U.S. patent application number 12/479576 was filed with the patent office on 2009-12-17 for nasal and ophthalmic delivery of aqueous corticosteroid solutions.
This patent application is currently assigned to CYDEX PHARMACEUTICALS, INC.. Invention is credited to James D. Pipkin, John M. Siebert, Rupert O. Zimmerer.
Application Number | 20090312724 12/479576 |
Document ID | / |
Family ID | 41415443 |
Filed Date | 2009-12-17 |
United States Patent
Application |
20090312724 |
Kind Code |
A1 |
Pipkin; James D. ; et
al. |
December 17, 2009 |
Nasal and Ophthalmic Delivery of Aqueous Corticosteroid
Solutions
Abstract
The present invention is directed to methods of treating nasal
and/or ophthalmic diseases, symptoms, or disorders that are
therapeutically responsive to corticosteroid therapy by delivering
aqueous solution formulations comprising a corticosteroid to nasal
and ophthalmic tissues. The invention is also directed to methods,
systems, devices, and compositions for delivering aqueous solution
formulations comprising a corticosteroid and an antihistamine to
nasal and ophthalmic tissues.
Inventors: |
Pipkin; James D.; (Lenexa,
KS) ; Zimmerer; Rupert O.; (Lenexa, KS) ;
Siebert; John M.; (Lenexa, KS) |
Correspondence
Address: |
SWANSON & BRATSCHUN, L.L.C.
8210 SOUTHPARK TERRACE
LITTLETON
CO
80120
US
|
Assignee: |
CYDEX PHARMACEUTICALS, INC.
Lenexa
KS
|
Family ID: |
41415443 |
Appl. No.: |
12/479576 |
Filed: |
June 5, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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PCT/US2008/068872 |
Jun 30, 2008 |
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12479576 |
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PCT/US07/72387 |
Jun 28, 2007 |
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PCT/US2008/068872 |
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PCT/US07/72422 |
Jun 28, 2007 |
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PCT/US07/72387 |
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Current U.S.
Class: |
604/294 ;
128/207.18; 514/171 |
Current CPC
Class: |
A61K 31/55 20130101;
A61K 31/724 20130101; A61K 31/335 20130101; A61K 31/57 20130101;
A61K 45/06 20130101; A61K 9/0048 20130101; A61K 31/56 20130101;
A61K 9/0043 20130101; A61M 31/00 20130101; A61K 9/08 20130101; A61K
31/55 20130101; A61K 31/506 20130101; A61K 31/724 20130101; A61K
31/58 20130101; A61K 2300/00 20130101; A61K 31/56 20130101; A61K
47/40 20130101; A61K 31/58 20130101; A61K 2300/00 20130101; A61K
2300/00 20130101; A61K 2300/00 20130101 |
Class at
Publication: |
604/294 ;
514/171; 128/207.18 |
International
Class: |
A61M 37/00 20060101
A61M037/00; A61K 31/56 20060101 A61K031/56; A61F 9/00 20060101
A61F009/00 |
Claims
1. A method for treating an allergic symptom or disorder in a
subject in need thereof, comprising: nasally administering to the
subject a corticosteroid solution comprising a therapeutically
effective amount of a corticosteroid, SAE-CD, and a
pharmaceutically acceptable aqueous liquid carrier, wherein the
allergic symptom or disorder includes a non-nasal symptom selected
from the group consisting of itchy/gritty eyes, tearing/watery
eyes, red/burning eyes, itchy ears/palate and combinations
thereof.
2. The method of claim 1, wherein the allergic symptom or disorder
further comprises symptoms selected from the group consisting of
runny nose, itchy nose, nasal congestion, sneezing and combinations
thereof.
3. The method of claim 1, wherein said corticosteroid solution
further comprises a therapeutically effective amount of an
antihistamine.
4. The method of claim 3, wherein the antihistamine is azelastine,
olopatadine pharmaceutically acceptable salts thereof,
pharmaceutically active metabolites thereof, optically active
isomers or racemates, and mixtures thereof; the corticosteroid is
budesonide; and the SAE-CD is CAPTISOL cyclodextrin
(sulfobutylether .beta.-cyclodextrin).
5. The method of claim 4, wherein the azelastine is present in an
amount of about 30 .mu.g to about 275 .mu.g per unit dose, or the
olopatadine is present in an amount of about 150 .mu.g to about
1400 .mu.g per unit dose, the budesonide is present in an amount of
about 5 .mu.g to about 500 .mu.g per unit dose, and the CAPTISOL is
present in an amount of 100 .mu.g to 100 mg per unit dose.
6. The method of claim 1, wherein the corticosteroid solution is
administered 1-2 times per day.
7. A method for treating an ocular symptom or disorder in a subject
in need thereof, comprising: nasally administering to the subject a
corticosteroid solution comprising a therapeutically effective
amount of a corticosteroid, SAE-CD, and a pharmaceutically
acceptable aqueous liquid carrier, wherein the allergic symptom or
disorder includes a non-nasal symptom selected from the group
consisting of itchy/gritty eyes, tearing/watery eyes, red/burning
eyes, itchy ears/palate and combinations thereof.
8. The method of claim 7, wherein said corticosteroid solution
further comprises a therapeutically effective amount of an
antihistamine.
9. The method of claim 8, wherein the antihistamine is azelastine,
olopatadine, pharmaceutically acceptable salts thereof,
pharmaceutically active metabolites thereof, optically active
isomers or racemates, and mixtures thereof; the corticosteroid is
budesonide; and the SAE-CD is CAPTISOL cyclodextrin
(sulfobutylether .beta.-cyclodextrin).
10. The method of claim 9, wherein the azelastine is present in an
amount of about 30 .mu.g to about 275 .mu.g per unit dose or the
olopatadine is present in an amount of about 150 .mu.g to about
1400 .mu.g per unit dose, the budesonide is present in an amount of
about 5 .mu.g to about 500 .mu.g per unit dose, and the CAPTISOL is
present in an amount of 100 .mu.g to 100 mg per unit dose.
11. The method of claim 7, wherein the corticosteroid solution is
administered 1-2 times per day.
12. A method for treating ocular inflammation in a subject in need
thereof, comprising: ophthalmically administering to the subject a
corticosteroid solution comprising a therapeutically effective
amount of a corticosteroid, SAE-CD, and a pharmaceutically
acceptable aqueous liquid carrier, wherein the corticosteroid
solution provides more rapid reduction in ocular inflammation
compared with a corticosteroid suspension at the same unit
dose.
13. The method of claim 12, wherein said corticosteroid solution
further comprises a therapeutically effective amount of an
antihistamine.
14. The method of claim 13, wherein the antihistamine is
azelastine, olopatadine, pharmaceutically acceptable salts thereof,
pharmaceutically active metabolites thereof, optically active
isomers or racemates, and mixtures thereof; the corticosteroid is
budesonide; and the SAE-CD is CAPTISOL cyclodextrin
(sulfobutylether .beta.-cyclodextrin).
15. The method of claim 14, wherein the azelastine is present in an
amount of about 30 .mu.g to about 275 .mu.g per unit dose or the
olopatadine is present in an amount of about 150 .mu.g to about
1400 .mu.g per unit dose, the budesonide is present in an amount of
about 5 .mu.g to about 500 .mu.g per unit dose, and the CAPTISOL is
present in an amount of 100 .mu.g to 100 mg per unit dose.
16. The method of claim 12, wherein the corticosteroid solution is
administered 1-2 times per day.
17. A metered dose device for nasal or ophthalmic administration
comprising: corticosteroid solution comprising a therapeutically
effective amount of corticosteroid, a therapeutically effective
amount of an antihistamine, SAE-CD, and a pharmaceutically
acceptable aqueous liquid carrier.
18. The device of claim 17, wherein the antihistamine is
azelastine, olopatadine, pharmaceutically acceptable salts thereof,
pharmaceutically active metabolites thereof, optically active
isomers or racemates, and mixtures thereof; the corticosteroid is
budesonide; and the SAE-CD is CAPTISOL cyclodextrin
(sulfobutylether .beta.-cyclodextrin).
19. The device of claim 18, wherein the azelastine is present in an
amount of about 30 .mu.g to about 275 .mu.g per unit dose or the
olopatadine is present in an amount of about 150 .mu.g to about
1400 .mu.g per unit dose, the budesonide is present in an amount of
about 5 .mu.g to about 500 .mu.g per unit dose, and the CAPTISOL is
present in an amount of 100 .mu.g to 100 mg per unit dose.
20. A system for treating an allergic symptom comprising:
corticosteroid solution comprising a therapeutically effective
amount of a corticosteroid, a therapeutically effective amount of
an antihistamine, SAE-CD and a pharmaceutically acceptable aqueous
liquid carrier, and a metered dose device for nasal or ophthalmic
administration of the corticosteroid solution to the subject.
21. The system of claim 20, wherein the allergic symptom is
selected from the group consisting of runny nose, itchy nose, nasal
congestion, sneezing, itchy/gritty eyes, red/burning eyes,
tearing/watery eyes and itchy ears/palate and combinations
thereof.
22. The system of claim 21, wherein the allergic symptom is
selected from the group consisting of itchy/gritty eyes,
tearing/watery eyes, red/burning eyes, itchy ears and palate and
combinations thereof.
23. The system of claim 20, wherein the antihistamine is
azelastine, olopatadine, pharmaceutically acceptable salts thereof,
pharmaceutically active metabolites thereof, optically active
isomers or racemates, and mixtures thereof; the corticosteroid is
budesonide; and the SAE-CD is CAPTISOL cyclodextrin
(sulfobutylether .beta.-cyclodextrin).
24. The system of claim 23 wherein the azelastine is present in an
amount of about 30 .mu.g to about 275 .mu.g per unit dose or the
olopatadine is present in an amount of about 150 .mu.g to about
1400 .mu.g per unit dose, the budesonide is present in an amount of
about 5 .mu.g to about 500 .mu.g per unit dose, and the CAPTISOL is
present in an amount of 100 .mu.g to 100 mg per unit dose.
Description
RELATEDNESS OF THE APPLICATION
[0001] The subject application is a continuation-in-part of
PCT/US2008/068872, which claims the benefit of priority from
PCT/US07/72422, filed Jun. 29, 2007, and PCT/US07/72387, filed Jun.
28, 2007. PCT/US07/72422 and PCT/US07/72387 claim the benefit of
priority from U.S. Ser. No. 11/479,979, filed Jun. 30, 2006, which
is a continuation-in-part of PCT/US05/00082, filed Dec. 31, 2004,
now expired, which claims priority under 35 USC .sctn. 119 from
U.S. Ser. No. 60/533,628, filed Dec. 31, 2003, now expired. All
priority documents are incorporated herein in their entirety by
reference.
FIELD OF THE INVENTION
[0002] The present invention is directed to methods of treating
nasal and/or ophthalmic diseases, symptoms, or disorders that are
therapeutically responsive to corticosteroid therapy by delivering
aqueous solution formulations comprising a corticosteroid to nasal
and ophthalmic tissues. The invention is also directed to methods,
systems, devices, and compositions for delivering aqueous solution
formulations comprising a corticosteroid and an antihistamine to
nasal and ophthalmic tissues.
BACKGROUND OF THE INVENTION
[0003] The nasal administration of drugs allows for their
deposition to the nose, sinuses, and other nasal cavities.
Intranasal administration of drugs such as corticosteroids and
antihistamines may be used to treat nasal symptoms including
seasonal allergic rhinitis, perennial allergic rhinitis, perennial
non-allergic rhinitis, nasal polyps, as well as prevention of post
surgical polyps, chronic sinusitis, recurrent sinusitis, asthma,
grass pollen rhinitis, hay fever, snoring, cluster headache, and
other diseases and disorders.
[0004] The ophthalmic administration of drugs allows for their
deposition to the eye, including the ocular mucosa, eye surface,
cornea, conjuctiva, sclera, and posterior eye parts such as the
retina, choroid, and vitreous and optic nerves, as well as tissues
surrounding the eye. Ophthalmic administration of drugs such as
corticosteroids and antihistamines may be used to treat ocular
symptoms including conjunctivitis, inflammation of tissue(s) in the
eye, dry eye, filamentary keratitis, delayed tear clearance, pain,
keratoconjunctival dryness, keratoconjunctivitis sicca,
lesions/tumors of the eye, infectious processes of the eye,
bacterial infections, viral infections, glaucoma, uveitis, diabetic
retinopathy, eye trauma, blepharitis, blepharoconjunctivitis, and
other diseases or disorders.
[0005] Aqueous formulations containing a corticosteroid and a
solubilizing agent have been prepared: Saidi et al. (U.S. Pat. No.
6,241,969); Keller et al. (Respiratory Drug Delivery IX (2004)
221-231); Lintz et al. (AAPS Annual Meeting and Exposition,
Baltimore, Nov. 8, 2004; Poster M1128); Schueepp et al. (ATS
99.sup.th International Conference, Seattle, May 16-21, 2003;
poster 1607); Russian Patent No. 2180217 to Chuchalin; U.S.
Publication No. 2006/0045850; and Waldrep et al. (J. Aerosol Med.
(1994), 7(2), 135-145); PCT International Publications No. WO
06/108556, No. WO 03/35030, and No. WO 06/37246 and European
Publications No. EP1894559 and No. EP1712220 to PARI Pharma
GmbH.
[0006] Cyclodextrins have been included in nasal or ophthalmic
compositions: Kaur et al. (Curr. Drug Deliv. (2004), 1(4),
351-360); Shimpi et al. (Acta Pharm. (2005), 55(2), 139-56); Viegas
et al. (U.S. Pat. No. 6,136,334, No. 5,587,175, and No. 5,958,443);
Pate et al. (U.S. Pat. No. 5,977,180); Loftsson et al. (Acta
Opthalmol. Scand. (2002), 80(2), 144-50).
[0007] Underivatized and derivatized cyclodextrins can be used to
prepare aqueous formulations containing a corticosteroid: U.S. Pat.
No. 5,376,645 and No. 5,134,127 to Stella et al.; U.S. Pat. No.
5,914,122 to Otterbeck et al.; Worth et al. (24.sup.th
International Symposium on Controlled Release of Bioactive
Materials (1997)); Kinnarinen et al. (11.sup.th International
Cyclodextrin Symposium CD, (2002)); U.S. Pat. No. 5,472,954; U.S.
Pat. No. 5,089,482; Zimmerer et al. in Respiratory Drug Delivery IX
(2004) 461-464); Singh et al. (U.S. Pat. No. 7,128,928 and No.
6,696,426); Loftsson (U.S. Pat. No. 7,115,586, U.S. Pat. No.
5,472,954, and U.S. Pat. No. 5,324,718); Chang et al. (U.S. Pat.
No. 6,969,706); Beck et al. (U.S. Pat. No. 6,723,353 and No.
6,358,935); Buchanan et al. (U.S. Pat. No. 6,610,671); Pitha (U.S.
Pat. No. 6,576,261 and No. 5,935,941); Kis (U.S. Pat. No.
6,468,548); Muller et al. (U.S. Pat. No. 6,407,079); Wiebe et al.
(U.S. Pat. No. 5,739,121); Guy (U.S. Pat. No. 5,576,311); Babcock
et al. (U.S. Pat. No. 5,538,721); Folkman et al. (U.S. Pat. No.
5,227,372); Lipari (U.S. Pat. No. 4,383,992); PCT International
Publication No. WO 2004/087043 to Sun Pharmaceutical Industries
Ltd.; Saari et al. (Graefes Arch. Clin. Exp. Opthalmol. (2006),
244(5), 620-6); Kristinsson et al. (Invest. Opthalmol. Vis. Sci.
(1996), 37(6), 1199-203); Usayapant et al. (Pharm. Res. (1991),
8(12), 1495-9); Bary et al. (Eur. J. Pharm. Biopharm. (2000),
50(2), 237-244); U.S. Publication No. 2006/0193783; U.S.
Publication No. 2002/0198174; European Publication No. EP 0435682;
Lyons et al. (abstract in AAPS Annual Meeting and Exposition,
Denver, Colo. USA, Oct. 1-25, 2001); Amselem et al. (U.S. Pat. No.
5,747,061).
[0008] Sulfoalkyl ether cyclodextrin derivatives can be used to
prepare aqueous formulations containing a corticosteroid: U.S.
Publication No. 2007/0020336; U.S. Publication No. 2006/0120967;
U.S. Publication No. 2002/0150616 to Van de Cruys; U.S.
Publications No. 20070249572, No. 20070197487, No. 20070197486, No.
20070191599, No. 20070191327; No. 20070191323, No. 20070185066, No.
20070178050, No. 20070178049, and No. 20070160542 and PCT
International Publications No. WO 07/95342, No. WO 07/95341, No. WO
07/95339, No. WO 07/75963, No. WO 07/75859, No. WO 07/75801, No. WO
07/75800, No. WO 07/75799, and No. WO 07/75798 to Hill; U.S.
Publications No. 20070202054, No. 20070020299, No. 20070020298, and
No. 20070020196, and PCT International Publications No. WO
08/05692, No. WO 08/05691, No. WO 08/05053, No. WO 05/065651, No.
WO 05/065649, No. WO 05/065435 to Pipkin et al.; U.S. Publication
No. 20060120967 and No. 20060045850 to Namburi et al.; and U.S.
Publications No. 2005085446 and No. 20070049552 to Babu.
[0009] Corticosteroid-containing formulations for ophthalmic use
have been described: Pflugfelder et al. (U.S. Pat. No. 6,153,607),
Sackeyfio et al. (U.S. Pat. No. 6,995,815), Guo et al. (U.S. Pat.
Nos. 6,548,078 and 6,217,895), Sher (U.S. Pat. No. 6,117,907),
Clarke et al. (U.S. Pat. Nos. 5,358,943 and 4,945,089), Schwartz
(U.S. Pat. Nos. 5,212,168 and 4,904,649), and Saidi et al. (U.S.
Pat. No. 6,241,969).
[0010] The nasal and/or ophthalmic delivery of an aqueous solution
formulation comprising a corticosteroid as a therapeutic agent
alone or in combination with another therapeutic agent, such as an
antihistamine, for the treatment of allergy-related disorders or
symptoms would be useful and especially desirable if it could
provide an improved clinical benefit over the delivery of other
formulations, such as suspension-based formulations.
SUMMARY OF THE INVENTION
[0011] 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. In
some embodiments, the corticosteroid-responsive disease or disorder
is a disease, disorder, symptom, or condition of the nose or
eye.
[0012] The invention provides a method for treating an allergic
symptom or disorder in a subject in need thereof, comprising:
[0013] nasally administering to the subject a corticosteroid
solution comprising a therapeutically effective amount of a
corticosteroid, SAE-CD, and a pharmaceutically acceptable aqueous
liquid carrier,
[0014] wherein the corticosteroid solution provides more rapid
relief from an allergic symptom or disorder compared to a
corticosteroid suspension at the same unit dose.
[0015] In some embodiments, the allergic symptom or disorder
includes a non-nasal symptom selected from the group consisting of
itchy/gritty eyes, tearing/watery eyes, red/burning eyes, itchy
eyes and palate, and combinations thereof.
[0016] The invention also provides a method for treating an ocular
symptom or disorder in a subject in need thereof, comprising:
[0017] nasally administering to the subject a corticosteroid
solution comprising a therapeutically effective amount of a
corticosteroid, SAE-CD, and a pharmaceutically acceptable aqueous
liquid carrier,
[0018] wherein the ocular symptom or disorder is itchy/gritty eyes,
tearing/watery eyes, red/burning eyes, or a combination
thereof.
[0019] The invention also provides a system for treating an
allergic symptom or disorder in a subject in need thereof,
comprising:
[0020] a corticosteroid solution comprising a therapeutically
effective amount of a corticosteroid, a therapeutically effective
amount of an antihistamine, SAE-CD, and a pharmaceutically
acceptable aqueous liquid carrier, and
[0021] a metered dose device for nasal administration of the
corticosteroid solution to the subject, wherein the corticosteroid
solution is provided in the device.
[0022] In some embodiments, the system is for treating an ocular
symptom or disorder in a subject in need thereof.
[0023] The invention also provides a metered dose device for nasal
administration comprising a corticosteroid solution comprising a
therapeutically effective amount of a corticosteroid, a
therapeutically effective amount of an antihistamine, SAE-CD, and a
pharmaceutically acceptable aqueous liquid carrier.
[0024] In some embodiments, the invention provides a method for
treating a nasal symptom or disorder in a subject in need thereof,
comprising:
[0025] nasally administering to the subject a corticosteroid
solution comprising a therapeutically effective amount of a
corticosteroid, SAE-CD, and a pharmaceutically acceptable aqueous
liquid carrier,
[0026] wherein the nasal symptom or disorder is selected from the
group consisting of: acute or chronic rhinitis, nasal polyps, post
surgical nasal polyps, snoring, cluster headache, and combinations
thereof.
[0027] In some embodiments of the method for treating a nasal
symptom or disorder in a subject in need thereof, the symptom or
disorder is instead selected from the group consisting of
obstructive sleep apnea, eustachian tube dysfunction, serous otitis
media, sleep disturbances, daytime somnolesence, nasal furuncles,
epistaxis, wounds of the nasal or sinunasal mucosa, dry nose
syndrome, nasal bleeding, and combinations thereof.
[0028] The invention also provides a method for treating an
allergic symptom or disorder in a subject in need thereof,
comprising:
[0029] ophthalmically administering to the subject a corticosteroid
solution comprising a therapeutically effective amount of a
corticosteroid, SAE-CD, and a pharmaceutically acceptable aqueous
liquid carrier,
[0030] wherein the corticosteroid solution provides more rapid
relief from an allergic symptom or disorder compared to a
corticosteroid suspension at the same unit dose.
[0031] The invention also provides a method for treating ocular
inflammation in a subject in need thereof, comprising:
[0032] ophthalmically administering to the subject a corticosteroid
solution comprising a therapeutically effective amount of a
corticosteroid, SAE-CD, and a pharmaceutically acceptable aqueous
liquid carrier,
[0033] wherein the corticosteroid solution provides a more rapid
reduction in ocular inflammation compared with a corticosteroid
suspension at the same unit dose.
[0034] The invention also provides a system for treating an
allergic symptom or disorder in a subject in need thereof,
comprising:
[0035] a corticosteroid solution comprising a therapeutically
effective amount of a corticosteroid, a therapeutically effective
amount of an antihistamine, SAE-CD, and a pharmaceutically
acceptable aqueous liquid carrier, and
[0036] a device for ophthalmic administration of the corticosteroid
solution to the subject, wherein the corticosteroid solution is
provided in the device.
[0037] The invention also provides a device for ophthalmic
administration comprising a corticosteroid solution comprising a
therapeutically effective amount of a corticosteroid, a
therapeutically effective amount of an antihistamine, SAE-CD, and a
pharmaceutically acceptable aqueous liquid carrier.
[0038] The administration device can be: 1) a metered dose device
such as a atomizer, sprayer, pump spray, dropper, squeeze tube,
squeeze bottle, pipette, ampule, nasal cannula, metered dose
device, nasal spray inhaler, nasal continuous positive air pressure
device, or breath actuated bi-directional delivery device; or 2) a
device for ophthalmic administration such as a dropper, drop
dispensing package, tube, eye spray device, or eye wash unit. The
device can be adapted to to emit 10 .mu.l to 500 .mu.l of
corticosteroid solution per unit dose. The device can also comprise
a nozzle, wherein the nozzle comprises a valve, and the valve
provides a release of a volume of 25 .mu.l to 260 .mu.l per unit
dose through the nozzle upon operation of the device.
[0039] In some embodiments, the corticosteroid is beclomethasone
dipropionate, beclomethasone monopropionate, betamethasone,
budesonide, ciclesonide, desisobutyryl-ciclesonide, dexamethasone,
flunisolide, fluticasone propionate, fluticasone furoate,
mometasone furoate, triamcinolone acetonide, or a combination
thereof.
[0040] The invention also includes embodiments wherein the
corticosteroid solution further comprises one or more additional
therapeutically effective agents, such as an anti-IgE antibody,
antibiotic agent, anticholinergic agent, antifungal agent,
anti-inflammatory agent, anti-infective agent, antihistamine agent,
analgesic agent, decongestant, expectorant, antitussive agent,
antimicrobial agent, leukotriene receptor antagonist, or a
combination thereof. Specific embodiments of these additional
therapeutically effective agents can be selected from those
disclosed herein or others suitable for nasal or ophthalmic
administration and for treatment of diseases, disorders or symptoms
of the nose or eye.
[0041] In some embodiments, the method further comprises
administering a therapeutically effective amount of an
antihistamine. In some embodiments, the antihistamine is
diphenhydramine, clemastine, chlorpheniramine, brompheniramine,
dexchlorpheniramine, dexbrompheniramine, triprolidine, doxylamine,
tripelennamine, heptadine, carbinoaxime, bromdiphenhydramine,
hydroxyzine, pyrilamine, acrivastine, AHR-11325, phenindamine,
astemizole, azatadine, azelastine, cetirizine, ebastine,
fexofenadine, ketotifen, Iodoxine, loratadine,
descarboethoxyloratadine, levocabastine, mequitazine, oxatomide,
setastine, tazifyline, temelastine, terfenadine, tripelennamine,
terfenadine carboxylate, phenyltoloxamine, pheniramine, or a
combination thereof. In some embodiments, the antihistamine is
carebastine, efletirizine, mapinastine, antazoline, bilastine,
bepotastine besilate, rupatadine, emedastine, tecastemizole,
epinastine, levocetirizine, mizolastine, noberastine,
norastemizole, olopatadine, or a combination thereof. In some
embodiments the antihistamine is azelastine. In some embodiments,
the antihistamine is azelastine, wherein the azelastine is present
at an amount of about 30 .mu.g to about 275 .mu.g per unit dose. In
some embodiments, the antihistamine is azelastine, wherein the
azelastine is present at a concentration of 0.5 to 10 mg/mL. In
some embodiments, the antihistamine is olopatadine. In some
embodiments, the antihistamine is azelastine, wherein the
olopatadine is present at an amount of about 330 .mu.g to about
2660 .mu.g per unit dose. In some embodiments, the antihistamine is
azelastine, wherein the olopatadine is present at a concentration
of 1 to 15 mg/mL. In some embodiments, the antihistamine is
cetirizine. In some embodiments, the antihistamine is cetirizine,
wherein the cetirizine is present at an amount of about 0.25 mg to
about 4.4 mg per unit dose. In some embodiments, the antihistamine
is cetirizine, wherein the cetirizine is present at a concentration
of 0.25 to 4.4 mg/mL.
[0042] In some embodiments, the administering of the corticosteroid
solution is performed once or twice daily.
[0043] In some embodiments, the allergic symptom or disorder is or
further includes a nasal symptom, non-nasal symptom, allergic
rhinitis, seasonal allergic rhinitis, perennial allergic rhinitis,
perennial non-allergic rhinitis, grass pollen rhinitis, have fever,
nasal polyps, or a combination thereof. In some embodiments, the
allergic symptom or disorder is or further includes ocular symptom,
bacterial rhinitis, fungal rhinitis, viral rhinitis, atrophic
rhinitis, vasomotor rhinitis, blocked nose, nasal congestion, or a
combination thereof.
[0044] In some embodiments, the nasal symptom is rhinorrhea, nasal
congestion, nasal itchiness, sneezing, nasal obstruction, or a
combination thereof.
[0045] In some embodiments, the non-nasal symptom is itchy/gritty
eyes, tearing/watery eyes, red/burning eyes, itchy ears and palate,
or a combination thereof.
[0046] In some embodiments, the corticosteroid is budesonide. In
some embodiments, the corticosteroid is budesonide, wherein the
budesonide is present at an amount of about 5 .mu.g to about 500
.mu.g per unit dose. In some embodiments, the corticosteroid is
budesonide, wherein the budesonide is present at a concentration of
40 to 2000 .mu.g/mL.
[0047] In some embodiments, the corticosteroid is fluticasone
propionate.
[0048] In some embodiments, the corticosteroid is fluticasone
furoate.
[0049] In some embodiments, the corticosteroid is mometasone
furoate.
[0050] In some embodiments, the molar ratio of the SAE-CD to the
corticosteroid is 1:1 or greater. In some embodiments, the molar
ratio of the SAE-CD to an additional therapeutic agent is 1:1 or
greater. In some embodiments, the molar ratio of the SAE-CD to an
antihistamine is greater than 2:1.
[0051] Some embodiments of the invention includes those wherein the
corticosteroid solution comprises: 1) a corticosteroid, such as
budesonide, fluticasone propionate, fluticasone furoate, mometasone
furoate, ciclesonide, or a combination thereof; and 2) another
therapeutically effective agent, such as azelastine, olopatadine,
cetirizine, loratadine, desloratadine, azithromycin, voriconazole,
or a combination thereof.
In some embodiments, the aqueous liquid carrier comprises water,
buffer, alcohol, organic solvent, glycerin, propylene glycol,
poly(ethylene glycol), poloxamer, surfactant or a combination
thereof. In some embodiments, the aqueous liquid carrier comprises
povidone, polyol or a combination thereof.
[0052] Some embodiments of the invention also provide a unit dose
of a therapeutic corticosteroid solution comprising: about 32 .mu.g
of budesonide; SAE-CD; pharmaceutically acceptable aqueous liquid
carrier; disodium edetate of about 0.005 to about 0.1% by weight of
the unit dose; and potassium sorbate of about 0.05 to about 0.2% by
weight of the unit dose, and wherein the corticosteroid solution is
suitable for nasal administration to a subject in need thereof.
[0053] Some embodiments of the invention also provide a method of
treating preventing or ameliorating in a subject a
corticosteroid-responsive disease or disorder, the method
comprising metering into the nose of the subject a therapeutically
effective amount of budesonide that is less than about 320 .mu.g
per day, delivered as 8 or more unit doses, wherein each unit dose
consists of about 32 .mu.g of budesonide; SAE-CD; disodium edetate
of about 0.005 to about 0.1% by weight of the unit dose; potassium
sorbate of about 0.05 to about 0.2% by weight of the unit dose; and
a pharmaceutically acceptable aqueous liquid carrier.
[0054] In some embodiments, the corticosteroid solution has a pH of
about 3.5 to about 5 or about 4.2 to about 4.6.
[0055] In some embodiments, the SAE-CD is a compound, or mixture of
compounds, of the Formula 1:
##STR00001##
wherein: [0056] n is 4, 5 or 6; [0057] 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 [0058]
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.
[0059] In some embodiments, the corticosteroid solution further
comprises one or more pharmaceutically acceptable excipients, such
as a preservative, an antioxidant, a buffering agent, an acidifying
agent, an alkalizing agent, a solubility-enhancing agent, a
complexation-enhancing agent, a diluent, an electrolyte, glucose, a
stabilizer, a bulking agent, an antifoaming agent, an oil, an
emulsifying agent, flavor, sweetener, a taste-masking agent, a
tonicity modifier, a surface tension modifier, a viscosity
modifier, a density modifier, or a combination thereof.
[0060] In some embodiments, the SAE-CD is present at a
concentration of about 10 to about 500 mg/mL of corticosteroid
solution, and/or the SAE-CD is present in an amount of 100 .mu.g to
1000 mg per unit dose.
[0061] 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.
[0062] 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
[0063] The following drawings are given by way of illustration
only, and thus are not intended to limit the scope of the present
invention.
[0064] FIG. 1A 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.
[0065] FIG. 1B depicts a phase solubility graph for budesonide
concentration (M) versus cyclodextrin concentration (M) for various
SBG-.gamma.-CD species and CAPTISOL.
[0066] FIG. 2 depicts a phase solubility diagram for fluticasone
propionate in the presence of several different cyclodextrins.
[0067] FIG. 3 depicts a phase solubility diagram for mometasone
furoate in the presence of several different cyclodextrins.
[0068] FIG. 4 depicts a phase solubility diagram for esterified and
non-esterified fluticasone in the presence of
SAE(5-6)-.gamma.-CD.
[0069] FIG. 5 depicts a bar chart summarizing the aqueous
solubility of beclomethasone dipropionate in the presence of
various SAE-CD derivatives.
[0070] FIGS. 6A to 6I depict charts detailing the results of a
clinical study conducted according to Example 33.
[0071] FIG. 7 depicts a graphical summary of the study protocol of
Example 33.
[0072] FIG. 8A depicts a chart the TNSS change from baseline with
onset of action for the first three time points in the study of
Example 33.
[0073] FIG. 8B depicts a chart the TNNSS change from baseline with
onset of action for the first three time points in the study of
Example 33.
[0074] FIGS. 9A-9C depict the results of the effect that the three
solutions of Example 33 have on the EEC-QOLQ as determined using
the Quality of Life Questionnaire.
[0075] FIGS. 10A-10C depict charts of the pH rate profile for
degradation of azelastine in the presence or absence of SAE-CD at
varying temperatures and pH's: FIG. 10A-Azelastine pH Rate Profile
Area % (25.degree. C.), 0.5 mg/mL azelastine HCl in 3 mM citrate @
pH 4, 5, & 6; with and without 1.75% CAPTISOL, Stored in
25.degree. C. Stability Chamber; FIG. 10B--Azelastine pH Rate
Profile Area % (40.degree. C.), 0.5 mg/mL azelastine HCl in 3 mM
citrate @ pH 4, 5, & 6; with and without 1.75% CAPTISOL, Stored
in 40.degree. C. Stability Chamber; FIG. 10C--Azelastine pH Rate
Profile Area % (60.degree. C.), 0.5 mg/mL azelastine HCl in 3 mM
citrate @ pH 4, 5, & 6; with and without 1.75% CAPTISOL, Stored
in 60.degree. C. Stability Chamber.
[0076] FIGS. 11A and 11B depict phase solubility diagrams for
budesonide in the presence of varying amounts of azelastine
hydrochloride and fixed amounts of SBE-.beta.-CD or
SBE-.gamma.-CD.
[0077] FIGS. 12A-12C depict charts for the change in baseline in
the TNSS, TOSS, and TSS, respectively, in the study of Example 34
using CAPTISOL Budesonide+Azelastine solution, and budesonide and
azelastine.
[0078] FIGS. 12D-12H depict charts of summaries for individual
symptom scores as described in Example 34.
[0079] FIG. 12I depicts the AUC in change from baseline for a
number of symptoms measured in the study of Example 34.
[0080] FIGS. 12J-12L depict charts relating to a meta-analysis of
the clinical studies of Examples 33 and 34.
[0081] FIGS. 13A-13B depict charts detailing the changes in ocular
pressure of rabbits treated according to Example 41.
DETAILED DESCRIPTION OF THE INVENTION
[0082] The present invention is directed to methods of treating
nasal and/or ophthalmic diseases, symptoms, or disorders that are
therapeutically responsive to corticosteroid therapy by delivering
aqueous solution formulations comprising a corticosteroid to nasal
and ophthalmic tissues. The invention is also directed to methods,
systems, devices, and compositions for delivering aqueous solution
formulations comprising a corticosteroid and an antihistamine to
nasal and ophthalmic tissues. The systems of the invention comprise
an administration device, and a composition of the invention. The
composition of the invention is a corticosteroid solution
comprising a corticosteroid and SAE-CD. The composition can be a
nasal or non-nasal composition or an ophthalmic composition. In
some embodiments, a non-nasal composition excludes an inhalable
composition for pulmonary delivery.
[0083] By including SAE-CD in a liquid composition containing
corticosteroid, the corticosteroid is dissolved. The corticosteroid
exhibits greater stability in the presence of SAE-CD than it does
in its absence. When a second active agent is present, the second
active agent can also exhibit greater stability in the presence of
SAE-CD than it does in its absence.
[0084] The methods, systems, devices, and compositions of the
invention can provide an enhanced pharmacokinetic profile over a
suspension formulation comprising approximately the same amount of
a therapeutic agent and delivered under substantially the same
conditions. The therapeutic agent is a corticosteroid alone or a
corticosteroid combined with one or more additional therapeutic
agents. As such, one or more therapeutic agents in the methods,
systems, devices, and compositions of the invention can demonstrate
an enhanced pharmacokinetic profile when compared with the same
therapeutic agent or agents in a suspension formulation. 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
therapeutic agent delivered or administered, a higher Cmax per
.mu.g of therapeutic agent delivered or administered, increased
bioavailability, absorption or distribution of the therapeutic
agent at the site of delivery, a shorter Tmax, or a longer Tmax.
The methods, systems, devices, and compositions of the invention
can also provide other enhancements over a suspension-based
formulation, such as enhanced drug delivery, increased rate of drug
administration, reduced treatment time, reduced toxicity, improved
stability, enhanced bioabsorption, increased output rate, increased
total output, reduced side effects associated with the therapeutic
agent, increased nasal cavity deposition, increased paranasal sinus
cavity deposition, increased ocular deposition, improved quality of
life, reduced mucociliary clearance, reduced ocular clearance,
and/or improved patient compliance.
[0085] Alternatively, the methods, systems, devices, and
compositions of the invention provide substantially the same
pharmacokinetic profile or an enhanced pharmacokinetic profile over
a suspension formulation comprising a higher amount of therapeutic
agent and delivered under substantially the same conditions. The
therapeutic agent in the formulation can be present at a dose that
is less than about 80%, less than about 70%, less than about 60%
less than about 50%, less than about 40%, less than about 20%, or
less than about 10% of that in the suspension.
[0086] The amount and/or concentration of SAE-CD in the composition
can be varied as needed or as described herein to provide a
composition that possesses a desired physical property, provide
therapeutic effectiveness in subjects to which the composition is
administered, and/or achieve a desired performance in an
administration device. SAE-CD can be present in an amount
sufficient to solubilize and/or stabilize the therapeutic agent
when the SAE-CD and therapeutic agent are placed in the aqueous
carrier. The aqueous carrier can be present in an amount sufficient
to aid in dissolution of the therapeutic agent and form a solution
of sufficient volume and sufficiently low viscosity to permit
administration with an administration device. SAE-CD can be present
in solid form or in solution in the aqueous carrier. The
therapeutic agent can be present in dry powder/particle form or in
suspension in the aqueous carrier. In some embodiments, SAE-CD is
present at a concentration of about 10 to about 500 mg/mL of
composition, and/or SAE-CD is present in an amount of 100 .mu.g to
1000 mg per unit dose.
[0087] In some embodiments, SAE-CD is present in an amount
sufficient to decrease the amount of unsolubilized therapeutic
agent in the suspension-based composition and to improve the
administration of the suspension-based composition. In some
embodiments, SAE-CD is present in an amount sufficient to
solubilize enough therapeutic agent such that the suspension-based
composition 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-based composition will not
completely dissolve in, or may separate out from, the solution.
[0088] In some embodiments, 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 therapeutic agent. 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 therapeutic agent is dissolved in the liquid
composition.
[0089] The compositions of the inventions are suitable for nasal
and/or ophthalmic administration. The compositions can be
administered via an administration device suitable for nasal
administration or ophthalmic administration of pharmaceutical
compositions. As used herein, an administration device is any
pharmaceutically acceptable device adapted to deliver a composition
of the invention to a subject's nose or eye(s). A nasal
administration device can be a metered administration device
(metered volume, metered dose, or metered-weight) or a continuous
(or substantially continuous) aerosol-producing device. Suitable
nasal administration devices also include devices that can be
adapted or modified for nasal administration. An ophthalmic
administration device can be a dropper, drop dispensing package,
tube, eye spray device, eye wash unit, and other devices known to
those of ordinary skill in the art. In some embodiments, the
nasally or ophthalmically administered dose can be absorbed into
the bloodstream of a subject.
[0090] A metered nasal administration device delivers a fixed
(metered) volume or amount (dose) of a nasal composition upon each
actuation. Exemplary metered dose devices for nasal administration
include, by way of example and without limitation, an atomizer,
sprayer, dropper, squeeze tube, squeeze-type spray bottle, pipette,
ampule, nasal cannula, metered dose device, nasal spray inhaler,
breath actuated bi-directional delivery device, pump spray,
pre-compression metered dose spray pump, monospray pump, bispray
pump, and pressurized metered dose device. The administration
device can be a single-dose disposable device, single-dose reusable
device, multi-dose disposable device or multi-dose reusable
device.
[0091] The compositions of the invention can be used with any known
metered administration device. In some embodiments, the device is a
pump nasal spray or a squeeze bottle. The performance of a
composition of the invention in a metered administration device is
detailed in Example 35.
[0092] A continuous aerosol-producing device delivers a mist or
aerosol comprising droplet of a nasal composition dispersed in a
continuous gas phase (such as air). A nebulizer, pulsating aerosol
nebulizer, and a nasal continuous positive air pressure device are
exemplary of such a device. Suitable nebulizers include, by way of
example and without limitation, an air driven jet nebulizer,
ultrasonic nebulizer, capillary nebulizer, electromagnetic
nebulizer, pulsating membrane nebulizer, pulsating plate (disc)
nebulizer, pulsating/vibrating mesh nebulizer, vibrating plate
nebulizer, a nebulizer comprising a vibration generator and an
aqueous chamber, a nebulizer comprising a nozzle array, and
nebulizers that extrude a liquid formulation through a
self-contained nozzle array.
[0093] Commercially available administration devices that are used
or can be adapted for nasal administration of a composition of the
invention include the AERONEB.TM. (Aerogen, San Francisco, Calif.),
AERONEB GO (Aerogen); PARI LC PLUS.TM., PARI BOY.TM. N, PARI eflow
(a nebulizer disclosed in U.S. Pat. No. 6,962,151), PARI LC SINUS,
PARI SINUSTAR.TM., PARI SINUNEB, VibrENT.TM. and PARI DURANEB.TM.
(PARI Respiratory Equipment, Inc., Monterey, Calif. or Munich,
Germany); 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-II (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, Colo.), FAN JET (Marquest, Englewood, Colo.),
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, Colo.), 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.),
ACCUSPRAY.TM. (BD Medical, Franklin Lake, N.J.), ViaNase ID .TM.
(electronic atomizer; Kurve, Bothell, Wash.), OptiMist device or
OPTINOSE (Oslo, Norway), MAD Nasal (Wolfe Tory Medical, Inc., Salt
Lake City, Utah), Freepod.TM. (Valois, Marly le Roi, France),
Dolphin.TM. (Valois), Monopowder.TM. (Valois), Equadel.TM.
(Valois), VP3.TM. and VP7.TM. (Valois), VP6 Pump.TM. (Valois),
Standard Systems Pumps (Ing. Erich Pfeiffer, Radolfzell, Germany),
AmPump (Ing. Erich Pfeiffer), Counting Pump (Ing. Erich Pfeiffer),
Advanced Preservative Free System (Ing. Erich Pfeiffer), Unit Dose
System (Ing. Erich Pfeiffer), Bidose System (Ing. Erich Pfeiffer),
Bidose Powder System (Ing. Erich Pfeiffer), Sinus Science.TM.
(Aerosol Science Laboratories, Inc., Camarillo, Calif.),
ChiSys.RTM. (Archimedes, Reading, UK), Fit-Lizer.RTM. (Bioactis,
Ltd, an SNBL subsidiary (Tokyo, J P), Swordfish V.TM. (Mystic
Pharmaceuticals, Austin, Tex.), DirectHaler.TM. Nasal (DirectHaler,
Copenhagen, Denmark) and SWIRLER.RTM. Radioaerosol System (AMICI,
Inc., Spring City, Pa.).
[0094] Particularly suitable administration devices include single
dose and multi-dose embodiments of: a pump spray bottle; the PARI
eFlow (a nebulizer equipped with a vibrating mesh nebulizer
comprising a vibration generator, an aerosol chamber, an inhalation
valve, and an exhalation valve; U.S. Pat. No. 5,954,047, U.S. Pat.
No. 6,026,808, U.S. Pat. No. 6,095,141, and U.S. Pat. No.
6,527,151, the entire disclosures of which are hereby incorporated
by reference); AERx Essence and AERx Ultra (from ARADIGM; an
aerosol generator comprising a nozzle array, whereby a liquid
formulation is extruded through a self-contained nozzle array);
Aeroneb Go (a nebulizer equipped with a vibrating mesh nebulizer
comprising a vibration generator, an aerosol chamber, an inlet and
an outlet); VibrENT.TM. (a nebulizer that delivers a
pressure-pulsed aerosol; the delivery rate of liquid composition is
about 0.160 mL/min; in PCT International Publications No. WP
2004/20029 and No. WO 2001/34232; Schuschnig et al. in European
Patent Publication No. EP 1820493, and Respiratory Drug Delivery
(2008), the entire disclosures of which are hereby incorporated by
reference); PARI SINUSTAR (a nebulizer adapted for nasal
administration that delivers an aqueous liquid composition at a
rate of about 0.18 mL/min); and the PARI SINUS (including PARI LC
Star, PARI LL and PARI Sprint).
[0095] The Aradigm AERx delivery system, 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
aerosol particle size, and management of the inspiration 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).
[0096] The parameters used to effect nebulization via an electronic
nebulizer, such as flow rate, mesh membrane size, aerosol
inhalation chamber size, mask size and materials, inlet and outlet
valves, outflow tube, internal channel plurality of air outputs
communicating with the internal chamber, vibration generator and
power source may be varied in accordance with the principles of the
present invention to maximize their use with different types of
aqueous corticosteroid compositions. In some embodiments,
substantially all of a dose (weight or volume) is delivered in less
than 1.5 minutes or continuously delivered over 1.5 to 60
minutes.
[0097] Valves and actuators can be obtained from Bespak (Milton
Keynes, UK). Actuators used in the administration device can be
horizontal or vertical. The administration device can incorporate
the Velocityjet.TM. micropump. The administration devices can be
equipped with different types of baffles, valves, tubes, channels,
reservoirs, mixing chambers, vortex chamber, particle dispersion
chamber, nasal adapter, vibrating pulse and/or sound wave
generator.
[0098] 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.
[0099] 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.
[0100] The volume or amount of composition administered can vary
according to the intended delivery target and administration device
used. The amount of active agent in a dose or unit dose can vary
according to the intended delivery target and administration device
used.
[0101] During operation of a nebulizer based system, the
corticosteroid can be delivered at a rate of at least about 20-50
.mu.g/min, or 10-200 .mu.g/min, wherein this range may increase or
decrease according to the concentration of corticosteroid in the
composition in the administration device.
[0102] The present invention provides SAE-CD based formulations,
wherein the SAE-CD is a compound of the Formula 1:
##STR00002##
wherein: [0103] n is 4, 5 or 6; [0104] 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 [0105]
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.
[0106] 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
[0107] "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. 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 I or a mixture
thereof.
[0108] The SAE-CD used is described in U.S. Pat. No. 5,376,645 and
U.S. Pat. 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.
[0109] 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 can be situated at any
position on the alkyl moiety. The term "cycloalkanol" includes
unsubstituted or substituted (e.g., by methyl or ethyl)cyclic
alcohols.
[0110] In some embodiments of the present invention, compositions
contain 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.
[0111] 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.
[0112] 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.
[0113] 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.
[0114] The liquid compositions and systems of the invention provide
an improved clinical benefit or therapeutic benefit over an
otherwise similar suspension-based formulations excluding SAE-CD
but comprising substantially the same dose of active agent, such as
corticosteroid. Exemplary advantages may include enhanced drug
delivery, increased rate of drug administration, reduced treatment
time, reduced toxicity, ease of manufacture, assurance of
sterility, improved stability, enhanced bioabsorption, no concern
for solid particle growth, enhanced pharmacokinetic profile,
reduced corticosteroid-related side effects, improved patient
quality of life, and/or improved clinical or pharmaceutical
performance over the suspension formulation.
[0115] 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>SB-
E9.7-.gamma.-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 phase solubility data is summarized
in Example 23 and FIGS. 2-3.
[0116] 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 in Example 23 summarizes the phase solubility data depicted
in FIG. 4 for fluticasone and fluticasone propionate with various
different SAE-.gamma.-CD species having a degree of substitution in
the range of 5-10.
[0117] SAE-.gamma.-CD is 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.
[0118] 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 can
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 binding 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.
[0119] 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.
[0120] Suitable basic compounds include but are not limited to
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.
[0121] 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.
[0122] 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.
[0123] 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.
[0124] 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
composition to solubilize the corticosteroid.
[0125] 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 can 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.
[0126] 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.
[0127] 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,
e.g., 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).
[0128] 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.).
[0129] The amount of derivatized cyclodextrin required to provide
the desired effect will vary according to the materials comprising
the formulation.
[0130] Different cyclodextrins are able to solubilize a
corticosteroid to different extents. FIG. 1A 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. Additional phase solubility data is depicted in
FIG. 1B for various SBE-.gamma.-CD derivatives (SBE4.9-.gamma.-CD,
SBE5.23-.gamma.-CD, SBE6-.gamma.-CD, SBE9.67-.gamma.-CD, and
SBE4.9-.gamma.-CD) and CAPTISOL. The data indicate that the
SBE-.gamma.-CD derivatives generally outperform CAPTISOL in
dissolution of budesonide.
[0131] The output rate (the rate at which the dose of the
therapeutically effective agent(s) in the corticosteroid solution
is administered or delivered) will vary according to the
performance parameters of the device used to administer the dose.
The higher the output rate of a given device, the lower the amount
of time required to deliver or administer the corticosteroid
solution, as defined herein, or the dose of the therapeutically
effective agent(s) in the corticosteroid solution.
[0132] 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 smaller droplet size of aerosolized
composition is favored for delivery of active agents such as a
corticosteroid to the paranasal sinus cavities and/or deep nasal
cavity.
[0133] CAPTISOL is emitted from a 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. The output
rate is highest for the CAPTISOL solution as compared to other
cyclodextrin solutions 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.
[0134] The compositions of the invention can be made from other
suspension-based aqueous formulations, which formulations can be
adapted for nasal delivery, by addition of SAE-CD thereto.
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).
[0135] 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
formulation. Moreover, the SAE-CD outperforms other cyclodextrin
derivatives.
[0136] In some embodiments, SAE-CD (in solid or liquid form) and a
suspension-based 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 can be optionally aseptically filtered or terminally
sterilized. The liquid is then nasally administered to a subject.
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.
[0137] In some embodiments, SAE-CD (in liquid form, as ready-to-use
liquid or as a concentrate) and a solid formulation comprising
corticosteroid are mixed to form a liquid composition. The SAE-CD
is present in an amount sufficient to solubilize a substantial
portion of the corticosteroid. The liquid is then administered
nasally or ophthalmically using a suitable administration
device.
[0138] In other embodiments, SAE-CD (in solid form) and a solid
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 nasally using an administration
device as defined herein.
[0139] In some embodiments, the nasal device is a nebulizer for
nasal administration. The size of the reservoir varies from one
type of nebulizer to another. The volume of the liquid formulation
can 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.
[0140] 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 nasal inspiration and delivery processes to optimize deep
paranasal sinus cavity penetration, an initial sample volume of
about 10 .mu.l to 100 .mu.l, or 50 .mu.l can be used to load AERx
Strip multiple 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 nasal
inspiration by a subject, i.e. 3-5 seconds) via nebulization. Based
on general performance expectations of such devices the
corticosteroid can be expected to be delivered to the nose in a
single dosing event using corticosteroid solutions prepared with
SAECD.
[0141] 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.
[0142] In some embodiments, a suspension-based formulation is
converted to a liquid formulation prior to administration (as a
mist or aerosol) 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 an administration device. In
order to form a liquid composition, 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.
[0143] Pharmacists working in compounding pharmacies can and do
prepare suspension-based formulations comprising corticosteroid.
Such pharmacists will now be able to prepare a single use or
multi-use liquid compositions by employing a method described
herein. Alternatively, a subject (patient) undergoing
corticosteroid treatment can 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.
[0144] 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-00002 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
[0145] 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.
[0146] In some embodiments, the composition comprises less than or
about 25% wt./wt. of SAE-CD for administration by nebulizer, or
less than or about 50% wt./wt. of SAE-CD for administration with
metered administration devices.
[0147] The nose comprises the nostrils, or nares, which admit and
expel air for respiration, nose hairs (vibrissae), which catch
airborne particulate contaminants and prevent them from reaching
the lungs, olfactory mucosa, and the nasal cavity. Within the nasal
cavity, target sites for delivery or active agent include the
middle meatus, superior turbinate and posterior regions. The
paranasal sinuses (paranasal sinus cavities) are connected to the
nasal cavity by small orifices call ostia. The paranasal sinuses
include the: (1) the maxillary sinuses, also called the antra,
which are located under the eyes, in the upper jawbone; (2) the
frontal sinuses, which lie above the eyes, in the bone of the
forehead; (3) the ethmoid sinuses, positioned between the nose and
the eyes, backwards into the skull; and (4) the sphenoid sinuses,
which are more or less in the centre of the skull base.
[0148] The nasal cavity and the paranasal sinuses are lined with
mucosa. These mucosae can be often affected by conditions such as
allergies and infections. Nasal administration of the solutions of
the methods, systems, devices, and compositions of the invention
provide improved means to deliver therapeutically useful active
agents to these mucosae and to treat diseases, disorders and/or
symptoms thereof.
[0149] Anatomically, the eyes and nose are connected via the
nasolacrimal duct and indirectly through local neurosensory (e.g.
the trigeminal nerve) mechanisms. Allergens and allergic treatments
from the ocular surface drain through the nasolcarimal duct into
the inferior turbinate of the nose. Through the nasolacrimal duct,
ocular treatments can affect nasal symptoms in patients suffering
from allergic rhinitis. Fluids can travel from the eyes to the nose
within five minutes, and topical treatments can positively affect
nasal symptoms induced by a conjunctival allergen challenge
(Spangler et al., Clin Ther 25(8): 2245-2267 (2003)). Thus, topical
ocular treatments can be beneficial in treating both ocular and
nasal symptoms of allergic rhinitis.
[0150] The paranasal sinuses are, under normal circumstances,
poorly ventilated during breathing. Most of the air exchange of the
sinuses occurs through the diffusion of air through the ostia,
whereas little or no convective flow is observed. If an aerosol,
such as a therapeutic aerosol generated by a conventional
nebuliser, is inspired through the nose, the aerosol will flow
through the nasal cavity. Since there is virtually no active flow
into the paranasal sinuses, very little or almost none of the
aerosol is deposited therein. However, the droplet size of the
aerosol or mist administered nasally to a subject can be varied to
provide preferential deposition in the nasal cavity versus
paranasal sinus cavities or vice versa. The relative percentage of
paranasal sinus cavity deposition can be increased by employing a
nasal administration device capable of generating appropriately
sized droplets and/or capable of generating a variable pressure
aerosolized plume.
[0151] The mass median diameter (MMD) which will lead to the
relatively largest aerosol deposition can depend on individual
factors, in particular on the geometry of the paranasal sinuses
including the ostia through which the aerosol reaches the sinuses.
For example, the volume of the sinuses and the diameter of the
ostia differ substantially between individuals. A larger diameter
of the ostia is believed to favor the entrance of larger aerosol
droplets into the sinuses, even though the diameters of the ostia
and of the droplets are of completely different magnitudes. If the
individual sinunasal anatomy, or a parameter derived therefrom, of
a person to be treated with an aerosol is at least partially known,
it is possible to select a particular MMD for optimised sinunasal
or sinus delivery.
[0152] The target site for delivery of the formulation will depend
upon the MMD of droplets (aerosol, mist, vapor, plume, or spray)
administered to a subject. Generally, the smaller the droplet size
the greater the percentage of paranasal sinus cavity, turbinate,
and/or posterior nasal cavity deposition, and vice versa. In order
to maximize nasal delivery (nose, sinus cavity, nasopharyngeal
cavity, nasal vestibule, anterior region, superior turbinate,
middle turbinate, inferior turbinate, and/or olfactory region), the
formulation can be administered nasally and the MMAD can be at
least about 3.5 microns, at least about 5 microns, at least about
10 microns, at least about 20 microns, at least about 35 microns,
at least about 50 microns, at least about 100 microns, or at least
about 150 microns.
[0153] In some embodiments, the MMD of the droplets in the aerosol
(liquid phase dispersed within a continuous gas phase) can range
from about 2 .mu.m to about 6 .mu.m, as measured by laser
diffraction. In some embodiments, the most useful MMD for
depositing the aerosol in the nasal cavity and in the paranasal
sinuses can range from 3 .mu.m to 3.5 .mu.m. In some embodiments,
the aerosol of the invention can have a MMD of about 2.5 .mu.m to
about 4.5 .mu.m, about 3 .mu.m to about 4 .mu.m, or about 2.8 .mu.m
to about 3.5 .mu.m. In further embodiments, the MMD is
approximately 2.8 .mu.m.+-.0.2 .mu.m, 3.0 .mu.m.+-.0.2 .mu.m, 3.2
.mu.m.+-.0.2 .mu.m, 3.4 .mu.m.+-.0.2 .mu.m, 3.6 .mu.m.+-.0.2 .mu.m,
3.8 .mu.m.+-.0.2 .mu.m, or 4.0 .mu.m.+-.0.2 .mu.m. Various
appropriate analytical apparatuses to determine the mass median
diameter are known and commercially available, such as the Malvern
MasterSizer X or Malvern SprayTec. The geometric distribution of
the aerosolised liquid particles or droplets can be determined
simultaneously with the mass median diameter.
[0154] Delivery of active agent to the deep nasal cavity or
paranasal sinus cavities can also be promoted by an aerosol
generating administration device comprising a droplet dispersion
chamber suitable to provide for vortical particle flow of the
aerosol prior to administration to a subject, wherein the
administration device is capable of producing droplets
substantially having a uniform mean diameter from about 5 .mu.m to
about 30 .mu.m, about 8 .mu.m to about 25 .mu.m, about 10 .mu.m to
about 20 .mu.m, about 10 .mu.m to about 17 .mu.m, about 10 .mu.m to
about 15 .mu.m, and about 12 .mu.m to about 17 .mu.m. In some
embodiments, the aerosol comprises droplets substantially having a
uniform mean diameter of about 2 .mu.m to about 50 .mu.m, about 5
.mu.m to about 50 .mu.m, about 5 .mu.m to about 40 .mu.m, about 5
.mu.m to about 35 .mu.m, about 5 .mu.m to about 30 .mu.m, about 5
.mu.m to about 20 .mu.m, about 5 .mu.m to about 17 .mu.m, about 5
.mu.m to about 15 .mu.m, about 8 .mu.m to about 30 .mu.m, about 8
.mu.m to about 25 .mu.m, about 8 .mu.m to about 20 .mu.m, about 10
.mu.m to about 30 .mu.m, about 10 .mu.m to about 25 .mu.m, about 11
.mu.m to about 40 .mu.m, about 11 .mu.m to about 30 .mu.m, about 11
.mu.m to about 20 .mu.m, about 11 .mu.m to about 15 .mu.m, about 15
.mu.m to about 25 .mu.m, about 15 .mu.m to about 20 .mu.m, or about
17 .mu.m to about 23 .mu.m. The phrase "substantially having a
uniform mean diameter," as used herein with respect to the particle
diameter ranges, refers to the use of particle collections, wherein
at least 50%, at least 60%, at least 70%, at least 80%, at least
90%, at least 95%, or at least 98% have the preferred diameter
range. In some embodiments, at least 60%, at least 70%, at least
80%, at least 90% or at least 95% of the nebulized particles are of
the particle diameter range. In some embodiments, at least 70%, at
least 80%, at least 90% or at least 95% of the nebulized particles
are of the particle diameter range. The ViaNase ID.TM. (Kurve,
Bothell, Wash.) electronic atomizer is particularly suitable for
this mode of administration, and it delivers an aqueous liquid
composition at a rate of about 0.1 mL/min.
[0155] Another method of promoting paranasal sinus cavity delivery
of the composition is by: providing the liquid composition; and
aerosolizing the liquid composition with an aerosol generator
capable of emitting an aerosol whose pressure pulsates with a
frequency in the range from about 10 Hz to about 90 Hz, wherein the
aerosol generator is adapted to maintain an amplitude of pressure
pulsation of the emitted aerosol of at least about 5 mbar. In some
embodiments, the liquid composition has a volume of less than or
about 5 mL. An aerosol flow which is superimposed with pressure
fluctuations, or pressure pulses, creates periodic transient
pressure gradients extending from the actively ventilated nasal
cavity through the ostia to the paranasal sinuses, which gradients
cause a short period of convective flow of air and aerosol into the
sinuses until the pressure therein has become equal to the air
pressure in the nasal cavity. A portion of the aerosol droplets
which thus enter the paranasal sinuses are deposited therein onto
the mucosa. The extent to which the aerosol is deposited depends on
the droplet size. Droplets that are smaller than the preferred
particle size are relatively likely to be expelled from the sinuses
during the subsequent pulsation phase in which the aerosol
pressure, and thus the pressure in the nasal cavity, is lower than
the pressure within the sinuses, and during which a convective flow
of air from the paranasal sinuses to the nasal cavity occurs. In
order that an effective flow of air and aerosol into the paranasal
sinuses is induced, it is important to generate the pulsating
aerosol with an appropriate device which is capable of emitting
such aerosol, such as the PARI SINUS (including PARI LC Star, PARI
LL and PARI Sprint) or VibrENT.TM. (PARI) nebulizer families whose
compressors are adapted to generate a pulsating aerosol by
employing pressure pulses of appropriate frequency and
altitude.
[0156] Following administration of a dose of active agent to a
subject, the relative percentage of the dose delivered to the nasal
cavity versus the paranasal sinus cavities can vary such that: 1) a
major portion (greater than 50% wt.) of the dose is delivered to
the nasal cavity and a minor portion (less than 50% wt.) of the
dose is delivered to the paranasal sinus cavities; 2) a major
portion (greater than 50% wt.) of the dose is delivered to the
paranasal sinus cavities and a minor portion (less than 50% wt.) of
the dose is delivered to the nasal cavity; or 3) approximately 50%
wt. of the dose is delivered to each the nasal cavity and the
paranasal sinus cavities.
[0157] The invention can provide at least about 30% wt., at least
about 40% wt., at least about 50% wt., at least about 60% wt., at
least about 70% wt., at least about 80% wt., at least about 90% wt.
or at least about 95% wt. for delivery of active agent into the
nasal cavity and/or paranasal sinus cavities based upon the emitted
dose.
[0158] 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
inspirable dose that can reach the paranasal sinus cavities.
[0159] The in-vitro spray characteristics of the budesonide
containing aqueous preparations of Example 33 were determined. The
spray pattern at 3 and 6 cm, droplet size using a Malvern SprayTec,
and respirable fraction using a cascade impactor were determined
for Solution A and Suspension B. There were no apparent differences
between Solution A and Suspension B in terms of axis lengths and
ovality ratios at each spray distance. The average droplet size
(D50) was 35 .mu.m and 38 .mu.m, respectively. The small droplets
(D10) were 17 .mu.m and 17 .mu.m, respectively. The respirable
fraction (%<9 .mu.m) averaged less than 1% for both Solution A
and Suspension B.
[0160] The performance of a solution of the invention in a
nebulizer can 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
composition can have an impact on percentage of nebulization
composition emitted from a nebulizer, output rate of nebulized
corticosteroid and droplet size distribution.
[0161] The amount of residual composition left in the reservoir of
the nebulizer may be greater for solutions containing SAE-CD than
for a budesonide-containing suspension. Under similar nebulization
conditions, some nebulizers more efficiently reduce the volume of
nebulization suspension than of nebulization solution in the
reservoir of the nebulizer; however, this does not necessarily
correspond with the total amount of drug emitted by the
nebulizer.
[0162] In other words, the output rate of an SAE-CD nebulization
solution versus that of a suspension can differ such that the
solution has a higher output rate (in terms of drug output) than
does the suspension.
[0163] An SAE-CD (SBE7-.beta.-CD) concentration of less than or
about 25% wt./wt. was identified as the approximate upper
acceptable level for a composition adapted for use in a nebulizer,
"acceptable" being defined as the upper concentration of SAE-CD
that can be used without building up excessive viscosity, which can
adversely affect the nebulization time and output rate. An SAE-CD
concentration of less than or about 50% wt./wt. was identified as
the approximate upper acceptable level for a composition adapted
for use in a metered administration device. The practical upper
limit for concentration of SAE-CD will vary among the particular
type of administration device used. The upper acceptable
concentration of SAE-CD in a liquid composition can 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.
[0164] Viscosity of the liquid composition can impact droplet size
and droplet size distribution of the aerosolized composition. For
example, the present compositions tend to form larger droplets, in
terms of Dv50, at the lower concentrations, and thereby lower
viscosity, of SAE-CD in the absence of corticosteroid, e.g.
budesonide. A significant portion of the aerosolized 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.
[0165] A solution (aqueous liquid composition) made by mixing a
suspension of corticosteroid with SAE-CD is suitable for use in a
variety of different air driven jet nebulizers.
[0166] The SAE-CD containing solutions are suitable for
administration with an administration device, e.g. by nebulization,
across a range of concentrations. Moreover, the droplet size
distribution can be partially controlled by adjusting the
concentration of SAE-CD.
[0167] 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. Use of
SAE-CD in a composition, however, can result in an increased output
rate of corticosteroid, e.g. budesonide, regardless of the format
of the administration device.
[0168] 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.
[0169] A comparison of the AUC data can be made by consideration of
the dose delivered to each subject ("dose to subject") or dose
delivered to the nasal or paranasal cavities of each subject ("dose
to nose") or dose delivered to the ocular surface of each subject
("dose to eye") or dose emitted by the administration device
("emitted dose") or dose available for administration or delivery
("nominal dose" or "nominal available dose" or "loaded dose").
[0170] Practice of the method or system of the invention with the
composition of the invention can result in differences in the
amount of corticosteroid absorbed systemically when compared to
administration of a suspension-based corticosteroid composition,
e.g. RHINOCORT AQUA. In some embodiments, the composition, method
and system of the invention provide a higher AUC ((pg*h/mL)/.mu.g
of corticosteroid administered), lower AUC, or approximately the
same AUC as does a suspension-based corticosteroid composition
administered under substantially the same conditions. Similarly, in
some embodiments, the composition, method and system of the
invention provide a higher Cmax (pg of corticosteroid/mL of
plasma), lower Cmax, or approximately the same Cmax as does a
suspension-based corticosteroid composition administered under
substantially the same conditions.
[0171] The solutions of the invention can provide an enhanced
pharmacokinetic profile over suspension-based formulations
following their nasal or ophthalmic administration.
[0172] 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 and 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, fluocinolone acetonide, fluocinonide, fluocortin
butyl, fluorocortisone, fluorocortolone, fluorometholone,
flurandrenolone, fluticasone, fluticasone valerate, halcinonide,
hydrocortisone, icomethasone, loteprednol etabonate, 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. In some embodiments, the
corticosteroid is beclomethasone dipropionate, budesonide,
flunisolide, fluticasone propionate, mometasone furoate,
triamcinolone acetonide, or a combination thereof. 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.
[0173] Corticosteroids can be provided as the UDB (unit dose
budesonide) formulation (Sheffield Pharmaceuticals, Inc.),
VANCENASE AQ (beclomethasone dipropionate aqueous suspension;
Schering Corporation, Kenilworth, N.J.), ATOMASE (beclomethasone
dipropionate aqueous suspension; Douglas Pharmaceuticals Ltd.,
Aukland, Australia), BECONASE (beclomethasone dipropionate aqueous
suspension; Glaxo Wellcome, NASACORT AQ (triamcinolone acetonide
nasal spray, Aventis Pharmaceuticals), TRI-NASAL (triamcinolone
acetonide aqueous suspension; Muro Pharmacaceuticals Inc.) and
AEROBID-M, (flunisolide inhalation aerosol, Forest
Pharmaceuticals), NASALIDE and NASAREL (flunisolide nasal spray,
Ivax Corporation), FLONASE (fluticasone propionate,
GlaxoSmithKline), VERAMYST (fluticasone furoate, GSK) and NASONEX
(mometasone furoate, Schering-Plough Corporation). Corticosteroids
commercially available for ophthalmic administration include
perdnisolone sodium phosphate ophthalmic solution (INFLAMASE) and
prednisolone acetate opthalmic solution (PRED FORTE). SAE-CD can be
added to all such commercial formulations to provide a composition
of the invention.
[0174] 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.
[0175] Some embodiments of the invention comprise a corticosteroid
having a lipophilicity approximating or exceeding that of
flunisolide. Some embodiments of the invention comprise a
corticosteroid having a lipophilicity less than 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,
and fluocortolone.
[0176] 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. Other embodiments of the invention
include corticosteroids that are more lipophilic than
flunisolide.
[0177] 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, and triamcinolone
acetonide.
[0178] 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 an anti-inflammatory corticosteroid that exhibits
potent glucocorticoid activity.
[0179] Commercial formulations of budesonide are sold by
AstraZeneca LP (Wilmington, Del.) under the trademarks ENTOCORT EC,
PULMICORT RESPULES, RHINOCORT AQUA, RHINOCORT NASAL INHALER and
PULMICORT TURBOHALER, and under its generic name. PULMICORT
RESPULES suspension, which is a sterile aqueous suspension of
micronized budesonide, is administered by inhalation using a
nebulizer. 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 NASAL
INHALER is a metered-dose pressurized aerosol unit containing a
suspension of micronized budesonide in a mixture of propellants.
RHINOCORT.RTM. AQUA.TM. (U.S. Pat. No. 6,986,904, U.S. Pat. No.
6,565,832, and U.S. Pat. No. 5,976,573; the entire disclosures of
which are hereby incorporated by reference) is an unscented
metered-dose manual-pump spray formulation (for nasal
administration) containing a suspension of micronized budesonide in
an aqueous medium. A unit dose of the formulation consists of: (a)
about 32 .mu.g budesonide; and (b) a mixture consisting of (1)
microcrystalline cellulose and sodium carboxymethyl cellulose, the
mixture present at about 0.5 to 2.5% by weight of the therapeutic
composition, (2) dextrose, (3) Polysorbate 80 present at about
0.005 to 0.5% by weight of the therapeutic composition, (4)
disodium edetate present at about 0.005 to 0.1% by weight of the
therapeutic composition, (5) and potassium sorbate present at about
0.05 to 0.2% by weight of the therapeutic composition, wherein the
budesonide is in the form of finely divided particles, at least 90%
of which have a mass equivalent sphere diameter of less than 20
.mu.m, suspended in an aqueous medium. Budesonide is commercially
available as a mixture of two isomers (22R and 22S) and can also be
prepared as a single isomer 22R-budesonide.
[0180] The invention also provides compositions comprising a water
soluble .gamma.-CD derivative, a corticosteroid (either esterified
or unesterified) and an aqueous liquid medium. In certain
embodiments, the invention also provides compositions comprising a
water soluble .beta.-CD derivative, and an aqueous liquid
carrier.
[0181] The suitability of a corticosteroid for use in the liquid
composition/formulation 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 data detailed in
Example 23 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.
[0182] Depending upon the corticosteroid used in the formulation,
the molar ratio of corticosteroid to SAE-CD (or of SAE-CD to
corticosteroid) can vary in order to obtain a solution suitable for
administration. Some embodiments of the invention include those
wherein 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, 0.1 (1:10) to
0.03 (1:33.33), 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). In some embodiments, the corticosteroid is budesonide
and the molar ratio of SAE-CD to budesonide is greater than 10:1,
or at least 14:1.
[0183] In some embodiments, the minimum molar ratio of SAE-CD to
corticosteroid is about 1:1 or greater, about 1.5:1 or greater,
about 1.6:1 or greater, about 1.8:1 or greater, about 2:1 or
greater, about 2.2:1 or greater, about 3:1 or greater, about 3.4:1
or greater, about 3.8:1 or greater, about 4:1 or greater, about 5:1
or greater, about 5.7:1 or greater, about 6:1 or greater, about 7:1
or greater, about 8:1 or greater, about 8.8:1 or greater, about 9:1
or greater, greater than about 10:1, about 12:1 or greater, greater
than about 11:1, greater than about 13:1, greater than about 14:1,
about 16:1 or greater, about 20:1 or greater, about 25:1 or
greater, about 30:1 or greater, about 40:1 or greater. In some
embodiments, the molar ratio of SAE-CD to corticosteroid ranges
about from >10:1 to about 1000:1, about from >10:1 to about
100:1, about from >10:1 to about 50:1, about from >10:1 to
about 30:1, about from >10:1 to about 500:1. In some
embodiments, the maximum molar ratio of SAE-CD to corticosteroid
can be about 4,000:1 or less, about 3,000:1 or less, about 2,000:1
or less, about 1,500:1 or less, about 1,400:1 or less, about
1,200:1 or less, about 1,000:1 or less, about 900:1 or less, about
800:1 or less, about 600:1 or less, about 500:1 or less, about
400:1 or less, about 360:1 or less, about 300:1 or less, about
275:1 or less, about 250:1 or less, about 200:1 or less, about
150:1 or less, about 100:1 or less, about 80:1 or less, or about
60:1 or less. Combinations of the upper and lower molar ratios are
useful.
[0184] The solubility of a corticosteroid in a composition is
affected by its intrinsic solubility in the aqueous medium and its
binding constant with SAE-CD. The higher the intrinsic solubility
of the corticosteroid, the lesser the amount of SAE-CD required to
solubilize a dose of it in the composition. The maximum
concentration of corticosteroid in an aqueous solution containing
SAE-CD is known as its concentration at saturated solubility. 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 higher the concentration at
saturated solubility, the more soluble the corticosteroid is in the
presence of SAE-CD. Example 45 summarizes saturated solubility data
for some 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.
[0185] The binding of a corticosteroid to the SAE-CD can be
characterized by its equilibrium binding constant. The higher the
binding constant, the more tightly the corticosteroid is bound to
the SAE-CD. Example 46 summarizes the equilibrium binding constants
(K) for some corticosteroids in the presence of CAPTISOL or
SBE6.1-.gamma.-CD (0.04 M).
[0186] The equilibrium binding constant data can be used in
combination with the phase solubility data (saturated solubility
data) to prepare compositions 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. In some embodiments, the invention
comprises a corticosteroid having an intrinsic solubility in water
that is greater than that of flunisolide.
[0187] 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.
[0188] 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
can be at least about 1%, at least about 2%, at least about 5%, at
least about 7.5%, at least about 10%, at least about 15%, at least
about 20%, at least about 25%, at least about 50%, at least about
75%, at least about 100%, or at least about 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 about 14.1:1 (for at
least 1% higher), at least about 14.3:1 (for at least 2% higher),
at least about 14.7:1 (for at least 5% higher), at least about
15.4:1 (for at least 10% higher), at least about 16.1:1 (for at
least 15% higher), at least about 16.8:1 (for at least 20% higher),
at least about 17.5:1 (for at least 25% higher), at least about
21:1 (for at least 50% higher), at least about 24.5:1 (for at least
75% higher), at least about 28:1 (for at least 100% higher), or at
least about 42:1 (for at least 100% higher).
[0189] 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. Generally, increasing the molar ratio results in
an increase in the rate of dissolution of the corticosteroid.
[0190] The corticosteroid compound can be present in the final,
diluted corticosteroid nebulizable composition 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.
[0191] 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 range from about 250 .mu.g/mL and about 1 mg/mL
or about 250 .mu.g/mL and about 6 mg/mL for triamcinolone
acetonide, and range from about 400 .mu.g/mL to about 1.6 mg/mL, 40
.mu.g/mL to about 6 mg/mL, 40 .mu.g/mL to about 3 mg/Ml, 250
.mu.g/mL to about 6 mg/mL, or about 250 .mu.g/mL to about 3 mg/mL
for budesonide, depending on the volume to be administered.
[0192] For the treatment of nasal cavity, paranasal sinus cavity,
and/or ophthalmic disease, symptoms or disorders, the
corticosteroid composition is prepared as described herein. The
corticosteroid for such treatment can be, beclomethasone
dipropionate, beclomethasone monopropionate, betamethasone,
budesonide, ciclesonide, desisobutyryl-ciclesonide, flunisolide,
fluticasone, fluticasone propionate, fluticasone furoate,
mometasone, mometasone furoate, or triamcinolone acetonide, and can
be formulated in the concentrations set forth herein.
[0193] The corticosteroid or any other therapeutic (active) agent
herein can be present in its neutral, ionic, salt, basic, acidic,
natural, synthetic, diastereomeric, isomeric, enantiomerically
pure, enantiomerically enriched, racemic, solvate, anhydrous,
hydrate, hemi-hydrate, sesqui-hydrate, chelate, derivative, analog,
esterified, non-esterfied, polymorph, co-crystal, other common
form, or a combination thereof. When used in reference to a
therapeutic agent, "combination thereof" is taken to mean a
combination of any two or more of the forms of the therapeutic
agent defined herein. Accordingly, whenever a therapeutic 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.
[0194] As used herein, a dose includes a unit dose, a nominal dose,
emitted dose, nominal available dose, dose to subject, dose to
nose, dose to eye, or other such term of art. Unless otherwise
specified, the term a "unit dose" is a single dose, such as a
single spray from a metered spray device. An administration of an
effective amount, effective dose, or therapeutically effective
amount to a subject can comprise one or more unit doses. In certain
embodiments, the effective dose can be a single unit dose
administered to one nostril or one eye. In certain embodiments, the
therapeutically effective amount can be two unit doses administered
to one nostril or one eye. In certain embodiments, the effective
dose can be two unit doses, with one unit dose administered to each
eye or each nostril. In some embodiments, the therapeutically
effective amount can be more than two unit doses, with more than
one dose administered to a nostril(s) or eye(s). The term
"effective amount" or "effective dose" or "therapeutically
effective amount" is the amount or quantity of active agent that is
sufficient to elicit the required or desired therapeutic effect, or
the amount that is sufficient to elicit an appreciable biological
response when administered to a subject when given at one event or
period of administration. A single period of administration can
comprise administration of 1, 2, 3, 4, 5, 6, 7, 8, or more unit
doses. For administration with a nebulizer, or any other device
that continuously generates an aerosol over a period of time, the
"period of administration" is that period of time required to
deliver a therapeutically effective amount of an active agent to
one or both nostrils of a subject. For administration with a
nebulizer, or any other device that continuously generates an
aerosol over a period of time, the unit dose is an amount contained
in the reservoir of the device that is delivered in one period of
administration, i.e., for a nebulizer, the unit dose is the
therapeutically effective dose delivered in one period of
administration. A nebulizer can contain a single unit dose that is
administered over a single period of administration. Alternatively,
a nebulizer can contain multiple unit doses that are administered
in multiple periods of administration, for example, 1 to 8 unit
doses administered in 1 to 8 periods of administration. A nebulizer
can also contain multiple reservoirs containing single or multiple
unit doses. For administration with a metered administration
device, i.e., a device that provides a fixed volume or amount of
composition upon actuation, e.g., pump nasal spray, squeeze bottle,
atomizer, dropper, and other similar devices, the event of
administration, for delivery of an effective dose, is a
predetermined number of actuations of the device which releases a
corresponding predetermined number of unit doses, e.g., 1 to 8
actuations of the administration device releases 1 to 8 unit doses
in one or both nostrils of a subject. The unit dose of active agent
delivered is assumed to be the amount of active agent emitted from
the administration device, i.e., the emitted dose.
[0195] The term "nominal dose" refers to an amount of active agent
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 active agent 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
active agent emitted from a nebulizer. The term "dose to subject"
refers to the amount of active agent delivered to and retained by a
subject following administration of a formulation of the invention
by nebulization. The term "dose to nose" refers to the amount of
active agent delivered to and retained by the nose (nasal cavity
and/or paranasal sinus cavities) of a subject following
administration of a formulation of the invention by
nebulization.
[0196] The daily dose of the corticosteroid is generally about 0.05
mg to 10 mg, depending on the drug and the disease, in accordance
with the 2006 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
can be lower than the corresponding dose indicated in the PDR.
[0197] The following table provides exemplary dosing regimens for
various corticosteroids as included in the commercially available
branded nasal administration products in particular dosage
strengths. The composition of the invention can be dosed according
to these same dosing regimens or other dosing regimens herein.
TABLE-US-00003 Drug Amount per Total unit dose Weight/ Generic
Name/ (Total Dose Range per Volume Brand Name Dosing Regimen day)
administered Beclomethasone 1-2 sprays in each nostril 42 mcg 100
mg Dipropionate twice daily (168-336 mcg/day) Beconase .RTM. AQ
(GSK) Ciclesonide 2 sprays in each nostril once 50 mcg 70 .mu.L
Omnaris .RTM. daily (200 mcg/day) (Sepracor) Fluticasone Starting:
2 sprays in each 50 mcg 100 mg Propionate nostril once daily or 1
spray Starting: (200 mcg/day) Flonase .RTM. twice daily
Maintenance: (100 mcg/ (GSK) Maintenance: day) 1 spray in each
nostril once daily Fluticasone Starting: 2 sprays in each 27.5 mcg
50 .mu.L Furoate nostril once daily Starting: (110 mcg/day)
Veramyst .RTM. Maintenance: Maintenance: (55 mcg/ (GSK) 1 spray in
each nostril once day) daily Budesonide 1-2 sprays in each nostril
32 mcg (64 mcg in 51 mg Rhinocort .RTM. once or twice daily Canada)
Aqua (64-320 mcg/day) (AZ) Triamcinolone 2 sprays in each nostril
once 55 mcg 100 mg Acetonide daily (220 mcg/day) Nasacort .RTM. AQ
(Sanofi- Aventis) Mometasone 2 sprays in each nostril once 50 mcg
100 mg Furoate daily (200 mcg/day) Nasonex .RTM. (Schering- Plough)
Flunisolide 2 sprays in each nostril 29 mcg-Nasarel (232-464 mcg/
100 mg Nasarel .RTM. twice daily day) (Ivax) Titrate: 2 sprays per
nostril three times daily Dexamethasone 84 mcg (inhalation Dexacort
.RTM. Turbinaire vapor) (USB) Betamethasone + 2-3 drops instilled
in each Strength: 1 mg/mL 0.13-0.20 mL Neomycin nostril 2-3 times
daily (1.04 mg-3.6 mg/day) sulphate Betnesol-N .RTM. Nasal Drops
(GSK) Fluticasone 1 nasule contents instilled in 400 mcg/Nasule 400
.mu.L Propionate each nostril 1-2 times daily (400-800 mcg/day)
Flixonase .RTM. Nasule Drops (Allen & Hanbury/GSK)
Dexamethasone + 1 spray per nostril up to 6 Dexamethasone: 20 mcg;
tramazoline times daily; not for use for (40-240 mcg/ HCl more than
14 consecutive day)_Tramazoline: (Dexa- days 120 mcg Rhinapray
.RTM. (240-1440 mcg/day) Duo
TABLE-US-00004 Dosing Total Drug Drug Regimen per Delivered Per
Generic Name Brand Name Strength Affected Eye Day* Dexamethasone
Maxidex .RTM. 0.1% w/v 1-2 drops every 0.16-0.48 mg* (susp) (Alcon)
4-6 hours Dexamethasone Decadron .RTM. 0.1% w/v 1-2 drops every
0.8-1.6 mg* Sodium (Merck) hour while Also assumes 20 phosphate
(soln) awake & every drops/day 12 hours at night
Fluorometholone Fluor-Op .RTM. 0.1%, 0.25% w/v 1 drop 2-4 0.06-0.24
mg (Novartis) times a day Loteprednol Alrex .RTM. 0.2% w/v 1 drop 4
times a 0.32 mg* etabonate (Bausch & day Lomb) Prednisolone
Pred-Forte .RTM. 0.12%, 0.125, 1% w/v 1-2 drops 2 to 4 1.2-9.4 mg
(for Acetate (susp) (Allergan) times a day the 1% susp)
Prednisolone Inflamase 0.125%, 0.1% w/v 1-2 drops every 0.8-2 mg*
Sodium Forte .RTM. hour while Also assumes 20 Phosphate (soln)
(Novartis) awake & every drops/day 12 hours at night
[0198] The following table provides exemplary dosing regimens for
various corticosteroids as included in the commercially available
branded ocular administration products in particular dosage
strengths. The composition of the invention can be dosed according
to these same dosing regimens or other dosing regimens herein.
*A typical volume of an eye drop has been found to range from 25 to
50 mcL. So if the volume is not specified in the product label, it
was assumed for the purposes of this chart that the volume is 40
mcL as indicated by a asterisk.
[0199] A dose of corticosteroid, such as budesonide, can also be
administered once daily, once every two days, seven days per week,
once every week, once every month, for an extended period of time,
such as several days, weeks, or even longer, or even less
frequently. A dose of budesonide, or corticosteroid, can be
administered twice, thrice or more times per day or on an as-needed
basis. Administration can be during the daytime and/or nighttime.
In some embodiments, such as set forth in U.S. Pat. No. 6,598,603
and U.S. Pat. No. 6,899,099, a dose comprises 0.05 to 2.0 mg or
0.25 to 1.0 mg of budesonide.
[0200] In some embodiments, a dose comprises about 1 .mu.g to about
20 mg, about 1 .mu.g to about 10 mg, about 0.01 mg to about 10 mg,
about 0.025 mg to about 10 mg, about 0.05 mg to about 5 mg, about
0.1 mg to about 5 mg, about 0.125 mg to about 5 mg, about 0.25 mg
to about 5 mg, about 0.5 mg to about 5 mg, about 0.05 mg to about 2
mg, about 0.1 mg to about 2 mg, about 0.125 mg to about 2 mg, about
0.25 mg to about 2 mg, about 0.5 mg to about 2 mg, about 10 .mu.g
to about 2.5 mg, about 5 .mu.g to about 500 .mu.g, about 5 .mu.g to
about 250 .mu.g, about 5 .mu.g to about 130 .mu.g, about 45 .mu.g
to about 1000 .mu.g, about 1 .mu.g, about 10 .mu.g, about 16 .mu.g,
about 25 .mu.g, about 27.5 .mu.g, about 29 .mu.g, about 32 .mu.g,
at least about 25 .mu.g, about 40 .mu.g, about 42 .mu.g, about 45
.mu.g, about 48 .mu.g, about 50 .mu.g, about 55 .mu.g, about 64
.mu.g, about 84 .mu.g, about 96 .mu.g, about 100 .mu.g, about 125
.mu.g, about 128 .mu.g, about 200 .mu.g, about 250 .mu.g, about 400
.mu.g, about 800 .mu.g, about 25 .mu.g to about 66 .mu.g, about 48
.mu.g to about 81 .mu.g, about 73 .mu.g to about 125 .mu.g, about
95 .mu.g, about 35 .mu.g to about 95 .mu.g, about 25 .mu.g to about
125 .mu.g, about 60 .mu.g to about 170 .mu.g, about 110 .mu.g,
about 170 .mu.g, about 45 .mu.g to about 220 .mu.g, about 45 .mu.g
to about 85 .mu.g, about 48 .mu.g to about 82 .mu.g, about 85 .mu.g
to about 160 .mu.g, about 140 .mu.g to about 220 .mu.g, about 120
.mu.g to about 325 .mu.g, about 205 .mu.g, about 320 .mu.g, about
325 .mu.g, about 90 .mu.g to about 400 .mu.g, about 95 .mu.g to
about 170 .mu.g, about 165 .mu.g to about 275 .mu.g, or about 275
.mu.g to about 400 .mu.g of corticosteroid, such as budesonide,
said dose being a unit dose, nominal dose, nominal available dose,
emitted dose, delivered dose, dose to subject, dose to eye, or dose
to nose.
[0201] Some embodiments of the invention also provide a unit dose
of a therapeutic corticosteroid solution comprising: about 32 .mu.g
to 64 .mu.g of budesonide; SAE-CD; pharmaceutically acceptable
aqueous liquid carrier; disodium edetate present at of about 0.005
to about 0.1% by weight of the therapeutic composition unit dose;
and potassium sorbate present at of about 0.05 to about 0.2% by
weight of the therapeutic composition unit dose, and wherein the
corticosteroid solution is suitable for nasal administration to a
mammal as a unit dose. subject in need thereof.
[0202] Some embodiments of the invention also provide a method of
treating, preventing or ameliorating in a subject a
corticosteroid-responsive disease or disorder, the method
comprising:
[0203] metering into the nose of a mammal a the subject a
therapeutically effective amount of budesonide that is less than
about 320 .mu.g per day, delivered as 8 or more unit doses, wherein
each unit dose consists of: about 32 .mu.g of budesonide; SAE-CD;
disodium edetate present at of about 0.005 to about 0.1% by weight
of the therapeutic composition unit dose; potassium sorbate present
at of about 0.05 to about 0.2% by weight of the therapeutic
composition unit dose; and a pharmaceutically acceptable aqueous
liquid carrier. In some embodiments, the therapeutically effective
amount of budesonide is delivered as 7 unit doses, 6 unit doses, 5
unit doses, 4 unit doses, 3 unit doses, 2 unit doses or as one unit
dose. In some embodiments, the unit dose comprises 64 .mu.g, 96
.mu.g, 128 .mu.g, 160 .mu.g, 192 .mu.g, 224 .mu.g, 256 .mu.g, 288
.mu.g, or 320 .mu.g of budesonide.
[0204] In some embodiments, the corticosteroid solution has a pH of
about 3.5 to about 5 or about 4.2 to about 4.6.
[0205] The corticosteroid can be present at a concentration of
about 20 .mu.g to about 30 mg of corticosteroid per mL of solution.
As a result, about 10 mg to 500 mg of SAE-CD, or 10 mg to 250 mg of
SAE-CD, or 10 mg to 300 mg of SAE-CD per mL or per g of solution in
order to dissolve a substantial portion of the corticosteroid.
[0206] Due to the wide range of reservoir volumes available for
administration devices 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. The compositions of the invention can comprises a dose or
unit dose of corticosteroid in an approximate solution volume of 10
.mu.l to 100 mL, 10 .mu.l to 5000 .mu.l, 10 .mu.l to 2.5 mL, 20
.mu.l to 5 mL, 10 .mu.l to 500 t, 10 .mu.l to 200 t, 101 to 400
.mu.l, 50 .mu.l to 50 mL, 50 .mu.l to 10 mL, 50 .mu.l to 5 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, 0.05 mL to 1
mL, 501 to 137 .mu.l, 50 .mu.l to 70 .mu.l, 137 .mu.l to 400 .mu.l,
50 .mu.l to 200 .mu.l, 25 .mu.l, 50 .mu.l, 75 .mu.l, 100 .mu.l, 150
.mu.l, 200 .mu.l, 250 .mu.l, 500 .mu.l, 750 .mu.l, 1 mL, 2 mL, 5
mL, or 10 mL.
[0207] An administration device can be adapted to emit about 10 to
about 500 .mu.l, about 0.2 to about 5 mL, or about 0.5 to about 100
mL of a liquid composition per actuation or per dose. In some
embodiments, the administration device comprises a nozzle which
comprises a valve. Together, the nozzle and valve can be adapted to
release 25 .mu.l to 260 .mu.l, 50 .mu.l to 137 .mu.l, 50 .mu.l to
70 .mu.l, 137 .mu.l to 400 .mu.l, or 51 to 100 mg of a liquid
composition of the invention.
[0208] The composition of the invention can be packaged for
single-use or multi-use. A single use package comprises a single
dose of corticosteroid and a multi-use package comprises two or
more doses of corticosteroid. The packaging can comprise one or
more containers. A container can comprise one or more doses. A
single use container comprises a single dose, and a multi-use
container comprises two or more doses. Suitable packaging and
containers include, by way of example and without limitation, a
bottle, vial, ampoule, syringe, blister, capsule, or blow/fill/seal
container, or other devices such as those detailed in the examples.
The packaging can in a preservative free system such as the
Advanced Preservative Free system from Pfeiffer, or the Freepod
from Valois, or in a single use spray device such as the Pfeiffer
Bidose System or Unitdose System.
[0209] The composition can exit the device as a liquid, gel, vapor,
fine aerosol, mist, cloud or plume. Depending upon the mode of
administration, the composition can be delivered to the nasal
cavity, paranasal sinus cavities, or delivered topically to the
eye(s) of a subject.
[0210] The administration device can employ single use (single
dose) or multi-use (multi-dose) packaging. An administration device
can be used repeatedly with single use or multi-use packages and/or
containers.
[0211] The fill volume for the reservoir of a multi-dose, metered
dose nasal spray must be sufficient to provide for the number of
actuations required to initially prime the spray pump, periodically
reprime the pump, and to provide the desired number of doses in a
consistent manor. Since the tail-off characteristics (performance
when container is nearly empty) can vary as a function of pump
design, container geometry and formulation, the fill volume should
be sufficient to compensate for all these variables. As such, the
reservoir in an administration device can comprise an overfill. As
used herein, "overfill" is the amount or percentage of extra
composition (either in terms of the volume or weight of the
composition or the amount of drug in the composition) added to the
composition in the reservoir to compensate for the tail-off
characteristics of the device. In some embodiments, the overfill is
at least about 1%, at least about 2.5%, at least about 5%, at least
about 7.5%, at least about 10%, at least about 15%, at least about
25%, at least about 35%, at least about 45%, at least about 50% of
the target volume or weight of composition in a unit dose or dose
of the composition.
[0212] The time required to administer or deliver a dose of the
invention will depend upon its mode of administration, i.e., the
administration device used. For administration with an
administration device that substantially continuously emits an
aerosol over a period of time, e.g. nebulizer, 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
min to 10 min, about 0.1 min to 5 min, about 0.1 min to 3 min,
about 0.1 min to 2 min, about 0.1 min to 1.5 min, about 0.5 min to
about 1.5 min, or about 1 min. The time will vary according to the
dose of active agent in, the concentration of active agent in, and
the volume of the composition in the reservoir of an administration
device, and it will also depend upon the format of the
administration device, aerosolization efficiency, and reservoir
volume. In a given administration device, the lower the volume of
the liquid composition, the more quickly a corresponding dose of
active agent is administered or delivered. The higher the
concentration of active agent in the composition, the faster a dose
of the active agent can be administered or delivered.
[0213] For metered volume (or metered weight) administration
devices that generate a plume or aerosol by actuation, e.g.,
squeeze bottle pump spray, pump spray, atomizer, the time for
administration of a dose is merely the time it takes to affect one,
two or more actuations of the device in one or both nostrils of a
subject or about the time it takes for a subject to take a single
breath (about 1 sec to 3 sec, or 1 sec to 5 sec).
[0214] 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.
[0215] A corticosteroid, such as budesonide, can be administered as
its isomeric pair or single isomer and 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, anti-infective agent, antibiotic,
antifungal agent; hormones such as insulin, growth hormone, growth
hormone releasing factor, glucagon, somatostatin, chorionic
gonadotropin, adrenocorticotropic hormone (ACTH), and interferon;
anti-inflammatory agents such as aspirin, aminopyrine,
acetaminophen, ibufenac, ibuprofen, indomethacin, colchicine,
sulpyrine, mefenamic acid, phenacetin, phenylbutazone, flufenamic
acid and probenecid; antibiotics such as penicillin or its
derivatives, cephalosporin or its derivatives; erythromycin,
tetracycline, furadiomycin, leucomycin; chemotherapeutic agents
such as sulfathiazole and nitrofurazone; cardiac agents such as
digitalis and digoxin; blood vein dilating agents such as
nitroglycerin and papaverine hydrochloride; cough curing agents
such as codeine; azulen; phenovalin; pepsin; enzymes such as
lysozyme hydrochloride; other systemic agents such as
antihypertensives and diuretic; tranquilizers; sex hormone;
vitamin; ulcer medication; analgesic; decongestant; expectorant;
antitussive; antihistamine agent; bronchodilator; topical
anesthetic; sensory agents; oral care agents; miscellaneous
respiratory agent; gastrointestinal agent; and combinations
thereof.
[0216] 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-isoquinolinediol); 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-pyridine-
methanol); 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).
[0217] Dopamine (D.sub.2) receptor agonists include, but are not
limited to, Apomorphine
((r)-5,6,6a,7-tetrahydro-6-methyl-4H-dibenzo[de,glquinoline-10,11-diol);
Bromocriptine ((5'.
alpha.)-2-bromo-12'-hydroxy-2'-(1-methylethyl)-5'-(2-methylpropyl)ergotam-
an-3',6', 18-trione); Cabergoline
((8.beta.)-N-(3-(dimethylamino)propyl)-N-((ethylamino)carbony-l)-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-N.sup.6-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.
[0218] 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.
[0219] 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, U.S. Pat. No.
5,683,983, U.S. Pat. No. 5,677,280, U.S. Pat. No. 6,071,910 and
U.S. Pat. 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'-bipyridine]-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, U.S. Pat. No.
5,877,191, U.S. Pat. No. 5,929,094, U.S. Pat. No. 5,750,549 and
U.S. Pat. No. 5,780,467, 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 Xolaimm (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, prilocalne, etidocaine
(U.S. Pat. No. 5,510,339, U.S. Pat. No. 5,631,267, and U.S. Pat.
No. 5,837,713, the relevant disclosures of which are hereby
incorporated by reference).
[0220] Analgesics useful for this invention include any narcotic
and non-narcotic analgesics, such as menthol, acetaminophen,
NSAIDs, salicylates including aspirin (acetylsalicylic acid),
salsalate, sodium salicylate, diflunisal, etc. and mixtures
thereof, indomethacin and optically active isomers or racemates or
active metabolites of NSAIDs (NSAIDs include propionic acid
derivatives, acetic acid derivatives, fenamic acid derivatives,
biphenylcarboxylic acid derivatives and oxicams) including
fenoprofen, flurbiprofen, ibuprofen, ketoprofen, naproxen,
oxaprozin, etodolac, indomethacin, ketorolac, nabumetone, sulindac,
tolmetin, meclofenamate, mefenamic acid, piroxicam, bromfenac,
carprofen, tiaprofenic acid, cicloprofen, diclofenac, benzydomine,
their pharmaceutically acceptable salts and mixtures thereof. All
of these, as well as acceptable dosage ranges, are described in the
following: U.S. Pat. No. 4,749,720 to Sunshine et al. issued Jun.
7, 1988; U.S. Pat. No. 4,749,721 to Sunshine et al. issued Jun. 7,
1988; U.S. Pat. No. 4,749,722 to Sunshine et al. issued Jun. 7,
1988; U.S. Pat. No. 4,749,723 to Sunshine et al. issued Jun. 7,
1988; U.S. Pat. No. 4,749,711 to Sunshine et al. issued Jun. 7,
1988, U.S. Pat. No. 4,749,697 to Sunshine et al. issued Jun. 7,
1988, U.S. Pat. No. 4,783,465 to Sunshine et al., issued Nov. 8,
1988, U.S. Pat. No. 4,619,934 to Sunshine et al., issued Oct. 28,
1986, U.S. Pat. No. 4,840,962 to Sunshine et al. issued Jun. 20,
1989; U.S. Pat. No. 4,906,625 to Sunshine et al. issued Mar. 6,
1990; U.S. Pat. No. 5,025,019 to Sunshine et al. issued Jun. 18,
1991; U.S. Pat. No. 4,552,899 to Sunshine et al. issued Nov. 12,
1985, Facts and Comparisons, 1998, p. 242-260, all of which are
incorporated by reference herein, in their entirety.
[0221] The decongestants used in the compositions of the present
invention include, for example, pseudoephedrine,
phenylpropanolamine, phenylephrine, epinephrine, ephedrine,
naphazoline, xylometazoline, oxymetazoline, propylhexedrine,
tetrahydrozoline, their pharmaceutically acceptable salts, and
mixtures thereof.
[0222] The expectorants (also known as mucolytic agents) used in
the present invention include, for example, guaifenesin, iodinated
glycerol, glyceryl guaiacolate, terpin hydrate, ammonium chloride,
N-acetylcysteine and bromhexine, ambroxol, iodide, their
pharmaceutically acceptable salts, and mixtures thereof.
[0223] The antitussives used in the present invention include, for
example, menthol (can also be used as an analgesic),
dextromethorphan, chlophedianol, car-betapentane, caramiphen,
noscapine, diphenhydramine, codeine, hydrocodone, hydromorphone,
fominoben, benzonatate, their pharmaceutically-acceptable salts,
and mixtures thereof.
[0224] Examples of antihistamine agent used in the present
invention include both sedating and non-sedating antihistamines,
such as diphenhydramine, clemastine, chlorpheniramine,
brompheniramine, dexchlorpheniramine, dexbrompheniramine,
triprolidine, doxylamine, tripelennamine, heptadine, carbinoaxime,
bromdiphenhydramine, hydroxyzine, pyrilamine, acrivastine,
AHR-11325, phenindamine, astemizole, azatadine, azelastine,
cetirizine, carebastine, efletirizine, mapinastine, ebastine,
fexofenadine, ketotifen, Iodoxine, loratadine,
descarboethoxyloratadine, levocabastine, mequitazine, oxatomide,
setastine, tazifyline, temelastine, terfenadine, tripelennamine,
terfenadine carboxylate, phenyltoloxamine, pheniramine, antazoline,
bilastine, bepotastine besilate, rupatadine, emedastine,
tecastemizole, epinastine, levocetirizine, mizolastine,
noberastine, norastemizole, olopatadine, pharmaceutically
acceptable salts thereof, pharmaceutically active metabolites
thereof, optically active isomers or racemates, and mixtures
thereof. All of these antihistamines, as well as their acceptable
dosage ranges, are described in: U.S. Patents to Sunshine et al.
listed above under analgesics; Facts and Comparisons, 1998, p.
188-195, which is incorporated by reference herein in its
entirety.
[0225] Antihistamines are commercially widely available. The
invention includes embodiments wherein the antihistamine is
azelastine, olopatadine, cetirizine, or loratadine. Azelastine
(4-[(4-chlorophenyl)methyl]-2-(1-methylazepan-4-yl)-phthalazin-1-one)
is an antihistamine and mast cell stabilizer commercially available
as ASTELIN (MedPointe Inc., Cranbury, N.J.; MEDA Pharmaceuticals,
Solna, Sweden) and indicated for the treatment of hay fever,
seasonal allergies, and allergic conjunctivitis. Olopatadine is
also an antihistamine and is commercially available as
PATANASE.RTM. (Alcon. Ft. Worth, Tex.). These drugs are
administered as follows. The compositions of the invention
comprising these drugs can be administered according to the dosing
regimens below or other dosing regimens disclosed herein.
TABLE-US-00005 Dosing Regimen per Total Drug Drug Affected
Delivered Generic Name Brand Name Strength Eye per Day* Ketotifen
Zaditor .RTM. 0.025% w/v 1 drop 0.02-0.04 mg Fumerate (Novartis)
every 12 hours Olopatadine HCl Patanol .RTM.; 0.1%; 0.2% w/v 1-2
drops 0.08-0.16 mg Pataday .TM. twice daily; (Alcon) 1 drop once
daily Azelastine HCl Optivar .RTM. 0.05% w/v 1 drop twice 0.03-0.06
mg (Meda) daily Epinastine HCl Elestat .RTM. 0.05% w/v 1 drop twice
0.04 mg* (Allergan) daily Emadastine Emadine .RTM. 0.05% w/v 1 drop
four 0.08 mg* Difumerate (Alcon) times daily Levocabastine HCl
Livostin .RTM. 0.05% w/v 1 drop four 0.06-0.12 mg (Novartis) times
daily *A typical volume of an eye drop has been found to range from
25 to 50 mcL. So if the volume is not specified in the product
label, it was assumed for the purposes of this chart that the
volume is 40 mcL as indicated by a asterisk.
[0226] In some embodiments, the composition of the invention
comprises a dose or unit dose of azelastine present at an amount of
about 30 .mu.g to about 275 .mu.g, about 65 mcg to about 1100 mcg,
about 130 mcg to about 650 mcg, about 30 .mu.g, about 65 .mu.g,
about 137 mcg, about 274 mcg, about 548 mcg, or about 1096 mcg.
[0227] In some embodiments, the composition of the invention
comprises a dose or unit dose of olopatadine present at an amount
of about 330 mcg to about 5500 mcg, about 330 mcg to about 2660
mcg, about 660 mcg to about 5320 mcg, about 660 mcg to about 2660
mcg, about 550 mcg to about 1330 mcg, about 665 mcg, about 1330
mcg, about 1995 mcg, about 2660 mcg, about 3325 mcg, about 3990
mcg, about 4655 mcg, or about 5320 mcg.
[0228] In some embodiments, the composition of the invention
comprises a dose or unit dose of cetirizine present at an amount of
about 0.25 mg to 5.55 mg, 0.25 mg to about 4.4 mg, 0.55 mg to 4.4
mg, 0.55 mg to 3.3 mg, 0.55 mg to 2.2 mg, about 0.55 mg, about 1.1
mg, about 2.2 mg, about 3.3 mg, about 4.4 mg, or about 5.5 mg per
unit dose.
[0229] Bronchodilators used in the invention include, for example,
terbutaline sulfate, isoetharine, aminophylline, oxtriphylline,
dyphylline, ethylnorepinephrine, isoproterenol, epinephrine,
isoprenaline, metaproterenol, bitoterol, theophylline, albuterol,
isoproterenol and phenylephrine bitartrate, bitolterol, ephedrine
sulfate, pirbuterol acetate, pharmaceutically acceptable salts
thereof, and mixtures thereof. All of these bronchodilators, as
well as their acceptable dosage ranges, are described in Facts and
Comparisons, 1998, p. 173b-179e, which is incorporated by reference
herein in its entirety.
[0230] Topical anesthetics include, for example, lidocaine,
dibucaine, dyclonine, benzocaine, butamben, tetracaine, pramoxine,
their pharmaceutically-acceptable salts, and mixtures thereof. All
of these agents, as well as their acceptable dosage ranges, are
described in Facts and Comparisons, 1998, p. 601-607, which is
incorporated by reference herein in its entirety.
[0231] Sensory agents include, for example, coolants, salivating
agents, and warming agents. These agents are present in the
compositions at a level of from about 0.001% to about 10%,
preferably from about 0.1% to about 1%, by weight of the
composition. Suitable cooling agents include carboxamides,
menthols, thymol, camphor, capsicum, phenol, eucalyptus oil, benzyl
alcohol, salicyl alcohol, ethanol, clove bud oil, and
hexylresorcinol, ketals, diols, and mixtures thereof. Coolants can
be paramenthan carboxyamide agents such as
N-ethyl-p-menthan-3-carboxamide (WS-3 supplied by Sterling
Organics), taught by U.S. Pat. No. 4,136,163, issued Jan. 23, 1979,
to Watson et al., which is incorporated herein by reference in its
entirety. Another paramenthan carboxyamide agent is
N,2,3-trimethyl-2-isopropylbutanamide, known as "WS-23", and
mixtures of WS-3 and WS-23. Additional coolants are selected from
menthol, 3-1-menthoxypropane-1,2-diol, known as TK-10 supplied by
Takasago Perfumery Co., Ltd., Tokyo, Japan, menthone glycerol
acetal known as MGA, manufactured by Haarmann and Reimer, menthyl
lactate known as Frescolat.TM. manufactured by Haarmann and Reimer,
and mixtures thereof. Additional cooling agents include cyclic
sulphones and sulphoxides and others, all of which are described in
U.S. Pat. No. 4,032,661, to Rowsell et al., which is herein
incorporated by reference. The terms "menthol" and "menthyl" as
used herein include dextro- and levoratotory isomers of these
compounds and racemic mixtures thereof. TK-10 is described in
detail in U.S. Pat. No. 4,459,425, to Amano et al. and incorporated
herein by reference.
[0232] Salivating agents include Jambu.TM. manufactured by Takasago
Perfumery Co., Ltd., Tokyo, Japan. Warming agents include capsicum
and nicotinate esters, such as benzyl nicotinate.
[0233] Miscellaneous respiratory agents include, for example,
leukotriene receptor antagonists such as zafirlukast, zileuton;
nasal inhalant products such as corticosteroids, other steroids,
beclomethasone, flunisolide, triamcinolone; mucolytics such as
acetylcysteine; anticholinergics such as ipratropium bromide;
cromolyn sodium, nedocromil sodium; surfactants; and mixtures
thereof. These agents can be present in the compositions at a level
of from about 0.001% to about 10%, or from about 0.1% to about 5%
by weight of the composition.
[0234] Antimicrobial agents can also be present. Such agents can
include, but are not limited to, triclosan,
5-chloro-2-(2,4-dichlorophenoxy)-phenol, as described in The Merck
Index, 11th ed. (1989), pp. 1529 (entry no. 9573) in U.S. Pat. No.
3,506,720, and in European Patent Application No. 0,251,591 of
Beecham Group, PLC, published Jan. 7, 1988; chlorhexidine (Merck
Index, no. 2090), alexidine (Merck Index, no. 222; hexetidine
(Merck Index, no. 4624); sanguinarine (Merck Index, no. 8320);
benzalkonium chloride (Merck Index, no. 1066); salicylanilide
(Merck Index, no. 8299); domiphen bromide (Merck Index, no. 3411);
cetylpyridinium chloride (CPC) (Merck Index, no. 2024;
tetradecylpyridinium chloride (TPC); N-tetradecyl-4-ethylpyridinium
chloride (TDEPC); octenidine; delmopinol, octapinol, and other
piperidino derivatives; nicin preparations; zinc/stannous ion
agents; antibiotics such as augmentin, amoxicillin, tetracycline,
doxycycline, minocycline, and metronidazole; nystatin, tannic acid
(forms protective film over cold sores, fever blisters, and canker
sores), clotrimazole, carbamide peroxide, amlexanox (indicated for
treatment of aphthous ulcers); and analogs and salts of the above
antimicrobial antiplaque agents. The antimicrobial agents generally
comprise from about 0.1% to about 5% by weight of the compositions
of the present invention.
[0235] Exemplary suitable antiinfective, antibiotic and antifungal
compounds for use in combination in a formulation of the invention
are listed in the table below. A combination composition of the
invention can comprise one or more corticosteroids and one or more
other therapeutic agents and can be administered according to the
dosing regimens below or other dosing regimens herein.
TABLE-US-00006 Generic Name Brand Name Class Dosing Range Amikacin
Amikin Aminoglycoside 50-500 mg Amphotericin B Fungizone Antifungal
2.5-45 mg Azithromycin Zithromax Macrolide 50-400 mg Aztreonam
Azactam Monobactam 250-1000 mg Cefazolin Ancef, Kefzol Cephlasporin
250-1000 mg (Gen I) Cefepime Maxipime Cephlasporin 125-1000 mg (Gen
IV) Cefonicid Moniacid Cephlasporin 250-1000 mg (Gen II)
Cefoperazone Cefobid Cephlasporin 250-1000 mg (Gen III) Cefotaxime
Claforan Cephlasporin 250-1000 mg (Gen III) Cefotetan Cefotan
Cephlasporin 250-1000 mg (Cephamycin) Cefoxitin Mefoxin
Cephlasporin 250-1000 mg (Cephamycin) Ceftazidime Fortaz, Ceptaz
Cephlasporin 250-1000 mg (Gen III) Ceftizoxime Cefizox Cephlasporin
250-1000 mg (Gen III) Ceftriaxone Rocephin Cephlasporin 250-1000 mg
(Gen III) Cefuroxime Ceftin Cephlasporin 100-600 mg (Gen II)
Cephapirin Cefadyl Cephlasporin 250-1000 mg (Gen I) Ciprofloxacin
Cipro Quinolone 25-200 mg Clindamycin Cleocin Lincosamide 50-600 mg
Doxycycline Vibramycin Tetracycline 10-100 mg Fluconazole Diflucan
Antifungal 12.5-150 mg Gentamycin Garamycin Aminoglycoside 10-200
mg Itraconazole Sporanox Antifungal 12.5-150 mg Levofloxacin
Levaquin Quinolone 40-200 mg Meropenem Merrin Carbapenem 200-750 mg
Mezlocillin Mezlin Penicillin 300-1500 mg Miconazole Monistat
Antifungal 12.5-300 mg Nafcilin Nafcil Penicillin 100-1000 mg
Ofloxacin Floxin Quinolone 25-200 mg Piperacillin Pipracil
Penicillin 100-1000 mg Rifampin Rifadin Miscellaneous 500-5000 mg
Ticarcillin + Timentin Penicillin 500-5000 mg Clavulanate
Tobramycin Nebcin Aminoglycoside 10-200 mg Vancomycin Vancocin
Antifungal 50-400 mg
[0236] Other suitable antifungal agents include butoconazole,
econazole, oxiconazole, sulconazole, tioconazole, posaconazole,
terconazole, tiniconazole, voriconazole, anidulafungin (LY303366,
VER-002), micafungin (FK463), Echinocandins, Cyclic Peptide
Antifungals, Triazoles, genaconazole, ravuconazole, TAK-456 and
TAK-457, ZD0870, UR-9625, UR-9746, UR-975 1 and UR-9825, T-8581,
CS-758, SS-750, Echinocandin B (A30912A), Cilofungin (LY 121 01 9),
FR901379 (echinocandin-type peptide, WF11899A), FR901469
(lipopeptidolactone), FR131535, FR203903, Aculeacin A-G,
Mulundocandin, Sporiofungin, Pneumocandin A, S3 17941F1,
Corynecandin, Mer-WF3010, Fusacandin, Arthrichitin, Furanocandin,
Azalomycins, LY 329960, DB 289, aminocandin, naftifine,
terbinafine, caspofungin, nystatin, flucytosine, griseofulvin, and
mixtures thereof.
[0237] The amount and/or concentration of corticosteroid and/or
other therapeutically effective agent in a unit dose or dose of the
composition can be as specified herein or as customarily present in
known dosage forms comprising the same drugs.
[0238] The corticosteroid and/or other therapeutically effective
agent, if present, can be administered to a subject in need thereof
according to a dosing regimen as described herein or as recognized
in the art as being suitable for the treatment of a disease,
disorder or symptom therapeutically responsive to the
corticosteroid and/or other therapeutically effective agent.
[0239] Methods of the invention can further comprise administering
an additional therapeutically effective agent. In some embodiments,
the corticosteroid and additional therapeutically effective agent
are administered simultaneously, sequentially, or separately.
[0240] 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. The amount of drug
included in the compositions of the present invention will be
whatever amount is therapeutically effective and will depend upon a
number of factors, including the identity and potency of the chosen
drug, the disorder being treated, the health of the subject being
treated and other such factors common to the pharmaceutical
industry for prescription of drugs to a subject. The drugs will
generally be administered according to their known dosing regimens
such as those disclosed in the Pharmaceutical Desk Reference or
those recognized as suitable by the Food and Drug Administration
(USA), European Medicines Agency (Europe), National Institute of
Health Sciences (Japan), and National Administration of Drugs,
Food, and Medical Technology (Administracion Nacional de
Medicamentos, Alimentos y Tecnologia Medica, Argentina).
[0241] Non-limiting exemplary compositions of the invention
comprising a corticosteroid and another active agent can comprise
the following components.
TABLE-US-00007 FORM. Corticosteroid (A) Other Active Ingredient (B)
I Budesonide Olopatadine* II Budesonide Azelastine* III Budesonide
Azithromycin IV Budesonide Voriconazole V Budesonide Azithromycin
and voriconazole VI Mometasone furoate Azelastine* VII Mometasone
furoate Olopatadine* VIII Mometasone furoate Azithromycin IX
Fluticasone Loratadine proprionate X Fluticasone Desloratadine
proprionate XI Fluticasone Cetirizine* propionate XII Fluticasone
Azelastine* propionate XIII Fluticasone Olopatadine* propionate XIV
Fluticasone furoate Azelastine* XV Fluticasone furoate Olopatadine*
XVI Ciclesonide Azelastine* XVII Ciclesonide Olopatadine* *denotes
use as its salt, e.g. hydrochloride salt, or free base
[0242] A combination formulation of the invention can comprise one
or more corticosteroids and one or more second therapeutic (active)
agents selected from azithromycin, clinafloxacin, gemifloxacin
(Factive.RTM.), moxifloxacin (Avelox.RTM.), gatifloxacin
(Tequin.RTM., Zymar.RTM.), sitafloxacin, roxithromycin,
norfloxacin, cetirizine hydrochloride, desloratadine, fexofenadine
hydrochloride, natamycin, fluconazole itraconazole ketoconazole,
capsaicin, benzocaine, tetrahydrozoline hydrochloride,
oxymetazoline HCl, epinephrine, zileuton, cromolyn sodium,
triazolam, a pharmaceutically acceptable salt thereof, and an
isomer thereof.
[0243] A composition comprising a corticosteroid and another active
agent can be prepared according to the examples below. In some
embodiments, the SAE-CD is present in an amount sufficient to
solubilize the corticosteroid and the other active agent. In other
embodiments, the SAE-CD is present in an amount sufficient to
solubilize the corticosteroid or the other active agent.
[0244] Depending upon the other active agent 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 agent 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 agent. In some embodiments, the SAE-CD has
approximately the same equilibrium binding constant for the other
active agent as it has for the corticosteroid. Alternatively, the
other active agent 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 agent, 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 agent, or of
each. The invention also provides embodiments wherein, the SAE-CD
does not solubilize the other active agent.
[0245] The molar ratio of SAE-CD to corticosteroid and SAE-CD to
other active agent 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 agent, or
both.
[0246] A composition of the invention can comprise SAE-CD,
corticosteroid, aqueous liquid carrier, and an antihistamine. In
some embodiments, the composition contains SAE-CD, budesonide,
water (or aqueous buffer) and azelastine. Example 14 details the
preparation of such a composition. Other solutions of azelastine in
buffer with varying amounts of SAE-CD, in the absence of
budesonide, were prepared and scanned by UV Spectrometer. The
change in absorption as a function of SAE-CD concentration was
plotted and used to determine the equilibrium binding constant of
azelastine with SAE-CD, according to the Benesi-Hildebrand
equation. The equilibrium binding constant of azelastine with
CAPTISOL was found to be approximately 10,000 at pH 4.5. The
binding constant for budesonide under similar conditions was
determined to be about 1000; therefore, azelastine will compete
with budesonide, or another corticosteroid, for binding to SAE-CD.
Accordingly, the amount of SAE-CD present can be increased to
permit complete dissolution of both drugs.
[0247] The equilibrium binding constant of the corticosteroid can
change when a second active agent is present in a composition of
the invention. Since azelastine hydrochloride (AZ-HCl) has an
approximately 10-fold higher binding constant for SBE-.beta.-CD
than does budesonide (BUD), the amount of SBE-.beta.-CD present in
an aqueous composition of the three needs to be sufficient to
solubilize both drugs. Example 19 details a procedure for
determination of the phase solubility of budesonide in the presence
of varying amounts of azelastine. The results are depicted in FIGS.
11A (for SBE-.beta.-CD) and 11B (for SBE-.beta.-CD and
SBE-.gamma.-CD). FIG. 11A is a chart of the phase solubility of BUD
as a function of AZ-HCl concentration in solution in the presence
of 20-40 mM CAPTISOL. The data indicate that the concentration of
BUD at saturated solubility decreases as the concentration of
AZ-HCl increases. FIG. 11B is a chart of the phase solubility of
BUD as a function of SBE-.beta.-CD or SBE-.gamma.-CD concentration
in solution using various different concentrations of AZ-HCl
(1.00-2.75 mg.mL). The data indicate that the concentration of BUD
at saturated solubility decreases as the concentration of AZ-HCl
increases and that higher concentrations of SBE-CD are required in
order to dissolve the BUD as the concentration of AZ-HCl increases.
Thus, increasing the amount of AZ-HCl in the solution decreases the
overall solubility of BUD. The equilibrium complex stability
constant between azelastine and SBE-.beta.-CD is surprisingly about
5-times greater than that between azelastine and SBE-.gamma.-CD
(.about.10000 M-1 versus 2200 M.sup.-1) while the equilibrium
complex stability constant for budesonide with SBE-.beta.-CD is
half that of the equilibrium complex stability constant for
budesonide with SBE-.gamma.-CD (i.e. 1000 M.sup.-1 versus 2000
M.sup.-1). Surprisingly, the nominal amount of SBE-.beta.-CD
required to solubilize a similar dose of budesonide in the presence
of azelastine is greater than in the absence of azelastine as well
as greater than the increase required if the cyclodextrin was
SBE-.gamma.-CD. Therefore, it is advantageous to prepare solution
compositions of these combinations using SBE-.gamma.-CD due to the
efficiency of interaction so as to require less of one SAExCD
versus another different SAEyCD to solubilize similar amounts of
actives in the presence of each other.
[0248] In some embodiments of the invention, the concentrations of
budesonide, azelastine (free base or HCl salt), and SAE-CD (e.g.
SBE-CD) in the composition are as follows:
[0249] a) budesonide is present at a concentration of about 0.627
mg/g (32 mcg/51 mg), about 0.457 mg/mL (32 mcg/70 mcL), 0.320 mg/mL
(32 mcg/100 mcL), about 0.320 mg/g (32 mcg/100 mg), from 0.04 mg/mL
to 2 mg/mL, or from 0.04 mg/mL to 1 mg/mL;
[0250] b) azelastine is present at a concentration of about 0.5 to
about 10 mg/mL, about 0.5 to about 6 mg/mL, about 1 to about 5
mg/mL, about 1 to about 3 mg/mL, about 2 to about 3 mg/mL, about
2.5 to about 3 mg/mL, about 2.75 mg/mL about 0.137 mg/51 mg, about
0.137 mg/0.137 mL, about 0.137 mg/0.050 mL, about 0.137 mg/0.070
mL, about 0.137 mg/0.1 mL, or about 1 mg/mL to 10 mg/mL (0.137
mg/0.020 mL); and/or
[0251] c) SAE-CD is present at a concentration of about 100 mg/mL,
about 10 to about 500 mg/mL, or about 10 to about 500 mg/g.
[0252] In some embodiments, the concentrations of budesonide,
azelasatine and SAE-CD in the composition are as set forth in the
table below.
TABLE-US-00008 [budesonide] [azelastine] [SBE-CD] 32 mcg/51 mg of
137 mcg/51 mg of 7 mg/51 mg composition composition 32 mcg/70 mcL
of 137 mcg/70 mcL of 7 mg/70 mcL composition composition 32 mcg/100
mg of 137 mcg/100 mg of 7 mg/100 mg composition composition 0.04 to
2 mg/mL of 1 to 10 mg/mL of 10 to 500 mg/mL of composition
composition composition (or per g of composition)
[0253] In some embodiments of the invention, the concentrations of
budesonide, olopatadine (free base or HCl salt), and SAE-CD (e.g.
SBE-CD) in the composition are as follows:
[0254] a) budesonide is present at a concentration of about 0.627
mg/g (32 mcg/51 mg), about 0.457 mg/mL (32 mcg/70 mcL), 0.320 mg/mL
(32 mcg/100 mcL), about 0.320 mg/g (32 mcg/100 mg), from 0.04 mg/mL
to 2 mg/mL, or from 0.04 mg/mL to 1 mg/mL;
[0255] b) olopatadine is present at a concentration of about 0.5 to
about 15 mg/mL, about 1 to about 10 mg/mL, about 1 to about 15
mg/mL, about 5 to about 10 mg/mL, about 6 to about 7 mg/mL, about
0.665 mg/0.10 mL, about 0.665 mg/0.70 mL, about 0.665 mg/0.50 mL,
5.32 mg/0.2 mL, or about 6.5 mg/5 mL; and/or
[0256] c) SAE-CD is present at a concentration of about 100 mg/mL,
about 10 to about 500 mg/mL, or about 10 to about 500 mg/g.
[0257] In some embodiments of the invention, the concentrations of
budesonide, cetirizine (free base or HCl salt), and SAE-CD (e.g.
SBE-CD) in the composition are as follows:
[0258] a) budesonide is present at a concentration of about 0.627
mg/g (32 mcg/51 mg), about 0.457 mg/mL (32 mcg/70 mcL), 0.320 mg/mL
(32 mcg/100 mcL), about 0.320 mg/g (32 mcg/100 mg), from 0.04 mg/mL
to 2 mg/mL, or from 0.04 mg/mL to 1 mg/mL;
[0259] b) cetirizine is present at a concentration of about 0.25 to
about 4.4 mg/mL, about 0.55 to about 4.4 mg/mL, about 1.1 to about
4.4 mg/mL, about 1.1 to about 2.2 mg/mL, about 1 to about 25 mg/mL,
about 2 to about 24 mg/mL, about 5 to about 20 mg/mL, about 7 to
about 15 mg/mL, about 10 to about 12 mg/mL, about 1.1 mg/0.1 mL,
about 1.1 mg/0.05 mL, about 1.1 mg/0.70 mL, about 1.1 mg/0.2 mL, or
about 2.2 mg/5 mL; and/or
[0260] c) SAE-CD is present at a concentration of about 100 mg/mL,
about 10 to about 500 mg/mL, or about 10 to about 500 mg/g.
[0261] In some embodiments of the invention, the concentrations of
mometasone furoate, olopatadine (free base or HCl salt), and SAE-CD
(e.g. SBE-CD) in the composition are as follows:
[0262] a) mometasone furoate is present at a concentration of about
0.5 mg/mL (50 mcg/100 mcL), about 0.71 mg/mL (50 mcg/70 mcL), about
1.0 mg/mL (50 mcg/100 mcL), about 1.0 mg/mL (200 mcg/200 mcL), or
about 0.1 mg/mL (500 mcg/5000 mcL);
[0263] b) olopatadine is present at a concentration of about 0.5 to
about 15 mg/mL, about 1 to about 10 mg/mL, about 1 to about 15
mg/mL, about 5 to about 10 mg/mL, about 6 to about 7 mg/mL, about
0.665 mg/0.10 mL, about 0.665 mg/0.70 mL, about 0.665 mg/0.50 mL,
5.32 mg/0.2 mL, or about 6.5 mg/5 mL; and/or
[0264] c) SAE-CD is present at a concentration of about 300 mg/mL,
about 10 to about 500 mg/mL, or about 10 to about 500 mg/g.
[0265] In some embodiments of the invention, the concentrations of
fluticasone propionate, cetirizine (free base or HCl salt), and
SAE-CD (e.g. SBE-CD) in the composition are as follows:
[0266] a) fluticasone propionate is present at a concentration of
about 0.5 mg/mL (50 mcg/100 mcL), about 0.71 mg/mL (50 mcg/70 mcL),
about 1.0 mg/mL (50 mcg/100 mcL), about 1.0 mg/mL (200 mcg/200
mcL), or about 0.1 mg/mL (500 mcg/5000 mcL);
[0267] b) cetirizine is present at a concentration of about 0.55 to
about 4.4 mg/mL, about 1.1 to about 4.4 mg/mL, about 1.1 to about
2.2 mg/mL, about 1 to about 25 mg/mL, about 2 to about 24 mg/mL,
about 5 to about 20 mg/mL, about 7 to about 15 mg/mL, about 10 to
about 12 mg/mL, about 1.1 mg/0.1 mL, about 1.1 mg/0.05 mL, about
1.1 mg/0.70 mL, about 1.1 mg/0.2 mL, or about 2.2 mg/5 mL;
and/or
[0268] c) SAE-CD is present at a concentration of about 300 mg/mL,
about 10 to about 500 mg/mL, or about 10 to about 500 mg/g.
[0269] Embodiments of the present invention allow for combination
compositions (those containing two or more active agents
(therapeutic agents)) to be prepared in a variety of ways:
[0270] 1) Mixing ready to use solutions of a second therapeutic
agent with a ready to use solution of a corticosteroid in
SAE-CD;
[0271] 2) Mixing ready to use solutions of a second therapeutic
agent with a concentrated solution of a corticosteroid dissolved
using SAE-CD;
[0272] 3) Mixing a ready to use solution of a second therapeutic
agent with substantially dry SAE-CD and a substantially dry
corticosteroid;
[0273] 4) Mixing a ready to use solution of a second therapeutic
agent 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);
[0274] 5) Mixing a ready to use solution of a corticosteroid such
as budesonide with a substantially dry second therapeutic agent;
or
[0275] 6) Dissolving a substantially dry second therapeutic agent
and a substantially dry SAE-CD plus a substantially dry
corticosteroid.
[0276] 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.
[0277] It is well understood by those of ordinary skill in the art
that the above solutions or powders can 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 nasally administered liquid
formulations.
[0278] A corticosteroid-responsive disease, symptom or disorder is
one wherein a subject suffering from such will receive a clinical
benefit after administration of a corticosteroid according to the
invention. A type of corticosteroid-responsive disease, symptom or
disorder is any allergic and/or inflammatory disease, symptom or
disorder. Exemplary ones include nasal symptom, non-nasal symptom,
ocular symptom, acute or chronic rhinitis, nasal polyps, post
surgical polyps, obstructive sleep apnea, Eustachian tube
dysfunction, serous otitis media, sleep disturbances, daytime
somnolesence, snoring, cluster headache, nasal furuncles,
epistaxis, wounds of the nasal or sinunasal mucosa, dry nose
syndrome, nasal bleeding, herpes, sarcoidosis, fibrosis, cancer,
autoimmune reaction, or a combination thereof.
[0279] In some embodiments, acute or chronic rhinitis is selected
from the group consisting of allergic rhinitis, seasonal allergic
rhinitis, perennial allergic rhinitis, perennial non-allergic
rhinitis, bacterial rhinitis, fungal rhinitis, viral rhinitis,
atrophic rhinitis, grass pollen rhinitis, have fever, blocked nose,
nasal congestion, vasomotor rhinitis, or a combination thereof.
[0280] In some embodiments, the nasal symptom is rhinorrhea, nasal
congestion, nasal itchiness, sneezing, nasal obstruction or a
combination thereof. In some embodiments, the non-nasal symptom is
itchy/gritty eyes, tearing/watery eyes, red/burning eyes, itchy
ears and palate, or a combination thereof.
[0281] In some embodiments, the invention excludes a method of or
system for treating asthma, allergic asthma, rhinosinusitis, and/or
sinusitis.
[0282] Conjunctivitis is an inflammation of the conjunctiva, the
membrane lining the external surface of the eye, and is most often
caused by an allergic reaction. Allergic conjuctivitis is one of
the most common eye conditions in children and adults with symptoms
including itching, stinging, burning, redness, tearing and swelling
of the eyelids and the whites of the eye. Allergic conjunctivitis
is most often associated with allergic rhinitis (Hay Fever) and can
be associated with asthma.
[0283] Allergic rhinitis is one of the most chronic atopic diseases
that is associated with considerable cost and co-morbidity.
Allergic rhinitis is initiated by an IgE-mediated response to
allergens and results in a consequent release of preformed
mediators and cytokines, which induce inflammatory cell recruitment
and their activation at the target organ. Seasonal allergic
rhinitis (SAR), triggered by pollen from trees, grasses and weeds,
is characterized by sneezing, nasal congestion, nasal itching,
rhinorrhea, and pruritic, watery red eyes.
[0284] Animal dander, mold, dust, and dust mites can also trigger
symptoms of rhinitis. Non-allergic rhinitis can also be induced by
viruses, and environmental factors such as toxins and tobacco
smoke.
[0285] Corticosteroids can also be used to treat ocular conditions
such as: (1) inflammatory conditions including conditions of the
palpebral and bulbar conjunctiva, cornea, and anterior segment of
the globe such as allergic conjunctivitis, acne rosacea,
superficial punctate keratitis, herpes zoster keratitis, iritis,
cyclitis, selected infective conjunctivitis; (2) corneal injuries
including injury from chemical, radiation, or thermal burns or
penetration by foreign bodies; and (3) ocular pain and
burning/stinging following ocular surgery such as corneal
refractive surgery.
[0286] The compositions of the invention can generally have a
storage shelf life of 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 composition. For example, for a
composition having a shelf life of at least six months, the
composition 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
composition 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 composition having
an unacceptable shelf-life will increase beyond the predetermined
value during the intended period of storage.
[0287] The method of Example 3 can be followed to determine the
stability of the active agent in solution. The shelf-life can be
defined as the time to loss of less than about 10%, less than about
5%, less than about 3%, less than about 2% or less than about 1%
potency. Under the conditions tested, the loss of potency was first
order. The shelf life of a CAPTISOL-ENABLED Budesonide Nasal
Solution (a solution comprising budesonide and SBE7-O-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 pH 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.
[0288] SAE-CD is also capable of stabilizing the isomers of
budesonide to different extents. 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-.beta.-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.degree. C.). Accordingly a solution comprising
SAE-CD and budesonide is stable at a pH from 4 to 6, from 4 to 5,
or about 4.5.
[0289] SBE7-.beta.-CD also significantly reduced the photode
composition of budesonide. The loss of budesonide was first order
and independent of pH.
[0290] SAE-CD is also capable of stabilizing a second active agent
included in the composition. Example 16 details a procedure for
evaluating the stability of azelastine in the presence of SAE-CD at
varying temperatures and in solutions of different pH's. The
results are depicted in FIGS. 10A to 10C. The SAE-CD stabilized the
azelastine for the period of sixteen weeks regardless of the
temperature or pH of the solution. The lower the temperature, the
greater the stabilization. Of the three pH values evaluated, the
greatest stabilization was observed at pH 5. Accordingly, a
solution comprising SAE-CD and azelastine is most stable at a pH
from 4 to 6 or from 4.5 to 5.5.
[0291] The composition of the invention can be provided as a powder
adapted to form an aqueous solution for nasal, non-nasal and/or
ophthalmic administration. The powder can also be adapted for
administration with a powder-administering device. The powder 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.
[0292] A powder composition of the invention can be prepared
according to any of the following processes. A liquid composition
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. Examples 25, 26, 27, 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.
[0293] A liquid vehicle (carrier) included in a formulation of the
invention comprises a pharmaceutically acceptable aqueous liquid
carrier, such as water or buffer, aqueous alcohol, propylene
glycol, glycerin, poly(ethylene glycol), poloxamer, povidone,
polyol (such as sorbitol), aqueous organic solvent or a combination
thereof. 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. For nasal administration, an aqueous liquid carrier
can be aqueous saline (which generally contains sodium chloride as
the salt, and is fully described in Remington's Pharmaceutical
Sciences, 19.sup.th edition (1995) p. 1502, which is herein
incorporated by reference). The salt can be present in the solution
at a level of about 0.01% to about 2%, preferably from about 0.5%
to about 1.0% by weight of solution. Suitable nontoxic
pharmaceutically acceptable nasal carriers are known to those
skilled in the art. The choice of a suitable carrier will depend on
the exact nature of the particular nasal dosage form required,
e.g., whether the active agent is to be formulated into a nasal
solution (for use as drops or as a spray), a nasal ointment, a
nasal gel or another nasal form.
[0294] The compositions of the invention can include a
preservative, antioxidant, buffering agent, acidifying agent,
alkalizing agent, colorant, solubilizing agent,
solubility-enhancing agent, complexation-enhancing agent, diluent,
electrolyte, glucose, stabilizer, bulking agent, antifoaming agent,
oil, emulsifying agent, cryoprotectant, plasticizer, flavors,
sweeteners, taste-masking agent, tonicity modifier, surface tension
modifier, surfactant, viscosity modifier, density modifier,
volatility modifier, saline, other excipients known by those of
ordinary skill in the art for use in preserved formulations, or a
combination thereof.
[0295] 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.
[0296] 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.
[0297] Inclusion of a preservative in the solution is optional,
since the formulation is self-preserved by SAE-CD depending upon
its concentration in solution. If a conventional preservative is
included in the composition, the corticosteroid, such as
budesonide, can have a greater binding with the SAE-CD than does a
conventional preservative. Nonetheless, a 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 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,
3-(trimethoxysilyl)propyldimethyloctadecylammonium chloride,
stearyldimethylbenzyl-ammonium chloride,
6-acetoxy-2,4-dimethylmetadioxane, alkali metal sorbates and
mixtures, ammonium sorbate, BAC, benzalkonium chloride,
benzethonium chloride, benzoic acid (and salts), benzyl alcohol,
boric acid, bronopol, butyl parabens, C.sub.16 benzalkonium halide
compounds, cetrimide, cetyldimethylbenzylammonium chloride,
cetylpyridinium bromide, cetylpyridinium chloride, chlorbutanol,
chlorhexidine, chlorine dioxide, chlorite components,
Chlorobutanol, chlorocresol, chlorohexidine gluconate,
chlorohexidine hydrochloride, cresol, distearyldimethylammonium
chloride, dodecylguanidine, dodecylguanidine hydrochloride,
domiphen bromide, ethanol, ethyl parabens, guanidines,
lauroylisoquinolium bromide, metacresol, Methylparaben,
myristylgamma picolinium chloride, paraben mixtures, phenol, phenol
derivative, phenoxyethanol, phenylethanol, phenylmercuric acetate,
phenylmercuric nitrate, phenylmercuric salts,
polyhexmethylenebiguanidine hydrochloride, polymeric quaternary
ammonium compounds, potassium sorbate, propylparaben, quaternary
ammonium alkylene glycol phospholipid derivatives, quaternary
ammonium salts, propyl parabens, sodium sorbate, sorbic acid (and
salts), stearylpentaethoxyammonium chloride,
stearyltolylmethyl-ammonium chloride, sulfites inorganic,
thiomersal, thymol, and others known to those of ordinary skill in
the art.
[0298] 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, hypophosphorous acid, monothioglycerol,
propyl gallate, sodium ascorbate, sodium citrate, sodium sulfide,
sodium sulfite, sodium bisulfite, sodium formaldehyde sulfoxylate,
thioglycolic acid, EDTA, pentetate, sodium metabisulfite, and
others known to those of ordinary skill in the art.
[0299] 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), HEPES
(N-(2-hydroxyethyl)piperazine-N'-(2-ethanesulfonic acid), DIPSO
(3-(N,N-bis(2-hydroxyethyl)amino)-2-hydroxypropanesulfonic acid),
MOBS (4-(N-morpholino)-butanesulfonic acid), TAPSO
(3-(N-tris(hydroxymethyl)methylamino)-2-hydroxypropanesulfonic
acid), TRIZMA.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.
[0300] A complexation-enhancing agent can be added to the
compositions 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.
[0301] 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.
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
Opthalmology & Visual Science, (1996), 37(6), 1199-1203;
Proceedings of the International Symposium on Controlled Release of
Bioactive Materials (1996), 23 rd, 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 U.S. Pat. No. 5,324,718; International Journal of
Pharmaceutics (Netherlands), (Dec. 29, 1995) 126, 73-78; Abstracts
of Papers of the American Chemical Society, (02 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.
[0302] 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 insulin, 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.
[0303] An emulsifying agent is intended to mean a compound that
aids the formation of an emulsion. An emulsifier can be used to wet
the corticosteroid and make it more amenable to dissolution.
Emulsifiers for use herein include, but are not limited to,
polyoxyethylene sorbitan fatty esters or polysorbates, including,
but not limited to, polyethylene sorbitan monooleate (Polysorbate
80), polysorbate 20 (polyoxyethylene (20) sorbitan monolaurate),
polysorbate 65 (polyoxyethylene (20) sorbitan tristearate),
polyoxyethylene (20) sorbitan mono-oleate, polyoxyethylene (20)
sorbitan monopalmitate, polyoxyethylene (20) sorbitan monostearate;
lecithins; alginic acid; sodium alginate; potassium alginate;
ammonium alginate; calcium alginate; propane-1,2-diol alginate;
agar; carrageenan; locust bean gum; guar gum; tragacanth; acacia;
xanthan gum; karaya gum; pectin; amidated pectin; ammonium
phosphatides; microcrystalline cellulose; methylcellulose;
hydroxypropylcellulose; hydroxypropylmethylcellulose;
ethylmethylcellulose; carboxymethylcellulose; sodium, potassium and
calcium salts of fatty acids; mono- and di-glycerides of fatty
acids; acetic acid esters of mono- and di-glycerides of fatty
acids; lactic acid esters of mono- and di-glycerides of fatty
acids; citric acid esters of mono- and di-glycerides of fatty
acids; tartaric acid esters of mono- and di-glycerides of fatty
acids; mono- and diacetyltartaric acid esters of mono- and
di-glycerides of fatty acids; mixed acetic and tartaric acid esters
of mono- and di-glycerides of fatty acids; sucrose esters of fatty
acids; sucroglycerides; polyglycerol esters of fatty acids;
polyglycerol esters of polycondensed fatty acids of castor oil;
propane-1,2-diol esters of fatty acids; sodium
stearoyl-2-lactylate; calcium stearoyl-2-lactylate; stearoyl
tartrate; sorbitan monostearate; sorbitan tristearate; sorbitan
monolaurate; sorbitan monooleate; sorbitan monopalmitate; extract
of quillaia; polyglycerol esters of dimerised fatty acids of soya
bean oil; oxidatively polymerised soya bean oil; and pectin
extract.
[0304] 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, sodium saccharin and other known to those of ordinary
skill in the art.
[0305] As used herein, the term "viscosity modifier" is intended to
mean a compound or mixture of compounds that can be used to adjust
the viscosity of an aqueous liquid composition of the invention.
The viscosity modifier can increase or decrease the viscosity.
Suitable viscosity modifiers include HPMC, CMC (sodium
carboxymethylcellulose), glycerin, PEG and others recognized by
artisans in the field. In some embodiments, the composition
excludes HPMC.
[0306] 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 some embodiments, the tonicity of the
liquid formulation approximates the tonicity of the tissues in the
respiratory tract.
[0307] 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. 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 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).
[0308] 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.
[0309] 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.
[0310] 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.
[0311] Suitable surfactants include phospholipids, among other
compounds, which include for example phosphocholines or
phosphatidylcholines, in which the phosphate group is additionally
esterified with choline, furthermore phosphatidyl ethanolamines,
phosphatidyl inositols, lecithins. Other ionic surfactants which
can serve as solubility-enhancing agents are, for example, sodium
lauryl sulfate, sodium cetylstearyl sulfate, sodium (or calcium or
potassium) docusate, medium and long chain fatty acids.
[0312] SAE-CD can serve as a taste-masking agent by complexation
with poor-tasting molecule. For example, SAE-CD can complex with a
bitter or sour tasting active agent in a composition of the
invention to reduce the bitterness or sourness of the agent as
compared to the uncomplexed active agent. Accordingly, "improved
taste" or "taste-masking" is taken to mean a reduction in the
bitterness or sourness of a composition or active agent. Active
agents can differ in the native bitterness or sourness. For
example, olopatadine is known to have reduced bitterness as
compared to azelastine. The invention includes taste-masked
embodiments, wherein the SAE-CD is complexed with an active agent
having reduced bitterness or reduced sourness as compared to
another active agent.
[0313] In some embodiments, the methods, systems, devices, and
compositions of the invention are associated with improved taste of
a therapeutic agent as compared to the therapeutic agent alone or
in existing formulations. In some embodiments, the improved taste
is associated with administration of an antihistamine. In some
embodiments, the improved taste is associated with administration
of azelastine. The effectiveness of SAE-CD at masking the taste of
a drug can be determined, for example, according to Example 31,
which details the procedure used to conduct an electronic tongue
study on a composition comprising SBE-.beta.-CD and azelastine.
[0314] If desired, the composition further comprises an aqueous
liquid carrier other than water. Suitable organic solvents that can
be used in the formulation include, for example, ethanol, glycerin,
poly(ethylene glycol), propylene glycol, poloxamer, aqueous forms
thereof, others known to those of ordinary skill in the art and
combinations thereof.
[0315] 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).
[0316] 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.
[0317] 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.
[0318] 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 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; and/or 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.
[0319] 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., 2005, the relevant disclosure of
which is hereby incorporated by reference.
[0320] 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.
[0321] As used herein, the term "patient" or "subject" are taken to
mean humans and non-humans, such as mammals, for example, cats,
dogs, mice, guinea pigs, horses, bovine cows, and sheep.
[0322] The utility and therapeutic efficacy of a nasal aqueous
liquid composition according to the invention for the treatment of
seasonal allergic rhinitis (SAR)/conjunctivitis (SARC) was
demonstrated in a clinical trial conducted according to Example
33.
[0323] The time to target or peak therapeutic effect is the period
of time after administration of a dose that it takes for the active
agent to achieve the target or peak therapeutic effect,
respectively, in a subject. The onset of a target or desired
therapeutic effect is the point in time that the beginning of the
target or desired therapeutic effect is first observed in the
subject after administration of a composition.
[0324] In some embodiments, the compositions, methods, and systems
of the invention relieve non-nasal symptoms sooner and to a greater
degree than an aqueous suspension-based formulation comprising the
same unit dose of corticosteroid and administered under
substantially the same conditions but excluding SAE-CD. In some
embodiments, the compositions and systems provide more rapid relief
of nasal symptoms than the aqueous suspension based formulation.
The compositions and systems of the invention also provide
simplified manufacture, improved administered-dose uniformity, and
improved taste-masking and odor-masking as compared to the aqueous
suspension-based formulation. In some embodiments, the
compositions, methods, and systems of the invention provide an
enhanced and/or more rapid onset of a target or desired therapeutic
effect and/or a more rapid time to target, desired or peak
therapeutic effect as compared to the aqueous suspension-based
compositions, methods, or systems excluding SAE-CD.
[0325] A therapeutic effect will be observed following
administration of a composition. The onset of a target or desired
therapeutic effect is the point in time that the beginning of the
target or desired therapeutic effect is first observed in the
subject after administration of a composition. In some embodiments,
the onset of a target or desired therapeutic effect generally
occurs within 0.1 min to 120 min, 1 min to 90 min, 1 min to 60 min,
1 min to 30 min, 1 min to 20 min, 1 min to 15 min, or 1 min to 10
min after nasal or ophthalmic administration of the
composition.
[0326] In some embodiments, the time to a target or peak
therapeutic effect can occur from minutes to hours after
administration. In some embodiments, the time to target can occur
from 8 to 10 hours, within 1 to 2 days, or within 1 to 2 weeks
after nasal or ophthalmic administration of the composition, said
administration being conducted according to a dosing regimen as
detailed herein.
[0327] In some embodiments, the methods, systems, devices, and
compositions of the invention comprise a combination of
corticosteroid and azelastine with SAE-CD in a solution that is
useful for treating nasal, non-nasal, and ocular symptoms. In some
embodiments, the symptoms are allergic symptoms resulting from
exposure of a subject to an airborne allergen.
[0328] A clinical study according to Example 34 was conducted to
demonstrate the therapeutic efficacy of a nasal composition
comprising budesonide, azelastine hydrochloride, CAPTISOL and
buffer as compared to the sequential administration of RHINOCORT
AQUA (RA) and ASTELIN (AST).
[0329] In some embodiments, the nasal compositions, systems, and
methods of the invention comprising a corticosteroid, SAE-CD and an
antihistamine provides a therapeutic effect (clinical benefit) that
approximates or is enhanced over the therapeutic effect provided by
the separate and sequential nasal administration of: a) an aqueous
suspension composition comprising the same unit dose of
corticosteroid; and b) an aqueous composition comprising the same
unit dose of antihistamine. In some embodiments, the therapeutic
effect is relief of nasal, non-nasal and ocular allergic symptoms.
In some embodiments, the nasal composition, system and method of
the invention provide an improved quality of life in subjects
suffering from an allergic disorder, such as SAR and/or SARC.
[0330] The compositions, methods, and systems of the invention can
provide an enhanced therapeutic effect as compared to a
suspension-based aqueous formulation of corticosteroid. The
enhanced therapeutic effect can be: 1) enhanced or better relief of
non-nasal symptoms (especially ocular symptoms); 2) a more rapid
onset of therapeutic effect; 3) a more rapid time to peak or target
therapeutic effect; 4) more rapid relief of nasal symptoms; 5)
enhanced or better relief of nasal symptoms; 6) more rapid relief
of non-nasal symptoms; 7) enhanced quality of life, especially
emotional status or practical problems; and/or 8) reduced
corticosteroid-related side effects, such as epistaxis, dryness, or
burning.
[0331] In some embodiments, the corticosteroid solutions of the
invention provide more rapid relief of a symptom or disorder, such
as an allergic symptom or disorder, when compared with a
corticosteroid suspension at the same unit dose and under
substantially similar conditions. In some embodiments, the
corticosteroid solutions of the invention provide a rate of relief
that is about 25%, about 35%, about 45%, about 50%, about 60%, or
about 75% more rapid when compared with a corticosteroid suspension
at the same unit dose and under substantially similar conditions.
In some embodiments, the corticosteroid solutions of the invention
provide a rate of relief that is about 1.2-fold greater, about
1.5-fold greater, about 2-fold greater, about 2.5-fold greater,
about 3-fold greater, about 4-fold greater, or about 5-fold greater
than a corticosteroid suspension at the same unit dose and under
substantially similar conditions.
[0332] An in vivo study according to Example 41 was conducted in
rabbits to compare the ability of budesonide to provide an
anti-inflammatory therapeutic effect or other clinical benefit.
[0333] In some embodiments, the corticosteroid solutions of the
methods, systems, devices, and compositions of the present
inventions are administered ophthalmically for the treatment of
ocular symptoms. In some embodiments, the corticosteroid solutions
of the inventions are administered for the treatment of nasal
symptoms when administered ophthalmically.
[0334] In some embodiments, the corticosteroid solutions of the
invention provide more rapid relief in the treatment of ocular and
nasal symptoms compared to other corticosteroid solutions or
suspensions at the same unit dose when administered ophthalmically.
In some embodiments, the ocular symptom is inflammation. In some
embodiments, the corticosteroid solutions of the invention allow
for a more rapid reduction in ocular inflammation compared to other
corticosteroid solutions or suspensions when administered
ophthalmically. In some embodiments, the corticosteroid solutions
of the invention provide more rapid relief of total ocular symptoms
based on a Total Ocular Symptom Score (TOSS) using a visual
analogue scale (TOSS-VAS) of subjects or a five point scale (0-4)
of subjects with allergic conjunctivitis exposed to controlled
ragweed pollen using an EEC model compared with other
corticosteroid solutions or suspensions at the same unit dose when
administered ophthalmically. In some embodiments, the
corticosteroid solutions of the invention provide a greater relief
of TNSS compared with other corticosteroid solutions or suspensions
at the same unit dose when administered ophthalmically. In some
embodiments, the corticosteroid solutions of the invention provide
more rapid onset of action in the treatment of allergic rhinitis
compared with other corticosteroid solutions or suspensions at the
same unit dose when administered ophthalmically. In some
embodiments, the corticosteroid solutions of the invention provide
a reduced dose of corticosteroid to elicit an equivalent or greater
therapeutic effect as provided by other corticosteroid solutions or
suspensions at higher unit doses when administered ophthalmically.
In some embodiments, the corticosteroid solutions of the invention
provide improved dose uniformity among separate unit doses compared
to unit doses provided by other corticosteroid solutions or
suspensions when administered ophthalmically. In some embodiments,
the corticosteroid solutions of the invention are more easily
manufactured than other corticosteroid solutions or suspensions for
ophthalmic administration. In some embodiments the corticosteroid
solution for ophthalmic administration comprises one or more
additional therapeutic agents, such as an antihistamine. In some
embodiments, the corticosteroid solution additionally comprises
azelastine.
[0335] When comparing the performance of a liquid composition of
the invention to the performance of a suspension-based composition,
it is assumed that administration of the two compositions will be
conducted using the same administration device, the same unit dose
or total dose, substantially the same dosing regimen, and/or
substantially the same administration procedure.
[0336] All the various embodiments or options described herein can
be combined in any and all variations. In some embodiments, the
subject invention comprises combinations of SAE-CD, corticosteroid
and a pharmaceutically acceptable aqueous liquid carrier, which
specifically exclude one or more (but not all) of the SAE-CDs and
one or more (but not all) of the corticosteroids described herein.
In additional embodiments, the subject invention may comprise
combinations of SAE-CDs, corticosteroids, antihistamines and an
aqueous liquid carrier, said combinations specifically excluding
one or more of the antihistamines described herein.
[0337] 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
[0338] Exemplary formulations according to the invention were made
according to the following general procedures.
Method A
[0339] 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 a solution.
Method B
[0340] 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 a solution.
Method C
[0341] 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
a solution.
[0342] The methods of this example can 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
[0343] 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.
[0344] 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
[0345] 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.
[0346] 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
[0347] Any of the methods herein are conducted in the presence of
heat, e.g. at a temperature of least 40.degree. C.
Method G
[0348] 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
[0349] 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
[0350] Any of the methods herein are conducted under reduced
pressure.
Method J
[0351] The aqueous corticosteroid solution can be prepared by
diluting a concentrated corticosteroid solution with water, buffer,
or other aqueous liquid carrier.
Example 2
[0352] The MMD of nebulized solutions containing SBE7-.beta.-CD and
budesonide was determined as follows.
[0353] 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
[0354] The content of corticosteroid in aqueous solutions
containing SAE-CD was determined by HPLC chromatography of aliquots
periodically drawn from the liquid in storage.
[0355] Citrate-phosphate (McIlvaines) 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.
[0356] The HPLC conditions included:
TABLE-US-00009 Instrument: PE Series 200 Column: Phenomenex Luna
C18(2) 4.6 .times. 150 mm 3um 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
[0357] The viscosity of aqueous solutions containing SAE-CD was
measured using a cone and plate viscometer.
[0358] 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 sheared 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 shear.
Example 5
[0359] Nebulizer output rate as a function of SAE-CD concentration
was measured according to the following general procedure.
[0360] 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
[0361] Preparation of a solution containing budesonide.
[0362] 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
[0363] Preparation of a solution containing budesonide.
[0364] 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
[0365] Preparation of a solution containing budesonide.
[0366] 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
[0367] Preparation of a solution containing SAE-CD and budesonide
as prepared from a PULMICORT RESPULES suspension.
Method A
[0368] 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
[0369] 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
5) 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.
[0370] The liquid composition prepared according to any of these
methods can be used in any known administration device. By
converting the suspension to a liquid, an improvement in delivery
of budesonide (a corticosteroid) is observed.
Example 10
[0371] Other solutions according to the invention can be prepared
as detailed below.
TABLE-US-00010 Mg per mL Mg per mL (as prepared) (per target)
Component Concentrate A Concentrate B Final Solution Budesonide EP
1 ~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 0 0 0-1 (TWEEN 80) Water Qs
Qs QS with buffer containing CAPTISOL or budesonide
[0372] 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%). [0373] 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
[0374] 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
[0375] The following method was used to determine the performance
of nebulization compositions emitted from a nebulizer.
[0376] 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 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.
[0377] The procedure above can be practiced with slight
modification on a MALVERN SPRAYTEC to determine the particle size
of droplets emitted by a nebulizer.
Example 13
[0378] 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
[0379] (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-00011 Instrument: PE Series 200 Column: Phenomenex Luna
C18(2) 4.6 .times. 150 mm 3um 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
[0380] Preparation of solution comprising SAE-CD (10% wt.),
budesonide (500 .mu.g/mL), and azelastine hydrochloride (0.2%
wt.).
[0381] CAPTISOL (2.37 g) was weight into an amber vial. Azelastine
hydrochloride (43.8 mg) was weighed into the same vial. PULMICORT
NEBUAMPs (10) were mixed vigorously for 1 min. The contents of each
NEBUAMP were dispensed into the amber vial containing CAPTISOL and
azelastine and mixed by vortexing, shaking, sonication and
overnight mixing on a roller mixer to permit equilibration. The
resulting solution was clear.
Example 15
[0382] The temperature stability of the composition of Example 14
was determined as follows.
[0383] The solution of Example 14 was divided into vials and
grouped and stored at 25.degree. C., 40.degree. C., or 60.degree.
C. A control sample was stored at 5.degree. C. The samples were
stored for 10 days and two vials were removed for analysis at 0, 3,
and 10 days. Assay samples were prepared by drawing one aliquot
from each vial, diluting 200 .mu.L with 800 .mu.L of mobile phase
(see below), and assaying the samples by HPLC according to the
European Pharmacopeia, Monograph 1633E for "azelastine
hydrochloride" (version 5.0 corrected January 2005).
Example 16
[0384] The pH and temperature stability of an aqueous liquid
composition comprising SAE-CD, azelastine, and buffer were
determined as follows.
[0385] Aqueous solutions comprising azelastine HCl (0.5 mg/mL) with
and without CAPTISOL (1.75% wt.) were prepared. Stock citrate
solutions (sodium citrate (3 mM) and citric acid solution (3 mM);
500 mL each) were prepared. The citrate solutions were combined and
titrated to prepare stock buffered solutions (at least 150 mL each)
having a pH of 4, 5, or 6. A stock solution of azelastine
hydrochloride (5 mg/mL) in water was prepared. Assay solutions
comprising CAPTISOL, azelastine and buffer were prepared by mixing
CAPTISOL (1.4 g) and stock solution of azelastine (7.5 mL) in stock
buffered solution (QS to final volume of 75 mL for each different
pH). Assay solutions comprising azelastine and buffer were prepared
by mixing stock solution of azelastine (7.5 mL) and stock buffered
solution (67.5 mL, or QS to final volume of 75 mL). Six assay
solutions were prepared as follows: 1) pH 4-azelastine only; 2) pH
4-azelastine+CAPTISOL; 3) pH 5-azelastine only; 4) pH
5-azelastine+CAPTISOL; 5) pH 6-azelastine only; 6) pH
6-azelastine+CAPTISOL. Portions of each assay solution were stored
at 25.degree. C., 40.degree. C., and 60.degree. C. for a period of
sixteen weeks. Aliquots of the assay solutions were taken at 0, 1,
2, 4, 8, 12, and 16 weeks. The aliquots were assayed by HPLC as
described herein. Control samples for each assay solution were
stored at 5.degree. C. to provide reference points.
Example 17
[0386] Exemplary compositions of the invention packaged in various
multi-dose volume metered dose pump spray devices are made to
include the following ingredients in the amounts specified
according to the procedure below.
TABLE-US-00012 100 .mu.L 137 .mu.L 50 .mu.L Spray 70 .mu.L Spray
Spray Spray Ingredient Function (mg/mL) (mg/mL) (mg/mL) (mg/mL)
Budesonide Active Substance 0.64 0.46 0.32 0.234 CAPTISOL
Solubilizer/Stabilizer 96 68 48 36 Disodium edetate, Antioxidant
0.1 0.1 0.1 0.1 Sodium chloride, Tonicity modifier 0 27 45 56
Citric acid, Buffer 0.3 0.3 0.3 0.3 Sodium citrate Buffer 0.5 0.5
0.5 0.5 dihydrate Polysorbate 80 Surfactant optional optional
optional optional 0.05 mg/mL Potassium Sorbate Antimicrobial
optional optional optional optional 1 mg/mL Sterile water for
Solvent q.s. to 1.0 mL q.s. to 1.0 mL q.s. to 1.0 mL q.s. to 1.0 mL
injection, Budesonide Active Substance 0.64 0.46 0.32 0.234
Azelastine HCl Active Substance 2.74 1.96 1.37 1.00 CAPTISOL
Solubilizer/Stabilizer 128 91 64 48 Disodium edetate, Antioxidant
0.1 0.1 0.1 0.1 Sodium chloride, Tonicity modifier 0 27 45 56
Citric acid, Buffer 0.3 0.3 0.3 0.3 Sodium citrate Buffer 0.5 0.5
0.5 0.5 dihydrate Polysorbate 80 Surfactant optional optional
optional optional 0.05 mg/mL Potassium Sorbate Antimicrobial
optional optional optional optional 1 mg/mL Sterile water for
Solvent q.s. to 1.0 mL q.s. to 1.0 mL q.s. to 1.0 mL q.s. to 1.0 mL
injection,
[0387] Compositions comprising the specified concentrations of
ingredients are prepared and packaged into multi-dose metered
volume pump spray devices. The compositions optionally comprise
potassium sorbate at a concentration of about 1 mg/mL and/or
polysorbate 80 at a concentration of about 0.005%. Each package
contains approximately 120 doses plus an overfill of the
composition. Suitable packages for the specified spray volumes
include: [0388] 1. 50 .mu.L Spray volume: 9 mL of composition in a
10 mL bottle; for example 20242 02 001 diagnostic 6/8 amber glass
type 1 400 20 neck finish bottle fitted with Nasal Spray Pump
having a 50 .mu.L dose volume, 20/400 screw closure, and 42.0 mm
dip tube length; [0389] 2. 70 .mu.L Spray volume: 13 mL of
composition in a 15 mL amber glass bottle; [0390] 3. 100 .mu.L
Spray volume: 17 mL of composition in a 20 mL amber glass vial;
[0391] 4. 137 .mu.L Spray volume: 24 mL of composition in a 24 mL
amber glass vial.
Example 18
[0392] Comparative evaluation of various forms of SAE-CD in the
solubilization of corticosteroid derivatives.
[0393] 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.
[0394] 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-00013 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)
[0395] 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.
[0396] 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.
[0397] 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.
[0398] 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. The data are detailed
below.
TABLE-US-00014 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
[0399] 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. 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. 5. Therefore, it has been determined that
SAE-.gamma.-CD cyclodextrin derivatives are unexpectedly better at
solubilizing corticosteroids than are SAE-O-CD derivatives.
Formulations based upon SAE-.gamma.-CD are suitable for use in the
compositions of the invention.
Example 19
[0400] Determination of the phase solubility of budesonide in the
presence of SAE-CD and azelastine hydrochloride.
[0401] A stock solution of citrate buffer (3 mM, pH 4.5) was
prepared. Stock solutions of CAPTISOL in buffer having CAPTISOL
present in the varying concentrations (10 mM, 20 mM, 30 mM, and 40
mM) were prepared by mixing appropriate amounts of CAPTISOL and the
buffer stock solution. The stock solutions of CAPTISOL in buffer
were used to prepare stock solutions of azelastine
HCl/CAPTISOL/buffer having 1 mg/mL, 1.37 mg/mL, 1.96 mg/mL, or 2.74
mg/mL azelastine HCl. Budesonide (at a concentration of 2 mg/mL)
was added to the various stock solutions of azelastine
HCl/CAPTISOL/buffer and mixed and allowed to equilibrate at ambient
temperature for a period of four days. Any budesonide remaining
suspended in the solutions was removed by filtration and the
concentration of budesonide in each solution measured by HPLC as
described herein. The results are depicted in FIG. 11A.
[0402] The above procedure was repeated with 10 mM, 15 mM and 20 mM
solutions of SBE-.gamma.-CD and only one concentration of
azelastine HCl (2.74 mg/mL). The data are summarized in FIG.
11B.
Example 20
[0403] Exemplary compositions of the invention packaged in various
multi-dose volume metered dose pump spray devices and nebulizers
are made to include the following ingredients in the amounts
specified according to the procedure below.
TABLE-US-00015 For a 50 .mu.L For a 70 .mu.L For a 100 .mu.L 200
.mu.L 5000 .mu.L Spray Spray Spray Ampoule Ampoule Ingredient.sup.1
Function (mg/mL) (mg/mL) (mg/mL) (mg/mL) (mg/mL) Mometasone Active
Substance 1.0 0.71 0.50 1.00 0.1 Furoate Olopatadine Active
Substance 13.3 9.5 6.65 26.6 1.3 HCl SBE .gamma.-CD
Solubilizer-Stabilizer 452/500 323/429 226/300 452/500 45.2/60
Nominal/Practical amts Disodium Antioxidant 0.1 0.1 0.1 0.1 0.1
edetate, dihydrate Citric acid, Buffer 0.3 0.3 0.3 0.3 0.3 Sodium
Buffer 0.5 0.5 0.5 0.5 0.5 citrate dihydrate Sterile water Solvent
q.s. to 1.0 mL q.s. to 1.0 mL q.s. to 1.0 mL q.s. to 1.0 mL q.s. to
1.0 mL for injection,
[0404] To prepare the above formulation, the mometasone furoate and
olopatadine HCl are dissolved using SBE(6.1) .gamma.-CD and citrate
buffer at about pH 4.5. Vigorous mixing and sonication may be
required for a day or more under an inert atmosphere to effect
total dissolution. If after assaying the solution it is determined
to be below the desired target for the active ingredients,
additional active ingredient can be added to the solution and
stirring continued. Once both drugs have dissolved completely in
the CD solution, confirmed by assay, the product is filtered using
a 0.22 .mu.m PVDF filter. The solution is then dispensed under an
inert atmosphere into a preservative free multidose container
fitted with a suitable pump spray or filled into blow-fill-seal
LDPE containers for use in a suitable nebulizer or as a drop.
Optionally, compositions could contain potassium sorbate present at
a concentration of about 1 mg/mL and or polysorbate 80 present at a
concentration of about 0.005% and be filled in suitable multi dose
containers and fitted with a suitable metering pump spray
device.
[0405] Each package contains approximately 120 doses plus an
overfill as defined herein. Suitable packages for the specified
spray volumes include: [0406] 1. 50 .mu.L Spray volume: 9 mL of
composition in a 10 mL bottle; for example 20242 02 001 diagnostic
6/8 amber glass type 1 400 20 neck finish bottle fitted with Nasal
Spray Pump having a 50 .mu.L dose volume, 20/400 screw closure, and
42.0 mm dip tube length; [0407] 2. 70 .mu.L Spray volume: 13 mL of
composition in a 15 mL amber glass bottle; [0408] 3. 100 .mu.L
Spray volume: 17 mL of composition in a 20 mL amber glass vial;
[0409] 4. 200 .mu.L ampoule: a single blow-fill-seal LDPE (or
comparable substance ampoule used for nebulization; [0410] 5. 5000
.mu.L ampoule: a single blow-fill-seal LDPE (or comparable
substance ampoule used for nebulization.
Example 21
[0411] Evaluation of the AERONEB GO nebulizer versus a RAINDROP
nebulizer with a solution comprising budesonide, aqueous liquid
carrier and SAE-CD.
[0412] 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.
[0413] The RAINDROP nebulizer is available from Nellcor (Tyco
Healthcare).
[0414] The solution of the invention used for this study was
prepared according to Example 28.
[0415] Characterization of droplet size distribution of an
aerosolized solution using a cascade impactor was determined
according to Example 26.
[0416] 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
[0417] 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 Budesonide Aerosols
Generated via a Pari Electronic Nebulizer
[0418] 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.
[0419] 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 Budesonide Nasal 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. 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.
[0420] 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 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
[0421] 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
[0422] 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.
[0423] 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.
[0424] 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
[0425] On each occasion, the nebulizer weight was recorded after
delivery of the dose. The nebulizer was imaged as described
below.
Image Processing
[0426] 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.
[0427] A rectangular ROI was also applied to the USP Inlet
image.
[0428] 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).
[0429] 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
[0430] The expelled contents of five PULMICORT RESPULES (1 mg/mL)
were combined together. CAPTISOL (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.
[0431] The mixture was vortexed briefly to disperse and dissolve
the CAPTISOL. 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
then 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 Budesonide Nasal Solution and vortexed
briefly.
Example 23
[0432] Determination of the phase solubility curve for
corticosteroid dissolution with SAE-CD.
[0433] The solubility of corticosteroid solutions containing SAE-CD
was determined by HPLC chromatography of aliquots from equilibrated
filtered or centrifuged corticosteroid solutions as follows.
[0434] 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. The
results are detailed below.
TABLE-US-00016 [Fluticasone] .times. [Mometasone] .times. 10.sup.5M
10.sup.5M [Triamcinolone as non As non [Budesonide] .times.
acetonide] .times. -CD [CD] M propionate esterified furoate
esterified 10.sup.5M 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
Solubility of Selected Steroids Enhanced by Alpha-Cyclodextrins
TABLE-US-00017 [0435] [Fluticasone] .times. 10.sup.5M [Mometasone]
.times. 10.sup.5M [Triamcinolone as non non [Budesonide] .times.
acetonide] .times. -CD [CD] M propionate esterified as furoate
esterified 10.sup.5M 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
Solubility of Selected Steroids Enhanced by Gamma-Cyclodextrins
TABLE-US-00018 [0436] [Fluticasone] .times. [Mometasone] .times.
10.sup.5M 10.sup.5M [Triamcinolone as non as non [Budesonide]
.times. acetonide] .times. -CD [CD] M propionate esterified furoate
esterified 10.sup.5M 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
[0437] The phase solubility data, determined according to this
example or Example 18, can be used to determine the molar ratio of
SAE-CD to corticosteroid necessary to dissolve the corticosteroid
in an aqueous medium. The table below details relevant molar ratio
data.
TABLE-US-00019 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 86 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 X-1 corticosteroid SAE-.beta.-CD 190
X-1 corticosteroid SAE-.gamma.-CD 1390 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 78 Fluticasone Propionate SAE-.alpha.-CD 501
Hydrocortisone SAE-.beta.-CD 1.6 Hydrocortisone SAE-.gamma.-CD 1.8
Methylprednisolone SAE-.beta.-CD 5.7 Methylprednisolone
SAE-.gamma.-CD 3.4 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
Prednisolone SAE-.beta.-CD 2.2 Prednisolone SAE-.gamma.-CD 2
Prednisone SAE-.beta.-CD 2.2 Prednisone SAE-.gamma.-CD 3.2
Triamcinolone acetonide SAE-.beta.-CD 8.8 Triamcinolone acetonide
SAE-.gamma.-CD 3.8 *This value was determined in the presence of
SAE-CD under the conditions detailed in Example 18 or this
example.
Example 24
[0438] Exemplary compositions of the invention packaged in various
multi-dose volume metered dose pump spray devices are made to
include the following ingredients in the amounts specified
according to the procedure below.
TABLE-US-00020 50 .mu.L 70 .mu.L 100 .mu.L 200 .mu.L 5000 .mu.L
Spray Spray Spray Ampule Ampule Ingredient.sup.1 Function (mg/mL)
(mg/mL) (mg/mL) (mg/mL) (mg/mL) Fluticasone Active Substance 1.0
0.71 0.50 1.00 0.1 Propionate Cetirizine HCl Active Substance 22
15.7 11 11 0.22 SBE .gamma.-CD Solubilizer- 452/500 323/429 226/300
452/500 45.2/60.0 Stabilizer nominal/practical Disodium Antioxidant
0.1 0.1 0.1 0.1 0.1 edetate, dihydrate Citric acid, Buffer 0.3 0.3
0.3 0.3 0.3 Sodium citrate Buffer 0.5 0.5 0.5 0.5 0.5 dihydrate
Sterile water Solvent q.s. to 1.0 mL q.s. to 1.0 mL q.s. to 1.0 mL
q.s. to 1.0 mL q.s. to for injection, 1.0 mL
[0439] To prepare the above formulation, the fluticasone propionate
and cetirizine HCl are dissolved using SBE .gamma.-CD and citrate
buffer at about pH 4.5 to 5. Vigorous mixing and sonication may be
required for a day or more under an inert atmosphere to effect
total dissolution. If after assaying the solution it is determined
to be below the desired target for the active ingredients,
additional active ingredient can be added to the solution and
stirring continued. Once both drugs have dissolved completely in
the CD solution, confirmed by assay, the product is filtered using
a 0.22 .mu.m PVDF filter. The solution is then dispensed under an
inert atmosphere into a preservative free multidose container
fitted with a suitable pump spray or filled into blow-fill-seal
LDPE containers for use in a suitable nebulizer or as drops.
Optionally, compositions can contain potassium sorbate present at a
concentration of about 1 mg/mL and/or polysorbate 80 present at a
concentration of about 0.005% and be filled in suitable multi-dose
containers and fitted with a suitable metering pump spray
device.
[0440] Suitable packaging is detailed in Example 20. The packaging
can be in a preservative free pump spray system such as the
Advanced Preservative Free system from Pfeiffer, or the Freepod
from Valois, or in a single use pump spray device such as the
Pfeiffer Bidose System or Unitdose System. For the nebulized
solutions the Kurve ViaNase.TM. or another comparable nasal
nebulizer device could be used.
Example 25
[0441] A composition comprising a corticosteroid and antifungal
agent is prepared as follows.
[0442] The following ingredients are combined in the amounts
indicated.
TABLE-US-00021 1 mL vial 2 mL vial 5 mL vial Ingredient Function
(mg/mL) (mg/2 mL) (mg/5 mL) Budesonide Active Substance 0.05 0.1
0.25 Voriconazole Active Substance 10 20 50 CAPTISOL
Solubilizer/Stabilizer 165 330 825 Disodium Antioxidant 0.1 0.2 0.5
edetate dehydrate Citric acid, Buffer 0.3 0.6 1.5 Sodium citrate
Buffer 0.5 1.0 2.5 dihydrate Sterile water for Solvent q.s. to 1.0
mL q.s. to 2.0 mL q.s. to 5.0 mL injection* *The water is removed
during processing by lyophilization or spray drying or other
suitable drying technique to form a powdered composition. Hence the
contents are reconstituted just prior to use.
Example 26
[0443] A composition comprising a corticosteroid and antimicrobial
agent is prepared as follows.
TABLE-US-00022 Method A. For 50 .mu.L For 70 .mu.L For 100 .mu.L
200 .mu.L 5000 .mu.L Spray Spray Spray Ampoule Ampoule Ingredient
Function (mg/mL) (mg/mL) (mg/mL) (mg/mL) (mg/mL) Budesonide Active
Substance 0.64 0.46 0.32 0.16 0.0064 Azithromycin Active Substance
0.4 0.29 0.2 0.1 0.004 CAPTISOL Solubilizer/ 64 46 32 16 0.64
Stabilizer Disodium Antioxidant 0.1 0.1 0.1 0.1 0.1 edetate
dehydrate Citric acid, Buffer 0.3 0.3 0.3 0.3 0.3 Sodium Buffer 0.5
0.5 0.5 0.5 0.5 citrate dehydrate Sterile water Solvent q.s. to 1.0
mL q.s. to 1.0 mL q.s. to 1.0 mL q.s. to 1.0 mL q.s. to 1.0 mL for
injection
[0444] To prepare the above formulation the budesonide and
azithromycin is dissolved using CAPTISOL and citrate buffer at
about pH 4.5. Vigorous mixing and sonication may be required for a
day or more under an inert atmosphere to effect total dissolution.
If after assaying the solution it is determined to be below the
desired target for the active ingredients, additional active
ingredient can be added to the solution and stirring continued.
Once both drugs have dissolved completely in the CD solution,
confirmed by assay, the product is filtered using a 0.22 .mu.m PVDF
filter. The solution can then be dispensed under an inert
atmosphere into a preservative free multidose container fitted with
a suitable pump spray or filled into blow-fill-seal LDPE containers
for use in a suitable nebulizer or as a drop. Optionally,
compositions can contain potassium sorbate present at a
concentration of about 1 mg/mL and/or polysorbate 80 present at a
concentration of about 0.005% and be filled in suitable multi-dose
containers and fitted with a suitable metering pump spray device.
Suitable packaging is detailed in Example 24.
TABLE-US-00023 Method B. 1 mL vial 2 mL vial 5 mL vial Ingredient
Function (mg/mL) (mg/mL) (mg/mL) Budesonide Active Substance 0.05
0.1 0.25 Azithromycin Active Substance 10 20 100 CAPTISOL
Solubilizer/Stabilizer 7.5 15 37.5 Disodium Antioxidant 0.1 0.2 0.5
edetate dihydrate Citric acid, Buffer 0.3 0.6 1.5 Sodium citrate
Buffer 0.5 1.0 2.5 dihydrate Sterile water for Solvent q.s. to 1.0
mL q.s. to 2.0 mL q.s. to 5.0 mL injection* *The water is removed
during processing by lyophilization or spray drying or other
suitable drying technique to prepare a powdered composition. Hence
the contents are reconstituted just prior to use.
Example 27
[0445] A powdered composition of budesonide and azelastine can be
prepared as follows.
[0446] The following ingredients are combined in the amounts
indicated to prepare an active composition.
TABLE-US-00024 Amount needed Ingredient Function (mg/mL) Budesonide
Active Substance 0.457 Azelastine HCL Active Substance 1.96
CAPTISOL Solubilizer/Stabilizer 100 Disodium Antioxidant 0.1
edetate, (0.05 to 0.15) dihydrate Citric acid Buffer 0.3 Sodium
citrate Buffer 0.5 dihydrate (0.45 to 0.55) Sterile water Solvent
q.s. to 1 mL for injection,* *Water is removed during processing by
lyophilization or spray drying or other suitable technique. If
necessary, the concentration used for the processing method can be
adjusted to assist in achieving the desired particle size.
[0447] The budesonide and azelastine HCL are dissolved in the
CAPTISOL and citrate buffer (about pH 4.5) using a vigorous
stirring method. During processing and packaging the liquid product
is further protected using an inert atmosphere. In addition the
water used for the process may be sparged with nitrogen to reduce
oxygen. Once both drugs are dissolved, the solution is lyophilized
using a suitable method that will produce a stable, uniform cake.
The lyophilized product is then sized to obtain an average particle
size of Dv(50) between 10-100 .mu.m or about 65 .mu.m as the active
composition.
[0448] The active composition can be mixed with a bulking agent to
prepare a powder formulation for administration with an
administration device capable of emitting and nasally delivering
the powder. The powder formulation can be prepared according to the
table below.
TABLE-US-00025 20 mg Powder 50 mg Powder Ingredient Function Nasal
Aerosol Nasal Aerosol Actives Active Substances 7.225 mg 7.225 mg
Composition (Includes: (0.032 mg, (0.032 mg, (see below)
budesonide, 0.137 mg) 0.137 mg) azelastine) Lactose Diluent/Bulking
12.775 mg 42.775 mg Agent
[0449] The following procedure can be used. A bulking agent, such
as lactose suitable for inhalation (Lactohale.RTM.), is dry mixed
with the sized lyophilized product to provide a total administered
amount of 20 to 50 mg as needed for a unit dose powder nasal spray
such as the Monopowder (Valois) or DirectHaler.TM.
(DirectHaler).
Example 28
[0450] Preparation of a liquid formulation comprising SAE-CD and
budesonide, optionally containing TWEEN.
[0451] 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.
[0452] 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.
[0453] 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.
[0454] 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 inspiration by a subject) via
nebulization.
Example 29
[0455] Preparation and dissolution of a lyophilized formulation
comprising SAE-CD and budesonide.
[0456] An excess of budesonide, 3.5 mg/mL, was added to 3 L 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.
[0457] 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
[0458] Preparation of an aqueous liquid formulation comprising
SAE-CD, ethanol and budesonide.
[0459] 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
[0460] An electronic tongue study can be conducted as follows to
determine the effectiveness of SAE-CD at masking the bitter taste
of an active agent, such as azelastine.
[0461] The e-tongue (Astree II, Alpha M.O.S., Toulouse, France) has
been used to demonstrate an increasing change in the taste of
azelastine HCl solution upon the addition of increasing amounts of
CAPTISOL. Solutions containing 2 mg/mL azelastine HCL in 3 mM, pH=4
citrate buffer, with different amounts of CAPTISOL were prepared.
The e-tongue uses a seven-sensor probe assembly to detect dissolved
organic and inorganic compounds. The probes consist of a silicon
transistor with proprietary organic coatings, which govern the
probe's sensitivity and selectivity. Measurement is potentiometric,
with readings taken against an Ag/AgCl reference electrode. Samples
are placed in an autosampler carrousel where the electrodes are
introduced into each sample. Each probe is cross-selective to allow
coverage of full taste profile. The system samples, quantifies,
digitizes, and records potentiometer readings. Taste cognition
happens not in the probe, but in the computer, where the e-tongue's
statistical software interprets the sensor data into taste
patterns. The distance from the azelastine HCL in buffer to the
solutions containing 5%, 10% or 15% CAPTISOL were 334.03, 418.96,
and 491.76 respectively indicating a large change in taste.
Example 32
[0462] To investigate how the incorporation of CAPTISOL at 5% w/v
into PULMICORT RESPULES impact performance of different types of
nebulizers.
[0463] 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:
[0464] 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 [0465] 2) Summing the amount of
budesonide on the cascade impactor stages after nebulization.
[0466] The results are detailed below. (ND means "not
determined.)
TABLE-US-00026 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% 247.4 .+-. 11.3 172.4 .+-. 6.6 CAPTISOL Omron MicroAir NE-U22
Pulmicort 179.9 .+-. 17.2 168.8 .+-. 30.1 Pulmicort + 5% 380.1 .+-.
8.5 349.6 .+-. 10.0 CAPTISOL AirSep Mystique (Ultrasonic) Pulmicort
32.9 .+-. 6.4 ND* Pulmicort + 5% 120.8 .+-. 19.6 ND* CAPTISOL
Aerogen AeroNeb Pulmicort 90.7 .+-. 4.5 ND* Pulmicort + 5% 301.2
.+-. 19.5 ND* CAPTISOL
Example 33
[0467] A clinical trial was conducted to evaluate the performance
of a formulation of the invention in the treatment of nasal
symptoms and non-nasal symptoms caused by exposure of subjects to
an allergen.
[0468] Three aqueous based formulations were made: Solution
A--comprising CAPTISOL, budesonide and aqueous liquid carrier;
Suspension B--comprising RHINOCORT AQUA suspension of budesonide in
aqueous liquid carrier; and Solution C (placebo)--comprising
buffered saline. Solution A was made by mixing two NEBUAMPS (500
.mu.g/mL nominal) to a bottle containing 348 mg CAPTISOL, followed
by mixing overnight to form a solution containing 424 .mu.g/mL of
budesonide and 75 mg/mL of CAPTISOL in a total volume of 4.4 mL.
Solution B was purchased and used as is (32 .mu.g of budesonide per
spray) using a spray volume of 50 .mu.l with the supplied valve.
Bottles containing Solutions A and C were equipped with a 70 .mu.l
Pfeiffer spray valve. Bottles were masked prior to use. Solutions A
and B were administered at a dose of 32 .mu.g per spray. Dosing of
Solutions A or C or Suspension B was as a single spray in each
nostril.
[0469] The bulk solution concentration of budesonide in Solution A
ranged from 418-439 .mu.g/mL with an average of 432.+-.6 .mu.g/mL.
Based upon HPLC analysis, each spray of Solution A contained about
31 .mu.g of budesonide.
[0470] Clinical Protocol.
[0471] A randomized, double-blind, placebo-controlled,
single-center, three-way cross-over study was conducted to compare
the relative efficacy of budesonide, administered via nasal spray
using Solution A and Solution B, with Solution C as the placebo
control, in the treatment of SAR in an environmental exposure
chamber. Sixty five subjects were enrolled in the study and exposed
to ragweed pollen using an EEC model. The total nasal symptom score
(TNSS) and total non-nasal symptom score (TNNSS) for each subject
was determined. A graphical summary of the study protocol is
depicted in FIG. 7. Patients were exposed to 3000 to 4000 particles
per cubic meter of ragweed pollen using an Environmental Exposure
Chamber model of the disease. After the initial exposure to pollen,
patients were then treated with Solution A (CAPTISOL, budesonide,
aqueous carrier solution), Suspension B (RHINOCORT AQUA:
budesonide, aqueous carrier suspension), or Solution C (saline
placebo) in a crossover design. Each patient remained in the
chamber exposed to pollen and rated their nasal symptom and their
non-nasal symptoms over a period of 10 hours.
[0472] The primary objective of the study was to compare the
relative efficacy of budesonide administered via CAPTISOL-ENABLED
Budesonide nasal solution and RHINOCORT AQUA in patients with SAR
exposed to controlled ragweed pollen using an EEC model. Secondary
objectives of the study were to: 1) assess the onset of action of
Solution A and Solution B as compared to placebo; 2) compare the
tolerance of each as determined by patient questionnaire and
adverse events recorded; and 3) compare the effect of the three
solutions on the EEC-specific Quality of Life Questionnaire
(EEC-QOLQ).
[0473] This was a randomized, double-blind, placebo-controlled,
single-center, 3-way cross-over study with three periods of
two-four 3 h priming visits followed by a 12 h treatment visit.
Following an initial 30-minute exposure to ragweed pollen in the
EEC, the patients evaluated four nasal symptoms (itchy nose, runny
nose, congestion and sneezing) and four non-nasal symptoms
(itchy/gritty eyes, tearing/watery eyes, red/burning eyes, and
itchy ears/palate) every 30 minutes for 1.5 hours to determine
adequate baseline symptoms. Each symptom was rated on a scale of 0
to 3 (none, mild, moderate, and severe). Patients who met the
predetermined minimum TNSS score of 6 out of a maximum of 12,
including a minimum score of 2 out of 3 for runny nose on the last
two diary cards prior to treatment, were randomized to receive one
of three treatments in a double-blind manner. Patients who did not
meet the predetermined TNSS were not dosed and were withdrawn from
the study.
[0474] Following administration of the study drug, the patients
were asked to assess their NSS (nasal symptom score), OSS (ocular
symptom score), and NNSS (non-nasal symptom score) at 15, 30, 45,
60, 90 and 120 minutes post dosing; then every hour up to 10 hours
post-dose. TSS was the sum score of 4 nasal symptoms: runny-,
itchy-, stuffy-nose and sneezing; and 4 non-nasal symptoms: 3
ocular symptoms (TOSS): redness, itching, tearing and 1 non-nasal,
non-ocular: itchy ears/palate. During the entire time the patients
were in the EEC, they were exposed to ragweed pollen at a
concentration of 3500.+-.500 particles per m.sup.3.
[0475] Patients rated nasal symptoms (rhinorrhea, nasal congestion,
nasal itchiness, and sneezing) and non-nasal symptoms (itchy/gritty
eyes, tearing/watery eyes, red/burning eyes, itchy ears and
palate). See FIGS. 6A-6C and 6F. Area under the curve (AUC) was
calculated based on the mean change from baseline for TNSS, TNNSS
and TSS and was compared using analysis of covariance. See FIGS.
6G, 6H and 6I. Secondary efficacy assessed the onset of action of
CAPTISOL-ENABLED Budesonide compared to RHINOCORT AQUA and placebo.
The TNSS and TNNSS scores were then totaled. This data was
evaluated to determine efficacy and speed of action.
[0476] The effect of CAPTISOL-ENABLED Budesonide compared to
placebo on ocular symptoms was determined. The mean AUC for
itchy/gritty eyes demonstrated significant efficacy of
CAPTISOL-ENABLED Budesonide (-4.21.+-.7.00) over placebo
(-2.10.+-.6.62) (p=0.042). The mean AUC for tearing/watery eyes
also demonstrated significant efficacy of CAPTISOL-ENABLED
Budesonide (-3.05.+-.7.08) over placebo (-1.67.+-.6.66) (p=0.047).
Unlike CAPTISOL-ENABLED Budesonide, micronized suspension
(RHINOCORT AQUA) did not demonstrate significant efficacy compared
to placebo in ocular symptoms. The effect of CAPTISOL-ENABLED
Budesonide compared to placebo on itchy/gritty eyes was greatest at
timepoints 1.5, 2 and 3 hr post-dose with changes from baseline of
-0.70.+-.0.84 (p=0.031), -0.67.+-.0.83 (p=0.020) and -0.58.+-.0.83
(p=0.044), respectively. Similarly, the effect on tearing/watery
eyes was greatest at 3 hr with changes from baseline of
-0.55.+-.0.89 (p=0.004) and the effect on red/burning eyes was
greatest at 0.5, 1 and 2 hr with changes from baseline of
-0.47.+-.0.74 (p=0.010), -0.58.+-.0.88 (p=0.030) and -0.55.+-.0.97
(p=0.022), respectively. Based on the mean change from baseline,
the onset of action for CAPTISOL-ENABLED Budesonide for improvement
in itchy/gritty eyes was 1.5 hr. CAPTISOL-ENABLED Budesonide also
demonstrated significance on itchy/gritty eyes over RHINOCORT AQUA
at 0.5 hr (p=0.008) and 0.75 hr (p=0.014). The data for these
symptoms is summarized in FIGS. 6D-6E.
[0477] In FIG. 6F, the MCFB in TSS was greater at hours 0.25, 0.5,
0.75, 1.0, and 1.5 for CAPTISOL-ENABLED Budesonide (-2.33, -4.01,
-4.30, -4.57, -4.77 and -4.86, respectively) than for RHINOCORT
AQUA (-1.5, -2.34, -2.95, -3.43, -4.03, and -3.91, respectively)
with an onset of action of 0.5 h compared to 4 h onset for
RHINOCORT AQUA.
[0478] The mean AUC TNSS was significant for CAPTISOL-ENABLED
Budesonide (-18.02.+-.22.7) versus placebo (-11.12.+-.23.1)
(p=0.036). Likewise, AUC TNSS for RHINOCORT AQUA was -18.23.+-.27.2
versus placebo at -11.+-.23.1 At 0.25 h, 0.5 h and 0.75 h, the mean
change from baseline TNSS was greater for CAPTISOL-ENABLED
Budesonide (-1.22, -2.11, -2.27 respectively) than for RHINOCORT
AQUA (-0.87, -1.44, -1.73, respectively) with an onset of action
for ocular symptoms at 0.5 h. RHINOCORT AQUA had no onset of action
for ocular symptoms. Overall TNNSS AUC was significant (p=0.012)
for CAPTISOL-ENABLED Budesonide (mean decrease of -16.61.+-.27.3)
compared to placebo (-7.62.+-.24.0) (p values <0.05). Of note,
at 0.5 h, 0.75 h and 1 h, the changes from baseline for the
CAPTISOL-ENABLED Budesonide were -1.90.+-.2.41, -2.03.+-.2.92 and
-2.41.+-.3.11, respectively (all p values <0.05 compared to
RHINOCORT AQUA and placebo). The onset of action of
CAPTISOL-ENABLED Budesonide versus RHINOCORT AQUA and placebo was
significantly different at 0.5 h-1 h (p values <0.05). No deaths
or clinically significant adverse events were reported in this
study. The CAPTISOL-ENABLED Budesonide reduced TOSS versus placebo
(-11.40.+-.20.5 vs -5.38.+-.19.0 p<0.05) while RHINOCORT AQUA
did not (-8.57.+-.23.1). Further, each ocular symptom of
itchy/gritty eyes and tearing/watery eyes demonstrated significant
efficacy of CAPTISOL-ENABLED Budesonide over placebo while
RHINOCORT AQUA did not for any ocular symptom. The onset of action
for CAPTISOL-ENABLED Budesonide on TOSS was 1.5 hr. The average
TOSS is shown as a function of time in FIG. 6C.
[0479] The data are depicted in FIGS. 6A-6G and summarized in the
table below.
TABLE-US-00027 CE- Budesonide Nasal RHINOCORT Time Solution AQUA
Placebo Point (N = 65) (N = 65) (N = 65) (hour) Mean SE Mean SE
Mean SE 0 0 0 0 0.25 -1.22 0.32 -0.87 0.26 -0.85 0.25 0.5 -2.11
0.32 -1.44 0.32 -1.33 0.32 0.75 -2.27 0.35 -1.73 0.33 -1.72 0.36 1
-2.16 0.36 -2 0.36 -1.84 0.36 1.5 -2.37 0.34 -2.25 0.39 -1.78 0.34
2 -2.48 0.34 -2.32 0.41 -1.79 0.39 3 -2.14 0.35 -2.43 0.42 -1.67
0.36 4 -2.3 0.37 -2.1 0.4 -1.21 0.36 5 -1.81 0.35 -1.94 0.43 -1.22
0.37 6 -1.56 0.34 -1.63 0.41 -0.98 0.33 7 -1.65 0.33 -1.73 0.44
-0.93 0.33 8 -1.76 0.35 -1.9 0.45 -0.65 0.3 9 -1.59 0.34 -1.62 0.44
-0.62 0.34 10 -1.3 0.35 -1.43 0.41 -0.61 0.32
[0480] The table below includes a summary of the TNNSS data for the
study.
TABLE-US-00028 CE- Budesonide Nasal RHINOCORT Time Solution AQUA
Placebo Point (N = 65) (N = 65) (N = 65) (hour) Mean SE Mean SE
Mean SE 0 0 0 0 0.25 -1.11 0.31 -0.63 0.28 -0.48 0.24 0.5 -1.9 0.3
-0.9 0.33 -1.02 0.3 0.75 -2.03 0.37 -1.22 0.36 -1.16 0.33 1 -2.41
0.39 -1.43 0.38 -1.55 0.37 1.5 -2.4 0.38 -1.78 0.42 -1.48 0.36 2
-2.38 0.39 -1.59 0.41 -1.19 0.35 3 -2.11 0.37 -1.89 0.44 -1.04 0.35
4 -1.76 0.39 -1.41 0.42 -0.92 0.35 5 -1.73 0.37 -1.38 0.45 -0.73
0.36 6 -1.51 0.41 -1.14 0.42 -0.65 0.35 7 -1.38 0.44 -1.14 0.44
-0.58 0.34 8 -1.43 0.44 -1.13 0.43 -0.68 0.36 9 -1.3 0.41 -0.84
0.45 -0.36 0.34 10 -1.13 0.4 -0.68 0.44 -0.38 0.34
[0481] The efficacy, as determined from the area under the TNSS
rating-time curve (AUC), for Solution A and Suspension B was better
than placebo. There was little difference in efficacy between
Solution A and Suspension B although the median score for Solution
A was better. Also, nasal itchiness trended better for Solution A
than for Suspension B or Solution C.
[0482] The efficacy, based on TNNSS AUC, shows that Solution A was
better than Solution C, while Suspension B was equivalent to
Solution C. Overall, Solution A was substantially better than
Solution C in three out of the four non-nasal categories and
trended better than Solution C in the fourth non-nasal
category.
[0483] The initial reduction in TNSS was greatest for Solution A.
This shows that the speed of action of Solution A was faster than
either Suspension B or Solution C. Even though it was faster, the
reduction in TNSS lasted as long as Suspension B.
[0484] The Onset of Action in reducing TNNSS was determined to be
0.5 hours for Solution A. Suspension B never met the previously
established criterion.
[0485] When comparing mean change from baseline TNSS values for the
first three time points (0.25 hr, 0.5 hr and 0.75 hr), the mean
decrease in TNSS was greater for CAPTISOL-ENABLED Budesonide than
for RHINOCORT AQUA. However, statistical significance for
CAPTISOL-ENABLED Budesonide versus placebo was only achieved for
the 0.5 hr time point. While CAPTISOL-ENABLED Budesonide lowered
TNSS after 0.25 hours, the critical level of significance when
compared to placebo was not achieved for most of the time points.
See FIG. 8A. The chart for the onset of action for the first three
time points for TNNSS is set forth in FIG. 8B.
[0486] CAPTISOL-ENABLED Budesonide reduced non-nasal symptom scores
at 30 minutes. This effect was not observed with RHINOCORT AQUA.
There was no significant difference in the efficacy of
CAPTISOL-ENABLED Budesonide and RHINOCORT AQUA for the primary
efficacy variable of TNSS. The mean AUC for TNSS illustrates a
significant treatment effect for both CAPTISOL-ENABLED Budesonide
versus placebo and RHINOCORT AQUA versus placebo. CAPTISOL-ENABLED
Budesonide is a well tolerated, effective treatment for SAR.
EEC-QOLQ
[0487] The EEC-QOLQ consisted of the following questions by way of
which subjects rated their overall symptoms before and after
administration of the three solutions.
[0488] The EEC-RQOLQ consists of Non-nose/Eye Symptoms, Practical
Problems, and Emotional domains to assess the QOL experienced by
patients in the EEC. The higher the score, the worse patients feel.
The Practical Problems domain is important in the EEC-RQOLQ as it
assesses the need to rub nose/eyes and to blow nose repeatedly,
thus having an impact on daily activity.
[0489] Baseline was defined as the QOL questionnaire administered
prior to EEC entry, after exposure in the EEC and after treatment.
Comparisons between treatments were completed using ANCOVA. The
EEC-RQOLQ was administered at -0.75 hours pre-dose, and at 2, 6 and
10 hours post-dose. Quality of life was improved in patients
treated with CAPTISOL-ENABLED Budesonide compared to placebo in all
domains. The mean change from baseline in EEC-RQOLQ scores for
CAPTISOL-ENABLED Budesonide versus placebo were, for each domain,
respectively: Emotional: 2 h: -0.3; -0.1; 6 h: 0.1; 0.3; 10 h: 0.4;
0.4. Non-nose/Eye symptoms 2 h:-0.1; 0.1; 6 h: 0.1; 0.3; 10 h: 0.3;
0.5. Practical Problems: 2 h: -0.9; -0.2 (p=0.008); 6 h: -0.5; 0.1
(p=0.016), 10 h: -0.3; 0.3 (p=0.019). The effects of the three
solutions on the EEC-QOLQ are summarized in FIGS. 9A to 9C.
Subjects receiving CAPTISOL-ENABLED Budesonide demonstrated
improved QOL in the Emotional Domain and Practical Problems Domain.
There was no significant difference in RQLQ between the two
treatments at ay time point.
[0490] This study demonstrates that this EEC-RQOLQ is a good
indicator of QOL in the EEC. Practical Problems is an important
domain in the EEC-RQOLQ as it assesses the need to rub nose/eyes
and to blow nose repeatedly, thus having an impact on daily
activity. QOL scores in this domain were significantly improved in
patients treated with CAPTISOL-ENABLED Budesonide compared to
placebo.
Example 34
[0491] A clinical trial was conducted to evaluate the performance
of a combination composition of the invention in the treatment of
nasal symptoms and non-nasal symptoms caused by exposure of
subjects to an allergen.
[0492] Four aqueous based formulations were made: Solution
A--comprising CAPTISOL, budesonide, azelastine hydrochloride, and
aqueous liquid carrier; Suspension B-comprising RHINOCORT AQUA
suspension of budesonide in aqueous liquid carrier; Solution
C--comprising ASTELIN solution of azelastine hydrochloride in
aqueous liquid carrier, and Solution D (placebo)--comprising
buffered saline. Solution A was made by mixing twenty NEBUAMPS (500
.mu.g/mL nominal) to a bottle containing 4.71 mg CAPTISOL and 87.6
mg azelastine hydrochloride followed by mixing overnight to form a
solution containing 424 .mu.g/mL of budesonide and 100 mg/mL of
CAPTISOL. A 4 mL portion of the solution was placed in a smaller
bottle fitted with a spray valve. Solution B was purchased and used
as is (32 .mu.g of budesonide per spray) using a spray volume of 50
.mu.l with the supplied valve. Solution C was purchased, poured
into a smaller bottle and used with the supplied valve. Bottles
containing Solutions A and D were equipped with a 70 .mu.l Pfeiffer
spray valve. Bottles were masked prior to use.
[0493] Clinical Protocol.
[0494] A Randomized, Double-Blind, Placebo-Controlled, Three-Way
Cross-Over Study to Compare the Relative Efficacy of
CAPTISOL-ENABLED Budesonide+Azelastine Nasal Spray (Single
Solution) and RHINOCORT AQUA+ASTELIN Nasal Spray (Two Separate
Solutions) against Placebo Nasal Spray Solution in the Treatment of
Allergic Rhinitis in an Environmental Exposure Chamber (EEC)
Model
[0495] All study drugs were administered as one spray in each
nostril. The test treatment (CAPTISOL-ENABLED Budesonide+Azelastine
Nasal Solution) were administered along with a placebo in a blinded
fashion ensuring that the CAPTISOL-ENABLED formulation is
administered first. The reference treatment (RHINOCORT AQUA Nasal
Spray+ASTELIN Nasal Spray) were administered in a blinded fashion
ensuring that the ASTELIN Nasal Spray formulation is administered
first. Two bottles were used for Treatment C (the placebo
treatment). All study medications were administered intranasally
using metered-dose nasal spray pumps. In this particular study, the
allergic symptoms were due to allergic rhinitis and
rhinoconjunctivitis. The test treatment delivered a single spray of
32 .mu.g/spray of budesonide and 137 .mu.g/spray of azelastine in
each nostril. The reference treatment delivered separate single
sprays of 32 .mu.g/spray of budesonide and 137 .mu.g/spray of
azelastine in each nostril. The placebo was a single spray in each
nostril.
[0496] Subjects enrolled in the study (108) were exposed to ragweed
pollen using an EEC model. The nasal symptoms, non-nasal symptoms,
and quality of life for each subject were determined.
[0497] After passing the initial Screening Visit (Visit 1), which
occurred within 30 days prior to randomization (Visit 3), patients
attended two 3-hour Priming Visits (Visits 2a and 2b) in the EEC.
During the Priming Visits, patients were exposed to ragweed pollen
at an average session concentration of approximately 3500.+-.500
particles per m.sup.3 for a total duration of approximately 3
hours. Following an initial 30-minute exposure, patients were asked
to record their instantaneous nasal symptom scores (NSS) and
non-nasal symptom scores (NNSS) every 30 minutes for 2.5 hours.
Patients were required to meet a minimum threshold response on one
Priming Visit to be eligible to be randomized on Treatment Day 1
(Visit 3). The minimum threshold is a TNSS of 6 units, including a
score of at least 2 for congestion on at least one diary card on at
least one priming visit.
[0498] Patients were not permitted to use rescue medications
throughout the study. Use of rescue medications would result in
removal from the study at the discretion of the investigator.
Patients were monitored for adverse events throughout the exposure
sessions.
[0499] On Treatment Day 1 (Visit 3), patients reported to the
clinic approximately 1 hour prior to entry into the EEC. The
patients were questioned regarding changes in their health and
concomitant medications. All patients entered the EEC within an
approximate 10-minute window and were exposed to ragweed pollen in
the EEC for a period of 12 hours.
[0500] Over the first 1.5 hours in the EEC, the patients evaluated
their nasal and non-nasal symptoms every 30 minutes to determine
adequate baseline symptoms. Patients who met the predetermined
minimum TNSS of 6 units, including a minimum score of 2 for
congestion on at least one diary card prior to treatment, were
randomized to receive one of three treatments in a double-blind
manner. Patients who did not meet the predetermined TNSS were not
dosed and were withdrawn from the study.
[0501] Following administration of the study drug, patients were
asked to assess their nasal and ocular symptoms (TSS, TNSS and
TOSS) at 10, 20, 40, 60, 90 and 120 minutes post dose, then every
hour up to 10 hours post-dose. During the entire time (a total of
about 12 hours) patients were in the EEC, they were exposed to
ragweed pollen controlled at an average session concentration of
approximately 3500.+-.500 particles per m.sup.3. An EEC-RQLQ was
administered prior to entering the EEC, at -0.75 hours pre-dose,
and post-dose at 2, 6 and 10 hours. At the end of the session,
patients were asked to globally assess the study drug efficacy
compared to how they felt prior to its administration (using a
7-point scale).
[0502] Patients were asked to return to the EEC for two priming
visits prior to each of Treatment Days 2 and 3. However, patients
were not required to achieve a minimum threshold response on these
follow-up priming visits (Visits 4a and 4b and Visits 6a and
6b).
[0503] The procedures for Treatment Days 2 and 3 (Visits 5 and 7)
was the same as for Treatment Day 1 described above, except that
patients did not need to meet the predetermined minimum TNSS to
proceed in the study. There was a washout period of at least 10
days between treatment periods.
[0504] The total duration of a patient's participation in this
study did not exceed 75 days.
[0505] The primary objective of this study was to evaluate the
relative efficacy of CAPTISOL-ENABLED Budesonide+Azelastine Nasal
Spray Solution and RHINOCORT AQUA+ASTELIN Nasal Spray compared to
Placebo using Total Nasal Symptom Score (TNSS) in patients with SAR
exposed to controlled ragweed pollen using an EEC model.
[0506] The secondary objectives were to evaluate the relative
efficacy of: [0507] CAPTISOL-ENABLED Budesonide+Azelastine Nasal
Spray (Single Solution) and Budesonide+Azelastine Nasal Spray (Two
Separate Solutions) compared to Placebo by evaluating Total Symptom
Score (TSS) and Total Ocular Symptom Score (TOSS) [0508] The three
study treatments on an EEC-Rhinoconjunctivitis Quality of Life
Questionnaire (EEC-RQLQ). [0509] The three study treatments on the
global rating score.
[0510] The questions included in the Rhinoconjunctivitis Quality of
Life Questionnaire for use in the Environmental Exposure Chamber
(RQLQ-EEC) were developed using focus groups and were used in the
current study as a secondary efficacy measurement. Patients were
asked to complete the RQLQ-EEC 5 times at each treatment visit,
once before entering the EEC, 3 times while in the EEC, and once
following the completion of the final Symptom Diary Card in the
EEC. The RQLQ-EEC was administered before entering the EEC and
during the EEC was divided into 3 domains: non-nose/eye symptoms
(10 questions), practical problems (2 questions), and emotions (3
questions). The non-nose/eye symptoms and practical problems
domains were scored between 0 (not troubled) and 6 (extremely
troubled), and the emotions domain were scored between 0 (none of
the time) and 6 (all of the time). The mean score of the 3 domains
yielded an overall quality-of-life score. The RQLQ-EEC administered
at the end of the EEC session consisted of the 3 domains and an
additional global assessment domain. The global assessment was
scored between 0 (very much better) and 6 (very much worse).
[0511] Patients rated nasal symptoms (rhinorrhea, nasal congestion,
nasal itchiness, and sneezing) and non-nasal symptoms (itchy/gritty
eyes, tearing/watery eyes, red/burning eyes, itchy ears and
palate).
[0512] The severity of the nasal and non-nasal symptoms of allergic
rhinitis was recorded on a diary card using the severity rating
scale shown below. The nasal and non-nasal symptoms are as follows:
1) nasal: runny nose (anterior rhinorrhea/postnasal drainage),
itchy nose, nasal congestion (stuffy nose) and sneezing; 2)
non-nasal: itchy/gritty eyes, red/burning eyes, tearing/watery
eyes, itchy ear/palate; and 3) ocular: itchy/gritty eyes,
red/burning eyes, tearing/watery eyes.
[0513] Severity Rating Scale for Allergy Symptoms
TABLE-US-00029 Score Definition 0 = none Symptom is not present 1 =
mild Sign/symptom is clearly present but minimal awareness; easily
tolerated 2 = moderate Definite awareness of sign/symptom that is
bothersome but tolerable 3 = severe Sign/symptom is hard to
tolerate; causes interference with activities of daily living
and/or sleep
[0514] The TNSS, TOSS and TSS scores were then totaled. The data
are set forth in FIGS. 12A-12C.
[0515] For every symptom except watery eyes, the AUC of
CAPTISOL-ENABLED Budesonide+Azelastine HCl showed a rank order
greater improvement than the reference treatment (see FIG.
12I).
[0516] The data demonstrate that the composition of the invention
is at least as good as (provides at least the same overall relief
of nasal, ocular and total symptoms as does the) combined
sequential administration of the two commercial products RA and
AST.
[0517] The data demonstrated the following trends as regards the
performance of the CAPTISOL ENABLED Budesonide nasal solution (the
combination solution, "CDX-313") compared to placebo and the
separate and sequential administration of RHINOCORT AQUA and
ASTELIN:
TABLE-US-00030 Total symptom scores: Better than placebo
Combination at least as good as drugs administered separately Total
nasal symptom scores Better than placebo Combination at least as
good as drugs administered separately Total ocular symptom Better
than placebo scores Combination comparable to drugs administered
separately Duration of action Longer duration of action than
placebo for relief of nasal symptoms Longer duration of action than
drugs administered separately for relief of nasal symptoms
[0518] A meta analysis was conducted to compare the clinical
studies of Examples 33 (2007) and 34 (2008). Statistical analyses
were first performed to ensure that the placebo arms between
studies behaved similarly. An analysis of covariance (ANCOVA) was
then performed on baseline adjusted Area under the Curve (AUC) for
TNSS and overall mean change from baseline in TNSS (placebo arms
were pooled). The model included fixed terms for sequence, period
and treatment and a random effect for subject nested within
sequence. Baseline TNSS was used as a covariate in the model after
verifying homogeneity of slopes. All comparisons were adjusted for
multiple testing.
[0519] Meta analyses revealed no significant difference in the
placebo effect and that placebo effects were comparable (p=0.64) in
the two studies, thus allowing pooling of data and comparisons to
be made between test products with CE and the comparators for both
studies. Baseline adjusted AUC and overall mean change from
baseline in TNSS showed similar trends for both studies (FIGS. 12A
and 12I). Change from baseline in AUC for TNSS revealed that when
CE-BUD was compared to CE-BUD+AZ there was a significantly greater
relief of nasal symptoms with the combination product than CE-BUD
alone (p=0.005) and when RA was compared with CE-BUD-AZ there was a
significantly greater relief of nasal symptoms with the combination
product than with RA alone (p=0.009) (FIGS. 12K and 12L). RA was
compared to AS+RA and there was no statistically significant
difference after adjustment for multiple testing (p=0.085) and this
was also true when CE-BUD was compared with RA (p=0.999). A
comparison of CE-BUD+AZ with AS+RA indicated no statistically
significant difference in nasal relief with the solubilized product
compared with each product given individually and consecutively.
However, TNSS was numerically lower for CE-BUD+AZ.
[0520] In FIGS. 12D and 12E, NSS of runny nose and congestion
showed similar onset and duration of action as TNSS. In FIGS. 12F
and 12G, onset of action of itchy nose and sneezing were
significantly faster at 10 mins for CAPTISOL-ENABLED
Budesonide+Azelastine compared to RHINOCORT AQUA. RHINOCORT
AQUA/ASTELIN did not show an effect until 0.33 hour. As with the
other parameters, both treatments had the same duration (10 hours)
for itchy nose and sneezing.
[0521] The CAPTISOL-ENABLED Budesonide+Azelastine formulation
provides long-lasting relief of all allergic rhinitis symptoms
similar to consecutive administration of RHINOCORT AQUA and
ASTELIN. However, faster immediate relief of itchy nose and
sneezing was obtained in a more convenient combination dose
format.
[0522] As shown in FIG. 12H, CAPTISOL-ENABLED
Budensonide+Azelastine provided the same or greater numerical TOSS
relief (did not reach statistical difference) than RHINOCORT
AQUA+ASTELIN for 11 of 14 time points and longer-lasting relief of
red/burning eyes (7 h vs. 6 h).
[0523] Thus, CAPTISOL-ENABLED Budesonide+Azelastine provided
significant long-lasting relief of all ocular symptoms. It also
provided a longer duration of action for the red/burning eyes
symptom compared to the RHINOCORT AQUA+ASTELIN format.
Additionally, CAPTISOL-ENABLED Budesonide+Azelastine is provided in
a more convenient combination single spray/dose format.
[0524] The mean AUC for TSS was significant for CAPTISOL-ENABLED
Budesonide+Azelastine HCl (-45.2.+-.45.02) vs. placebo
(-13.3.+-.35.88) (p<0.0001) but was not significantly different
from the reference treatment (-37.3.+-.47.69). The onset of action
(defined as the first time point after initiation of treatment when
the drug demonstrated a statistically significant greater change
from baseline in the efficacy endpoint compared to placebo that
proved durable from that point onward for at least three
consecutive time points) of both CAPTISOL-ENABLED
Budesonide+Azelastine HCl and the reference treatment was 0.33
hours. At every time point from 0.33 hours onward, both active
treatments were significantly different from placebo. The reference
treatment and test treatment were never significantly different
from each other although the test treatment was numerically
superior from 0.33 hours onward. The duration of action for each
active treatment was 10 hours. The TSS maximum mean decrease from
baseline was statistically significant for each of the active
treatments vs. placebo (both p values <0.0001). The mean maximum
change was -8.8.+-.5.51 for CAPTISOL-ENABLED Budesonide+Azelastine
HCl, -7.9.+-.5.45 for RHINOCORT AQUA+ASTELIN, and -5.2.+-.4.55 for
placebo.
[0525] For the non-nasal symptom of itchy ear/palate,
CAPTISOL-ENABLED Budesonide+Azelastine had an onset of action at
the 0.33 hr time point while RHINOCORT AQUA+ASTELIN showed efficacy
beginning at the 0.66 hr time point. For this symptom, both
treatments maintained efficacy to the 10 hr time point. When
compared to each other, no significant difference was observed
between the two active treatments for itchy ear/palate at any time
point.
[0526] For the Overall RQLQ, which groups all of the RQLQ domains
together, a significant treatment effect was observed for
CAPTISOL-ENABLED Budesonide+Azelastine at each of the 2, 6 and 10
hr time points. This treatment effect was not observed for
RHINOCORT AQUA+ASTELIN at any time point. This difference between
the two active treatments was also evident when comparing the two
active treatments to each other at the 6 and 10 hr time points.
This confirms a significant difference between the two active
treatments with CAPTISOL-ENABLED Budesonide+Azelastine showing
efficacy while RHINOCORT AQUA+ASTELIN did not.
[0527] CAPTISOL-ENABLED Budesonide+Azelastine HCl was demonstrated
to have a rapid and durable onset of action against the nasal and
ocular symptoms of ragweed allergy. The CAPTISOL-ENABLED Budesonide
formulation provided a more convenient combination of a single
spray/dose format than sequential RHINOCORT AQUA+ASTELIN. The
single spray format offers potential advantages, such as consistent
ratio of actives in every drop of the spray, increased uniformity
of dosing, elimination of need to re-suspend drug before use, and
ease of manufacture including aseptic filtration to allow the use
of valves designed for preservative-free formulations.
Example 35
[0528] Performance of an aqueous liquid composition of the
invention in a multi-dose pump nasal spray was evaluated to
determine the spray content uniformity (SCU), pump delivery, spray
pattern, droplet size distribution. The spray content of a
delivered dose or emitted dose is the quantity of drug outside of
the device that is available to a subject on a unit dose basis,
i.e. after a single actuation of the pump nasal spray.
[0529] The composition comprised a corticosteroid and
antihistamine, e.g., combination of budesonide (425 .mu.g/mL),
azelastine HCl (0.2%), CAPTISOL (10%). The pump nasal spray was
adapted to provide a target pump delivery (the weight of
composition emitted by the device) of 70 mg of composition upon
each actuation.
[0530] Results from evaluation of performance of an aqueous liquid
composition (budesonide (425 .mu.g/mL), azelastine HCl (0.2%),
CAPTISOL (10%) in buffer) in a pump nasal spray.
[0531] Droplet Distribution Data:
TABLE-US-00031 Dv10 (.mu.m) Dv50 (.mu.m) Dv90 (.mu.m) Span <10
.mu.m (%) 16.73 .+-. 0.28 32.78 .+-. 0.14 67.48 .+-. 0.31 1.55 .+-.
0.03 2.66 .+-. 0.13 17.11 .+-. 0.82 33.45 .+-. 1.63 69.55 .+-. 5.82
1.57 .+-. 0.07 2.47 .+-. 0.36 19.68 .+-. 0.05 39.18 .+-. 0.88 88.33
.+-. 2.04 1.75 .+-. 0.01 1.68 .+-. 0.08 19.30 .+-. 0.17 38.10 .+-.
0.34 88.36 .+-. 1.54 1.81 .+-. 0.04 1.9 .+-. 0.05 17.31 .+-. 0.5
36.74 .+-. 0.63 80.74 .+-. 3.26 1.73 .+-. 0.08 2.51 .+-. 0.21 17.39
.+-. 0.43 35.95 .+-. 1.25 77.57 .+-. 4.88 1.67 .+-. 0.08 2.48 .+-.
0.21 17.33 .+-. 0.31 35.74 .+-. 2.52 76.99 .+-. 8.21 1.66 .+-. 0.12
2.5 .+-. 0.21
[0532] Spray Pattern Data:
TABLE-US-00032 Unit # Dmin (mm) Dmax (mm) Ovality Ratio 3 cm
Distance to the Laser Beam SP3-COMBO1 20.0 24.5 1.225 SP3-COMBO2
23.3 33.0 1.416 SP3-COMBO3 24.7 29.9 1.211 Mean 22.7 29.1 1.284 SD
2.41 4.30 0.11 % CV 10.65 14.77 8.92 6 cm Distance to the Laser
Beam SP6-COMBO1 32.8 57.3 1.747 SP6-COMBO2 36.8 60.1 1.634
SP6-COMBO3 33.4 47.7 1.428 Mean 34.3 55.0 1.603 SD 2.16 6.50 0.16 %
CV 6.28 11.82 10.09 3 cm Distance to 6 cm Distance to Laser Beam
Laser Beam Spray Weight Spray Weight Unit # (mg) Unit # (mg)
SP3-COMBO1 55.5 SP6-COMBO1 71.7 SP3-COMBO2 73.0 SP6-COMBO2 75.1
SP3-COMBO3 70.4 SP6-COMBO3 70.8 Mean 66.3 Mean 72.5 SD 9.44 SD 2.27
% CV 14.24 % CV 3.13 Unit # Spray Weight (mg) COMBO1-DSD3 69.6
COMBO2-DSD3 72.8 COMBO3-DSD3 68.0 Mean 70.1 SD 2.44 % CV 3.48
[0533] The results indicate that the mean pump delivery ranged from
72.5 to 74.5 mg per actuation with a standard deviation ranging
from .+-.0.54 to .+-.1.6. The plume emitted by the nasal spray was
characterized by laser diffraction to determine the droplet size
distribution (Dv10, Dv50, Dv90), span and percentage of droplets
having a droplet size of <10 .mu.m. The mean Dv10 ranged from
16.73 to 19.68 .mu.m with a standard deviation ranging from
.+-.0.05 to .+-.0.82 .mu.m. The mean Dv50 ranged from 32.78 to
39.18 .mu.m with a standard deviation ranging from .+-.0.14 to
.+-.1.63 .mu.m. The mean Dv90 ranged from 67.48 to 88.36 .mu.m with
a standard deviation ranging from .+-.0.31 to .+-.5.82 .mu.m. The
mean span ranged from 1.55 to 1.81 with a standard deviation
ranging from .+-.0.01 to .+-.0.08 .mu.m. The percentage of droplets
<10 .mu.m in size ranged from 1.68 to 2.66% with a standard
deviation ranging from .+-.0.05 to .+-.0.36%.
Example 36
[0534] An ophthalmic solution comprising a corticosteroid and
SAE-CD is prepared as follows.
Method A. Fluticasone Propionate
[0535] A citrate buffer solution at a pH of 4.5 was prepared by
mixing various portions of 0.003M citric acid with 0.003M of
trisodium citrate. A phosphate buffer solution at a pH of 6.0 was
prepared by mixing various portions of 0.003M monobasic sodium
phosphate with 0.003M of dibasic sodium phosphate. These stock
solutions contained 10% w/v SBE-Gamma (D.S.=6.1) and 0.01% TWEEN.
An excess of fluticasone propionate was added to the vials and
equilibrated on a rocker for three days. The samples were then
filtered using a PVDF 0.22 .mu.m syringe filter. Aliquots of the
solutions were placed into clear glass 2 mL serum vials with
aluminum crimp caps and Dalkyo Fluorotec septums. The concentration
of the pH 4.5 solution was 232 .mu.g/mL. The concentration of the
pH 6.0 solution was 238 .mu.g/mL.
Method B. Mometasone Furoate
[0536] A 50 mL solution of 0.08M CAPTISOL with 80 .mu.g/mL of
mometasone furoate was prepared by weighing approximately 9.6 grams
of CAPTISOL into a 50 mL volumetric flask and qs with a 3 mM
citrate buffer pH 4.5. The approximately 4 mg of mometasone furoate
was weighed into a media bottle and the CAPTISOL/buffer solution
was added to the drug and the bottles were vortexed and sonicated
for approximately 5 minutes. The bottles were then placed on a
roller mixer (Stuart Scientific SRT2 33 rpm rise/fall 16 mm)
protected from light and mixed overnight. After the overnight
mixing on the roller mixer the bottles were transferred to a
magnetic stirrer, set at 330 RPM, for three days. The solutions
were filtered using a PVDF 0.22 .mu.m filter and a sample was
assayed from each bottle. The results from the assay were about 6%
low from target so additional mometasone furoate anhydrous was
added to each bottle and were placed back onto the roller mixer for
another 3 days. The solutions were aseptically filtered again and 2
mLs were transferred to the 2 mL clear vials with Teflon
stoppers.
Method C. Mometasone Furoate and SBE-.gamma.-CD
[0537] A 50 mL solution of 0.08M SBE .gamma.-CD with 400 .mu.g/mL
of mometasone furoate was prepared by weighing approximately 9.1
grams of SBE .gamma.-CD into a 50 mL volumetric flask and qs with a
3 mM citrate buffer pH 4.5. The approximately 20 mg of mometasone
furoate was weighed into a media bottle and the SBE
.gamma.-CD/buffer solution was added to the drug and the bottles
were vortexed and sonicated for approximately 5 minutes. The
bottles were then placed on a roller mixer (Stuart Scientific SRT2
33 rpm rise/fall 16 mm) protected from light and mixed overnight.
After the overnight mixing on the roller mixer the bottles were
transferred to a magnetic stirrer, set at 330 RPM, for three days.
The solutions were filtered using a PVDF 0.22 .mu.m filter and a
sample was assayed from each bottle. The results from the assay
were about 6% low from target so additional mometasone furoate
anhydrous was added to each bottle and were placed back onto the
roller mixer for another 3 days. The solutions were aseptically
filtered again and 2 mLs were transferred to the 2 mL clear vials
with Teflon stoppers.
Example 37
[0538] Preparation of ophthalmic budesonide solution and its
placebo for in vivo-testing.
Method A
[0539] A buffered, isotonic CAPTISOL solution was prepared. 100 mL
water was placed in a suitable vessel. Approximately 4.2 grams of
CAPTISOL, approximately 32.3 milligrams of citric acid monohydrate,
approximately 43.3 milligrams of sodium citrate dihydrate, and
approximately 580 milligrams of sodium chloride were added to the
vessel. The solution was mixed with a magnetic stir-bar until all
solids were dissolved. The measured pH was 4.5 and the tonicity was
300mOs.
Method B
[0540] The same procedure was followed as was in Method A, with the
addition of budesonide and polysorbate-80 after the CAPTISOL,
citric acid monohydrate, sodium citrate dihydrate, and sodium
chloride were dissolved. Approximately 26.2 milligrams of
budesonide was added to the vessel and allowed to mix for
approximately 2.5 hours. Approximately 5.0 microliters of
polysorbate-80 was added to the vessel and allowed to mix for an
additional approximately 2.5 hours. This solution was filtered to
remove undissolved excess budesonide, then assayed by HPLC to
determine the final budesonide concentration, which was 251
micrograms per milliliter. The measured pH was 4.5 and the tonicity
was 300 mOs.
Example 38
[0541] Preparation and use of a combination solution containing
SAE-CD, budesonide, and azelastine. A solution can be made
according to Example 37, except that 500 mg of azelastine is added
to the vessel with the budesonide.
Example 39
[0542] Preparation and use of a combination solution containing
SAE-CD, budesonide, and diclofenac.
[0543] A citrate buffer (3 mM pH 4.5) is prepared as follows.
Approximately 62.5 mg of citric acid is dissolved in and brought to
volume with water in one 100 mL volumetric flask. Approximately
87.7 mg of sodium citrate is dissolved in and brought to volume
with water in another 100 mL volumetric flask. In a beaker the
sodium citrate solution is added to the citric acid solution until
the pH is approximately 4.5.
[0544] Approximately 10.4 mg of budesonide, 100 mg of diclofenac
and 1247.4 mg of CAPTISOL are ground together with a mortar and
pestle and transferred to a 10 mL flask. Buffer solution is added,
and the mixture is vortexed, sonicated and an additional 1.4 mg
budesonide added. After shaking overnight, the solution is filtered
through a 0.22 .mu.m Durapore Millex-GV Millipore syringe filter
unit. The resulting budesonide concentration will be approximately
1 mg/mL and the concentration of diclofenac will be approximately
10 mg/mL.
Example 40
[0545] Preparation and use of a combination ophthalmic solution
comprising CAPTISOL, ofloxacin, and mometasone furoate.
[0546] A 50 mL solution of 0.08M CAPTISOL with 80 .mu.g/mL of
mometasone furoate and 3 mg/mL ofloxacin can be prepared by
weighing approximately 9.6 grams of CAPTISOL into a 50 mL
volumetric flask and qs with a 3 mM citrate buffer pH 4.5. The
approximately 4 mg of mometasone furoate and 150 mg ofloxacin are
weighed into a media bottle and the CAPTISOL/buffer solution was
added to the drug and the bottles vortexed and sonicated for
approximately 5 minutes. The bottles are then placed on a roller
mixer (Stuart Scientific SRT2 33 rpm rise/fall 16 mm) protected
from light and mixed overnight. After the overnight mixing on the
roller mixer the bottles are transferred to a magnetic stirrer, set
at 330 RPM, for three days. The solutions are filtered using a PVDF
0.22 .mu.m filter and a sample assayed from each bottle.
Example 41
[0547] In vivo evaluation of a dosage form according to the
invention was conducted in rabbits as follows.
[0548] A pilot study to test the effectiveness of CE-Budesonide on
ocular wound healing was conducted in rabbits. The effectiveness of
CE-Budesonide (250 mcg/mL) from Example 37 was compared with
commercial products--PULMICORT RESPULES (a suspension of
budesonide, 250 mcg/mL) and prednisolone acetate (Pred Forte
suspension, 1%) and a CAPTISOL placebo.
[0549] Treatment Protocol:
[0550] The animals were administered 40 microliter (10 .mu.g) of
test material each to both eyes of animals four times a day (6
hours apart) for 3 days prior to induction of eye injury by laser
energy on Day 0 (the day of induction of eye injury). Each animal
was placed in the left lateral position and thermal injury was made
to the right eye with a semiconductor, diode laser. Laser energy
was directed through the peripheral clear cornea to the iris
surface using a hand-held fiberoptic laser probe injuring three
separate sites measuring 2 mm in diameter. Laser energy treatment
of the eyes resulted in inflammatory responses of the iris along
with proteinaceous and cellular inflammation in the anterior
chamber of the eye on Day 0. The injury was graded for inflammation
based on the study Ophthalmologist's routine criteria (0: no
inflammation, 1: trace flare or cells (very faint), 2: flare/cell
mild but clearly visible in anterior chamber, 3: flare/cell turbity
moderate in anterior chamber, 4: flare/cell severe in anterior
chamber). Ocular pressure was determined using an applanation
tonometer.
TABLE-US-00033 Anterior Anterior chamber chamber Number Of Eye drop
flare.sup.1 cell.sup.1 Animals volume score Score Group Treatment
Concentration M microliter D0 D1 D0 D1.sup.2 1 Vehicle Control 0
mcg/mL 4 40 1.75 1 1.25 0 (~4% CAPTISOL) 2 PUMICORT RESPULES 250
mcg/mL 4 40 1.75 1 1.25 0.25 (a suspension of budesonide) 3
prednisolone 1% 4 40 1.75 0.75 1.25 0.25 acetate (Pred Forte
suspension) 4 CAPTISOL- 250 mcg/mL 4 40 2 0 1.25 0 ENABLED
Budesonide .sup.1Average score of 4 animals. Day 0: the day injury
was induced. .sup.2Group 2 and 3 each had one animal scored as 1+,
all others were 0.
[0551] Slit lamp examinations revealed aqueous flare,
conjunctivitis, iritis, and/or superficial keratitis of the right
eye following the laser injury in all animals. Aqueous flare had
resolved by Day 3 in all animals but one in the PULMICORT RESPULES
group.
[0552] Decreased eye pressure in the right eye was observed in all
animals following laser injury on Day 0. Eye pressure returned to
normal values in the CAPTISOL-ENABLED Budesonide solution group by
Day 1, and in CAPTISOL vehicle controls, PULMICORT RESPULES, and
PRED FORTE by Day 3, 7, and 3, respectively. The results are
summarized in the table below and in FIGS. 9a and 9b.
TABLE-US-00034 Eye Pressure (Mean .+-. SD) CAPTISOL- Surgical
PULMICORT ENABLED day CAPTISOL RESPULES Pred Forte Budesonide Left
Eye D-1 17.00 .+-. 2.71 20.00 .+-. 1.83 21.25 .+-. 0.96 17.25 .+-.
5.12 D0 19.25 .+-. 2.22 18.75 .+-. 2.22 19.25 .+-. 1.50 19.50 .+-.
1.91 D1 21.75 .+-. 2.50 21.00 .+-. 3.37 20.75 .+-. 2.75 19.75 .+-.
2.50 D3 20.75 .+-. 1.26 18.75 .+-. 2.22 20.50 .+-. 2.08 21.75 .+-.
1.50 D7 19.25 .+-. 2.50 21.25 .+-. 2.36 20.00 .+-. 1.41 19.50 .+-.
1.73 Right Eye D-1 16.75 .+-. 3.69 18.25 .+-. 2.06 20.25 .+-. 2.22
17.75 .+-. 4.35 D0 17.00 .+-. 2.71 20.00 .+-. 1.83 21.25 .+-. 0.96
17.25 .+-. 5.12 D1 13.75 .+-. 5.62 16.00 .+-. 3.92 13.25 .+-. 2.50
20.25 .+-. 0.96 D3 15.75 .+-. 3.10 11.25 .+-. 4.43 18.50 .+-. 3.00
20.75 .+-. 2.50 D7 21.00 .+-. 2.16 19.75 .+-. 2.06 18.25 .+-. 3.40
19.25 .+-. 1.71
[0553] The results showed that CE-Budesonide solution effectively
reduced inflammatory reactions following laser injury to the iris
of rabbits. The resolution of laser-induced eye injury by
CAPTISOL-ENABLED Budesonide occurs more rapidly than by either
PULMICORT RESPULES, or PRED FORTE. Intraocular pressure returned to
normal values more quickly in the CE-Budesonide solution treatment
group than in all other treatment groups and the vehicle
control.
Example 42
[0554] Preparation and use of a combination ophthalmic solution
containing SAE-CD, budesonide and tobramycin.
[0555] An ophthalmic solution of the invention can be made to
contain the following ingredients in the approximate amounts
indicated per mL of solution.
TABLE-US-00035 Ingredient Amount in 1 mL of solution Tobramycin
0.3% (3 mg) Budesonide 0.025% (250 .mu.g) Benzalkonium chloride
0.01% SBE-.gamma.-CD 2% Edentate disodium 0.1% Sodium chloride
0.01% Sulfuric acid and/or sodium To adjust pH to physiologic pH
hydroxide Water Qs. to 1 mL
Example 43
[0556] Preparation and use of a combination ophthalmic solution
containing SAE-CD, budesonide and azithromycin.
TABLE-US-00036 Ingredient Amount in 1 mL of solution Azithromycin
0.5% (5 mg) Budesonide 0.025% (250 .mu.g) Benzalkonium chloride
0.01% SBE-.gamma.-CD 2% Edentate disodium 0.1% Sodium chloride
0.01% Sodium sulfate, sulfuric acid To adjust pH to physiologic pH
and/or sodium hydroxide Water Qs. to 1 mL
Example 44
[0557] Preparation of ophthalmic solution of SBE .gamma.-CD,
Mometasone Furoate, and Timolol
[0558] A 50 mL solution of 0.08M SBE .gamma.-CD with 400 .mu.g/mL
of mometasone furoate and 2.5 mg/mL of timolol can be prepared by
weighing approximately 9.1 grams of SBE .gamma.-CD into a 50 mL
volumetric flask and qs with a 3 mM citrate buffer pH 4.5. The
approximately 20 mg of mometasone furoate and 125 mg of timolol are
weighed into a media bottle and the SBE .gamma.-CD/buffer solution
is added to the drugs. The bottles are vortexed and sonicated for
approximately 5 minutes. The bottles are then placed on a roller
mixer (Stuart Scientific SRT2 33 rpm rise/fall 16 mm) protected
from light and mixed overnight. After the overnight mixing on the
roller mixer the bottles are transferred to a magnetic stirrer, set
at 330 RPM, for three days. The solutions are filtered using a PVDF
0.22 .mu.m filter.
Example 45
[0559] 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-00037 [Steroid] .times.10.sup.5 M Intrinsic Solubility
0.04 M 0.04 M Steroid ID (H.sub.2O) CAPTISOL (SBE).sub.6.1 .gamma.
Hydrocortisone 92.4 2656.3 2369.3 Methylprednisolone 43.6 743.1
1215.3 Prednisolone 62.5 1995.3 2095 Prednisone 50.5 1832.7 1313.7
Flunisolide 11.3 261.5 455.1 Beclomethasone 0.41 11.6 46.8
Dipropionate Budesonide 6.6 254.8 306.6 Fluticasone Propionate 0.39
5.41 51.8 Mometasone Fuorate 1.82 16.4 41.5 Triamcinolone Acetonide
3.56 457 1059.5
Example 46
[0560] The table below summarizes the equilibrium binding constants
(K) for some corticosteroids in the presence of CAPTISOL or SBE6.
1-.gamma.-CD (0.04 M).
TABLE-US-00038 Binding Constant-K Steroid ID CAPTISOL (SBE).sub.6.1
.gamma. Hydrocortisone 1932 1430 Methylprednisolone 486 950
Prednisolone 1496 1653 Prednisone 1591 914 Flunisolide 590 1104
Beclomethasone 684 2862 Dipropionate Budesonide 1002 1229
Fluticasone Propionate 322 3338 Mometasone Fuorate 201 551
Triamcinolone Acetonide 3591 10075
Example 47
[0561] An aqueous budesonide/olopatadine solution was prepared. The
target composition was budesonide 320 .mu.g/mL, olopatadine HCl 6.6
mg/mL, and CAPTISOL 5, 7.5 and 10% w/v.
Part A
[0562] Three mM citrate buffer was prepared at pH 4.5.
Approximately 0.32 grams of citric acid monohydrate and
approximately 0.44 grams of sodium citrate dihydrate were dissolved
with water in 500 mL volumetric flasks, respectively. Those citrate
solutions were mixed to adjust the pH to 4.5. Three CAPTISOL
solutions (5, 7.5 and 10% w/v) were prepared with the 3 mM citrate
buffer at pH 4.5. Approximately 5.2, 7.9 and 10.5 grams of CAPTISOL
were dissolved with 3 mM citrate buffer at pH 4.5 in 100 mL
volumetric flasks, respectively. The solutions were transferred
into 250 mL amber beakers with a magnetic stir disk. The solutions
were mixed with a magnetic stir disk at 900 rpm at a temperature of
35.degree. C.
[0563] Approximately 34 milligrams of budesonide was suspended in
each CAPTISOL solution. The samples were mixed with a magnetic stir
disk at 900 rpm and 35.degree. C. After 24 hours, the samples were
filtered through 0.22 .mu.m PVDF filter. The budesonide in the
aliquots was assayed by an HPLC assay method and the concentrations
were .about.340 .mu.g/mL. The measured pHs were .about.4.4 and the
tonicities with CAPTISOL 5, 7.5 and 10% w/v were 132, 202 and 277
mOsm, respectively.
Part B
[0564] Approximately 27 milligrams of olopatadine HCl was weighed
into each of three 2 drams amber vials. The olopatadine HCl was
suspended to 4 mL of budesonide/CAPTISOL solutions prepared in Part
A. The samples were mixed on a roller mixer at RT. After 24 hours,
the samples were filtered through 0.22 .mu.m PVDF filter. The
olopatadine and budesonide in the aliquots was assayed by HPLC
assay methods, respectively. All olopatadine HCl concentrations
were >6.6 mg/mL and all budesonide concentrations were >320
.mu.g/mL. The ratio of budesonide epimer B to budesonide epimer A
(R/S ratio) of budesonide solution with 5% w/v CAPTISOL was 1.09
and it was decreased to 1.07 after olopatadine dissolved. The R/S
ratios of other samples were 1.09. The measured pHs were .about.3.8
and the tonicities with CAPTISOL 5, 7.5 and 10% w/v were 154, 224
and 297 mOsm, respectively.
Part C
[0565] Approximately 27 milligrams of olopatadine HCl were weighed
into each of three 2 drams amber vials. The olopatadine HCl was
suspended to 4 mL of budesonide/CAPTISOL solutions prepared in Part
A. The samples were mixed on a roller mixer at RT. After 1 hour,
the pH of each sample was adjusted to 4.5 with 1N NaOH. Again, the
samples were mixed on a roller mixer at RT. After 23 hours, a
precipitation was observed in the presence of 5% w/v CAPTISOL at pH
4.5. All samples were filtered through 0.22 .mu.m PVDF filter. The
olopatadine and budesonide in the aliquots were assayed by HPLC
assay methods, respectively. The olopatadine HCl concentrations
with CAPTISOL 7.5 and 10% w/v were >6.6 mg/mL, but the
concentration with CAPTISOL 5% w/v was 6.5 mg/mL. The budesonide
concentrations with CAPTISOL 7.5 and 10% w/v were >320 .mu.g/mL,
but the concentration with CAPTISOL 5% w/v was 210 .mu.g/mL. The
R/S ratio of budesonide solution with 5% w/v CAPTISOL from Part A
was 1.09 and it was decreased to 0.6 after olopatadine dissolved.
The R/S ratios of other samples were 1.09. The measured pHs were
.about.4.5 and the tonicities with CAPTISOL 5, 7.5 and 10% w/v were
159, 228 and 301 mOsm, respectively.
[0566] 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.
* * * * *