U.S. patent application number 12/269765 was filed with the patent office on 2009-06-11 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 Elaine Phillips.
Application Number | 20090149433 12/269765 |
Document ID | / |
Family ID | 40639386 |
Filed Date | 2009-06-11 |
United States Patent
Application |
20090149433 |
Kind Code |
A1 |
Phillips; Elaine |
June 11, 2009 |
COMPOSITIONS FOR THE TREATMENT OF INFLAMMATION OF THE
GASTROINTESTINAL TRACT
Abstract
Provided herein are methods for preventing or alleviating the
symptoms of and inflammation associated with inflammatory diseases
and conditions of the gastrointestinal tract, for example, those
involving the esophagus. Also provided herein are pharmaceutical
compositions useful for the methods of the present invention.
Inventors: |
Phillips; Elaine; (San
Diego, 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: |
40639386 |
Appl. No.: |
12/269765 |
Filed: |
November 12, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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60987720 |
Nov 13, 2007 |
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61012012 |
Dec 6, 2007 |
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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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61035348 |
Mar 10, 2008 |
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61054103 |
May 16, 2008 |
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61054104 |
May 16, 2008 |
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61054105 |
May 16, 2008 |
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61054106 |
May 16, 2008 |
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61054107 |
May 16, 2008 |
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61090568 |
Aug 20, 2008 |
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Current U.S.
Class: |
514/174 |
Current CPC
Class: |
A61K 31/573 20130101;
A61K 9/0095 20130101; A61P 43/00 20180101; A61P 35/00 20180101;
A61K 47/36 20130101; A61K 47/32 20130101; A61K 9/0053 20130101;
A61P 5/38 20180101; A61K 31/41 20130101; A61P 1/08 20180101; A61K
47/38 20130101; A61K 31/575 20130101; A61K 9/0065 20130101; A61K
9/006 20130101; A61K 47/26 20130101; A61P 17/00 20180101; A61P 1/04
20180101; A61K 9/10 20130101; A61P 5/44 20180101; A61P 37/08
20180101; A61K 31/58 20130101; A61K 31/341 20130101; A61K 45/06
20130101; A61K 9/06 20130101; A61P 1/00 20180101; A61K 31/4439
20130101; A61P 1/12 20180101; A61P 1/14 20180101; A61P 29/00
20180101; A61K 31/58 20130101; A61K 2300/00 20130101; A61K 31/341
20130101; A61K 2300/00 20130101; A61K 31/41 20130101; A61K 2300/00
20130101; A61K 31/573 20130101; A61K 2300/00 20130101; A61K 31/4439
20130101; A61K 2300/00 20130101 |
Class at
Publication: |
514/174 |
International
Class: |
A61K 31/58 20060101
A61K031/58; A61P 29/00 20060101 A61P029/00 |
Claims
1. A method of treating, preventing or alleviating inflammation of
the gastrointestinal tract comprising orally administering to an
individual in need thereof a composition comprising a
corticosteroid, a preservative, a chelating agent, an isotonic
agent, a surfactant, and an excipient that increases the
interaction of the composition with a surface of the
gastrointestinal tract.
2. The method of claim 1, wherein the corticosteroid is
budesonide.
3. The method of claim 1, wherein the corticosteroid is present in
the composition in an amount of about 0.01 mg to about 1.0 mg of
corticosteroid per gram of composition.
4. The method of claim 1, wherein the corticosteroid is present in
the composition in an amount of about 0.01 mg to about 1.0 mg of
corticosteroid per mL of composition.
5. A method of claim 4, wherein the method comprises administering
about 5 mL to about 50 mL of the composition to the individual.
6. The method of claim 1, wherein the preservative is potassium
sorbate.
7. The method of either of claims 1 or 6, wherein the preservative
is present in the composition in an amount of about 0.0002% to
about 0.5% w/w of the composition.
8. The method of claim 1, wherein the chelating agent is
edetate.
9. The method of claim 1, wherein the chelating agent is present in
the composition in an amount of about 0.0005% to about 0.1% w/w of
the composition.
10. The method of claim 1, wherein the isotonic agent is
dextrose.
11. The method of claim 1, wherein the surfactant is polysorbate
80.
12. The method of claim 1, wherein the surfactant is present in the
composition in an amount of about 0.0005% to about 2% w/w of the
composition.
13. The method of claim 1, wherein the excipient that increases the
interaction of the composition with a surface of the
gastrointestinal tract is a viscosity enhancing agent.
14. The method of claim 13, wherein the viscosity enhancing agent
is selected from microcrystalline cellulose, carboxymethyl
cellulose sodium and a combination thereof.
15. The method of claim 14, wherein the viscosity enhancing agent
is a combination of microcrystalline cellulose and carboxymethyl
cellulose sodium.
16. The method of claim 13, wherein the viscosity enhancing agent
is present in the composition in about 0.01% to about 3.0% w/w of
the composition.
17. The method of claim 15, wherein the viscosity enhancing agent
is a combination of a CMC and MCC.
18. The method of claim 1, wherein the composition is formulated as
a micronized suspension of the corticosteroid in an aqueous
vehicle.
19. The method of claim 1, wherein the composition has a target pH
of about 4.5.
20. The method of claim 19, wherein the target pH of the
composition is attained by adding a pH adjusting agent to the
composition.
21. The method of claim 20, wherein the pH adjusting agent is
hydrochloric acid.
22. The method of claim 1, wherein the composition further
comprising a sweetener, a flavoring agent or a combination
thereof.
23. The method of claim 1, wherein the composition comprises: a.
about 0.01 mg to about 1.0 mg of budesonide per mL of composition;
b. about 0.0002% to about 0.5% w/w of potassium sorbate; c. about
0.0005% to about 0.1% w/w of disodium edetate; d. about 0.0005% to
about 2% w/w of polysorbate 80; and e. about 0.01% to about 3.0%
w/w of a combination of microcrystalline cellulose and
carboxymethyl cellulose sodium.
24. The method of claim 1, comprising administering about 0.1 mg to
about 20 mg of corticosteroid per day.
25. The method of claim 1, wherein the inflammation of the
gastrointestinal tract is inflammation of the esophagus.
26. The method of claim 1, wherein the inflammation of the
gastrointestinal tract is eosinophilic esophagitis, an inflammatory
bowel disease involving the esophagus, Crohn's disease, celiac
disease, intermediate esophagitis, epithelial hyperplasia, basal
cell hyperplasia, elongated papillae, dilated vessels in papillae,
fungal esophagitis, viral esophagitis, bacterial esophagitis,
corrosive esophagitis, radiation esophagitis, chemotherapy
esophagitis, graft vs. host disease, a skin disease with esophageal
involvement, bullous pemphigoid, pemphigus vulgaris, epidermolysis
bollosa, Stevens-Johnson syndrome, Behcet's disease, sarcoidosis,
idiopathic esophagitis, eosinophilic gastritis, Menetrier's
disease, parasitic gastritis, lymphocytic esophagitis, inflammatory
bowel disease-associated esophagitis, parasitic gastritis,
lymphocytic esophagitis, inflammatory bowel disease-associated
esophagitis, eosinophilic duodenitis, functional dyspepsia,
esophageal inflammation secondary to caustic/irritant ingestion,
persistent/recurrent esophageal strictures of any cause and
including caustic/irritant ingestion, pill-induced esophagitis,
systemic diseases, congenital diseases or post-surgery
inflammation.
27. The method of claim 25, wherein the individual has eosinophilic
esophagitis.
28. The method of claim 25, wherein the individual has been
diagnosed with gastroesophageal reflux disease (GERD), nonerosive
reflux disease (NERD), or erosive esophagitis.
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 December 06, 2007; U.S.
Provisional Application No. 61/015,998, filed December 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] Esophageal inflammation disorders are gaining increased
recognition in both adults and children. One example is
eosinophilic esophagitis (EE), which is an emerging, and
fast-growing disorder characterized by high levels of eosinophils
in the esophagus, as well as basal zone hyperplasia. EE is thought
to be provoked, in at least a subset of patients, by food allergies
or airborne allergen exposure (1-5, 44). EE diagnosis is often
associated with other hypersensitivity disorders, including asthma,
rhinitis, and other food and aeroallergen inhalant sensitivities
(39-40). Diagnosis is often made, e.g., in young children and
depends on the finding of 15 to 20 or more to 24 or more
eosinophils per high power field (eos/hpf) within esophageal
mucosal biopsies (6-12).
[0003] In parallel with other atopic disorders, the incidence of BE
appears to be increasing (15, 35). The disorder may present with
reflux-like symptoms, pain and dysphagia, clinical symptoms similar
to the presentation of gastroesophageal reflux disease ("GERD")
(42). Symptoms of EE include, for example, abdominal pain, chest
pain, choking, difficulty swallowing, failure to thrive, nausea,
reflux not relieved by standard anti-flux therapy, skin rash or
hives, vomiting, and weight loss. In one series, 15% of EE patients
had concurrent developmental delay (45).
[0004] Although EE is becoming more frequently diagnosed throughout
developing countries (7, 8, 13-16) many aspects of the disease
remain unclear including its etiology, natural history and optimal
therapy. Symptoms of EE often mimic those of GERD and include
vomiting, dysphagia, pain and food impaction (8, 14, 17-20).
However, treatment of EE and GERD differ and it is important to
distinguish between them, particularly as untreated EE may be
associated with esophageal narrowing in 10-30% of cases (14, 18,
20, 21). The overlap of GERD and EE symptoms is common; failure to
respond to high PPI GERD treatment may be one diagnostic guideline
for EE (42). The common occurrence regarding misdiagnosis of EE for
GERD often results in delayed treatment for patients with EE.
(42).
[0005] Long term systemic steroid therapy can result in significant
secondary side effects on growth and bone development. Although
treatment with anti-IL-5 monoclonal antibody has been reported to
be successful in EE, this therapy is currently not approved for use
in children (36).
[0006] Current treatments include elimination diets (22, 23), and
elemental formulas (2, 24). Identifying true inciting food
allergens can be difficult and elemental formulas are often
unpalatable, thereby making dietary interventions complicated (1,
22). Improvised puff and swallow techniques may be difficult for
patients, especially smaller children, and especially children with
developmental delays, to perform efficiently. This may result in a
less than effective dose of a topical steroid being delivered to
the esophagus.
SUMMARY OF THE INVENTION
[0007] Certain embodiments of the present invention provide a
method of treating, preventing or alleviating inflammation of the
gastrointestinal tract comprising orally administering to an
individual in need thereof a composition comprising a
corticosteroid, a preservative, a chelating agent, an isotonic
agent, a surfactant, and an excipient that increases the
interaction of the composition with a mucosal layer. In some
embodiments, the corticosteroid is, by way of non-limiting example,
budesonide. In specific embodiments, the corticosteroid is present
in the composition in an amount of about 0.01 mg to about 1.0 mg of
corticosteroid per gram of composition. In some embodiments, the
corticosteroid is present in the composition in an amount of about
0.01 mg to about 1.0 mg of corticosteroid per mL of
composition.
[0008] In certain embodiments, the present invention provides for
methods of administering about 5 mL to about 50 ma of the
corticosteroid containing composition to the individual.
[0009] In some embodiments, the preservative is, by way of
non-limiting example, potassium sorbate. In specific embodiments,
the preservative is present in the composition in an amount of
about 0.0002% to about 0.5% w/w of the composition. In some
embodiments, the chelating agent is, by way of non-limiting
example, disodium edetate. In specific embodiments, the chelating
agent is present in the composition in an amount of about 0.0005%
to about 0.1% w/w of the composition. In certain embodiments, the
isotonic agent is, by way of non-limiting example, dextrose. In
some embodiments, the surfactant is, by way of non-limiting
example, polysorbate 80. In specific embodiments, the surfactant is
present in the composition in an amount of about 0.0005% to about
2% w/w of the composition. In certain embodiments, the excipient
that increases the interaction of the composition with a mucosal
layer is a viscosity modulator and/or modifier. In specific
embodiments, the viscosity modulator and/or modifier is selected
from, by way of non-limiting example, microcrystalline cellulose,
carboxymethyl cellulose sodium and a combination thereof. In more
specific embodiments, the viscosity modulator and/or modifier is a
combination of microcrystalline cellulose and carboxymethyl
cellulose sodium. In some embodiments, the viscosity modulator
and/or modifier is present in the composition in about 0.01% to
about 3.0% w/w of the composition. In certain embodiments, the
viscosity modulator and/or modifier is Avicel.RTM. RC-591.
[0010] In some embodiments, the composition has a first and a
second excipient. In specific embodiments, the second excipient is
selected from an excipient that increases the interaction of the
composition with a mucosal layer, a binder, a filler, a
disintegrant, a diluent, a carrier, a vehicle and combinations
thereof. In other embodiments, the second excipient that increases
the interaction of the composition with a mucosal layer is a second
viscosity modulator and/or modifier. In some embodiments, the
second excipient is a vehicle (including a diluent) and is present
in the composition in an amount of about 50% to about 99.5% w/w of
the composition. In specific embodiments, the vehicle is selected
from, by way of non-limiting example, a liquid vehicle, a solid
vehicle and combinations thereof. In some embodiments, the vehicle
is a solid vehicle and is selected from, by way of non-limiting
example, talc, bentonite, kaolin calcium carbonate, and
combinations thereof. In certain embodiments, the vehicle is a
liquid vehicle and is selected from, by way of non-limiting
example, water, ethanol, an organic solvent, an oil (e.g., corn
oil) and combinations thereof. In specific embodiments, the
corticosteroid containing composition is formulated as a micronized
suspension of the corticosteroid in an aqueous vehicle.
[0011] In some embodiments, the corticosteroid containing
composition has a target pH of about 4.5. In certain embodiments,
the target pH of the composition is attained by adding a pH
adjusting agent to the composition. In specific embodiments, the pH
adjusting agent is, by way of non-limiting example, hydrochloric
acid or sodium hydroxide.
[0012] In certain embodiments, the corticosteroid containing
composition also contains, by way of non-limiting example, a
sweetener, a flavoring agent or a combination thereof.
[0013] In specific embodiments of the present invention, the
corticosteroid containing composition contains budesonide as the
corticosteroid, potassium sorbate as the preservative, disodium
edetate as the chelating agent, dextrose as the isotonic agent,
polysorbate 80 as the surfactant, a combination of microcrystalline
cellulose and carboxymethyl cellulose sodium as the excipient that
increases the interaction of the composition with a mucosal layer,
and hydrochloric acid as the pH adjusting agent. In more specific
embodiments, the corticosteroid containing composition contains
about 0.01 mg to about 1.0 mg of budesonide per mL of composition,
about 0.0002% to about 0.5% w/w of potassium sorbate, about 0.0005%
to about 0.1% W/W of disodium edetate, about 0.0005% to about 2%
w/w of polysorbate 80, and about 0.01% to about 3.0% w/w of a
combination of microcrystalline cellulose and carboxymethyl
cellulose sodium In still more specific embodiments, the
composition is further comprises an aqueous vehicle. In some
embodiments, the corticosteroid containing composition is
formulated as a micronized suspension of the budesonide in the
aqueous vehicle. In yet more specific embodiments, the composition
has a pH of about 4.5. In some embodiments, the composition
comprises a second excipient that increases the interaction of the
composition with a mucosal layer.
[0014] In certain embodiments, a pharmaceutical composition
described comprises or a method described herein comprises
administering (e.g., per day or per dose) to an individual about
0.1 mg to about 20 mg corticosteroid, about 1 to about 2 mg
corticosteroid, about 2 to about 3 mg corticosteroid, or about
0.25- to about 2.5 mg, or about 0.25 to about 3 mg of
corticosteroid. In certain embodiments, the methods described
herein of treating, preventing or alleviating inflammation of the
gastrointestinal tract include treating, preventing or alleviating
inflammation of the esophagus. In certain embodiments, the
individual has been diagnosed with (or has inflammation associated
with), by way of non-limiting example, eosinophilic esophagitis, an
inflammatory bowel disease involving the esophagus, Crohn's
disease, esophageal inflammation secondary to caustic/irritant
ingestion, persistent/recurrent esophageal strictures of any cause
and including caustic/irritant ingestion, pill-induced esophagitis,
systemic diseases, congenital diseases or post-surgery
inflammation. In specific embodiments, the individual has been
diagnosed with (or has inflammation associated with), by way of
non-limiting example, eosinophilic esophagitis. In some
embodiments, the individual has been diagnosed with (or has
inflammation associated with), by way of non-limiting example,
gastroesophageal reflux disease (GERD), nonerosive reflux disease
(NERD), or erosive esophagitis. It is to be understood that
disclosure of treating an individual diagnosed with or inflammation
associated with a certain inflammatory disorder includes a method
of treating, preventing or alleviating inflammation associated with
the certain inflammatory disorder.
[0015] In certain embodiments, the individual treated with the
methods disclosed herein is a child or infant. In some embodiments,
the child less than 19 years old, less than 16 years old, 12 years
old, 8 years old, 6 years old, 4 years old, or 2 years old. In
other embodiments, the individual is an adult.
INCORPORATION BY REFERENCE
[0016] 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.
BRIEF DESCRIPTION OF THE DRAWINGS
[0017] The novel features of the invention are set forth with
particularity in the appended claims. A better understanding of the
features and advantages of the present invention will be obtained
by reference to the following detailed description that sets forth
illustrative embodiments, in which the principles of the invention
are utilized, and the accompanying drawings of which:
[0018] FIG. 1 illustrates the percent amount of composition present
in the esophagus as a function of time following oral
administration (by measuring the amount of radiolabel present in
the esophagus).
DETAILED DESCRIPTION OF THE INVENTION
[0019] In certain embodiments, the present invention is directed to
methods and pharmaceutical compositions for treating, preventing or
alleviating the symptoms of and inflammation associated with
inflammatory diseases involving the gastrointestinal tract,
including the upper-gastrointestinal tract (e.g., inflammatory
diseases involving pre-colonic gastrointestinal inflammation),
esophagus, stomach and/or digestive tract. Provided herein are
methods of treating, preventing or alleviating, for example,
esophageal inflammation in an individual. In certain embodiments,
these methods comprise orally administering to said individual a
corticosteroid in association with at least one excipient that
increases the interaction of the composition with a 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). In some
embodiments, the viscosity modulator and/or modifier provides an
increased viscosity and the increased viscosity of the composition
allows the composition to be in contact with the in esophagus for
an extended period of time following administration.
[0020] An individual suitable for treatment with the compositions
disclosed herein may, for example, have been diagnosed with a
disease or condition including, but not limited to, eosinophilic
esophagitis, inflammatory bowel diseases involving the esophagus,
Crohn's disease, esophageal inflammation secondary to
caustic/irritant ingestion, persistent/recurrent esophageal
strictures of any cause and including caustic/irritant ingestion,
pill-induced esophagitis, celiac disease, intermediate esophagitis,
epithelial hyperplasia, basal cell hyperplasia, elongated papillae,
dilated vessels in papillae, fungal esophagitis, viral esophagitis,
bacterial esophagitis, corrosive esophagitis, radiation
esophagitis, chemotherapy esophagitis, graft vs. host disease, a
skin disease with esophageal involvement, bullous pemphigoid,
pemiphigus vulgaris, epidermolysis bollosa, Stevens-Johnson
syndrome, Behget's disease, sarcoidosis, idiopathic esophagitis,
eosinophilic gastritis, Menetrier's disease, parasitic gastritis,
lymphocytic esophagitis, inflammatory bowel disease-associated
esophagitis, parasitic gastritis, lymphocytic esophagitis,
inflammatory bowel disease-associated esophagitis, eosinophilic
duodenitis, functional dyspepsia, systemic diseases, congenital
diseases or post-surgery inflammation. The composition may also be
used in treating other gastrointestinal disorders, including
stomach and duodenal ulcers, hyperactive acidic discharge
disorders, such as Zollinger-Ellison syndrome and laryngeal
disorders.
[0021] Provided herein are methods for treating, preventing and
alleviating any chronic inflammatory or malignant state that
involves the gastrointestinal tract, such as the esophagus, and
responds to steroid therapy. The methods of the present invention
are useful, for example, for treating, preventing and alleviating
inflammation and/or symptoms and associated with eosinophilic
esophagitis, inflammatory bowel diseases involving the esophagus,
Crohn's disease, esophageal inflammation secondary to
caustic/irritant ingestion, persistent/recurrent esophageal
strictures of any cause and including caustic/irritant ingestion,
pill-induced esophagitis, systemic diseases, congenital diseases,
Epidermolysis bullosa, and post-surgery inflammation. The present
methods are also useful for treating, preventing or alleviating
symptoms and/or inflammation associated with other diseases or
conditions of the gastrointestinal tract, for example, the upper
gastrointestinal tract, where it is beneficial to target a
particular target site, rather than provide systemic therapy. Also
provided herein are pharmaceutical compositions useful in the
methods of the present application. As used herein, inflammation
and/or symptoms associated with a disorder or disease disclosed
herein includes inflammation and/or symptoms associated with,
caused by and/or resulting from the disorder or disease.
[0022] As used herein, unless otherwise stated, the use of the
terms "a", "an" and "the" include both singular and multiple
embodiments. 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. In
yet other embodiments, the human is an infant. 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. As used herein,
the phrase "an effective amount" and "a therapeutically effective
amount" is an amount sufficient to elicit a change in the symptoms
of or inflammation associated with gastrointestinal disorders,
including but not limited to esophageal inflammation. As used
herein, the term "or" includes "and" and "or".
[0023] As used herein, the phrase "treating inflammatory diseases
involving the esophagus" includes treating symptoms of such
diseases and treating inflammation associated with the
diseases.
[0024] Methods and Compositions
[0025] In certain embodiments, the corticosteroids used in the
present invention include topical steroids including, for example,
budesonide. In some embodiments, corticosteroids are selected from,
by way of non-limiting example, aclometasone, amcinomide,
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, fluticasone, fuprednidene,
formocortal, halcinonide, balometasone, hydrocortisone aceponate,
hydrocortisone buteprate, hydrocortisone butyrate, loteprednol,
medrysone, meprednisone, methylprednisolone, methylprednisolone
aceponate, mometasone furoate, paramethasone, prednicarbate,
prednisone, prednisolone, prednylidene, remexolone, tixocortol,
triamcinolone and ulobetasol, and combinations thereof. In a
specific embodiment, the corticosteroid is budesonide.
[0026] Provided herein are methods and pharmaceutical compositions
for treating, preventing or alleviating the symptoms of, and
inflammation associated with, inflammatory diseases of the
gastrointestinal tract, including but not limited to the
esophagus.
[0027] In certain embodiments, a corticosteroid (e.g., budesonide)
that is administered in oral form, in a formulation with increased
fluid viscosity, is delivered to the esophagus in an effective dose
to reduce the inflammation of the esophagus.
[0028] In one aspect, an exemplary corticosteroid is budesonide.
Budesonide, 16,17-(butylidenebis(oxy))-11,21-dihydroxy-,
(11-.beta.,16-.alpha.)-pregna-1,4-diene-3,20-dione, is a
corticosteroid sometimes used in inhaled form to treat pulmonary
conditions.
[0029] In certain embodiments, the pharmaceutical composition
described herein includes one or more excipients. Excipients useful
herein include, by way of nonlimiting example, binders, fillers,
lubricants, isotonic agents, surfactants, antioxidants (e.g.,
chelating agents), preservatives, buffers, pH adjusting agents,
solvents, flavoring agents, coloring agents, sweeteners, excipients
that increase the interaction of the composition with a 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) and combinations
thereof. Excipients that 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)
include excipients that modulate and/or modify (e.g., enhance) the
viscosity of the composition, excipients that impart a mucoadhesive
characteristic to the composition, and excipients that enhance the
absorption of the composition through a 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). In some embodiments
wherein the composition is a suspension, surfactants are utilized
in order to obtain an efficient dispersion of corticosteroid (e.g.,
budesonide) particles in the suspension.
[0030] Sweeteners include, by way of non-limiting example, sucrose,
lactose, glucose, fructose, arabinose, xylose, ribose, mannoase,
galactose, dextrose, sorbose, sorbitol, mannitol, maltose,
cellobiose, xylitol and the like. Flavoring agent include, by way
of non-limiting example, peppermint, wintergreen, grape and
cherry.
[0031] In some embodiments, surfactants include, by way of
non-limiting example, polysorbates (e.g., polysorbate 80),
Tween.RTM., poloxamers, polyoxyethylene alkyl ethers,
polyoxyethylene castor oil derivatives and combinations thereof. In
a specific embodiment, the surfactant is polysorbate 80.
[0032] In certain embodiments, an isotonic agent includes, by way
of non-limiting example, dextrose, glycerin, mannitol, sodium
chloride, potassium chloride and combinations thereof. In specific
embodiments, the isotonic agent is dextrose (e.g., dextrose
anhydrous).
[0033] In some embodiments, antioxidants or chelating agents
include, by way of non-limiting example, edetate (e.g., disodium
edetate) (EDTA). As used herein, "edetate" 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, edetate is selected from, by way of
non-limiting example, disodium edetate, calcium edetate,
ethylenediaminetetraacetic acid and the like.
##STR00001##
[0034] Preservatives include, by way of non-limiting example,
benzalkonium chloride, methylparaben, propylparaben, potassium
sorbate and sodium benzoate. In specific embodiments, the
preservative is potassium sorbate.
[0035] In some embodiments, the compositions comprise an excipient
that increases the interaction of the composition with a 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). 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, by at least 5-fold,
by at least 10 fold, or by at least 20 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 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) may be measured by
measuring the retention time of the material along a length of a
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), wherein the
retention time is increased in the presence of the excipient as
compared to its absence. In some embodiments, a portion composition
is retained on the esophagus after oral administration (e.g., after
initial swallowing) for at least 5 seconds, for at least 6 seconds
at least 10 seconds, for at least 12 seconds, for at least 15
seconds, for at least 30 seconds, for at least 60 seconds, for at
least 2 minutes, for at least 4 minutes, for at least 10 minutes,
for at least 15 minutes, for at least 30 minutes, or the like. In
certain embodiments, the portion of the composition that is
retained on or within the esophagus is 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%, or the like. In certain
embodiments, the composition is retained on the esophagus after
oral administration for about 15 seconds to about 120 seconds, or
for about 30 to about 90 seconds. In another embodiment, an
increased interaction may be measured by the decrease in
physiological manifestations or symptoms of the disease or ailment
to be treated, including a decrease in total eosinophil counts in a
particular gastrointestinal tissue sample.
[0036] 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.
[0037] 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, for
example, from about 1 to about 3 mg of budesonide in the absence of
excipient to about 500 .mu.g to about 2 mg of budesonide in the
presence thereof. Accordingly, the compositions provided herein may
provide an additional advantage of decreasing the amount of active
agent needed to treat subjects afflicted with inflammatory diseases
involving the gastrointestinal tract, including the esophagus,
stomach and/or digestive tract.
[0038] In certain embodiments, the corticosteroid is administered
in combination with an excipient that enhances the viscosity of the
composition. It is to be understood that in various embodiments of
the present invention, the viscosity of the oral dosage form is at
a level that is sufficient to deliver an effective amount of the
composition to the site of gastrointestinal inflammation, e.g., 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 and/or the
duodenum. In certain embodiments, the viscosity of the 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 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 inflammatory diseases involving the
gastrointestinal tract, including the esophagus, are reduced
following administration of the corticosteroid containing oral
dosage form.
[0039] One method for determining sufficient viscosity may include
monitoring changes in the interaction of the composition with a
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), 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.
[0040] 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. The viscosity of a liquid generally
decreases as the temperature is raised. 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 inflamed portion of the gastrointestinal tract. In some
embodiments, the viscosity of the composition is at least about 2
centipoise (cP), at least about 25 cP, or at least about 50 cP. In
some embodiments, the viscosity of the composition is at least
about 100 cP. In one aspect the viscosity of the composition is
from about 25 centipoise (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 eP to about 800 cP. In
another aspect, the 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 100
cP, about 200 cP, about 300 cP, about 400 cP or about 500 cP, as
measured with a Brookfield viscometer at 25 degrees Celsius (e.g.,
equipped with an ultra low adapter).
[0041] 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.
[0042] 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 25 cP, at
least about 30 cP, at least about 35 cP, about 35 cP, at least
about 40 cP, 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 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 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 oP, about 500 oP, or about 250,000 cP.
[0043] In some embodiments, the viscosity of the composition is
measured at room temperature (about 25 degrees C.) with a shear
rate of about 15 sec.sup.-1 (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 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.
[0044] Viscosity-enhancing excipients that may be used in
pharmaceutical compositions described herein include, but are not
limited to, acacia (gum arabic), agar, aluminum magnesium silicate,
sodium alginate, sodium stearate, bladderwrack, bentonite,
carbomer, carrageenan, Carbopol, xanthan, 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 2004500), 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) 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.RTM. RC-591
(manufactured by FMC Corporation; colloid forming attrited mixture
of microcrystalline cellulose and carboxymethylcellulose sodium,
NF, BP; Avicel.RTM. RC-591 product brochure, RC-591 (5/99) is
hereby incorporated by reference in its entirety)). In more
specific embodiments, a composition described herein comprises a
first viscosity enhancing agent (e.g., Avicel.RTM.3 RC-591) and a
second viscosity enhancing agent (e.g., Splenda.RTM.).
[0045] Mucoadhesive agents including, but 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.
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 one
non-limiting example, the mucoadhesive agent is maltodextrin. Those
of ordinary skill in the art will recognize that the mucoadhesive
character imparted to the composition should be at a level that 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 and/or the duodenum. Also,
the mucoadhesiveness should be 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 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), 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. 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).
[0046] Mucoadhesive agents have 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.
[0047] In one non-limiting example, the mucoadhesive agent is
maltodextrin. Maltodextrin is a carbohydrate produced by the
hydrolysis of starch that may be derived from corn, potato, wheat
or other plant products. Maltodextrin may be used either alone or
in combination with other mucoadhesive agents to impart
mucoadhesive characteristics on the compositions disclosed herein.
In one embodiment, a combination of maltodextrin and a carbopol
polymer are used to increase the mucoadhesive characteristics of
the compositions disclosed herein. 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% wows 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.
[0048] 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.
[0049] In specific embodiments, provided herein are compositions
comprising a viscosity enhancing agent and a mucoadhesive agent. In
specific embodiments, the composition comprises about 0.005% (w/w)
to about 3% (w/w) of a viscosity enhancing excipient (e.g., a
CMC/MCC combination having a ratio as described herein), and about
1% (w/w) to about 30% (wsw) of a mucoadhesive agent (e.g.,
maltodextrin).
[0050] 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, dihydrofuisidates, 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 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).
Examples of absorption enhancing agents are disclosed in WO
2005/113008, which is hereby incorporated by reference in its
entirety.
[0051] 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.
[0052] In certain embodiments, the pharmaceutical compositions
provided herein is used to treat, prevent or alleviate inflammatory
diseases involving the gastrointestinal tract, including the
esophagus, stomach and/or digestive tract. In specific embodiments,
the pharmaceutical composition is in liquid form. Liquid forms
include, by way of non-limiting example, solutions, suspensions,
syrups, slurries, dispersions, colloids and the like. In specific
embodiments, the liquid is a suspension.
[0053] The methods and compositions of the present invention are
used by individuals of any age. By "individual" is meant any
animal, for example, a mammal, or, for example, a human, including,
for example, patients in need of treatment. In some embodiments,
the individual is a human adult. In other embodiments, the
individual is a human child or infant. In certain embodiments, the
human 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.
[0054] Formulations
[0055] While the compositions of the present invention will
typically be used in therapy for human patients, in certain
embodiments, they are used in veterinary medicine to treat similar
or identical diseases. In some embodiments, the compositions are
used, for example, to treat mammals, including, but not limited to,
primates and domesticated mammals. In some embodiments, the
compositions are used, for example, to treat herbivores. The
compositions of the present invention include geometric and optical
isomers.
[0056] Pharmaceutical compositions suitable for use in the present
invention include compositions wherein the active ingredient or
ingredients are contained in an effective amount to achieve its
intended purpose. In light of the detailed disclosure provided
herein, determination of the effective amounts is well within the
capability of those skilled in the art. It is expected that a
skilled pharmacologist may adjust the amount of drug in a
pharmaceutical composition or administered to a patient based upon
standard techniques well known in the art.
[0057] 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.
[0058] Generally, a therapeutically effective dose is desired. A
therapeutically effective dose refers to the amount of the
corticosteroid that results in a degree of amelioration of symptoms
and inflammation relative to the status of such symptoms prior to
treatment. The dosage forms containing effective amounts are within
the scope of the instant invention. In various embodiments, the
amount of corticosteroid (e.g., budesonide) 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) used in a method or in a
combination disclosed herein includes, by way of non-limiting
example, 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. In an illustrative embodiment, the dosage is
provided in a sufficient volume to allow the composition to reach
the esophagus in an effective amount.
[0059] 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 1-20 mL, or 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
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, 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. 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.
[0060] 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 some embodiments, 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.
[0061] 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 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.
[0062] In some embodiments, provided herein is a multiple unit
container comprising about 2 to about 180, about 10 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 or metered device is
incorporated into the container (e.g., a nebulizer, an aerosolizer,
a pump, or the like). In some embodiments, the delivery or metered
device is separate from the container. In certain embodiments, the
pharmaceutical composition contained within any of the multiple
unit containers described herein is physically and chemically
stable.
[0063] In some embodiments, the corticosteroid is budesonide and
the composition comprises about 0.01 mg to about 1.0 mg of
budesonide/g of composition. In some embodiments, the composition
comprises about 0.1 mg to about 1.0 mg of budesonide/g of
composition. In certain embodiments, the composition comprises
about 0.3 mg to about 0.6 mg of budesonide/g of composition. In
specific embodiments, the composition comprises about 0.4 mg or
0.44 mg of budesonide/g of composition. In certain specific
embodiments, the composition comprises about 3.8 mg/8.6 g of
composition. In some embodiments, the composition comprises about
0.01 mg to about 1.0 mg of budesonide/mL of composition (about
0.001 to about 0.1% w/w). 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).
[0064] In one embodiment, the corticosteroid containing composition
comprises budesonide, a viscosity enhancing agent, a preservative,
an antioxidant (including, e.g., a chelating agent), an isotonic
agent, a surfactant, an aqueous vehicle, an optional pH adjusting
agent and an optional sweetener. In certain embodiments, the
composition is a liquid. In specific embodiments, the liquid
composition is a suspension.
[0065] In certain embodiments, a viscosity enhancing agent is
present in about 0.005% to about 3.0% w/w of the composition. In
certain embodiments, a viscosity enhancing agent is present in
about 0.1% to about 3.0% w/w of the composition. In specific
embodiments, a viscosity enhancing agent is a combination of
microcrystalline cellulose and carboxymethyl cellulose (e.g.,
carboxymethyl cellulose sodium), such as Avicel RC-591. In more
specific embodiments, the combination of MCC and CMC are present in
an amount of about 0.05% to about 2.5% w/w (or about 0.5% to about
2.5% w/w) of the composition. In some embodiments, a viscosity
enhancing agent is selected from, by way of non-limiting example,
xanthan gum at about 0.03% to about 3% w/w (or about 0.3% to about
3% w/w), carbomer at about 0.01% to about 2% w/w (or about 0.1% to
about 2% w/w), guar gum at about 0.03% to about 2% w/w (or about
0.3% to about 2% w/w), or RPMC at about 0.05% to about 3.0% w/w (or
about 0.5% to about 3.0% w/w) of the composition. In some
embodiments, one or more additional viscosity enhancing agents are
added so as to provide a viscosity as described herein.
Alternatively, the amount of an aforementioned viscosity enhancing
agent present in the composition is increased so as to provide a
viscosity as described herein. 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.
[0066] In some embodiments, surfactants include, by way of
non-limiting example, polysorbates (e.g., polysorbate 80),
poloxamers, polyoxyethylene alkyl ethers, polyoxyethylene castor
oil derivatives and combinations thereof. In certain embodiments,
surfactants are present in an amount of about 0.0005% to about 2%
w/w (or about 0.005% to about 2% w/w) of the composition. In a
specific embodiment, the surfactant is polysorbate 80. In specific
embodiments, polysorbates are present in an amount of about 0.0005%
to about 2% w/w (or about 0.005% to about 2% w/w) of the
composition. In some embodiments, poloxamers are present in an
amount of about 0.001% to about 2% w/w (or about 0.01% to about 2%
w/w) of the composition, polyoxyethylene alkyl ethers are present
in an amount of about 0.001% to about 1% w/w (or about 0.01% to
about 1% w/w) of the composition, and/or polyoxyethylene castor oil
derivatives are present in an amount of about 0.001% to about 1%
w/w (or 0.01% to about 1% w/w) of the composition.
[0067] In certain embodiments, an isotonic agent includes, by way
of non-limiting example, dextrose, glycerin, mannitol, sodium
chloride, potassium chloride and combinations thereof. In specific
embodiments, the isotonic agent is dextrose (e.g., dextrose
anhydrous). In certain embodiments, the isotonic agent is included
in any suitable amount, such as, by way of non-limiting example,
between about 0.5 mg and about 0.5 g per gram of composition. In
specific embodiments, the isotonic agent is included in an amount
of about 10 mg and about 100 mg or about 40 mg to about 60 mg per
gram of composition.
[0068] In some embodiments, chelating agents include, by way of
non-limiting example, disodium edetate (EDTA). In certain
embodiments, the chelating agent is present in an amount of about
0.0005% to about 0.1% w/w (or about 0.005% to about 0.1% w/w) of
the composition.
[0069] Preservatives include, by way of non-limiting example,
benzalkonium chloride, methylparaben, propylparaben, potassium
sorbate and sodium benzoate. In specific embodiments, the
preservative is potassium sorbate. In some embodiments, the
preservative is present in an amount of about 0.0002% to about 0.5%
w/w (or about 0.002% to about 0.5% w/w) of the composition. In
specific embodiments, benzalkonium chloride is present in an amount
of about 0.0002% to about 0.02% w/w (or about 0.002% to about 0.02%
w/w) of the composition, methylparaben is present in an amount of
about 0.005% to about 0.25% w/w (or about 0.05% to about 0.25% w/w)
of the composition, propylparaben is present in an amount of about
0.001% to about 0.2% w/w (or about 0.01% to about 0.2% w/w) of the
composition, potassium sorbate is present in an amount of about
0.005% to about 2.0% w/w (or about 0.05% to about 2.0% w/w) of the
composition, and/or sodium benzoate is present in an amount of
about 0.01% to about 0.5% w/w (or about 0.1% to about 0.5% w/w) of
the composition.
[0070] Sweeteners include, by way of non-limiting example,
sucralose, sucrose, lactose, glucose, fructose, arabinose, xylose,
ribose, mannose, galactose, dextrose, sorbose, sorbitol, mannitol,
maltose, cellobiose, xylitol, honey and the like. In general, when
utilized, the sweetener is utilized in an amount sufficient to at
least partially mask the taste of the composition and/or the
corticosteroid (e.g., budesonide).
[0071] In some embodiments, the corticosteroid containing
composition comprises micronized budesonide, microcrystalline
cellulose, carboxymethyl cellulose sodium, dextrose anhydrous,
polysorbate 80, disodium edetate, potassium sorbate, water,
optionally hydrochloric acid and optionally one or more additional
excipient. In specific embodiments, the composition has a pH of
about 4.5. In a specific embodiment, at least one of the optional
excipients is a sweetener, a flavoring agent, or a combination
thereof.
[0072] In specific embodiments, the composition administered
comprises a micronized suspension of budesonide in an aqueous
medium. In some specific embodiments, microcrystalline cellulose
and carboxymethyl cellulose sodium, dextrose anhydrous, polysorbate
80, disodium edetate, potassium sorbate, and purified water are
contained in the aqueous medium. In more specific embodiments,
hydrochloric acid is added to adjust the pH to a target of about
4.5. 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). In an exemplary embodiment, the composition
comprises Rhinocort Aqua.RTM. (manufactured by AstraZeneca;
Rhinocort Aqua.RTM. Nasal Spray; 32 mcg of budesonide per spray and
120 metered sprays after initial priming; package insert 30516-00,
Rev. 01/05, is hereby incorporated by reference in its entirety),
an optional diluent, and an optional sweetener. In some
embodiments, the diluent is any carrier suitable for oral
administration, including, by way of non-limiting example, water,
ethanol, and combinations thereof. In a specific embodiment, the
diluent is water. In some embodiments, the composition comprises
Rhinocort Aqua.RTM., an additional viscosity enhancing agent (e.g.,
Splenda), an optional diluent, and an optional sweetener and/or
flavoring agent. In some embodiments, a composition useful herein
includes a composition comprising a composition described in U.S.
Pat. No. 6,291,445, U.S. Pat. No. 6,686,346, or U.S. Pat. No.
6,986,904, an optional additional viscosity enhancing agent or
"thickener", an optional diluent, and an optional sweetener and/or
flavoring agent. In some embodiments, the composition comprises
Rhinocort Aqua.RTM. and a diluent wherein the Rhinocort Aqua.RTM.
and diluent are present in a ratio between about 1:0.5 and about
1:100. In more specific embodiments, the diluted Rhinocort
Aqua.RTM. composition further comprises an excipient that increases
the interaction of the composition with a surface of the
gastrointestinal tract (e.g., a viscosity enhancing agent).
[0073] 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 treatments 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, dietary therapy, 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. In
certain embodiments, a patient combines treatment with a
composition described herein with a treatment with another
medication, and/or dietary therapy. 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.
[0074] In various embodiments, the compositions of the present
invention include pharmaceutically acceptable salts.
Pharmaceutically acceptable salts are generally well known to those
of ordinary still in the art and include, by way of non-limiting
example, acetate, atosylate, benzenesulfonate, besylate, benzoate,
bicarbonate, bitartrate, bromide, calcium edetate, carnsylate,
carbonate, citrate, edetate, edisylate, estolate, esylate,
fumarate, gluceptate, gluconate, glutarnate, 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). In specific embodiments, 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. In certain
embodiments, such salts are used for any of the corticosteroids
described herein.
[0075] In certain embodiments, the compositions is 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).
In specific embodiments, the composition is formulated as a liquid
dosage form. In more specific embodiments, the liquid dosage form
is a suspension of micronized corticosteroid (e.g., budesonide)
particles.
[0076] 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, gels, syrups, slurries, suspensions and
the like, for oral ingestion by a patient to be treated.
[0077] In certain embodiments, pharmaceutical preparations for oral
use are obtained by combining an aqueous formulation of a
corticosteroid (e.g., budesonide) 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. In certain embodiments, solid oral dosage
forms (e.g., tablets, dragee cores, capsules, push-fit capsules,
soft capsules, lozenges, etc.) are formulated such that the dosage
forms substantially dissolve or disintegrate in the mouth and/or
esophagus. In some embodiments, solid oral dosage forms are
formulated such that the dosage forms substantially dissolve or
disintegrate prior to reaching the stomach. In certain embodiments,
an oral dosage form has substantially dissolved or disintegrated if
at least 50%, by weight, of the dosage form has dissolved or
disintegrated. In other embodiments, substantial dissolution or
disintegration includes at least 60%, 70%, 80%, 90% or 95% by
weight. Suitable excipients include, by way of non-limiting
example, fillers such as sugars or starches, including dextrose,
lactose, maltodextrin, sucrose, sucralose, mannitol, or sorbitol;
cellulose preparations, for example, maize starch, wheat starch,
rice starch, potato starch, or a combination thereof. In certain
embodiments, the aqueous formulation comprises budesonide, a
viscosity enhancing agent, a preservative, a chelating agent, an
isotonic agent, a surfactant, an optional pH adjusting agent and an
optional sweetener. In more specific embodiments, the aqueous
formulation comprises budesonide, microcrystalline cellulose and
carboxymethyl cellulose sodium, dextrose anhydrous, polysorbate 80,
disodium edetate, potassium sorbate, and hydrochloric acid to
adjust the pH to a target of about 4.5 (e.g., Rhinocort Aqua.RTM.).
In some embodiments, prior to mixing the aqueous suspension with
the solid excipients, the aqueous solvent is removed (e.g., by
evaporation). Disintegrating agents are optionally added, such as
the cross-linked polyvinylpyrrolidone, agar, or alginic acid or a
salt thereof such as sodium alginate. In some embodiments, the
pharmaceutical compositions used herein include excipients suitable
for rendering the dissolving tablet palatable, such as sweeteners
or flavoring agents.
[0078] In some embodiments, the pharmaceutical compositions
described herein are in liquid form. Appropriate excipients for use
in liquid form pharmaceutical compositions include, for example,
those that increase the liquid viscosity of the liquid composition.
Optional excipients also include, by way of non-limiting example,
those that render the liquid composition palatable. Optional
excipients include, by way of non-limiting example, sugars,
including dextrose, lactose, sucrose, sucralose, maltodextrin,
mannitol, or sorbitol; honey or combinations thereof.
[0079] 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.
[0080] 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.
[0081] In one embodiment, the present invention provides for a
corticosteroid that has a low bioavailability. Due to the low
bioavailability, the corticosteroid is used in certain embodiments
of the invention, the corticosteroid remains 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.
[0082] Diseases
[0083] In certain embodiments, diseases or conditions that are
treated, prevented, or exhibit an alleviation of symptoms by
administering a composition described herein include any disease or
condition that involves inflammation of the gastrointestinal tract,
including the esophagus, stomach and/or digestive tract. This
includes, by way of non-limiting example, any chronic inflammatory
or malignant state that involves the gastrointestinal tract (e.g.,
the esophagus, stomach and/or digestive tract) and responds to
steroid therapy. The methods of the present invention are useful,
for example, for treating, preventing and alleviating the symptoms
of eosinophilic esophagitis, inflammatory bowel diseases involving
the esophagus, Crohn's disease, celiac disease, epithelial
hyperplasia, basal cell hyperplasia, elongated papillae, dilated
vessels in papillae, fungal esophagitis, viral esophagitis,
bacterial esophagitis, corrosive esophagitis, radiation
esophagitis, chemotherapy esophagitis, graft vs. host disease, a
skin disease with esophageal involvement, bullous pemphigoid,
pemphigus vulgaris, epidermolysis bollosa, Stevens-Johnson
syndrome, Behcet's disease, sarcoidosis, idiopathic esophagitis,
eosinophilic gastritis, Menetrier's disease, parasitic gastritis,
lymphocytic esophagitis, inflammatory bowel disease-associated
esophagitis, parasitic gastritis, lymphocytic esophagitis,
inflammatory bowel disease-associated esophagitis, eosinophilic
duodenitis, functional dyspepsia, acute esophageal inflammation
secondary to caustic/irritant ingestion, persistent/recurrent
esophageal strictures secondary to caustic/irritant, conditions due
to ingestion, systemic diseases, congenital diseases, and
post-surgery inflammation. The methods of the present invention are
also useful, for example, for treating, preventing and alleviating
the symptoms of gastroesophageal reflux disease (GERD), nonerosive
reflux disease (NERD) and/or erosive esophagitis.
[0084] It will be appreciated that reference herein to treatment
extends to prophylaxis as well as the treatment of inflammation or
other symptoms.
[0085] In certain embodiments, provided herein is a method of
treating, preventing or alleviating inflammation of the
gastrointestinal tract, including the esophagus, stomach and/or
digestive tract, in an individual comprising orally administering
to said individual any of the compositions described herein. In
certain embodiments, oral administration includes the oral
administration of a solid dosage form (e.g., tablets, dragee cores,
capsules, push-fit capsules, soft capsules etc.) that is formulated
such that the dosage form substantially dissolves or disintegrates
in the mouth and/or esophagus. In some embodiments, solid oral
dosage forms are formulated such that the dosage forms
substantially dissolve or disintegrate prior to reaching the
stomach. In certain embodiments, an oral dosage form has
substantially dissolved or disintegrated if at least 50%, by
weight, of the dosage form has dissolved or disintegrated. In other
embodiments, substantial dissolution or disintegration includes at
least 60%, 70%, 80%, 90% or 95% by weight. In certain embodiments,
the oral dosage form is a liquid (e.g., a slurry, suspension,
syrup, dispersion, solution, etc.)
[0086] In one aspect, a patient is administered a topical
corticosteroid such as, for example, budesonide.
[0087] In some embodiments, the inflammation treated by the methods
and compositions described herein is associated with eosinophilic
inflammation and/or neutrophilic inflammation. In some embodiments,
individuals (e.g., patients) to be treated with compositions
described herein include those that have been diagnosed
eosinophilic esophagitis, an inflammatory bowel disease involving
the esophagus, Crohn's disease, celiac disease, epithelial
hyperplasia, basal cell hyperplasia, elongated papillae, dilated
vessels in papillae, fungal esophagitis, viral esophagitis,
bacterial esophagitis, corrosive esophagitis, radiation
esophagitis, chemotherapy esophagitis, eosinophilic gastric outlet
obstruction and related inflammation, graft vs. host disease, a
skin disease with esophageal involvement, bullous pemphigoid,
pemphigus vulgaris, epidermolysis bollosa, Stevens-Johnson
syndrome, Behcet's disease, sarcoidosis, idiopathic esophagitis,
eosinophilic gastritis, Menetrier's disease, parasitic gastritis,
lymphocytic esophagitis, inflammatory bowel disease-associated
esophagitis, parasitic gastritis, lymphocytic esophagitis,
inflammatory bowel disease-associated esophagitis, eosinophilic
duodenitis, functional dyspepsia, esophageal inflammation secondary
to caustic/irritant ingestion, persistent/recurrent esophageal
strictures of any cause and including caustic/irritant ingestion,
pill-induced esophagitis, systemic diseases, congenital diseases or
post-surgery inflammation. In one non-limiting example, the patient
has eosinophilic esophagitis. In some embodiments, individuals
(e.g., patients) to be treated with the compositions described
herein include those that have been diagnosed with gastroesophageal
reflux disease (GERD), nonerosive reflux disease (NERD) and/or
erosive esophagitis. In some embodiments, the patient is an adult.
In other embodiments, the patient is a child or infant. In various
aspects, a patient is a child or infant 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.
[0088] In some embodiments, a composition is in a unit dose
formulation for oral administration of a patient. In some
embodiments, a unit dose of the corticosteroid is administered from
a metered dose device, such as a metered dose inhaler. In certain
aspects, from about 0.1 mg to about 20 mg, or about 0.25 to about 5
mg (e.g., about 1-2 mg/day or about 2-3 mg/day) corticosteroid per
day is administered to the patient. In some embodiments, the
corticosteroid is present in a unit dose in an amount of between
about 0.1 mg and about 20 mg, or about 0.25 mg to about 5 mg. In
some embodiments, the amount of corticosteroid administered daily
or in a unit dose is between about 0.3 mg and about 4 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.
[0089] 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 (per
day or per dose) is about 100 .mu.g to about 20 mg, about 300 .mu.g
to about 4 mg, about 50 mg 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 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.
[0090] 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 mr/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 50th 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 50th 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 50th 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 128 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.
[0091] 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 50th 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 50th percentile for the age of
the individual to whom the composition is administered.
[0092] 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.
[0093] The entirety of each patent, patent application, publication
and document referenced herein is hereby 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.
[0094] 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.
[0095] 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 elements) 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.
[0096] In some embodiments, the dose or volume of a composition
administered herein is adjusted based on the efficacy of treatment.
In certain embodiments, a diagnosis of eosinophilic esophagitis is
achieved by administering a composition described herein and
determining the efficacy of the treatment. In certain embodiments,
a composition described herein and separately determined to be
effective in treating eosinophilic esophagitis is utilized.
Efficacy of treatment can be determined in any suitable manner
including, e.g., symptom score assessment, gastrointestinoscopy
(e.g., esophagogastroduodenoscopy), gastrointestinal (e.g.,
esophageal) biopsy, histological evaluation, or a combination
thereof. Processes of diagnosing eosinophilic esophagitis and/or
determining efficacy of treatment include any suitable process
including, by way of non-limiting example, processes as set forth
in Aceves et al., J Allergy Clin Immunol, February 2008; abstract
270, or Aceves et al., Am J. Gastroenterol., October 2007,
102(10):2271-9, both of which are incorporated herein in their
entirety.
[0097] In some embodiments, a process for determining efficacy of a
treatment (e.g., for eosinophilic esophagitis) described herein is
a clinical symptom score assessment comprising (i) administering a
composition described herein to an individual diagnosed with or
suspected of having eosinophilic esophagitis; and (ii) evaluating
one or more symptom of the individual. In certain embodiments,
prior to administering the composition, the process comprises
evaluating the one or more symptom of the individual. Symptoms that
are optionally scored include, by way of non-limiting example,
nausea, vomiting, pain, and heartburn. Total score or change in
score is optionally utilized to diagnose a disorder and/or
determine efficacy of treatment.
[0098] In certain embodiments, a process for determining efficacy
of a treatment described herein comprises (i) administering a
composition described herein to an individual diagnosed with or
suspected of suffering from inflammation of the gastrointestinal
tract (e.g., eosinophilic esophagitis); (ii) endoscoping the
gastrointestinal surface of the individual; (iii) biopsying the
gastrointestinal surface tissue; and (iv) evaluating the biopsied
tissue and optionally determining an endoscopy score of the tissues
biopsied In specific embodiments, the process further comprises
comparing the evaluated biopsied tissue and/or the endoscopy score
obtained prior to administration of the composition to the biopsied
tissue and/or endoscopy score subsequent to administration of the
composition.
[0099] In some embodiments, provided herein is a process of
diagnosing an individual with gastrointestinal inflammation by (i)
detecting and/or measuring symptoms of the individual prior to
administering to the individual a composition described herein;
(ii) administering to the individual any composition described
herein; (iii) detecting and/or measuring symptoms of the individual
following administration of the composition; and (iv) comparing the
symptoms measured or detected prior to and following administration
of a composition described herein. If the symptoms exhibited by the
individual are reduced (e.g., by a statistically significant or
clinically relevant amount), a positive diagnosis occurs. In
specific embodiments, the process of diagnosing an individual with
gastrointestinal inflammation is diagnosing an individual with
eosinophilic esophagitis.
EXAMPLE 1
[0100] This example illustrates the increased interaction between a
composition described herein and the esophagus when compared to a
radiolabeled oral composition made by combining Pulmicort
Respules.RTM. (4 mL) with .sup.99mTc pertechnetate, and diluting
with saline to about 7-8 mL (M0). The M0 composition has a
viscosity of about 1 cP at 13.2 sec.sup.-1. Also administered to a
population of healthy individuals was a radiolabeled budesonide
composition (Rhinocort Aqua.RTM., M1), which has a viscosity of
about 39 at 13.2 sec.sup.-1. Increased interaction of the
budesonide composition was determined by measuring the amount of
radiolabel present in the esophagus following oral administration
of the M1 budesonide composition. FIG. 1 illustrates the percent
amount of composition present in the esophagus as a function of
time following oral administration (by measuring the amount of
radiolabel present in the esophagus).
[0101] The area under the curve (AUCr) of the percent of the dose
administered as a function of time (% dose-time(min)) was
determined from the time of 50% swallow (i.e., 50% of the
administered dose had passed from the mouth), until esophageal
activity had peaked and fallen to 10% of the peak value. The area
under the curve from t=0 min to t=1 min (AUC.sub.0-1); and from t=0
min to t=2 min (AUC.sub.0-2) was also determined. These results
(including the ratio of the non-viscous sample to the viscous
sample) are set forth below:
TABLE-US-00001 AUCr AUC.sub.0-1 AUC.sub.0-2 geometric geometric
geometric Formulation mean ratio mean ratio mean ratio M0 3.95 5.51
6.93 M1 9.39 0.42 11.07 0.5 14.16 0.49
EXAMPLE 2
[0102] This example details the efficacy and safety of once daily
and twice daily use of budesonide formulations described herein in
5 mL, 7 mL, 10 mL, 12 mL, 15 mL, or 17.5 mL doses in inducing and
maintaining remission of disease activity in children with EE. A
number of children (e.g., 20 per budesonide dose frequency, amount,
and volume) are evaluated to determine the highest eosinophil count
(eos/hpf) and the mean highest eosinophil count for the group.
Evaluation of the highest eosinophil count (eos/hpf) and the mean
highest eosinophil count for the group is also determined following
therapy. Symptom scores and mean symptom scores are also determined
before and after therapy.
[0103] In some instances, individuals who received previous therapy
with proton pump inhibitor, elimination diet based upon skin or
blood allergy testing, or elimination diet or refused elimination
diet, but continued to have .gtoreq.24 eos/hpf on esophageal biopsy
are included in the review. Patients are defined as having food or
aeroallergen sensitization if RAST and/or skin prick testing are
positive. No changes are made to longstanding therapy used for
treating chronic conditions such as asthma or eczema and none of
the children receive concurrent immunomodulatory treatment.
[0104] Endoscopy is performed using the Olympus P160 endoscope (by
RD) and pan-esophageal, gastric and duodenal biopsies are taken.
Eosinophilic esophagitis is diagnosed when .gtoreq.24 eos/hpf are
found in at least one of the esophageal sites biopsied. Two mucosal
biopsies re taken from the proximal esophagus (3 cm below the
crycopharyngeus muscle), distal esophagus (3 cm above the
gastroesophageal junction (GEJ), and mid-esophagus (midpoint
between the crycopharyngeus muscle and the GEJ). Biopsies are
processed routinely and evaluated by a pediatric pathologist (RN).
The highest number of eosinophils per .times.400 high power field
are counted. Basal zone hyperplasia (BZH) is reported when basal
zone cells extend towards the luminal surface of the epithelium
(>25% of epithelial thickness).
[0105] Follow-up endoscopy with biopsies are taken after 34 months
treatment. Counting the highest number of eos/hpf within biopsies
determined the response to therapy and patients are categorized
into responders (0-7 eos/hpf), partial-responders (8-23 eos/hp) and
non-responders (.gtoreq.24 eos/hpf).
[0106] An EE Endoscopy Score is devised to compare findings before
and after treatment. It is calculated from procedure reports and
photographs. Four categories, (1) pallor and diminshed vascular
markings; (2) furrowing with "thickened" mucosa; (3) white mucosal
plaques; (4) concentric rings or strictures. For each category, one
point is allocated if 1 or 2 esophageal sites are involved, and two
points for pan-esophageal involvement. The maximum score is 8.
[0107] Patients receive a formulation described herein for between
0.25 and 2 mg daily and are instructed not to ingest any solids or
liquids for 30 minutes afterwards. No dietary changes are made in
patients already on dietary restrictions.
[0108] A modified symptom score based on children with acid-peptic
disease is used routinely in the EE clinic. The symptom categories
include (1) heartburn or regurgitation; (2) abdominal pain or
unexplained irritability in younger children; (3) nausea or
vomiting; (4) anorexia or early satiety; (5) dysphagia or
odynophagia, (6) nocturnal wakening with symptoms; (7)
gastrointestinal bleeding (previous 4 months). Each category scored
0-2 points with a maximum of 14 points. Zero points are awarded if
the symptom is absent; one point if the symptom is mild, did not
interfere with daily activities; 2 points if the symptoms are
severe enough to interrupt daily activities. Previous GI bleeding
is considered mild (1 point) if there is no associated hemodynamic
compromise or anemia, and severe (2 points) if bleeds are multiple,
caused anemia, or required blood transfusion.
[0109] All statistical analysis is carried out using NCSS
Statistical Softward Package. Two-tailed p values are calculated
using paired t-tests to compare the means of patient values for
eos/hpf, EE Endoscopy Scores and Symptom Scores before and after
budesonide therapy. Two-tailed unpaired t-tests are utilized in
order to compare variables grouped by responders versus
non-responders. Spearman's correlation coefficients are generated
using GraphPad Prism software. Results with p values <0.05 are
considered statistically significant. Both mean and median
statistics re generated, both are equivalent and mean statistics
are presented.
[0110] Subjects. Chart reviews are undertaken on a number of
children. All children have >24 eos/hpf on repeat esophageal
biopsy before starting therapy.
[0111] Treatment. Patients received formulations described herein
for a designated amount of time (e.g., 1 week, 2 weeks, 1 month, 2
months, 3 months, 4 months, 6 months, or the like) before repeat
endoscopy. Various patients received budesonide in amounts ranging
from 0.25 to 2 mg/day.
[0112] Histology. Before treatment the mean highest eosinophil
count is measured for all patients, including distal, mid and
proximal esophageal sites. All sites are likewise evaluated aver
the designated amount of time, and again if desired.
[0113] Upper Gastrointestinal Endoscopy. Before treatment, the mean
EE Endoscopy Score for all patients is determined. Following
treatment the mean EU Endoscopy Score is repeated. Decreases in
endoscopy scores (e.g., of >95%, >90%, >85%, >75%,
>50%, >25%, or the like) in an individual indicate successful
treatment.
[0114] Symptom Score. Before treatment the mean symptom score for
all patients is determined. It is again determined following
treatment. Decreases in symptom scores (e.g., of >95%, >90%,
>85%, >75%, >50%, >25%, or the like) in an individual
indicate successful treatment (alone or in combination with the
above referenced decreases in endoscopy scores).
[0115] Adults: these parameters are repeated in adults to determine
efficacy and safety therein.
EXAMPLE 3
[0116] This example details the efficacy and safety of once daily
and twice daily use of budesonide in a formulation described herein
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, 3-4 mg, 4-5 mg, and 5-6 mg per daily dose are
administered once a day, b.i.d. or t.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 and a 0 to a lack
of symptoms) and utilized to determine the efficacy of the
treatment.
[0117] 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.
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