administration via inhalation for the treatment of a
respiratory disease or disorder. In some embodiments, the
nebulization composition comprises at least 4.8.+-.0.5% wt./vol of
SAE-CD to provide a self-preserved formulation for a period
predetermined period of time. In some embodiments, the nebulization
composition comprises less than or about 21.5.+-.2% wt./wt. of
SAE-CD. In some embodiments, the SAE-CD is present in an amount
sufficient to provide a clear solution. For example, the
nebulization composition can be visibly clear as viewed by the
unaided eye.
[0091] Some suitable SAE-CD's include, for example, sulfobutyl
ether 4-.beta.-CD or sulfobutyl ether 7-.beta.-CD, sulfobutyl ether
6-.gamma.-CD, sulfobutyl ether 4-.gamma.-CD, sulfobutyl ether 3 to
8-.gamma.-CD, or a sulfobutyl ether 5-.gamma.-CD, or a compound of
the formula 1 or a mixture thereof.
[0092] A composition of the invention can further comprise a
conventional preservative, an antioxidant, a buffering agent, an
acidifying agent, a solubilizing agent, a complexation enhancing
agent, saline, an electrolyte, another therapeutic agent, an
alkalizing agent, a tonicity modifier, surface tension modifier,
viscosity modifier, surfactant, density modifier, volatility
modifier, or a combination thereof. If desired, the composition
further comprises a liquid carrier other than water. If a
conventional preservative is included in the composition, the
corticosteroid, such as budesonide, may have a greater binding with
the SAE-CD than does a conventional preservative. A composition can
be purged with an inert gas prior to storage to remove
substantially all of the oxygen contained in the formulation. In
general, the formulation or composition of the invention has a
shelf-life of at least 6 months depending upon the intended
use.
[0093] The formulation can be prepared at a temperature at or above
5.degree. C., at or above 25.degree. C., at or above 35.degree. C.,
at or above 45.degree. C. or at or above 50.degree. C. Specific
embodiments of the methods of preparing a liquid formulation
include those wherein: 1) the method further comprises the step of
sterile filtering the formulation through a filtration medium
having a pore size of 0.1 microns or larger; 2) the liquid
formulation is sterilized by irradiation or autoclaving; 3) the
nebulization solution is purged with nitrogen or argon or other
inert pharmaceutically acceptable gas prior to storage such that a
substantial portion of the oxygen dissolved in, and/or in surface
contact with the solution is removed.
[0094] The invention provides a method of stabilizing
corticosteroid in an aqueous corticosteroid-containing formulation
comprising the step of adding SAE-CD to an aqueous
corticosteroid-containing suspension or solution formulation in an
amount sufficient to reduce the rate of degradation of
corticosteroid as compared to a control sample excluding
SAE-CD.
[0095] The invention also provides a method of improving the
administration of an inhalable aqueous corticosteroid-containing
suspension unit dose formulation by nebulization, the method
comprising the step of adding SAE-CD to an aqueous
corticosteroid-containing suspension unit dose formulation in an
amount sufficient to solubilize the corticosteroid to form an
inhalable aqueous corticosteroid-containing solution unit dose
formulation, the improvement comprising increasing the output rate
and/or extent of nebulized corticosteroid.
[0096] The invention provides a method of reducing the amount of
time required to provide a therapeutically effective amount of
corticosteroid to a subject by inhalation of an
corticosteroid-containing composition with a nebulizer, the method
comprising the steps of: including SAE-CD in the composition in an
amount sufficient to solubilize the corticosteroid to form an
inhalable aqueous corticosteroid-containing solution; and
administering the solution to the subject by inhalation with a
nebulizer, wherein the amount of time required to provide a
therapeutically effective amount of corticosteroid to the subject
with the solution is reduced as compared to the amount of time
required to provide a therapeutically effective amount of
corticosteroid to the subject with a corticosteroid-containing
suspension comprising the same amount or concentration of
corticosteroid when the suspension and solution are administered
under otherwise similar nebulization conditions. In some
embodiments, the time required to administer or deliver a dose of
corticosteroid is less than 30 min, less than 20 min, less than 10
min, less than 7 min, less than 5 min, less than 3 min, or less
than 2 min, or the time is about 0.05 to 10 min, about 0.1 to 5
min, about 0.1 to 3 min, about 0.1 to 2 min, about 0.1 to 1.5 min,
about 0.5 min to about 1.5 min, or about 1 min, or about the time
it takes for a subject to take a single breath (about 1 to 3 sec,
or 1 to 5 sec). The time will vary according to the dose of
corticosteroid in, the concentration of corticosteroid in, and the
volume of the inhalable composition in the reservoir of a
nebulizer, and it will also depend upon the nebulizer format,
nebulization efficiency, and reservoir volume. In a given
nebulizer, the lower the volume of the inhalable composition, the
more quickly a corresponding dose of corticosteroid is nebulized.
The higher the concentration of corticosteroid in an inhalable
composition, the faster a dose of the corticosteroid can be
administered or delivered.
[0097] The output rate (the rate at which the dose corticosteroid
is administered or delivered) will vary according to the
performance parameters of the nebulizer used to administer it. The
higher the output rate of a given nebulizer, the lower the amount
of time required to deliver or administer an inhalable composition,
as defined herein, or dose of corticosteroid.
[0098] The invention also provides an inhalable composition
comprising a water soluble .gamma.-CD derivative, a corticosteroid
(either esterified or unesterified) and an aqueous liquid medium.
Another embodiment of the invention also provides an inhalable
composition comprising a water soluble .beta.-CD derivative, a
corticosteroid (unesterified) and an aqueous liquid medium.
[0099] Also, the invention provides an improved system for
administering a corticosteroid-containing inhalable formulation by
inhalation, the improvement comprising including SAE-CD in the
inhalable formulation such that SAE-CD is present in an amount
sufficient to provide an increased rate of inhaled corticosteroid
as compared to administration of a control inhalable formulation
excluding SAE-CD but otherwise being administered under
approximately the same conditions.
[0100] The invention can be used to provide a system for
administration of a corticosteroid by inhalation, the system
comprising an inhalation device, such as a nebulizer, and a drug
composition comprising a therapeutically effective amount of
corticosteroid, liquid carrier and SAE-CD present in an amount
sufficient to solubilize the corticosteroid when presented to an
aqueous environment, wherein the molar ratio of corticosteroid to
SAE-CD is in the range of about 0.072 (1:13.89 or about 1:14) to
0.0001 (1:10,000)or 0.063 (1:15.873 or about 1:16) to 0.003
(1:333.33 or about 1:333). The molar ratio of SAE-CD to
corticosteroid ranges from >10:1 to about 1000:1, about from
>10:1 to about 100:1, from >10:1 to about 50:1, from >10:1
to about 30:1, from >10:1 to about 500:1. During operation, the
system forms droplets having a MMAD in the range of about 1-8.mu.
or 3-8.mu.. The corticosteroid is delivered at a rate of at least
about 20-50 .mu.g/min, wherein this range may increase or decrease
according to the concentration of corticosteroid in the
nebulization solution in the reservoir of the nebulizer.
[0101] As a result of using SAE-CD corticosteroid therapy with an
inhalable nebulization solution, one can expect advantages such as
enhanced drug delivery, enhanced delivery especially to the
peripheral or small airways facilitated by the finer aerosol
produced, potentially improved treatment of nocturnal, asymptomatic
asthma and recovery from acute asthma attacks, increased rate of
drug administration, enhanced pharmacokinetic profile, reduced
treatment time, improved formulation stability and/or improved
patient compliance as compared to comparable corticosteroid therapy
with an inhalable nebulization suspension or suspension
chlorofluorocarbon (CFC) or hydrofluoroalkanes (HFA) pressurized
metered-dose inhaler (pMDI).
[0102] The invention can be employed in a kit comprising SAE-CD, an
aqueous carrier, and corticosteroid, wherein the kit is adapted for
the preparation of a nebulization solution. Embodiments of the kit
are detailed below. The invention provides the potential to
accommodate combination products to overcome incompatibilities with
suspension by other solution dosage forms.
[0103] The liquid formulation and composition of the invention
provide an enhanced bioavailability/bioabsorption of the
corticosteroid as compared to a suspension-based aqueous
formulation containing approximately the same amount of
corticosteroid and excluding SAE-CD. The liquid formulation or
composition provides a higher ratio of AUCi (or AUCt) to amount of
budesonide delivered to a subject than does the suspension based
formulation. Thus, the liquid formulation and/or composition
provides an improved clinical benefit or therapeutic benefit over
the suspension-based formulation.
[0104] The invention also provides a method of administering a
corticosteroid to a subject comprising the step of administering
via inhalation to a subject an aqueous liquid composition
comprising a unit dose of corticosteroid dissolved therein, wherein
the composition provides a mean AUCt, normalized for dose of the
corticosteroid, of at least 6 (pg*h/ml) per .mu.g of corticosteroid
administered. In some embodiments, the unit dose comprises at least
45 .mu.g, at least 48 .mu.g, 45-1000 .mu.g, about 1 .mu.g to 20 mg,
about 1 .mu.g to 10 mg, 0.01 mg to 10 mg, 0.025 mg to 10 mg, 0.05
mg to 5 mg, 0.1 mg to 5 mg, 0.125 mg to 5 mg, 0.25 mg to 5 mg, 0.5
mg to 5 mg, 0.05 mg to 2 mg, 0.1 mg to 2 mg, 0.125 mg to 2 mg, 0.25
mg to 2 mg, 0.5 mg to 2 mg, 1 .mu.g, 10 .mu.g, 25 .mu.g, 50 .mu.g,
100 .mu.g, 125 .mu.g, 200 .mu.g, 250 .mu.g, 25 to 66 .mu.g, 48 to
81 .mu.g, 73 to 125 .mu.g, 40 g, 64 .mu.g, 95 .mu.g, 35 to 95
.mu.g, 25 to 125 .mu.g, 60 to 170 .mu.g, 110 .mu.g, 170 .mu.g, 45
to 220 .mu.g, 45 to 85 .mu.g, 48 to 82 .mu.g, 85 to 160 .mu.g, 140
to 220 .mu.g, 120 to 325 .mu.g, 205 .mu.g, 320 .mu.g, 325 .mu.g, 90
to 400 .mu.g, 95 to 170 .mu.g, 165 to 275 .mu.g, or 275 to 400
.mu.g of corticosteroid. In some embodiments, the normalized AUCt
is based upon the dose to subject, the normalized AUCt is based
upon the dose to lung of subject, or the normalized AUCt is based
upon the emitted dose or nominal dose. As used herein, AUCt (or
AUC.sub.last, AUC.sub.0-t) is the area under the plasma level
versus time curve to the last time point t for which there is a
quantifiable value.
[0105] The invention also provides a method of administering a
corticosteroid to a subject comprising the step of administering
via inhalation to a subject an aqueous liquid composition
comprising a unit dose of corticosteroid dissolved therein, wherein
the composition provides a mean AUCi, normalized for dose of the
corticosteroid, of at least 8 (pg*h/ml) per .mu.g of corticosteroid
administered. In some embodiments, the unit dose comprises at least
45 .mu.g, at least 48 .mu.g, or 45-1000 .mu.g, about 1 .mu.g to 20
mg, about 1 .mu.g to 10 mg, 0.01 mg to 10 mg, 0.025 mg to 10 mg,
0.05 mg to 5 mg, 0.1 mg to 5 mg, 0.125 mg to 5 mg, 0.25 mg to 5 mg,
0.5 mg to 5 mg, 0.05 mg to 2 mg, 0.1 mg to 2 mg, 0.125 mg to 2 mg,
0.25 mg to 2 mg, or 0.5 mg to 2 mg of corticosteroid. In some
embodiments, the normalized AUCi is based upon the dose to subject,
the normalized AUCi is based upon the dose to lung of subject, or
the normalized AUCi is based upon the emitted dose or nominal dose.
As used herein, the AUCi (AUC.sub.inf, AUC.sub.(o.fwdarw..infin.)
is the AUC extrapolated to infinity.
[0106] When the aqueous liquid solution formulation of the
invention is administered via inhalation it can provide at least a
two-fold increase in the AUCt or AUCi, normalized for dose of the
corticosteroid, per microgram of corticosteroid administered as
compared to administration via inhalation of an aqueous liquid
suspension formulation comprising substantially the same amount of
corticosteroid suspended therein. In some embodiments, the
formulation provides at least a 1.6 to five-fold (range as
determined on an individual subject basis or a mean of 3 with a
standard deviation of .+-.1 as determined from the individual
subject data) or a two to four-fold increase (as determined using
the geometric mean across a patient population) in the AUCt or
AUCi, normalized for dose of the corticosteroid, per microgram of
corticosteroid administered. The basis for amount of
"corticosteroid administered" can be "dose to subject" or "dose to
lung" or "emitted dose" or "nominal dose" or "nominal available
dose" or "loaded dose".
[0107] The aqueous liquid formulation can be administered with any
type of device suitable for administration of a liquid formulation
to the lung. For example, the formulation can be administered with
an air driven jet, ultrasonic, capillary, electromagnetic,
pulsating membrane, pulsating plate (disc), pulsating mesh
nebulizer, a nebulizer comprising a vibration generator and an
aqueous chamber, and a nebulizer comprising a nozzle array.
[0108] In some embodiments, the invention provides a system
comprising a nebulizer and an aqueous liquid
formulation/composition as described herein. When charged with a
liquid formulation of the invention comprising a dose of
corticosteroid, the nebulizer can provide a decreasing rate of
increasing concentration (RIC) of corticosteroid in the formulation
in the reservoir of the nebulizer, in particular when comparing the
performance of the liquid formulation to the performance of a
suspension-based formulation, e.g. PULMICORT RESPULES, in the
nebulizer. In some embodiments, the percentage decrease in the RIC
ranges from 10% to 60%, 15% to 60%, 20% to 60%, 30% to 60%, or 40%
to 60%. In some embodiments, the system may provide a RIC of 0 to
40, 1 to 40, 5 to 30, or 10 to 30 mcg of corticosteroid/mL of
solution volume per min of operation/nebulization.
[0109] The pharmacokinetic enhancement provided by the system and
formulation/composition of the invention can be determined by
comparison of Cmax, AUC and Tmax parameters. In some embodiments,
the formulation and system of the invention can provide a C.sub.max
(pg of corticosteroid/ml) of 90 to 900, 200 to 600, 200 to 550, 200
to 250, 400 to 450, 500 to 600, 225, 437, or 545 on a dose
non-normalized basis. The formulation and system of the invention
can provide a dose normalized C.sub.max (pg/ml/.mu.g) of: 1) 0.3 to
2, 0.35 to 2, 0.6 to 1.5, 0.5 to 1.2, 0.8 to 1, 0.8 to 0.9, 0.7 to
0.8, 0.4, 1.9, 0.6, 1.5, 0.5, 1.2, 0.35, 2, 0.7, 0.8, or 0.9 on a
nominal available dose normalized basis; 2) 3.4 to 9.2, 3.5 to 8.5,
5.5 to 9.2, 4.5 to 7.5, 5.8 to 7, 3.4, 3.5, 4.5, 5.5, 9.2, 8.5,
7.5, 5.8, 5.9, 6, or 7 on a dose to lung normalized basis; 3) 1.7
to 7.5, 3.2 to 4.1, 1.9 to 6, 3.2 to 7.5, 1.7 to 5.2, 3.6, 4.1,
3.2, 1.9, 6, 3.2, 7.4, 7.5, 1.7, 5.2 or 5.3 on a dose to subject
normalized basis; 4) 0.9 to 3.3, 1.7 to 2.2, 0.9 to 3, 1 to 3, 1.7
to 3.3, 1 to 2.7, 1.9, 2.1, 2.2, 1.7, 0.9, 1, 2, 3, 2.9, 3.2, 3.3,
or 2.7 on an emitted dose normalized basis.
[0110] In some embodiments, on the basis of the non-normalized dose
of corticosteroid, the Cmax provided by the corticosteroid solution
is 1.6 to 2, 1.5 to 3, 1.5 to 2.5, 1.5 to 2, 1.5, 1.6, 2, 2.5, or 3
fold higher than the Cmax provided by the suspension-based
formulation when the dose of corticosteroid in the solution and the
suspension is approximately the same amount loaded. On the basis of
normalization to the nominal available dose of corticosteroid, the
Cmax provided by the corticosteroid solution is 1.8 to 6.2, 1.5 to
6.5, 2 to 6.5, 1.5 to 5.5, 2 to 4, 1.5 to 4, 1.5 to 3, 2.7, 3.3,
3.4, 1.5, 6.5, 2, 5.5, 4, or 3 fold higher than the Cmax provided
by the suspension-based formulation. On the basis of normalization
to the dose of corticosteroid to lung, the Cmax provided by the
corticosteroid solution is 1.4 to 4.3, 1.4 to 4.5, 1.5 to 4.5, 1.5
to 3.5, 1.5 to 3, 1.4 to 3, 1.5 to 2.5, 1.5 to 2, 2, 2.3, 1.4, 4.5,
3.5, 3, 1.5 or 2.5 fold higher than the Cmax provided by the
suspension-based formulation. On the basis of normalization to the
dose of corticosteroid to subject, the Cmax provided by the
corticosteroid solution is 2 to 3.5, 2 to 5, 1.7 to 3.8, 1.7 to 5,
2.7, 3, 2.4, 2, 3.5, 5, 1.7, or 3.8 fold higher than the Cmax
provided by the suspension-based formulation. On the basis of
normalization to the emitted dose of corticosteroid, the Cmax
provided by the corticosteroid solution is 1.9 to 6.3, 1.75 to 6.5,
2.2 to 4.2, 2.2 to 6.3, 1.9 to 4.2, 3.2, 3.5, 3.6, 2.8, 1.75, 6.5,
2.2, 4.2, or 6.3 fold higher than the Cmax provided by the
suspension-based formulation.
[0111] In some embodiments, the Cmax provided by the corticosteroid
solution is at least 1.5, 1.6, 2, 2.6, and 3 fold higher than the
Cmax provided by the suspension-based formulation when the dose of
corticosteroid in the solution is about 2 fold lower than the dose
in the suspension.
[0112] In some embodiments, the formulation and system of the
invention can provide an AUC.sub.inf (pg*h/ml) of 500 to 1700, 530
to 1650, 250 to 2500, 280 to 1300, 780 to 1300, 980 to 2450, 275,
775, 980, 2400, 2500, 1300, 1290, 530, 1650, 250, 280 or 780 on a
dose non-normalized basis. The formulation and system of the
invention can provide a dose normalized AUC.sub.inf (pg/ml/.mu.g)
of: 1) 1 to 5.5, 2 to 2.2, 1 to 5.3, 1.1 to 5.2, 1.5 to 2.6, 1.3 to
3.3, 2, 2.1, 2.2, 1, 5.5, 5.3, 5.2, 1.5, 2.6, 1.3 or 3.3 on a
nominal available dose normalized basis; 2) 10 to 25, 14 to 18,
10.2 to 20, 13.6 to 18.8, 11.2 to 24.7, 10.2, 20, 13.6, 14, 19,
18.8, 11, 11.2, 25, 24.7, 14.2, 16.2, 17.3 on a dose to lung
normalized basis; 3) 4 to 16, 4.2 to 16.1, 8 to 12.2, 5.4 to 16,
5.4 to 17, 8.5 to 9.6, 8.5, 9.5, 9.6, 4.2, 16.1, 8, 12.2, 12, 5.4,
16, 17, or 16.5 on a dose to subject normalized basis; 4) 2.5 to 9,
2.6 to 8.5, 4.5 to 5.1, 2.5 to 8, 2.6 to 7.9, 4.2 to 6.7, 3.1 to
8.5, 3.2 to 8.5, 4.5, 4.6, 5, 5.1, 2.5, 2.6, 4.2, 3.1, 9, 8.5, 5.1,
8, 7.9, or 6.7 to on an emitted dose normalized basis.
[0113] In some embodiments, on the basis of the non-normalized dose
of corticosteroid, the AUC.sub.inf provided by the corticosteroid
solution is 1.6 to 2.5, 1.6 to 3.1, 1.5 to 3.5, 1.5 to 3.3, 2.5 to
3.3, 3.1, 1.5, 3.3, 1.6, or 2.5 fold higher than the AUC.sub.inf
provided by the suspension-based formulation when the dose of
corticosteroid in the solution and the suspension is approximately
the same. On the basis of normalization to the nominal available
dose of corticosteroid, the AUC.sub.inf provided by the
corticosteroid solution is 1.75 to 6.5, 1.75 to 6.1, 2 to 6.5, 2 to
6.1, 2 to 4.5, 2 to 4.4, 3.3, 3.2, 3.5, 3.4, 1.75, 6.5, 6.1, 2,
4.5, or 4.4 fold higher than the AUC.sub.inf provided by the
suspension-based formulation. On the basis of normalization to the
dose of corticosteroid to lung, the AUC.sub.inf provided by the
corticosteroid solution is 1.2 to 3.5, 1.2 to 4, 1.2 to 3, 1.2 to
2.85, 1.5 to 3.5, 1.4 to 3.5, 2, 2.2, 2.3, 2.4, 1.2, 3, 4, 2.85,
1.5, 3.5, or 1.4 fold higher than the AUC.sub.inf provided by the
suspension-based formulation. On the basis of normalization to the
dose of corticosteroid to subject, the AUC.sub.inf provided by the
corticosteroid solution is 1.6 to 4.9, 1.5 to 5, 1.6 to 5, 1.6 to
3.7, 1.6 to 3.6, 2 to 4.9, 1.9 to 4, 2.6, 1.5, 5, 1.6, 3.7, 3.6, 2,
4.9, 1.9, or 4 fold higher than the AUC.sub.inf provided by the
suspension-based formulation. On the basis of normalization to the
emitted dose of corticosteroid, the AUC.sub.inf provided by the
corticosteroid solution is 1.5 to 6, 1.7 to 6, 1.9 to 6, 1.9 to
5.4, 2.3 to 5.8, 1.9 to 5.5, 1.9 to 5.8, 1.5, 6, 1.7, 1.9, 5.4,
2.3, 5.8, 5.8, 3.2, 3.5, or 3.6 fold higher than the AUC.sub.inf
provided by the suspension-based formulation.
[0114] In some embodiments, the AUC.sub.inf provided by the
corticosteroid solution is at least 1.5, 1.6, 2, 2.5, 3 and 3.1
fold higher than the AUC.sub.inf provided by the suspension-based
formulation when the dose of corticosteroid in the solution is
about 2 fold lower than the dose in the suspension.
[0115] The formulation and system of the invention can provide an
AUC.sub.0-8 hr (pg*h/ml) of 2000 to 3000, 2500 to 2700, 2000, 3000,
or 2600 on a dose non-normalized basis for the corticosteroid. The
formulation and system of the invention can provide a dose
normalized AUC.sub.inf (pg/ml/.mu.g) of: 1) 2 to 3, 2.5 to 2.7, or
2.6 on a loaded dose nominal normalized basis for the
corticosteroid; 2) 3 to 4, 3.4 to 3.5, or 3.4 on an emitted dose
normalized basis for the corticosteroid.
[0116] In some embodiments, on the basis of the normalized nominal
(loaded) dose of corticosteroid, the AUC.sub.0-8 hr provided by the
corticosteroid solution is at least 1.7, 1.8, 1.9, or 2 fold higher
than the AUC.sub.0-8 hr provided by the suspension-based
formulation when the dose of corticosteroid in the solution and the
suspension is approximately the same. On the basis of normalization
to the emitted dose of corticosteroid, the AUC.sub.0-8 hr provided
by the corticosteroid solution is at least 1.5, 1.6, to 2 fold
higher than the AUC.sub.0-8 hr provided by the suspension-based
formulation.
[0117] The formulation and system of the invention can provide a
C.sub.max (pg/ml) of 1600 to 1800, 1650 to 1750, or 1700 on a dose
non-normalized basis. The formulation and system of the invention
can provide a dose normalized C.sub.max (pg/ml/.mu.g) of: 1) 1 to
2, 1.6 to 1.8, or 1.7 on a loaded dose nominal normalized basis; 2)
2 to 2.5, or 2.2 on an emitted dose normalized basis.
[0118] In some embodiments, on the basis of the normalized nominal
(loaded) dose of corticosteroid, the C.sub.max provided by the
corticosteroid solution is at least 1.7, 1.8, 1.9, or 2 fold higher
than the C.sub.max provided by the suspension-based formulation
when the dose of corticosteroid in the solution and the suspension
is approximately the same. On the basis of normalization to the
emitted dose of corticosteroid, the C.sub.max provided by the
corticosteroid solution is at least 1.5, 1.6, to 2 fold higher than
the C.sub.max provided by the suspension-based formulation.
[0119] In some embodiments, greater than 20%, greater than 25%,
greater than 29%, greater than 35% of the emitted dose may be
absorbed into the bloodstream of the patient. In some embodiments,
greater than 40%, greater than 50%, greater than 55% of the dose to
subject may be absorbed into the bloodstream of the patient. In
some embodiments, greater than 10%, greater than 12%, greater than
15% of the nominal available dose may be absorbed into the
bloodstream of the patient.
[0120] Some aspects of the invention provide a method of
administering or delivering a dose of corticosteroid to the air
passageways of a subject in need thereof, the method comprising
administering or delivering the corticosteroid with a nebulizer
comprising a charge of an aqueous liquid formulation, the
formulation comprising an aqueous liquid carrier, sulfoalkyl ether
cyclodextrin, and the corticosteroid dissolved therein, wherein,
during operation, the system provides enhanced drug delivery,
increased rate of drug administration, reduced treatment time,
reduced toxicity, improved stability, enhanced bioabsorption,
increased output rate, increased total output, enhanced
pharmacokinetic profile, reduced corticosteroid-related side
effects, enhanced pulmonary deposition, reduced oropharyngeal
deposition, and/or improved nebulization performance over another
system comprising the nebulizer and a suspension based formulation
of the corticosteroid. The systems can be operated under similar
conditions or dissimilar conditions.
[0121] The invention includes all combinations of the embodiments
and aspects disclosed herein. Accordingly, the invention includes
the embodiments and aspects specifically disclosed, broadly
disclosed, or narrowly disclosed herein, as well as combinations
thereof and subcombinations of the individual elements of said
embodiments and aspects.
[0122] These and other aspects of this invention will be apparent
upon reference to the following detailed description, examples,
claims and attached figures.
BRIEF DESCRIPTION OF THE FIGURES
[0123] The following drawings are given by way of illustration
only, and thus are not intended to limit the scope of the present
invention.
[0124] FIG. 1 depicts a graph of the hemolytic behavior of the
CAPTISOL.RTM. as compared to the same for the parent
.beta.-cyclodextrin, the commercially available hydroxypropyl
derivatives, ENCAPSIN.TM. (degree of substitution .about.3-4) and
MOLECUSOL.RTM. (degree of substitution .about.7-8), and two other
sulfobutyl ether derivatives, SBE1-.beta.-CD and
SBE4-.beta.-CD.
[0125] FIG. 2 depicts a graph of the osmolality of SBE-CD
containing solutions of various degrees of substitution and
HP-.beta.-CD containing solutions comprising similar concentrations
of cyclodextrin derivative.
[0126] FIG. 3 depicts a phase solubility graph of the concentration
(molar) of cyclodextrin versus the concentration (molar) of
budesonide for .gamma.-CD, HP-.beta.-CD and SBE7-.beta.-CD.
[0127] FIG. 4 depicts a chart of the estimated percentage of
nebulization composition emitted from three different nebulizers
(PARI LC PLUS, HUDSON UPDRAFT II NEB-U-MIST, and MYSTIQUE) for each
of four different nebulization compositions (PULMICORT RESPULES
suspension, 5% w/v SBE7-.beta.-CD solution, 10% w/v SBE7-.beta.-CD
solution and 20% w/v SBE7-.beta.-CD solution).
[0128] FIGS. 5a-5b depict droplet size data for nebulization of
solutions with a PARI LC PLUS nebulizer.
[0129] FIG. 6 depicts droplet size data for nebulization of
solutions with a HUDSON UPDRAFT II NEBUMIST nebulizer.
[0130] FIG. 7 depicts droplet size data for nebulization of
solutions with a MYSTIQUE ultrasonic nebulizer.
[0131] FIG. 8 depicts comparative Dv.sub.50 droplet size data for
nebulization of composition with the three nebulizers PARI LC PLUS,
HUDSON UPDRAFT II NEBUMIST, and MYSTIQUE.
[0132] FIG. 9 is a graph depicting the relationship between
concentration of SAE-CD versus output rate of SAE-CD in various
different nebulizers.
[0133] FIGS. 10a-10b depict comparative droplet size data for
nebulization solutions with the PARI LC PLUS and MYSTIQUE
nebulizers of PULMICORT RESPULES suspension and a modified
PULMICORT RESPULES-based SAE-CD solution.
[0134] FIG. 11 depicts a semi-log plot of the % of initial
concentration of the R-- and S-isomers of budesonide in solutions
with and without CAPTISOL versus time at 60.degree. C. in
solution.
[0135] FIG. 12 depicts a semi-log plot of the % of initial
concentration of budesonide versus Lux hours when the samples are
exposed to fluorescent lamps.
[0136] FIG. 13 depicts a phase solubility diagram for fluticasone
propionate in the presence of several different cyclodextrins.
[0137] FIG. 14 depicts a phase solubility diagram for mometasone
furoate in the presence of several different cyclodextrins.
[0138] FIG. 15 depicts a phase solubility diagram for esterified
and non-esterified fluticasone in the presence of
SAE(5-6)-.gamma.-CD.
[0139] FIG. 16 depicts a bar chart summarizing the aqueous
solubility of beclomethasone dipropionate in the presence of
various SAE-CD derivatives.
[0140] FIG. 17 depicts a plot of the geometric mean of dose (of
corticosteroid, .mu.g) to subject versus the geometric mean of AUC
(pg*hr/ml) when budesonide is administered to subjects according to
Example 17.
[0141] FIG. 18 depicts a plot of the geometric mean of dose (of
corticosteroid, .mu.g) to lung of subject versus the geometric mean
of AUC (pg*hr/ml) when budesonide is administered to subjects
according to Example 17.
[0142] FIG. 19 depicts a plot of dose (of corticosteroid, .mu.g) to
subject versus the AUC (pg*hr/ml) for each individual when
budesonide is administered to subjects according to Example 17.
[0143] FIG. 20 depicts a plasma concentration profile for
budesonide for individual subjects according to Example 17.
[0144] FIG. 21 depicts a plasma concentration profile for
budesonide for dogs according to Example 31.
[0145] FIG. 22 is a chart detailing the approximate distribution of
a dose of budesonide upon administration of a solution of the
invention according the procedure of Example 17.
DETAILED DESCRIPTION OF THE INVENTION
[0146] The presently claimed formulation overcomes many of the
undesired properties of other known aqueous inhalable solution or
suspension corticosteroid-containing formulations. By including
SAE-CD, in an inhalable liquid formulation containing
corticosteroid, the corticosteroid is dissolved. Unexpectedly, the
nebulization of corticosteroid is improved in both an air driven
jet nebulizer and an ultrasonic nebulizer. Moreover, the
corticosteroid exhibits greater stability in the presence of SAE-CD
than it does in its absence.
[0147] The inhalable formulation and system of the invention
provides an improved pharmacokinetic profile over a suspension
formulation comprising approximately the same amount of
corticosteroid and delivered under substantially the same
conditions. The term "enhanced pharmacokinetic profile" is taken to
mean a higher AUC (e.g. AUC.sub.last or AUC.sub.(0.fwdarw..infin.))
per .mu.g of corticosteroid delivered or administered, a higher
Cmax per .mu.g of corticosteroid delivered or administered,
increased bioavailability, absorption or distribution of the
corticosteroid at the site of delivery, a shorter Tmax or a longer
Tmax.
[0148] Alternatively, the inhalable formulation and system of the
invention provides substantially the same pharmacokinetic profile
or an enhanced pharmacokinetic profile over a suspension
formulation comprising approximately a higher amount of
corticosteroid and delivered under substantially the same
conditions. The corticosteroid in the formulation can be present at
a dose that is less than 80%, less than 70% less than 60% less than
50%, less than 40%, less than 20%, and less than 10% of that in the
suspension.
[0149] The corticosteroid can be present in an amount sufficient
for single dose or multi-dose administration. SAE-CD can be present
in an amount sufficient to solubilize the corticosteroid when the
two are placed in the aqueous carrier. The aqueous carrier can be
present in an amount sufficient to aid in dissolution of the
corticosteroid and form a nebulization solution of sufficient
volume and sufficiently low viscosity to permit single dose or
multi-dose administration with a nebulizer. SAE-CD can be present
in solid form or in solution in the aqueous carrier. The
corticosteroid can be present in dry powder/particle form or in
suspension in the aqueous carrier.
[0150] Commercially available air driven jet, ultrasonic or
pulsating membrane nebulizers include the AERONEB.TM. (Aerogen, San
Francisco, Calif.), AERONEB GO (Aerogen); PARI LC PLUS.TM., PARI
BOY.TM. N, PARI eflow, PARI LC SINUS, PARI SINUSTAR.TM., PARI
SINUNEB, and PARI DURANEB.TM. (PARI Respiratory Equipment, Inc.,
Monterey, Calif.); MICROAIR.TM. (Omron Healthcare, Inc, Vernon
Hills, Ill.), HALOLITE.TM. (Profile Therapeutics Inc, Boston,
Mass.), RESPIMAT.TM. (Boehringer Ingelheim Ingelheim, Germany)
AERODOSE.TM. (Aerogen, Inc, Mountain View, Calif.), OMRON ELITE.TM.
(Omron Healthcare, Inc, Vernon Hills, Ill.), OMRON MICROAIR.TM.
(Omron Healthcare, Inc, Vernon Hills, Ill.), MABISMIST.TM. II
(Mabis Healthcare, Inc, Lake Forest, Ill.), LUMISCOPE.TM. 6610,
(The Lumiscope Company, Inc, East Brunswick, N.J.), AIRSEP
MYSTIQUE.TM., (AirSep Corporation, Buffalo, N.Y.), ACORN-1 and
ACORN-11 (Vital Signs, Inc, Totowa, N.J.), AQUATOWER.TM. (Medical
Industries America, Adel, Iowa), AVA-NEB (Hudson Respiratory Care
Incorporated, Temecula, Calif.), AEROCURRENT.TM. utilizing the
AEROCELL.TM. disposable cartridge (AerovectRx Corporation, Atlanta,
Ga.), CIRRUS (Intersurgical Incorporated, Liverpool, N.Y.), DART
(Professional Medical Products, Greenwood, S.C.), DEVILBISS.TM.
PULMO AIDE (DeVilbiss Corp; Somerset, Pa.), DOWNDRAFT.TM.
(Marquest, Englewood, Co.), FAN JET (Marquest, Englewood, Co.),
MB-5 (Mefar, Bovezzo, Italy), MISTY NEB.TM. (Baxter, Valencia,
Calif.), SALTER 8900 (Salter Labs, Arvin, Calif.), SIDESTREAM.TM.
(Medic-Aid, Sussex, UK), UPDRAFT-II.TM. (Hudson Respiratory Care;
Temecula, Calif.), WHISPER JET.TM. (Marquest Medical Products,
Englewood, Co.), AIOLOS.TM. (Aiolos Medicnnsk Teknik, Karlstad,
Sweden), INSPIRON.TM. (Intertech Resources, Inc., Bannockburn,
Ill.), OPTIMIST.TM. (Unomedical Inc., McAllen, Tex.), PRODOMO.TM.,
SPIRA.TM. (Respiratory Care Center, Hameenlinna, Finland), AERx.TM.
Essence.TM. and Ultra.TM., (Aradigm Corporation, Hayward, Calif.),
SONIK.TM. LDI Nebulizer (Evit Labs, Sacramento, Calif.), and
SWIRLER.RTM. Radioaerosol System (AMICI, Inc., Spring City, Pa.).
Nebulizers that nebulize liquid formulations containing no
propellant are suitable for use with the compositions provided
herein. Any of these and other known nebulizers can be used to
deliver the formulation of the invention including but not limited
to the following: nebulizers available from Pari GmbH (Starnberg,
Germany), DeVilbiss Healthcare (Heston, Middlesex, UK), Healthdyne,
Vital Signs, Baxter, Allied Health Care, Invacare, Hudson, Omron,
Bremed, AirSep, Luminscope, Medisana, Siemens, Aerogen, 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 other companies. The AERx and RESPIMAT nebulizers are
described by D. E. Geller (Respir. Care (2002), 47 (12),
1392-1404), the entire disclosure of which is incorporated by
reference.
[0151] Nebulizers for use herein include, but are not limited to,
jet nebulizers (optionally sold with compressors), ultrasonic
nebulizers, vibrating membrane, vibrating mesh nebulizers,
vibrating plate nebulizers, vibrating cone nebulizer, 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, Pari LC plus/Pari Master, Pari
LC star, Omron CompAir XL Portable Nebulizer System (NE-C18 and
JetAir Disposable nebulizer), Omron compare Elite Compressor
Nebulizer System (NE-C21 and Elite Air Reusable Nebulizer, Pari LC
Plus or Pari LC Star nebulizer with Proneb Ultra compressor,
Pulomo-aide, Pulmo-aide LT, Pulmo-aide traveler, Invacare Passport,
Inspiration Healthdyne 626, Pulmo-Neb Traverler, DeVilbiss 646,
Whisper Jet, Acorn II, Misty-Neb, Allied aerosol, Schuco Home Care,
Lexan Plasic 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, Siemens Ultra Nebulizer 145, CompAir,
Pulmosonic, Scout, 5003 Ultrasonic Neb, 5110 Ultrasonic Neb, 5004
Desk Ultrasonic Nebulizer, Mystique Ultrasonic, Lumiscope's
Ultrasonic Nebulizer, Medisana Ultrasonic Nebulizer, Microstat
Ultrasonic Nebulizer, and Mabismist Hand Held Ultrasonic Nebulizer.
Other nebulizers for use herein include 5000 Electromagnetic Neb,
5001 Electromagnetic Neb 5002 Rotary Piston Neb, Lumineb I Piston
Nebulizer 5500, Aeroneb Portable Nebulizer System, Aerodose.TM.
Inhaler, and AeroEclipse Breath Actuated Nebulizer. Exemplary
vibrating membrane, mesh or plate nebulizers are described by R.
Dhand (Respiratory Care, (December 2002), 47(12), p. 1406-1418),
the entire disclosure of which is hereby incorporated by
reference.
[0152] Other suitable nebulizers are described in U.S. Pat. No.
5,954,047, No. 6,026,808, No. 6,095,141, and No. 6,527,151, the
entire disclosures of which are hereby incorporated by
reference.
[0153] The present invention provides SAE-CD based formulations,
wherein the SAE-CD is a compound of the Formula 1: ##STR2##
wherein: [0154] n is 4, 5 or 6; [0155] R.sub.1, R.sub.2, R.sub.3,
R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8 and R.sub.9 are each,
independently, --O-- or a --O--(C.sub.2-C.sub.6
alkylene)-SO.sub.3.sup.- group, wherein at least one of R.sub.1 to
R.sub.9 is independently a --O--(C.sub.2-C.sub.6
alkylene)-SO.sub.3.sup.- group, preferably a
--O--(CH.sub.2).sub.mSO.sub.3.sup.- group, wherein m is 2 to 6,
preferably 2 to 4, (e.g. --OCH.sub.2CH.sub.2CH.sub.2SO.sub.3.sup.-
or --OCH.sub.2CH.sub.2CH.sub.2CH.sub.2SO.sub.3.sup.-); and [0156]
S.sub.1, S.sub.2, S.sub.3, S.sub.4, S.sub.5, S.sub.6, S.sub.7,
S.sub.8 and S.sub.9 are each, independently, a pharmaceutically
acceptable cation which includes, for example, H.sup.+, alkali
metals (e.g. Li.sup.+, Na.sup.+, K.sup.+), alkaline earth metals
(e.g., Ca.sup.+2, Mg.sup.+2), ammonium ions and amine cations such
as the cations of (C.sub.1-C.sub.6)-alkylamines, piperidine,
pyrazine, (C.sub.1-C.sub.6)-alkanolamine and
(C.sub.4-C.sub.8)-cycloalkanolamine.
[0157] Exemplary embodiments of the SAE-CD derivative of the
invention include derivatives of the Formula II (SAEx-.alpha.-CD),
wherein "x" ranges from 1 to 18; of the Formula III
(SAEy-.beta.-CD), wherein"y" ranges from 1 to 21; and of the
Formula IV (SAEz-.gamma.-CD), wherein "z" ranges from 1 to 24 such
as: TABLE-US-00001 SAEx-.alpha.-CD SAEy-.beta.-CD SAEz-.gamma.-CD
Name SEEx-.alpha.-CD SEEy-.beta.-CD SEEz-.gamma.-CD Sulfoethyl
ether CD SPEx-.alpha.-CD SPEy-.beta.-CD SPEz-.gamma.-CD Sulfopropyl
ether CD SBEx-.alpha.-CD SBEy-.beta.-CD SBEz-.gamma.-CD Sulfobutyl
ether CD SptEx-.alpha.-CD SptEy-.beta.-CD SptEz-.gamma.-CD
Sulfopentyl ether CD SHEx-.alpha.-CD SHEy-.beta.-CD SHEz-.gamma.-CD
Sulfohexyl ether CD
[0158] "SAE" represents a sulfoalkyl ether substituent bound to a
cyclodextrin. The values "x", "y" and "z" represent the average
degree of substitution as defined herein in terms of the number of
sulfoalkyl ether groups per CD molecule.
[0159] The SAE-CD used is described in U.S. Pat. No. 5,376,645 and
No. 5,134,127 to Stella et al, the entire disclosures of which are
hereby incorporated by reference. U.S. Pat. No. 3,426,011 to
Parmerter et al. discloses anionic cyclodextrin derivatives having
sulfoalkyl ether substituents. Lammers et al. (Recl. Trav. Chim.
Pays-Bas (1972), 91(6), 733-742); Staerke (1971), 23(5), 167-171)
and Qu et al. (J. Inclusion Phenom. Macro. Chem., (2002), 43,
213-221) disclose sulfoalkyl ether derivatized cyclodextrins. U.S.
Pat. No. 6,153,746 to Shah et al. discloses a process for the
preparation of sulfoalkyl ether cyclodextrin derivatives. An SAE-CD
can be made according to the disclosures of Stella et al.,
Parmerter et al., Lammers et al. or Qu et al., and if processed to
remove the major portion (>50%) of the underivatized parent
cyclodextrin, used according to the present invention. The SAE-CD
can contain from 0% to less than 50% wt. of underivatized parent
cyclodextrin.
[0160] The terms "alkylene" and "alkyl," as used herein (e.g., in
the -0-(C.sub.2-C.sub.6-alkylene)SO.sub.3.sup.- group or in the
alkylamines), include linear, cyclic, and branched, saturated and
unsaturated (i.e., containing one double bond) divalent alkylene
groups and monovalent alkyl groups, respectively. The term
"alkanol" in this text likewise includes both linear, cyclic and
branched, saturated and unsaturated alkyl components of the alkanol
groups, in which the hydroxyl groups may be situated at any
position on the alkyl moiety. The term "cycloalkanol" includes
unsubstituted or substituted (e.g., by methyl or ethyl) cyclic
alcohols.
[0161] An embodiment of the present invention provides compositions
containing a mixture of cyclodextrin derivatives, having the
structure set out in formula (I), where the composition overall
contains on the average at least 1 and up to 3n+6 alkylsulfonic
acid moieties per cyclodextrin molecule. The present invention also
provides compositions containing a single type of cyclodextrin
derivative, or at least 50% of a single type of cyclodextrin
derivative. The invention also includes formulations containing
cyclodextrin derivatives having a narrow or wide and high or low
degree of substitution. These combinations can be optimized as
needed to provide cyclodextrins having particular properties.
[0162] The present invention also provides compositions containing
a mixture of cyclodextrin derivatives wherein two or more different
types of cyclodextrin derivatives are included in the composition.
By different types, is meant cyclodextrins derivatized with
different types of functional groups e.g., hydroxyalkyl and
sulfoalkyl. Each independent different type can contain one or more
functional groups, e.g. SBE-CD where the cyclodextrin ring has only
sulfobutyl functional groups, and hydroxypropyl-ethyl-.beta.-CD
where the cyclodextrin ring has both hydroxypropyl functional
groups and ethyl functional groups. The amount of each type of
cyclodextrin derivative present can be varied as desired to provide
a mixture having the desired properties.
[0163] Exemplary SAE-CD derivatives include SBE4-.beta.-CD,
SBE7-.beta.-CD, SBE11-.beta.-CD, SBE3.4-.gamma.-CD,
SBE4.2-.gamma.-CD, SBE4.9-.gamma.-CD, SBE5.2-.gamma.-CD,
SBE6.1-.gamma.-CD, SBE7.5-.gamma.-CD, SBE7.8-.gamma.-CD and
SBE5-.gamma.-CD which correspond to SAE-CD derivatives of the
formula I wherein n=5, 5, 5 and 6; m is 4; and there are on average
4, 7, 11 and 5 sulfoalkyl ether substituents present, respectively.
These SAE-CD derivatives increase the solubility of poorly water
soluble active agents to varying degrees.
[0164] Since SAE-CD is a poly-anionic cyclodextrin, it can be
provided in different salt forms. Suitable counterions include
cationic organic atoms or molecules and cationic inorganic atoms or
molecules. The SAE-CD can include a single type of counterion or a
mixture of different counterions. The properties of the SAE-CD can
be modified by changing the identity of the counterion present. For
example, a first salt form of SAE-CD can have a greater
corticosteroid stabilizing and/or solubilizing power than a
different second salt form of SAE-CD. Likewise, an SAE-CD having a
first degree of substitution can have a greater corticosteroid
stabilizing and/or solubilizing power than a second SAE-CD having a
different degree of substitution. The enhanced solubilization of a
corticosteroid by one SAE-CD versus another is demonstrated by the
data in the following tables which depict the molar solubility for
fluticasone propionate with different SAE-CDs at about 0.03 to
0.12M concentrations such that the solubilizing power followed
about this rank order over this concentration range of SAE-CD:
SBE5.2-.gamma.-CD>SPE5.4-.gamma.-CD>SBE6.1-.gamma.-CD>SBE9.7-.ga-
mma.-CD>>SBE7-.alpha.-CD>SBE6.7-.beta.-CD>SPE7-.beta.-CD.
For mometasone furoate, the solubilizing power followed about this
rank order over this concentration range of SAE-CD:
SBE9.7-.gamma.-CD>SBE6.1-.gamma.-CD>SBE5.2-.gamma.-CD>>SPE5.4-
-.gamma.-CD>SBE7-.alpha.-CD>SBE6.7-.beta.-CD>SPE7-.beta.-CD.
Differences were also observed for the binding of budesonide and
triamcinolone with specific embodiments of SAE-CD. According to the
invention, a SAE-.gamma.-CD binds a corticosteroid better than a
SAE-.beta.-CD does. Also, a SAE-.beta.-CD binds budesonide better
than a SAE-.alpha.-CD does. The data is summarized in FIGS. 13-14.
TABLE-US-00002 [Fluticasone] [Mometasone] .times.10.sup.5M
.times.10.sup.5M [Triamcinolone as non as non [Budesonide]
acetonide] -CD [CD] M propionate esterified furoate esterified
.times.10.sup.5M .times.10.sup.5M H.sub.2O NA 0.39 0.16 1.82 0.00
6.59 3.56 .beta. 0.015M 1.36 12.9 81.3 (SBE).sub.6.7 .beta. 0.0465
5.41 126.4 16.4 121.7 254.8 457.0 0.0950 7.99 215.9 31.1 226.1
428.1 1023.3 (SBE).sub.2.4 .beta. 0.04 1.70 12.8 0.08 2.46
(SPE).sub.7 .beta. 0.04 1.05 93.9 7.23 122.4 0.08 2.12 151.2 10.8
223.3 241.6
[0165] TABLE-US-00003 Solubility of selected steroids enhanced by
alpha-cyclodextrins [Fluticasone] [Mometasone] .times.10.sup.5M
.times.10.sup.5M [Triamcinolone as non as non [Budesonide]
acetonide] -CD [CD] M propionate esterified furoate esterified
.times.10.sup.5M .times.10.sup.5M H.sub.2O NA 0.39 0.16 1.82 0.00
6.59 3.56 A 0.04 0.00 8.4 0.08 0.27 28.5 (SBE).sub.7 .alpha. 0.04
8.37 30.1 55.0 348.1 0.08 11.4 35.5 116.9 597.9
[0166] TABLE-US-00004 Solubility of selected steroids enhanced by
gamma-cyclodextrins [Fluticasone] [Mometasone] .times.10.sup.5M
.times.10.sup.5M [Triamcinolone as non as non [Budesonide]
acetonide] -CD [CD] M propionate esterified furoate esterified
.times.10.sup.5M .times.10.sup.5M H.sub.2O NA 0.39 0.16 1.82 0.00
6.59 3.56 .GAMMA. 0.035 73.5 14.1 2.71 10.1 197.8 0.1 22.1 82.2
65.8 0.09 4.1 138.6 (SBE).sub.5.2 .gamma. 0.04 79.12 375.8 0.1
215.3 1440.4 93.9 889.2 861.6 (SBE).sub.6.1 .gamma. 0.04 51.82
575.6 41.5 841.1 306.6 1059.5 0.08 120.8 949.0 92.9 1423.1 698.8
2386.1 (SBE).sub.9.7 .gamma. 0.04 54.5 0.075 103.1 895.0 94.0 889.6
453.4 (SPE).sub.5.4 .gamma. 0.04 71.7 759.5 28.7 400.9 0.08 140.1
1387.8 51.3 1467.1 774.2
[0167] The inventors have also discovered that SAE-.gamma.-CD is
particularly suitable for use in complexing esterified and
non-esterified corticosteroids as compared to complexation of the
same corticosteroids with SAE-.beta.-CD or SAE-.alpha.-CD. The
table above also summarizes the phase solubility data depicted in
FIG. 15 for fluticasone and fluticasone propionate with various
different SAE-.gamma.-CD species having a degree of substitution in
the range of 5-10.
[0168] The present inventors have discovered that SAE-.gamma.-CD is
also much more effective at binding with a particular regioisomer
of esterified corticosteroids than is SAE-.beta.-CD or
SAE-.alpha.-CD. The procedure set forth in Example 18 details the
comparative evaluation of the binding of SAE-.gamma.-CD and
SAE-.beta.-CD with a series of structurally related corticosteroid
derivatives. The table below summarizes the results of a study
comparing the binding of SBEx-.gamma.-CD, wherein x represents the
average degree of substitution, derivatives and SBE-.beta.-CD
derivative with different forms of beclomethasone. TABLE-US-00005
Beclomethasone Beclomethasone Beclomethasone 17-mono- 21-mono-
Beclomethasone dipropionate propionate propionate (unesterified) CD
(.mu.g/mL) (.mu.g/mL) (.mu.g/mL) (.mu.g/mL) SBE.sub.3.4 0.04M
.fwdarw.336.8 0.04M .fwdarw.10621.6 0.04M .fwdarw.172.6 0.04M
.fwdarw.11360.2 .gamma.-CD SBE.sub.5.24 0.04M .fwdarw.267.0 0.04M
.fwdarw.9500.8 0.04M .fwdarw.139.8 0.04M .fwdarw.10949.9 .gamma.-CD
SBE.sub.6.1 0.04M .fwdarw.243.8 0.04M .fwdarw.11666.9 0.04M
.fwdarw.153.8 0.04M .fwdarw.11007.0 .gamma.-CD SBE.sub.7.5 00.04M
.fwdarw.168.5 0.04M .fwdarw.8539.1 0.04M .fwdarw.122.4 0.04M
.fwdarw.9635.2 .gamma.-CD SBE.sub.6.7 0.04M .fwdarw.60.4 0.04M
.fwdarw. 6799.6 0.04M .fwdarw.50.6 0.04M .fwdarw.6927.0 .beta.-CD
.gamma.-CD 0.04M .fwdarw.105.8 0.04M .fwdarw.136.9 0.04M
.fwdarw.9.4 0.04M .fwdarw.114.8
[0169] The survey study shows that in the presence of SBE(3.4)
.gamma.-CD (0.04M), all of the forms of beclomethasone were at or
near their highest solubilities. B17P, the active metabolite of
BDP, has the highest solubility of the esterified beclomethasone
forms in any of the derivatized CDs. The results indicate that
SBE-.gamma.-CD complexes with beclomethasone dipropionate better
than Captisol or .gamma.-CD alone. Of the SAE-CD derivatives
evaluated, the optimal degree of substitution of the SBE .gamma.-CD
that provides the greatest enhancement in solubility of BDP is
DS=3.4, and solubility decreases almost linearly as the degree of
substitution increases. This is true for both the 24 hr and 5 day
equilibration times. So in terms of BDP solubilization with SAE-CD:
SBE(3.4).gamma.-CD>SBE(5.2).gamma.-CD>SBE(6.1).gamma.-CD>SBE(7.5-
).gamma.-CD>.gamma.-CD>Captisol (SBE7-.beta.-CD). The data is
summarized in FIG. 16. Therefore, the present inventors have
discovered that SAE-.gamma.-CD cyclodextrin derivatives are
unexpectedly better at solubilizing corticosteroids than are
SAE-.beta.-CD derivatives. Moreover, the formulations based upon
SAE-.gamma.-CD are suitable for use in inhalable formulations
contrary to the disclosure of Worth et al. (above), which suggests
that SAE-CD derivatives are not.
[0170] By "complexed" is meant "being part of a clathrate or
inclusion complex with", i.e., a complexed therapeutic agent is
part of a clathrate or inclusion complex with a cyclodextrin
derivative. By "major portion" is meant at least about 50% by
weight. Thus, a formulation according to the present invention may
contain an active agent of which more than about 50% by weight is
complexed with a cyclodextrin. The actual percent of active agent
that is complexed will vary according to the complexation
equilibrium constant characterizing the complexation of a specific
cyclodextrin to a specific active agent. The invention also
includes embodiments wherein the active agent is not complexed with
the cyclodextrin or wherein a minor portion of the active agent is
complexed with the derivatized cyclodextrin. It should be noted
that an SAE-CD, or any other anionic derivatized cyclodextrin, can
form one or more ionic bonds with a positively charged compound.
This ionic association can occur regardless of whether the
positively charged compound is complexed with the cyclodextrin
either by inclusion in the cavity or formation of a salt
bridge.
[0171] The binding of a drug to the derivatized cyclodextrin can be
improved by including an acid or base along with the drug and
cyclodextrin. For example, the binding of a basic drug with the
cyclodextrin might be improved by including an acid along with the
basic drug and cyclodextrin. Likewise, the binding of an acidic
drug with the cyclodextrin might be improved by including a base
(alkaline material) along with the acidic drug and cyclodextrin.
The binding of a neutral drug might be improved by including a
basic, acidic or other neutral compound along with the neutral drug
and cyclodextrin. Suitable acidic compounds include inorganic and
organic acids. Examples of inorganic acids are mineral acids, such
as hydrochloric and hydrobromic acid. Other suitable acids include
sulfuric acid, sulfonic acid, sulfenic acid, and phosphoric acid.
Examples of organic acids are aliphatic carboxylic acids, such as
acetic acid, ascorbic acid, carbonic acid, citric acid, butyric
acid, fumaric acid, glutaric acid, glycolic acid,
.alpha.-ketoglutaric acid, lactic acid, malic acid, mevalonic acid,
maleic acid, malonic acid, oxalic acid, pimelic acid, propionic
acid, succinic acid, tartaric acid, or tartronic acid. Aliphatic
carboxylic acids bearing one or more oxygenated substituents in the
aliphatic chain are also useful. A combination of acids can be
used.
[0172] Suitable basic compounds include inorganic and organic
bases. Suitable inorganic bases include ammonia, metal oxide and
metal hydroxide. Suitable organic bases include primary amine,
secondary amine, tertiary amine, imidazole, triazole, tetrazole,
pyrazole, indole, diethanolamine, triethanolamine, diethylamine,
methylamine, tromethamine (TRIS), aromatic amine, unsaturated
amine, primary thiol, and secondary thiol. A combination of bases
can be used.
[0173] An anionic derivatized cyclodextrin can complex or otherwise
bind with an acid-ionizable agent. As used herein, the term
acid-ionizable agent is taken to mean any compound that becomes or
is ionized in the presence of an acid. An acid-ionizable agent
comprises at least one acid-ionizable functional group that becomes
ionized when exposed to acid or when placed in an acidic medium.
Exemplary acid-ionizable functional groups include a primary amine,
secondary amine, tertiary amine, quaternary amine, aromatic amine,
unsaturated amine, primary thiol, secondary thiol, sulfonium,
hydroxyl, enol and others known to those of ordinary skill in the
chemical arts.
[0174] The degree to which an acid-ionizable agent is bound by
non-covalent ionic binding versus inclusion complexation formation
can be determined spectrophotometrically using methods such as
.sup.1HNMR, .sup.13CNMR, or circular dichroism, for example, and by
analysis of the phase solubility data for the acid-ionizable agent
and anionic derivatized cyclodextrin. The artisan of ordinary skill
in the art will be able to use these conventional methods to
approximate the amount of each type of binding that is occurring in
solution to determine whether or not binding between the species is
occurring predominantly by non-covalent ionic binding or inclusion
complex formation. An acid-ionizable agent that binds to
derivatized cyclodextrin by both means will generally exhibit a
bi-phasic phase solubility curve. Under conditions where
non-covalent ionic bonding predominates over inclusion complex
formation, the amount of inclusion complex formation, measured by
NMR or circular dichroism, will be reduced even though the phase
solubility data indicates significant binding between the species
under those conditions; moreover, the intrinsic solubility of the
acid-ionizable agent, as determined from the phase solubility data,
will generally be higher than expected under those conditions.
[0175] As used herein, the term non-covalent ionic bond refers to a
bond formed between an anionic species and a cationic species. The
bond is non-covalent such that the two species together form a salt
or ion pair. An anionic derivatized cyclodextrin provides the
anionic species of the ion pair and the acid-ionizable agent
provides the cationic species of the ion pair. Since an anionic
derivatized cyclodextrin is multi-valent, an SAE-CD can form an ion
pair with one or more acid-ionizable agents.
[0176] The parent cyclodextrins have limited water solubility as
compared to SAE-CD and HPCD. Underivatized .alpha.-CD has a water
solubility of about 14.5% w/v at saturation. Underivatized
.beta.-CD has a water solubility of about 1.85% w/v at saturation.
Underivatized .gamma.-CD has a water solubility of about 23.2% w/v
at saturation. Dimethyl-beta-cyclodextrin (DMCD) forms a 43% w/w
aqueous solution at saturation. The SAE-CD can be combined with one
or more other cyclodextrins or cyclodextrin derivatives in the
inhalable solution to solubilize the corticosteroid.
[0177] Other water soluble cyclodextrin derivatives that can be
used according to the invention include the hydroxyethyl,
hydroxypropyl (including 2- and 3-hydroxypropyl) and
dihydroxypropyl ethers, their corresponding mixed ethers and
further mixed ethers with methyl or ethyl groups, such as
methylhydroxyethyl, ethyl-hydroxyethyl and ethyl-hydroxypropyl
ethers of alpha-, beta- and gamma-cyclodextrin; and the maltosyl,
glucosyl and maltotriosyl derivatives of alpha, beta- and
gamma-cyclodextrin, which may contain one or more sugar residues,
e.g. glucosyl or diglucosyl, maltosyl or dimaltosyl, as well as
various mixtures thereof, e.g. a mixture of maltosyl and dimaltosyl
derivatives. Specific cyclodextrin derivatives for use herein
include hydroxypropyl-beta-cyclodextrin,
hydroxyethyl-beta-cyclodextrin, hydroxypropyl-gamma-cyclodextrin,
hydroxyethyl-gamma-cyclodextrin, dihydroxypropyl-beta-cyclodextrin,
glucosyl-alpha-cyclodextrin, glucosyl-beta-cyclodextrin,
diglucosyl-beta-cyclodextrin, maltosyl-alpha-cyclodextrin,
maltosyl-beta-cyclodextrin, maltosyl-gamma-cyclodextrin,
maltotriosyl-beta-cyclodextrin, maltotriosyl-gamma-cyclodextrin and
dimaltosyl-beta-cyclodextrin, and mixtures thereof such as
maltosyl-beta-cyclodextrin/dimaltosyl-beta-cyclodextrin, as well as
methyl-beta-cyclodextrin. Procedures for preparing such
cyclodextrin derivatives are well-known, for example, from Bodor
U.S. Pat. No. 5,024,998 dated Jun. 18, 1991, and references cited
therein. Other cyclodextrins suitable for use in the present
invention include the carboxyalkyl thioether derivatives such as
ORG 26054 and ORG 25969 made by ORGANON (AKZO-NOBEL),
hydroxybutenyl ether derivatives made by EASTMAN,
sulfoalkyl-hydroxyalkyl ether derivatives, sulfoalkyl-alkyl ether
derivatives, and other derivatives as described in US Pregrant
Patent Application Publications No. 2002/0128468, No. 2004/0106575,
No. 2004/0109888, and No. 2004/0063663, or U.S. Pat. No. 6,610,671,
No. 6,479,467, No. 6,660,804, or No. 6,509,323.
[0178] The HP-.beta.-CD can be obtained from Research Diagnostics
Inc. (Flanders, N.J.). HP-.beta.-CD is available with different
degrees of substitution. Exemplary products include ENCAPSIN.TM.
(degree of substitution.about.4; HP4-.beta.-CD) and MOLECUSOL.TM.
(degree of substitution.about.8; HP8-.beta.-CD); however,
embodiments including other degrees of substitution are also
available. Since HPCD is non-ionic, it is not available in salt
form.
[0179] Dimethyl cyclodextrin is available from FLUKA Chemie (Buchs,
CH) or Wacker (Iowa). Other derivatized cyclodextrins suitable in
the invention include water soluble derivatized cyclodextrins.
Exemplary water-soluble derivatized cyclodextrins include
carboxylated derivatives; sulfated derivatives; alkylated
derivatives; hydroxyalkylated derivatives; methylated derivatives;
and carboxy-.beta.-cyclodextrins, e.g. succinyl-.beta.-cyclodextrin
(SCD), and
6.sup.A-amino-6.sup.A-deoxy-N-(3-carboxypropyl)-.beta.-cyclodextrin.
All of these materials can be made according to methods known in
the prior art. Suitable derivatized cyclodextrins are disclosed in
Modified Cyclodextrins: Scaffolds and Templates for Supramolecular
Chemistry (Eds. Christopher J. Easton, Stephen F. Lincoln, Imperial
College Press, London, UK, 1999) and New Trends in Cyclodextrins
and Derivatives (Ed. Dominique Duchene, Editions de Sante, Paris,
France, 1991).
[0180] Sulfobutyl ether .beta.-cyclodextrin (CAPTISOL, CyDex Inc.,
degree of substitution=6.6), 2-hydroxypropyl .beta.-cyclodextrin
(HP-.beta.-CD, CERESTAR, degree of substitution=5.5),
succinylated-.beta.-cyclodextrin (S-CD, Cyclolab), and
2,6,di-o-methyl-.beta.-cyclodextrin (DM-CD, Fluka) % w/w solutions
were prepared at their native pH or buffered as needed. Sulfoalkyl
ether .gamma.-CD and sulfoalkyl ether .alpha.-CD derivatives were
obtained from CyDex, Inc. (Lenexa, Kans.) and The University of
Kansas (Lawrence, Kans.).
[0181] The amount of derivatized cyclodextrin required to provide
the desired effect will vary according to the materials comprising
the formulation.
[0182] Different cyclodextrins are able to solubilize a
corticosteroid to different extents. FIG. 3 depicts a molar phase
solubility curve for budesonide with HP-.beta.-CD, SBE7-.beta.-CD,
and .gamma.-CD as compared to water. The inventors have found that
SAE-CD is superior to other cyclodextrins and cyclodextrin
derivatives at solubilizing budesonide. On a molar basis,
SBE-.beta.-CD is a better solubilizer of budesonide than
HP-.beta.-CD. In addition, the solubilizing power among the SAE-CD
derivatives followed about this rank order for budesonide over a
SAE-CD concentration range of 0.04 to 0.1 M:
SBE5.2-.gamma.-CD.about.SPE5.4-.gamma.-CD>SBE6.1-.gamma.-CD>SBE7-.a-
lpha.-CD>SBE9.7-.gamma.-CD.about.SBE6.7-.beta.-CD>SPE7-.beta.-CD.
For example, a 0.1 M concentration of SBE7-.beta.-CD was able to
solubilize a greater amount of budesonide than either .gamma.-CD or
HP-.beta.-CD. Moreover, SAE-CD-containing nebulizable formulations
provide a greater output rate for corticosteroid by nebulization as
compared to .gamma.-CD or HP-.beta.-CD administered under otherwise
similar conditions.
[0183] It was unexpectedly discovered that the nebulization of
Captisol solutions provides several advantages with respect to
other cyclodextrins. The droplets leaving the nebulizer are of a
more advantageous size and the Captisol solutions are nebulized
faster than similar solutions of other Cyclodextrins. The table
below shows that the average particle size (Dv50) of Captisol
solutions is smaller than that of HP-.beta.-CD or .gamma.-CD. More
importantly, as seen in the table below, the Dv90 shows that the
other cyclodextrins had significant number of very large droplets.
The data (Malvern particle size) was obtained for each formulation
as emitted from a PARI LC PLUS nebulizer equipped with a PARI
PRONEB ULTRA air compressor. The smaller droplet size is favored
for an inhalable composition as it permits deeper lung delivery of
active agents such as a corticosteroid. TABLE-US-00006 Formulation
Dv10 (.mu.m) Dv 50 (.mu.m) Dv 90 (.mu.m) 5% Captisol 1.9 .+-. 0.04
3.84 .+-. 0.08 10.52 .+-. 0.2 10% Captisol 1.82 .+-. 0.05 3.61 .+-.
0.25 11.18 .+-. 1.92 20% Captisol 1.78 .+-. 0.04 3.12 .+-. 0.11
10.02 .+-. 0.23 5% Hydroxypropyl 1.89 .+-. 0.04 3.99 .+-. 0.13
14.89 .+-. 2.45 .beta.-Cyclodextrin 10% Hydroxypropyl 1.95 .+-.
0.03 4.62 .+-. 0.34 120.1 .+-. 172.67 .beta.-Cyclodextrin 20%
Hydroxypropyl 1.91 .+-. 0.02 4.26 .+-. 0.16 13.77 .+-. 1.00
.beta.-Cyclodextrin 5% .gamma.-Cyclodextrin 1.94 .+-. 0.05 3.99
.+-. 0.36 205.62 .+-. 222.10 10% .gamma.-Cyclodextrin 2.03 .+-.
0.05 4.84 .+-. 0.49 451.55 .+-. 25.92 20% .gamma.-Cyclodextrin 1.96
.+-. 0.04 4.97 .+-. 0.12 286.46 .+-. 235.13
[0184] This advantage is further shown in the output rate of these
solutions. The table below shows that Captisol is emitted from the
nebulizer faster and also to a greater extent than the other
cyclodextrins, thus the output rate of the nebulizer is greater
when Captisol is nebulized. TABLE-US-00007 Percent Sputter Output
Rate Formulation Emitted Time (min) mg/min 5% Captisol 56.42 3.81
296 10% Captisol 55.13 3.84 287 20% Captisol 50.56 4.06 249 5%
Hydroxypropyl .beta.- 43.32 4.14 209 Cyclodextrin 10% Hydroxypropyl
.beta.- 46.22 4.27 216 Cyclodextrin 20% Hydroxypropyl .beta.- 46.90
4.01 234 Cyclodextrin 5% .gamma.-Cyclodextrin 52.74 5.41 195 10%
.gamma.-Cyclodextrin 53.75 4.98 216 20% .gamma.-Cyclodextrin 51.91
4.81 216 Nebulization is stopped when the sound changes (time to
sputter) or visible particles are no longer produced. Sputter
occurs at substantial completion of delivery of solution in the
reservoir of the nebulizer.
[0185] The advantage of Captisol was further demonstrated by
preparing solutions containing budesonide dissolved in various
cyclodextrins and comparing their performance in nebulization to
the performance of commercial PULMICORT.RTM. RESPULES.RTM., a
commercially available suspension-based unit dose formulation. The
suspension obtained from several unit dose ampoules of
PULMICORT.TM. was pooled to form a multi-use suspension based unit
dose formulation, and and SAE-CD (specifically, CAPTISOL),
HP-.beta.- or .gamma.-cyclodextrin powder was added to achieve a
0.25 mg/ml budesonide solution concentration. These
budesonide-containing solutions contained 5% w/v Captisol (P5C), 1%
w/v gamma-CD (P1.gamma.CD) and 5% w/v
hydroxypropyl-beta-cyclodextrin (P5HP.beta.CD). Each was prepared
at least 30 minutes prior to all testing. All three formulations
were clear, colorless solutions. (Note: a 250 mg/mL solution of
budesonide cannot be achieved in a 5% w/v solution of
.gamma.-cyclodextrin as it exhibits "B" type solubility behavior) A
2 ml aliquot of the suspension or solution was placed in the same
Pari LC Plus nebulizer setup and the amount of budesonide in the
emitted droplets was determined by collecting them onto a filter
and measuring the budesonide using HPLC. As shown in the table
below, the total output rate (.mu.g budesonide collected/time to
sputter) for each suspension or solution. TABLE-US-00008 Total
Output Rate SD Sample ID (.mu.g/min) (.mu.g/min) Pulmicort 33.85
3.85 Pulmicort + 5% Captisol 44.04 1.42 Pulmicort + 5% HP-.beta.-CD
21.37 2.44 Pulmicort + 1% .gamma.-CD 40.36 5.73
[0186] The output rate is highest for the Captisol solution
indicating that an equivalent amount of drug can be delivered in a
shorter period of time. Under the conditions used, .beta.-CD is
unable to solubilize an equivalent amount of corticosteroid due to
the limited solubility of .beta.-CD in water.
[0187] The present invention can be used with other
suspension-based aqueous formulations, which formulations may be
adapted for nasal delivery or pulmonary delivery. Exemplary
suspension-based aqueous formulations include the UDB formulation
(Sheffield Pharmaceuticals, Inc.), VANCENASE.TM. AQ (beclomethasone
dipropionate aqueous suspension; Schering Corporation, Kenilworth,
N.J.), ATOMASE.TM. (beclomethasone dipropionate aqueous suspension;
Douglas Pharmaceuticals Ltd., Aukland, Australia), BECONASE.TM.
(beclomethasone dipropionate aqueous suspension; Glaxo Wellcome,
NASACORT AQ.TM. (triamcinolone acetonide nasal spray, Aventis
Pharmaceuticals), TRI-NASAL.TM. (triamcinolone acetonide aqueous
suspension; Muro Pharmacaceuticals Inc.) and AEROBID-M.TM.,
(flunisolide inhalation aerosol, Forest Pharmaceuticals),
NASALIDE.TM. and NASAREL.TM. (flunisolide nasal spray, Ivax
Corporation), FLONASE.TM. (fluticasone propionate,
GlaxoSmithKline), and NASONEX.TM. (mometasone furoate,
Schering-Plough Corporation).
[0188] The suspension formulation can comprise corticosteroid
present in particulate, microparticulate, nanoparticulate or
nanocrystalline form. Accordingly, an SAE-CD can be used to improve
the administration of a corticosteroid suspension-based unit dose
formulation. Moreover, the SAE-CD outperforms other cyclodextrin
derivatives.
[0189] According to one embodiment, SAE-CD (in solid or liquid
form) and a suspension-based unit dose formulation comprising
corticosteroid are mixed. The SAE-CD is present in an amount
sufficient to increase the amount of solubilized corticosteroid,
i.e. decrease the amount of unsolubilized corticosteroid, therein.
Prior to administration, the liquid may be optionally aseptically
filtered or terminally sterilized. The liquid is then administered
to a subject by inhalation using a nebulizer. As a result, the
amount of drug that the subject receives is higher than the subject
would have received had the unaltered suspension formulation been
administered.
[0190] According to another embodiment, SAE-CD (in liquid form, as
ready-to-use liquid or as a concentrate) and a solid unit dose
formulation comprising corticosteroid are mixed to form a liquid
formulation. The SAE-CD is present in an amount sufficient to
solubilize a substantial portion of the corticosteroid. The liquid
is then administered via inhalation using a nebulizer.
[0191] According to another embodiment, SAE-CD (in solid form) and
a solid unit dose formulation comprising corticosteroid are mixed
to form a solid mixture to which is added an aqueous liquid carrier
in an amount sufficient to form a nebulizable formulation. Mixing
and/or heating are optionally employed upon addition of the liquid
carrier to form the formulation. The SAE-CD is present in an amount
sufficient to solubilize a substantial portion of the
corticosteroid. The formulation is then administered via inhalation
using a nebulizer.
[0192] The size of the reservoir varies from one type of nebulizer
to another. The volume of the liquid formulation may be adjusted as
needed to provide the required volume for loading into the
reservoir of a particular type or brand of nebulizer. The volume
can be adjusted by adding additional liquid carrier or additional
solution containing SAE-CD. In general, the reservoir volume of a
nebulizer is about 10 .mu.l to 100 ml. Low volume nebulizers, such
as ultrasonic and vibrating mesh/vibrating plate/vibrating
cone/vibrating membrane nebulizers, pre-filled reservoir strips
inclusive of delivery nozzle typically have a reservoir volume of
10 .mu.l to 6 ml or 10 .mu.l to 5 ml. The low volume nebulizers
provide the advantage of shorter administration times as compared
to large volume nebulizers.
[0193] Example 28 details a procedure for preparation of a solution
of the invention to be used with a low volume (low reservoir volume
and/or low reservoir residual volume) nebulizer, such as an AERx
nebulizer. The solutions of the invention can be nebulized with any
nebulizer; however, with an AERx delivery system that coordinates
both the inhalation and delivery processes to optimize deep lung
penetration, an initial sample volume of about 10 to 100, or 50
.mu.l can be used to load AERx Strip unit dose container.
Administration of this solution with the system makes it feasible
for a therapeutic dose to be administered to a subject in a single
puff (a single full inhalation by a subject, i.e. 3-5 seconds) via
nebulization. Based on general performance expectations of such
devices where the emitted dose is 60-65% and the subsequent lung
doses are 65-85%, about 10 .mu.g to 60 .mu.g or 10 .mu.g to 110
.mu.g of budesonide may be expected to be delivered to the lung in
a single dosing event using budesonide solutions prepared with
SAECD.
[0194] Example 32 details a procedure for the comparison of
nebulization parameters in four different nebulizers using a
formulation of the invention and PULMICORT RESPULES
(suspension-based formulation). In each case, the formulation of
the invention out performs the suspension-based formulation. The
solution of the invention provide a 1.25, 1.4, 2.1, 3.3, 3.67, 1.25
to 3.7, or 1.25 to 4 fold increase in the amount of budesonide
delivered. Under the conditions tested, the AIRSEP MYSTIQUE was
most efficient at emitting/nebulizing the SAE-CD/budesonide
formulation.
[0195] Unless otherwise specified, the term "dose", which is
understood to include an effective dose, is taken to mean a nominal
dose, emitted dose, nominal available dose, dose to subject, dose
to lung or other such term of art. The term "nominal dose" refers
to an amount of corticosteroid placed in the reservoir of a
nebulizer, wherein the volume of liquid in the reservoir is
determined according the size of the reservoir. The term "nominal
available dose" refers to the amount of corticosteroid that is
determined could be or should have been available to a subject when
administered a formulation of the invention by nebulization but
formulation is/was not administered in its entirety. The term
"emitted dose" refers to the amount of corticosteroid emitted from
a nebulizer. The term "dose to subject" refers to the amount of
corticosteroid delivered to and retained by a subject following
administration of a formulation of the invention by nebulization.
The term "dose to lung" refers to the amount of corticosteroid
delivered to and retained by the lungs of a subject following
administration of a formulation of the invention by
nebulization.
[0196] In general, a single-use suspension-based unit dose
formulation of corticosteroid contains about 0.125, 0.25, 0.5, 1,
2, or about 0.125 to about 2 mg of corticosteroid suspended in
about 50 .mu.l to 10 ml of liquid carrier. Alternatively, the
corticosteroid is present at a concentration of about 20 mcg to
about 30 mg of corticosteroid per ml of suspension. As a result,
about 10 to 500 mg of SAE-CD, or 10 to 250 mg of SAE-CD, or 10 to
300 mg of SAE-CD, be it in solid form or dissolved in a liquid
carrier, is added to each ml the suspension in order to dissolve a
substantial portion of the corticosteroid and form a nebulizable
unit dose liquid formulation that is then administered to a
subject.
[0197] The formulation, method or system can employ a dose of about
1 .mu.g to 20 mg, 1 .mu.g to 10 mg, 0.01 mg to 10 mg, 0.025 mg to
10 mg, 0.05 mg to 5 mg, 0.1 mg to 5 mg, 0.125 mg to 5 mg, 0.25 mg
to 5 mg, 0.5 mg to 5 mg, 0.05 mg to 2 mg, 0.1 mg to 2 mg, 0.125 mg
to 2 mg, 0.25 mg to 2 mg, 0.5 mg to 2 mg of corticosteroid. These
dose amounts are suitable for the corticosteroids of the invention,
in particular corticosteroids that are as lipophilic as or more
lipophilic than flunisolide, which corticosteroids include
beclomethasone, beclomethasone dipropionate, beclomethasone
monopropionate, budesonide, ciclesonide, desisobutyryl-ciclesonide,
flunisolide, fluticasone, fluticasone propionate, mometasone,
mometasone furoate, triamcinolone acetonide.
[0198] The formulation of the invention comprises a dose of
corticosteroid in an approximate solution volume of 10 .mu.l to 100
ml, 50 .mu.l to 50 ml, 50 .mu.l to 10 ml, 0.1 to 10 ml, 0.1 ml to
less than 10 ml, 0.1 ml to 7.5 ml, 0.1 ml to 5 ml, 0.1 ml to 3 ml,
0.1 ml to 2 ml, 0.1 ml to 1 ml, 0.05 ml to 7.5 ml, 0.05 ml to 5 ml,
0.05 ml to 3 ml, 0.05 ml to 2 ml, or 0.05 ml to 1 ml.
[0199] Due to the wide range of nebulizer reservoir volumes
available and of varying dose requirements among the
corticosteroids, a formulation of the invention can comprise 1
.mu.g to 20 mg of corticosteroid in 0.01 ml to 100 ml of solution
volume.
[0200] In general, a multi-use suspension-based unit dose
formulation of corticosteroid contains approximately 0.125 to 2 mg
of corticosteroid suspended in 1 to 100 ml of liquid carrier. A
multi-use formulation actually contains two or more unit doses of
corticosteroid. Single unit dose aliquots are taken from a
multi-use unit dose formulation, and the single unit dose are
typically administered one-at-a-time to a subject. As a result,
about 10 to 500 mg of SAE-CD, be it in solid form or dissolved in a
liquid carrier, is added to each ml the suspension in order to
dissolve a substantial portion of the corticosteroid and form a
multi-use unit dose liquid formulation that is then administered to
a subject in single unit dose aliquots.
[0201] One aspect of the invention is that a suspension-based unit
dose formulation is converted to a liquid unit dose formulation
prior to pulmonary administration via inhalation (of a nebulized
mist) to a subject. The conversion can take place in the same
container in which the suspension is provided, in a different
container, or in the reservoir of a nebulizer. In order to form a
liquid formulation, a substantial portion of the corticosteroid
must be dissolved. As used in reference to the amount of dissolved
corticosteroid, a "substantial portion" is at least 20% wt., at
least 30% wt., at least 40% wt., or at least 20% wt and less than
50% wt. of the corticosteroid. As used in reference to the amount
of dissolved corticosteroid, a "major portion" is at least 50% wt.
of the corticosteroid.
[0202] It is well known that pharmacists working in compounding
pharmacies can and do prepare a suspension-based unit dose
formulation comprising corticosteroid. Such pharmacists will now be
able to prepare a single use or multi-use liquid unit dose
formulation by employing a method described herein. Alternatively,
a subject (patient) undergoing corticosteroid treatment may convert
the suspension-based formulation to a liquid formulation of the
invention by employing a method described herein. Instead of
preparing the liquid formulation from the suspension at the
pharmacy, a kit containing the suspension formulation and SAE-CD
can be prepared.
[0203] The concentration of SAE-CD in solution can be expressed on
a weight to weight or weight to volume basis; however, these two
units are interconvertible. When a known weight of cyclodextrin is
dissolved in a known weight of water, the % w/w cyclodextrin
concentration is determined by dividing the cyclodextrin weight in
grams by the total weight (cyclodextrin+water weight) in like units
and multiplying by 100. When a known weight of cyclodextrin is
dissolved to a known total volume, the % w/v cyclodextrin
concentration is determined by dividing the cyclodextrin weight in
grams by the total volume in milliliters and multiplying by 100.
The correlation between the two cyclodextrin concentration
percentages was experimentally determined by preparing various %
w/w cyclodextrin solutions and measuring the density of each with a
pycnometer at 25.degree. C. The density (g/mL) of each % w/w
CAPTISOL solution is presented in the table below. TABLE-US-00009
Captisol Density Viscosity % w/w (g/mL) (Cp, 25 C.) 59.4 1.320
527.0 49.4 1.259 51.9 39.7 1.202 17.0 29.8 1.149 5.91 19.7 1.095
2.78 8.5 1.041 1.75 0.0 1.002 1 slope = 0.0053 y-intercept = 0.995
correlation = 0.9989
[0204] The resulting linear relationship readily enables the
conversion of CAPTISOL concentrations expressed in % w/w to that of
% w/v by the following equation: % w/v=((% w/w*slope)+y-intercept)*
% w/w where the slope and intercept values are determined from a
linear regression of the density data in the table. For example, by
using the above equation, a 40% w/w CAPTISOL solution would be
equivalent to a .about.48.3% w/v CAPTISOL solution.
[0205] The performance of an inhalable solution of the invention in
a nebulizer may depend upon the viscosity of the solution in its
reservoir, the nebulization solution. The viscosity of an aqueous
solution of SBE7-.beta.-CD changes with respect to concentration
approximately as indicated in the table above. Viscosity of the
inhalable composition can have an impact on percentage of
nebulization composition emitted from a nebulizer, output rate of
nebulized corticosteroid and droplet size distribution.
[0206] The amount of residual nebulization inhalable composition
left in the reservoir of the nebulizer may be greater for solutions
containing SAE-CD than for a budesonide-containing suspension. For
example, FIG. 4 depicts a chart of the estimated percentage of
nebulization composition emitted from three different nebulizers
(PARI LC PLUS, HUDSON UPDRAFT II NEB-U-MIST, and MYSTIQUE) for each
of four different nebulization compositions (PULMICORT RESPULES
suspension, 5% w/w SBE7-.beta.-CD solution, 10% w/w SBE7-.beta.-CD
solution and 20% w/w SBE7-.beta.-CD solution). The PULMICORT
RESPULES suspension was used as the control. The PARI LC PLUS,
MYSTIQUE and HUDSON nebulizers were used for the comparison. The
MYSTIQUE nebulizer was unable to nebulize the suspension and
concentrated SAE-CD solution (20% w/w) efficiently so they were not
evaluated with that nebulizer. The results suggest that, under the
conditions tested, nebulization of PULMICORT RESPULES suspension
results in a greater percentage of nebulized composition, meaning
that, with the suspension, less nebulization composition is left in
the reservoir of the nebulizer upon completion of nebulization as
compared to with the solution. In some cases, nebulization of the
suspension resulted in the greatest percentage by weight of total
composition emitted by a nebulizer. In other words, under similar
nebulization conditions, the PARI LC PLUS and HUDSON nebulizers
more efficiently reduced the volume of nebulization suspension than
of nebulization solution; however, this did not correspond with the
total amount of drug emitted by the nebulizer.
[0207] Output rate of an SAE-CD nebulization solution versus that
of a suspension, each containing budesonide, was compared. A
modified version of the method of Example 10 was followed to
determine output rate. The tables below summarize the data
observed. TABLE-US-00010 2 minutes Total Bud Total Neb Total Neb
Out Put Rate Total Bud recvr'd Recovered Time Time 2 minutes Out
Put Rate Sample ID (ug) (ug) (min:sec) (min) (ug/min) (ug/min)
1-PUL-1 84.021 164.199 5:34 5.57 42.01 29.48 1-PUL-2 90.395 175.63
4:58 4.97 45.20 35.34 1-PUL-3 82.046 174.546 4:45 4.75 41.02 36.75
Mean 171.458 Mean 42.74 33.85 SD 6.310 SD 2.18 3.85 CV 3.680 CV
5.10 11.38 2-P5C-1 131.412 258.894 5:42 5.7 65.71 45.42 2-P5C-2
126.945 246.987 5:36 5.6 63.47 44.10 2-P5C-3 128.464 236.371 5:33
5.55 64.23 42.59 Mean 247.417 Mean 64.47 44.04 SD 11.268 SD 1.14
1.42 CV 4.554 CV 1.76 3.22
[0208] Data obtained using a PARI LC PLUS nebulizer equipped with a
PARI PRONEB ULTRA air compressor. TABLE-US-00011 2 minutes Total
Bud Total Neb Total Neb Out Put Rate Total Bud recvr'd Recovered
Time Time 2 minutes Out Put Rate Sample ID (ug) (ug) (min:sec)
(min) (ug/min) (ug/min) 10-PUL-1 11.200 27.926 5:20 5.33 5.60 5.24
10-PUL-2 29.015 40.11 4:15 4.25 14.51 9.44 10-PUL-3 25.363 30.516
4:17 4.28 12.68 7.13 Mean 32.851 Mean 10.93 7.27 SD 6.419 SD 4.71
2.10 CV 19.539 CV 43.05 28.93 11-P5C-1 41.049 98.155 5:47 5.78
20.52 16.98 11-P5C-2 44.495 131.8 6:00 6 22.25 21.97 11-P5C-3
53.374 132.31 5:55 5.92 26.69 22.35 Mean 120.755 Mean 23.15 20.43
SD 19.574 SD 3.18 2.99 CV 16.210 CV 13.73 14.66
[0209] Data obtained using a MYSTIQUE ultrasonic nebulizer.
[0210] All of the above formulations contain approximately 250
.mu.g/mL of budesonide. The samples identified as "P5C" contain 50
mg/mL (or about 5%) SBE7-.beta.-CD.
[0211] The table below shows the nebulizer output rate for
solutions containing various levels of SAE-CD. TABLE-US-00012
Nebulizer % Emitted Viscosity Volume (By Weight Nebulization Time
Sample ID (Cp) (ml) Difference) (Minutes:Seconds) Output Rate 21.5%
w/w 3.06 3 47.47 10:51 4.52 SBE7-.beta.-CD 10.75% w/w 1.84 3 51.36
8:53 6.02 SBE7-.beta.-CD 5.15% w/w 1.23 3 55.47 9:59 5.78
SBE7-.beta.-CD H.sub.2O 3 50.36 9:21 5.47
[0212] Surprisingly, nebulization of the SAE-CD-containing solution
provided a higher budesonide output rate than nebulization of the
PULMICORT RESPULES suspension even though the nebulizer emitted a
greater total amount of the suspension. Higher SAE-CD
concentrations, above 25% w/v led to slightly longer nebulization
times and lower output rates once the viscosity exceeded an
approximate upper limit.
[0213] Without being held bound to a particular mechanism, it is
believed that the nebulizer preferentially nebulizes the water
(supernatant) of the suspension rather than the particles of the
suspension thereby causing an increase in the molar concentration
of budesonide in the suspension in the reservoir. Since the
corticosteroid is dissolved in the solution of the invention, this
type of separation does not occur to a significant degree. As a
result, the rate of increasing concentration of corticosteroid in
the reservoir is lower for a solution than it is with a suspension.
Further support for this phenomenon is detailed in the following
table. TABLE-US-00013 RIC RIC over 2 over min. TTS, Initial Final
mcg/mL mcg/mL Conc Conc per min per min Pulmicort 250 572 31.26
64.37 Respules CEB 250 398 14.96 26.69
[0214] The data above was obtained by comparing the nebulization of
a solution of the invention (CEB, SAE-CD, 5% wt./v, 2 ml;
budesonide, 250 .mu.g/ml) and PULMICORT RESPULES suspension 2 ml;
budesonide, 250 .mu.g/ml) using a PARI LC+ equipped with a PARI
PRONEB ULTRA air compressor. The concentration of budesonide in the
reservoir was measured at two minutes and at time to sputter (TTS).
The rate of increasing concentration (RIC) of the corticosteroid in
the solution in the reservoir was then calculated for each
formulation over each interval of time. The RIC of the solution of
the invention provided an approximately 48% decrease in the RIC
over two minutes and an approximately 42% decrease in the RIC over
the TTS. In some embodiments, the percentage decrease in the RIC
ranges from 10% to 60%, 15% to 60%, 20% to 60%, 30% to 60%, or 40%
to 60%. In some embodiments, the system may provide a RIC of 0 to
40, 1 to 40, 5 to 30, or 10 to 30 mcg of corticosteroid/mL of
solution volume per min of operation/nebulization.
[0215] Accordingly, the invention provides a system for
administration of a corticosteroid by nebulization comprising: a
nebulizer comprising a reservoir; and an inhalable aqueous
composition comprising SAE-CD and a dose of corticosteroid, whereby
the system provides a reduced RIC for the corticosteroid in the
reservoir as compared to the RIC provided by a suspension
comprising approximately the same amount of corticosteroid and
volume of aqueous composition operated under approximately the same
conditions.
[0216] Based on data above, 21.5.+-.5% w/w SBE7-.beta.-CD
concentration was identified as the approximate upper acceptable
level for the nebulizer tested, "acceptable" being defined as the
upper concentration of SBE7-.beta.-CD that can be used without
building up excessive viscosity, which may adversely affect the
nebulization time and output rate. The practical upper limit for
concentration of SAE-CD will vary among the nebulizer formats. The
upper acceptable concentration of SAE-CD in a liquid formulation
for use in a nebulizer may vary according to the DS of the
derivative, the alkyl chain length of the sulfoalkyl functional
group, and/or the CD ring size of the SAE-CD.
[0217] For administration to the respiratory tract, particularly
the lungs, a nebulizer is used to produce appropriately sized
droplets. Typically, the particle size of the droplet produced by a
nebulizer for inhalation is in the range between about 0.5 to about
5 microns. If it is desired that the droplets reach the lower
regions of the respiratory tract, i.e., the alveoli and terminal
bronchi, the particle size range can be between about 0.5 and about
2.5 microns. If it is desired that the droplets reach the upper
respiratory tract, the particle size range can be between 2.5
microns and 5 microns.
[0218] As noted above, viscosity of the nebulization composition
can impact droplet size and droplet size distribution. For example,
the present formulations tend to form larger droplets, in terms of
Dv50, at the lower concentrations, and thereby lower viscosity, of
SAE-CD in the absence of budesonide. FIGS. 5a-5b depict droplet
size data for nebulization of inhalable compositions with a PARI LC
PLUS nebulizer. For each of the figures, a MALVERN laser light
scattering device (Mastersizer S, Malvern Instruments Ltd. Malvern,
Worcs, U.K.) was used to measure MMAD. FIG. 5a depicts the results
obtained using .gamma.-CD solutions of varying concentrations (5%
w/v, 10% w/v and 20% w/v) in the absence of budesonide. The results
indicate that .gamma.-CD on its own would not behave acceptably in
a nebulizer, since almost all of the mass of the solution is of an
unacceptable droplet size range. Even with extensive recycling and
droplet size selection by a nebulizer, a .gamma.-CD based
nebulization solution containing corticosteroid would require an
extremely long dosing period due to the low percentage of mass that
is of the appropriate droplet size range, especially since
.gamma.-CD is not an effective solubilizer of budesonide at the
concentrations tested.
[0219] In comparison, FIG. 5b depicts the results obtained using
the same nebulizer with PULMICORT RESPULES suspension or a modified
PULMICORT RESPULES solution containing SAE-CD of different
concentrations (5% w/v, 10% w/v and 20% w/v). With each of these
samples, a significant portion of the nebulized mass is of a
respirable size range. Moreover, the solutions containing SAE-CD
apparently form droplets that are comparable in size to those of
the nebulized suspension.
[0220] FIG. 6 depicts droplet size data for nebulization of
inhalable compositions with a HUDSON UPDRAFT II NEBUMIST nebulizer
charged with PULMICORT RESPULES suspension or a solution containing
SAE-CD at different concentrations. (5% w/v, 10% w/v and 20% w/v).
As compared to the PARI LC PLUS nebulizer, the NEB-U-MIST forms a
slightly larger particle size distribution, a significant portion
of the nebulized mass is still in the appropriate size range.
Accordingly, the nebulization solution made from the suspension and
containing SAE-CD is suitable for use in a variety of different air
driven jet nebulizers.
[0221] The package insert for PULMICORT RESPULES suspension states
that the suspension should not be nebulized with an ultrasonic
nebulizer. FIG. 7 depicts droplet size data for nebulization of
inhalable compositions with a MYSTIQUE ultrasonic nebulizer. The
compositions include three different SAE-CD containing solutions.
Unlike the suspension, the SAE-CD containing solution can be
nebulized with an ultrasonic nebulizer. Thus, the invention
provides a method of improving the pulmonary delivery of
corticosteroid in a suspension-based unit dose formulation from an
ultrasonic nebulizer, the method comprising the step of including
SAE-CD in the formulation in an amount sufficient to decrease the
amount of undissolved corticosteroid in the suspension-based unit
dose formulation.
[0222] The performance of nebulization compositions across a range
of nebulizers is typically compared by comparing the Dv50 of the
droplet size distribution for the respective compositions. FIG. 8
depicts comparative Dv50 droplet size data for nebulization of an
inhalable composition with the three above-mentioned nebulizers. In
each case, the SAE-CD containing solutions are suitable for
administration by nebulization across a range of concentrations.
Moreover, the droplet size distribution can be partially controlled
by adjusting the concentration of SAE-CD.
[0223] FIG. 9 is a graph depicting the relationship between
concentration of SAE-CD versus output rate of SAE-CD in various
different nebulizers with different sources of compressed air
required for the specific setup: the RAINDROP-Rat, RAINDROP-Dog,
PARI LC STAR-UNC, PARI LC STAR-Rat PARI LC PLUS and DEVILBISS PULMO
AIDE air jet driven nebulizers. The nebulizers were used in a
variety of setups including free standing as well as animal
exposure chambers and/or individual exposure masks. In general, the
data demonstrate that output of SAE-CD increases with increasing
SAE-CD concentration. Depending upon the nebulizer used, the
conditions under which the nebulizer is operated and the
concentration of SAE-CD in solution, different maximum output rates
can be achieved. For example, the maximum output rate in the
Raindrop-Dog setup is from a 250 mg/mL CAPTISOL concentration.
[0224] Even though nebulization of PULMICORT RESPULES suspension
with an ultrasonic nebulizer is not recommended, it can be
achieved. FIGS. 10a-10b depict comparative droplet size data for
nebulization solutions with the PARI LC PLUS and MYSTIQUE
nebulizers of PULMICORT RESPULES suspension and a modified
PULMICORT RESPULES-based SAE-CD solution. PULMICORT RESPULES
suspension with and without 5% w/v SBE7-.beta.-CD were used as the
test samples. The procedure of Example 12 was followed. FIG. 10a
depicts the Dv10 and Dv50 data for the solutions run on the PARI LC
PLUS air driven jet nebulizer and FIG. 10b depicts the Dv10 and
Dv50 data for the solutions run on the MYSTIQUE ultrasonic
nebulizer. In each case, the droplet size data for the two
different solutions is comparable. However, the budesonide output
rate for the two solutions was significantly different. Use of
SAE-CD in a nebulization composition, however, results in an
increased output rate of budesonide regardless of the format of the
nebulizer. The invention, thus, provides a method of increasing the
output rate of a corticosteroid-containing suspension-based unit
dose formulation being delivered by a nebulizer, the method
comprising the step of including SAE-CD in the formulation in an
amount sufficient to increase the amount of dissolved
corticosteroid in the formulation to form an altered formulation,
whereby the output rate of corticosteroid for the altered
formulation is greater than the output rate of corticosteroid for
the suspension formulation.
[0225] Two pulsating membrane nebulizers (AERONEB GO and the
nebulizer of U.S. Pat. No. 6,962,151) were evaluated according to
Examples 21 and 22, respectively, to determine the performance of
the devices with a solution of the invention and to demonstrate the
utility of using concentrated solutions of corticosteroids in an
efficient electronic nebulizer. Several in vitro parameters,
important for the clinical use of corticosteroids, were determined
and compared to these parameters of the solution formulation
described in Example 6 and the 2 mL commercial reference suspension
both in an air jet nebulizer. The total delivery/nebulization time
(time to sputter where production of aerosol is no longer visible),
MMAD droplet size and fine particle fraction parameters were
obtained for each device. A cascade impactor was engaged with the
output of each device to determine performance during nebulization
and characterize the in vitro aerosol drug output.
[0226] The solution used in the AERONEB GO device was compared
side-by-side with a RAINDROP air jet nebulizer employing a solution
(0.5 ml) comprising budesonide (500 .mu.g/0.5 ml), CAPTISOL (10%
w/v), water, and Tween 80 (optional), wherein the solution was made
by adding CAPTISOL to a suspension of budesonide particles
(RESPULES) as detailed below. In each device, the control
suspension-based sample was the RESPULES suspension (2 ml
containing 500 .mu.g of budesonide). The RAINDROP nebulizer was
equipped with a PARI PRONEB ULTRA compressor. The AERONEB GO
micropump nebulizer was equipped with the OnQ Aerosol Generator.
The total output of budesonide at cessation of aerolization (at
sputter) was quantified. The emitted dose and fine particle dose
were measured with the cascade impactor. The solution in the
nebulizer of the '151 Patent comprised budesonide, CAPTISOL, water,
and technetium-99 radiolabel in the form of
diethylenetriaminepenta-acetic acid as a surrogate marker for
budesonide. The data from the two studies is summarized in the
table below. TABLE-US-00014 Aerosol Performance Using NGI Cascade
Impactor Nebulizer device Raindrop/Pari AeroNeb Go Proneb Ultra
Formulation CEB #1 Pulmicort CEB #2 Pulmicort Amount of drug
(.mu.g)* 500.00 500.00 500.00 500.00 Nebulization Time (min)+ 1.0
4.0 5.0 5.5 Amt of drug exiting nebulizer 405.93 266.06 150.27
92.42 (.mu.g)* Percent of drug exiting 81.26 53.24 30.03 18.49
nebulizer (%) Amt of drug exiting nebulizer 262.17 131.73 131.44
76.27 in fine particle fraction (% <5 .mu.m) (.mu.g)* Percent of
drug exiting 66.33 49.54 87.43 82.55 nebulizer in fine particle
fraction (<5 .mu.m,) Percent of total drug in fine 53.91 26.38
26.27 15.26 particle fraction (<5 .mu.m, %) MMAD (um, estimated
by 4.10 5.54 2.22 2.86 linear regression) GSD (sigma g, estimated
by 2.02 1.55 2.37 2.21 linear regression) *Data normalized to 500
.mu.g budesonide in each nebulizer using total of recovered drug.
+Note: Nebulizers were run 30 seconds past end of nebulization time
to insure complete emptying into the NGI impactor.
[0227] Using the electronic pulsating membrane nebulizers (AERONEB
GO nebulizer and the nebulizer of the '151 Patent), delivery of a
unit dose of corticosteroid was completed within less than one
minute. The RAINDROP nebulizer completed delivery of a unit dose in
just over 5.5 min with the RESPULES and just over 5 min with a
solution of the invention. In addition, the pulsating membrane
nebulizers delivered a substantially greater percentage of
corticosteroid in the FPF, which is generally defined as the
fraction of particles less than 5.mu. or the fraction of particles
on cascade impactor stages with a cut-off of less than 6.mu..
Accordingly, the total nebulization time of the AERONEB GO is one
fourth the time to sputter for the Pari LC+ air jet nebulizer. As a
result, treatment time would be reduced with the pulsating membrane
nebulizer as compared to the air jet nebulizer, and the amount of
budesonide emitted from the pulsating membrane nebulizer is 2 to 3
times more than from the air jet nebulizer. It was also determined
that the percent of drug exiting the nebulizer (the emitted dose)
was 81% of the amount initially loaded into the reservoir (the
nominal dose). Hence, less drug would need to be loaded into the
pulsating membrane nebulizer to treat the patient in need thereof
to provide the same "dose to subject" as provided by an air jet
nebulizer.
[0228] Aerosol droplet size was determined using a Malvern Spraytec
instrument. The Dv10, Dv50, and Dv90 from the pulsating membrane
nebulizer are very similar to those for the reference product
(PULMICORT RESPULES) and a CAPTISOL solution of the same
concentration in an air jet nebulizer. This suggests that the
formulation would be similarly distributed within the patient after
inhalation.
[0229] A clinical study according to Example 17 was conducted to
compare the pulmonary disposition of budesonide from a radiolabeled
liquid formulation and the clearance of budesonide from the lung as
determined by appearance of budesonide in the plasma. A solution
formulation of the invention was compared to a suspension-based
formulation of budesonide. At various times up to 24 hours, plasma
samples were collected and assayed for budesonide and various
pharmacokinetic parameters determined. The area under the plasma
concentration-time curve (AUC) is a measure of the delivery of
budesonide to the lung, since oral absorption of the corticosteroid
was blocked by the administration of charcoal. A comparison of the
AUC data was made by consideration of the dose delivered to each
subject ("dose to subject") or dose delivered to the lungs of each
subject ("dose to lung") or dose emitted by the nebulizer or device
("emitted dose") or dose available for nebulization or delivery
("nominal dose" or "nominal available dose" or "loaded dose"). The
AUC data (.sub.0-t, and .sub.0-.infin.) was normalized in terms of
the budesonide (.mu.g) delivered to each subject by dividing the
AUC data by the corresponding dose to subject. As used herein the
term "dose to subject" is taken to mean the amount of
corticosteroid delivered to a subject following completion of a
dosing cycle with a nebulizer and is calculated by subtracting the
sum of drug remaining in the nebulizer, drug removed from the mouth
of a subject, and the amount collected from the exhalation filter
from the amount of drug initially present in the reservoir of the
nebulizer. The following expression can be used to calculate the
dose to subject (Ds): Ds=Dr.sub.init-(D.sub.mw+D.sub.dev), wherein
Dr.sub.init denotes the amount of drug initially present in the
reservoir of the nebulizer, D.sub.mw denotes the amount of drug
removed from the mouth of a subject by using a mouthwash, D.sub.deV
denotes the amount of drug remaining in the device following
completion of an administration dosing cycle. The term D.sub.dev
includes drug remaining in the reservoir after completion of
dosing, and drug remaining in the remainder of the device after
completion of dosing. As used herein, the term "dose to lung" is
taken to mean the amount of drug delivered to the lungs of a
subject, which amount is a subset of "dose to subject". The dosing
parameters used in this example are detailed below and are provided
on the basis of arithmetic means. TABLE-US-00015 Arithmetic Means
Pulmicort Parameter Captisol Enabled Budesonide Respules
Normalization or Ratio 25% TTS 50% TTS 75% TTS 100% TTS Intended
.mu.g 1000 1000 1000 1000 Nominal Ratio 1 1 1 1 Loaded Dose CEB/PR
Nominal .mu.g 250 500 750 1000 Available Ratio 0.25 0.50 0.75 1
Dose CEB/PR Dose to Lung .mu.g 39.56 63.85 94.38 90.17 Range =
Range = Range = Range = 24.61.fwdarw.65.65 48.27.fwdarw.80.70
72.81.fwdarw.123.79 76.21.fwdarw.100.75 Ratio 0.44 0.72 1.05 1
CEB/PR Range = Range = Range = 0.27.fwdarw.0.78 0.57.fwdarw.0.95
0.87.fwdarw.1.46 Dose to .mu.g 64.1 109.1 169.8 199.9 Subject Range
= Range = Range = Range = 47.57.fwdarw.81.75 85.43.fwdarw.156.67
142.48.fwdarw.219.03 159.58.fwdarw.249.88 Ratio 0.33 0.55 0.86 1
CEB/PR Range = Range = Range = 0.23.fwdarw.0.48 0.41.fwdarw.0.64
0.74.fwdarw.1.04 Emitted Dose .mu.g 119.5 205.9 321.8 440.2 Range =
Range = Range = Range = 93.40.fwdarw.166.2 164.0.fwdarw.272.9
277.9.fwdarw.391.0 396.7.fwdarw.481.10 Ratio 0.27 0.47 0.73 1
CEB/PR Range = Range = Range = 0.20.fwdarw.0.37 0.41.fwdarw.0.57
0.66.fwdarw.0.87
[0230] The pharmacokinetic data obtained from the study of Example
17 is summarized below. The data is presented on a geometric mean
or individual subject basis. The data in the table below is based
upon the "dose to subject". TABLE-US-00016 Geometric Means
Pulmicort Captisol Enabled Budesonide Respules 25% TTS.sup.1 50%
TTS.sup.1 75% TTS.sup.1 100% TTS Dose to Dose to Dose to Dose to
Subject = 62.7 .mu.g Subject = 107.1 .mu.g Subject = 168.2 .mu.g
Subject = 197.7 .mu.g Range.sup.3 = Range.sup.3 = Range.sup.3 =
Range.sup.3 = Parameter 47.6.fwdarw.81.8 85.4.fwdarw.156.7
142.5.fwdarw.219.0 159.6.fwdarw.249.9 Non- AUC.sub.0-t 370 875 1130
516 normalized (pg h/ml) Range = Range = Range = Range =
162.fwdarw.1209 647.fwdarw.1122 865.fwdarw.1588 378.fwdarw.631
AUC.sub.0-.infin. 533 1022 1617 644 (pg h/ml) Range = Range = Range
= Range = 279.fwdarw.1309 778.fwdarw.1285 978.fwdarw.2351
421.fwdarw.864 Normalized AUC.sub.0-t 6 8 7 3 for dose to (pg
h/ml)/ Range = Range = Range = Range = subject .mu.g 3.fwdarw.15
7.fwdarw.11 4.fwdarw.11 2.fwdarw.5 AUC.sub.0-.infin. 8 10 10 3 (pg
h/ml)/ Range = Range = Range = Range = .mu.g 4.fwdarw.16
8.fwdarw.12 5.fwdarw.16 2.fwdarw.5 .sup.1TTS = Time to Sputter. The
percentage value can be used to calculate a nominal available dose
for the corticosteroid in the study conducted according to Example
17. .sup.2Using the added radioactive tracer, the dose of
budesonide delivered may be calculated by subtracting the amount of
budesonide remaining in the nebulizer post-dose, on the exhalation
filter, and in the mouthwash from the amount initially added to the
nebulizer. .sup.3The ranges in the table above are based upon the
geometric means for a respective value as determined with each
individual.
[0231] Based upon the above data, the formulation of the invention
provides a normalized AUCt of 3-15 (or about at least 6)
(pg*h/ml)/.mu.g of budesonide when about 60-65 .mu.g of budesonide
were delivered, a normalized AUCt of 7-11 (or about at least 8)
(pg*h/ml)/.mu.g of budesonide when about 105-110 .mu.g of
budesonide were delivered, and a normalized AUCt of 4-11 (or about
at least 7) (pg*h/ml)/.mu.g of budesonide when 165-170 .mu.g of
budesonide were delivered, based upon the "dose to subject". In
addition, the formulation of the invention provided a normalized
AUCi of 4-16 (or about at least 8) (pg*h/ml)/.mu.g of budesonide
when about 60-65 .mu.g of budesonide were delivered, a normalized
AUCi of 8-12 (or about at least 10) (pg*h/ml)/.mu.g of budesonide
when about 105-110 .mu.g of budesonide were delivered, and a
normalized AUCi of 5-16 (or about at least 10) (pg*h/ml)/.mu.g of
budesonide when 165-170 .mu.g of budesonide were delivered, based
upon the "dose to subject". The data is also summarized in FIG. 17,
which is a plot of the geometric mean of "dose to subject" (.mu.g
budesonide) versus the geometric mean of AUC (pg*h/ml), and FIG.
18, which is a plot of the geometric mean of "dose to lung" (.mu.g
budesonide) versus the geometric mean of AUC (pg*h/ml).
[0232] In some embodiments, the invention includes a method of
providing in a subject a mean plasma AUCt, normalized for dose of
corticosteroid to subject, of at least 6 (pg*h/ml)/.mu.g of
corticosteroid delivered, as dose to subject, comprising:
administering to the subject via nebulization a unit dose
comprising at least 45 .mu.g, at least 48 .mu.g, or 45 .mu.g to
1000 .mu.g, about 1 .mu.g to 20 mg, about 1 .mu.g to 10 mg, 0.01 mg
to 10 mg, 0.025 mg to 10 mg, 0.05 mg to 5 mg, 0.1 mg to 5 mg, 0.125
mg to 5 mg, 0.25 mg to 5 mg, 0.5 mg to 5 mg, 0.05 mg to 2 mg, 0.1
mg to 2 mg, 0.125 mg to 2 mg, 0.25 mg to 2mg, or 0.5 mg to 2 mg of
corticosteroid dissolved in an aqueous liquid carrier comprising
sulfoalkyl ether cyclodextrin.
[0233] FIG. 19 is a plot of the "dose to subject" (.mu.g
budesonide) versus the corresponding AUC (pg*h/ml) for each
individual subject of the study. The slope of the substantially
linear solid line, taken from data across three different doses
delivered, defines a dose response curve for a patient receiving
the corticosteroid. As a result, the slope can be used to predict
the dose a patient would need to provide a target plasma level at a
second dose if the patient has received a first dose and the
patient's AUC per .mu.g of corticosteroid has been determined. The
slope ranges from 5.7 to 16, or more specifically from 9 to 10,
when the data is viewed on an individual subject basis
[0234] The plasma concentration profile for budesonide for the
subjects of the clinical study is depicted in FIG. 20.
[0235] This normalized AUC data and associated radiolabel
distribution data show that more of the dose delivered to the
subject made it into the lung and from there into systemic
circulation when budesonide was administered as a solution than
when the budesonide was administered as a suspension. Assuming that
an equivalent dose deposited in the lung results in a similar
efficacy and systemic absorption, these results suggest that 1.6 to
5 times or 2 to 4 times less dose to subject is required when
administered in solution to be as effective as the reference
suspension product. Depending upon whether it is determined on an
individual basis or a geometric mean basis, administration of a
solution of the invention provides a 1.6-fold increase, 2.2-fold
increase, a 2.5-fold increase, a five-fold increase, a 1.6 to five
fold increase, a two to four-fold increase, a two to 3.5-fold
increase, a two to 3.3-fold increase or at least a two-fold
increase in the AUCt or AUCi per .mu.g of budesonide delivered as
compared to administration of the PULMICORT RESPULES
suspension-based aqueous formulation. The AUCt or AUCi per .mu.g of
budesonide delivered was observed as varying per individual, with
the value being higher than the above-noted values for some
individuals and lower than the above-noted values for other
individuals.
[0236] The data in the table below is based upon the various
different doses measured or determined during the study and
summarizes the level (factor) of enhancement in the pharmacokinetic
profile parameter C.sub.max non-normalized or normalized on the
basis of nominal available dose, dose to lung, dose to subject, or
emitted dose. TABLE-US-00017 Geometric Means Pulmicort Parameter
Captisol Enabled Budesonide Respules Normalization or Ratio 25% TTS
50% TTS 75% TTS 100% TTS Non- C.sub.max 225.8 437.2 545.5 266.3
normalized (pg/mL) Range = Range = Range = Range =
91.6.fwdarw.483.3 297.1.fwdarw.739.1 376.6.fwdarw.891.6
155.8.fwdarw.331.5 Ratio 0.85 1.64 2.05 1 CEB/PR Range = Range =
Range = 0.55.fwdarw.1.55 0.90.fwdarw.2.60 1.50.fwdarw.2.86
Normalized (pg/mL) 0.90 0.87 0.73 0.27 for nominal .mu.g Range =
Range = Range = Range = available 0.37.fwdarw.1.93 0.59.fwdarw.1.48
0.50.fwdarw.1.19 0.16.fwdarw.0.33 dose.sup.1 Ratio 3.39 3.28 2.73 1
CEB/PR Range = Range = Range = 2.20.fwdarw.6.21 1.79.fwdarw.5.20
2.01.fwdarw.3.82 Normalized (pg/mL) 6.03 6.93 5.86 2.97 for dose to
.mu.g Range = Range = Range = Range = lung.sup.2 3.49.fwdarw.8.51
5.49.fwdarw.9.16 4.52.fwdarw.7.45 1.59.fwdarw.3.95 Ratio 2.03 2.33
1.97 1 CEB/PR Range = Range = Range = 1.48.fwdarw.2.59
1.56.fwdarw.4.30 1.38.fwdarw.3.17 Normalized (pg/mL) 3.60 4.08 3.24
1.35 for dose to .mu.g Range = Range = Range = Range =
subject.sup.3 1.93.fwdarw.5.94 3.22.fwdarw.7.44 1.72.fwdarw.5.23
0.75.fwdarw.1.85 Ratio 2.67 3.03 2.41 1 CEB/PR Range = Range =
Range = 1.99.fwdarw.3.21 2.17.fwdarw.5.01 1.72.fwdarw.3.76
Normalized (pg/mL) 1.93 2.15 1.71 0.61 for emitted .mu.g Range =
Range = Range = Range = dose.sup.4 0.98.fwdarw.2.91
1.71.fwdarw.3.25 1.00.fwdarw.2.68 0.34.fwdarw.0.84 Ratio 3.18 3.55
2.82 1 CEB/PR Range = Range = Range = 2.19.fwdarw.4.20
2.17.fwdarw.6.26 1.93.fwdarw.4.23
[0237] According to the table above, the formulation and system of
the invention can provide a C.sub.max (pg/ml) of 90 to 900, 200 to
600, 200 to 550, 200 to 250, 400 to 450, 500 to 600, 225, 437, or
545 on a dose non-normalized basis. The formulation and system of
the invention can provide a dose normalized C.sub.max (pg/ml/.mu.g)
of: 1) 0.3 to 2, 0.35 to 2, 0.6 to 1.5, 0.5 to 1.2, 0.8 to 1, 0.8
to 0.9, 0.7 to 0.8, 0.4, 1.9, 0.6, 1.5, 0.5, 1.2, 0.35, 2, 0.7,
0.8, or 0.9 on a nominal available dose normalized basis; 2) 3.4 to
9.2, 3.5 to 8.5, 5.5 to 9.2, 4.5 to 7.5, 5.8 to 7, 3.4, 3.5, 4.5,
5.5, 9.2, 8.5, 7.5, 5.8, 5.9, 6, or 7 on a dose to lung normalized
basis; 3) 1.7 to 7.5, 3.2 to 4.1, 1.9 to 6, 3.2 to 7.5, 1.7 to 5.2,
3.6, 4.1, 3.2, 1.9, 6, 3.2, 7.4, 7.5, 1.7, 5.2 or 5.3 on a dose to
subject normalized basis; 4) 0.9 to 3.3, 1.7 to 2.2, 0.9 to 3, 1 to
3, 1.7 to 3.3, 1 to 2.7, 1.9, 2.1, 2.2, 1.7, 0.9, 1, 2, 3, 2.9,
3.2, 3.3, or 2.7 on an emitted dose normalized basis.
[0238] The solution of the invention provides an enhanced
pharmacokinetic profile over the suspension-based formulation. On
the basis of the non-normalized dose of corticosteroid, the Cmax
provided by the corticosteroid solution is 1.6 to 2, 1.5 to 3, 1.5
to 2.5, 1.5 to 2, 1.5, 1.6, 2, 2.5, or 3 fold higher than the Cmax
provided by the suspension-based formulation when the dose of
corticosteroid in the solution and the suspension is approximately
the same amount loaded. On the basis of normalization to the
nominal available dose of corticosteroid, the Cmax provided by the
corticosteroid solution is 1.8 to 6.2, 1.5 to 6.5, 2 to 6.5, 1.5 to
5.5, 2 to 4, 1.5 to 4, 1.5 to 3, 2.7, 3.3, 3.4, 1.5, 6.5, 2, 5.5,
4, or 3 fold higher than the Cmax provided by the suspension-based
formulation. On the basis of normalization to the dose of
corticosteroid to lung, the Cmax provided by the corticosteroid
solution is 1.4 to 4.3, 1.4 to 4.5, 1.5 to 4.5, 1.5 to 3.5, 1.5 to
3, 1.4 to 3, 1.5 to 2.5, 1.5 to 2, 2, 2.3, 1.4, 4.5, 3.5, 3, 1.5 or
2.5 fold higher than the Cmax provided by the suspension-based
formulation. On the basis of normalization to the dose of
corticosteroid to subject, the Cmax provided by the corticosteroid
solution is 2 to 3.5, 2 to 5, 1.7 to 3.8, 1.7 to 5, 2.7, 3, 2.4, 2,
3.5, 5, 1.7, or 3.8 fold higher than the Cmax provided by the
suspension-based formulation. On the basis of normalization to the
emitted dose of corticosteroid, the Cmax provided by the
corticosteroid solution is 1.9 to 6.3, 1.75 to 6.5, 2.2 to 4.2, 2.2
to 6.3, 1.9 to 4.2, 3.2, 3.5, 3.6, 2.8, 1.75, 6.5, 2.2, 4.2, or 6.3
fold higher than the Cmax provided by the suspension-based
formulation.
[0239] Alternatively, the Cmax provided by the corticosteroid
solution is at least 1.5, 1.6, 2, 2.6, and 3 fold higher than the
Cmax provided by the suspension-based formulation when the dose of
corticosteroid in the solution is about 2 fold lower than the dose
in the suspension.
[0240] The data in the table below is based upon the various
different doses measured or determined during the study and
summarize the level (factor) of enhancement in the pharmacokinetic
profile parameter AUC.sub.inf non-normalized or normalized on the
basis of nominal available dose, dose to lung, dose to subject, or
emitted dose. TABLE-US-00018 Geometric Means Pulmicort Parameter
Captisol Enabled Budesonide Respules Normalization or Ratio 25% TTS
50% TTS 75% TTS 100% TTS Non-normalized AUCinf 533.0 1022.2 1616.8
643.6 (pg * h/mL) Range = Range = Range = Range = 278.6.fwdarw.1309
777.5.fwdarw.1285 977.5.fwdarw.2438.2 420.6.fwdarw.864.1 Ratio 0.83
1.59 2.51 1 CEB/PR Range = Range = Range = 0.44.fwdarw.1.51
1.00.fwdarw.3.06 1.53.fwdarw.3.28 Normalized for (pg * h/mL) 2.13
2.04 2.16 0.64 nominal .mu.g Range = Range = Range = Range =
available dose 1.11.fwdarw.5.23 1.55.fwdarw.2.57 1.30.fwdarw.3.25
0.42.fwdarw.0.86 Ratio 3.31 3.18 3.35 1 CEB/PR Range = Range =
Range = 1.77.fwdarw.6.06 2.00.fwdarw.6.11 2.04.fwdarw.4.37
Normalized for (pg * h/mL) 14.24 16.20 17.37 7.17 dose to lung
.mu.g Range = Range = Range = Range = 10.17.fwdarw.19.94
13.59.fwdarw.18.77 11.16.fwdarw.24.69 5.52.fwdarw.10.22 Ratio 1.98
2.26 2.42 1 CEB/PR Range = Range = Range = 1.19.fwdarw.2.85
1.47.fwdarw.3.40 1.37.fwdarw.3.52 Normalized for (pg * h/mL) 8.50
9.54 9.61 3.26 dose to subject .mu.g Range = Range = Range = Range
= 4.23.fwdarw.16.08 8.01.fwdarw.12.23 5.41.fwdarw.16.5
1.68.fwdarw.5.14 Ratio 2.61 2.93 2.95 1 CEB/PR Range = Range =
Range = 1.60.fwdarw.3.64 2.00.fwdarw.4.87 1.93.fwdarw.3.93
Normalized for (pg * h/mL) 4.55 5.04 5.07 1.43 emitted dose .mu.g
Range = Range = Range = Range = 2.62.fwdarw.7.87 4.23.fwdarw.6.66
3.16.fwdarw.8.48 0.81.fwdarw.2.31 Ratio 3.18 3.52 3.55 1 CEB/PR
Range = Range = Range = 1.92.fwdarw.5.37 2.31.fwdarw.5.82
1.91.fwdarw.5.47
[0241] According to the table above, the formulation and system of
the invention can provide an AUC.sub.inf (pg*h/ml) of 500 to 1700,
530 to 1650, 250 to 2500, 280 to 1300, 780 to 1300, 980 to 2450,
275, 775, 980, 2400, 2500, 1300, 1290, 530, 1650, 250, 280 or 780
on a dose non-normalized basis. The formulation and system of the
invention can provide a dose normalized AUC.sub.inf (pg/ml/.mu.g)
of: 1) 1 to 5.5, 2 to 2.2, 1 to 5.3, 1.1 to 5.2, 1.5 to 2.6, 1.3 to
3.3, 2, 2.1, 2.2, 1, 5.5, 5.3, 5.2, 1.5, 2.6, 1.3 or 3.3 on a
nominal available dose normalized basis; 2) 10 to 25, 14 to 18,
10.2 to 20, 13.6 to 18.8, 11.2 to 24.7, 10.2, 20, 13.6, 14, 19,
18.8, 11, 11.2, 25, 24.7, 14.2, 16.2, 17.3 on a dose to lung
normalized basis; 3) 4 to 16, 4.2 to 16.1, 8 to 12.2, 5.4 to 16,
5.4 to 17, 8.5 to 9.6, 8.5, 9.5, 9.6, 4.2, 16.1, 8, 12.2, 12, 5.4,
16, 17, or 16.5 on a dose to subject normalized basis; 4) 2.5 to 9,
2.6 to 8.5, 4.5 to 5.1, 2.5 to 8, 2.6 to 7.9, 4.2 to 6.7, 3.1 to
8.5, 3.2 to 8.5, 4.5, 4.6, 5, 5.1, 2.5, 2.6, 4.2, 3.1, 9, 8.5, 5.1,
8, 7.9, or 6.7 to on an emitted dose normalized basis.
[0242] Accordingly, the solution of the invention provides an
enhanced pharmacokinetic profile over the suspension-based
formulation. On the basis of the non-normalized dose of
corticosteroid, the AUC.sub.inf provided by the corticosteroid
solution is 1.6 to 2.5, 1.6 to 3.1, 1.5 to 3.5, 1.5 to 3.3, 2.5 to
3.3, 3.1, 1.5, 3.3, 1.6, or 2.5 fold higher than the AUC.sub.inf
provided by the suspension-based formulation when the dose of
corticosteroid in the solution and the suspension is approximately
the same. On the basis of normalization to the nominal available
dose of corticosteroid, the AUC.sub.inf provided by the
corticosteroid solution is 1.75 to 6.5, 1.75 to 6.1, 2 to 6.5, 2 to
6.1, 2 to 4.5, 2 to 4.4, 3.3, 3.2, 3.5, 3.4, 1.75, 6.5, 6.1, 2,
4.5, or 4.4 fold higher than the AUC.sub.inf provided by the
suspension-based formulation. On the basis of normalization to the
dose of corticosteroid to lung, the AUC.sub.inf provided by the
corticosteroid solution is 1.2 to 3.5, 1.2 to 4, 1.2 to 3, 1.2 to
2.85, 1.5 to 3.5, 1.4 to 3.5, 2, 2.2, 2.3, 2.4, 1.2, 3, 4, 2.85,
1.5, 3.5, or 1.4 fold higher than the AUC.sub.inf provided by the
suspension-based formulation. On the basis of normalization to the
dose of corticosteroid to subject, the AUC.sub.inf provided by the
corticosteroid solution is 1.6 to 4.9, 1.5 to 5, 1.6 to 5, 1.6 to
3.7, 1.6 to 3.6, 2 to 4.9, 1.9 to 4, 2.6, 1.5, 5, 1.6, 3.7, 3.6, 2,
4.9, 1.9, or 4 fold higher than the AUC.sub.inf provided by the
suspension-based formulation. On the basis of normalization to the
emitted dose of corticosteroid, the AUC.sub.inf provided by the
corticosteroid solution is 1.5 to 6, 1.7 to 6, 1.9 to 6, 1.9 to
5.4, 2.3 to 5.8, 1.9 to 5.5, 1.9 to 5.8, 1.5, 6, 1.7, 1.9, 5.4,
2.3, 5.8, 5.8, 3.2, 3.5, or 3.6 fold higher than the AUC.sub.inf
provided by the suspension-based formulation.
[0243] Alternatively, the AUC.sub.inf provided by the
corticosteroid solution is at least 1.5, 1.6, 2, 2.5, 3 and 3.1
fold higher than the AUC.sub.inf provided by the suspension-based
formulation when the dose of corticosteroid in the solution is
about 2 fold lower than the dose in the suspension.
[0244] The data in the table below is based upon the various
different doses measured or determined during the study and
summarize the level (factor) of enhancement in the pharmacokinetic
profile parameter AUC.sub.last non-normalized or normalized on the
basis of nominal available dose, dose to lung, dose to subject, or
emitted dose. TABLE-US-00019 Geometric Means Pulmicort Parameter
Captisol Enabled Budesonide Respules Normalization or Ratio 25% TTS
50% TTS 75% TTS 100% TTS Non- AUCtlast 396.7 874.5 1130 516.2
normalized (pd * h/mL) Range = Range = Range = Range =
162.3.fwdarw.1209 646.7.fwdarw.1122 864.6.fwdarw.1588
377.6.fwdarw.630.9 Ratio 0.77 1.69 2.19 1 CEB/PR 0.32.fwdarw.1.92
1.14.fwdarw.2.97 1.55.fwdarw.2.93 Normalized (pd * h/mL) 1.59 1.75
1.51 0.52 for nominal .mu.g 0.65.fwdarw.4.84 1.29.fwdarw.2.24
1.15.fwdarw.2.12 0.38.fwdarw.0.63 available Ratio 3.07 3.39 2.92 1
dose.sup.1 CEB/PR 1.29.fwdarw.7.66 2.28.fwdarw.5.94
2.07.fwdarw.3.90 Normalized (pd * h/mL) 10.60 13.86 12.14 5.75 for
dose to .mu.g 6.18.fwdarw.18.41 11.12.fwdarw.16.82
9.44.fwdarw.17.96 4.96.fwdarw.7.47 lung.sup.2 Ratio 1.84 2.41 2.11
1 CEB/PR 1.21.fwdarw.2.49 1.68.fwdarw.3.31 1.53.fwdarw.3.38
Normalized (pd * h/mL) 6.33 8.16 6.72 2.61 for dose to .mu.g
3.34.fwdarw.14.85 6.56.fwdarw.10.74 3.95.fwdarw.11.15
1.51.fwdarw.3.75 subject.sup.3 Ratio 2.42 3.13 2.57 1 CEB/PR
1.40.fwdarw.3.96 2.27.fwdarw.4.74 2.09.fwdarw.3.50 Normalized (pd *
h/mL) 3.39 4.31 3.54 1.18 for emitted .mu.g 1.74.fwdarw.7.27
3.46.fwdarw.6.01 2.30.fwdarw.5.72 0.78.fwdarw.1.42 dose.sup.4 Ratio
2.88 3.67 3.02 1 CEB/PR 1.59.fwdarw.5.19 2.52.fwdarw.5.24
2.36.fwdarw.4.03
[0245] A determination of dose distribution in subjects (Example
17) was made to determine the efficiency of dose deposition to the
lungs. The results are detailed in the table below and in FIG. 22.
TABLE-US-00020 1(A) 2(B) 3(C) 4(D) Lung Scintigraphy (mean values)
Dose in lungs 90.17 39.56 63.85 94.39 (.mu.g) % wt. in lungs 20.61
32.61 31.30 29.61 % wt. in oropharyngeal/ 24.79 21.13 21.68 23.39
stomach region % wt. in exhalation 54.61 46.26 47.02 47.00 filter/
mouthpiece Mass Balance 100.47 100.97 103.21 103.49 1(A) Budesonide
Suspension nebulized to sputter - 100% TTS (time to sputter) 2(B)
Captisol-Enabled .RTM. Budesonide Formulation - 25% TTS 3(C)
Captisol-Enabled .RTM. Budesonide Formulation - 50% TTS 4(D)
Captisol-Enabled .RTM. Budesonide Formulation - 75% TTS
[0246] The data demonstrate that administration of the solution of
the invention resulted in a lower oropharyngeal deposition of the
corticosteroid as compared to administration of the control
suspension formulation. Moreover, the formulation provided at least
a 20% to 85%, or 30% to 80%, or at least 30%, at least 40%, at
least 56%, at least 59%, at least 62% wt. pulmonary deposition of
corticosteroid based upon the emitted dose. The percentage of
pulmonary deposition can be further increased by employing a
nebulizer capable of providing a higher respirable fraction and
lower MMAD for the nebulized mist. Suitable nebulizers are
ultrasonic, vibrating mesh, vibrating cone, vibrating plate
nebulizers or those that extrude a liquid formulation through a
self-contained nozzle array. For example, the Aradigm AERx
pulmonary delivery systems, the AERx Essence and AERx Ultra, is
particularly suitable for use according to the invention, as it is
recognized in the art as providing controlled dose expression,
control of generated aerosol particle size, control of inhaled
aerosol particle size, and management of the inhalation and
delivery process (Farr et al., Drug Delivery Technology May 2002
Vol. 2, No. 3, 42-44). For example, the PARI eFlow vibrating plate
nebulizer is particularly suitable for use according to the
invention, as it is recognized in the art as providing the
above-mentioned desired performance parameters (Keller et al. (ATS
99.sup.th International Conference, Seattle, May 16-21, 2003;
poster 2727).
[0247] By virtue of the improved systemic bioavailability of a
corticosteroid delivered to the lungs by pulmonary administration
according to the invention, the composition or formulation of the
invention will provide an improved therapeutic benefit or improved
clinical benefit over an equivalent dose of corticosteroid
administered as an aqueous suspension.
[0248] Example 30 details a study conducted on dogs wherein a
budesonide solution of the invention and a reference formulation
(PULMICORT RESPULES suspension) was administered via nebulization
with a Pari LC air-jet nebulizer. The results depicted in FIG. 21
demonstrate an average plasma level of budesonide as a function of
time. The AUC.sub.0.fwdarw.8 hr of the solution formulation was 1.9
times greater than the reference suspension formulation. The
solution formulation also emitted 1.23 times as much budesonide as
the reference formulation in the same length of time. Detailed
results are also provided in the table below. TABLE-US-00021 Dog PK
Study Captisol Enabled Pulumicort Ratio Parameter Budesonide
Respules CEB/PR Loaded Dose 1000 .mu.g 1000 .mu.g 1 (nominal dose)
Emitted Dose 769 .mu.g 626 .mu.g 1.23 Average 2599 pg .times. hr/mL
1355 pg .times. hr/mL 1.91 AUC.sub.0.fwdarw.8 hr Average C.sub.max
1685 pg/mL 901 pg/mL 1.87 Loaded Dose - 2.60 (pg .times. hr/mL)/
1.36 (pg .times. hr/mL)/ 1.91 normalized .mu.g .mu.g AUC.sub.0-8 hr
Emitted Dose - 3.38 (pg .times. hr/mL)/ 2.16 (pg .times. hr/mL)/
1.56 normalized .mu.g .mu.g AUC.sub.0-8 hr Loaded Dose - 1.69
(pg/mL)/.mu.g 0.90 (pg/mL)/.mu.g 1.88 normalized C.sub.max Emitted
Dose - 2.19 (pg/mL)/.mu.g 1.44 (pg/mL)/.mu.g 1.52 normalized
C.sub.max
[0249] According to the table above, the formulation and system of
the invention can provide an AUC.sub.0-8 hr (pg*h/ml) of 2000 to
3000, 2500 to 2700, 2000, 3000, or 2600 on a dose non-normalized
basis. The formulation and system of the invention can provide a
dose normalized AUC.sub.inf (pg/ml/.mu.g) of: 1) 2 to 3, 2.5 to
2.7, or 2.6 on a loaded dose nominal normalized basis; 2) 3 to 4,
3.4 to 3.5, or 3.4 on an emitted dose normalized basis.
[0250] The formulation, system and method of the invention provided
a higher AUC.sub.0-8 hr than did the suspension-based PULMICORT
RESPULES formulation. On the basis of the normalized nominal
(loaded) dose of corticosteroid, the AUC.sub.0-8 hr provided by the
corticosteroid solution is at least 1.7, 1.8, 1.9, or 2 fold higher
than the AUC.sub.0-8 hr provided by the suspension-based
formulation when the dose of corticosteroid in the solution and the
suspension is approximately the same. On the basis of normalization
to the emitted dose of corticosteroid, the AUC.sub.0-8 hr provided
by the corticosteroid solution is at least 1.5, 1.6, to 2 fold
higher than the AUC.sub.0-8 hr provided by the suspension-based
formulation.
[0251] According to the table above, the formulation and system of
the invention can provide an C.sub.max (pg/ml) of 1600 to 1800,
1650 to 1750, or 1700 on a dose non-normalized basis. The
formulation and system of the invention can provide a dose
normalized C.sub.max (pg/ml/.mu.g) of: 1) 1 to 2, 1.6 to 1.8, or
1.7 on a loaded dose nominal normalized basis; 2) 2 to 2.5, or 2.2
on an emitted dose normalized basis.
[0252] The formulation, system and method of the invention provided
a higher C.sub.mas than did the suspension-based PULMICORT RESPULES
formulation. On the basis of the normalized nominal (loaded) dose
of corticosteroid, the C.sub.max provided by the corticosteroid
solution is at least 1.7, 1.8, 1.9, or 2 fold higher than the
C.sub.max provided by the suspension-based formulation when the
dose of corticosteroid in the solution and the suspension is
approximately the same. On the basis of normalization to the
emitted dose of corticosteroid, the C.sub.max provided by the
corticosteroid solution is at least 1.5, 1.6, to 2 fold higher than
the C.sub.max provided by the suspension-based formulation.
[0253] In some aspects, the method and dosage form of the invention
thus provides an improved method of administering a corticosteroid
suspension-based unit dose, the method comprising the step of
adding a sufficient amount of SAE-CD to convert the suspension to a
clear solution and then administering the clear solution to a
subject. As a result, the method of the invention provides
increased total delivery of the corticosteroid as well as increased
rate of administration as compared to the initial unit dose
suspension formulation.
[0254] The data herein can also be used to estimate the percentage
of the dose of corticosteroid emitted or delivered that is absorbed
into the bloodstream of a patient. In some embodiments, greater
than 20%, greater than 25%, greater than 29%, greater than 35% of
the emitted dose may be absorbed into the bloodstream of the
patient. In some embodiments, greater than 40%, greater than 50%,
greater than 55% of the dose to subject may be absorbed into the
bloodstream of the patient. In some embodiments, greater than 10%,
greater than 12%, greater than 15% of the nominal available dose
may be absorbed into the bloodstream of the patient.
[0255] The corticosteroids that are useful in the present invention
generally include any steroid produced by the adrenocortex,
including glucocorticoids and mineralocorticoids, and synthetic
analogs and derivatives of naturally occurring corticosteroids
having anti-inflammatory activity. Suitable synthetic analogs
include prodrugs, ester derivatives Examples of corticosteroids
that can be used in the compositions of the invention include
aldosterone, beclomethasone, betamethasone, budesonide, ciclesonide
(Altana Pharma AG), cloprednol, cortisone, cortivazol,
deoxycortone, desonide, desoximetasone, dexamethasone,
difluorocortolone, fluclorolone, flumethasone, flunisolide,
fluocinolone, fluocinonide, fluocortin butyl, fluorocortisone,
fluorocortolone, fluorometholone, flurandrenolone, fluticasone,
halcinonide, hydrocortisone, icomethasone, meprednisone,
methylprednisolone, mometasone, paramethasone, prednisolone,
prednisone, rofleponide, RPR 106541, tixocortol, triamcinolone, and
their respective pharmaceutically acceptable derivatives, such as
beclomethasone dipropionate (anhydrous or monohydrate),
beclomethasone monopropionate, dexamethasone 21-isonicotinate,
fluticasone propionate, icomethasone enbutate, tixocortol
21-pivalate, and triamcinolone acetonide. Particularly preferred
are compounds such as beclomethasone dipropionate, budesonide,
flunisolide, fluticasone propionate, mometasone furoate, and
triamcinolone acetonide. Other corticosteroids not yet
commercialized, but that are commercialized subsequent to the
filing of this application, are considered useful in the present
invention unless it is otherwise established experimentally that
they are not suitable.
[0256] Corticosteroids can be grouped according to their relative
lipophilicity as described by Barnes et al. (Am. J. Respir. Care
Med. (1998), 157, p. S1-S53), Miller-Larsson et al. (Am J. Respir.
Crit. Care Med. (2003), 167, A773), D. E. Mager et al. (J. Pharm.
Sci. (November 2002), 91(11), 2441-2451) or S. Edsbacker (Uptake,
retention, and biotransformation of corticosteroids in the lung and
airways. In: Schleimer R P, O'Byrne PMO, Szefler S J, Brattsand R,
editor(s). Inhaled steroids in asthma: optimizing effects in the
airways. New York: Marcel Dekker, 2002: 213-246). Generally, the
less lipophilic a corticosteroid is, the lower the amount of SAE-CD
required to dissolve it in an aqueous medium and vice versa.
Corticosteroids that are less lipophilic than flunisolide generally
require a SAE-CD to corticosteroid molar ratio of less than 10:1 to
dissolve the corticosteroid in an aqueous medium. Exemplary
corticosteroids of this group include hydrocortisone, prednisolone,
prednisone, dexamethasone, betamethasone, methylprednisolone,
triamcinolone, and fluocortolone. Some embodiments of the invention
exclude corticosteroids that are less lipophilic than
flunisolide.
[0257] Corticosteroids that are at least as lipophilic as or more
lipophilic than flunisolide generally require a SAE-CD to
corticosteroid molar ratio of more than 10:1 to dissolve the
corticosteroid in an aqueous medium. In some embodiments, the
corticosteroid used in the invention is at least as lipophilic as
or more lipophilic than flunisolide. Exemplary corticosteroids of
this group include beclomethasone, beclomethasone dipropionate,
beclomethasone monopropionate, budesonide, ciclesonide,
desisobutyryl-ciclesonide, flunisolide, fluticasone, fluticasone
propionate, mometasone, mometasone furoate, triamcinolone
acetonide.
[0258] The suitability of a corticosteroid for use in the inhalable
liquid composition/formulaion can be determined by performing a
phase solubility binding study as detailed in Example 23. Phase
solubility binding data is used to determine the saturated
solubility of a corticosteroid in the presence of varying amounts
of SAE-CD in an aqueous liquid carrier. The phase solubility
binding curve depicted in FIG. 3 demonstrates the saturated
solubility of budesonide in an aqueous liquid carrier comprising
.gamma.-CD, HP-.beta.-CD or SBE7-.beta.-CD. A phase solubility
curve in the graph defines the boundary for the saturated
solubility the corticosteroid in solutions containing various
different concentrations of cyclodextrin. A molar phase solubility
curve can be used to determine the molar ratio of SAE-CD to
corticosteroid or of corticosteroid to SAE-CD at various
concentrations of corticosteroid. The area below the phase
solubility curve, e.g. of FIG. 3, denotes the region where the
corticosteroid is solubilized in an aqueous liquid medium to
provide a substantially clear aqueous solution. In this region, the
SAE-CD is present in molar excess of the corticosteroid and in an
amount sufficient to solubilize the corticosteroid present in the
liquid carrier. The boundary defined by the phase solubility curve
will vary according to the corticosteroid and SAE-CD within a
composition or formulation of the invention. The table below
provides a summary of the minimum molar ratio of SAE-CD to
corticosteroid required to achieve the saturated solubility of the
corticosteroid in the composition or formulation of the invention
under the conditions studied. TABLE-US-00022 Approximate Molar
Ratio at Saturated Solubility of Corticosteroid* Corticosteroid
SAE-CD (SAE-CD: corticosteroid) Beclomethasone dipropionate
SAE-.beta.-CD 358 Beclomethasone dipropionate SAE-.gamma.-CD 62
Budesonide SAE-.beta.-CD 16 Budesonide SAE-.gamma.-CD 13 (SBE6.1),
10.8 (SBE5.2), 10.1 (SPE5.4) Budesonide SAE-.alpha.-CD 12
Flunisolide SAE-.beta.-CD 16 Flunisolide SAE-.gamma.-CD 9
Fluticasone SAE-.beta.-CD 32 Fluticasone Propionate SAE-.beta.-CD
797 Fluticasone Propionate SAE-.gamma.-CD 51 Fluticasone Propionate
SAE-.alpha.-CD 501 Mometasone SAE-.alpha.-CD 73 Mometasone
SAE-.beta.-CD 33 Mometasone furoate SAE-.alpha.-CD 141 Mometasone
furoate SAE-.beta.-CD 274 Mometasone furoate SAE-.gamma.-CD 101
Triamcinolone acetonide SAE-.beta.-CD 9 *This value was determined
in the presence of SAE-CD under the conditions detailed in Examples
18, 23 accompanying the solubility values presented in the
preceding and following text.
[0259] The saturated solubility of a corticosteroid in the presence
of a fixed amount of SAE-CD will vary according to the identity of
the corticosteroid and the SAE-CD. The table below summarizes some
solubility data for the listed corticosteroids in the absence
(intrinsic solubility of corticosteroid in the aqueous test medium)
and in the presence of two different SAE-CD's as determined herein.
TABLE-US-00023 [Steroid] .times.10.sup.5 M Intrinsic Solubility
Captisol (SBE).sub.6.1 .gamma.-CD Steroid (in H.sub.2O) (0.04 M)
(0.04 M) Hydrocortisone 92.4 2656.3 2369.3 Methylprednisolone 43.6
743.1 1215.3 Prednisolone 62.5 1995.3 2095.0 Prednisone 50.5 1832.7
1313.7 Triamcinolone Acetonide 3.56 457.0 1059.5 Flunisolide 11.3
261.5 455.1 Budesonide 6.6 254.8 306.6 Fluticasone Propionate 0.39
5.41 51.8 Beclomethasone 0.41 11.6 46.8 Dipropionate Mometasone
Fuorate 1.82 16.4 41.5
[0260] The above data can be used in combination with the phase
solubility data to prepare formulations according to the invention
having a target concentration of corticosteroid and SAE-CD.
Accordingly, some embodiments of the invention comprise a
corticosteroid having an intrinsic solubility in water that
approximates or is less than the intrinsic solubility of
flunisolide (less than about 11.times.10.sup.-5 M or less than
about 11.3.times.10.sup.-5 M) in water as determined herein.
[0261] Even though a composition or formulation of the invention
can comprise the corticosteroid present in an aqueous medium at a
concentration up to its saturated solubility in the presence of a
particular concentration of SAE-CD, some embodiments of the
invention include those wherein the corticosteroid is present at a
concentration that is less than its saturated solubility in the
presence of that concentration of SAE-CD. The corticosteroid can be
present at a concentration that is 95% or less, 90% or less, 85% or
less, 80% or less, or 50% or less of its saturated solubility as
determined in the presence of SAE-CD. It is generally easier to
prepare solutions that comprise the corticosteroid at a
concentration that is less than its saturated solubility in the
presence of SAE-CD.
[0262] Therefore, the molar ratio of SAE-CD to corticosteroid in a
formulation or composition of the invention can exceed the molar
ratio obtained at the saturated solubility of the corticosteroid in
the presence of SAE-CD, such as defined by the phase solubility
binding curve for the corticosteroid. In such a case, the molar
ratio of SAE-CD to corticosteroid in the composition or formulation
will be at least 1%, at least 2%, at least 5%, at least 7.5%, at
least 10%, at least 15%, at least 20%, at least 25%, at least 50%,
at least 75%, at least 100%, or at least 200% greater than the
molar ratio at the saturated solubility of the corticosteroid in
the presence of SAE-CD. For example, if the molar ratio at the
saturated solubility is about 14:1, then the molar ratio in the
composition or formulation can be at least 14.1:1 (for at least 1%
higher), at least 14.3:1 (for at least 2% higher), at least 14.7:1
(for at least 5% higher), at least 15.4:1 (for at least 10%
higher), at least 16.1:1 (for at least 15% higher), at least 16.8:1
(for at least 20% higher), at least 17.5:1 (for at least 25%
higher), at least 21:1 (for at least 50% higher), at least 24.5:1
(for at least 75% higher), at least 28:1 (for at least 100%
higher), or at least 42:1 (for at least 100% higher).
[0263] Changes in the molar ratio of SAE-CD to corticosteroid can
have an impact upon the total output of a nebulizer. A study was
conducted using a PARI LC PLUS air jet nebulizer and solutions
containing varying amounts of SAE-CD in 2 ml of 250 .mu.g/ml
PULMICORT RESPULES. Each preparation was nebulized for until no
further sustained vapor was visibly being emitted. At the end of
each run, the amount of budesonide remaining in the reservoir of
the nebulizer was determined. The SAE-CD to corticosteroid molar
ratios used were 10:1, 14:1, and 20:1. The data indicate that
increasing the molar ratio resulted in an increase of the amount of
budesonide delivered and a decrease in the amount of budesonide
remaining in the reservoir.
[0264] Changes in the molar ratio of SAE-CD to corticosteroid can
also have an impact upon the dissolution rate of corticosteroid in
an aqueous medium. A study was conducted on a roller mixer having
containers with solutions containing varying amounts of SAE-CD,
e.g. CAPTISOL, and a fixed amount of fluticasone propionate or
mometasone furoate. The samples were prepared by mixing the
corticosteroid with a solution containing the SAE-CD in a vortexer
for about 30 seconds and then placing the containers on the roller
mixer. Aliquots were taken periodically from each container and the
amount of dissolved corticosteroid was determined. The SAE-CD to
corticosteroid molar ratios used were 10:1, 14:1, and 20:1. The
data indicate that increasing the molar ratio resulted in an
increase in the rate of dissolution of the corticosteroid.
[0265] The corticosteroid compound is present in the final, diluted
corticosteroid composition designed for inhalation in an amount
from about 1 .mu.g/ml to about 10 mg/ml, about 10 .mu.g/ml to about
1 mg/ml, or about 20 .mu.g/ml to about 500 .mu.g/ml. For example,
the drug concentration can be between about 30 and 1000 .mu.g/ml
for triamcinolone acetonide, and between about 50 and 2000 .mu.g/ml
for budesonide, depending on the volume to be administered. By
following the preferred methods of the present invention,
relatively high concentrations of the corticosteroid can be
achieved in an aqueous-based composition.
[0266] Similarly, the corticosteroid compound is present in the
final, diluted corticosteroid composition designed for nasal
administration in an amount from about 10 .mu.g/ml to 6 mg/ml, 50
.mu.g/ml to about 10 mg/ml, about 100 .mu.g/ml to about 2 mg/ml, or
about 300 .mu.g/ml to about 1 mg/ml. For example, the drug
concentration can be between about 250 .mu.g/ml and 1 mg/ml or 250
.mu.g/ml and 6 mg/ml for triamcinolone acetonide, and between about
400 .mu.g/ml and 1.6 mg/ml or 250 .mu.g/ml and 6 mg/ml for
budesonide, depending on the volume to be administered.
[0267] For the treatment of pulmonary disorders and sinus-related
disorders, the diluted corticosteroid composition is prepared as
described herein. The corticosteroid for such treatment is
preferably, beclomethasone dipropionate, beclomethasone
monopropionate, betamethasone, budesonide, ciclesonide,
desisobutyryl-ciclesonide, flunisolide, fluticasone, fluticasone
propionate, fluticasone furoate, mometasone, mometasone furoate, or
triamcinolone acetonide, and is formulated in the concentrations
set forth herein. The daily dose of the corticosteroid is generally
about 0.05 to 10 mg, depending on the drug and the disease, in
accordance with the Physician's Desk Reference (PDR). However, in
view of the improved bioavailability of a corticosteroid when
administered as a solution of the invention, the dose required to
achieve a desired clinical endpoint, clinical benefit or
therapeutic benefit may be lower than the corresponding dose
indicated in the PDR.
[0268] A unit dose of budesonide may also be administered once
daily, once every two days, once every week, once every month, or
even less frequently as set forth in U.S. Pat. No. 6,598,603 and
No. 6,899,099, wherein a dose comprises 0.05 to 2.0 mg or 0.25 to
1.0 mg of budesonide. Administration can be during the daytime
and/or nighttime. A dose of budesonide, or corticosteroid, can be
administered twice, thrice or more times per day or on an as-needed
basis.
[0269] In some embodiments, a dose comprises 1 .mu.g to 20 mg, 0.01
mg to 10 mg, 0.025 mg to 10 mg, 0.05 mg to 5 mg, 0.1 mg to 5 mg,
0.125 mg to 5 mg, 0.25 mg to 5 mg, 0.5 mg to 5 mg, 0.05 mg to 2 mg,
0.1 mg to 2 mg, 0.125 mg to 2 mg, 0.25 mg to 2 mg, 0.5 mg to 2 mg,
1 .mu.g, 10 .mu.g, 25 .mu.g, 50 .mu.g, 100 .mu.g, 125 .mu.g, 200
.mu.g, 250 .mu.g, 25 to 66 .mu.g, 48 to 81 .mu.g, 73 to 125 .mu.g,
40 .mu.g, 64 .mu.g, 95 .mu.g, 35 to 95 .mu.g, 25 to 125 .mu.g, 60
to 170 .mu.g, 110 .mu.g, 170 .mu.g, 45 to 220 .mu.g, 45 to 85
.mu.g, 48 to 82 .mu.g, 85 to 160 .mu.g, 140 to 220 .mu.g, 120 to
325 .mu.g, 205 .mu.g, 320 .mu.g, 325 .mu.g, 90 to 400 .mu.g, 95 to
170 .mu.g, 165 to 275 .mu.g, or 275 to 400 .mu.g of budesonide,
said dose being a nominal dose, nominal available dose, emitted
dose, delivered dose, dose to subject, or dose to lung.
[0270] The corticosteroid can be present in its neutral, ionic,
salt, basic, acidic, natural, synthetic, diastereomeric, isomeric,
isomeric, enantiomerically pure, racemic, solvate, anhydrous,
hydrate, chelate, derivative, analog, esterified, non-esterfied, or
other common form. Whenever an active agent is named herein, all
such forms available are included. For example, all known forms of
budesonide are considered within the scope of the invention.
[0271] The formulation of the invention can be used to deliver two
or more different active agents (active ingredients, therapeutic
agents, etc.). Particular combinations of active agents can be
provided by the present formulation. Some combinations of active
agents include: 1) a first drug from a first therapeutic class and
a different second drug from the same therapeutic class; 2) a first
drug from a first therapeutic class and a different second drug
from a different therapeutic class; 3) a first drug having a first
type of biological activity and a different second drug having
about the same biological activity; 4) a first drug having a first
type of biological activity and a different second drug having a
different second type of biological activity. Exemplary
combinations of active agents are described herein.
[0272] A corticosteroid, such as budesonide, can be administered in
combination with one or more other drugs (active ingredients,
therapeutic agents, active agents, etc., the terms being used
interchangeably herein unless otherwise specified). Such other
drugs include: B.sub.2 adrenoreceptor agonist, topical anesthetic,
D.sub.2 receptor agonist, anticholinergic agent.
[0273] B.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-benzenedime-
thanol); 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-phenyleneester);
Broxaterol
(3-bromo-alpha-(((1,1-dimethylethyl)amino)methyl)-5-isoxazolemethanol);
Isoproterenol
(4-(1-hydroxy-2-((1-methylethyl-)amino)ethyl)-1,2-benzene-diol);
Trimetoquinol
(1,2,3,4-tetrahydro-1-((3,4-,5-trimethoxyphenyl)-methyl)-6,7-isoquinoline-
diol); Clenbuterol
(4-amino-3,5-dichloro-alpha-(((1,1-diemthylethyl)amino)methyl)benzenemeth-
anol); 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-methyl-ethyl)amino-
)methyl)benzenemethanol); Hexoprenaline
(4,4'-(1,6-hexane-diyl)-bis(imino(1-hydroxy-2,1-ethanediyl)))bis-1,2-benz-
enediol); Isoetharine
(4-(1-hydroxy-2-((1-methylethyl)amino)butyl)-1,2-benzenediol);
Isoprenaline
(4-(1-hydroxy-2-((1-methylethyl)amino)ethyl)-1,2-benzenediol);
Meta-proterenol
(5-(1-hydroxy-2-((1-methylethyl)amino)ethyl)-1,3-benzened-iol);
Picumeterol
(4-amino-3,5-dichloro-alpha-(((6-(2-(2-pyridinyl)ethoxy)hexyl)-amino)meth-
yl)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)-quinolin-one); 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-b-en-
zenedimethanol); (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).
[0274] 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)er-
gotaman-3',6', 18-trione); Cabergoline
((8.beta.)-N-(3-(dimethylamino)propyl)-N-((ethylamino)carbony-1)-6-(2-pro-
penyl)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-N6-prop-yl-2,6-benzothiazolediamine);
Quinpirole hydrochloride
(trans-(-)-4aR-4,4a,5,6,7,8,8a,9-octahydro-5-propyl-1H-pyrazolo[3,4-g]qui-
noline hydrochloride); Ropinirole
(4-(2-(dipropylamino)ethyl)-1,3-dihydro-2H-indol-2-one); and
Talipexole
(5,6,7,8-tetrahydro-6-(2-propenyl)-4H-thia-zolo[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, the relevant disclosure of which is hereby incorporated
by reference.
[0275] 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.
[0276] 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. No. 5,668,110, No. 5,683,983, No.
5,677,280, No. 6,071,910 and No. 5,654,276, the relevant
disclosures of which are hereby incorporated by reference;
antisense modulators of IL-5 such as those disclosed in U.S. Pat.
No. 6,136,603, the relevant disclosure of which is hereby
incorporated by reference; milrinone
(1,6-dihydro-2-methyl-6-oxo-[3,4'-bipyridinel-5-carbonitrile);
milrinone lactate; tryptase inhibitors such as those disclosed in
U.S. Pat. No. 5,525,623, the relevant disclosure of which is hereby
incorporated by reference; tachykinin receptor antagonists such as
those disclosed in U.S. Pat. No. 5,691,336, No. 5,877,191, No.
5,929,094, No. 5,750,549 and No. 5,780,467, the relevant
disclosures of which are hereby incorporated by reference;
leukotriene receptor antagonists such as montelukast sodium
(Singular.TM.,
R-(E)]-1-[[[1-[3-[2-(7-chloro-2-quinolinyl)ethenyl-]phenyl]-3-[2-(1-hydro-
xy-1-methylethyl)phenyl]-propyl]thio]methyl]cyclopro-paneacetic
acid, monosodium salt), 5-lypoxygenase inhibitors such as zileuton
(Zyflo.TM., Abbott Laboratories, Abbott Park, Ill.), and anti-IgE
antibodies such as Xolair.TM. (recombinant humanized anti-IgE
monoclonal antibody (CGP 51901; IGE 025A; rhuMAb-E25), Genentech,
Inc., South San Francisco, Calif.), and topical anesthetics such as
lidocaine, N-arylamide, aminoalkylbenzoate, prilocaine, etidocaine
(U.S. Pat. No. 5,510,339, No. 5,631,267, and No. 5,837,713, the
relevant disclosures of which are hereby incorporated by
reference).
[0277] Exemplary combination formulations of the invention comprise
the following components. TABLE-US-00024 FORM. Corticosteroid (A)
Other Active Ingredient (B) I Budesonide Formoterol II Budesonide
Salmeterol III Budesonide Albuterol IV Fluticasone Salmeterol
propionate
[0278] A formulation comprising a corticosteroid and another active
ingredient can be prepared according to the examples below. In one
embodiment, the SAE-CD is present in an amount sufficient to
solubilize the corticosteroid and the other active ingredient. In
another embodiment, the SAE-CD is present in an amount sufficient
to solubilize the corticosteroid or the other active
ingredient.
[0279] Depending upon the other active ingredient used, it may or
may not bind competitively against the corticosteroid with the
SAE-CD. In some embodiments, the SAE-CD has a higher equilibrium
binding constant for the other active ingredient than it has for
the corticosteroid. In some embodiments, the SAE-CD has a higher
equilibrium binding constant for the corticosteroid than it has for
the other active ingredient. In some embodiments, the SAE-CD has
approximately the same equilibrium binding constant for the other
active ingredient as it has for the corticosteroid. Alternatively,
the other active ingredient does not bind with the SAE-CD even
though the corticosteroid does. Accordingly, the invention provides
embodiments wherein, the SAE-CD solubilizes the corticosteroid, the
other active ingredient, or a combination thereof. The invention
also provides embodiments wherein, the SAE-CD solubilizes at least
a major portion of the corticosteroid, the other active ingredient,
or of each. The invention also provides embodiments wherein, the
SAE-CD does not solubilize the other active ingredient.
[0280] The molar ratio of SAE-CD to corticosteroid and SAE-CD to
other active ingredient can vary as needed to provide a combination
formulation as described herein. The SAE-CD is generally present in
molar excess over the corticosteroid, the other active ingredient,
or both.
[0281] The phase solubility binding curve for Salmeterol xinafoate
and budesonide was determined as described herein, and the
approximate equilibrium binding constant (Ki) of each with CAPTISOL
was determined. The approximate Ki for Salmeterol xinafoate was
approximately 3,500, and the approximate Ki for budesonide was 600
under the test conditions used. The molar ratio of CAPTISOL to
Salmeterol xinafoate at saturated solubility was about 3.2 under
the test conditions used. Their may be a reduction in the amount of
budesonide solubilized by CAPTISOL in the presence of Salmeterol
xinafoate; however, clear aqueous liquid solution formulations
comprising therapeutically effective amounts of budesonide and
Salmeterol xinafoate were prepared.
[0282] A formulation comprising budesonide, albuterol and SAE-CD
was prepared according to Example 25. The formulation was clear
after preparation. The combination of budesonide and albuterol has
been shown to be physically and chemically stable and would be
expected to provide the same improved aerosol performance and AUC
per .mu.g budesonide dosed as the solution of budesonide alone.
Furthermore, the patient would benefit from the simultaneous
administration of the two drugs.
[0283] The invention includes methods for the treatment,
prevention, or amelioration of one or more symptoms of a
corticosteroid-responsive disorder, a disease or disorder of the
air passageways e.g. respiratory or pulmonary disorders such as
bronchoconstrictive disorders; sinus disorders such as sinusitis.
The method further includes administering one or more of (a), (b),
(c) or (d) as follows: (a) a b.sub.2-adrenoreceptor agonist; (b) a
dopamine (D.sub.2) receptor agonist; (c) a prophylactic
therapeutic, such as a steroid; or (d) an anticholinergic agent;
simultaneously with, prior to or subsequent to the composition
provided herein.
[0284] Embodiments of the present invention allow for combinations
to be prepared in a variety of ways:
[0285] 1) Mixing ready to use solutions of a .beta.2-agonist such
as levalbuterol or anticholinergic such as ipatropium bromide with
a ready to use solution of a corticosteroid in SAE-CD;
[0286] 2) Mixing ready to use solutions of a .beta.2-agonist or
anticholinergic with a concentrated solution of a corticosteroid
dissolved using SAE-CD;
[0287] 3) Mixing a ready to use solution of a .beta.2-agonist or
anticholinergic with substantially dry SAE-CD and a substantially
dry corticosteroid;
[0288] 4) Mixing a ready to use solution of a .beta.2-agonist or
anticholinergic with a substantially dry mixture of SAE-CD and a
corticosteroid or more conveniently a pre-measured amount of the
mixture in a unit container such as a capsule (empty a capsule into
ready to use solution);
[0289] 5) Mixing a ready to use solution of a corticosteroid such
as budesonide with a substantially dry long acting or short acting
.beta.2-agonist and/or with a substantially dry anticholinergic
such as ipatropium bromide or tiotropium bromide; or
[0290] 6) Dissolving a substantially dry .beta.2-agonist, and/or a
substantially dry anticholinergic and a substantially dry SAE-CD
plus a substantially dry corticosteroid.
[0291] The materials used herein can be used in micronized or
non-micronized form and crystalline, polymorphic or amorphous form.
This is particularly true of the corticosteroids and other active
ingredients.
[0292] It is well understood by those of ordinary skill in the art
that the above solutions or powders may optionally contain other
ingredients such as buffers and/or tonicity adjusters and/or
antimicrobials and/or additives or other such excipients as set
forth herein or as presently used in inhalable liquid formulations
to improve the output of the nebulizer.
[0293] Dosing, use and administration of the therapeutic agents
disclosed herein is generally intended to follow the guidelines set
forth in the Physician's Desk Reference, 55.sup.th Edition
(Thompson Healthcare, Montvale, N.J., 2005) the relevant disclosure
of which is hereby incorporated by reference.
[0294] 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.
[0295] A formulation according to the invention will generally have
a storage shelf life of no less than 6 months. In this case, shelf
life is determined only as regards the increase in the amount of
corticosteroid degradation by-products or a reduction in the amount
of corticosteroid remaining in the formulation. For example, for a
formulation having a shelf life of at least six months, the
formulation will not demonstrate an unacceptable and substantial
increase in the amount of degradants during the storage period of
at least six months. The criteria for acceptable shelf-life are set
as needed according to a given product and its storage stability
requirements. In other words, the amount of degradants in a
formulation having an acceptable shelf-life will not increase
beyond a predetermined value during the intended period of storage.
On the other hand, the amount of degradants of a formulation having
an unacceptable shelf-life will increase beyond the predetermined
value during the intended period of storage.
[0296] The method of Example 3 was followed to determine the
stability of budesonide in solution. The shelf-life was defined as
the time to loss of 10% potency. Under the conditions tested, the
loss of potency was first order. The shelf life of a
Captisol-Enabled.RTM. Budesonide Inhalation Solution (a solution
comprising budesonide and SBE7-.beta.-CD) is greater than about 3
years at a pH between 4 and 5, i.e. about 90 months at pH 4.0 and
about 108 months at pHII 5.0 without the need to add any other
stabilizers, such as EDTA, in water in the presence of about 5%
wt./vol. SAE-CD. This shelf-life is greater than that reported by
Otterbeck (U.S. Pat. No. 5,914,122; up to six weeks at pHII 4.0-6.0
in water in the presence of EDTA, HP-.beta.-CD and other
additives.)
[0297] The inventors have also discovered that SAE-CD is capable of
stabilizing the isomers of budesonide to different extents. A study
to determine if SBE7-.beta.-CD stabilized budesonide solutions and
if it preferentially stabilized one isomer was conducted according
to Example 13. FIG. 11 is a semi-log plot of the % of initial
concentration at each time point for the samples stored at
60.degree. C. Loss of budesonide was first order at each
temperature. The table below shows the pseudo-first order rate
constants calculated for each isomer at 60.degree. C. and
80.degree. C. TABLE-US-00025 Pseudo 1.sup.st Order Rate constant
(hours.sup.-1) Temperature 60.degree. C. R/S With/without
With/without rate Rate CAPTISOL Rate CAPTISOL con- constant ratio
for constant ratio for stant Ph R-isomer R-isomers S-isomer
S-isomers ratio 4 w/ 0.000597 0.547 0.00012 0.323 5.06 CAPTISOL 4
no 0.00109 0.0037 2.99 CAPTISOL 6 w/ 0.001661 0.385 0.000361 0.193
4.60 CAPTISOL 6 no 0.00432 0.001872 2.31 CAPTISOL
[0298] TABLE-US-00026 Pseudo 1.sup.st Order Rate constant
(hours.sup.-1) Temperature 80.degree. C. R/S With/without
With/without rate Rate CAPTISOL Rate CAPTISOL con- Constant ratio
for R- constant ratio for S- stant pH R-isomer isomers S-isomer
isomers ratio 4 w/ 0.002250 0.607 0.000644 0.491 3.49 CAPTISOL 4 no
0.003704 0.00131 2.83 CAPTISOL 6 w/ 0.00732 0.529 0.00254 0.384
2.88 CAPTISOL 6 no 0.0138 0.00661 2.09 CAPTISOL
[0299] SBE7-.beta.-CD stabilized both R-- and S-isomers of
budesonide in solutions at both pH 4 and 6. The with/without
CAPTISOL ratio of rate constants was much less than 1 at all
temperatures. SBE7-.beta.-CD had a greater effect on the stability
of both the R and S-isomer at pH 6 than at pH 4. At a given
temperature the ratio of rate constants with/without SBE7-.beta.-CD
was less at pH 6 than at pH 4. Although SBE7-.beta.-CD stabilized
both isomers, the S-isomer appears to be stabilized to an even
greater extent than the R. At all temperatures and pHs tested, the
ratio of rate constants with/without SBE7-.mu.-CD was lower for the
S isomer. The degree of stabilization affected by SBE7-.beta.-CD at
60.degree. C. is greater than at 80.degree. C. An even greater
degree of stabilization would be expected at 40.degree. C. and/or
room temperature (20-30 C).
[0300] Samples of the above solutions were also placed in a chamber
under a bank of fluorescent lights. Vials were periodically removed
and assayed for budesonide. FIG. 12 shows the semi-log plot of the
% of initial value remaining as a function of light exposure (light
intensity*time). As noted in the table below, SBE7-.beta.-CD
significantly reduced the photodecomposition of budesonide. The
loss of budesonide was first order and independent of pH.
TABLE-US-00027 Light Stability of Budesonide Pseudo 1st Order Rate
constant (hour.sup.-1) pH 4 pH 6 Captisol 0.0585 0.0562 No Captisol
0.0812 0.0822
[0301] The formulation of the invention can be provided as a kit
adapted to form an inhalable solution for nebulization. The kit can
comprise a corticosteroid, SAE-CD, an aqueous carrier, and
optionally one or more other components. The corticosteroid and
SAE-CD can be provided together or separately in solid, suspended
or dissolved form. After mixing SAE-CD with corticosteroid in the
presence of an aqueous carrier, the solids will dissolve to form an
inhalable solution rather than suspension for nebulization. Each
component can be provided in an individual container or together
with another component. For example, SAE-CD can be provided in an
aqueous solution while budesonide is provided in dry solid form or
wet suspended form. Alternatively, SAE-CD is provided in dry form
and budesonide is provided as an aqueous suspension, e.g.,
PULMICORT RESPULES.TM.. The kit can instead comprise an admixture
of a solid derivatized cyclodextrin and solid corticosteroid and,
optionally, at least one solid pharmaceutical excipient, such that
a major portion of the active agent is not complexed with the
derivatized cyclodextrin prior to reconstitution of the admixture
with an aqueous carrier. Alternatively, the composition can
comprise a solid mixture comprising the inclusion complex of a
derivatized cyclodextrin and an active agent, wherein a major
portion of the active agent is complexed with the derivatized
cyclodextrin prior to reconstitution of the solid mixture with an
aqueous carrier. Depending upon the storage temperature of the kit,
the aqueous carrier may be a liquid or frozen solid. In one
embodiment, the kit excludes the aqueous carrier during storage,
but the aqueous carrier is added to the SAE-CD and corticosteroid
prior to use to form the nebulization solution. The corticosteroid
and SAE-CD can be complexed and present in aqueous concentrated
form prior to addition of the aqueous carrier, which is later added
to bring the solution to volume and proper viscosity and
concentration for nebulization. A reconstitutable formulation can
be prepared according to any of the following processes. A liquid
formulation of the invention is first prepared, then a solid is
formed by lyophilization (freeze-drying), spray-drying, spray
freeze-drying, antisolvent precipitation, various processes
utilizing supercritical or near supercritical fluids, or other
methods known to those of ordinary skill in the art to make a solid
for reconstitution. Example 29 details a method for the preparation
of a lyophilized solid composition comprising corticosteroid and
SAE-CD by lyophilization of a liquid composition or formulation of
the invention. The lyophilized solid can be dissolved in an aqueous
liquid carrier prior to administration via nebulization. The dried
powder would provide a stable form for long-term storage and would
also be useful to rapidly prepare inhalation compositions on a
larger scale, or as an additive to another inhalation solution
medication to prepare combination products.
[0302] While the liquid composition or formulation of the invention
can be administered to the lung, it would also be suitable for
nasal, oral, ophthalmic, otic or topical administration. The liquid
composition or formulation may also be administered via inhalation
using a device such as a pump spray, metered dose inhaler, or
pressurized metered dose inhaler. Accordingly, the invention
provides a method of treating a corticosteroid-responsive disease
or disorder by administration of the liquid to a subject in need of
such treatment.
[0303] A liquid vehicle (carrier) included in a formulation of the
invention comprises an aqueous liquid carrier, such as water,
aqueous alcohol, propylene glycol, or aqueous organic solvent.
Example 30 details the preparation of a liquid formulation
comprising 20% w/v SAE-CD, corticosteroid, water and ethanol
(0-5%). Increasing the concentration of the ethanol in the liquid
resulted in a decrease in the maximum saturated solubility of the
corticosteroid.
[0304] Although not necessary, the formulation of the present
invention may include a conventional preservative, antioxidant,
buffering agent, acidifying agent, alkalizing agent, colorant,
solubility-enhancing agent, complexation-enhancing agent,
electrolyte, glucose, stabilizer, tonicity modifier, bulking agent,
antifoaming agent, oil, emulsifying agent, cryoprotectant,
plasticizer, flavors, sweeteners, a tonicity modifier, surface
tension modifier, viscosity modifier, density modifier, volatility
modifier, other excipients known by those of ordinary skill in the
art for use in preserved formulations, or a combination
thereof.
[0305] As used herein, the term "alkalizing agent" is intended to
mean a compound used to provide alkaline medium, such as for
product stability. Such compounds include, by way of example and
without limitation, ammonia solution, ammonium carbonate,
diethanolamine, monoethanolamine, potassium hydroxide, sodium
borate, sodium carbonate, sodium bicarbonate, sodium hydroxide,
triethanolamine, diethanolamine, organic amine base, alkaline amino
acids and trolamine and others known to those of ordinary skill in
the art.
[0306] As used herein, the term "acidifying agent" is intended to
mean a compound used to provide an acidic medium for product
stability. Such compounds include, by way of example and without
limitation, acetic acid, acidic amino acids, citric acid, fumaric
acid and other alpha hydroxy acids, hydrochloric acid, ascorbic
acid, phosphoric acid, sulfuric acid, tartaric acid and nitric acid
and others known to those of ordinary skill in the art.
[0307] Inclusion of a conventional preservative in the inhalable
solution formulation is optional, since the formulation is
self-preserved by SAE-CD depending upon its concentration in
solution. Nonetheless, a conventional preservative can be further
included in the formulation if desired. Preservatives can be used
to inhibit microbial growth in the compositions. The amount of
preservative is generally that which is necessary to prevent
microbial growth in the composition for a storage period of at
least six months. As used herein, a conventional preservative is a
compound used to at least reduce the rate at which bioburden
increases, but preferably maintains bioburden steady or reduces
bioburden after contamination has occurred. Such compounds include,
by way of example and without limitation, benzalkonium chloride,
benzethonium chloride, benzoic acid, benzyl alcohol,
cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl
alcohol, phenylmercuric nitrate, phenylmercuric acetate,
thimerosal, metacresol, myristylgamma picolinium chloride,
potassium benzoate, potassium sorbate, sodium benzoate, sodium
propionate, sorbic acid, thymol, and methyl, ethyl, propyl or butyl
parabens and others known to those of ordinary skill in the
art.
[0308] As used herein, the term "antioxidant" is intended to mean
an agent that inhibits oxidation and thus is used to prevent the
deterioration of preparations by the oxidative process. Such
compounds include, by way of example and without limitation,
acetone, potassium metabisulfite, potassium sulfite, ascorbic acid,
ascorbyl palmitate, citric acid, butylated hydroxyanisole,
butylated hydroxytoluene, hypophophorous acid, monothioglycerol,
propyl gallate, sodium ascorbate, sodium citrate, sodium sulfide,
sodium sulfite, sodium bisulfite, sodium formaldehyde sulfoxylate,
thioglycolic acid, EDTA, pentetate, and sodium metabisulfite and
others known to those of ordinary skill in the art.
[0309] As used herein, the term "buffering agent" is intended to
mean a compound used to resist change in pH upon dilution or
addition of acid or alkali. Buffers are used in the present
compositions to adjust the pH to a range of between about 2 and
about 8, about 3 to about 7, or about 4 to about 5. Such compounds
include, by way of example and without limitation, acetic acid,
sodium acetate, adipic acid, benzoic acid, sodium benzoate, boric
acid, sodium borate, citric acid, glycine, maleic acid, monobasic
sodium phosphate, dibasic sodium phosphate, HEPES, lactic acid,
tartaric acid, potassium metaphosphate, potassium phosphate,
monobasic sodium acetate, sodium bicarbonate, tris, sodium tartrate
and sodium citrate anhydrous and dihydrate and others known to
those of ordinary skill in the art. Other buffers include citric
acid/phosphate mixture, acetate, barbital, borate,
Britton-Robinson, cacodylate, citrate, collidine, formate, maleate,
Mcllvaine, phosphate, Prideaux-Ward, succinate,
citrate-phosphate-borate (Teorell-Stanhagen), veronal acetate, MES
(2-(N-morpholino)ethanesulfonic acid), BIS-TRIS
(bis(2-hydroxyethyl)imino-tris(hydroxymethyl)methane), ADA
(N-(2-acetamido)-2-iminodiacetic acid), ACES
(N-(carbamoylmethyl)-2-aminoethanesulfonaic 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-aminoethanesulfonaic acid), MOPS
(3-(N-morpholino)propanesulfonic acid), TES
(N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid), IIEPES
(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.TM. (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.
[0310] A complexation-enhancing agent can be added to a formulation
of the invention. When such an agent is present, the ratio of
cyclodextrin/active agent can be changed. A complexation-enhancing
agent is a compound, or compounds, that enhance(s) the complexation
of the active agent with the cyclodextrin. Suitable complexation
enhancing agents include one or more pharmacologically inert water
soluble polymers, hydroxy acids, and other organic compounds
typically used in liquid formulations to enhance the complexation
of a particular agent with cyclodextrins.
[0311] Hydrophilic polymers can be used as complexation-enhancing,
solubility-enhancing and/or water activity reducing agents to
improve the performance of formulations containing a cyclodextrin.
Loftsson has disclosed a number of polymers suitable for combined
use with a cyclodextrin (underivatized or derivatized) to enhance
the performance and/or properties of the cyclodextrin. Suitable
polymers are disclosed in Pharmazie (2001), 56(9), 746-747;
International Journal of Pharmaceutics (2001), 212(1), 29-40;
Cyclodextrin: From Basic Research to Market, International
Cyclodextrin Symposium, 10th, Ann Arbor, Mich., United States, May
21-24, 2000 (2000), 10-15 (Wacker Biochem Corp.: Adrian, Mich.);
PCT International Publication No. WO 9942111; Pharmazie, 53(11),
733-740 (1998); Pharm. Technol. Eur., 9(5), 26-34 (1997); J. Pharm.
Sci. 85(10), 1017-1025 (1996); European Patent Application
EP0579435; Proceedings of the International Symposium on
Cyclodextrins, 9th, Santiago de Comostela, Spain, May 31-Jun. 3,
1998 (1999), 261-264 (Editor(s): Labandeira, J. J. Torres;
Vila-Jato, J. L. Kluwer Academic Publishers, Dordrecht, Neth);
S.T.P. Pharma Sciences (1999), 9(3), 237-242; ACS Symposium Series
(1999), 737 (Polysaccharide Applications), 24-45; Pharmaceutical
Research (1998), 15(11), 1696-1701; Drug Development and Industrial
Pharmacy (1998), 24(4), 365-370; International Journal of
Pharmaceutics (1998), 163(1-2), 115-121; Book of Abstracts, 216th
ACS National Meeting, Boston, Aug. 23-27 (1998), CELL-016, American
Chemical Society; Journal of Controlled Release, (1997), 44/1
(95-99); Pharm. Res. (1997) 14(11), S203; Investigative
Ophthalmology & Visual Science, (1996), 37(6), 1199-1203;
Proceedings of the International Symposium on Controlled Release of
Bioactive Materials (1996), 23rd, 453-454; Drug Development and
Industrial Pharmacy (1996), 22(5), 401-405; Proceedings of the
International Symposium on Cyclodextrins, 8th, Budapest, Mar.
31-Apr. 2, (1996), 373-376. (Editor(s): Szejtli, J.; Szente, L.
Kluwer: Dordrecht, Neth.); Pharmaceutical Sciences (1996), 2(6),
277-279; European Journal of Pharmaceutical Sciences, (1996) 4
(SUPPL.), S144; Third European Congress of Pharmaceutical Sciences
Edinburgh, Scotland, UK Sep. 15-17, 1996; Pharmazie, (1996), 51(1),
39-42; Eur. J. Pharm. Sci. (1996), 4 (Suppl.), S143; U.S. Pat. No.
5,472,954 and No. 5,324,718; International Journal of Pharmaceutics
(Netherlands), (Dec. 29, 1995) 126, 73-78; Abstracts of Papers of
the American Chemical Society, (2 Apr. 1995) 209(1), 33-CELL;
European Journal of Pharmaceutical Sciences, (1994) 2, 297-301;
Pharmaceutical Research (New York), (1994) 11(10), S225;
International Journal of Pharmaceutics (Netherlands), (Apr. 11,
1994) 104, 181-184; and International Journal of Pharmaceutics
(1994), 110(2), 169-77, the entire disclosures of which are hereby
incorporated by reference.
[0312] Other suitable polymers are well-known excipients commonly
used in the field of pharmaceutical formulations and are included
in, for example, Remington's Pharmaceutical Sciences, 18th Edition,
Alfonso R. Gennaro (editor), Mack Publishing Company, Easton, Pa.,
1990, pp. 291-294; Alfred Martin, James Swarbrick and Arthur
Commarata, Physical Pharmacy. Physical Chemical Principles in
Pharmaceutical Sciences, 3rd edition (Lea & Febinger,
Philadelphia, Pa., 1983, pp. 592-638); A. T. Florence and D.
Altwood, (Physicochemical Principles of Pharmacy, 2nd Edition,
MacMillan Press, London, 1988, pp. 281-334. The entire disclosures
of the references cited herein are hereby incorporated by
references. Still other suitable polymers include water-soluble
natural polymers, water-soluble semi-synthetic polymers (such as
the water-soluble derivatives of cellulose) and water-soluble
synthetic polymers. The natural polymers include polysaccharides
such as inulin, pectin, algin derivatives (e.g. sodium alginate)
and agar, and polypeptides such as casein and gelatin. The
semi-synthetic polymers include cellulose derivatives such as
methylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose,
their mixed ethers such as hydroxypropyl methylcellulose and other
mixed ethers such as hydroxyethyl ethylcellulose and hydroxypropyl
ethylcellulose, hydroxypropyl methylcellulose phthalate and
carboxymethylcellulose and its salts, especially sodium
carboxymethylcellulose. The synthetic polymers include
polyoxyethylene derivatives (polyethylene glycols) and polyvinyl
derivatives (polyvinyl alcohol, polyvinylpyrrolidone and
polystyrene sulfonate) and various copolymers of acrylic acid (e.g.
carbomer). Other natural, semi-synthetic and synthetic polymers not
named here which meet the criteria of water solubility,
pharmaceutical acceptability and pharmacological inactivity are
likewise considered to be within the ambit of the present
invention.
[0313] An emulsifying agent is intended to mean a compound that
aids the formation of an emulsion. An emulsifier can be used to wet
the corticorsteroid and make it more amenable to dissolution.
Emulsifiers for use herein include, but are not limited to,
polyoxyetheylene 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 monooleate;
sorbitan monopalmitate; extract of quillaia; polyglycerol esters of
dimerised fatty acids of soya bean oil; oxidatively polymerised
soya bean oil; and pectin extract.
[0314] As used herein, the term "stabilizer" is intended to mean a
compound used to stabilize the therapeutic agent against physical,
chemical, or biochemical process that would reduce the therapeutic
activity of the agent. Suitable stabilizers include, by way of
example and without limitation, albumin, sialic acid, creatinine,
glycine and other amino acids, niacinamide, sodium
acetyltryptophonate, zinc oxide, sucrose, glucose, lactose,
sorbitol, mannitol, glycerol, polyethylene glycols, sodium
caprylate and sodium saccharin and other known to those of ordinary
skill in the art.
[0315] As used herein, the term "tonicity modifier" is intended to
mean a compound or compounds that can be used to adjust the
tonicity of the liquid formulation. Suitable tonicity modifiers
include glycerin, lactose, mannitol, dextrose, sodium chloride,
sodium sulfate, sorbitol, trehalose and others known to those of
ordinary skill in the art. Other tonicity modifiers include both
inorganic and organic tonicity adjusting agents. Tonicity modifiers
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, proplyene 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 one embodiment, the tonicity of the
liquid formulation approximates the tonicity of the tissues in the
respiratory tract.
[0316] An osmotic agent can be used in the compositions to enhance
the overall comfort to the patient upon delivery of the
corticosteroid composition. Osmotic agents can be added to adjust
the tonicity of SAE-CD containing solutions. Osmolality is related
to concentration of SAE-CD in water. At SBE7-.beta.-CD
concentrations below about 11-13% w/v, the solutions are hypotonic
or hypoosmotic with respect to blood and at SBE7-.beta.-CD
concentrations above about 11-13% w/v the SBE7-.beta.-CD containing
solutions are hypertonic or hyperosmotic with respect to blood.
When red blood cells are exposed to solutions that are hypo- or
hypertonic, they can shrink or swell in size, which can lead to
hemolysis. As noted above and in FIG. 1, SBE-CD is less prone to
induce hemolysis than other derivatized cyclodextrins. Suitable
osmotic agents include any low molecular weight water-soluble
species pharmaceutically approved for pulmonary and nasal delivery
such as sodium chloride, lactose and glucose. The formulation of
the invention can also include biological salt(s), potassium
chloride, or other electrolyte(s).
[0317] As used herein, the term "antifoaming agent" is intended to
mean a compound or compounds that prevents or reduces the amount of
foaming that forms on the surface of the liquid formulation.
Suitable antifoaming agents include dimethicone, simethicone,
octoxynol, ethanol and others known to those of ordinary skill in
the art.
[0318] As used herein, the term "bulking agent" is intended to mean
a compound used to add bulk to the lyophilized product and/or
assist in the control of the properties of the formulation during
lyophilization. Such compounds include, by way of example and
without limitation, dextran, trehalose, sucrose,
polyvinylpyrrolidone, lactose, inositol, sorbitol,
dimethylsulfoxide, glycerol, albumin, calcium lactobionate, and
others known to those of ordinary skill in the art.
[0319] As used herein, the term "cryoprotectant" is intended to
mean a compound used to protect an active therapeutic agent from
physical or chemical degradation during lyophilization. Such
compounds include, by way of example and without limitation,
dimethyl sulfoxide, glycerol, trehalose, propylene glycol,
polyethylene glycol, and others known to those of ordinary skill in
the art.
[0320] A solubility-enhancing agent or solubility enhancer can be
added to the formulation of the invention. A solubility-enhancing
agent is a compound, or compounds, that enhance(s) the solubility
of the corticosteroid when in an aqueous liquid carrier. When
another solubility enhancing agent is present, the ratio of SAE-CD
to corticosteroid can be changed, thereby reducing the amount of
SAE-CD required to dissolve the corticosteroid. Suitable solubility
enhancing agents include one or more cyclodextrins, cyclodextrin
derivatives, SAE-CD, organic solvents, detergents, soaps,
surfactant and other organic compounds typically used in parenteral
formulations to enhance the solubility of a particular agent.
Exemplary solubility enhancers are disclosed in U.S. Pat. No.
6,451,339; however, other surfactants used in the pharmaceutical
industry can be used in the formulation of the invention. Some
suitable cyclodextrin include underivatized cyclodextrins and
cyclodextrin derivatives, such as SAE-CD, SAE-CD derivatives,
hydroxyalkyl ether cyclodextrin and derivatives, alkyl ether
cyclodextrin and derivatives, sulfated cyclodextrin and
derivatives, hydroxypropyl-.beta.-cyclodextrin, 2-HP-.beta.-CD,
methyl-.beta.-cyclodextrin, carboxyalkyl thioether derivatives,
succinyl cyclodextrin and derivatives, and other cyclodextrin
suitable for pharmaceutical use. SAE-CD cyclodextrins are
particularly advantageous.
[0321] Suitable organic solvents that can be used in the
formulation include, for example, ethanol, glycerin, poly(ethylene
glycol), propylene glycol, poloxamer, aqueous forms thereof and
others known to those of ordinary skill in the art.
[0322] It should be understood that compounds used in the art of
pharmaceutical formulations generally serve a variety of functions
or purposes. Thus, if a compound named herein is mentioned only
once or is used to define more than one term herein, its purpose or
function should not be construed as being limited solely to that
named purpose(s) or function(s).
[0323] An active agent contained within the present formulation can
be present as its pharmaceutically acceptable salt. As used herein,
"pharmaceutically acceptable salt" refers to derivatives of the
disclosed compounds wherein the active agent is modified by
reacting it with an acid or base as needed to form an ionically
bound pair. Examples of pharmaceutically acceptable salts include
conventional non-toxic salts or the quaternary ammonium salts of
the parent compound formed, for example, from non-toxic inorganic
or organic acids. Suitable non-toxic salts include those derived
from inorganic acids such as hydrochloric, hydrobromic, sulfuric,
sulfonic, sulfamic, phosphoric, nitric and others known to those of
ordinary skill in the art. The salts prepared from organic acids
such as amino acids, acetic, propionic, succinic, glycolic,
stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic,
hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic,
sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic,
methanesulfonic, ethane disulfonic, oxalic, isethionic, and others
known to those of ordinary skill in the art. The pharmaceutically
acceptable salts of the present invention can be synthesized from
the parent active agent which contains a basic or acidic moiety by
conventional chemical methods. Lists of other suitable salts are
found in Remington's Pharmaceutical Sciences, 17.sup.th. ed., Mack
Publishing Company, Easton, Pa., 1985, the relevant disclosure of
which is hereby incorporated by reference.
[0324] The phrase "pharmaceutically acceptable" is employed herein
to refer to those compounds, materials, compositions, and/or dosage
forms which are, within the scope of sound medical judgment,
suitable for use in contact with the tissues of human beings and
animals without excessive toxicity, irritation, allergic response,
or other problem or complication, commensurate with a reasonable
benefit/risk ratio.
[0325] As used herein, the term "patient" or "subject" are taken to
mean warm blooded animals such as mammals, for example, cats, dogs,
mice, guinea pigs, horses, bovine cows, sheep and humans.
[0326] A formulation of the invention will comprise an active agent
present in an effective amount, effective dose or therapeutically
effective dose. By the term "effective amount" or "effective dose"
or "therapeutically effective dose", is meant the amount or
quantity of active agent that is sufficient to elicit the required
or desired response, or in other words, the amount that is
sufficient to elicit an appreciable biological response when
administered to a subject.
[0327] In view of the above description and the examples below, one
of ordinary skill in the art will be able to practice the invention
as claimed without undue experimentation. The foregoing will be
better understood with reference to the following examples that
detail certain procedures for the preparation of formulations
according to the present invention. All references made to these
examples are for the purposes of illustration. The following
examples should not be considered exhaustive, but merely
illustrative of only a few of the many embodiments contemplated by
the present invention.
EXAMPLE 1
[0328] Exemplary formulations according to the invention were made
according to the following general procedures.
Method A
[0329] Cyclodextrin is dissolved in water (or buffer) to form a
solution containing a known concentration of cyclodextrin. This
solution is mixed with an active agent in solid, suspension, gel,
liquid, paste, powder or other form while mixing, optionally while
heating to form an inhalable solution.
Method B
[0330] A known amount of substantially dry cyclodextrin is mixed
with a known amount of substantially dry active agent. A liquid is
added to the mixture to form a suspension, gel, solution, syrup or
paste while mixing, optionally while heating and optionally in the
presence of one or more other excipients, to form an inhalable
solution.
Method C
[0331] A known amount of substantially dry cyclodextrin is added to
a suspension, gel, solution, syrup or paste comprising a known
amount of active agent while mixing, optionally while heating and
optionally in the presence of one or more other excipients, to form
an inhalable solution.
[0332] The methods of this example may be modified by the inclusion
of a wetting agent in the composition in order to facilitate
dissolution and subsequent inclusion complexation of the
corticosteroid. A surfactant, soap, detergent or emulsifying agent
can be used as a wetting agent.
Method D
[0333] To a solution comprising a known concentration or amount of
SAE-CD, aqueous liquid carrier, and optionally one or more other
excipients, is added a molar excess of the corticosteroid based
upon the molar ratio of SAE-CD to corticosteroid at the point of
saturated solubility of the corticosteroid, in the presence of the
SAE-CD, as determined herein. For example, corticosteroid would be
added at a 5%, 10%, 15%, 20%, 25%, 30% or greater molar excess. The
components are mixed until equilibration, the point at which there
is only a minor change in the concentration of budesonide over a
one-hour period of time. Then, the excess corticosteroid is removed
leaving behind the target solution of the invention.
[0334] The budesonide is added to the SAE-CD-containing solution as
either a solid or suspension in an aqueous liquid carrier, which
can be water, buffer, aqueous alcohol, aqueous organic solvent or a
combination thereof. The alcohol and organic solvent are of a
pharmaceutically acceptable grade, such as ethanol, propylene
glycol, and others as described herein.
Method E
[0335] The SAE-CD and corticosteroid are triturated to form a
mixture. Then, an aqueous liquid carrier is added to the mixture
form the target solution of the invention.
[0336] The trituration can be conducted dry or in the presence of
moisture, water, buffer, alcohol, surfactant, organic solvent,
glycerin, poly(ethylene glycol), poloxamer, or a combination
thereof.
Method F
[0337] Any of the methods herein are conducted in the presence of
heat, e.g. at a temperature of least 40.degree. C.
Method G
[0338] Any of the methods herein are conducted with cooling, e.g.
at a temperature of less than 20.degree. C. or less than 10.degree.
C. or less than 5.degree. C.
Method H
[0339] Any of the methods herein are conducted in the presence of
high shear mixing such as with a sonicator, narrow gauge
syringe(s), mixer/homogenizer (POLYTRON from KINEMATICA, Europe;
FLUKO, Shanghai, China; ULTIMAGRAL from GEA Niro, Inc., Columbia,
Md.), rotor-stator mixer, or saw tooth mixer.
Method I
[0340] Any of the methods herein are conducted under reduced
pressure.
EXAMPLE 2
[0341] The MMD of nebulized solutions containing SBE7-.beta.-CD and
budesonide was determined as follows.
[0342] Placebo solutions of three different cyclodextrins were
prepared at different concentrations. Two ml of the solutions were
added to the cup of a Pari LC Plus nebulizer supplied with air from
a Pari Proneb Ultra compressor. The particle size of the emitted
droplets was determined using a Malvern Mastersizer S laser light
scattering instrument.
EXAMPLE 3
[0343] The stability of liquid formulations containing SAE-CD was
determined by HPLC chromatography of aliquots periodically drawn
from the liquid in storage.
[0344] Citrate-phosphate (Mcllvaines) buffer solutions at a pH of
4, 5, 6, 7, or 8 were prepared by mixing various portions of 0.01M
citric acid with 0.02 M Na.sub.2HPO.sub.4. These stock solutions
contained 5% w/w Captisol. Approximately 250 .mu.g/mL of budesonide
was dissolved in each buffer solution. Aliquots of the solutions
were stored at 40.degree. C., 50.degree. C. and 60.degree. C.
Control samples were stored at 5.degree. C. but are not reported
here. HPLC analysis of the samples was performed initially and
after 1, 2, and 3 months storage.
[0345] The HPLC conditions included: TABLE-US-00028 Instrument: PE
Series 200 Column: Phenomenex Luna C18(2) 4.6 .times. 150 mm 3 um
Mobile Phase: 58% Phosphate Buffer pH 3.4/39.5% ACN/ 2.5% MeOH
Mobile Phase Program: 100% A (isocratic) Wavelength 240 Flow Rate:
0.6 mL/min Standard Range: Seven standards - 1 to 500 .mu.g/mL
EXAMPLE 4
[0346] The viscosity of aqueous solutions containing SAE-CD were
measured using a cone and plate viscometer.
[0347] A Brookfield Programmable DV-III+ Rheometer, CPE-40 cone and
CPE 40Y plate (Brookfield Engineering Laboratories, Middleboro,
Mass.) was used to make measurements on 0.5 ml samples at 1, 2, 3,
5 and 10 rpm. Samples were sheered for approximately 5 revolutions
prior to each measurement. This allowed accurate rheological
characterization of the samples. The temperature of all samples was
equilibrated to 25.+-.1 degree centigrade using a double wall
viscometer cone supplied with water from an electronically
controlled thermostatic circulating water bath (Model, 8001, Fisher
Scientific, Pittsburgh, Pa.). The viscometer was calibrated using 5
and 50 centipoise using silicon oil calibration standards.
Viscosity measurements were made at 5 or more rotation speeds to
look for sheer thinning behavior (viscosities that decrease as the
rate of sheer increases). Higher rotation speeds result in
increased rates of sheer.
EXAMPLE 5
[0348] Nebulizer output rate as a function of SAE-CD concentration
was measured according to the following general procedure.
[0349] Nebulizer Output was tested using Pari LC Plus Nebulizer
with a Pari ProNeb Ultra Air Compressor (Minimum Nebulizer Volume=2
ml, Maximum Nebulizer Volume=8 ml) for solutions containing 43%,
21.5%, 10.75% and 5.15% w/w SBE7-.beta.-CD. Percentage of sample
emitted was estimated gravimetrically. The nebulizer cup was
weighed before and after nebulization was complete. Nebulization
Time was defined as the duration of time when nebulizer run was
started until the time of first sputter. Nebulizer Output Rate was
calculated by dividing % Emitted with Nebulization Time.
EXAMPLE 6
[0350] Preparation of an inhalable solution containing
budesonide.
[0351] A buffer solution containing 3 mM Citrate Buffer and 82 mM
NaCl at pH 4.45 is prepared. .about.12.5 grams of CAPTISOL was
placed into a 250 ml volumetric flask. .about.62.5 mg of budesonide
was placed into the same flask. Flask was made to volume with the 3
mM citrate buffer/82 mM NaCl solution. The flask was well-mixed on
a vortexer for 10 minutes and sonicated for 10 minutes. The flask
was stirred over weekend with magnetic stirrer. Stirring was
stopped after .about.62 hours and flask was revortexed and
resonicated again for 10 minutes each. The solution was filtered
through a 0.22 .mu.m Durapore Millex-GV Millipore syringe filter
unit. The first few drops were discarded before filter rest of
solution into an amber glass jar with a Teflon-lined screw cap.
Sample concentration was .about.237 .mu.g/ml.
EXAMPLE 7
[0352] Preparation of an inhalable solution containing
budesonide.
[0353] Approximately 5 grams of CAPTISOL was placed into a 100 mL
volumetric flask. .about.26.3 mg of budesonide was placed into the
same flask. The flask was made to volume with the 3 mM citrate
buffer/82 mM NaCl solution. The mixture was well-mixed on a
vortexer for 10 minutes and sonicated for 10 minutes. The mixture
was stirred overnight with a magnetic stirrer. Stirring was stopped
after .about.16 hours and flask was revortexed and resonicated
again for 10 minutes each. The solution was filtered through 0.22
.mu.m Durapore Millex-GV Millipore syringe filter unit. The first 5
drops were discarded before filter rest of solution into an amber
glass jar with a Teflon-lined screw cap. Sample was analyzed to be
233 .mu.g budesonide/ml.
EXAMPLE 8
[0354] Preparation of an inhalable solution containing
budesonide.
[0355] The procedure of Example 7 was followed except that 12.5 g
of CAPTISOL, 62.5 mg of budesonide and about 250 ml of buffer were
used. Sufficient disodium EDTA was added to prepare a solution
having an EDTA concentration of about 0.01 or 0.05% wt/v EDTA.
EXAMPLE 9
[0356] Preparation of a solution containing SAE-CD and budesonide
as prepared from a PULMICORT RESPULES suspension.
Method A
[0357] To the contents of one or more containers of the Pulmicort
Respules (nominally 2 mL of the suspension), about 50 mg (corrected
for water content) of CAPTISOL was added per mL of Respule and
mixed or shaken well for several minutes. After standing from about
30 minutes to several hours, the solution was used as is for in
vitro characterization. In addition to budesonide and water, the
PULMICORT RESPULE (suspension) also contains the following inactive
ingredients per the label: citric acid, sodium citrate, sodium
chloride, disodium EDTA and polysorbate 80.
Method B
[0358] Weigh approximately 200 mg amounts of CAPTISOL (corrected
for water content) into 2-dram amber vials. Into each vial
containing the weighed amount of CAPTISOL empty the contents of two
Pulmicort Respules containers (0.5 mg/2 mL, Lot #308016 February
2005) by gently squeezing the deformable plastic container to the
last possible drop. The Respules were previously swirled to
re-suspend the budesonide particles. The vials are screw capped,
mixed vigorously by vortex and then foil wrapped. The material can
be kept refrigerated until use.
[0359] The inhalable liquid composition prepared according to any
of these methods can be used in any known nebulizer. By converting
the suspension to a liquid, an improvement in delivery of
budesonide (a corticosteroid) is observed.
EXAMPLE 10
[0360] Other solutions according to the invention can be prepared
as detailed below. TABLE-US-00029 Mg per ml Mg per ml (as prepared)
(per target) Component Concentrate A Concentrate B Final Solution
Budesonide EP 1 .about.1.6 (sat'd) 0.250 CAPTISOL 200 200 50 Sodium
Citrate tribasic 0 0 0.44 dihydrate Citric Acid 0 0 0.32 Sodium
Chloride 0 0 4.8 Disodium EDTA 0 0 0-0.5 Polysorbate 80 (Tween 0 0
0-1 80) Water Qs Qs QS with buffer containing CAPTISOL or
budesonide
[0361] Dilute Concentrate A at a ratio of 1 to 4 with pH 4.5
salinated citrate buffer (4 mM containing 109 mM sodium chloride)
to contain 5% w/v CAPTISOL on an anhydrous basis. Filter the
diluted concentrate through a 0.22 .mu.m Millipore Durapore
Millex-GV syringe filter unit. Assay the filtered solution by HPLC
then add supplemental budesonide as needed to give a solution final
concentration of about 250 .mu.g/mL (.+-.<5%). [0362] Dilute
Concentrate B at a ratio of 1 to 4 with pH 4.5 salinated citrate
buffer (4 mM containing 109 mM sodium chloride) to contain 5% w/v
CAPTISOL on an anhydrous basis. Filter the diluted concentrate
through a 0.22 .mu.m Millipore Durapore Millex-GV syringe filter
unit. Assay the filtered solution by HPLC then dilute further with
pH 4.5 salinated citrate buffer (3 mM containing 82 mM sodium
chloride containing 5% w/v CAPTISOL) as required to give a final
solution concentration of about 250 .mu.g/mL (.+-.<5%). This
technique takes advantage of the excess solid budesonide used to
saturate the solution.
EXAMPLE 11
[0363] Clarity of solutions was determined by visual inspection or
instrumentally. A clear solution is at least clear by visual
inspection with the unaided eye.
EXAMPLE 12
[0364] The following method was used to determine the performance
of nebulization compositions emitted from a nebulizer according to
FIGS. 10a-10b.
[0365] Two ml of the test CD solution or Pulmicort suspension was
accurately pipetted by volumetric pipettes into a clean nebulizer
cup prior to starting each experiment. The test nebulizer was
assembled and charged with the test inhalation solution or
suspension according to the manufacturer instructions. The end of
the mouthpiece was placed at a height of approximately 18 cm from
the platform of the MALVERN MASTERSIZER to the middle point of tip
of the nebulizer mouthpiece. A vacuum source was positioned
opposite the mouthpiece approximately 6 cm away to scavenge aerosol
after sizing. The distance between the mouthpiece and the detector
was approximately 8 cm. The center of the mouthpiece was level with
the laser beam (or adjusted as appropriate, depending on the
individual design of each nebulizer). The laser passed through the
center of the emitted cloud when the nebulizer was running.
Measurements were manually started 15 seconds into nebulization.
Data collection started when beam obscuration reached 10% and was
averaged over 15,000 sweeps (30 seconds). Scattered light intensity
data on the detector rings was modeled using the "Standard-Wet"
model. Channels 1 and 2 were killed due to low relative humidity
during measurement to prevent beam steering. The volume diameter of
droplets defining 10, 50 (volume median), and 90% of the cumulative
volume undersize was determined. (Dv10 is the size below which 10%
of the volume of material exists, Dv50 is the size below which 50%
of the volume of material exists and Dv90 is the size below which
90% of the volume of material exists.
[0366] The procedure above may be practiced with slight
modification on a MALVERN SPRAYTEC to determine the particle size
of droplets emitted by a nebulizer.
EXAMPLE 13
[0367] Solutions of budesonide with and without SBE7-.beta.-CD were
prepared at two different pHs (4 and 6) and stored at 2 different
temperatures (60.degree. C. and 80.degree. C). Citrate buffers (50
mM) at each pH value were prepared by mixing differing portions of
50 mM citric acid and 50 mM sodium citrate (tribasic, dihydrate)
solutions. To achieve a concentration of budesonide in the buffers
without SBE7-.beta.-CD sufficient for accurate measurement, the
budesonide was dissolved first in 100% ethyl alcohol. An aliquot of
the ethanol/budesonide solution was then added drop-wise with
stirring to each buffer solution. The theoretical budesonide
concentration was 100 .mu.g/mL with a final ethanolic content of 5%
in each buffer. All solution preps and procedures involving
budesonide were done in a darkened room under red light. After
shaking solutions for 24 hours, both buffer solutions were filtered
through Millipore Millex-GV 0.22 .mu.m syringe filters to remove
any solid that had precipitated (no significant amounts observed)
from the solutions. The final budesonide concentration was about 50
.mu.g/mL. Both the pH 4 and 6 solutions were split in two, and
solid SBE7-.beta.-CD was added to one of the portions to create
solutions with and without 1% w/v SBE7-.beta.-CD at each pH. Each
solution was aliquoted into individual amber vials. They were then
placed in ovens at 60.degree. C. and 80.degree. C. Sample vials
were removed from the ovens and analyzed by HPLC at 0, 96, 164, and
288 hours. The HPLC assay conditions are summarized below.
Chromatographic Conditions
[0368] (Adapted from Hou, S., Hindle, M., and Byron, P. R. A.
Stability-Indicating HPLC Assay Method for Budesonide. Journal of
Pharmaceutical and Biomedical Analysis, 2001; 24: 371-380.)
TABLE-US-00030 Instrument: PE Series 200 Column: Phenomenex Luna
C18(2) 4.6 .times. 150 mm 3 um Mobile Phase: 58% Phosphate Buffer
pH 3.4/39.5% ACN/ 2.5% MeOH Mobile Phase Program: 100% A
(isocratic) Wavelength 240 nm Flow Rate: 0.6 mL/min Standard Range:
Seven standards - 1 to 500 .mu.g/mL
EXAMPLE 14
[0369] Preparation and use of a combination solution containing
SAE-CD, budesonide, and albuterol sulfate.
[0370] A budesonide solution is prepared per EXAMPLE 9 (mixing
SAE-CD with the PULMICORT RESPULES suspension) and added to 3 ml of
a solution containing 2.5 mg albuterol (The World Health
Organization recommended name for albuterol base is salbutamol)
provided as albuterol sulfate. The albuterol solution is
commercially available prediluted and sold under the name
PROVENTIL.RTM. Inhalation Solution, 0.083%, or prepared from a
commercially available concentrate 0.5% (sold under the names:
PROVENTIL.RTM. Solution for inhalation and VENTOLIN.RTM. Inhalation
Solution).
[0371] To provide the required dose for children 2 to 12 years of
age, the initial dosing should be based upon body weight (0.1 to
0.15 mg/kg per dose), with subsequent dosing titrated to achieve
the desired clinical response. Dosing should not exceed 2.5 mg
three to four times daily by nebulization. The appropriate volume
of the 0.5% inhalation solution should be diluted in sterile normal
saline solution to a total volume of 3 mL prior to administration
via nebulization. To provide 2.5 mg, 0.5 mL of the concentrate is
diluted to 3 mL with sterile normal saline. The albuterol aqueous
solutions also contain benzalkonium chloride; and sulfuric acid is
used to adjust the pH to between 3 and 5. Alternatively, an aqueous
solution of an appropriate strength of albuterol may be prepared
from albuterol sulfate, USP with or without the added preservative
benzalkonium chloride and pH adjustment using sulfuric acid may
also be unnecessary when combining with the corticosteroid
solution. Furthermore the volume containing the appropriate dose of
corticosteroid may be decreased four-fold as described in the
following example allowing the total volume to be less and the time
of administration to diminish accordingly.
EXAMPLE 15
[0372] Preparation and use of a combination solution containing
SAE-CD, budesonide, and albuterol sulfate or levalbuterol HCl
(XOPENEX).
[0373] A citrate buffer (3 mM pH 4.5) was prepared as follows.
Approximately 62.5 mg of citric acid was dissolved in and brought
to volume with water in one 100 ml volumetric flask. Approximately
87.7 mg of sodium citrate was dissolved in and brought to volume
with water in another 100 mL volumetric flask. In a beaker the
sodium citrate solution was added to the citric acid solution until
the pH was approximately 4.5.
[0374] Approximately 10.4 mg of budesonide and 1247.4 mg of
Captisol were ground together with a mortar and pestle and
transferred to a 10 mL flask. Buffer solution was added, and the
mixture was vortexed, sonicated and an additional 1.4 mg budesonide
added. After shaking overnight, the solution was filtered through a
0.22 .mu.m Durapore Millex-GV Millipore syringe filter unit. The
resulting budesonide concentration was .about.1 mg/ml.
Approximately 0.5 ml of the budesonide solution was added to a unit
dose of either Proventil (2.5 mg/3 mL) or Xopenex (1.25 mg/3 mL)
thereby forming the combination clear liquid dosage form of the
invention. The resulting mixture remained essentially clear for a
period of at least 17 days at ambient room conditions protected
from light.
EXAMPLE 16
[0375] Preparation and use of a combination solution containing
SAE-CD, budesonide, and formoterol (FORADIL.RTM. (formoterol
fumarate inhalation powder)).
[0376] The contents of one capsule containing 12 mcg of formoterol
fumarate blended with 25 mg of lactose was emptied into a vial to
which was added 3-mL of 3 mM citrate buffer (pH 4.5) prepared as
described in the previous example. The contents of the vial were
vortexed to dissolve the solids present. The budesonide concentrate
was prepared as described in the previous example to provide a
concentration of .about.1 mg/mL. Approximately 1 ml of the
budesonide solution was added to the formoterol fumarate buffered
solution. The resulting solution remained essentially clear for a
period of at least one month at room ambient conditions protected
from light.
EXAMPLE 17
[0377] Clinical evaluation of a dosage form according to the
invention was conducted by performing gamma scintigraphy analyses
on subjects before and after administration of the dosage form by
nebulization.
[0378] A single centre, four-way crossover gamma scintigraphy study
to compare pulmonary delivery of budesonide via Pulmicort
Respules.RTM., and Captisol-Enabled.RTM. budesonide formulations
using a Pari LC air-jet nebulizer was conducted. The purpose of the
study was to determine, by gamma scintigraphy, the intra-pulmonary
deposition of radiolabeled budesonide following nebulization of a
budesonide suspension (Pulmicort Respules.RTM., Astra Zeneca,
reference formulation) and a Captisol.RTM.-Enabled budesonide
solution (test formulation) in healthy male volunteers. During the
course of the study, blood was collected periodically up to 24
hours, and the plasma was isolated. The concentration of budesonide
in the plasma was determined using a validated HPLC MS-MS method in
order to determine pharmacokinetic parameters. Dosing was conducted
using a Pari LC Plus air-jet nebulizer. The use of gamma
scintigraphy in conjunction with radiolabeled study drug and/or
vehicle is the standard technique for the quantitative assessment
of pulmonary deposition and clearance of inhaled drugs and/or
vehicle.
[0379] The study dosage forms consisted of: 1) 1 mg Budesonide as 2
mL.times.0.5 mg/mL Pulmicort Respules.RTM.; or 2) 1 mg Budesonide
as 2 mL.times.0.5 mg/mL Pulmicort Respules to which 7.5% w/v
Captisol.RTM. has been added.
[0380] Each subject received each of four study administrations of
radiolabeled Budesonide in a non-randomized manner. A
non-randomized design was utilized for this study since the
reference formulation (Pulmicort Respule.RTM.) must be administered
first to all subjects in order to determine the time to sputter
(TTS). The TTS differed between subjects. For subsequent
administrations the dose administered was controlled by the length
of administration, expressed as a fraction of the time to sputter
determined following administration of the reference formulation
(i.e. 25% TTS, 50% TTS and 75% TTS). It was expected that even
though the same concentration of budesonide would be nebulized for
a shorter time, the amount of drug reaching the volunteers lungs
would be essentially the same as the reference suspension for one
of the legs of the study. Scintigraphic images were acquired using
a gamma camera immediately after completion of dosing the
volunteers.
[0381] Comparison of the image from the reference product and the
25% TTS leg indicated that a greater percentage of the budesonide
from the Respule was in the stomach and throat immediately after
administration. Thus a greater percentage of the budesonide reached
the target lung tissue when Captisol was used to dissolve the
budesonide. This could reduce undesirable side effects caused by
the drug. One aspect of the method and dosage form of the invention
thus provides an improved method of administering a corticosteroid
suspension-based unit dose, the method comprising the step of
adding a sufficient amount of SAE-CD to convert the suspension to a
clear solution and then administering the clear solution to a
subject. As a result, the method of the invention provides
increased rate of administration as well as increased total
pulmonary delivery of the corticosteroid as compared to the initial
unit dose suspension formulation.
EXAMPLE 18
[0382] Comparative evaluation of various forms of SAE-CD in the
solubilization of corticosteroid derivatives.
[0383] The solubility of beclomethasone dipropionate (BDP),
beclomethasone 17-monopropionate (B17P), beclomethasone
21-monopropionate (B21P) and beclomethasone (unesterifed) in
solutions containing CAPTISOL and various SBE.sub.n.gamma.-CD was
evaluated. BDP, B17P and B21P were obtained from Hovione.
Beclomethasone was obtained from Spectrum Chemicals. CAPTISOL,
SBE(3.4) .gamma.-CD, SBE(5.23) .gamma.-CD and SBE(6.1) .gamma.-CD
were provided by CyDex, Inc. (Lenexa, Kans.). .gamma.-CD was
obtained from Wacker Chemical Co. SBE(5.24) .gamma.-CD and SBE(7.5)
.gamma.-CD were provided by the University of Kansas.
[0384] A 0.04M solution of each selected CD was prepared. Each form
of beclomethasone required 2 ml of CD solution, therefore the 0.04M
solutions were prepared in 20 or 25 mL volumetric flasks in
duplicate (N=2). The following table indicates the amount of each
CD used after accounting for the content of water in each CD.
TABLE-US-00031 CD MW (g/mole) mg of CD (volume) SBE(6.7) .beta.-CD
2194.6 2297.0 (25 ml) .gamma.-CD 1297 1433.0 (25 ml) SBE(3.4)
.gamma.-CD 1834.9 1891.6 (25 ml) SBE(5.24) .gamma.-CD 2119.5 1745.7
(20 ml) SBE(6.1) .gamma.-CD 2261.9 1866.8 (20 ml) SBE(7.5)
.gamma.-CD 2483.3 2560.0 (25 ml)
[0385] Beclomethasone forms were weighed in amounts in excess of
the anticipated solubilities directly into 2-dram Teflon-lined
screw-capped vials. These amounts typically provided approximately
6 mg/mL of solids. Each vial then received 2 ml of the appropriate
CD solution. The vials were vortexed and sonicated for about 10
minutes to aid in wetting the solids with the fluid. The vials were
then wrapped in aluminum foil to protect from light and placed on a
lab quake for equilibration. The vials were visually inspected
periodically to assure that the solids were adequately being wetted
and in contact with the fluid. The time points for sampling were at
24 hrs for all samples and 72 hours for BDP only.
[0386] Solutions of SBE(6.1) .gamma.-CD were prepared at 0.04,
0.08, and 0.1M and solutions of SBE (5.23) .gamma.-CD were prepared
at only 0.04 and 0.08M. Beclomethasone dipropionate was weighed in
amounts in excess of the anticipated solubilities directly into
2-dram teflon-lined screw-capped vials. These amounts typically
provided approximately 2 mg/mL of solids. Each vial then received 2
mL of the appropriate CD solution (N=1). The vials were vortexed
and sonicated for about 10 minutes to aid in wetting the solids
with the fluid. The vials were then wrapped in aluminum foil to
protect from light and placed on a lab quake for a five-day
equilibration.
[0387] Solutions of .gamma.-CD were prepared at 0.01 and 0.02M.
Beclomethasone dipropionate was weighed in amounts in excess of the
anticipated solubilities directly into 2-dram teflon-lined
screw-capped vials. These amounts typically provided approximately
2 mg/mL of solids. Each vial then received 2 mLs of the .gamma.-CD
solution (N=2). A solution was also prepared to measure the
intrinsic solubility of BDP using HPLC grade water in place of the
CD. The samples were wrapped in foil and placed on a lab quake for
five days.
[0388] At the end of the equilibration time for each stage, the
vials were centrifuged and 1 ml of the supernatant removed. The
removed supernatant was then filtered using the Durapore PVDF 0.22
.mu.m syringe filter (discarded first few drops), and diluted with
the mobile phase to an appropriate concentration within the
standard curve. The samples were then analyzed by HPLC to determine
concentration of solubilized corticosteroid.
EXAMPLE 19
[0389] Preparation and use of a combination solution containing
SAE-CD, budesonide, and formoterol fumarate.
[0390] Formoterol fumarate dry powder is blended with Captisol dry
powder which are both sized appropriately to provide for content
uniformity at a weight ratio of 12 mcg formoterol fumarate/100 mg
Captisol. An amount of powder blend corresponding to a unit dose of
formoterol fumarate is placed in a suitable unit dose container
such as a HPMC capsule for later use or is added directly to a unit
dose of Pulmicort Respules budesonide inhalation suspension (500
mcg/2 mL), then mixed to achieve dissolution of all solids (a clear
solution) and placed in the nebulizer reservoir for
administration.
EXAMPLE 20
[0391] Preparation and use of a combination solution containing
SAE-CD, budesonide, and ipratropium bromide.
[0392] A budesonide solution is prepared as per EXAMPLE 9 and added
to a ipratropium bromide solution that is commercially available
and sold under the name ATROVENT.RTM. Inhalation Solution Unit
Dose. ATROVENT.RTM. (ipratropium bromide) Inhalation Solution is
500 mcg (1 unit dose Vial) administered three to four times a day
by oral nebulization, with doses 6 to 8 hours apart. ATROVENT.RTM.
inhalation solution unit dose Vials contain 500 mcg ipratropium
bromide anhydrous in 2.5 ml sterile, preservative-free, isotonic
saline solution, pH-adjusted to 3.4 (3 to 4) with hydrochloric
acid. Furthermore the volume containing the appropriate dose of
corticosteroid may be decreased four-fold as described in the above
example (budesonide concentrate .about.1 mg/mL) allowing the total
volume to be less and the time of administration to diminish
accordingly.
EXAMPLE 21
[0393] Evaluation of the AERONEB GO nebulizer versus a RAINDROP
nebulizer with a solution comprising budesonide, aqueous liquid
carrier and SAE-CD.
[0394] The AERONEB GO nebulizer (AEROGEN Inc., Mountainview,
Calif.) is detailed in U.S. Pregrant Publication No. 2005-011514 to
Power et al. (Application U.S. Ser. No. 10/833,932 filed Apr. 27,
2004), PCT International Publication No. WO 2005/009323 to Aerogen,
Inc. et al. (PCT Application No. PCT/US2004/021268 filed Jul. 6,
2004), and European Application No. EP 16426276, the entire
disclosures of which are hereby incorporated by reference.
[0395] The RAINDROP nebulizer is available from Nellcor (Tyco
Healthcare).
[0396] The solution of the invention used for this study was
prepared according to Example 28.
[0397] Characterization of droplet size distribution of an
aerosolized solution using a cascade impactor was determined
according to Example 26.
[0398] Determination of total drug output and drug output rate from
a nebulizer containing a liquid of the invention was determined
according to Example 27.
EXAMPLE 22
[0399] Evaluation of the pulsating membrane nebulizer of U.S. Pat.
No. 6,962,151 with a solution comprising budesonide, aqueous liquid
carrier and SAE-CD. Inertial Impaction Characterization of
Tc.sup.99m-DTPA Labelled Captisol-Enabled.RTM. Budesonide Aerosols
Generated via a Pari Electronic Nebulizer
[0400] The nebulizer detailed in U.S. Pat. No. 6,962,151, is also
described in PCT International Application No. PCT/US00/29541 filed
Oct. 27, 2000, and U.S. application Ser. No. 11/269,783 filed Nov.
7, 2005.
[0401] Aerosol characterization was conducted by standard in vitro
inertial impaction tests using an Andersen Cascade Impactor (ACI).
Technetium-99m (.sup.99mTc), in the form of
diethylenetriaminepenta-acetic acid (DTPA, GE Healthcare), was
added to the Captisol-Enabled.RTM. Budesonide Inhalation Solution
(CEBUD). The suitability of .sup.99mTc-DTPA to function as a
surrogate for budesonide in CEBUD preparations was validated in the
course of an earlier clinical trial (see Example 17). Preparation
of the budesonide solution formulation for testing was conducted as
per the description below. It was calculated that approximately 10
MBq of .sup.99mTc should be added to the budesonide formulation
(11.05 g) on the day of testing, in order to provide sufficient
activity for in vitro imaging.
[0402] Two Pari electronic vibrating membrane nebulizers were used.
At the core of this electronic nebulizer is a stainless steel
membrane with thousands of laser drilled holes. Laser drilling
allows flexibility to customize particle size, ensure
reproducibility, and maintain a high output rate with smaller
particles. The perforated membrane is vibrated at high frequencies
in a resonant "bending" mode which yields high particle output
rates. The nebulizer provides rapid drug delivery, efficiency,
ideal particle sizing, low residual volume, and optimal performance
matched to the inhaled drug formulation (See Rajiv Dhand,
Respiratory Care 2002;(12): 1406-1416). Approximately 0.5 mL of
drug solution was loaded and subsequently delivered via each
nebulizer on 3 separate occasions. Runs 1, 3 and 5 were conducted
with Device 1 and runs 2, 4 and 6 were conducted with Device 2.
Pre-Dose
[0403] On each occasion, prior to dose delivery, the filled
nebulizer was imaged for 60 seconds on Head I of the dual head
gamma camera (Axis, Philips Medical Systems). Also, the nebulizers
were weighed before and after addition of the budesonide
formulation.
Inertial Impaction Testing
[0404] The nebulizer was positioned at the USP (United States
Pharmacopoeia) inlet of the ACI and a flow rate of 28.3 L/min was
drawn through the impactor using a vacuum pump. Flow through the
impactor was started prior to activation of the electronic
nebulizer. A stopwatch was used in order to measure the duration of
dose delivery.
[0405] The ACI test conditions were the same as those used for Pari
LC Plus air-jet nebulizer evaluation in the course of the earlier
clinical study.
[0406] Following deposition the USP throat was removed from the ACI
and imaged for 120 seconds. The collection plates were removed from
the impactor and placed on Head I of the gamma camera and imaged
for 120 seconds. The plates were subsequently washed and dried
before conduct of further impaction tests.
Post-Dose
[0407] On each occasion, the nebulizer weight was recorded after
delivery of the dose. The nebulizer was imaged as described
below.
Image Processing
[0408] A rectangular ROI was applied to image to the nebulizer
pre-dose. This ROI was then re-applied to image the nebulizer after
dose delivery.
[0409] A rectangular ROI was also applied to the USP Inlet
image.
[0410] A circular ROI was drawn around collection plate 0, copied
and placed around plate 1. This was repeated for plates 2-7 and the
filter. A rectangular ROI was also drawn to assess the background
counts. Raw counts were corrected for background activity and
adjusted to counts per minute (cpm).
[0411] Aerosol performance is characterized in the table, in terms
of the fine particle fraction (FPF) i.e. % emitted dose with a
particle size <5.8 .mu.m, mass median aerodynamic diameter
(MMAD), geometric standard deviation (GSD) and the nebulization
delivery time.
CEBUD Preparation
[0412] The expelled contents of five Pulmicort Respules (1 mg/mL)
were combined together. Captisol.RTM. (165 mg) on a dried basis was
added per Respule used to the combined contents of the commercial
suspension to provide a Captisol concentration of about 7.5%
w/v.
[0413] The mixture was vortexed briefly to disperse and dissolve
the Captisol.RTM.. Then placed on a roller-bed mixer and allowed to
mix for two-four or several hours. Aliquots of the equilibrated
mixture were used to recover any budesonide retained in the
original Respule container, and the recombined together. The
mixture was the further equilibrated overnight (.about.20 hours) on
the roller-bed mixer. After visually checking that all the
suspended solids had dissolved, the required volume of 99m
Tc-D5PA/saline solution (provided by Medical Physical Department,
UHW) was added. So about 180 .mu.l of the Radiolabel solution was
added to the Captisol-Enabled.RTM. Budesonide Inhalation Solution
and vortexed briefly.
EXAMPLE 23
[0414] Determination of the phase solubility curve for
corticosteroid dissolution with SAE-CD.
[0415] The solubility of coritcosteroid solutions containing SAECD
was determined by HPLC chromatography of aliquots from equilibrated
filtered or centrifuged corticosteroid solutions as follows.
[0416] SAE-CD/steroid solutions were prepared by weighing dry
solids of SAE-CD (to provide 0.04 molar) and excess steroid drug (6
mg/mL) together into a screw-capped vial. A volume of water was
aliquoted to each vial (separate vial for each steroid). Intrinsic
solubility was determined by weighing excess steroid (6 mg/mL) and
adding a volume of water in the absence of CD. Vials were capped,
initially vortexed and sonicated. Vials were then placed on a
roller-mixer (model: SRT2; Manufacturer: Stuart Scientific; Serial
number: R000100052) or rocker/mixer (Model: LabQuake; Manufacturer:
Barnstead/Thermolyne; Serial number: 1104010438202). Higher
excesses of solid steroid (up to 10 mg/mL) were then added to any
vial where the liquid contents clarified overnight (e.g.
prednisolone, hydrocortisone, and prednisone). Samples were rolled
and mixed on the roller or rocker for 72 hours. At various times
during the equilibration, samples were additionally vortexed or
sonicated briefly (up to 30 minutes). After the designated
equilibration time, samples were filtered (0.22 .mu.m, 25 mm,
Duropore--PVDF, manufacturer: Millipore) into clean vials except
for the intrinsic solubility sample for Beclomethasone Dipropionate
which was centrifuged and the supernatant transferred to a clean
vial. Samples were analyzed by conventional HPLC methods.
EXAMPLE 24
[0417] Preparation of clear liquid formulations containing SAE-CD,
budesonide and Salmeterol xinafoate. A formulation of this kind can
be prepared according to other examples herein containing a
combination of corticosteroid, SAE-CD and a second therapeutic
agent.
EXAMPLE 25
[0418] Preparation of clear liquid formulations containing SAE-CD,
budesonide and albuterol sulfate.
[0419] A stock solution containing CAPTISOL (40.0 g), water (1 L),
citric acid (387.6 mg), sodium citrate (519.6 mg), EDTA (120 mg),
and NaCl (6.36 mg) was prepared by mixing the components
together.
[0420] Budesonide (37.5 mg) and albuterol sulfate (150 mg) were
added to an aliquot (150 ml) of the stock solution and mixed on a
roller mixer at ambient temperature until dissolution of all
components. The final solution was clear, however, it could be
filtered if needed. The final concentration of components in the
formulation was as follows: CAPTISOL (0.018 M); budesonide (5.9 mM
or 254 .mu.g/ml); and albuterol sulfate (1 mg/ml).
EXAMPLE 26
[0421] Characterization of droplet size distribution of an
aerosolized solution using a cascade impactor.
[0422] The droplet size distribution of an aerosolized solution of
the invention was characterized using an NGI cascade impactor.
Approximately 0.5 mL of the 1000 .mu.g/mL was placed into a
nebulizer, such as the AERONEB GO. The vacuum pump associated with
the impactor was turn on. The nebulizer mouthpiece was positioned
into the center of the USP induction port and sealed to it with
parafilm. The nebulizer was turned on until no more vapors were
visible. Collection continued for an additional 45 seconds to
ensure complete collection of the sample. Vacuum was turned off and
the impactor disassembled. The collection cups at each stage were
extracted with known volumes of HPLC mobile phase and assayed for
budesonide. The cumulative amount of budesonide on each stage was
quantified. The percent of drug exiting the nebulizer was 81%, and
the percent of drug in the fine particle fraction (<5 .mu.m) was
66%.
EXAMPLE 27
[0423] Determination of total drug output and drug output rate from
a nebulizer containing a liquid of the invention.
[0424] A dose collection apparatus was constructed with a 300 ml
glass filter unit of the type used to filter HPLC mobile phases. A
specially fabricated Plexiglas lid covered the reservoir and had an
opening to admit aerosol into the reservoir. The reservoir tapered
towards a glass fiber filter supported by a metal mesh. The mesh
was contained in a conical glass housing that terminated in a glass
tube, which was attached to a flow controller and vacuum pump. The
reservoir and filter support housing were clamped together. Two
filters were sandwiched together in the apparatus to collect the
emitted aerosol. This was necessary to avoid saturation of the
filter, which can result in it tearing with subsequent drug loss
into the vacuum, and changes in airflow rate over the course of
aerosol collection. The end of nebulization was judged by
intermittent aerosol output and/or a change in pitch of the
nebulizer sound. To prevent loss of nebulized budesonide to the
atmosphere, air was drawn into the filter faster than it was
ejected from the nebulizers. By visually confirming that no aerosol
escaped from the back of any nebulizer, a flow rate of 15.+-.5%
l/min was deemed satisfactory. This was regulated by a TPK flow
controller (Copley Instruments, 4312) and vacuum pump, and
confirmed before each experiment using a calibrated flow meter.
EXAMPLE 28
[0425] Preparation of a liquid formulation comprising SAE-CD and
budesonide, optionally containing Tween.
[0426] A 3 mM citrate buffer at pH 4.5 was added to 2 grams of
CAPTISOL and 25 mg of budesonide in a serum vial to make the final
volume 10 mL. The suspension was well mixed by vortexing and
sonication. A 20% stock solution of CAPTISOL without budesonide was
also prepared in 3 mM citrate buffer. These mixtures, along with
the buffer were sealed in separate vials and autoclaved using the
20-minute hold at 121.degree. C. cycle. HPLC analysis of the clear
budesonide solution showed the concentration was 2100 .mu.g/mL. The
20% CAPTISOL stock solution was used to dilute the sample to 2000
.mu.g/mL. A portion of the above resulting solution was optionally
diluted with an equal volume of the 3 mM citrate buffer. HPLC
analysis showed the final concentration was 990 .mu.g of
budesonide/mL.
[0427] The Tween could be added to the above solution as follows. A
solution of 0.02% Tween was prepared with the autoclaved buffer
only solution to form a Tween stock solution for use as a diluent
for the above solutions. The dilutions for the 10% captisol/1 mg/mL
budesonide were done by weight. Approximately 9 grams of the 20%
captsiol/2000 .mu.g/mL was mixed with .about.9 grams of either the
autoclaved buffer only solution or the autoclaved buffer/0.02%
Tween solution. These solutions were well-mixed, filtered and
reassayed by HPLC.
[0428] The budesonide concentrations of the above formulations were
found to be 986 .mu.g/mL for the solution without Tween and 962
.mu.g/mL for the solution with Tween.
[0429] The solutions can be nebulized with any nebulizer; however,
with an AERx nebulizer, an initial sample volume of 50 .mu.l can be
used. Administration of this solution with the nebulizer makes it
feasible for a therapeutic dose to be administered to a subject in
a single puff (a single full inhalation by a subject) via
nebulization.
EXAMPLE 29
[0430] Preparation and dissolution of a lyophilized formulation
comprising SAE-CD and budesonide.
[0431] An excess of budesonide, 3.5 mg/mL, was added to 3L of 30%
Captisol in 3 mM citrate buffer containing 0.1 mg/mL EDTA. After
mixing for 2 days, an additional 1 mg/mL budesonide was added and
equilibrated an additional 4 days. The preparation was filtered
through a 0.22.mu. Durapore filter and placed in three stainless
steel trays in a freeze dryer. The solution was frozen at
-30.degree. C. for one hour and lyophilized over 30 hours to remove
essentially all the water. The lyophile was powdered, screened and
the powder transferred to a plastic bottle. The final composition
contained 8.2 mg budesonide per gram of powder.
[0432] When approximately 65 mg of powder was added to 2 mL of
water, an essentially clear solution containing the same amount of
budesonide as in the reference suspension product was rapidly
obtained.
EXAMPLE 30
[0433] Preparation of an aqueous liquid formulation comprising
SAE-CD, ethanol and budesonide.
[0434] Captisol/Ethanol solutions were prepared by making a stock
captisol solution at 22.2% (.about.0.1 M) w/v which was diluted
with either ethanol or water in varying amounts to create four
solutions of 0, 1, 2, 5% ethanol and about 20% w/v Captisol.
Captisol/Ethanol/Budesonide solutions were prepared by adding dry
Budesonide (2.5 mg/mL) to a volume of the prepared Captisol/ethanol
solutions and then these were equilibrated on a Labquake for 72
hours. These solutions were filtered (Duropore syringe filters) and
analyzed by HPLC to determine the concentration (.mu.g/ml) of
budesonide dissolved in the formulation.
EXAMPLE 31
[0435] An in-vivo evaluation of a dosage form according to the
invention was conducted by performing a pharmacokinetic analysis on
budesonide after administration of the dosage form by
nebulization.
[0436] A four dog crossover study to compare pulmonary delivery of
budesonide via Pulmicort Respules.RTM., and a Captisol-Enabled.RTM.
budesonide formulation using a Pari LC air-jet nebulizer was
conducted. The purpose of the study was to determine, by HPLC-MS/MS
analysis, the pharmacokinetics of budesonide the plasma, following
nebulization of a budesonide suspension (Pulmicort Respules.RTM.,
AstraZeneca, reference formulation) and a Captisol-Enabled.RTM.
budesonide inhalation solution (test formulation) in healthy dogs.
Dosing was conducted using a Pari LC Star air-jet nebulizer and
anesthesia masks.
[0437] The study dosage forms consisted of: 1) 1 mg Budesonide as
two 2 mL.times.0.25 mg/mL Pulmicort Respules.RTM.; or 2) 1 mg
Budesonide as two 2 mL.times.0.25 mg/mL Pulmicort Respules to which
5% w/v Captisol.RTM. was added.
[0438] Prior to dosing, two capsules containing activated charcoal
followed with approximately 30 mL of water were administered to
each dog to block oral absorption of the budesonide. Each dog
received each of the study administrations one week apart in a
randomized manner. Administration time was the same for each
formulation (23.9 min. for test formulation and 23.4 min. for
reference). Blood was collected periodically up to 8 hours, the
plasma was isolated and stored at -70.degree. C. until analysis.
After each administration, the nebulizer and test solution
container were assayed for residual budesonide to determine the
amount of drug delivered.
EXAMPLE 32
[0439] To investigate how the incorporation of Captisol at 5% w/v
into Pulmicort Respules impact performance of different types of
nebulizers.
[0440] The emitted dose of budesonide from four different
nebulizers (PARI LC PLUS (air jet), OMRON MICROAIR NE-U22, AIRSEP
MYSTIQUE(ultrasonic), AEROGEN AERONEB) was determined. The package
insert-approved Pari air jet system was used as the benchmark to
judge performance of the other nebulizers. The emitted dose was
from 1.25 to 3.7 times higher when Captisol was added to the
budesonide suspension. The Emitted dose (ED) was determined by:
[0441] 1) Drawing the nebulized formulations through a 300 mL glass
filter apparatus at 15 l/min, and collecting drug on double or
triple layers of glass fiber depth filter and the interior walls.
Collection was stopped every two minutes, the budesonide
quantitatively recovered, and filters were changed to prevent
filter saturation or alterations in airflow. Budesonide recovery
was quantified by HPLC; and/or [0442] 2) Summing the amount of
budesonide on the cascade impactor stages after nebulization.
[0443] The results are detailed below. (ND means "not determined.)
TABLE-US-00032 Total Delivered (ED) Total Delivered (ED) (.mu.g,
mean & SD), (.mu.g, mean & SD), Formulation Filter.sup.1
Impactor.sup.2 Pari LC Plus (Air Jet) Listed in the Pulmicort
package insert Pulmicort 171.5 .+-. 6.3 137.8 .+-. 14.9 Pulmicort +
5% Captisol 247.4 .+-. 11.3 172.4 .+-. 6.6 Omron MicroAir NE-U22
Pulmicort 179.9 .+-. 17.2 168.8 .+-. 30.1 Pulmicort + 5% Captisol
380.1 .+-. 8.5 349.6 .+-. 10.0 AirSep Mystique (Ultrasonic)
Pulmicort 32.9 .+-. 6.4 ND* Pulmicort + 5% Captisol 120.8 .+-. 19.6
ND* Aerogen AeroNeb Pulmicort 90.7 .+-. 4.5 ND* Pulmicort + 5%
Captisol 301.2 .+-. 19.5 ND*
[0444] All documents cited herein are each incorporated by
reference herein in its entirety. The above is a detailed
description of particular embodiments of the invention. It will be
appreciated that, although specific embodiments of the invention
have been described herein for purposes of illustration, various
modifications may be made without departing from the spirit and
scope of the invention. Accordingly, the invention is not limited
except as by the appended claims. All of the embodiments disclosed
and claimed herein can be made and executed without undue
experimentation in light of the present disclosure.
* * * * *