U.S. patent application number 12/269740 was filed with the patent office on 2009-06-04 for compositions for the treatment of inflammation of the gastrointestinal tract.
This patent application is currently assigned to MERITAGE PHARMA, INC.. Invention is credited to Malcolm Hill.
Application Number | 20090143343 12/269740 |
Document ID | / |
Family ID | 40623896 |
Filed Date | 2009-06-04 |
United States Patent
Application |
20090143343 |
Kind Code |
A1 |
Hill; Malcolm |
June 4, 2009 |
COMPOSITIONS FOR THE TREATMENT OF INFLAMMATION OF THE
GASTROINTESTINAL TRACT
Abstract
Provided herein are methods for treating the symptoms of and
inflammation associated with gastroesophageal reflux disease (GERD)
and other conditions. Also provided herein are pharmaceutical
compositions useful for the methods of the present invention.
Inventors: |
Hill; Malcolm; (Solana
Beach, CA) |
Correspondence
Address: |
WILSON SONSINI GOODRICH & ROSATI
650 PAGE MILL ROAD
PALO ALTO
CA
94304-1050
US
|
Assignee: |
MERITAGE PHARMA, INC.
San Diego
CA
|
Family ID: |
40623896 |
Appl. No.: |
12/269740 |
Filed: |
November 12, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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61035348 |
Mar 10, 2008 |
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61054103 |
May 16, 2008 |
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61054105 |
May 16, 2008 |
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61012012 |
Dec 6, 2007 |
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61054107 |
May 16, 2008 |
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61015998 |
Dec 21, 2007 |
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61019818 |
Jan 8, 2008 |
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61034941 |
Mar 7, 2008 |
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61054106 |
May 16, 2008 |
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61090658 |
Aug 21, 2008 |
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60987720 |
Nov 13, 2007 |
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61054104 |
May 16, 2008 |
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Current U.S.
Class: |
514/171 ;
514/174; 514/178 |
Current CPC
Class: |
A61K 31/4439 20130101;
A61K 31/58 20130101; A61K 9/0065 20130101; A61P 1/06 20180101; A61P
29/00 20180101; A61K 9/0053 20130101; A61P 25/00 20180101; A61P
1/00 20180101; A61K 47/36 20130101; A61K 9/0095 20130101; A61K
47/32 20130101; A61K 31/575 20130101; A61K 9/006 20130101; A61K
31/341 20130101; A61K 45/06 20130101; A61K 47/38 20130101; A61K
31/58 20130101; A61K 2300/00 20130101; A61K 31/341 20130101; A61K
2300/00 20130101; A61K 31/4439 20130101; A61K 2300/00 20130101 |
Class at
Publication: |
514/171 ;
514/174; 514/178 |
International
Class: |
A61K 31/56 20060101
A61K031/56; A61K 31/58 20060101 A61K031/58; A61P 1/06 20060101
A61P001/06 |
Claims
1. A method of treating or alleviating the symptoms of or
inflammation associated with gastroesophageal reflux disease (GERD)
in an individual by administering to an individual a
therapeutically effective amount of a corticosteroid.
2. The method of claim 1, wherein the gastroesophageal reflux
disease is nonerosive reflux disease (NERD).
3. The method of claim 1, wherein the gastroesophageal reflux
disease is erosive esophagitis (EE).
4. The method of claim 1, wherein the corticosteroid is a topical
corticosteroid.
5. The method of claim 4, wherein the topical corticosteroid is
budesonide.
6. The method of claim 4, wherein the topical corticosteroid is
fluticasone propionate.
7. The method of claim 1, wherein about 100 .mu.g/day to about 20
mg of the corticosteroid is administered to the individual.
8. The method of claim 7, wherein between 300 .mu.g/day and 4
mg/day of the corticosteroid is administered to the individual.
9. The method of claim 1, wherein the gastroesophageal reflux
disease (GERD) is refractory to an acid inhibitor.
10. The method of claim 1, further comprising administering a
therapeutically effective amount of an H.sub.2RA to said
individual.
11. The method of claim 10, wherein the corticosteroid and
H.sub.2RA are administered concurrently.
12. The method of claim 10, wherein the H.sub.2RA is selected from
cimetidine, famotidine, nizatidine, and ranitidine.
13. The method of claim 12, wherein the H.sub.2RA is
ranitidine.
14. The method of claim 10, wherein the H.sub.2RA is administered
in an amount of between 1 mg and 500 mg.
15. The method of claim 1, further comprising administering a
therapeutically effective amount of a proton pump inhibitor to said
individual.
16. The method of claim 15, wherein the corticosteroid and the
proton pump inhibitor are administered concurrently.
17. The method of claim 15, wherein the proton pump inhibitor is
selected from omeprazole, hydroxyomeprazole, esomeprazole,
tenatoprazole, lansoprazole, pantoprazole, rabeprazole,
dontoprazole, habeprazole, perprazole, ransoprazole, pariprazole,
leminoprazole, S-tenatoprazole-Na, and dexlansoprazole.
18. The method of claim 17, wherein the proton pump inhibitor is
omeprazole.
19. The method of claim 15, wherein the proton pump inhibitor is
administered in an amount of between 1 mg and 600 mg.
20. The method of claim 15, further comprising administering a
therapeutically effective amount of an H.sub.2RA to said
individual.
21. The method of claim 1, wherein the corticosteroid is
administered in the form of a pharmaceutical composition comprising
the corticosteroid and at least one excipient.
22. The method of claim 21, wherein the excipient increases the
interaction of the composition with the individual's esophagus.
23. The method of claim 22, wherein the viscosity of the
composition is about 2 cP, or greater, and wherein the viscosity is
measured at 25 degrees Celsius and a shear rate of about 13.2
sec.sup.-1.
24. The method of claim 23, wherein the viscosity of the
composition is about 200 cP to about 600 cP, and wherein the
viscosity is measured at 25 degrees Celsius and a shear rate of
about 13.2 sec.sup.-1.
25. The method of claim 22, wherein the excipient is a viscosity
enhancer, a mucoadhesive agent an absorption enhancing agent, or a
combination thereof.
26. The method of claim 25, wherein the viscosity-enhancing
excipient is selected from acacia (gum arabic), agar, aluminum
magnesium silicate, sodium alginate, sodium stearate, bladderwrack,
bentonite, carbomer, carrageenan, Carbopol, cellulose,
microcrystalline cellulose (MCC), ceratonia, chondrus, dextrose,
furcellaran, gelatin, Ghatti gum, guar gum, hectorite, lactose,
sucrose, maltodextrin, mannitol, sorbitol, honey, maize starch,
wheat starch, rice starch, potato starch, gelatin, sterculia gum,
xanthum gum, polyethylene glycol (e.g. PEG 200-4500), gum
tragacanth, ethyl cellulose, ethylhydroxyethyl cellulose,
ethylmethyl cellulose, methyl cellulose, hydroxyethyl cellulose,
hydroxyethylmethyl cellulose, hydroxypropyl cellulose,
poly(hydroxyethyl methacrylate), oxypolygelatin, pectin,
polygeline, povidone, propylene carbonate, methyl vinyl
ether/maleic anhydride copolymer (PVM/MA), poly(methoxyethyl
methacrylate), poly(methoxyethoxyethyl methacrylate), hydroxypropyl
cellulose, hydroxypropylmethyl-cellulose (HPMC), sodium
carboxymethyl-cellulose (CMC), silicon dioxide,
polyvinylpyrrolidone (PVP: povidone), Splenda.RTM. (dextrose,
maltodextrin and sucralose) and combinations thereof.
27. The method of claim 26, wherein the viscosity-enhancing
excipient is a combination of MCC and CMC.
28. The method of claim 27, wherein the CMC/MCC combination has a
mixed weight ratio of about 11/89.
29. The method of claim 25, wherein the mucoadhesive agent is
selected from a soluble polyvinylpyrrolidone polymer (PVP); a
water-swellable, but water-insoluble, fibrous, cross-linked
carboxy-functional polymer, a cross-linked poly(acrylic acid), a
carbomer homopolymer, a carbomer copolymer, a hydrophilic
polysaccharide gum, maltodextrin, a cross-linked alignate gum gel,
a water-dispersible polycarboxylated vinyl polymer, and
combinations thereof.
30. The method of claim 25, wherein the mucoadhesive agent is
selected from at least of titanium dioxide, silicon dioxide, and
clay, and mixtures thereof.
31. The method of claim 25, wherein the absorption enhancing agent
is selected from acylcarnitines, surfactants, sodium lauryl
sulfate, saponins, bile salts or bile acids including but not
limited to cholanic acid, chilic acid, deoxycholic acid,
glycocholic acid, tautocholic acid, chenodeoxycholic acid,
lithocholic acid, ursocholic acid, ursodeoxycholic acid, isourosde
oxycholic acid, lagodeoxycholic acid, glycodeoxycholic acid,
glycochenodeoxycholic acid, dehydrocholic acid, hyocholic acid,
hyodeoxycholic acid, or combinations thereof, dihydrofusidates,
fatty acid derivatives, chitosan, carbopol, cellulosic agents,
sterols, including but not limited to alcohols structurally related
to steroids, including but not limited to cholestanol, coprostanol,
cholesterol, epicholesterol, ergosterol, ergocalciferol, or
combinations thereof starch, dextran, cyclodextrin, and
combinations thereof.
32. The method of claim 1, wherein the corticosteroid is
administered in a unit dose formulation for oral administration.
Description
CROSS-REFERENCE
[0001] This application claims the benefit of U.S. Provisional
Application No. 60/987,720, filed Nov. 13, 2007; U.S. Provisional
Application No. 61/012,012, filed Dec. 6, 2007; U.S. Provisional
Application No. 61/015,998, filed Dec. 21, 2007; U.S. Provisional
Application No. 61/019,818, filed Jan. 8, 2008; U.S. Provisional
Application No. 61/034,941, filed Mar. 7, 2008; U.S. Provisional
Application No. 61/035,348, filed Mar. 10, 2008; U.S. Provisional
Application No. 61/054,103, filed May 16, 2008; U.S. Provisional
Application No. 61/054,104, filed May 16, 2008; U.S. Provisional
Application No. 61/054,105, filed May 16, 2008; U.S. Provisional
Application No. 61/054,106, filed May 16, 2008; U.S. Provisional
Application No. 61/054,107, filed May 16, 2008; and U.S.
Provisional Application No. 61/090,658, filed Aug. 20, 2008, which
applications are incorporated herein by reference.
BACKGROUND OF THE INVENTION
[0002] Gastroesophageal reflux disease (GERD) is among the most
common gastrointestinal (GI) problems. GERD is caused by abnormal
reflux in the esophagus. Heartburn is a common symptom that is
indicative of GERD. Other symptoms associated with GERD include, by
way of non-limiting example, odynophagia, bitter taste in the
mouth, belching, nausea, dysphagia, regurgitation, laryngitis,
cough, hoarseness and asthma are also associated with GERD.
SUMMARY OF THE INVENTION
[0003] Accordingly, certain embodiments of the present invention
provide for a method of treating or alleviating the symptoms of or
inflammation associated with gastroesophageal reflux disease
(GERD). Specifically, some embodiments of the present invention
provide for a method of treating or alleviating the symptoms of or
inflammation associated with gastroesophageal reflux disease (GERD)
in an individual by administering to an individual a
therapeutically effective amount of a corticosteroid. In specific
embodiments, the gastroesophageal reflux disease treated nonerosive
reflux disease (NERD). In other specific embodiments, the
gastroesophageal reflux disease is erosive esophagitis (EE). In
some embodiments of the present invention, the corticosteroid
utilized in the methods described herein is a topical
corticosteroid. Specific topical corticosteroid include, by way of
non-limiting example, budesonide and fluticasone.
[0004] In certain embodiments, the methods described herein include
administration of about 0.1 mg to about 20 mg/day; or at least 250
.mu.g/day of the corticosteroid to the individual. In specific
embodiments, between about 300 .mu.g/day and about 4 mg/day, or
between about 500 .mu.g/day and about 6 mg/day of the
corticosteroid is administered to the individual. In more specific
embodiments, between about 500 .mu.g/day and about 3 mg/day of the
corticosteroid is administered to the individual. In some
embodiments, less than 500 .mu.g/day of the corticosteroid is
administered to the individual.
[0005] In some embodiments, the methods described herein further
include administering a therapeutically effective amount of an acid
inhibitor to the individual.
[0006] In certain embodiments, the acid inhibitor is an H.sub.2RA.
In some embodiments, the corticosteroid and H.sub.2RA are
administered concurrently. In specific embodiments, the H.sub.2RA
is selected for, by way of non-limiting example, cimetidine,
famotidine, nizatidine, and ranitidine. In more specific
embodiments, the H.sub.2RA is ranitidine. In some embodiments, the
H.sub.2RA is administered in an amount of between 1 mg and 500
mg.
[0007] In other embodiments, the acid inhibitor is a proton pump
inhibitor. In some embodiments, the corticosteroid and the proton
pump inhibitor are administered concurrently. In specific
embodiments, the proton pump inhibitor is selected from, by way of
non-limiting example, omeprazole, hydroxyomeprazole, esomeprazole,
tenatoprazole, lansoprazole, pantoprazole, rabeprazole,
dontoprazole, habeprazole, perprazole, ransoprazole, pariprazole,
leminoprazole, S-tenatoprazole-Na, and dexlansoprazole. In a more
specific embodiment, the proton pump inhibitor is omeprazole. In
certain embodiments, the proton pump inhibitor is administered in
an amount of between 1 mg and 600 mg. Furthermore, in addition to
administering therapeutically effective amounts of a corticosteroid
and a proton pump inhibitor, certain embodiments of the present
invention include methods further comprising administering a
therapeutically effective amount of an H.sub.2RA to said
individual.
[0008] In any of the methods described herein, the present
invention includes methods wherein the corticosteroid is
administered in the form of a pharmaceutical composition comprising
the corticosteroid and at least one excipient. In specific
embodiments, such a pharmaceutical composition is viscous. In other
embodiments, the pharmaceutical composition is non-viscous. In some
embodiments, the excipient increases the interaction of the
composition with the individual's esophagus. In certain
embodiments, the excipient is a viscosity enhancer, a mucoadhesive
agent, an absorption enhancing agent, or a combination thereof. As
used herein, a mucoadhesive agent is an agent that adheres to a
gastrointestinal surface (e.g., either or both of a
gastrointestinal epithelia or mucosa).
[0009] In some embodiments, the viscosity-enhancing excipient is
selected from, by way of non-limiting example, cellulose (including
cellulose derivatives), acacia (gum arabic), agar, aluminum
magnesium silicate, sodium alginate, sodium stearate, bladderwrack,
bentonite, carbomer, carrageenan, Carbopol, cellulose,
microcrystalline cellulose (MCC), ceratonia, chondrus, dextrose,
furcellaran, gelatin, Ghatti gum, guar gum, hectorite, lactose,
sucrose, maltodextrin, mannitol, sorbitol, honey, maize starch,
wheat starch, rice starch, potato starch, gelatin, sterculia gum,
xanthum gum, polyethylene glycol (e.g. PEG 200-4500), gum
tragacanth, ethyl cellulose, ethylhydroxyethyl cellulose,
ethylmethyl cellulose, methyl cellulose, hydroxyethyl cellulose,
hydroxyethylmethyl cellulose, hydroxypropyl cellulose,
poly(hydroxyethyl methacrylate), oxypolygelatin, pectin,
polygeline, povidone, propylene carbonate, methyl vinyl
ether/maleic anhydride copolymer (PVM/MA), poly(methoxyethyl
methacrylate), poly(methoxyethoxyethyl methacrylate), hydroxypropyl
cellulose, hydroxypropylmethyl-cellulose (HPMC), sodium
carboxymethyl-cellulose (CMC), silicon dioxide,
polyvinylpyrrolidone (PVP: povidone), Splenda.RTM. (distributed by
McNeil Nutritionals, LLC Fort Washington, Pa. 19034-2299;
comprising dextrose, maltodextrin and sucralose) and combinations
thereof. In specific embodiments, the viscosity-enhancing excipient
is a combination of MCC and CMC (e.g., Avicel RC-591).
[0010] In some embodiments, the viscosity of the pharmaceutical
composition is greater than about 2 cP, greater than about 50 cP,
about 50 cP to about 800 cP, or about 90 cP to about 200 cP, or
about 300 cP to about 800 cP, or about 300 cP to about 500 cP or
about 400 cP to about 600 cP, and wherein the viscosity is measured
at 25 degrees Celsius. In specific embodiments, the viscosity of
the pharmaceutical composition is about 250 cP to about 600 cP.
[0011] In certain embodiments, the mucoadhesive agent is selected
from, by way of non-limiting example, a soluble
polyvinylpyrrolidone polymer (PVP); a water-swellable, but
water-insoluble, fibrous, cross-linked carboxy-functional polymer,
a cross-linked poly(acrylic acid), a carbomer homopolymer, a
carbomer copolymer, a hydrophilic polysaccharide gum, maltodextrin,
a cross-linked alignate gum gel, a water-dispersible
polycarboxylated vinyl polymer, and combinations thereof. In other
embodiments, the mucoadhesive agent is selected from at least of
titanium dioxide, silicon dioxide, and clay, and mixtures
thereof.
[0012] In some embodiments, the absorption enhancing agent is
selected from, by way of non-limiting example, acylcarnitines,
surfactants, sodium lauryl sulfate, saponins, bile salts or bile
acids including but not limited to cholanic acid, chilic acid,
deoxycholic acid, glycocholic acid, tautocholic acid,
chenodeoxycholic acid, lithocholic acid, ursocholic acid,
ursodeoxycholic acid, isourosde oxycholic acid, lagodeoxycholic
acid, glycodeoxycholic acid, glycochenodeoxycholic acid,
dehydrocholic acid, hyocholic acid, hyodeoxycholic acid, or
combinations thereof, dihydrofusidates, fatty acid derivatives,
chitosan, carbopol, cellulosic agents, sterols, including but not
limited to alcohols structurally related to steroids, including but
not limited to cholestanol, coprostanol, cholesterol,
epicholesterol, ergosterol, ergocalciferol, or combinations
thereof, starch, dextran, cyclodextrin, and combinations
thereof.
[0013] In certain embodiments, the present invention provides for
methods wherein the corticosteroid is administered in a unit dose
formulation for oral administration.
[0014] In some embodiments, the individual is an adult. In other
embodiments, the individual is a child or infant. In certain
embodiments, the child or infant is less than 19 years old, less
than 12 years old, less than 8 years old, less than 6 years old,
less than 4 years old or less than 2 years old.
INCORPORATION BY REFERENCE
[0015] All publications and patent applications mentioned in this
specification are herein incorporated by reference to the same
extent as if each individual publication or patent application was
specifically and individually indicated to be incorporated by
reference.
DETAILED DESCRIPTION OF THE INVENTION
[0016] In certain embodiments, the present invention is directed to
methods and pharmaceutical compositions for treating symptoms of
and/or inflammation associated inflammation of the gastrointestinal
tract. In some embodiments, compositions and methods provided
herein are used for the treatment of symptoms of and/or
inflammation associated with reflux disorders of the
gastrointestinal tract. In specific embodiments, provided herein
are compositions and methods for the treatment of symptoms and/or
inflammation associated with gastroesophageal reflux disease
(GERD). In some embodiments provided herein are methods for
treating the symptoms of and/or inflammation associated with the
gastrointestinal tract (e.g., associated with reflux disorders of
the gastrointestinal tract) in an individual comprising orally
administering to said individual a corticosteroid. In some
embodiments provided herein are methods for treating the symptoms
of and/or inflammation associated with gastroesophageal reflux
disease (GERD) in an individual comprising orally administering to
said individual a corticosteroid. In some embodiments, the symptom
of GERD treated is heartburn acid regurgitation, acid sensitivity,
chest pain and/or feeding intolerance.
[0017] Although most incidences of acid reflux are not sensed, GERD
symptoms occur in about 50% of patients at least once a month and
in about 20% of patients at least once a week. Patients with GERD
score lower in quality of life assessments than do patients with
congestive heart failure or even cardiac angina. Billions of
dollars are spent in the United States for the treatment of GERD
each year.
[0018] While transient reflux episodes may occur naturally, GERD is
associated with the impairment of normal esophageal defenses. In
GERD patients, gastroesophageal reflux may cause the display of
inflammation of the squamous mucosa of the esophagus and/or
hyperplasia of the epithelium. Inflammation resulting from GERD can
be found in the absence of Helicobacter pylori and other causes of
gastritis. In GERD, histologic changes to the squamous mucosa are
most likely to occur close to the squamo-columnar junction
(Z-line). Traditional reactive changes in the squamous mucosa are
typically found at least 3 cm above the Z-line.
[0019] Nonerosive reflux disease (NERD) and erosive esophagitis
(EE) are the main presentations of gastroesophageal reflux disease
(GERD), with NERD being the most common. Despite suffering from a
nonerosive form of GERD, NERD patients suffer from similar or
identical symptoms as those associated with EE. Furthermore, NERD
patients suffer from these symptoms with the same severity and are
experience the same level of impairment to their quality of life.
In some instances, patients with NERD actually suffer from more
severe heartburn symptoms than EE patients. Barrett's Esophagus is
a more rare and severe form of erosive GERD.
[0020] Approximately 50% of NERD patients display excess acid
reflux and an additional 50% appear to have esophageal acid
exposure within the normal physiological range. There are several
theories why these patients, particularly those with acid exposure
within the normal physiological range, experience GERD symptoms.
Some patients may be highly sensitive to physiological amounts of
acid exposure, some patients may experience GERD symptoms as a
result of nonacid related esophageal stimuli, and some patients may
be sensitive to changes in esophageal pH. Unlike NERD, about 75-90%
of EE patients are exposed to excess acid in the esophagus.
Furthermore, the increased exposure to the excess acid in the
esophagus is associated with the erosive characteristic of EE.
Finally, GERD patients suffering from Barrett's Esophagus appear to
be exposed to the highest level of esophageal acid when compared to
patients suffering from either NERD or EE.
[0021] In some embodiments, the present invention provides for
methods of treating the symptoms of and/or inflammation associated
with nonerosive reflux disease (NERD). In other embodiments, the
present invention provides methods of preventing the symptoms of
and/or inflammation associated with erosive esophagitis (EE). In
still other embodiments, the present invention provides for methods
of treating the symptoms of and/or inflammation associated with
Barrett's Esophagus. In some embodiments, the present invention
provides methods of treating neutrophilic inflammation associated
with GERD. In certain embodiments, the present invention provides
for a method of treating an individual suffering from symptoms of
and/or inflammation associated with GERD, wherein the individual is
not concurrently suffering from eosinophilic esophagitis. In
certain embodiments, the present invention provides for a method of
treating an individual suffering from symptoms of and/or
inflammation associated with GERD, wherein the individual has
<15 eosinophils/HPF. In certain embodiments, provided herein is
a method of treating non-eosinophilic esophagitis or gastritis by
administering to an individual a therapeutically effective amount
of corticosteroid, e.g., in a composition as described herein.
[0022] In some embodiments, an individual treated according to a
method described herein is diagnosed with, displaying the symptoms
of, or suspected of having GERD and eosinophilic esophagitis (EoE).
In some embodiments, an individual treated according to a method
described herein is diagnosed with, displaying the symptoms of, or
suspected of having GERD has an eosinophil count of greater than 0,
but less than 7 or less than 15 eosinophils/HPF. In certain
embodiments, provided herein is a method of treating
gastroesophageal reflux disease (GERD) in an individual by
administering to the individual a therapeutically effective amount
of a corticosteroid, wherein the GERD is refractory (e.g.,
non-responsive or substantially non-responsive) to at least one
acid inhibitor (e.g., at least one PPI and/or H.sub.2RA).
[0023] In some embodiments, the present invention provides for
methods of treating the symptoms of and/or inflammation associated
with gastroesophageal reflux disease (GERD) in an individual by
administering to the individual a therapeutically effective amount
of a corticosteroid and a therapeutically effective amount of a
second agent. In certain embodiments, the second agent is an acid
inhibitor. In some embodiments, the corticosteroid and the second
agent are administered in combination. In other embodiments, the
corticosteroid and the second agent are administered
sequentially.
[0024] As used herein, unless otherwise stated, the use of the
terms "a" and "the" include both singular and multiple
embodiments.
[0025] As used herein, the phrase "method of treating" or "method
for treating" encompasses methods of preventing, reducing the
incidences of, providing prophylactic treatment, treating and
alleviating.
[0026] As used herein, the term "or" includes "and" and "or".
[0027] As used herein, the phrase "treating GERD" includes treating
symptoms of GERD and treating inflammation associated with
GERD.
[0028] As used herein, the phrase "a therapeutically effective
amount" is an amount sufficient to elicit a change in the symptoms
of or inflammation associated with GERD, or other conditions as
appropriate within the context of the use of this term.
[0029] Compounds
[0030] Compounds useful in the present invention include topical
steroids that may be used to treat GERD, including erosive
esophagitis, non-erosive reflux disease, and/or Barrett's
Esophagus. In one embodiment, the topical steroid is budesonide. In
another embodiment, the topical steroid is fluticasone or
fluticasone propionate. In certain embodiments, the compounds
useful herein are corticosteroids.
[0031] Corticosteroids useful in any of the methods and/or
pharmaceutical compositions disclosed herein include, by way of
non-limiting example, alclometasone, amcinonide, beclometasone,
betamethasone, budesonide, ciclesonide, clobetasol, clobetasone,
clocortolone, cloprednol, cortivazol, deflazacort,
deoxycorticosterone, desonide, desoximetasone, dexamethasone,
diflorasone, diflucortolone, difluprednate, fluclorolone,
fludrocortisone, fludroxycortide, flumetasone, flunisolide,
fluocinolone acetonide, fluocinonide, fluocortin, fluocortolone,
fluorometholone, fluperolone, fluprednidene, fluticasone,
formocortal, halcinonide, halometasone, hydrocortisone aceponate,
hydrocortisone buteprate, hydrocortisone butyrate, loteprednol,
medrysone, meprednisone, methylprednisolone, methylprednisolone
aceponate, mometasone furoate, paramethasone, prednicarbate,
prednisone, prednisolone, prednylidene, rimexolone, tixocortol,
triamcinolone, ulobetasol, and combinations, pharmaceutically
acceptable salts and esters thereof. In one embodiment of the
present invention, the corticosteroid used herein is budesonide.
Budesonide is also known as
16,17-(butylidenebis(oxy))-11,21-dihydroxy-,
(11-.beta.,16-.alpha.)-pregna-1,4-diene-3,20-dione. In another
specific embodiment, the corticosteroid is fluticasone or
fluticasone propionate. As used herein, any reference to a topical
steroid or a corticosteroid, includes the disclosure of a
pharmaceutically acceptable salt thereof.
[0032] In certain embodiments, the corticosteroid(s) utilized
herein are utilized as particles (e.g., corticosteroid particles
suspended or dispersed in an aqueous medium). In specific
embodiments, the particles are microparticles. In some embodiments,
the microparticles have a mean diameter of about 0.1 microns to
about 50 microns. In specific embodiments, the microparticles have
a mean diameter of about 1 micron to about 20 microns. In certain
embodiments, at least 95%, at least 98%, or at least 99% of the
microparticles have a diameter of less than 10 microns.
[0033] In some embodiments, a composition or formulation described
herein comprises less than 50% w/w, less than 40% w/w, less than
30% w/w, less than 20% w/w, less than 10% w/w, less than 8% w/w,
less than 6% w/w, less than 5% w/w, less than 4% w/w, less than 3%
w/w, less than 2% w/w, or about 2% w/w, less than 1% W/W, less than
0.5% w/w, less than 0.3% w/w, less than 0.2% w/w, or about 0.2% w/w
of undissolved particles. In certain embodiments, a composition or
formulation described herein is substantially free of
non-corticosteroid particles.
[0034] Furthermore, any suitable additional active agent for
treating GERD is optionally included in a composition or method
described herein. In specific embodiments, a composition or
formulation described herein comprises a therapeutically effective
amount of a corticosteroid and a therapeutically effective amount
of at least one additional active agent. In some embodiments, the
at least one additional active agent is an agent that treats,
prevents, or alleviates the symptoms of and/or inflammation
associated with inflammatory diseases involving the
gastrointestinal tract (e.g., esophagus). It is to be understood
that in certain instances, when the corticosteroid is combined with
an additional active agent, the therapeutically effective amount of
the corticosteroid is less than it when the additional active agent
is absent.
[0035] In certain embodiments, the present invention provides for
methods and pharmaceutical compositions for preventing, reducing
the incidence of, treating or alleviating the symptoms of and
inflammation associated with gastroesophageal reflux disease (GERD)
in an individual by administering a therapeutically effective
amount of a corticosteroid and a therapeutically effective amount
of an additional active agent (e.g., an acid inhibitor). In some
embodiments, the therapeutically effective amount of the
corticosteroid is less when the corticosteroid therapy is
administered with (either concurrent with or separate from) an
additional active agent (e.g., an acid inhibitor) useful for
treating GERD than when administered without the additional active
agent (e.g., an acid inhibitor). Furthermore, in various
embodiments, the therapeutically effective amount of the additional
active agent (e.g., an acid inhibitor) is less than would have been
required if administered without the corticosteroid.
[0036] Furthermore, provided herein are methods of treating,
preventing or alleviating GERD in an individual comprising orally
administering to the individual a corticosteroid in association or
combination with at least one additional active agent. In certain
embodiments, the corticosteroid and the at least one additional
active agent is in a single dosage form. In other embodiments, the
corticosteroid and the at least one additional active agent are in
separate dosage forms and are administered in any manner,
including, by way of non-limiting example, simultaneously,
sequentially, or at different times. For example, in certain
embodiments, several doses of a corticosteroid composition are
administered over a period of time, after which administration of
the corticosteroid composition is discontinued and administration
of at least one additional active agent is administered at least
once.
[0037] In some embodiments, the at least one additional active
agent utilized in a composition, formulation or method described
herein is an agent that treats, prevents, or alleviates the
symptoms of and/or inflammation associated with GERD. In more
specific embodiments, the at least one additional active agent is
not a second corticosteroid. In certain embodiments, the at least
one additional active agent is an acid inhibitor (e.g., an H2
antagonist and/or a PPI). In certain embodiments, the at least one
additional active agent is, by way of non-limiting example, a
proton pump inhibitor (PPI), a H2 antagonist, a transient lower
esophageal sphincter relaxation (TLESR)-reducing agent, a
serotonergic agent/prokinetics, a potassium-competitive acid
blocker (P-CAB), a mucosal protectant, a histamine H3 agonist, an
anti-gastrin agent, mGluR.sub.5 antagonists, acetylcholine
modulator, 5HT.sub.4 receptor agonist, 5HT.sub.3 receptor
antagonist, 5HT.sub.1 receptor antagonist, or combinations
thereof.
[0038] In some embodiments, the acid inhibitor is a proton pump
inhibitor (PPI). In certain embodiments, the corticosteroid and the
PPI are administered in combination. In some embodiments, the
present invention provides for pharmaceutical compositions for
treating GERD that comprise a therapeutically effective amount of a
corticosteroid and a therapeutically effective amount of a PPI. In
some embodiments, the PPI may be coated with a protective layer,
for example, an enteric coating, to protect against an acidic
environment, such as the stomach, for later delivery at a target
area, such as the lower gastrointestinal tract, including the
duodenum.
[0039] PPIs useful herein include, by way of non-limiting example,
omeprazole, hydroxyomeprazole, esomeprazole, tenatoprazole,
lansoprazole, pantoprazole, rabeprazole, dontoprazole, habeprazole,
perprazole, ransoprazole, pariprazole, leminoprazole,
S-tenatoprazole-Na, and dexlansoprazole.
[0040] In various embodiments, the acid inhibitor is a histamine-2
or H.sub.2 receptor antagonist (H.sub.2RA) or H.sub.2 blocker. In
certain embodiments, the corticosteroid and the H.sub.2RA are
administered in combination. In some embodiments, the present
invention provides for pharmaceutical compositions for treating
GERD that comprise a therapeutically effective amount of a
corticosteroid and a therapeutically effective amount of an
H.sub.2RA. As used herein, use of the term "H.sub.2RA" includes
disclosure related to both H.sub.2 receptor antagonists and/or
H.sub.2 blockers.
[0041] H.sub.2RAs useful herein include, by way of non-limiting
example, cimetidine, rantitidine, famotidine and nizatidine.
[0042] In some embodiments, the TLESR-reducing agent is selected
from, by way of non-limiting example, GABA.sub.B agonists (e.g.,
baclofen), cholecystokinin (CCK-A or CCK-1) antagonists,
anticholinergic agents, NO synthase inhibitors and combinations
thereof. In some embodiments, the serotonergic agent/prokinetic is
a 5-HT.sub.4 receptor agonist (e.g., a selective 5-HT.sub.4
receptor agonist) including, by way of non-limiting example,
cisapride, mosapride, tegaserod, ATI-7505 and combinations thereof.
In some embodiments, potassium competitive acid blocker (P-CAB) is
selected from, by way of non-limiting example, soraprazan (BY359),
revaprazan (YH1885), AZDO865, CS-526 and combinations thereof. In
certain embodiments, mucosal protectants are selected from, by way
of non-limiting example, sucralfate. In some embodiments, mucosal
protectants include one or more of prostaglandin E.sub.2
(PGE.sub.2), epidermal growth factor (EGF) and/or transforming
growth factor-.alpha. (TGF-.alpha.), or analogs thereof. In a
specific embodiment, the mucosal protectant comprises the PGE.sub.2
analog trimoprostil. In some embodiments, the histamine H3 agonist
is selected from, by way of non-limiting example,
(R)-.alpha.-methyl-histamine. In certain embodiments, the
anti-gastrin agent is selected from, by way of non-limiting
example, cholecystokinin (CCK-B or CCK-2) antagonists.
Cholecystokinin (CCK-B or CCK-2) antagonists include, by way of
non-limiting example, Z-360.
[0043] In various embodiments, the corticosteroid described herein
is combined with at least one excipient. In some embodiments, the
excipient may increase the interaction of the composition with a
surface (e.g., a mucosal or epithelial layer) of the
gastrointestinal tract (e.g., esophagus), including excipients that
increase the viscosity of the composition, impart a mucoadhesive
characteristic to the composition, or enhance the absorption of the
composition through a surface (e.g., a mucosal or epithelial layer)
of the gastrointestinal tract (e.g., esophagus).
[0044] In certain embodiments, the excipient or excipients chosen
increase the interaction of the composition with the surface of the
gastrointestinal tract (e.g., the mucosa and/or epithelium of the
gastrointestinal tract or of a specific site of the
gastrointestinal tract, such as the esophagus) by at least 1.02
fold, by at least 1.05-fold, by at least 1.1 fold, by at least 1.2
fold, by at least 1.25-fold, by at least 1.5-fold, by at least
2-fold, by at least 3-fold, by at least 4-fold or by at least
5-fold. In certain embodiments, the increased interaction of the
composition is an at least 1.02 fold, by at least 1.05-fold, by at
least 1.1 fold, by at least 1.2 fold, by at least 1.25-fold, by at
least 1.5-fold, by at least 2-fold, by at least 3-fold, by at least
4-fold or by at least 5-fold of interaction of the composition with
the esophagus that occurs following passing of the bolus of the
composition being swallowed. In certain embodiments, these
increases are measured and compared to the measure of an otherwise
similar composition lacking the excipient or excipients that
increase the interaction of the composition with the surface of the
gastrointestinal tract. In certain instances, increased interaction
of the composition is measured as a function of the amount of
composition present in the esophagus (e.g., after the bolus has
passed through the esophagus). In specific instances, the amount of
composition present in the esophagus is measured in any suitable
manner, e.g., by radiolabeling the composition and measuring the
amount of the composition in the esophagus utilizing gamma
scintigraphy. An increase in the interaction of the composition
with the mucosal layer may be measured by a variety of means. In
one example, the retention time of the material along a length of a
mucosal layer may be measured, wherein the retention time is
increased in the presence of the excipients as compared to its
absence. In another aspect, the amount of composition absorbed may
also be quantified as a measurement of the interaction of the
composition with a mucosal layer. In yet another aspect, the
residence time of the composition may also be quantified, with the
residence time increased in the presence of the excipients as
compared to its absence. In another embodiment, uptake measurements
of the active agents may be compared in the presence and absence of
excipients, wherein the rate or amount of uptake may indicate an
increase in the interaction of the compositions disclosed herein
with a surface (e.g., a mucosal or epithelial layer) of the
gastrointestinal tract (e.g., esophagus). In yet another
embodiment, an increased interaction may be measured by the
decrease in physiological manifestations or symptoms of the disease
or ailment to be treated. In other embodiments, changes in
permeability or other cellular characteristics of a surface (e.g.,
a mucosal or epithelial layer) of the gastrointestinal tract (e.g.,
esophagus) may also be quantified, wherein a change in permeability
may indicate an increase in the interaction of the compositions
disclosed herein with a surface (e.g., a mucosal or epithelial
layer) of the gastrointestinal tract (e.g., esophagus).
[0045] In one aspect of the invention, the use of the excipients
may act to decrease the quantity of active agents needed to elicit
a response in the absence of the excipients. In some embodiments,
the excipients may decrease the amount of corticosteroid used.
Similarly, the excipients may decrease the amount of acid inhibitor
needed, for example, from about 1 mg to about 750 mg acid inhibitor
in the absence of excipient, to about 500 ug to about 600 mg acid
inhibitor in the presence of excipient.
[0046] Provided herein are methods and pharmaceutical compositions
for treating the symptoms of and/or inflammation associated with
gastroesophageal reflux disease (GERD), including erosive
esophagitis (EE), non-erosive reflux disease (NERD) and Barrett's
Esophagus.
[0047] In one aspect provided herein is an oral pharmaceutical
composition comprising (i) a corticosteroid and (ii) an
H.sub.2RA.
[0048] In another aspect, provided herein is an oral pharmaceutical
composition for treating the symptoms of and/or inflammation
associated with GERD comprising (i) a corticosteroid; (ii) an
H.sub.2RA; and (iii) an excipient or combination of excipients. In
some embodiments, the excipient may increase the interaction of the
composition with a surface (e.g., a mucosal or epithelial layer) of
the gastrointestinal tract (e.g., esophagus), including excipients
that increase the viscosity of the composition, impart a
mucoadhesive characteristic to the composition, or enhance the
absorption of the composition through a surface (e.g., a mucosal or
epithelial layer) of the gastrointestinal tract (e.g.,
esophagus).
[0049] In one aspect, provided herein is an oral pharmaceutical
composition for treating the symptoms of and/or inflammation
associated with GERD comprising (i) a corticosteroid and (ii) a
proton pump inhibitor (PPI).
[0050] In another aspect, provided herein is an oral pharmaceutical
composition for treating the symptoms of and/or inflammation
associated with GERD comprising (i) a corticosteroid; (ii) a proton
pump inhibitor (PPI); and (iii) an excipient or combination of
excipients. In some embodiments, the excipient may increase the
interaction of the composition with a surface (e.g., a mucosal or
epithelial layer) of the gastrointestinal tract (e.g., esophagus),
including excipients that increase the viscosity of the
composition, impart a mucoadhesive characteristic to the
composition, or enhance the absorption of the composition through a
surface (e.g., a mucosal or epithelial layer) of the
gastrointestinal tract (e.g., esophagus). In some embodiments, the
PPI may be coated with a protective layer, for example, an enteric
coating, to protect against an acidic environment, such as the
stomach, for later delivery at a target area, such as the lower
gastrointestinal tract, including the duodenum.
[0051] In one aspect, provided herein is an oral pharmaceutical
composition for treating the symptoms of and/or inflammation
associated with GERD comprising (i) a corticosteroid, (ii) a PPI,
(iii) an H.sub.2RA and (iv) an excipient or combination of
excipients thereof. In some embodiments, the excipient may increase
the interaction of the composition with a surface (e.g., a mucosal
or epithelial layer) of the gastrointestinal tract (e.g.,
esophagus), including excipients that increase the viscosity of the
composition, impart a mucoadhesive characteristic to the
composition, or enhance the absorption of the composition through a
surface (e.g., a mucosal or epithelial layer) of the
gastrointestinal tract (e.g., esophagus). In some embodiments, the
PPI may be coated with a protective layer, for example, an enteric
coating, to protect against an acidic environment, such as the
stomach, for later delivery at a target area, such as the lower
gastrointestinal tract, including the duodenum.
[0052] In certain embodiments, pharmaceutical compositions
disclosed herein and used herein comprise one or more excipients
and/or one or more additional active agents. Excipients useful
herein include, by way of non-limiting example, mucoadhesive
agents, viscosity enhancing agents, binders, fillers, lubricants,
solvents, suspension agents, flavoring agents, coloring agents,
sweeteners, preservatives, antioxidants, buffering agents,
humectants, chelating agents, surfactants, and the like. Additional
active agents useful herein include, by way of non-limiting
example, a proton pump inhibitor (PPI), a H2 antagonist, a
transient lower esophageal sphincter relaxation (TLESR)-reducing
agent, a serotonergic agent/prokinetics, a potassium-competitive
acid blocker (P-CAB), a mucosal protectant a histamine H3 agonist,
an anti-gastrin agent, mGluR.sub.5 antagonists, acetylcholine
modulator, 5HT.sub.4 receptor agonist, 5HT.sub.3 receptor
antagonist, 5HT.sub.1 receptor antagonist, antibiotics, or
combinations thereof. In certain instances, an additional active
agent useful herein also serves to extend the time of contact
between the composition and a surface (e.g., a mucosal or
epithelial layer) of the gastrointestinal tract (e.g., esophagus).
For example, in certain embodiments, the additional active agent
also increases the viscosity of the composition, imparts a
mucoadhesive character upon the composition and/or enhances
absorption of the composition through a surface (e.g., a mucosal or
epithelial layer) of the gastrointestinal tract (e.g.,
esophagus).
[0053] In certain embodiments, the acid inhibitor is an H.sub.2RA.
H.sub.2RAs includes, by way of non-limiting example, cimetidine,
ranitidine, ebrotidine, pabutidine, lafutidine, loxtidine and
famotidine. In a specific embodiment, the H.sub.2RA is
ranitidine.
[0054] In certain embodiments, the acid inhibitor is a PPI. PPIs
include, by way of non-limiting example, omeprazole,
hydroxyomeprazole, esomeprazole, tenatoprazole, lansoprazole,
pantoprazole, rabeprazole, dontoprazole, habeprazole, perprazole,
ransoprazole, pariprazole and leminoprazole. In one non-limiting
example, the PPI is omeprazole.
[0055] In certain embodiments, the corticosteroid is administered
in combination with an excipient. In some embodiments, excipients
are included in the corticosteroid containing composition to
increase the viscosity of the delivered composition. In various
embodiments, the liquid viscosity is increased in the oral dosage
form of the corticosteroid containing composition. In other
embodiments, the excipient increases the viscosity of the oral
dosage form of the corticosteroid containing composition once the
oral dosage form is dissolved (e.g., in saliva). It is to be
understood that in various embodiments of the present invention,
the viscosity of the oral dosage form (or of the dissolved oral
dosage form) is at a level that is sufficient to deliver an
effective amount of the composition to the esophagus. In some
embodiments, the effective amount of the composition delivered to
the esophagus is an amount sufficient to coat the esophagus, and
thereafter deliver the composition to the affected areas, including
by way of example only, the lower esophagus, the esophageal-stomach
juncture, the stomach, the duodenum and/or within 3 cm of the
Z-line. In certain embodiments, the viscosity of the oral dosage
form (or of the dissolved oral dosage form) is such that when
administered orally, it is not so thick as to cause difficulty in
swallowing, cause gagging, or be unpalatable. Those of ordinary
skill in the art can determine the viscosity of the compositions
provided herein, and may thus determine appropriate ranges. In
certain embodiments, the viscosity of the oral dosage form (or of
the dissolved oral dosage form) is a viscosity that is sufficient
to provide exposure of the corticosteroid to the esophagus for a
sufficient period of time such that the symptoms of and/or
inflammation associated with GERD are reduced following
administration of the corticosteroid containing oral dosage
form.
[0056] One method for determining sufficient viscosity may include
monitoring changes in the interaction of the composition with a
surface (e.g., a mucosal or epithelial layer) of the
gastrointestinal tract (e.g., esophagus), including but not limited
to measuring changes in residence or retention time of the
composition in the absence and presence of the excipient. Another
method for determining whether the composition is sufficiently
viscous is by determining whether the inflammation of the esophagus
is reduced after treatment with the composition.
[0057] Viscosity can also be determined by any method that will
measure the resistance to shear offered by the substance or
preparation. Many viscometers are available to those in the
pharmaceutical field, and include those built by, for example,
Brookfield.
[0058] Viscosity-enhancing excipients that may be used in
pharmaceutical compositions described herein include, but are not
limited to, cellulose or a cellulose derivative, acacia (gum
arabic), agar, aluminum magnesium silicate, sodium alginate, sodium
stearate, bladderwrack, bentonite, carbomer, carrageenan, Carbopol,
cellulose, microcrystalline cellulose (MCC), ceratonia, chondrus,
dextrose, furcellaran, gelatin, Ghatti gum, guar gum, hectorite,
lactose, sucrose, maltodextrin, mannitol, sorbitol, honey, maize
starch, wheat starch, rice starch, potato starch, gelatin,
sterculia gum, xanthum gum, polyethylene glycol (e.g. PEG
200-4500), gum tragacanth, ethyl cellulose, ethylhydroxyethyl
cellulose, ethylmethyl cellulose, methyl cellulose, hydroxyethyl
cellulose, hydroxyethylmethyl cellulose, hydroxypropyl cellulose,
poly(hydroxyethyl methacrylate), oxypolygelatin, pectin,
polygeline, povidone, propylene carbonate, methyl vinyl
ether/maleic anhydride copolymer (PVM/MA), poly(methoxyethyl
methacrylate), poly(methoxyethoxyethyl methacrylate), hydroxypropyl
cellulose, hydroxypropylmethyl-cellulose (HPMC), sodium
carboxymethyl-cellulose (CMC), silicon dioxide,
polyvinylpyrrolidone (PVP: povidone), Splenda.RTM. (distributed by
McNeil Nutritionals, LLC Fort Washington, Pa. 19034-2299) or
combinations thereof. In one non-limiting example, the
viscosity-enhancing excipient is Splenda.RTM.. In specific
embodiments, the viscosity-enhancing excipient is a combination of
MCC and CMC (e.g., Avicel RC-591). In some embodiments, the CMC/MCC
combination (e.g., Avicel.RTM. RC-591) is present in the
composition in an amount of about 1 mg/mL to about 150 mg/mL, 1
mg/mL to about 75 mg/mL, or about 5 mg/mL to about 40 mg/mL. In
certain embodiments, the CMC/MCC mixed weight ratio is between
about 1/99 and about 99/1, about 20/80 and about 5/95, or about
15/85 and about 10/90. In a specific embodiment, the CMC is NaCMC
and the CMC/MCC mixed weight ratio is about 11/89.
[0059] In some embodiments, the viscosity of the composition is at
least about 1 centipoise (cP), at least about 2 cP, at least about
3 cP, at least about 5 cP, at least about 10 cP, at least about 15
cP, at least about 20 cP, at least about 25 cP, at least about 30
cP, at least about 35 cP, at least about 40 cP, or at least about
50 cP. In some embodiments, the viscosity of the composition is at
least about 100 cP. In certain embodiments, the viscosity of the
composition, measured at 25 degrees Celsius, is about 50 cP to
about 250,000 cP, about 50 cP to about 70,000 cP, about 50 cP to
about 25,000 cP, about 50 cP to about 10,000 cP, about 50 cP to
about 3,000 cP, or about 50 cP to about 2,000 cP. In one aspect,
the viscosity of the composition, as measured at 25 degrees
Celsius, is from about 25 centipoise (cP) to about 800 cP, about 50
cP to about 800, or about 300 cP to about 800 cP (e.g., measured by
a Brookfield viscometer). In another aspect, the viscosity of the
composition may range from about 100 cP to about 200 cP, about 200
cP to about 300 cP, about 250 cP to about 600 cP or about 400 cP to
about 600 cP. In specific embodiments, the viscosity of the
formulation is about 30 cP, about 100 cP, about 200 cP, about 300
cP, about 400 cP, about 500 cP, or about 250,000 cP (e.g., as
measured with a Brookfield viscometer at 25 degrees Celsius
equipped with an ultra low adapter). In some embodiments, a
composition or formulation described herein comprises a viscosity
enhancing agent that imparts on the composition a viscosity
sufficient to provide increased residence on the esophagus while
also allowing migration of the active agent(s) (solute or
particles) when the composition is orally administered to an
individual. In other words, in some embodiments, the viscosity is
high enough to increase residence time of the composition on a
surface (e.g., a mucosal or epithelial layer) of the
gastrointestinal tract (e.g., esophagus), but not so high as to
prevent migration of the active agent(s) within the composition,
e.g., toward the surface (e.g., a mucosal or epithelial layer) of
the gastrointestinal tract (e.g., esophagus).
[0060] Viscosity can also be determined by any method that will
measure the resistance to shear offered by the substance or
preparation. Many viscometers are available to those in the
pharmaceutical field, and include those built by, for example,
Brookfield.
[0061] In certain embodiments, a pharmaceutical composition
described herein is a non-Newtonian fluid or a Newtonian fluid. In
some embodiments, a composition described herein is non-Newtonian.
In specific embodiments, the non-Newtonian fluid is a plastic,
pseudo-plastic or dilatant non-Newtonian fluid. In some specific
embodiments, the non-Newtonian fluid is thixotropic. In certain
embodiments, the non-Newtonian fluid composition thins with shear,
and thickens upon the absence of shear. Thus, in some embodiments,
provided herein is a fluid pharmaceutical composition that is
suitable for easy pouring following mild or moderate agitation.
Furthermore, in some embodiments, provided herein is a fluid
pharmaceutical composition that while being suitable for easy
pouring following mild or moderate agitation becomes viscous enough
upon oral administration to allow the pharmaceutical composition to
at least partially coat the esophagus and topically deliver a
therapeutically effective amount of corticosteroid to the
esophagus. In some embodiments, the at least one additional
excipient is selected from a non-Newtonian viscosity enhancing
agent (i.e., an agent that provides a composition herein with a
non-Newtonian character). Non-Newtonian viscosity enhancing agents
include, by way of non-limiting example, acacia (e.g., used in
about 5-10% w/w of a pharmaceutical composition described herein),
alginic acid (e.g., about 0.5-20% w/w), carbomer, CaCMC, NaCMC,
carrageenan (e.g., about 0.3-12% w/w), ceratonia (e.g., about
0.1-1% w/w), chitosin (e.g., about 0.5-2% w/w), colloidal silicon
dioxide (e.g., about 2-10% w/w), ethylcellulose (e.g., about 5-25%
w/w), gelatin, guar gum (e.g., about 1-2.5% w/w), HEC,
hydroxyethylmethyl cellulose (e.g., about 1-5% w/w), hydroxypropyl
cellulose (e.g., about 1-10% w/w), HPMC, magnesium aluminum
silicate (e.g., about 2-10% w/w), one or more maltodextrin,
methylcellulose (e.g., about 1-2% w/w), polyethylene glycol (e.g.,
about 45-60% w/w), povidone (e.g., about 10-15% w/w), saponite,
sodium alginate (e.g., about 1-5% w/w), sucrose (e.g., about 50-70%
w/w), tragacanth (e.g., about 0.1-2% w/w), xanthan gum (e.g., about
0.1-1% w/w), an combinations thereof.
[0062] A Newtonian fluid can be described as a fluid whose
viscosity is equal to the shear stress exerted by the fluid divided
by the velocity gradient perpendicular to the direction of the
shear. In certain embodiments, the at least one additional
excipient is selected from a Newtonian viscosity enhancing agent
(i.e., an agent that provides a composition herein with a Newtonian
character). Newtonian viscosity enhancing agents include, by way of
non-limiting example, glycerin (e.g., about 50-80% w/w),
polydextrose (e.g., about 50-70% w/w), and combinations
thereof.
[0063] In some embodiments, a pharmaceutical composition described
herein is sufficiently spreadable and/or has an appropriate flow
characteristic on a surface (e.g., a mucosal or epithelial layer)
of the gastrointestinal tract (e.g., esophagus). In certain
embodiments, the spreadability and/or flow characteristic of the
composition is suitable so as to allow a pharmaceutical composition
or a unit dose of a pharmaceutical composition described herein to
spread across and/or flow upon a surface (e.g., a mucosal or
epithelial layer) of the gastrointestinal tract (e.g., esophagus)
and at least partially coat the surface (e.g., a mucosal or
epithelial layer) of the gastrointestinal tract (e.g., esophagus).
In some embodiments, by at least partially coating the surface
(e.g., a mucosal or epithelial layer) of the gastrointestinal tract
(e.g., esophagus), topical delivery of the corticosteroid to the
gastrointestinal site is achieved.
[0064] Excipients, such as, for example, those listed herein, may
be included in the composition are mucoadhesive agents including,
but not limited to, at least one soluble polyvinylpyrrolidone
polymer (PVP); a carbopol; a water-swellable, but water-insoluble,
fibrous, cross-linked carboxy-functional polymer; a crosslinked
poly(acrylic acid) (e.g. Carbopol 947P); a carbomer homopolymer; a
carbomer copolymer; a hydrophilic polysaccharide gum, one or more
maltodextrin, a cross-linked alignate gum gel, a water-dispersible
polycarboxylated vinyl polymer, at least two particulate components
selected from the group consisting of titanium dioxide, silicon
dioxide, and clay, or a mixture thereof. The mucoadhesive agent may
be used in combination with a viscosity increasing excipient, or
may be used alone to increase the interaction of the composition
with the esophagus. In certain embodiments, the mucoadhesive agent
also imparts an increased viscosity character on the composition
(as compared to a composition lacking the mucoadhesive agent). In
other embodiments, the mucoadhesive agent does not substantially
affect the viscosity of the composition.
[0065] In certain embodiments, the mucoadhesive agent and/or
viscosity enhancing agent comprises one or more maltodextrin. In
various aspects, the physical characteristics of maltodextrins vary
depending, e.g., on the dextrose equivalent of the specific
maltodextrin. In certain aspects, the dextrose equivalent of a
specific maltodextrin may affect the viscosity, hygroscopicity,
sweetness, humectancy, plasticity, solubility and or
mucoadhesiveness of the maltodextrin. Thus, in various embodiments,
a maltodextrin is selected based on the specific character that is
desired to be imparted upon the pharmaceutical composition
described herein. In certain embodiments, a maltodextrin is
selected that increases the mucoadhesive character of a composition
described herein without substantially increasing the viscosity of
the composition (e.g., compared to an otherwise identical
composition lacking the maltodextrin). In other embodiments, a
maltodextrin is selected that increases the viscosity of a
composition described herein without substantially increasing the
mucoadhesiveness of the composition (e.g., compared to an otherwise
identical composition lacking the maltodextrin). In some
embodiments, the oral pharmaceutical composition comprises a first
maltodextrin that increases the viscosity of the oral
pharmaceutical composition and a second maltodextrin that increases
the mucoadhesive character of the oral pharmaceutical composition
(e.g., compared to an otherwise identical composition lacking the
second maltodextrin).
[0066] In some embodiments, a composition or formulation described
herein comprises less than about 0.1 g or less than about 1 g of
maltodextrin for every mL of liquid vehicle in the oral
pharmaceutical composition. In certain embodiments, a composition
or formulation described herein comprises at least one
maltodextrin. In certain instances, a composition or formulation
described herein comprises less than 2 g of maltodextrin/mL of
composition, less than 1.5 g of maltodextrin/mL of composition,
less than 1 g of maltodextrin/mL of composition, less than 0.5 g of
maltodextrin/mL of composition, less than 0.25 g/mL of
maltodextrin/mL of composition, about 0.05 g of maltodextrin/mL of
composition to about 0.5 g of maltodextrin/mL of composition, about
0.05 g of maltodextrin/mL of composition to about 0.4 g of
maltodextrin/mL of composition, about 0.05 g of maltodextrin/mL of
composition to about 0.3 g of maltodextrin/mL of composition, about
0.1 g of maltodextrin/mL of composition to about 0.5 g of
maltodextrin/mL of composition, about 0.1 g of maltodextrin/mL of
composition to about 0.4 g of maltodextrin/mL of composition, about
0.1 g of maltodextrin/mL of composition to about 0.3 g of
maltodextrin/mL of composition, about 0.2 g of maltodextrin/mL of
composition to about 0.5 g of maltodextrin/mL of composition, about
0.2 g of maltodextrin/mL of composition to about 0.4 g of
maltodextrin/mL of composition, or about 0.2 g of maltodextrin/mL
of composition to about 0.3 g of maltodextrin/mL of composition. In
some embodiments, any composition or formulation described herein
comprises greater than about 7% w/w, greater than about 8% w/w,
greater than about 9% w/w, greater than about 10% w/w, greater than
about 11% w/w, greater than about 12% w/w, greater than about 13%
w/w, greater than about 14% w/w, greater than about 15% w/w,
greater than about 16% w/w, greater than about 17% w/w, greater
than about 18% w/w, greater than about 19% w/w, greater than about
20% w/w, greater than about 21% w/w, greater than about 22% w/w,
greater than about 23% w/w, greater than about 24% w/w, greater
than about 25% w/w, greater than about 26% w/w, greater than about
27% w/w, greater than about 28% w/w, greater than about 29% w/w or
greater than about 30% w/w of maltodextrin. In specific
embodiments, the maltodextrin is substantially dissolved in a
liquid vehicle of the composition or formulation. In certain
embodiments, the maltodextrin has a dextrose equivalents (DE) of
greater than 4, greater than 5, greater than 10, greater than 11,
greater than 12, greater than 13, greater than 14, greater than 15,
about 15, about 4 to about 10, about 4 to about 9, about 4 to about
8, about 11 to about 20, about 12 to about 19, about 13 to about
18, or about 14 to about 16. In specific embodiments, the first
maltodextrin has a DE of about 4 to about 10, about 4 to about 9,
or about 4 to about 8 and the second maltodextrin has a DE of about
10 to about 20, about 12 to about 19, or about 13 to about 18. In
some embodiments, at least one maltodextrin utilized in a
composition described herein has a molecular weight high enough to
increase the solubility of a corticosteroid, or to increase the
suspendability of a corticosteroid particle.
[0067] In some embodiments, an excipient that enhances the
interaction of a composition or formulation described herein (e.g.,
maltodextrin) is substantially dissolved in a liquid vehicle of the
composition or formulation.
[0068] In certain instances, the mucoadhesive character and/or
viscosity imparted to a composition described herein is sufficient
to deliver an effective amount of the composition to, for example,
the esophagus in an amount that may coat the esophagus, and
thereafter deliver the composition to the affected areas, including
by way of example only, the lower esophagus, the esophageal-stomach
juncture, the stomach, the duodenum and/or within 3 cm of the
Z-line. Also, in some instances, the mucoadhesive character and/or
viscosity is at a level that may be given orally, i.e. allows a
patient to swallow, limits a gagging reaction, and is palatable.
Those of ordinary skill in the art can determine the mucoadhesive
characteristics of the compositions provided herein, and may thus
determine appropriate ranges. One method for determining sufficient
mucoadhesiveness may include monitoring changes in the interaction
of the composition with a surface (e.g., a mucosal or epithelial
layer) of the gastrointestinal tract (e.g., esophagus), including
but not limited to measuring changes in residence or retention time
of the composition in the absence and presence of the excipient.
Another method for determining whether the composition is
sufficiently mucoadhesive is by determining whether the
inflammation of the esophagus is reduced after treatment with the
corticosteroid.
[0069] Mucoadhesive agents have also been described, for example,
in U.S. Pat. Nos. 6,638,521, 6,562,363, 6,509,028, 6,348,502,
6,319,513, 6,306,789, 5,814,330, and 4,900,552, each of which is
hereby incorporated by reference in its entirety.
[0070] In another non-limiting example, a mucoadhesive agent can
be, for example, at least two particulate components selected from
titanium dioxide, silicon dioxide, and clay, wherein the
composition is not further diluted with any liquid prior to
administration and the level of silicon dioxide, if present is from
about 3% to about 15%, by weight of the composition. Silicon
dioxide, if present, may be selected from the group consisting of
fumed silicon dioxide, precipitated silicon dioxide, coacervated
silicon dioxide, gel silicon dioxide, and mixtures thereof. Clay,
if present, may be kaolin minerals, serpentine minerals, smectites,
illite or a mixture thereof. For example, clay can be laponite,
bentonite, hectorite, saponite, montmorillonites or a mixture
thereof.
[0071] Excipients, such as, for example, those listed herein, that
may be included in the composition are absorption enhancing agents.
Examples of absorption enhancing include, but are not limited to,
acylcarnitines, surfactants, sodium lauryl sulfate, saponins, bile
salts or bile acids including but not limited to cholanic acid,
chilic acid, deoxycholic acid, glycocholic acid, tautocholic acid,
chenodeoxycholic acid, lithocholic acid, ursocholic acid,
ursodeoxycholic acid, isourosde oxycholic acid, lagodeoxycholic
acid, glycodeoxycholic acid, glycochenodeoxycholic acid,
dehydrocholic acid, hyocholic acid, hyodeoxycholic acid, or
combinations thereof, dihydrofusidates, fatty acid derivatives,
chitosan, carbopol, cellulosic agents, sterols, including but not
limited to alcohols structurally related to steroids, including but
not limited to cholestanol, coprostanol, cholesterol,
epicholesterol, ergosterol, ergocalciferol, or combinations
thereof, starch, dextran, cyclodextrin, or combinations thereof.
Absorption enhancing agents may act by increasing absorption of the
active agent, including corticosteroids and acid inhibitors,
through a surface (e.g., a mucosal or epithelial layer) of the
gastrointestinal tract (e.g., esophagus). Examples of absorption
enhancing agents are disclosed in WO 2005/113008, which is hereby
incorporated by reference in its entirety.
[0072] The compositions contemplated herein may also include a
combination of excipients that are viscosity enhancing agents,
mucoadhesive agents and/or absorption enhancing agents. Moreover,
an excipient may exhibit multiple characteristics, i.e. may be both
a viscosity enhancing agent and a mucoadhesive agent. The
composition may also include excipients that do not impart
characteristics of viscosity enhancing, mucoadhesive agents or
absorption enhancing activity.
[0073] In certain embodiments, a composition provided herein
comprises or is prepared by combining the components set forth in
any of Tables 1-13. In various embodiments, one or more of
maltodextrin, dextrose, HEC, CMC, MCC, Carbomer and HPMC are
utilized therein.
TABLE-US-00001 TABLE 1 Budesonide Composition #1 Ingredient Amount
Budesonide 1 mg to 150 mg CMC, MCC, Carbomer, HPMC and/or HEC 0.5 g
to 10 g Dextrose 0 g to 100 g Maltodextrin 0 g to 100 g EDTA (e.g.,
disodium edetate) 5 mg to 200 mg Citric Acid 10 mg to 1 g Citrate
(e.g., sodium citrate) 10 mg to 2 g Polysorbate 80 (e.g., Tween 80)
5 mg to 100 mg Flavoring Agent optional Sweetener optional
Preservative optional Water q.s. to 100 mL
TABLE-US-00002 TABLE 2 Budesonide Composition #2 Ingredient Amount
Budesonide 1 mg to 150 mg CMC, MCC, Carbomer, HPMC and/or HEC 0 g
to 10 g Dextrose 1 g to 100 g Maltodextrin 0 g to 100 g EDTA (e.g.,
disodium edetate) 5 mg to 200 mg Citric Acid 10 mg to 1 g Citrate
(e.g., sodium citrate) 10 mg to 2 g Polysorbate 80 (e.g., Tween 80)
5 mg to 100 mg Flavoring Agent optional Sweetener optional
Preservative optional Water q.s. to 100 mL
TABLE-US-00003 TABLE 3 Budesonide Composition #3 Ingredient Amount
Budesonide 1 mg to 150 mg CMC, MCC, Carbomer, HPMC and/or HEC 0 g
to 10 g Dextrose 0 g to 100 g Maltodextrin 1 g to 100 g EDTA (e.g.,
disodium edetate) 5 mg to 200 mg Citric Acid 10 mg to 1 g Citrate
(e.g., sodium citrate) 10 mg to 2 g Polysorbate 80 (e.g., Tween 80)
5 mg to 100 mg Flavoring Agent optional Sweetener optional
Preservative optional Water q.s. to 100 mL
TABLE-US-00004 TABLE 4 Budesonide Composition #4 Ingredient Amount
Budesonide 0.5 mg to 2 mg CMC and MCC (e.g., Avicel RC-591) 0.01 g
to 0.3 g Dextrose 0.1 g to 1 g Maltodextrin 0.5 g to 2 g EDTA
(e.g., disodium edetate) 1 mg to 10 mg Citric Acid 0.1 mg to 100 mg
Citrate (e.g., sodium citrate) 0.1 mg to 200 mg Polysorbate 80
(e.g., Tween 80) 0.1 mg to 10 mg Cherry Flavor 1 mg to 100 mg
Sweetener 100 mg to 1 g Sodium Benzoate 1 mg to 50 mg Potassium
Sorbate 1 mg to 50 mg Water q.s. to 5 mL
TABLE-US-00005 TABLE 5 Budesonide Composition #5 Ingredient Amount
Budesonide 0.5 mg to 2 mg CMC and MCC (e.g., Avicel RC-591) 0.02 g
to 0.6 g Dextrose 0.2 g to 2 g Maltodextrin 1 g to 4 g EDTA (e.g.,
disodium edetate) 2 mg to 20 mg Citric Acid 0.2 mg to 200 mg
Citrate (e.g., sodium citrate) 0.2 mg to 400 mg Polysorbate 80
(e.g., Tween 80) 0.2 mg to 20 mg Cherry Flavor 2 mg to 200 mg
Sweetener 200 mg to 2 g Sodium Benzoate 2 mg to 100 mg Potassium
Sorbate 2 mg to 100 mg Water q.s. to 10 mL
TABLE-US-00006 TABLE 6 Budesonide Composition #6 Ingredient Amount
(mg/mL) Budesonide 0.01 to 0.5 CMC and MCC (e.g., Avicel RC-591) 2
to 100 Dextrose 10 to 500 Maltodextrin (M150) 10 to 500 EDTA (e.g.,
disodium edetate) 0.01 to 10 Citric acid 0.1 to 10 Citrate (e.g.,
sodium citrate) 0.1 to 10 Polysorbate 80 (e.g., Tween 80) 0.01 to 1
Flavoring agent (e.g., Cherry Flavor) 0.1 to 100 Glycerin 10 to 100
Acesulfame potassium 0.1 to 40 Magnasweet 110 0.1 to 40 Sodium
Benzoate 0.1 to 10 Potassium Sorbate 0.1 to 10 Water q.s. to 1-15
mL
TABLE-US-00007 TABLE 7 Budesonide Composition #7 Ingredient Amount
(mg/mL) Budesonide about 0.05 to about 0.2 CMC and MCC (e.g.,
Avicel RC-591) 5 to 50 Dextrose 50 to 250 Maltodextrin (M150) 200
to 500 EDTA (e.g., disodium edetate) 0.1 to 1 Citric acid 0.5 to 5
Citrate (e.g., sodium citrate) 0.2 to 2 Polysorbate 80 (e.g., Tween
80) 0.01 to 0.4 Flavoring agent (e.g., Cherry Flavor) 1 to 10
Glycerin 30 to 80 Acesulfame potassium 1 to 10 Magnasweet 110 1 to
10 Sodium Benzoate 0.5 to 4 Potassium Sorbate 0.5 to 4 Water q.s.
to 1-15 mL
TABLE-US-00008 TABLE 8 Budesonide Composition #8 Ingredient Amount
(mg/mL) Amount % w/w Budesonide 0.05 0.004 Avicel RC-591 23.6 2
Dextrose 118 10 Maltodextrin (M150) 306.8 26 Disodium edetate 0.59
0.05 Citric acid 1.77 0.15 Sodium citrate 0.59 0.05 Polysorbate 80
0.12 0.01 Cherry Flavor 5.9 0.5 Glycerin 59 5 Acesulfame potassium
5.9 0.5 Magnasweet 110 5.9 0.5 Sodium Benzoate 2.36 0.2 Potassium
Sorbate 2.36 0.2 Water q.s. to 1, 2, 3, 4, 5, q.s. to 1, 2, 3, 4,
5, 6, 7, 8, 9, 10, 11, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 mL 12,
13, 14, or 15 mL
TABLE-US-00009 TABLE 9 Budesonide Composition #9 Ingredient Amount
(mg/mL) Amount % w/w Budesonide 0.2 0.17 Avicel RC-591 23.6 2
Dextrose 118 10 Maltodextrin (M150) 306.8 26 Disodium edetate 0.59
0.05 Citric acid 1.77 0.15 Sodium citrate 0.59 0.05 Polysorbate 80
0.12 0.01 Cherry Flavor 5.9 0.5 Glycerin 59 5 Acesulfame potassium
5.9 0.5 Magnasweet 110 5.9 0.5 Sodium Benzoate 2.36 0.2 Potassium
Sorbate 2.36 0.2 Water q.s. to 1, 2, 3, 4, 5, q.s. to 1, 2, 3, 4,
5, 6, 7, 8, 9, 10, 11, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 mL 12,
13, 14, or 15 mL
TABLE-US-00010 TABLE 10 Fluticasone Propionate Composition #1
Ingredient Amount Fluticasone Propionate 0.5 mg to 150 mg CMC, MCC,
Carbomer, HPMC and/or HEC 0.5 g to 10 g Dextrose 0 g to 100 g
Maltodextrin 0 g to 100 g EDTA (e.g., disodium edetate) 5 mg to 200
mg Citric Acid 10 mg to 1 g Citrate (e.g., sodium citrate) 10 mg to
2 g Polysorbate 80 (e.g., Tween 80) 5 mg to 100 mg Flavoring Agent
optional Sweetener optional Preservative optional Water q.s. to 100
mL
TABLE-US-00011 TABLE 11 Fluticasone Propionate Composition #2
Ingredient Amount Fluticasone Propionate 0.5 mg to 150 mg CMC, MCC,
Carbomer, HPMC and/or HEC 0 g to 10 g Dextrose 1 g to 100 g
Maltodextrin 0 g to 100 g EDTA (e.g., disodium edetate) 5 mg to 200
mg Citric Acid 10 mg to 1 g Citrate (e.g., sodium citrate) 10 mg to
2 g Polysorbate 80 (e.g., Tween 80) 5 mg to 100 mg Flavoring Agent
optional Sweetener optional Preservative optional Water q.s. to 100
mL
TABLE-US-00012 TABLE 12 Fluticasone Propionate Composition #3
Ingredient Amount Fluticasone Propionate 0.5 mg to 150 mg CMC, MCC,
Carbomer, HPMC and/or HEC 0 g to 10 g Dextrose 0 g to 100 g
Maltodextrin 1 g to 100 g EDTA (e.g., disodium edetate) 5 mg to 200
mg Citric Acid 10 mg to 1 g Citrate (e.g., sodium citrate) 10 mg to
2 g Polysorbate 80 (e.g., Tween 80) 5 mg to 100 mg Flavoring Agent
optional Sweetener optional Preservative optional Water q.s. to 100
mL
TABLE-US-00013 TABLE 13 Corticosteroid Composition Ingredient
Amount % w/w Corticosteroid 0.001 to 1 Sodium methylparaben 0.0001
to 0.1 Sorbitol 5 to 30 Sucrose 1 to 40 Corn starch 1 to 10 MCC 0.1
to 5 CMC (NaCMC) 0.1 to 5 Xanthan 0.001 to 1 Glycerin 0.1 to 10
Calcium carbonate 0 to 30 Magnesium hydroxide 0 to 5 Color (e.g.,
FD&C Red No. 3) optional Water q.s. to 1, 2, 3, 4, 5, 6, 7, 8,
9, 10, 11, 12, 13, 14, or 15 mL
[0074] In certain embodiments, compositions provided herein are
used in methods of treating GERD. In some embodiments, the present
invention provides for pharmaceutical compositions comprising a
therapeutically effective amount of a corticosteroid (e.g., a
topical corticosteroid, such as budesonide or fluticasone). In some
embodiments, the pharmaceutical compositions used herein comprise a
therapeutically effective amount of a corticosteroid and a
therapeutically effective amount of an acid inhibitor. In specific
embodiments, the acid inhibitor is selected from, e.g., a PPI, a
H.sub.2RA or a combination thereof. In some embodiments, the
pharmaceutical compositions described herein further comprise an
excipient, or combination of excipients, that increases the
interaction of the composition with the esophagus or target area.
In specific embodiments, the excipient or excipients impart an
increased viscosity on the composition, an increased mucoadhesive
character on the composition, or a combination thereof.
[0075] In various embodiments of the present invention, the
pharmaceutical compositions provided herein are in liquid form.
Liquid forms include, by way of non-limiting example, neat liquids,
solutions, suspensions, dispersions, colloids and the like. In
other embodiments, the pharmaceutical compositions provided herein
are in the form of a dissolvable oral dosage form. Dissolvable oral
dosage forms include any pharmaceutically acceptable oral dosage
form that becomes fluid upon contact with saliva. Dissolvable oral
dosage forms include, by way of non-limiting example, lozenges,
tablets, dissolving wafers, capsules, or gel capsules. In some
embodiments, a pharmaceutical composition described herein is in
liquid, semi-solid or solid form. In specific embodiments, a
pharmaceutical composition described herein is in semi-solid form,
e.g., a gel, a gel matrix, a cream, a paste, or the like. In some
embodiments, semi-solid forms comprise a liquid vehicle.
[0076] In some embodiments, any composition or formulation
described herein is stable. In specific embodiments, the
composition is chemically and physically stable. In certain
embodiments, chemical stability is evidenced by a composition that
comprises at least 80%, 90%, 95%, 98%, or 99% of the initial amount
or label amount of corticosteroid and/or optional additional active
agent therein for, by way of non-limiting example, 1 week, 2 weeks,
3 weeks, 1 month, 3 months, 6 months, 1 year, 2 years, or for the
duration of the shelf life. In some embodiments, physical stability
is evidenced by a pharmaceutical composition that is able to
substantially obtain uniformity, remain substantially uniform
(e.g., for at least 1 day, 3 days, 1 week, 2 weeks, 3 weeks, 1
month, 3 months, 6 months, 1 year, 2 years, etc.), or substantially
regain uniformity (e.g., via mild or moderate agitation after being
undisturbed for 1 day, 3 days, 1 week, 2 weeks, 3 weeks, 1 month, 3
months, 6 months, 1 year, 2 years, etc.). In certain embodiments,
physical stability is evidenced by a composition that comprises at
least 80%, 90%, 95%, 98%, or 99% of the initial amount or label
amount of corticosteroid and/or optional additional active agent
therein for, by way of non-limiting example, 2 days, 1 week, 2
weeks, 3 weeks, 1 month, 3 months, 6 months, 1 year, 2 years, or
for the duration of the shelf life. In certain embodiments,
uniformity as described herein is evidenced by the uniformity of
the dispersion of the corticosteroid particles throughout the
pharmaceutical composition, the uniformity of the dispersed mass of
corticosteroid throughout the pharmaceutical composition, the
uniformity of the concentration of one or more of the components in
the composition throughout the pharmaceutical composition, and the
like. In certain embodiments, mild or moderate agitation includes,
by way of non-limiting example, shaking, shaking well, swirling,
gentle swirling, and the like. In some embodiments, mild or
moderate agitation includes agitation without a special apparatus.
In some embodiments, uniformity of the pharmaceutical composition
refers to dose uniformity (e.g., each dose delivered or withdrawn
from the composition comprises a substantially similar amount of
corticosteroid), or the concentration of corticosteroid in at least
some or all of the doses from the multiple dose formulations are
substantially similar. In certain embodiments, substantially
similar includes, e.g., within 20%, 15%, 10%, 7%, 5%, 3%, 2%, or
1%.
[0077] In various embodiments, these pharmaceutical compositions
are used in treating GERD in an individual by administering such
compositions to an individual. In certain embodiments, the
individual is an individual in need of treatment (i.e. an
individual suffering from GERD). As used herein, the term
"individual" includes any animal. In some embodiments, the animal
is a mammal. In certain embodiments, the mammal is a human. In
specific embodiments, the human is an adult. In other embodiments,
the human is a child or infant. In certain embodiments, the child
or infant is less than 16 years old, less than 12 years old, less
than 8 years old, less than 6 years old, less than 4 years old or
less than 2 years old. In certain embodiments, the individual is an
individual suffering from symptoms of or inflammation associated
with GERD. In some embodiments, the individual is a patient in need
of a therapy for the treatment of symptoms of or inflammation
associated with GERD.
[0078] Formulations
[0079] In certain embodiments, the methods provided herein are used
in therapies for the treatment of animals. In some embodiments, the
methods provided herein are used in the treatment of humans,
primates or domesticated animals.
[0080] Pharmaceutical compositions suitable for use in the present
invention include compositions wherein the active ingredient(s)
is/are contained in an effective amount to achieve the intended
purpose. In certain embodiments, the therapeutically effective
amount of an active used in either a pharmaceutical composition or
a method described herein is an amount sufficient to provide a
therapeutically beneficial effect. In specific embodiments, the
therapeutically beneficial effect is the prevention of, the
reduction in the incidences of, the alleviation of, the relief from
or the treatment of a symptom of or inflammation associated with
GERD. In light of the discussion provided herein, determination of
the effective amounts is well within the capability of those
skilled in the art.
[0081] The exact dosage will depend upon the route of
administration, the form in which the composition is administered,
the subject to be treated, the age, body weight/height of the
subject to be treated, and the preference and experience of the
attending physician. In certain embodiments, the optimal
concentration of the corticosteroid in the composition depends upon
the specific corticosteroid used, the characteristics of the
patient, and the nature of the inflammation for which the treatment
is sought. In various embodiments, these factors are determined by
those of skill in the medical and pharmaceutical arts in view of
the present disclosure.
[0082] Generally, a therapeutically effective dose of the active(s)
is desired. A therapeutically effective dose refers to the amount
of the active(s) that results in a degree of amelioration of
symptoms and/or inflammation relative to the status of such
symptoms and/or inflammation prior to treatment. The dosage forms
and methods of applying dosage forms containing effective amounts
are within the scope of the instant invention.
[0083] In various embodiments, the amount of corticosteroid (e.g.,
budesonide or fluticasone propionate) used in a method or in a
composition described herein is from about 2.5 to 400 .mu.g/kg of
body weight per day, or for example, in the range of 5 to 300
.mu.g/kg per day, or for example in the range of 5 to 200 .mu.g/kg
per day, or for example in the range of 5 to 100 .mu.g/kg per day,
or for example in the range of 10 to 100 .mu.g/kg per day, or for
example in the range of 10-50 .mu.g/kg per day, or for example in
the range of 10-100 .mu.g/kg/day, or for example in the range of
5-50 .mu.g/kg/day, or in an illustrative embodiment in the range of
10-60 .mu.g/kg/day. In some embodiments, the amount of
corticosteroid (e.g., budesonide or fluticasone propionate) used in
a method, in a combination or a dose of a combination disclosed
herein includes, by way of non limiting example, about 100 ug to
about 20 mg, about 300 ug to about 4 mg, about 50 .mu.g to about
500 mg, about 50 .mu.g to about 200 mg, about 50 .mu.g to about 100
mg, about 50 .mu.g to about 50 mg, about 250 .mu.g to about 20 mg,
about 250 .mu.g to about 15 mg, about 250 .mu.g to about 10 mg,
about 250 .mu.g to about 5 mg, about 250 .mu.g to about 3 mg, or
about 500 .mu.g to about 3 mg, about 375 .mu.g to about 1.5 mg, or
about 500 .mu.g to about 2 mg, or about 1 mg to about 3 mg. In an
illustrative embodiment, the dosage is provided in a sufficient
volume to allow the composition to reach the esophagus in an
effective amount. In some embodiments, a composition described
herein comprises 1 or more doses. In certain embodiments, a
composition described herein is contained in a multiple unit
container. Thus, provided herein is a kit comprising a composition
described herein and a container (e.g., a multiple unit or single
unit container). In certain embodiments, provided herein is a
composition or a kit comprising a composition that comprises from
about 2 and about 180, about 10 to about 60, about 14 or about 30
doses.
[0084] In certain embodiments of the present invention, the
corticosteroid is provided in the form of a lozenge. In some
embodiments, the lozenge is dissolved in the mouth, thus reaching
and coating the esophagus. In various embodiments, the lozenge or
other similar tablet, capsule, or other solid, dissolve rapidly in
the mouth or esophagus to produce a dissolved oral dosage form
(e.g., a solution) that can then coat the esophagus. In other
embodiments, e.g., for children or other patients that may have
difficulty with a dissolving lozenge, the lozenge is ground or
otherwise dissolved in a small volume of water or other
pharmaceutically suitable liquid, which is then administered. In
other illustrative embodiments of the invention, the corticosteroid
is provided in the form of a tablet, a capsule, or, for example a
gel capsule, designed for slow release and delivery to the
esophagus.
[0085] In some embodiments, initial treatment continues, for
example, for about 3 days to 2 weeks for an acute condition, or
about 4 weeks to about 16 weeks for a chronic condition, or about 8
weeks to about 12 weeks for a chronic condition. In various
embodiments, longer therapy is needed, such as, for example,
therapy similar to chronic therapy for persistent asthma. In some
aspects of the present invention, patients are, for example, be
treated for up to 6 months, or up to one year. In certain aspects,
maintenance treatment last up to or longer than one year. In some
embodiments, patients are treated on a maintenance basis or on an
as needed basis during a problematic episode, depending on the
severity of the condition. In certain embodiments, patients are
treated on a rotating treatment basis, where treatment is provided
for a period of time and then the patient is taken off of the drug
for a period before treatment resumes again. When off the drug, the
patient may be given no treatment, treatment with another
medication, or treatment with a reduced dosage. In certain
embodiments, patients are given treatment with a higher dose of the
composition until a desired reduced disease state is achieved, and
then continued on a lower dose of the composition.
[0086] In one embodiment of the instant invention, specific
excipients that may effect viscosity and increase interaction with
a surface (e.g., a mucosal or epithelial layer) of the
gastrointestinal tract (e.g., esophagus), may be included in the
composition. Such viscosity enhancing agents include but are not
limited to, acacia (gum arabic), agar, aluminum magnesium silicate,
sodium alginate, sodium stearate, bladderwrack, bentonite,
carbomer, carrageenan, Carbopol, cellulose, microcrystalline
cellulose, ceratonia, chondrus, dextrose, furcellaran, gelatin,
Ghatti gum, guar gum, hectorite, lactose, sucrose, maltodextrin,
mannitol, sorbitol, honey, maize starch, wheat starch, rice starch,
potato starch, gelatin, sterculia gum, xanthum gum, polyethylene
glycol (e.g. PEG 200-4500) gum tragacanth, ethyl cellulose,
ethylhydroxyethyl cellulose, ethylmethyl cellulose, methyl
cellulose, hydroxyethyl cellulose, hydroxyethylmethyl cellulose,
hydroxypropyl cellulose, poly(hydroxyethyl methacrylate),
oxypolygelatin, pectin, polygeline, povidone, propylene carbonate,
methyl vinyl ether/maleic anhydride copolymer (PVM/MA),
poly(methoxyethyl methacrylate), poly(methoxyethoxyethyl
methacrylate), hydroxypropyl cellulose,
hydroxypropylmethyl-cellulose, sodium carboxymethyl-cellulose
(CMC), silicon dioxide, polyvinylpyrrolidone (PVP: povidone),
Splenda.RTM. (dextrose, maltodextrin and sucralose) or combinations
thereof. In certain embodiments, a viscosity-increasing excipient
that may be used is Splenda.RTM.. In specific embodiments, the
viscosity-enhancing excipient is a combination of MCC and CMC
(e.g., Avicel RC-591).
[0087] In one aspect, viscosity of the composition is from about 2
centipoise (cP) or greater, or about 25 cP to about 800 cP, as
measured with a Brookfield viscometer at 25 degrees Celsius, more
preferably at about 50 cP to about 800, or about 300 cP to about
800 cP. In another aspect, a viscosity of the composition may range
from about 250 cP to about 600 cP or about 400 cP to about 600 cP.
In specific embodiments, the viscosity of the formulation is about
40 cP, about 35 cP, or about 400 cP or about 500 cP, as measured
with a Brookfield viscometer at 25 degrees Celsius. A non-limiting
example of a viscosity measurement within the parameters disclosed
herein is exemplified in a suspension prepared by adding about 5 to
about 15 grams of Splenda.RTM. to 4 ml of water, or a suspension
prepared by adding about 10 to about 12 grams of Splenda to 4 ml of
water, wherein the viscosity is measured with a Brookfield
viscometer at 25 degrees Celsius. In certain embodiments,
viscosities are measured at a shear of about 13.2 sec.sup.-1.
[0088] In another aspect, excipients that impart mucoadhesive
characteristics to a composition, thereby increasing interaction of
the composition with a surface (e.g., a mucosal or epithelial
layer) of the gastrointestinal tract (e.g., esophagus), are also
included. Specific mucoadhesive agents may be used as an excipient,
including, but are not limited to, at least one soluble
polyvinylpyrrolidone polymer (PVP); a water-swellable, but
water-insoluble, fibrous, cross-linked carboxy-functional polymer,
a crosslinked poly(acrylic acid) (e.g. Carbopol 947P), a carbomer
homopolymer, a carbomer copolymer, a hydrophilic polysaccharide
gum, maltodextrin, a cross-linked alignate gum gel, a
water-dispersible polycarboxylated vinyl polymer, at least two
particulate components selected from the group consisting of
titanium dioxide, silicon dioxide, and clay, or a mixture
thereof.
[0089] In yet another aspect, agents that enhance absorption of the
composition through a surface (e.g., a mucosal or epithelial layer)
of the gastrointestinal tract (e.g., esophagus), may be used to
increase the interaction of the compositions disclosed herein with
a surface (e.g., a mucosal or epithelial layer) of the
gastrointestinal tract (e.g., esophagus). Such agents include, but
are not limited to, acylcarnitines, surfactants, sodium lauryl
sulfate, saponins, bile salts or bile acids including but not
limited to cholanic acid, chilic acid, deoxycholic acid,
glycocholic acid, tautocholic acid, chenodeoxycholic acid,
lithocholic acid, ursocholic acid, ursodeoxycholic acid, isourosde
oxycholic acid, lagodeoxycholic acid, glycodeoxycholic acid,
glycochenodeoxycholic acid, dehydrocholic acid, hyocholic acid,
hyodeoxycholic acid, or combinations thereof, dihydrofusidates,
fatty acid derivatives, chitosan, carbopol, cellulosic agents,
sterols, including but not limited to alcohols structurally related
to steroids, including but not limited to cholestanol, coprostanol,
cholesterol, epicholesterol, ergosterol, ergocalciferol, or
combinations thereof, starch, dextran, cyclodextrin, or
combinations thereof.
[0090] In other embodiments, the excipient used is a mucoadhesive
agent, in others a viscosity enhancing agent, and in yet other
embodiments the excipient used as an absorption enhancer. It is
also contemplated that the excipient used is a combination of one
or more of these agents, or alternatively may not include a
mucoadhesive agent, viscosity enhancing or an absorption enhancing
agent as the excipient.
[0091] In certain embodiments, following administration of a
composition or formulation described herein to a surface (e.g., a
mucosal or epithelial layer) of the gastrointestinal tract (e.g.,
esophagus), at least 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%,
20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 95% by weight of the
corticosteroid administered adheres to, resides on and/or is
absorbed at a surface (e.g., a mucosal or epithelial layer) of the
gastrointestinal tract (e.g., esophagus) after at least 5 seconds,
10 seconds, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10,
15, 20, 25, 30, 35, 40, 45, 50, 55 or 60 minutes following
application of the composition to the surface (e.g., a mucosal or
epithelial layer) of the gastrointestinal tract (e.g., esophagus).
In specific embodiments, the surface (e.g., a mucosal or epithelial
layer) of the gastrointestinal tract (e.g., esophagus) is the site
of gastrointestinal inflammation. In some embodiments, one or more
excipient that increases the interaction of the composition with a
surface (e.g., a mucosal or epithelial layer) of the
gastrointestinal tract (e.g., esophagus) is selected and selected
in an amount sufficient to cause a composition or formulation
described herein to cause at least 1%, at least 2%, at least 3%, at
least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at
least 9%, at least 10%, at least 15%, at least 20%, at least 30%,
at least 40%, at least 50%, at least 60%, at least 70%, at least
80%, at least 90% or at least 95% by weight of the corticosteroid
containing composition or formulation or the corticosteroid to
adhere to or reside on a surface (e.g., a mucosal or epithelial
layer) of the gastrointestinal tract (e.g., esophagus) for or 5
seconds, 10 seconds, or 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 7,
8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55 or 60 minutes is after
administration to the surface (e.g., a mucosal or epithelial layer)
of the gastrointestinal tract (e.g., esophagus).
[0092] In specific embodiments, following oral administration of a
composition described herein to the esophagus (e.g., following
initial swallowing or drinking of the composition), at least 1%,
2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 30%, 40%, 50%, 60%,
70%, 80%, 90% or 95% by weight of the corticosteroid or composition
administered is present within the esophagus (e.g., as measured by
gamma scintigraphy) after at least 5 seconds, 10 seconds, 15
seconds, 20 seconds, 25 seconds, 30 seconds, 40 seconds, 45
seconds, 50 seconds, or 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20,
25, 30, 35, 40, 45, 50, 55 or 60 minutes following application of
the composition to the esophagus. In certain instances, even small
differences (e.g., increases) in adherence times (e.g., residence
times) between formulations can result in therapeutically
significant or clinically significant results or improvements.
[0093] One embodiment of the invention includes the use of liquid
suspensions of the compositions disclosed herein. In some
embodiments, liquid suspensions include a unit dosage form of a
composition comprising a corticosteroid. In certain embodiments,
liquid suspensions include a unit dosage form of a combination of a
corticosteroid and an optional additional active agent (e.g., acid
inhibitor). In some embodiments, liquid suspensions include a unit
dosage form of a combination of a corticosteroid, additional active
agent (e.g., acid inhibitor) and an excipient that increases the
interaction of the compositions disclosed herein with a surface
(e.g., a mucosal or epithelial layer) of the gastrointestinal tract
(e.g., esophagus). Unit dosage forms include the bulk preparation
of a composition disclosed herein, such as multiple doses of a
liquid suspension contained in a single container or vial. Unit
dosage forms may also include doses of a corticosteroid, the
combination of a corticosteroid and an additional active agent
(e.g., acid inhibitor), or the combination of a corticosteroid, an
additional active agent (e.g., acid inhibitor) and an excipient
disclosed herein in individual vials or containers. Alternatively,
liquid suspensions may include multiple unit dosage forms of a
corticosteroid, the combination of a corticosteroid and an
additional active agent (e.g., acid inhibitor), or the combination
of a corticosteroid, an additional active agent (e.g., acid
inhibitor) and an excipient disclosed herein. Multiple unit dosage
forms may include the liquid formulations of the individual active
agents, e.g. a corticosteroid, or a corticosteroid and an
additional active agent (e.g., acid inhibitor). For example, liquid
suspensions of the present invention may include those prepared by
adding about 5 to about 25 grams of Splenda.RTM., or about 7 to
about 20 grams of Splenda.RTM., or about 5 to about 15 grams of
Splenda.RTM., or about or about 7 to about 15 grams of
Splenda.RTM., or about 8 to about 12 grams of Splenda.RTM., or
about 10 to about 11 grams of Splenda.RTM., or 1, 2, 3, 4, 5, 6, 7,
8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24,
or 25 grants of Splenda.RTM.g, added to 4 ml of budesonide, such as
that obtained from a Budesonide respule, or larger volumes having
the same ratios of Splenda.RTM. to budesonide. Alternatively the
liquid suspension may include the formulation above and an
additional active agent (e.g., acid inhibitor such as
omeprazole).
[0094] In other embodiments of the inventions, the formulation may
include tablets or capsules for administration to a patient. A
tablet or capsule may contain anywhere from 1 mg to as much as 1 g
of the active agents, including a corticosteroid, or a
corticosteroid and an acid inhibitor. Compositions can be provided
in a unit dose formulation for oral administration of a patient. In
other embodiments, the table or capsule may be in the form of
multiple unit form dosages. In certain embodiments, oral dosage
forms of the present invention include between 1 mg and 1 g of an
acid inhibitor. In some embodiments, the oral dosage form is a
single unit dosage form. In other embodiments, the oral dosage form
is a metered dosage form, wherein each metered dose (i.e. the unit
dose) includes between 1 mg and 1 g of an acid inhibitor. Likewise,
certain embodiments of the present invention provide for methods
comprising the administration of between 1 mg and 1 g of an acid
inhibitor.
[0095] In one aspect, an H.sub.2RA is present in the unit dose in
an amount of between 1 mg and 500 mg in combination with a
corticosteroid at about 500 .mu.g to 3 mg. In another aspect, a PPI
is present in the unit dose with a corticosteroid in an amount of
between 1 mg and 600 mg. In yet another aspect, a H.sub.2RA and/or
PPI is present in an amount effective to alleviate gastrointestinal
reflux by about 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, 20-fold,
30-fold, 50-fold, 100-fold or more (or any fold therebetween).
[0096] In specific embodiments, the amount of H.sub.2RA included in
either the oral dosage form or in the method described herein is
selected from, by way of non-limiting example: cimetidine, 100 to
800 mg/unit dose; ranitidine, 50-300 mg/unit dose; famotidine,
5-100 mg/unit dose; ebrotidine 400-800 mg/unit dose; pabutidine 40
mg/unit dose; lafutidine 5-20 mg/unit dose; and nizatidine, 50-600
mg/unit dose.
[0097] In certain embodiments, the amount of PPI included in either
the oral dosage form or in the method described herein is from
about 5 mg to 600 mg per unit dose. In specific embodiments, the
PPI omeprazole is present in an amount from 5 to 50 mg, with about
20 mg per unit dosage form being preferred. In other embodiments,
the amount of PPI included in either a oral dosage form or in a
method described herein is, by way of non-limiting embodiment:
esomeprazole, 5-100 mg/unit dose; lansoprazole, 15-150 mg/unit
dose; pantoprazole, 10-200 mg/unit dose; and rabeprazole, 5-100
mg/unit dose. In more specific embodiments, esomeprazole is
included in an amount of about 40 mg/unit dose. In another specific
embodiment, lansoprazole is included in an amount of about 30
mg/unit dose. In still another specific embodiment, pantoprazole is
included in an amount of about 50 mg/unit dose. In yet another
specific embodiment, rabeprazole is included in an amount of about
40 mg/unit dose.
[0098] The formulation may also be coated with an enteric coating,
which protects an active agent, for example a PPI, from degradation
in an acidic environment, such as the stomach, and allows a delayed
release into a target area, for example the duodenum, for uptake.
The enteric coating may be, for example, methacrylate copolymer
(for example, Eudragit L100 and Eudragit L100-55),
hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl
cellulose acetate succinate, carboxymethylethyl cellulose, acetate
phthalate (CAP), cellulose acetate trimellitate (CAT),
hydroxypropylmethylcellulose phthalate (HPMCP), copolymer of
methacrylic acid and ethyl acrylate, hydroxypropylmethylcellulose
acetate succinate (HPMCAS), shellac, chitosan succinate, chitosan
phthlate, cellulose acetate trimelliate and polyvinyl acetate
phthalate (PVAP), or combinations thereof. A sustained-release
substrate may also be used, such as methacrylic acid polymers
[e.g., Eudragit NE30D (trade name), Eudragit RL30D (trade name),
Eudragit RS30D (trade name), etc.]; water-soluble polymers;
plasticizers such as triethyl citrate, polyethylene glycol,
acetylated monoglycerides, triacetine alkyl celluloses, e.g.
carboxymethylcellulose, other cellulosic materials or compounds
(e.g., cellulose acetate phthalate, hydroxypropylmethylcellulose
phthalate), methyl cellulose, ethyl cellulose or propyl cellulose,
more preferably ethyl cellulose. polyvinyl acetate polymers (e.g.,
polyvinyl acetate phthalate), polymers or copolymers derived from
acrylic and/or methacrylic acid esters, zein, waxes (alone or in
admixture with fatty alcohols), shellac, hydrogenated vegetable
oils, and mixtures thereof. In addition, an inactive intermediate
film may be provided between the active agent, for example, a PPI,
and the enteric coating to prevent interaction of the active agent
with the enteric coating.
[0099] In certain embodiments, a composition described herein
comprises a buffering agent. In some instances, an active agent may
be protected from the stomach's acidic environment and later
release in the duodenum or lower gastrointestinal tract through
other means, including buffering the active agent, for example a
PPI, with a buffering agent, including sodium bicarbonate, sodium
carbonate, calcium carbonate, magnesium oxide, magnesium hydroxide,
magnesium carbonate, aluminum hydroxide, or combinations thereof.
In certain instances, the stomach's acidic environment interacts
with an effervescent buffering agent, e.g., a carbonate or
bicarbonate (e.g., sodium bicarbonate, sodium carbonate, calcium
carbonate, magnesium carbonate), so as to deliver the active agent
to the esophagus (e.g., lower esophagus).
[0100] In some embodiments of the invention, the composition
includes a combination of a corticosteroid and an acid inhibitor,
together with an excipient that increases the interaction of the
composition with a surface (e.g., a mucosal or epithelial layer) of
the gastrointestinal tract (e.g., esophagus). The combination may
include, for example, about 0.25 mg to about 20 mg, about 0.25 mg
to about 15 mg, about 0.25 mg to about 10 mg, about 0.25 mg to
about 5 mg, 250 .mu.g to 3 mg, or 500 .mu.g to 3 mg, or 500 .mu.g
to 2 mg, or 1 mg to 3 mg of a corticosteroid, such as budesonide,
together with 50 to 300 mg, 100 to 300 mg, 200-300 mg ranitidine.
Other embodiments of the invention may include more than one
corticosteroid and/or acid inhibitor, for example, a combination of
budesonide and fluticasone together with ranitidine, or a
combination of budesonide together with ranitidine and
omeprazole.
[0101] The exact dosage will depend upon the route of
administration, the form in which the composition is administered,
the subject to be treated, the age, body weight/height of the
subject to be treated, and the preference and experience of the
attending physician. The optimal concentration of the
corticosteroid and/or acid inhibitor in the composition will depend
upon the specific active agent used, the characteristics of the
patient, and the nature of the inflammation and/or acid reduction
for which the treatment is sought. These factors can be determined
by those of skill in the medical and pharmaceutical arts in view of
the present disclosure.
[0102] Similarly, a therapeutically effective dose of acid
inhibitor refers to the amount of acid inhibitor that results in a
degree of amelioration of symptoms and acid reduction relative to
the status of such symptoms prior to treatments. The dosage forms
containing effective amounts are within the bounds of routine
experimentation, and therefore, well within the scope of the
instant invention. Such doses of acid inhibitors may include 1
.mu.g to 10 mg/kg of body weight per day, or for example, in the
range of 2.5 .mu.g to 1 mg/kg of body weight per day. In a
preferred embodiment, 100 .mu.g-1 mg/kg of body weight per day of
an acid inhibitor is administered.
[0103] In an illustrative embodiment, a dosage or amount (including
a divided dose) of corticosteroid is provided in a composition of
sufficient volume to allow any of the compositions disclosed herein
to reach the targeted and/or inflamed portion of the
gastrointestinal tract, including, e.g., the esophagus, in an
effective amount. In some embodiments, the effective amount of the
composition delivered to the esophagus is an amount sufficient to
coat or at least partially coat the esophagus, and deliver the
composition to the affected areas, including by way of example
only, the lower esophagus, the esophageal-stomach juncture, the
stomach and/or the duodenum. In certain embodiments, a composition
described herein as a volume of, for example about 1-50 mL, or for
example about 1-40 mL, or for example about 1-30 mL, or for example
about 1-25 mL, or for example, about 1-20 mL, or for example about
5-25 mL, or for example about 10-20 mL, or for example about 10 mL,
or for example, about 15 mL, or for example, about 20 mL, or for
example about 1-15 mL, or for example about 1-10 mL, or for example
about 2-8 mL, or for example about 3-7 mL, or for example, about
4-6 mL, or for example, about 5 mL, or for example about 6-14 mL,
or for example about 8-12 mL, or for example, about 9-11 mL, or for
example, about 10 mL. In more specific embodiments, about 0.25 mg
to about 6 mg, about 0.375 mg, about 0.5 mg, about 0.75 mg, about 1
mg, about 1.25 mg, about 1.5 mg, or about 2 mg of corticosteroid
(e.g., budesonide) is formulated into a single or unit dose of a
pharmaceutical composition described herein, the single or unit
dose having a total volume of about 1-20 mL, about 10-20 mL, or for
example about 10 mL, or for example, about 15 mL, or for example,
about 20 mL, or for example about 1-15 mL, or for example about
1-10 mL, or for example about 2-8 mL, or for example about 3-7 mL,
or for example, about 4-6 mL, or for example, about 5 mL, or for
example about 6-14 mL, or for example about 8-12 mL, or for
example, about 9-11 mL, or for example, about 10 mL. As discussed
herein, "liquid" encompasses slurries, solutions, suspensions,
dispersions or any combination thereof, depending on the
solubilities and amounts of the individual components and the
vehicles and solvents used. In some embodiments, an appropriate
palatable dosage is in a volume sufficient to coat or at least
partially coat the esophagus, and in an illustrative embodiment,
the volume is sufficient to coat or at least partially coat the
esophagus and deliver the corticosteroid to the affected areas,
including by way of example only, the lower esophagus, the
esophageal-stomach juncture, the stomach, the duodenum and/or
within 3 cm of the Z-line. The composition may be delivered, for
example, four times a day, three times a day, twice a day, once a
day, every other day, three times a week, twice a week, or once a
week. The dosage may, for example, be divided into multiple doses
throughout the day, or be provided, for example, in four, three,
two, or one dose a day. In certain instances, administration more
frequent administration (e.g., b.i.d. versus once a day) provides
for a shorter overall therapy or a quicker onset of symptom
resolution. In one illustrative example, the dose is provided once
a day.
[0104] In certain embodiments, a dose or composition described
herein is administered with food. In some embodiments, a dose or
composition described herein is administered without food. In
certain embodiments, a dose or composition described herein is
administered in a fed or fasted state. In some embodiments, a dose
or composition described herein is administered in the morning, in
the afternoon, in the evening, at night, or a combination thereof.
In one embodiment, the dose is administered at night. In another
aspect, the dose is administered about 30 minutes prior to bed,
with no food or water given after administration of the
compositions herein. In yet another embodiment of the instant
invention, the dose is administered prior to bedtime, wherein after
administration of the composition, the patient or individual is in
a substantially supine position for at least 30 minutes, at least 1
hour, at least 2 hours, at least 4 hours or at least 8 hours.
[0105] In some embodiments, provided herein are methods of
treating, preventing, or alleviating inflammation or symptoms
associated with inflammation of the gastrointestinal tract, e.g.,
the esophagus, comprising administering to an individual in need
thereof a single unit dose of a pharmaceutical composition
described herein from a multidose container. In specific
embodiments, administering a single unit dose from a multi dose
container comprises (1) shaking a multidose container, the
multidose container comprising at least one unit dose of a
pharmaceutical composition described herein; (2) pouring (or
otherwise dispensing) a single unit dose from the multidose
container into an administration device (e.g., a device suitable
for administering to a human individual, such as a spoon, cup or
syringe); and (3) administering the single unit dose to the
individual in need thereof. In more specific embodiments, shaking
of the multidose container occurs until the fluid therein has a
viscosity suitable for pouring (e.g., easy pouring). In some
specific embodiments, the process further comprises waiting after
pouring the single unit dose and prior to administering the single
unit dose to the individual in need thereof. In specific
embodiments, the wait time is a time sufficient to allow the
viscosity of composition to achieve a desired level, e.g., a
viscosity to improve the coating capabilities of the composition.
In some embodiments, the wait time is, e.g., about 3 seconds, or
more; about 5 seconds, or more; about 10 seconds, or more; about 15
seconds, or more; about 20 seconds, or more; about 25 seconds, or
more; about 30 seconds, or more; about 40 seconds, or more; about
45 seconds, or more; about 50 seconds, or more; or about 60
seconds, or more. In other specific embodiments, the composition is
administered immediately following pouring the composition into the
administration device. In some embodiments, the process comprises
shaking the multidose container well.
[0106] In other illustrative embodiments of the invention, any of
the compositions disclosed herein are provided in the form of a
lozenge which may be dissolved in the mouth, thus reaching and
coating the esophagus, and thereafter deliver the composition to
the affected areas, including by way of example only, the lower
esophagus, the esophageal-stomach juncture, the stomach, the
duodenum and/or within 3 cm of the Z-line. The lozenge or other
similar tablet capsule, or other solid, would dissolve in the mouth
or esophagus to produce a solution that can then coat the
esophagus, and thereafter deliver the composition to the affected
areas, including by way of example only, the lower esophagus, the
esophageal-stomach juncture, the stomach and/or the duodenum. Or,
for children, infants or other patients that may have difficulty
with a dissolving lozenge, the lozenge may be ground or otherwise
dissolved in a small volume of water or other pharmaceutically
suitable liquid, for example, reaching a total volume presented in
embodiments herein. In other illustrative embodiments of the
invention, the compositions disclosed herein are provided in the
form of a tablet, a capsule, or, for example a gel capsule,
designed for slow release and delivery to the gastrointestinal
tract, including the esophagus.
[0107] The compositions of the present invention may include
pharmaceutically acceptable salts. Pharmaceutically acceptable
salts are generally well known to those of ordinary skill in the
art and may include, by way of example but not limitation, acetate,
atosylate, benzenesulfonate, besylate, benzoate, bicarbonate,
bitartrate, bromide, calcium edetate, carnsylate, carbonate,
citrate, edetate, edisylate, estolate, esylate, fumarate,
gluceptate, gluconate, glutamate, glycollylarsanilate,
hexylresorcinate, hydrabamine, hydrobromide, hydrochloride,
hydroxynaphthoate, iodide, isethionate, lactate, lactobionate,
malate, maleate, mandelate, mesylate, mucate, napsylate, nitrate,
pamoate (embonate), pantothenate, phosphate/diphosphate,
polygalacturonate, salicylate, stearate, subacetate, succinate,
sulfate, tannate, tartrate, or teoclate. Other pharmaceutically
acceptable salts may be found in, for example, Remington: The
Science and Practice of Pharmacy (20th ed.) Lippincott, Williams
& Wilkins (2000). Preferred pharmaceutically acceptable salts
include, for example, acetate, benzoate, bromide, carbonate,
citrate, gluconate, hydrobromide, hydrochloride, maleate, mesylate,
napsylate, pamoate (embonate), phosphate, salicylate, succinate,
sulfate, or tartrate. Such salts may be used for the steroid, the
PPI, the H.sub.2RA or any combination of the above.
[0108] Depending on the specific conditions being treated, the
compositions may be formulated into liquid or solid dosage forms
and administered systemically or locally. In some embodiments, the
agents are delivered, for example, in a timed- or sustained-low
release form as is known to those skilled in the art. Techniques
for formulation and administration may be found in Remington: The
Science and Practice of Pharmacy (20th ed.) Lippincott, Williams
& Wilkins (2000).
[0109] In addition to the active or actives, various embodiments of
the present invention provide for pharmaceutical compositions that
contain suitable pharmaceutically acceptable excipients and
auxiliaries. For example, in some embodiments, pharmaceutically
acceptable excipients and/or auxiliaries are used to formulate the
corticosteroids herein disclosed for the practice of the invention
into dosages suitable for systemic administration is within the
scope of the invention. In some embodiments, the corticosteroid is
formulated readily using pharmaceutically acceptable excipients
and/or auxiliaries well known in the art into dosages suitable for
oral administration. Such excipients and/or auxiliaries enable the
compositions of the invention to be formulated as tablets, pills,
dragees, capsules, liquids, soft chews, creams, pastes, chewable
tablets, gels or gel matrices, syrups, slurries, suspensions, gums,
lozenges, and the like, for oral ingestion by a patient to be
treated. In certain instances, oral formulations (e.g.,
suspensions, creams or gel matrices) are formulated such that upon
oral administration, an interface layer between the oral
formulation (e.g., suspension, cream or gel matrix) and a surface
(e.g., a mucosal or epithelial layer) of the gastrointestinal tract
(e.g., esophagus). In some instances, an oral formulations (e.g.,
suspensions, creams or gel matrices) in contact with a surface
(e.g., a mucosal or epithelial layer) of the gastrointestinal tract
(e.g., esophagus) delivers a corticosteroid to the surface (e.g., a
mucosal or epithelial layer) of the gastrointestinal tract (e.g.,
esophagus) via the interface layer and as the oral formulations
(e.g., suspensions, creams or gel matrices) near the interface
layer is depleted of corticosteroid, a concentration gradient
results. In certain instances, portions of the oral formulations
(e.g., suspensions, creams or gel matrices) with high
concentrations of corticosteroid relative to the portions of the
oral formulations (e.g., suspensions, creams or gel matrices)
proximate to the interface layer replenishes corticosteroid in the
portion of the oral formulations (e.g., suspensions, creams or gel
matrices) proximate to the interface layer. In certain instances,
upon oral administration of an oral formulation described herein to
an individual, an interface layer is formed between a surface
(e.g., a mucosal or epithelial layer) of the gastrointestinal tract
(e.g., esophagus) and a mixture of the oral formulation (e.g.,
chewable tablet) and saliva of the individual.
[0110] In certain embodiments, pharmaceutical preparations for oral
use are obtained by combining the corticosteroids and/or acid
inhibitors with solid excipients, optionally grinding a resulting
mixture, and processing the mixture of granules, after adding
suitable auxiliaries, if desired, to obtain tablets or dragee
cores. Suitable excipients may be, in particular, fillers such as
sugars or starches, including dextrose, lactose, sucrose,
sucralose, mannitol, or sorbitol; and maize starch, wheat starch,
rice starch, or potato starch, or a combination thereof. If
desired, disintegrating agents may be added, such as the
cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt
thereof such as sodium alginate. Appropriate excipients may also,
for example, include those that render the dissolving tablet
palatable.
[0111] In some embodiments, the pharmaceutical compositions
described herein are in liquid form. Appropriate excipients for use
in liquid form, appropriate excipients may be used, for example, to
render the liquid composition palatable. Excipients may include,
for example, either sugars, including dextrose, lactose, sucrose,
sucralose, maltodextrin, mannitol, or sorbitol; honey or a
combination thereof. Other flavoring or flavor-enhancing agents may
also be used.
[0112] Liquid suspensions useful herein include, for example, those
prepared by adding about 5 to about 25 grams of Splenda.RTM., or
about 7 to about 20 grams of Splenda.RTM., or about 5 to about 15
grams of Splenda.RTM., or about 7 to about 15 grams of
Splenda.RTM., or about 8 to about 12 grams of Splenda.RTM., or
about 10 to about 11 grams of Splenda.RTM., or 1, 2, 3, 4, 5, 6, 7,
8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 18, 19, 20, 21, 22, 23,
24, or 25 grams of Splenda.RTM., added to 4 ml or 8 ml of a
budesonide suspension, such as that obtained from commercially
available Pulmicort Respules unit dose, or larger volumes having
the same ratios of Splenda.RTM. to budesonide.
[0113] Any of the compositions or formulations described herein
optionally comprise one or more binder, optionally comprise one or
more filler, optionally comprise one or more lubricant, optionally
comprise one or more solvent, optionally comprise one or more
suspension agent, optionally comprise one or more flavoring agent,
optionally comprise one or more coloring agent, optionally comprise
one or more sweetener, optionally comprise one or more
preservative, optionally comprise one or more antioxidant
optionally comprise one or more buffering agent, optionally
comprise one or more humectant, optionally comprise one or more
chelating agent, optionally comprise one or more surfactant, or
combinations thereof.
[0114] Preservatives include, by way of non-limiting example,
benzalkonium chloride, cetrimide (cetyltrimethylammonium bromide)
benzoic acid, benzyl alcohol, methyl-, ethyl-, propyl- and
butyl-esters of para-hydroxybenzoic acid, chlorhexidine,
chlorobutanol, phenylmercuric acetate, borate and nitrate,
potassium sorbate, sodium benzoate, sorbic acid, thiomersal
(mercurithiosalicylate), combinations thereof, or the like.
Compositions and formulations described herein optionally include
any suitable amount of preservative including, by way of
non-limiting example, about 0.1% w/w to about 5% w/w, about 0.1%
w/w to about 3% w/w, about 0.1% w/w to about 1% W/W, about 0.1% w/w
to about 0.5% w/w of one or more preservative(s).
[0115] Antioxidants include, by way of non-limiting example,
ascorbyl palmitate, butylated hydroxyanisole, butylated
hydroxytoluene, monothioglycerol, sodium ascorbate, sodium
formaldehyde sulfoxylate, sodium metahisulfite, BHT, BHA, sodium
bisulfite, vitamin E or a derivative thereof, propyl gallate,
edetate (EDTA) (e.g., disodium edetate),
Diethylenetriaminepentaacetic acid (DTPA), Triglycollamate (NT),
combinations thereof, or the like. Compositions and formulations
described herein optionally include any suitable amount of
antioxidant including, by way of non-limiting example, about 0.01%
w/w to about 0.5% w/w, about 0.01% w/w to about 0.3% w/w, or about
0.01% w/w to about 0.1% w/w one or more antioxidant(s).
[0116] Buffering agents include, by way of non-limiting example,
citrate buffers (i.e., citric acid and citrate), phosphate buffers,
acetate buffers, combinations thereof, or the like. In various
embodiments, any suitable amount of buffering agent(s) are utilized
and any suitable pH is achieved.
[0117] As used herein, "citrate" includes all compounds of Formula
I wherein each R is independently selected from an H and a negative
charge (e.g., as a salt or as a disassociated salt or acid). In
certain embodiments, citrate is selected from, by way of
non-limiting example, sodium citrate, citric acid and the like.
##STR00001##
[0118] Humectants include, by way of non-limiting example,
glycerine, propylene glycol, ethylene glycol, glyceryl triacetate,
polyols (e.g., sorbitol, xylitol, maltitol, polydextrose), and the
like. Compositions and formulations described herein optionally
include any suitable amount of humectant including, by way of
non-limiting example, about 0.1% w/w to about 10% w/w, about 1% w/w
to about 10% w/w, about 1% to about 8% w/w, or about 5% w/w of a
humectant. In certain embodiments, humectants inhibit precipitation
and/or crystallization of one or more component of a composition or
formulation described herein (e.g., a sweetener, mucoadhesive agent
or a viscosity enhancing agent).
[0119] Chelating agents include, by way of non-limiting example,
edetate (EDTA) (e.g., disodium edetate),
Diethylenetriaminepentaacetic acid (DTPA), Triglycollamate (NT), or
the like. Compositions and formulations described herein optionally
include any suitable amount of chelating agent including, by way of
non-limiting example, about 0.01% w/w to about 0.5% w/w, about
0.01% w/w to about 0.3% W/W, or about 0.01% w/w to about 0.1% w/w,
or about 0.05% w/w of one or more chelating agent.
[0120] As used herein, "edetate" includes all compounds of Formula
II wherein each R is independently selected from an H and a
negative charge (e.g., as a salt or as a disassociated salt or
acid). In certain embodiments, edetate is selected from, by way of
non-limiting example, disodium edetate, calcium edetate,
ethylenediaminetetraacetic acid and the like.
##STR00002##
[0121] In certain embodiments, sweeteners include, by way of
non-limiting example, glycerin, acesulfame potassium (AceK),
mono-ammonium glycyrrhizinate (e.g., Magnasweet.RTM., sucrose,
lactose, glucose, fructose, arabinose, xylose, ribose, manose,
galactose, dextrose, sorbose, sorbitol, mannitol, maltose,
cellobiose, xylitol and the like. In some embodiments, flavoring
agents include, by way of non-limiting example, peppermint, orange,
bubble guru wintergreen, grape and cherry. In various embodiments,
any amount of sweetener and/or flavoring agent is optionally
utilized. In specific embodiments, enough sweetener and/or
flavoring agent is utilized to render any composition described
herein palatable. In certain embodiments, a composition or
formulation described herein comprises dextrose. In some
embodiments, the composition or formulation comprises less than 50%
w/w, 40% w/w, 30% w/w, 20% w/w, 15% w/w, 10% w/w, 5% w/w, or 3% w/w
of dextrose. In certain embodiments, the dextrose is substantially
dissolved in a liquid vehicle of the composition or formulation. In
certain embodiments, coloring agents include yellow agents (e.g.,
FD&C 5 and/or 6), red agents (e.g., FD&C Red 40), blue, or
the like.
[0122] Surfactants include, e.g., anionic, cationic, non-ionic, or
zwitterionic surfactants, such as, by way of non-limiting example,
polysorbate (e.g., polysorbate 20, polysorbate 60, polysorbate 40,
polysorbate 80, polysorbate 81, polysorbate 85, polysorbate 120),
bile acids or their salts (e.g., sodium taurocholates, sodium
deoxytaurocholates, chenodeoxycholic acid, and ursodeoxycholic
acid), nonoxynol or polyoxyethylene glycol fatty acid esters,
pluronic or poloxamers such as Pluronic F68, Pluronic L44, Pluronic
L101, combinations thereof, or the like. Compositions and
formulations described herein optionally include any suitable
amount of surfactant including, by way of non-limiting example,
about 0.001% w/w to about 0.5% W/W, about 0.001% w/w to about 0.3%
w/w, or about 0.001% w/w to about 0.1% w/w of one or more
surfactant.
[0123] Dragee cores are provided with suitable coatings. In some
embodiments, concentrated sugar solutions are used for this
purpose, which optionally contain gum arabic, talc,
polyvinylpyrrolidone, carbopol gel, polyethylene glycol (PEG),
and/or titanium dioxide, lacquer solutions, and suitable organic
solvents or solvent mixtures. Dye-stuffs or pigments are optionally
added to the tablets or dragee coatings for identification or to
characterize different combinations of active corticosteroid
doses.
[0124] In various embodiments, pharmaceutical preparations that are
used orally include push-fit capsules made of gelatin, as well as
soft, sealed capsules made of gelatin, and a plasticizer, such as
glycerol or sorbitol. In some embodiments, the push-fit capsules
contain the active ingredient or ingredients in admixture with a
filler, binder, lubricant, stabilizer or a combination thereof.
Fillers include, by way of non-limiting example, lactose. Binders
include, by way of non-limiting example, starches. Lubricants
include, by way of non-limiting example, talc and magnesium
stearate. In soft capsules, the corticosteroids may be dissolved or
suspended in suitable liquids, such as fatty oils, liquid paraffin,
or liquid polyethylene glycols (PEGs). In addition, stabilizers are
optionally added.
[0125] In one embodiment, the present invention provides for an
active agent or agents that have a low bioavailability. Due to the
low bioavailability, the corticosteroid and/or acid inhibitors are
used in certain embodiments of the invention, the active agent(s)
remain in the gastrointestinal tract, for example, in the
esophagus. In some embodiments, the low bioavailability results in
decreased systemic side effects and complications, allowing
patients with chronic conditions to receive treatment for longer
periods of time.
[0126] In some embodiments, a pharmaceutical composition or dosage
form described herein is a suspension or a solution comprising a
corticosteroid (e.g., budesonide). In some embodiments,
compositions (e.g., suspensions) comprise a certain concentration
of corticosteroid (e.g., budesonide) that is dissolved in the
liquid medium (e.g., the solvent or liquid vehicle used, such as
water, alcohol, aqueous alcohol, or the like). In certain
embodiments, the amount of corticosteroid (e.g., budesonide)
dissolved in the liquid medium is greater than 4 .mu.g/mL, greater
than 5 .mu.g/mL, greater than 10 .mu.g/mL, greater than 15
.mu.g/mL, greater than 20 .mu.g/mL, greater than 21 .mu.g/mL,
greater than 22 .mu.g/mL, greater than 23 .mu.g/mL, greater than 24
.mu.g/mL, greater than 25 .mu.g/mL, about 25 .mu.g/mL, greater than
30 .mu.g/mL, about 25 .mu.g/mL to about 80 .mu.g/mL, about 30
.mu.g/mL to about 80 .mu.g/mL, about 30 .mu.g/mL, about 35
.mu.g/mL, about 40 .mu.g/mL, about 45 .mu.g/mL, about 50 .mu.g/mL,
about 55 .mu.g/mL, about 60 .mu.g/mL, about 65 .mu.g/mL, or about
70 .mu.g/mL.
[0127] In some embodiments, compositions (e.g., suspensions)
comprise a certain concentration of budesonide that is dissolved in
the liquid medium (e.g., the solvent or liquid vehicle used, such
as water, alcohol, aqueous alcohol, or the like). In specific
embodiments, the amount of R epimer of the dissolved budesonide
(compared to the overall weight of the budesonide) is greater than
28% w/w, greater than 30% w/w, greater than 39% w/w, greater than
40%, about 39-50%, about 40-50%, less than 38% w/w, about 29%-37%
w/w, less than 27% w/w, or the like. In some instances, the %
epimers are obtained in a composition having an overall % R epimer
(compared to overall budesonide) of about 50-55% w/w, or about
53-54% w/w. In certain instances, equilibration of the sample is
accomplished once the concentration of the corticosteroid (e.g.,
budesonide) dissolved in the liquid is substantially stable, e.g.,
after 2 days, 3 days, 4 days, 5 days, a week, a month, or the like.
In specific instances, equilibration of the sample is accomplished
after 2 days.
[0128] In certain embodiments, the compositions provided herein are
prepared utilizing any suitable source of active agents. In some
embodiments, corticosteroid (e.g., budesonide) used in the
compositions described herein are neat corticosteroid (e.g.,
budesonide). In some embodiments, the neat corticosteroid (e.g.,
budesonide) is neat, bulk corticosteroid. In certain embodiments,
the neat corticosteroid (e.g., budesonide) is powder corticosteroid
(e.g., budesonide). In specific embodiments, the neat
corticosteroid (e.g., budesonide) is micronized corticosteroid
(e.g., budesonide).
[0129] In some embodiments, the corticosteroid is administered in a
commercially available formulation. In other embodiments, the
corticosteroid is administered in a composition comprising a
commercially available formulation of a corticosteroid and
formulated as described herein. For example, in some embodiments,
the corticosteroid containing composition provided herein comprises
a commercially available formulation and an excipient, such as a
diluents, a flavoring agent, a mucoadhesive agent, a viscosity
enhancing agent, a binder, a filler, a lubricant, a solvent, a
suspension agent, a coloring agent, a sweetener, a preservative, an
antioxidant, a buffering agent, a humectant, a chelating agent, a
surfactant, combinations thereof, or the like. In some embodiments,
wherein the corticosteroid is budesonide, the commercially
available formulation is Pulmicort Respules.RTM. (distributed by
AstraZeneca, e.g., as set forth in NDA 20-929, which is hereby
incorporated by reference in its entirety). In other embodiments,
wherein the corticosteroid is budesonide, the commercially
available formulation is Rhinocort Aqua.RTM. (distributed by
AstraZeneca LP, Wilmington, Del. 19850, e.g., as set forth in NDA
20-746, which is, including all supplements, hereby incorporated
herein by reference in its entirety). In still other embodiments,
wherein the corticosteroid is budesonide, the commercially
available formulation is Symbicort.RTM. (manufactured by
AstraZeneca Dunkerque Production, Dunkerque, France, e.g., as set
forth in NDA 21-929, which is, including all supplements, hereby
incorporated herein by reference in its entirety). In some
embodiments, wherein the corticosteroid is fluticasone, the
commercially available formulation is Flonase.RTM.. In some
embodiments, the ratio of commercially available formulation to the
optional diluent is between about 1:0.5 and about 1:100. Diluents
include any pharmaceutically acceptable oral diluent including,
e.g., powder diluents (such as tale) and liquid diluents (such as
water, ethanol and combinations thereof). In certain embodiments,
the commercially available formulation is Entocort.RTM.
(manufactured by AstraZeneca AB, S-151 85 Sodertalje, Sweden,
distributed by Prometheus Laboratories Inc, San Diego, Calif.
92121, as set forth in NDA 21-324, which is, including all
supplements, hereby incorporated herein by reference in its
entirety). In certain embodiments, Entocort.RTM. formulations are
dissolved and/or dispersed in an aqueous vehicle. In specific
embodiments, the Entocort.RTM. formulation is dispersed in a liquid
vehicle that has a pH sufficient to remove the enteric coating from
the budesonide particles. In other embodiments, the Entocort.RTM.
formulation is pre-treated with a solvent having a pH sufficient to
remove the enteric coating from the budesonide particles therein,
and the particles are subsequently formulated into a composition
described herein.
[0130] In certain embodiments, a corticosteroid composition
described herein comprises a corticosteroid, a commercially
available formulation, and, optionally, one or more additional
excipient. In some embodiments, a corticosteroid composition
described herein comprises a corticosteroid formulated in a manner
similar to a commercial formulation (e.g., lacking one or more of
the active ingredients of the formulation), and, optionally, one or
more additional excipient. The one or more additional excipients
can be utilized to achieve a formulation as described herein. In
specific embodiments, the commercially available formulation is
Ultra XCID (manufactured by Matrixx Initiatives, Inc., Phoenix,
Ariz.).
[0131] In certain embodiments, the corticosteroid containing
composition comprises micronized budesonide, disodium edetate,
sodium chloride, sodium citrate, citric acid, polysorbate (e.g.,
polysorbate 80), water, and optionally one or more excipients,
wherein the excipients are selected from any of those recited
herein. In certain embodiments, the composition comprises about 0.1
mg to about 1.0 mg budesonide/2 mL composition. In some
embodiments, the composition comprises about 0.2 mg to about 0.6 mg
budesonide/2 mL composition. In specific embodiments, the
composition comprises about 0.25 mg/2 mL composition. In other
specific embodiments, the composition comprises about 0.5 mg/2 mL
composition.
[0132] In other embodiments, the corticosteroid containing
composition comprises micronized budesonide, microcrystalline
cellulose, carboxymethyl cellulose sodium, dextrose anhydrous,
polysorbate (e.g., polysorbate 80), disodium edetate, potassium
sorbate, water, optionally hydrochloric acid and optionally one or
more excipients, wherein the excipients are selected from any of
those recited herein. In specific embodiments, the composition has
a pH of about 4.5. In some embodiments, the composition comprises
about 0.1 mg to about 1.0 mg of budesonide/g composition. In
certain embodiments, the composition comprises about 0.3 mg to
about 0.6 mg of budesonide/g composition. In specific embodiments,
the composition comprises about 0.4 mg or 0.44 mg of budesonide/g
composition. In certain specific embodiments, the composition
comprises about 3.8 mg/8.6 g composition. In some embodiments, the
composition comprises about 0.1 mg to about 1.0 mg of budesonide/mL
of composition (about 0.01 to about 0.1% w/w). In certain
embodiments, the composition comprises about 0.3 mg to about 0.8 mg
of budesonide/mL of composition (about 0.03 to about 0.08% w/w). In
specific embodiments, the composition comprises about 0.6 to about
0.7 mg of budesonide/mL of composition (about 0.06 to about 0.07%
w/w). In more specific embodiments, the composition comprises about
0.63 mg of budesonide/mL of composition (about 0.063% w/w).
[0133] In some embodiments, the corticosteroid containing
composition comprises microfine fluticasone propionate,
microcrystalline cellulose, carboxymethylcellulose sodium,
dextrose, benzalkonium chloride, polysorbate (e.g., polysorbate
80), phenylethylalcohol, and optionally one or more excipients,
wherein the excipients are selected from those recited herein. In
some embodiments, the composition has a pH of between about 5 and
about 7. In certain embodiments, the composition comprises about 20
to about 80 .mu.g fluticasone propionate/mg composition. In some
embodiments, the composition comprises about 40 to about 60 .mu.g
fluticasone propionate/mg composition. In specific embodiments, the
composition comprises about 50 .mu.g fluticasone propionate/mg
composition. In some embodiments, the composition comprises about
0.02% w/w benzalkonium sodium and about 0.25% w/w phenylethyl
alcohol.
[0134] Disorders
[0135] It will be appreciated by those skilled in the art that
reference herein to treatment extends to prophylaxis as well as the
treatment of inflammation or other symptoms.
[0136] Thus, provided herein is a method of treating, preventing or
alleviating inflammation associated with GERD in an individual
comprising orally administering to said individual any of the
compositions described herein. Furthermore, provided herein is a
method of treating, preventing or alleviating the symptoms of GERD
in an individual comprising orally administering to said individual
any of the compositions described herein.
[0137] In one embodiment, the present invention embodies a method
of treating, preventing or alleviating the symptoms of GERD in an
individual comprising orally administering to said individual a
composition comprising (i) a corticosteroid; and (ii) an excipient
or combination of excipients. In some embodiments, the excipient
may increase the interaction of the composition with the esophagus,
including excipients that increase the viscosity of the composition
or impart a mucoadhesive characteristic to the composition. In
other embodiments, the excipient may enhance absorption of the
active agents across a surface (e.g., a mucosal or epithelial
layer) of the gastrointestinal tract (e.g., esophagus). In yet
other embodiments, the excipient may include a combination of a
viscosity increasing agent, a mucoadhesive agent or an absorption
enhancing agent. In other aspects, the excipient may not impart the
characteristic of viscosity increasing, mucoadhesiveness or
absorption enhancing to the composition. In some embodiments, the
excipient is a binder, filler, lubricant or a combination
thereof.
[0138] One aspect of the invention provided herein is a method of
treating, preventing or alleviating the symptoms of GERD in an
individual comprising orally administering to said individual a
composition comprising (i) a corticosteroid; and (ii) an H.sub.2RA.
In some embodiments, the composition further comprises an excipient
or combination of excipients. In some embodiments, the excipient
may increase the interaction of the composition with the esophagus,
including excipients that increase the viscosity of the composition
or impart a mucoadhesive characteristic to the composition. In
other embodiments, the excipient may enhance absorption of the
active agents across a surface (e.g., a mucosal or epithelial
layer) of the gastrointestinal tract (e.g., esophagus). In yet
other embodiments, the excipient may include a combination of a
viscosity increasing agent, a mucoadhesive agent or an absorption
enhancing agent. In other aspects, the excipient may not impart the
characteristic of viscosity increasing, mucoadhesiveness or
absorption enhancing to the composition. In some embodiments, the
composition also comprises an excipient including, e.g., a binder,
filler, lubricant or a combination thereof.
[0139] Another aspect of the invention provided herein is a method
of preventing or alleviating esophageal inflammation in an
individual comprising orally administering to said individual a
composition comprising (i) a corticosteroid, and (ii) a PPI. In
some embodiments, the composition further comprises an excipient or
combination of excipients. In some embodiments, the excipient may
increase the interaction of the composition with the esophagus,
including excipients that increase the viscosity of the composition
or impart a mucoadhesive characteristic to the composition. In
other embodiments, the excipient may enhance absorption of the
active agents across a surface (e.g., a mucosal or epithelial
layer) of the gastrointestinal tract (e.g., esophagus). In yet
other embodiments, the excipient may include a combination of a
viscosity increasing agent, a mucoadhesive agent or an absorption
enhancing agent. In other aspects, the excipient may not impart the
characteristic of viscosity increasing, mucoadhesiveness or
absorption enhancing to the composition. In some embodiments, the
composition also comprises an excipient including, e.g., a binder,
filler, lubricant or a combination thereof.
[0140] Yet another aspect of the invention provided herein is a
method of preventing or alleviating esophageal inflammation in an
individual comprising orally administering to said individual a
composition comprising (i) a corticosteroid, (ii) an H.sub.2RA, and
(iii) a PPI. In some embodiments, the composition further comprises
an excipient or combination of excipients. In some embodiments, the
excipient may increase the interaction of the composition with the
esophagus, including excipients that increase the viscosity of the
composition or impart a mucoadhesive characteristic to the
composition. In other embodiments, the excipient may enhance
absorption of the active agents across a surface (e.g., a mucosal
or epithelial layer) of the gastrointestinal tract (e.g.,
esophagus). In yet other embodiments, the excipient may include a
combination of a viscosity increasing agent, a mucoadhesive agent
or an absorption enhancing agent. In other aspects, the excipient
may not impart the characteristic of viscosity increasing,
mucoadhesiveness or absorption enhancing to the composition. In
some embodiments, the composition also comprises an excipient
including, e.g., a binder, filler, lubricant or a combination
thereof.
[0141] Viscosity may be, for example, measured at room temperature,
at about 20-25 degrees Celsius, or at about 37 degrees Celsius to
mimic body temperature. In various embodiments of the present
invention the viscosity of the composition described herein is any
viscosity suitable for delivery of the corticosteroid to the
targeted and/or inflamed portion of the gastrointestinal tract. In
some embodiments, the viscosity of the composition is at least
about 1 centipoise (cP), at least about 2 cP, at least about 3 cP,
at least about 5 cP, at least about 10 cP, at least about 15 cP, at
least about 20 cP, at least about 25 cP, at least about 30 cP, at
least about 35 cP, at least about 40 cP, at least about 50 cP, at
least about 200 cP, or at least about 225 cP. In some embodiments,
the viscosity of the composition is at least about 100 cP. In
certain embodiments, the viscosity of the composition, measured at
25 degrees Celsius, is about 50 cP to about 250,000 cP, about 50 cP
to about 70,000 cP, about 50 cP to about 25,000 cP, about 50 cP to
about 10,000 cP, about 50 cP to about 3,000 cP, or about 50 cP to
about 2,000 cP. In one aspect, the viscosity of the composition, as
measured at 25 degrees Celsius, is from about 25 centipoise (cP) to
about 800 cP, about 50 cP to about 800, or about 300 cP to about
800 cP (e.g., measured by a Brookfield viscometer). In another
aspect, the viscosity of the composition may range from about 100
cP to about 200 cP, about 200 cP to about 300 cP, about 250 cP to
about 600 cP or about 400 cP to about 600 cP. In specific
embodiments, the viscosity of the formulation is about 30 cP, about
100 cP, about 200 cP, about 300 cP, about 400 cP, about 500 cP, or
about 250,000 cP (e.g., as measured with a Brookfield viscometer at
25 degrees Celsius equipped with an ultra low adapter).
[0142] In some embodiments, the viscosity of the composition is
measured at room temperature (about 25 degrees C.) with a shear
rate of about 13.2 sec.sup.-1. In certain embodiments, provided
herein is a composition having a viscosity under such conditions
that is at least about 2 centipoise (cP), at least about 3 cP, at
least about 5 cP, at least about 10 cP, at least about 15 cP, at
least about 20 cP, at least about 25 cP, at least about 30 cP, at
least about 35 cP, at least about 40 cP, at least about 50 cP, at
least about 200 cP, at least about 225 cP, at least about 250 cP,
at least about 300 cP, or at least about 400 cP. In some
embodiments, the viscosity of the composition under such conditions
is about 50 cP to about 250,000 cP, about 50 cP to about 70,000 cP,
about 50 cP to about 25,000 cP, about 50 cP to about 10,000 cP,
about 50 cP to about 3,000 cP, about 50 cP to about 2,000 cP, about
250 cP to about 250,000 cP, about 250 cP to about 70,000 cP, about
250 cP to about 25,000 cP, about 250 cP to about 10,000 cP, about
250 cP to about 3,000 cP, or about 250 cP to about 2,000 cP. In one
aspect, the viscosity of the composition, as measured at 25 degrees
Celsius, is from about 2 centipoise (cP) to about 800 cP, about 25
cP to about 800, about 50 cP to about 800, or about 300 cP to about
800 cP (e.g., measured by a Brookfield viscometer). In another
aspect, the viscosity of the composition under such conditions may
range from about 100 cP to about 200 cP, about 200 cP to about 300
cP, about 250 cP to about 600 cP or about 400 cP to about 600 cP.
In specific embodiments, the viscosity of the formulation measured
under such conditions is about 30 cP, about 40 cP, about 100 cP,
about 200 cP, about 300 cP, about 400 cP, about 500 cP, or about
250,000 cP.
[0143] In some embodiments, the viscosity of the composition is
measured at room temperature (about 25 degrees C.) with a shear
rate of about 15 sect (e.g., with a gap between the spindle and the
sample chamber wall of about 6 mm or greater). In certain
embodiments, provided herein is a composition having a viscosity
under such conditions that is at least about 2 centipoise (cP), at
least about 3 cP, at least about 5 cP, at least about 10 cP, at
least about 15 cP, at least about 20 cP, at least about 25 cP, at
least about 50 cP, at least about 100 cP, at least about 150
centipoise (cP), at least about 160 cP, at least about 170 cP, at
least about 180 cP, at least about 190 cP, or at least about 200
cP. In some embodiments, the viscosity of the composition under
such conditions is about 150 cP to about 250,000 cP, 160 cP to
about 250,000 cP, 170 cP to about 250,000 cP, 180 cP to about
250,000 cP, or 190 cP to about 250,000 cP.
[0144] In certain embodiments of the invention, the viscosity of
the composition is about that of a suspension prepared by adding
about 5 to about 15 grams of Splenda.RTM. to 4 ml of water, wherein
the viscosity is measured at 25 degrees Celsius.
[0145] In other embodiments of the invention, the viscosity of the
composition is about that of a suspension prepared by adding about
10 to about 12 grams of Splenda.RTM. to 4 ml of water, wherein the
viscosity is measured at 25 degrees Celsius.
[0146] In any of such methods, a viscosity-enhancing excipient can
be, for example acacia (gum arabic), agar, aluminum magnesium
silicate, sodium alginate, sodium stearate, bladderwrack,
bentonite, carbomer, carrageenan, Carbopol, cellulose,
microcrystalline cellulose, ceratonia, chondrus, dextrose,
furcellaran, gelatin, Ghatti gum, guar gum, hectorite, lactose,
sucrose, maltodextrin, mannitol, sorbitol, honey, maize starch,
wheat starch, rice starch, potato starch, gelatin, sterculia gum,
xanthum gum, polyethylene glycol (e.g. PEG 200-4500) gum
tragacanth, ethyl cellulose, ethylhydroxyethyl cellulose,
ethylmethyl cellulose, methyl cellulose, hydroxyethyl cellulose,
hydroxyethylmethyl cellulose, hydroxypropyl cellulose,
poly(hydroxyethyl methacrylate), oxypolygelatin, pectin,
polygeline, povidone, propylene carbonate, methyl vinyl
ether/maleic anhydride copolymer (PVM/MA), poly(methoxyethyl
methacrylate), poly(methoxyethoxyethyl methacrylate), hydroxypropyl
cellulose, hydroxypropylmethyl-cellulose, sodium
carboxymethyl-cellulose (CMC), silicon dioxide,
polyvinylpyrrolidone (PVP: povidone), Splenda.RTM. (dextrose,
maltodextrin and sucralose) or combinations thereof. In certain
embodiments, a viscosity-increasing excipient that may be used is
Splenda.RTM.. In specific embodiments, the viscosity-enhancing
excipient is a combination of MCC and CMC (e.g., Avicel
RC-591).
[0147] In any such methods of the above, the excipients that impart
mucoadhesive characteristics to a composition may include, but are
not limited to, at least one soluble polyvinylpyrrolidone polymer
(PVP); a water-swellable, but water-insoluble, fibrous,
cross-linked carboxy-functional polymer, a crosslinked poly(acrylic
acid) (e.g. Carbopol 947P), a carbomer homopolymer, a carbomer
copolymer, a hydrophilic polysaccharide guru, maltodextrin, a
cross-linked alignate gum gel, a water-dispersible polycarboxylated
vinyl polymer, at least two particulate components selected from
the group consisting of titanium dioxide, silicon dioxide, and
clay, or a mixture thereof.
[0148] In any such methods of the above, the excipient that
enhances absorption of the composition through a surface (e.g., a
mucosal or epithelial layer) of the gastrointestinal tract (e.g.,
esophagus), may include, but are not limited to, acylcarnitines,
surfactants, sodium lauryl sulfate, saponins, bile salts or bile
acids including but not limited to cholanic acid, chilic acid,
deoxycholic acid, glycocholic acid, tautocholic acid,
chenodeoxycholic acid, lithocholic acid, ursocholic acid,
ursodeoxycholic acid, isourosde oxycholic acid, lagodeoxycholic
acid, glycodeoxycholic acid, glycochenodeoxycholic acid,
dehydrocholic acid, hyocholic acid, hyodeoxycholic acid, or
combinations thereof, dihydrofusidates, fatty acid derivatives,
chitosan, carbopol, cellulosic agents, sterols, including but not
limited to alcohols structurally related to steroids, including but
not limited to cholestanol, coprostanol, cholesterol,
epicholesterol, ergosterol, ergocalciferol, or combinations
thereof, starch, dextran, cyclodextrin, or combinations
thereof.
[0149] In one aspect, a patient is administered a topical
corticosteroid such as, for example, budesonide or fluticasone.
[0150] H.sub.2RAs of the present invention include, but are not
limited to, cimetidine, ranitidine, ebrotidine, pabutidine,
lafutidine, loxtidine or famotidine. In one non-limiting example,
the H2RA is ranitidine.
[0151] PPIs of the present invention include, but are not limited
to, omeprazole, hydroxyomeprazole, esomeprazole, tenatoprazole,
lansoprazole, pantoprazole, rabeprazole, dontoprazole, habeprazole,
perprazole, ransoprazole, pariprazole or leminoprazole. In one
non-limiting example, the PPI is omeprazole.
[0152] Patients to be treated with compositions described herein
include those that have been diagnosed with GERD. In some
embodiments, the patient suffering from GERD is suffering from
NERD. In other embodiments, the patient suffering from GERD is
suffering from erosive esophagitis (FE). In some embodiments, the
patient suffering from GERD is suffering from Barrett's Esophagus.
In still other embodiments, the patient suffering from GERD is
suffering from Barrett's Esophagus. A patient can be an adult, a
child or an infant. In one aspect, a patient is a child less than
16 years old, less than 12 years old, less than 8 years old, less
than 6 years old, less than 4 years old or less than 2 years old.
In one aspect, a patient is an infant less than one year old, less
than 6 months old or less than 3 months old.
[0153] A composition of the invention disclosed herein may be in a
unit dose formulation for oral administration of a patient. In one
aspect, a H2RA is present in the unit dose in an amount of between
about 1 mg and about 1 g. In some embodiments, the amount of H2RA
present in a unit dose is between about 1 mg and about 500 mg,
between about 2.5 mg and about 250 mg, or between about 5 mg and
about 100 mg. In some embodiments, a PPI is present in the unit
dose in an amount of between about 1 mg and about 1.5 g. In certain
embodiments, a PPI is present in a unit dose in the amount of
between about 1 mg and about 600 mg. In yet another aspect, about
0.1 mg to about 20 mg, about 0.3 mg to about 4 mg, about 0.01 mg to
about 20 mg, about 0.01 mg to about 15 mg, or from about 0.25 mg to
about 5 mg (e.g., about 1-2 mg/day or about 2-3 mg/day)
corticosteroid per day is administered to said individual. In some
embodiments, the corticosteroid is present in a unit dose in an
amount of between about 0.25 mg and about 5 mg. In some
embodiments, the amount of corticosteroid administered daily or in
a unit dose is between about 0.5 mg and about 3 mg. In other
embodiments, the amount of corticosteroid present in a unit dose or
administered daily is between about 1 and about 3 mg, or between
about 1 and about 2 mg, or between about 2 and about 3 mg. In other
aspects, the unit dose formulation includes a combination of a
corticosteroid and an acid inhibitor, including but not limited to
an H2RA and/or a PPI.
[0154] In certain aspects, about 0.01 mg to about 20 mg, about 0.01
mg to about 15 mg, or about 0.25 mg to about 5 mg (e.g., about 0.1
to about 5 mg, about 0.25 to about 2.5 mg, about 0.3 mg to about 2
mg, about 0.5 mg to about 1 mg, about 0.7 mg to about 1.5 mg, about
0.375 mg, about 0.75 mg, about 1 mg, about 1.25 mg, about 1.5 mg or
about 2 mg) corticosteroid per day is administered to a patient. In
some embodiments, the corticosteroid is present in a unit dose in
an amount of between about 0.25 mg and about 5 mg. In some
embodiments, the amount of corticosteroid administered daily or in
a unit dose is between about 0.5 mg and about 3 mg. In other
embodiments, the amount of corticosteroid present in a unit dose or
administered daily is between about 1 and about 3 mg, or between
about 1 and about 2 mg, or between about 2 and about 3 mg.
[0155] In some embodiments, the corticosteroid is present in a
pharmaceutical composition described herein in any effective
amount. In some embodiments, an effective amount is an amount
sufficient to reduce inflammation or symptoms of inflammation
associated with an inflammatory disease or condition of the
gastrointestinal tract (e.g., the esophagus) as compared to the
level of inflammation or symptoms of inflammation associated with
an inflammatory disease prior to administration of the effective
amount. In certain embodiments, effective amount is an amount
sufficient to maintain a reduction in inflammation or symptoms of
inflammation achieved in any manner including, but not limited to,
by the administration of an effective amount sufficient to achieve
such a reduction. In some embodiments, the effective amount is
about 0.05 mg to about 20 mg, about 0.05 mg to about 15 mg, about
0.05 mg to about 10 mg, about 0.05 mg to about 7.5 mg, about 0.05
mg to about 5 mg, about 0.25 mg to about 3 mg, about 0.25 mg to
about 2.5 mg, about 0.5 mg to about 3 mg, about 0.5 mg to about 2
mg, about 0.5 mg to about 0.1 mg, about 0.5 mg to about 5 mg, about
0.5 mg to about 4 mg, about 1 mg to about 4 mg, about 1 mg to about
3 mg, about 2 mg to about 3 mg, or about 2 mg to about 4 mg. In
specific embodiments, the effective amount of corticosteroid is
about 0.05 mg, about 0.1 mg, about 0.15 mg, about 0.25 mg, about
0.3 mg, about 0.35 mg, about 0.4 mg, about 0.37 mg, about 0.375 mg,
about 0.7 mg, about 0.8 mg, about 0.75 mg, about 1 mg, about 1.2
mg, about 1.25 mg, about 1.3 mg, about 1.5 mg, about 2 mg, about
2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, about 5
mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, or about
7.5 mg or more. In certain embodiments, the corticosteroid is
present in a pharmaceutical composition at a concentration of about
0.01 mg/mL to about 2 mg/mL of composition. In specific
embodiments, the corticosteroid is present in a pharmaceutical
composition at a concentration of about 0.01 mg/mL to about 1.5
mg/mL, about 0.02 mg/mL to about 1.5 mg/mL, about 0.04 mg/mL to
about 1.5 mg/mL about 0.03 mg/mL to about 1.5 mg/mL, about 0.05
mg/mL to about 1.5 mg/mL, or about 0.07 mg/mL to about 1.5 mg/mL.
In more specific embodiments, the corticosteroid is present in a
pharmaceutical composition at a concentration of about 0.07 mg/mL
to about 1 mg/mL.
[0156] In some embodiments, the corticosteroid is selected from by
way of non-limiting example, budesonide, fluticasone propionate and
combinations thereof. In specific embodiments, corticosteroid is
present in the composition in an amount of about 0.01 mg/mL to
about 3 mg/mL, about 0.01 mg/mL to about 2 mg/mL, about 0.01 mg/mL
to about 1.5 mg/mL, about 0.07 mg/mL to about 1.5 mg/mL, or about
0.07 mg/mL to about 1 mg/mL. In more specific embodiments,
budesonide is present in an amount of about 0.01 mg/mL to about 3
mg/mL, about 0.01 mg/mL to about 1.5 mg/mL, or about 0.07 mg/mL to
about 1 mg/mL. In other specific embodiments, fluticasone
propionate is present in an amount of about 0.005 mg/mL to about
1.5 mg/mL, or about 0.01 mg/mL to about 1 mg/mL.
[0157] In some embodiments, the volume of a composition or dose of
a composition described herein is an amount sufficient to
substantially coat (e.g., at least 50%, at least 60%, at least 70%,
at least 80%, at least 90%, at least 95%, at least 98% or at least
99% of) the length of the esophagus of an individual to whom the
composition is administered. In certain embodiments, the volume of
a composition or a dose of a composition described herein is about
0.05 mL/cm esophageal length to about 1 mL/cm esophageal length,
about 0.1 mL/cm esophageal length to about 0.8 mL/cm esophageal
length, about 0.2 mL/cm esophageal length to about 0.6 mL/cm
esophageal length, or about 0.3 mL/cm esophageal length to about
0.5 mL/cm esophageal length, wherein the esophageal length is the
esophageal length of the individual to whom the composition is
administered. In some embodiments, the volume of a composition or
dose of a composition described herein is based on the esophageal
length of an individual (e.g., male, female, or both) that is in
the 50.sup.th percentile of height for their age. Therefore, in
some embodiments, the volume of a composition or dose of a
composition described herein is about 0.05 mL/cm esophageal length
to about 1 mL/cm esophageal length, about 0.1 mL/cm esophageal
length to about 0.8 mL/cm esophageal length, about 0.2 mL/cm
esophageal length to about 0.6 mL/cm esophageal length, about 0.3
mL/cm esophageal length to about 0.5 mL/cm esophageal length, about
0.32 mL/cm esophageal length to about 0.41 mL/cm esophageal length
or about 0.3 mL/cm esophageal length to about 0.46 mL/cm esophageal
length, wherein the esophageal length is the esophageal length of
an individual having a height in the 50.sup.th percentile for the
age of the individual to whom the composition is administered. In
certain instances, esophageal length is the actual esophageal
length of the individual or is calculated based on the equation:
esophageal length=1.048(cm)+(0.167*height(cm)). In certain
instances, for example, the 50.sup.th percentile height (CDC 2000)
for male children age 2 is 87 cm, age 3 is 95 cm, age 4 is 102 cm,
age 5 is 109 cm, age 6 is 115 cm, age 7 is 122 cm, age 8 is 12 cm,
age 9 is 134 cm, age 10 is 139 cm, age 11 is 144 cm, age 12 is 149
cm, age 13 is 156 cm, age 14 is 164 cm, age 15 is 170 cm, age 16 is
174 cm, age 17 is 175 cm, and age 18 is 176 cm.
[0158] Furthermore, in certain embodiments, the amount of a
therapeutic agent (e.g., a corticosteroid such as budesonide) in a
composition or a dose of a composition described herein is about
0.005 mg/cm esophageal length to about 0.3 mg/cm esophageal length,
about 0.008 mg/cm esophageal length to about 0.2 mg/cm esophageal
length, about 0.01 mg/cm esophageal length to about 0.15 mg/cm
esophageal length, or about 0.015 mg/cm esophageal length to about
0.1 mg/cm esophageal length, wherein the esophageal length is the
esophageal length of the individual to whom the composition is
administered. In some embodiments, the volume of a composition or
dose of a composition described herein is based on the esophageal
length of an individual (e.g., male, female, or both) that is in
the 50.sup.th percentile of height for their age. Therefore, in
some embodiments, the amount of a therapeutic agent (e.g., a
corticosteroid such as budesonide) in a composition or dose of a
composition described herein is about 0.005 mg/cm esophageal length
to about 0.3 mg/cm esophageal length, about 0.008 mg/cm esophageal
length to about 0.2 mg/cm esophageal length, about 0.01 mg/cm
esophageal length to about 0.15 mg/cm esophageal length, or about
0.015 mg/cm esophageal length to about 0.1 mg/cm esophageal length,
wherein the esophageal length is the esophageal length of an
individual having a height in the 50.sup.th percentile for the age
of the individual to whom the composition is administered.
[0159] In some embodiments, any pharmaceutical composition or dose
of a pharmaceutical composition described herein is provided or
administered in a volume sufficient to provide a bolus when orally
administered to an individual. In certain embodiments, the
composition has a volume that does not systemically deliver
excessive amounts of the active agent. In some embodiments, the
pharmaceutical composition or dose is provided in a volume
sufficient to provide a bolus when administered to an individual,
wherein the size of the bolus at the distal end of the esophagus
(e.g., the size of the bolus prior, e.g., immediately prior, to
entering or passing the lower esophageal sphincter) is less than
90%, less than 85%, less than 80%, less than 75%, less than 70%,
less than 65%, less than 60%, less than 55%, less than 50%, less
than 45%, less than 40%, less than 35%, less than 30%, less than
25%, less than 20%, less than 15%, less than 10% or less than 5% of
size of the bolus that entered the esophagus (e.g., the size of the
bolus after, e.g., immediately after, passing the upper esophageal
sphincter). In some embodiments, the size of the bolus is
determined as a measure of diameter or of volume. In certain
embodiments, diameter of the sphincter can be determined using
gamma scintigraphy techniques. In specific embodiments, the volume
of the composition or dose is adjusted given the length and/or
diameter of the esophagus of the individual to whom the composition
or dose is administered.
[0160] In some embodiments, provided herein is a multiple unit
container comprising about 2 to about 180, about 1 to about 60,
about 14, or about 30 unit doses of any pharmaceutical composition
described herein. In more specific embodiments, each dose comprises
about 1 mL to about 25 mL, about 1 mL to about 20 mL, about 7 mL to
about 25 mL, about 10 to about 20 mL, about 15 mL, about 20 mL,
about 3 to about 7 mL, about 5 mL, about 8 mL to about 12 mL, or
about 10 mL. In still more specific embodiments, each dose
comprises about 0.1 to about 20 mg, about 0.1 to about 10 mg, about
0.1 to about 7.5 mg, about 0.1 to about 5 mg, about 0.3 to about 4
mg, about 0.25 to about 2.5 mg, about 0.3 mg to about 2 mg, about
0.5 mg to about 1 mg, about 0.7 mg to about 1.5 mg, about 0.375 mg,
about 0.75 mg, about 1 mg, about 1.25 mg, about 1.5 mg or about 2
mg of corticosteroid. In certain embodiments, provided herein is a
multiple unit container comprising about 10 mL to about 1500 mL,
about 50 mL to about 600 mL, about 150 mL, about 300 mL, about 600
mL, or about 1,200 mL of any pharmaceutical composition described
herein. In specific embodiments, the multidose container comprises
about 330 mL or about 55 mL of a composition described herein. In
some embodiments, a kit provided herein comprises any multidose
container as described herein, a pharmaceutical composition as
described herein (e.g., in a volume described), and a delivery or
metered device (e.g., a syringe, a cup, a spoon, or the like). In
specific embodiments, the delivery device is incorporated into the
container (e.g., a nebulizer, an aerosolizer, a pump, or the like).
In certain embodiments, the pharmaceutical composition contained
within any of the multiple unit containers described herein is
physically and chemically stable. The entirety of each patent,
patent application, publication and document referenced herein
hereby is incorporated by reference. Citation of the above patents,
patent applications, publications and documents is not an admission
that any of the foregoing is pertinent prior art, nor does it
constitute any admission as to the contents or date of these
publications or documents.
[0161] Unless defined otherwise, all technical and scientific terms
used herein have the same meanings as commonly understood by one of
ordinary skill in the art to which this invention belongs. Although
any methods and systems similar or equivalent to those described
herein can be used in the practice or testing of the present
invention, the methods, devices, and materials are now described.
All publications mentioned herein are incorporated herein by
reference for the purpose of describing and disclosing the
processes, systems, and methodologies which are reported in the
publications which might be used in connection with the invention.
Nothing herein is to be construed as an admission that the
invention is not entitled to antedate such disclosure by virtue of
prior invention.
[0162] Modifications may be made to the foregoing without departing
from the basic aspects of the invention. Although the invention has
been described in substantial detail with reference to one or more
specific embodiments, those of ordinary skill in the art will
recognize that changes may be made to the embodiments specifically
disclosed in this application, and yet these modifications and
improvements are within the scope and spirit of the invention. The
invention illustratively described herein suitably may be practiced
in the absence of any element(s) not specifically disclosed herein.
Thus, for example, in each instance herein any of the terms
"comprising", "consisting essentially of", and "consisting of" may
be replaced with either of the other two terms. Thus, the terms and
expressions which have been employed are used as terms of
description and not of limitation, equivalents of the features
shown and described, or portions thereof, are not excluded, and it
is recognized that various modifications are possible within the
scope of the invention.
[0163] While preferred embodiments of the present invention have
been shown and described herein, it will be obvious to those
skilled in the art that such embodiments are provided by way of
example only. Numerous variations, changes, and substitutions will
now occur to those skilled in the art without departing from the
invention. It should be understood that various alternatives to the
embodiments of the invention described herein may be employed in
practicing the invention. It is intended that the following claims
define the scope of the invention and that methods and structures
within the scope of these claims and their equivalents be covered
thereby.
EXAMPLE 1
[0164] This example details the efficacy and safety of once daily
and twice daily use of budesonide in inducing and maintaining
remission of disease activity in individuals (children and/or
adults) with GERD. Doses of 0-1 mg, 1-2 mg, 2-3 mg, 34 mg, 4-5 mg,
and/or 5-6 mg per dose are administered once a day or b.i.d. in
volumes of 3, 5, 7, 10, 12, 15, or 17.5 mL. A number of individuals
(e.g., 20 per budesonide dose frequency, amount, and volume) are
evaluated to determine the symptoms prior to therapy, during
therapy and following therapy. Administration is conducted for 7
days, 14 days, and 28 days. Primary Outcome Measures include
complete resolution of heartburn and regurgitation (e.g., no more
than one day with either mild heartburn or regurgitation over the
seven days prior to the assessment time-point). Secondary Outcome
Measures include: Number of days with heartburn (daytime and
night-time); Number of days with regurgitation (daytime and
night-time); Number of heartburn and regurgitation-free days (24
hrs); Composite score of heartburn and regurgitation frequency and
severity; Time to resolution of symptoms of
heartburn/regurgitation; Severity of additional GERD symptoms;
Quality of Life (assessed using PAGI-QOL to PGIC (Patient Global
Impression of Change); Complete resolution of heartburn; Complete
resolution of regurgitation; Average severity of heartburn (daytime
and night-time); Average severity of regurgitation (daytime and
night-time). These symptoms are scored (e.g., assigning a 3 to the
most severe symptoms, a 2 to moderate symptoms, a 1 to mild
symptoms, and a 0 to a lack of symptoms) and utilized to determine
the efficacy of the treatment.
REFERENCES
[0165] 1. Riddell, R H. The Biopsy Diagnosis of Gastroesophageal
Reflux Disease, `Carditis,` and Barrett's Esophagus, and Sequelae
of Therapy. The American Journal of Surgical Pathology (1996)
20(S1):S31-S50. [0166] 2. Fass, R et al. Gastroesophageal Reflux
Disease--Should We Adopt a New Conceptual Framework? The American
Journal of Gastroenterology (2002) 97(8):1901-1909. [0167] 3.
Lembo, T et al. Inflammation of the gastro-oesophageal junction
(carditis) in patients with sympomatic gastro-oesophageal reflux
disease: a prospective study. Gut (1999) 45:484-488. [0168] 4.
Haggit, R C. Histophathology of Reflux--Induced Esophageal and
Supraesophageal Injuries. The American Journal of Medicine (2000)
108(4A): 109S-111S.
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