U.S. patent application number 14/509446 was filed with the patent office on 2015-05-14 for formulations and uses of 2-hydroxy-5-phenylazobenzoic acid derivatives for the treatment of males.
This patent application is currently assigned to SALIX PHARMACEUTICALS, LTD. The applicant listed for this patent is Enoch Bortey, William Forbes, Lorin K. Johnson. Invention is credited to Enoch Bortey, William Forbes, Lorin K. Johnson.
Application Number | 20150132381 14/509446 |
Document ID | / |
Family ID | 44861888 |
Filed Date | 2015-05-14 |
United States Patent
Application |
20150132381 |
Kind Code |
A1 |
Forbes; William ; et
al. |
May 14, 2015 |
FORMULATIONS AND USES OF 2-HYDROXY-5-PHENYLAZOBENZOIC ACID
DERIVATIVES FOR THE TREATMENT OF MALES
Abstract
The instant application provides methods and compositions for
the treatment of male subjects having ulcerative colitis.
Inventors: |
Forbes; William; (Raleigh,
NC) ; Bortey; Enoch; (Chapel Hill, NC) ;
Johnson; Lorin K.; (Palo Alto, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Forbes; William
Bortey; Enoch
Johnson; Lorin K. |
Raleigh
Chapel Hill
Palo Alto |
NC
NC
CA |
US
US
US |
|
|
Assignee: |
SALIX PHARMACEUTICALS, LTD
Raleigh
NC
|
Family ID: |
44861888 |
Appl. No.: |
14/509446 |
Filed: |
October 8, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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13938777 |
Jul 10, 2013 |
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14509446 |
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13094261 |
Apr 26, 2011 |
8497256 |
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13938777 |
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61328151 |
Apr 26, 2010 |
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Current U.S.
Class: |
424/474 ;
514/150 |
Current CPC
Class: |
A61P 1/06 20180101; A61K
31/655 20130101; A61P 1/04 20180101; A61K 9/50 20130101; A61K 9/28
20130101; A61P 1/00 20180101 |
Class at
Publication: |
424/474 ;
514/150 |
International
Class: |
A61K 31/655 20060101
A61K031/655; A61K 9/50 20060101 A61K009/50 |
Claims
1. A method treating a gastrointestinal disorder comprising
administering to a male subject in need of treatment a
therapeutically effective amount of balsalazide.
2. The method claim 1, wherein the therapeutically effective amount
comprises about 6.5 to about 6.8 g per day.
3. The method claim 1, wherein the therapeutically effective amount
comprises about 6.6 g per day.
4. The method claim 1, wherein the therapeutically effective amount
comprises about 6.75 g per day.
5. The method of claim 1, wherein the therapeutically effective
amount is a dosage regimen of three tablets of the formulation two
times each day, wherein each tablet comprises about 1100 mg of
balsalazide.
6. The method of claim 5, wherein the balsalazide tablet is a
film-coated tablet.
7. The method of claim 1, wherein the therapeutically effective
amount is a dosage regimen of three capsules of the formulation
three times each day, wherein each capsule comprises about 750 mg
of balsalazide.
8. The method of claim 1, wherein the administration to the subject
occurs between about 30 minutes prior to about 1 hour after
consuming food.
9. The method of claim 1, wherein the gastrointestinal disorder
comprises ulcerative colitis.
10. The method of claim 9, wherein the ulcerative colitis is mild
to moderately active ulcerative colitis.
11. A method of decreasing a MMDAI score in a male subject having
ulcerative colitis comprising administering to the subject a
therapeutically effective amount of balsalazide, thereby decreasing
the MMDAI score.
12. The method claim 11, wherein the therapeutically effective
amount comprises between about 6.5 to about 6.8 g per day.
13. The method claim 11, wherein the therapeutically effective
amount comprises about 6.6 g per day.
14. The method claim 11, wherein the therapeutically effective
amount comprises about 6.75 g per day.
15. The method of claim 12, wherein the therapeutically effective
amount is a dosage regimen of three tablets of the formulation two
times each day, wherein each tablet comprises about 1100 mg of
balsalazide.
16. The method of claim 15, wherein the balsalazide tablet is a
film-coated tablet.
17. The method of claim 11, wherein the therapeutically effective
amount is a dosage regimen of three capsules of the formulation
three times each day, wherein each capsule comprises about 750 mg
of balsalazide.
18. The method of claim 11, wherein the MMDAI score is decreased by
3 or more points.
19. The method of claim 11, wherein the rectal bleeding component
of the MMDAI score is decreased by 1 or more points.
20. A method of inducing clinical remission of ulcerative colitis
in a male subject comprising; administering to the subject a
therapeutically effective amount of balsalazide, thereby inducing
remission in the subject.
21. The method claim 20, wherein the therapeutically effective
amount comprises between about 6.5 to about 6.8 g per day.
22. The method claim 20, wherein the therapeutically effective
amount comprises about 6.6 g per day.
23. The method claim 20, wherein the therapeutically effective
amount comprises about 6.75 g per day.
24. The method of claim 21, wherein the therapeutically effective
amount is a dosage regimen of three tablets of the formulation two
times each day, wherein each tablet comprises about 1100 mg of
balsalazide.
25. The method of claim 24, wherein the balsalazide tablet is a
film-coated tablet.
26. The method of claim 20, wherein the therapeutically effective
amount is a dosage regimen of three capsules of the formulation
three times each day, wherein each capsule comprises about 750 mg
of balsalazide.
27. The method of claim 20, wherein remission is defined by MMDAI
component scores of zero for rectal bleeding and a combined score
of 2 or less for bowel frequency and physician's assessment.
28. A method of inducing mucosal healing in a male subject having
ulcerative colitis comprising administering to the subject a
therapeutically effective amount of balsalazide, thereby inducing
mucosal healing in the subject.
29. The method claim 28, wherein the therapeutically effective
amount comprises between about 6.5 to about 6.8 g per day.
30. The method claim 28, wherein the therapeutically effective
amount comprises about 6.6 g per day.
31. The method claim 28, wherein the therapeutically effective
amount comprises about 6.75 g per day.
32. The method of claim 29, wherein the therapeutically effective
amount is a dosage regimen of three tablets of the formulation two
times each day, wherein each tablet comprises about 1100 mg of
balsalazide.
33. The method of claim 32, wherein the balsalazide tablet is a
film-coated tablet.
34. The method of claim 28, wherein the therapeutically effective
amount is a dosage regimen of three capsules of the formulation
three times each day, wherein each capsule comprises about 750 mg
of balsalazide.
35. The method of claim 28, wherein the mucosal healing is defined
as an improvement in endoscopy/sigmoidoscopy score to 0 or 1.
Description
RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 13/938,777, filed Jul. 10, 2013, which is a continuation of
U.S. application Ser. No. 13/094,261, filed Apr. 26, 2011, now U.S.
Pat. No. 8,497,256, which claims the benefit of U.S. Provisional
Application No. 61/328,151, filed on Apr. 26, 2010. The entire
contents of each of the aforementioned application is hereby
expressly incorporated herein by reference.
BACKGROUND OF THE INVENTION
[0002] Balsalazide disodium is indicated for the treatment of
gastrointestinal diseases, for example mild to moderately active
ulcerative colitis, radiation protosigmoidits, diverticulitis,
irritable bowel syndrome (IBS) and colon cancer (see WO 95/18622).
Balsalazide is a colon-specific, non-steroidal, anti-inflammatory
aminosalicylate derivative. Balsalazide is also a prodrug
containing 5-ASA, linked to 4-amino benzoyl-.beta.-alanine
("4-ABA") by a diazo bond.
SUMMARY OF THE INVENTION
[0003] This invention relates to the use of balsalazide to treat,
prevent, or ameliorate gastrointestinal disorders in male subjects,
e.g., mildly to moderately active ulcerative colitis (see, for
example, Schroeder et al. (1987) N Engl J Med. 24;
317(26):1625-9).
[0004] More specifically, this invention relates to the use of
balsalazide to treat male subjects having ulcerative colitis,
irritable bowel syndrome and other non-inflammatory
gastrointestinal (GI) conditions responding to mesalamine and
balsalazide (see, for example, U.S. Pat. Nos. 326,364; 6,551,632;
6,475,518; 6,426,338; 6,277,836; 5,519,014; 5,476,669; 5,196,205
and 6,645,530, which are hereby incorporated by reference). The
invention also relates to the use of balsalazide to treat
gastrointestinal disease in male subjects, alone or in combination
with other therapies.
[0005] The invention is due, in part, to the unexpected finding
that administration of balsalazide is more effective for treating
male subjects as compared to female subjects.
[0006] In one embodiment, the bioavailability of balsalazide is
increased compared to administering balsalazide without food.
[0007] In one aspect, provided herein are methods for treating a
gastrointestinal disorder comprising administering to a male
subject in need of treatment a therapeutically effective amount of
balsalazide. In one embodiment, the therapeutically effective
amount comprises about 6.5 to about 6.8 g per day. In one
embodiment, the therapeutically effective amount comprises about
6.6 g per day. In one embodiment, the therapeutically effective
amount comprises about 6.75 g per day. In one embodiment, the
therapeutically effective amount is a dosage regimen of three
tablets of the formulation two times each day, wherein each tablet
comprises about 1100 mg of balsalazide. In one embodiment, the
balsalazide tablet is a film-coated tablet. In one embodiment, the
therapeutically effective amount is a dosage regimen of three
capsules of the formulation three times each day, wherein each
capsule comprises about 750 mg of balsalazide. In one embodiment,
the administration to the subject occurs between about 30 minutes
prior to about 1 hour after consuming food. In one embodiment, the
gastrointestinal disorder comprises ulcerative colitis. In one
embodiment, the ulcerative colitis is mild to moderately active
ulcerative colitis.
[0008] In one aspect, provided herein are methods of decreasing a
MMDAI score in a male subject having ulcerative colitis comprising
administering to the subject a therapeutically effective amount of
balsalazide, thereby decreasing the MMDAI score. In one embodiment,
the therapeutically effective amount comprises between about 6.5 to
about 6.8 g per day. In one embodiment, the therapeutically
effective amount comprises about 6.6 g per day. In one embodiment,
the therapeutically effective amount comprises about 6.75 g per
day. In one embodiment, the therapeutically effective amount is a
dosage regimen of three tablets of the formulation two times each
day, wherein each tablet comprises about 1100 mg of balsalazide. In
one embodiment, the balsalazide tablet is a film-coated tablet. In
one embodiment, the therapeutically effective amount is a dosage
regimen of three capsules of the formulation three times each day,
wherein each capsule comprises about 750 mg of balsalazide. In one
embodiment, the MMDAI score is decreased by 3 or more points. In
one embodiment, the rectal bleeding component of the MMDAI score is
decreased by 1 or more points.
[0009] In one aspect, provided herein are methods of inducing
clinical remission of ulcerative colitis in a male subject
comprising; administering to the subject a therapeutically
effective amount of balsalazide, thereby inducing remission in the
subject. In one embodiment, the therapeutically effective amount
comprises between about 6.5 to about 6.8 g per day. In one
embodiment, the therapeutically effective amount comprises about
6.6 g per day. In one embodiment, the therapeutically effective
amount comprises about 6.75 g per day. In one embodiment, the
therapeutically effective amount is a dosage regimen of three
tablets of the formulation two times each day, wherein each tablet
comprises about 1100 mg of balsalazide. In one embodiment, the
balsalazide tablet is a film-coated tablet. In one embodiment, the
therapeutically effective amount is a dosage regimen of three
capsules of the formulation three times each day, wherein each
capsule comprises about 750 mg of balsalazide. In one embodiment,
remission is defined by MMDAI component scores of zero for rectal
bleeding and a combined score of 2 or less for bowel frequency and
physician's assessment.
[0010] In one aspect, provided herein are methods of inducing
mucosal healing in a male subject having ulcerative colitis
comprising administering to the subject a therapeutically effective
amount of balsalazide, thereby inducing mucosal healing in the
subject. In one embodiment, the therapeutically effective amount
comprises between about 6.5 to about 6.8 g per day. In one
embodiment, the therapeutically effective amount comprises about
6.6 g per day. In one embodiment, the therapeutically effective
amount comprises about 6.75 g per day. In one embodiment, the
therapeutically effective amount is a dosage regimen of three
tablets of the formulation two times each day, wherein each tablet
comprises about 1100 mg of balsalazide. In one embodiment, the
balsalazide tablet is a film-coated tablet. In one embodiment, the
therapeutically effective amount is a dosage regimen of three
capsules of the formulation three times each day, wherein each
capsule comprises about 750 mg of balsalazide. In one embodiment,
the mucosal healing is defined as an improvement in
endoscopy/sigmoidoscopy score to 0 or 1.
[0011] Other embodiments of the invention are disclosed infra.
DETAILED DESCRIPTION OF THE FIGURES
[0012] FIG. 1 shows plasma levels of balsalazide and metabolites in
fed and fasted states.
[0013] FIG. 2 shows the ratios of NASA/5-ASA of the capsules and
tablets of balsalazide in the fed and fasted states.
[0014] FIG. 3 presents the balsalazide, 5-ASA and NASA plasma
levels as a ratio of the female levels divided by the male levels.
A value of 1.0 in the graph would be indicative of equal absorption
in both sexes.
DETAILED DESCRIPTION
[0015] Disclosed herein are compositions and methods of treating
gastrointestinal disorders in male subjects by administering
balsalazide. In one embodiment, the balsalazide can be administered
in the form of a film-coated tablet containing 1.1 g balsalazide or
for example as 750 mg capsules. For example, an adult male dose is
three 750 mg capsules of balsalazide administered 3 times a day
(6.75 g/day) with or without food for 8 weeks.
[0016] Before further description and in order that the invention
may be more readily understood, certain terms are first defined and
collected here for convenience.
[0017] Common pharmacologic term used herein refer are as follows:
T.sub.max (time to maximum concentration); C.sub.max (observed
maximum concentration); kel (slope of terminal linear portion of
concentration/time curve); T.sub.112 (half-life of balsalazide
calculated as: 0.693/Kel); AUC.sub.(last) (area under the curve to
last quantifiable concentration as measured by the trapezoidal
rule); and AUC.sub.(inf) (the AUC value extrapolated to infinity
calculated as: AUC.sub.(inf)=AUC.sub.(last)+C.sub.(t)last/Kel where
C.sub.(t)last is the last measurable concentration).
[0018] The term "administration" or "administering" includes routes
of introducing balsalazide to a subject to perform their intended
function. The pharmaceutical preparations may be given by forms
suitable for each administration route. Oral administration is
preferred. Depending on the route of administration, balsalazide
can be coated with or disposed in a selected material to protect it
from natural conditions that may detrimentally affect its ability
to perform its intended function. Balsalazide can be administered
alone, or in conjunction with either another agent or agents as
described herein or with a pharmaceutically-acceptable carrier, or
both. Balsalazide can be administered prior to the administration
of the other agent, simultaneously with the agent, or after the
administration of the agent.
[0019] "Chemotherapy," as used herein, includes therapies
administered systemically for the treatment of neoplastic disease
processes (commonly cancer), and may include, for example,
biological therapies such as small molecule inhibitors, monoclonal
antibodies (e.g., Iressa, Tarceva, Erbitux), or other biological
agents administered with a similar objective which may result in
symptoms such as those herein described, e.g., inflammation of the
intestine, those causing a disproportionate incidence of diarrhea
or an increased risk of diarrhea.
[0020] The term "effective amount" includes an amount effective, at
dosages and for periods of time necessary, to achieve the desired
result, e.g., sufficient to treat or prevent an inflammatory bowel
disease. An effective amount of balsalazide may vary according to
factors such as the disease state, age, and weight of the subject,
and the ability of balsalazide to elicit a desired response in the
subject. Dosage regimens may be adjusted to provide the optimum
therapeutic response. An effective amount is also one in which any
side effects of balsalazide are outweighed by the therapeutically
beneficial effects.
[0021] "Ameliorate," "amelioration," "improvement" or the like
refers to, for example, a detectable improvement or a detectable
change consistent with improvement that occurs in a subject or in
at least a minority of subjects, e.g., in at least about 2%, 5%,
10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%,
95%, 98%, 100% or in a range between about any two of these values.
Such improvement or change may be observed in treated subjects as
compared to subjects not treated with balsalazide, where the
untreated subjects have, or are subject to developing, the same or
similar disease, condition, symptom or the like. Amelioration of a
disease, condition, symptom or assay parameter may be determined
subjectively or objectively, e.g., self-assessment by a subject(s),
by a clinician's assessment or by conducting an appropriate assay
or measurement, including, e.g., a quality of life assessment, a
slowed progression of a disease(s) or condition(s), a reduced
severity of a disease(s) or condition(s), or a suitable assay(s)
for the level or activity(ies) of a biomolecule(s), cell(s) or by
detection of enteritis or diarrhea within a subject. Amelioration
may be transient, prolonged or permanent or it may be variable at
relevant times during or after balsalazide is administered to a
subject or is used in an assay or other method described herein or
a cited reference, e.g., within timeframes described infra, or
about 1 hour after the administration or use of balsalazide to
about 3, 6, 9 months or more after a subject(s) has received
balsalazide.
[0022] As used herein, "administered with food" refers to, for
example, any food product, solid or liquid, with caloric content.
Preferably the food is a solid food with sufficient bulk and fat
content that it is not rapidly dissolved and absorbed in the
stomach. More preferably the food is a meal, such as breakfast,
lunch or dinner. The dosage of balsalazide may be administered to
the subject, for example, between about 30 minutes prior to about 2
hours after eating a meal, most advantageously the dosage is
administered within 15 minutes of eating a meal. The terms "without
food", "fasted" and "an empty stomach" refer to, for example, the
condition of not having consumed solid food for about 1 hour prior
to until about 2 hours after such consumption.
[0023] The "modulation" of, e.g., a symptom, level or biological
activity of a molecule, or the like, refers, for example, that the
symptom or activity, or the like is detectably increased or
decreased. Such increase or decrease may be observed in treated
subjects as compared to subjects not treated with balsalazide,
where the untreated subjects have, or are subject to developing,
the same or similar disease, condition, symptom or the like. Such
increases or decreases may be at least about 2%, 5%, 10%, 15%, 20%,
25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 100%,
150%, 200%, 250%, 300%, 400%, 500%, 1000% or more or within any
range between any two of these values. Modulation may be determined
subjectively or objectively, e.g., by the subject's
self-assessment, by a clinician's assessment or by conducting an
appropriate assay or measurement, including, e.g., quality of life
assessments or suitable assays for the level or activity of
molecules, cells or cell migration within a subject. Modulation may
be transient, prolonged or permanent or it may be variable at
relevant times during or after balsalazide is administered to a
subject or is used in an assay or other method described herein or
a cited reference, e.g., within times descried infra, or about 1
hour of the administration or use of balsalazide to about 3, 6, 9
months or more after a subject(s) has received balsalazide. The
term "modulate" may also refer to increases or decreases in the
activity of a cell in response to exposure to a balsalazide, e.g.,
the inhibition of proliferation and/or induction of differentiation
of at least a sub-population of cells in an animal such that a
desired end result is achieved, e.g., a therapeutic result of
balsalazide used for treatment may increase or decrease over the
course of a particular treatment.
[0024] The term "obtaining" as in "obtaining balsalazide" is
intended to include purchasing, synthesizing or otherwise acquiring
balsalazide.
[0025] As used herein, the term "prophylactically effective amount"
refers to the amount of a therapy (e.g., a composition comprising
balsalazide) which is sufficient to result in the prevention of the
development, recurrence, or onset of enteritis and/or diarrhea or
one or more symptoms thereof, or to enhance or improve the
prophylactic effect(s) of another therapy. In one embodiment, the
language "a prophylactically effective amount" of a compound refers
to an amount of balsalazide which is effective, upon single or
multiple dose administration to the subject, in preventing or
treating, for example, colitis, Crohn's disease, diverticulits,
irritable bowel syndrome (IBS), enteritis and/or diarrhea.
[0026] The phrases "systemic administration," "administered
systemically," "peripheral administration," and "administered
peripherally," as used herein mean the administration of
balsalazide, drug or other material, such that it enters the
subject's system and, thus, is subject to metabolism and other like
processes, for example, subcutaneous administration.
[0027] The language "therapeutically effective amount" of
balsalazide refers to an amount of balsalazide which is effective,
upon single or multiple dose administration to the subject, in
inhibiting the bacterial growth and/or invasion, or in decreasing
symptoms of bacterial infection in a subject with such a bacterial
infection sooner than expected in the absence of such treatment.
"Therapeutically effective amount" also refers to the amount of a
therapy (e.g., a composition comprising balsalazide), which is
sufficient to reduce the severity of enteritis and/or diarrhea,
reduce the duration of enteritis and/or diarrhea, prevent the
advancement of enteritis and/or diarrhea, cause regression of
enteritis and/or diarrhea, ameliorate one or more symptoms
associated with enteritis and/or diarrhea, or enhance, facilitate,
or improve the therapeutic effect(s) of another therapy.
[0028] As used herein, the terms "prevent," "preventing," and
"prevention" refer to the prevention of the recurrence, onset, or
development of colitis (including, ulcerative, active, moderate,
mild or severe colitis), enteritis and/or diarrhea or one or more
symptoms thereof in a subject resulting from the administration of
an abdominopelvic therapy or from travel. Preventing includes
protecting against radiation induced enteritis, protecting against
radiation induced injury to the mucosa of the colon, protecting
against radiation induced colorectal inflammation, and/or
radiation-induced inflammation or bacterial invasion of other
portions of the alimentary tract. For example, balsalazide may be
formulated as a mouthwash to treat or ameliorate radiation-induced
esophagitis or other radiation-induced mucositis. For example,
balsalazide may be given to a traveler prior to travel to reduce or
prevent enteritis or diarrhea.
[0029] As used herein, the terms "subject" and "subjects" includes
male organisms which are capable of suffering from a
gastrointestinal disease, e.g., colitis, e.g., ulcerative colitis,
e.g., mild, moderate or severe, or who could otherwise benefit from
the administration of a balsalazide and refer to an animal,
preferably a mammal, including a non-primate (e.g., a cow, pig,
horse, cat, or dog), a primate (e.g., a monkey, chimpanzee, or
human), and more preferably a human male.
[0030] Susceptible to gastrointestinal diseases, e.g., enteritis,
diarrhea, colon cancer, ulcerative colitis, is meant to include
subjects at risk of developing the gastrointestinal diseases, and
the like, and subjects who have suffered from colitis in the past,
subjects having a family history of colitis or cancer and the
like.
[0031] As used herein, the terms "treat," "treatment," and
"treating" refer to the reduction of the progression, severity,
and/or duration of colitis, enteritis and/or diarrhea or
amelioration of one or more symptoms thereof, wherein such
reduction and/or amelioration result from the administration of one
or more therapies (e.g., a composition comprising balsalazide).
[0032] In some embodiments, "clinical improvement" is defined as
having both a .gtoreq.3 point improvement from baseline in the
MMDAI score and a .gtoreq.1 point improvement from baseline in the
rectal bleeding subscore. In some embodiments, "clinical remission"
is defined as a score of 0 for rectal bleeding and a combined score
of .ltoreq.2 for bowel frequency and physician's assessment using
the MMDAI subscale. In some embodiments, "mucosal healing" is
defined as an endoscopy/sigmoidoscopy score of 0 or 1, where a
score of 1 includes signs of erythema or decreased vascular
pattern; by definition, the presence of friability indicates a
score of 2 or 3.
[0033] The phrase "pharmaceutically acceptable" refers to
compositions containing such compounds, and/or dosage forms which
are, within the scope of sound medical judgment, suitable for use
in contact with the tissues of human beings and animals without
excessive toxicity, irritation, allergic response, or other problem
or complication, commensurate with a reasonable benefit/risk
ratio.
[0034] Determining a subject in need thereof may be by one or more
of colonoscopy, symptom analysis, or medical assessment and other
methods described infra.
Balsalazide and Pharmaceutical Compositions
[0035] Balsalazide is a prodrug of mesalamine (5-aminosalicylic
acid, 5-ASA). The mechanism of action of 5-ASA is unknown, but
appears to be local to the colonic mucosa rather than systemic.
Mucosal production of arachidonic acid metabolites, both through
the cyclooxygenase pathways, i.e., prostanoids, and through the
lipoxygenase pathways, i.e., leukotrienes and
hydroxyeicosatetraenoic acids, is increased in patients with
ulcerative colitis, and it is possible that 5-ASA diminishes
inflammation by blocking production of arachidonic acid metabolites
in the colon.
[0036] Balsalazide disodium is a prodrug that is enzymatically
cleaved to produce mesalamine (5-aminosalicylic acid, 5-ASA), an
anti-inflammatory drug. It is a stable, odorless, orange to yellow,
microcrystalline powder. It is freely soluble in water and isotonic
saline, sparingly soluble in methanol and ethanol, and practically
insoluble in all other organic solvents. Balsalazide disodium has
the chemical name
(E)-5-[[-4-[[(2-carboxyethyl)aminocarbonyl]phenyl]azo]-2-hydroxybenzoic
acid, disodium salt, dihydrate (Molecular Weight: 437.32; Molecular
Formula: C.sub.17H.sub.13N.sub.3O.sub.6Na.sub.2.2H.sub.2O).
[0037] Balsalazide is the generic name for GIAZO.RTM.. Examples of
uses and manufacture of balsalazide may be found, for example in
U.S. Pat. Nos. 6,197,341; 5,905,073; 5,498,608; and 6,326,364;
which are hereby incorporated by reference in their entirety.
Balsalazide is useful in the methods described herein to increase
their bioavailability and efficacy.
[0038] Each GIAZO tablet contains 1.1 g of balsalazide disodium,
film-coated for oral delivery. Balsalazide disodium is insoluble in
acid, but soluble at a pH of at least 4.5. Inactive ingredients
comprise hypromellose, magnesium stearate, and Opadry II Yellow.
The sodium content of each tablet is approximately 126 mg.
[0039] Following oral administration, balsalazide is cleaved by
azoreductases produced by anaerobic bacteria, found in the gut, to
release equimolar quantities of 5-ASA, the active moiety, and
4-aminobenzoyl-.beta.-alanine (4-ABA), a carrier moiety. Both of
these moieties are N-acetylated to form N-Ac-5-ASA and N-Ac-4-ABA,
respectively.
[0040] The released 4-ABA carrier component is poorly absorbed and
largely eliminated in the feces (Ragunath K and Williams JG.
Aliment Pharmcol. Ther. 2001; 15:1549-1554). The local presence of
5-ASA is the basis for the effectiveness of this class of drugs and
mucosal 5-ASA concentrations are correlated inversely with UC
disease activity (Frieri G, Giacomelli R, Pimpo M. et al. Gut 2000;
47:410-414). While the actual mechanism of action of 5-ASA is not
completely understood, systemic exposure of 5-ASA is thought to be
responsible for the sides effects associated with treatment. Most
prevalent in studies on balsalazide is headache (Green JB
Gastroenterology 1999; 117:1513-1514) and lower systemic levels of
5-ASA may contribute to a lower incidence of headache as observed
in some trials (Levine D S, Riff D S, Pruitt R et al. Am. J.
Gastroenterol. 2002; 9:1398-1407). Dose regimens that increase the
local mucosal concentration of the active therapeutic moiety and
decrease the systemic absorption of 5-ASA are therefore
preferred.
[0041] While 5-ASA is the active therapeutic moiety of balsalazide,
it is rapidly converted to the metabolite N-acetyl-5-ASA
(5-Ac-5-ASA; NASA) in the mucosa (Allgayer H, Ahnfelt NO, Kruis W
et al Gastroenterology. 1989; 97:38-41). Approximately, 12% of the
oral dose can be measured in the blood as this metabolite as
compared to <2% of the oral dose of 5-ASA that is systemically
absorbed (van Hogezand R A, van Hees P A, van Gorp J P, van Lier H
J, Bakker J H, Double-blind comparison of 5-aminosalicylic acid and
acetyl-5-aminosalicylic acid suppositories in subjects with
idiopathic proctitis Aliment Pharmacol Ther. 1988 February;
2(1):33-40).
[0042] It has surprisingly been found that the administration of
balsalazide to a male subject experiencing ulcerative colitis,
e.g., mildly to moderately active ulcerative colitis, reduces
symptoms of the condition. Balsalazide is the generic name for a
2-hydroxy-5-phenylazobenzoic acid derivative in which an
aminosalicylate moiety, 5-aminosalicylic acid (5-ASA) (mesalamine),
is linked to a carrier molecule, 4-aminobenzoyl-.beta.-alanine
(4-ABA), through an azo-bond. Disodium balsalazide is highly
water-soluble and is cleaved in the colon to release mesalamine,
which is the therapeutically active portion of the molecule, as
well as 4-aminobenzol-.beta.-alamine, which is the carrier moiety.
Mesalamine is 5-aminosaliacylic acid and appears to act
topically.
[0043] One mechanism for the surprising observation of an increased
efficacy in males to balsalazide is the finding that that female
subjects display greater absorption of balsalazide and its
metabolites, 5-ASA and N-acetyl-5-ASA (NASA) in the blood, e.g.,
systemic bioavailability. Balsalazide and its metabolites work
topically in the colon, e.g., colonic bioavailability, to treat the
underlying pathology, the greater absorption into the blood
compartment would mean a lowering of their level in the colon and
less colonic bioavailability. This observation is shown in FIG. 3,
where the balsalazide, 5-ASA and NASA plasma levels are presented
as a ratio of the female levels divided by the male levels. Thus, a
value of 1.0 in the graph would be indicative of equal absorption
in both sexes. As is evident from FIG. 3, the female subjects
consistently display greater plasma levels relative to the male
subjects. These range from 10-60% greater in the fasted state to
25-120% greater in the fed state.
[0044] The use of balsalazide to treat gastrointestinal disorders
is especially beneficial because balsalazide is metabolized by
intestinal microflora to the active form, 5-ASA, thus ensuring
delivery of the active drug to the bowel without loss via
absorption more proximally in the intestinal tract. Balsalazide
also exhibits fewer side effects than other 5-ASA prodrugs and it
may be administered to subjects with sulpha allergies. Balsalazide
is also beneficial because the active component has been
demonstrated to directly scavenge free radicals, which may reduce
subsequent inflammatory response. Dosages, according to certain
preferred embodiments, range from between about 6.0 mg to about
14000 mg of balsalazide administered daily. For example, a dose is
three 1.1 g balsalazide tablets may be taken 2 times a day for a
total of 6.6 g per day. Other appropriate dosages for methods
according to this invention may be determined by health care
professionals or by the subject. The amount of balsalazide
administered daily may be increased or decreased based on the
weight, age, health, sex or medical condition of the subject. One
of skill in the art would be able to determine the proper dose for
a subject based on this disclosure.
Methods of Treatment
[0045] Described herein are methods of treating male subjects
suffering from or susceptible to gastrointestinal disorders by
administering balsalazide to a subject.
[0046] According to one aspect, provided herein are methods for
treating a male subject having or susceptible to developing a
gastrointestinal disorder, e.g., ulcerative colitis, comprising
administering to the male subject a therapeutically effective
amount of balsalazide.
[0047] Therapeutically effective amounts, according to the methods
described herein include doses of about 6.0 g/day to about 7 g/day,
for example, as tablets or capsules. Therapeutically effective
amounts and dosage regimens include, administering three tablets or
capsules of the formulation once, twice or three two times each
day, wherein each tablet or capsule comprises from about 750 mg to
about 1100 mg of balsalazide. For example, a therapeutically
effective amount of balsalazide may be administration of three 750
mg capsules three times a day (6.75 g/day). A more preferred
administration to males comprises administration of three 1.1 g
tablets two times a day.
[0048] The administration to the subject can occur, for example,
between about 30 minutes prior to about 2 hours after consuming
food. The administration with food may also be at the same time as
the consumption of the food. Also, the administration to the
subject may be, for example, immediately after the consumption of
food up to about 1 hour after the consumption. The food may
comprise, for example, applesauce or a high-fat meal.
[0049] According to one aspect, provided herein are methods of
decreasing the modified Mayo Disease Activity Index (MMDAI) score
of a male subject having ulcerative colitis by administering a
therapeutically effective amount of balsalazide to the subject. In
one embodiment, the MMDAI score is decreased by three or more
points or the rectal bleeding component of the MMDAI score is
decreased by one or more points. The modified Mayo Disease Activity
Index (MMDAI) is a sum of four subscores (bowel frequency, rectal
bleeding, endoscopic appearance, and physician's global
assessment), each ranging from 0 to 3, with higher scores
indicating worse disease. See for example, Schroeder et al. (1987)
N Engl J Med. 24; 317(26):1625-9.
[0050] According to one aspect, provided herein are methods of
inducing clinical remission of ulcerative colitis in male subjects.
In one embodiment, remission is defined as an MMDAI component score
of 0 for rectal bleeding and a combined score of two or less for
the MMDAI components of bowel frequency and physician's
assessment.
[0051] According to one aspect, provided herein are methods of
inducing mucosal healing in male subjects having ulcerative
colitis. In one embodiment, mucosal healing is determined by an
improvement in the endoscopy/sigmoidoscopy score of 0 to 1.
[0052] In one embodiment, the balsalazide is from a container
comprising labeling advising that balsalazide should be
administered with food.
[0053] According to one aspect, a method of treating a subject
suffering from a gastrointestinal disease, e.g., mild to moderately
active ulcerative colitis, comprises administering to the subject a
therapeutically effective amount of balsalazide. In one embodiment,
balsalazide is sodium balsalazide dihydrate. In one embodiment, the
pharmaceutical composition is administered orally to an individual
suffering from or at risk to develop a gastrointestinal disorder in
a daily dosage range of about 6 to about 7 grams per day, e.g., 6.6
g.
[0054] In another embodiment, the gastrointestinal disease is mild
to moderately active ulcerative colitis.
[0055] Yet another aspect of this invention relates to a method of
treating a male subject with balsalazide who is in need thereof.
Identifying a subject in need of such treatment can be in the
judgment of a subject or a health care professional and can be
subjective (e.g., opinion) or objective (e.g., measurable by a test
or diagnostic method).
[0056] Balsalazide may be administered prior to, during, and/or
after the treatment therapies or travel or exposure to other at
risk conditions. Balsalazide may be administered, for example, once
a day, twice a day, three times a day, or four times a day.
Balsalazide may be administered in doses, for example of about 6.6
g/day. Balsalazide may be administered, for example, in tablet
form, powered form, liquid for or in capsules. Balsalazide tablets
may be film-covered tablets marketed under the brand name
GIAZO.RTM..
[0057] In certain embodiments, balsalazide is administered to a
male subject from between about 2 weeks to about 6 weeks in
duration, from between about 8 weeks to about 12 weeks in duration,
or from between 1 day to about 7 days. Balsalazide may be
administered intermittently or continuously during the course of
treatment.
[0058] For any of the embodiments, balsalazide may be administered,
for example, once daily, twice daily, three times daily, or four
times daily to a subject. In some particularly preferred methods of
the present invention comprise administering balsalazide twice
daily to the subject because it may, for example, minimize the side
effects and increase subject compliance.
[0059] Dosages, according to certain preferred embodiments, are
about 6.6 g of balsalazide administered daily. Other appropriate
dosages for methods according to this invention may be determined
by health care professionals or by the subject. The amount of
balsalazide administered daily may be increased or decreased based
on the weight, age, health, sex or medical condition of the
subject. One of skill in the art would be able to determine the
proper dose for a subject based on this disclosure.
[0060] In certain embodiments, one or more formulations and one or
more other therapies (e.g., prophylactic or therapeutic agents) are
cyclically administered. Cycling therapy involves the
administration of a first therapy (e.g., a first prophylactic or
therapeutic agent) for a period of time, followed by the
administration of a second therapy (e.g., a second prophylactic or
therapeutic agent) for a period of time, optionally, followed by
the administration of a third therapy (e.g., prophylactic or
therapeutic agent) for a period of time and so forth, and repeating
this sequential administration, e.g., the cycle in order to reduce
the development of resistance to one of the therapies, to avoid or
reduce the side effects of one of the therapies, and/or to improve
the efficacy of the therapies.
[0061] In certain embodiments, the administration of the same
formulations of the invention may be repeated and the
administrations may be separated by at least 1 day, 2 days, 3 days,
5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3
months, or at least 6 months. In other embodiments, the
administration of the same therapy (e.g., prophylactic or
therapeutic agent) other than a gastro-resistant balsalazide
formulation may be repeated and the administration may be separated
by at least at least 1 day, 2 days, 3 days, 5 days, 10 days, 15
days, 30 days, 45 days, 2 months, 75 days, 3 months, or at least 6
months.
[0062] Certain indications may require longer treatment times.
Short-term treatments include, for example, treatment for 1 to
about 7 days. Long-term treatments with balsalazide, include for
example, treatment for 15 days, 3 months, 9 months, 7 days/month
for three months, 7 days/month for three to twelve months or any
time in-between or longer. One of skill in the art, having the
benefit of this disclosure would understand how to vary the dosage
for a particular subject or intended result. Dosage regimens will
vary depending on the age, size, and condition of the subject. For
example, depending on the severity of the disease, or injury
whether it is a new disease state or a relapse or recurrence,
etc.
[0063] Toxicity and efficacy of the prophylactic and/or therapeutic
protocols of the present invention can be determined by standard
pharmaceutical procedures in cell cultures or experimental animals,
e.g., for determining the LD.sub.50 (the dose lethal to 50% of the
population) and the ED.sub.50 (the dose therapeutically effective
in 50% of the population). The dose ratio between toxic and
therapeutic effects is the therapeutic index and it can be
expressed as the ratio LD.sub.50/ED.sub.50. Prophylactic and/or
therapeutic agents that exhibit large therapeutic indices are
preferred. While prophylactic and/or therapeutic agents that
exhibit toxic side effects may be used, care should be taken to
design a delivery system that targets such agents to the site of
affected tissue in order to minimize potential damage to uninfected
cells and, thereby, reduce side effects.
[0064] The total daily dosage of balsalazide formulations, for
example of balsalazide, can be about 6.6 g. For example, in
general, the total daily adult dosage of balsalazide in
formulations of the present invention ranges from about 6000 mg to
about 7000 mg, about, about 6200 to about 6800 mg, or any whole
number or fractional amount in between. In one embodiment, a single
dose contains about 1100 mg of balsalazide.
[0065] Balsalazide may be provided as a film-coated tablet
formulation.
[0066] Balsalazide formulations may be of any polymorphic or
amorphous form of balsalazide.
[0067] In an embodiment, balsalazide is administered to the subject
using a pharmaceutically-acceptable formulation, e.g., a
pharmaceutically-acceptable formulation that provides sustained
delivery of balsalazide to a subject for at least 12 hours, 24
hours, 36 hours, 48 hours, one week, two weeks, three weeks, or
four weeks after the pharmaceutically-acceptable formulation is
administered to the subject.
[0068] In some embodiments, it may be desirable to administer the
pharmaceutical compositions of the invention locally to the area in
need of treatment. This may be achieved by, for example, local
infusion during surgery, or topical application, e.g., in
conjunction with a wound dressing after surgery, by injection, by
means of a catheter, by means of a suppository, or by means of an
implant (the implant being of a porous, non-porous, or gelatinous
material, including membranes, such as sialastic membranes, or
fibers). In one embodiment, administration can be by direct
injection at the site, e.g., enema. In another embodiment,
balsalazide can be formulated in a viscous or non-viscous solution
for oral administration. In a separate embodiment, balsalazide can
be formulated in a viscous or non-viscous mixture containing a pain
reliever, e.g., lidocaine.
[0069] In certain embodiments, these pharmaceutical compositions of
balsalazide are suitable for topical or oral administration to a
subject. In other embodiments, as described in detail below, the
pharmaceutical compositions of the present invention may be
specially formulated for administration in solid or liquid form,
including those adapted for the following: (1) oral administration,
for example, drenches (aqueous or non-aqueous solutions or
suspensions), tablets, boluses, powders, granules, pastes; topical
application, for example, as a cream, ointment or spray applied to
the gastrointestinal tract; intrarectally, for example, as a
pessary, cream or foam; or aerosol, for example, as an aqueous
aerosol, liposomal preparation or solid particles containing the
compound.
[0070] The phrase "pharmaceutically acceptable" refers to
compositions containing such compounds, and/or dosage forms which
are, within the scope of sound medical judgment, suitable for use
in contact with the tissues of human beings and animals without
excessive toxicity, irritation, allergic response, or other problem
or complication, commensurate with a reasonable benefit/risk
ratio.
[0071] It is advantageous to administer balsalazide to males
because less of the molecule and metabolites are absorbed
systemically leaving more in the colon for local colonic
bioavailability. For example, see FIG. 3, which shows that with or
without food, less of the balsalazide and metabolites are
systemically absorbed in the men taking the compound. This was
previously an unappreciated aspect of administering balsalazide and
it was surprising to find that administration to males has
increased efficacy as compared to females.
Article of Manufacture
[0072] The article of manufacture comprises, for example, a
container holding a film-coated pharmaceutical composition or a
capsule or a combination of the two suitable for oral
administration of balsalazide in combination with printed labeling
instructions providing a discussion of when a particular dosage
form should be administered to male subjects. Exemplary dosage
forms and administration protocols are described infra. The
composition will be contained in any suitable container capable of
holding and dispensing the dosage form and which will not
significantly interact with the composition and will further be in
physical relation with the appropriate labeling. The labeling
instructions will be consistent with the methods of treatment as
described hereinbefore. The labeling may be associated with the
container by any means that maintain a physical proximity of the
two, by way of non-limiting example, they may both be contained in
a packaging material such as a box or plastic shrink wrap or may be
associated with the instructions being bonded to the container such
as with glue that does not obscure the labeling instructions or
other bonding or holding means.
[0073] Another aspect of this invention is an article of
manufacture that comprises a container containing a pharmaceutical
composition comprising balsalazide wherein the container holds
preferably balsalazide composition in unit dosage form and is
associated with printed labeling instructions advising of efficacy
of the pharmaceutical composition when administered to male
subjects.
[0074] The phrase "pharmaceutically-acceptable carrier" includes
pharmaceutically-acceptable material, composition or vehicle, such
as a liquid or solid filler, diluent, excipient, solvent or
encapsulating material, involved in carrying or transporting the
subject chemical from one organ, or portion of the body, to another
organ, or portion of the body. Each carrier is "acceptable" in the
sense of being compatible with the other ingredients of the
formulation and not injurious to the subject. Some examples of
materials which can serve as pharmaceutically-acceptable carriers
include: (1) sugars, such as lactose, glucose and sucrose; (2)
starches, such as corn starch and potato starch; (3) cellulose, and
its derivatives, such as sodium carboxymethyl cellulose, ethyl
cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt;
(6) gelatin; (7) talc; (8) excipients, such as cocoa butter and
suppository waxes; (9) oils, such as peanut oil, cottonseed oil,
safflower oil, sesame oil, olive oil, corn oil and soybean oil;
(10) glycols, such as propylene glycol; (11) polyols, such as
glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters,
such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering
agents, such as magnesium hydroxide and aluminum hydroxide; (15)
alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18)
Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer
solutions; and (21) other non-toxic compatible substances employed
in pharmaceutical formulations.
[0075] Wetting agents, emulsifiers and lubricants, such as sodium
lauryl sulfate and magnesium stearate, as well as coloring agents,
release agents, coating agents, sweetening, flavoring and perfuming
agents, preservatives and antioxidants can also be present in the
compositions.
[0076] Examples of pharmaceutically-acceptable antioxidants
include: (1) water soluble antioxidants, such as ascorbic acid,
cysteine hydrochloride, sodium bisulfate, sodium metabisulfite,
sodium sulfite and the like; (2) oil-soluble antioxidants, such as
ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated
hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol,
and the like; and (3) metal chelating agents, such as citric acid,
ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid,
phosphoric acid, and the like.
[0077] Compositions containing balsalazide include, for example,
those suitable for oral, nasal, topical (including buccal and
sublingual), rectal, vaginal, aerosol percutaneous, and/or
parenteral administration. For instance, to treat an infected
external biliary drain, balsalazide could be administered
percutaneously via that drain, thus resulting in an "intrabiliary"
administration. The compositions may conveniently be presented in
unit dosage form and may be prepared by any methods well known in
the art of pharmacy. The amount of active ingredient which can be
combined with a carrier material to produce a single dosage form
will vary depending upon the host being treated, the particular
mode of administration. The amount of active ingredient which can
be combined with a carrier material to produce a single dosage form
will generally be that amount of the compound which produces a
therapeutic effect. Generally, out of 100%, this amount will range
from about 1% to about 99% of active ingredient, preferably from
about 5% to about 70%, more preferably from about 10% to about 30%
active ingredient.
[0078] Methods of preparing these balsalazide compositions include
the step of bringing into association balsalazide with the carrier
and, optionally, one or more accessory ingredients. In general, the
formulations are prepared by uniformly and intimately bringing into
association with balsalazide with liquid carriers, or finely
divided solid carriers, or both, and then, if necessary, shaping
and coating the product.
[0079] Balsalazide compositions suitable for oral administration
may be in the form of capsules, cachets, pills, tablets, lozenges
(using a flavored basis, usually sucrose and acacia or tragacanth),
powders, granules, or as a solution or a suspension in an aqueous
or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid
emulsion, or as an elixir or syrup, or as pastilles (using an inert
base, such as gelatin and glycerin, or sucrose and acacia) and/or
as mouth washes and the like, each containing a predetermined
amount of balsalazide as an active ingredient. A compound may also
be administered as a bolus, electuary or paste.
[0080] A tablet may be made by compression or molding, optionally
with one or more accessory ingredients. Compressed tablets may be
prepared using binder (for example, gelatin or hydroxypropylmethyl
cellulose), lubricant, inert diluent, preservative, disintegrant
(for example, sodium starch glycolate or cross-linked sodium
carboxymethyl cellulose), surface-active or dispersing agent.
Molded tablets may be made by molding in a suitable machine a
mixture of the powdered active ingredient moistened with an inert
liquid diluent.
[0081] The tablets, and other solid dosage forms of the
pharmaceutical compositions of the present invention, such as
dragees, capsules, pills and granules, may optionally be scored or
prepared with coatings and shells, such as film coatings and other
coatings well known in the pharmaceutical-formulating art. They may
also be formulated so as to provide slow or controlled release of
the active ingredient therein using, for example,
hydroxypropylmethyl cellulose in varying proportions to provide the
desired release profile, other polymer matrices, liposomes and/or
microspheres. They may be sterilized by, for example, filtration
through a bacteria-retaining filter, or by incorporating
sterilizing agents in the form of sterile solid compositions which
can be dissolved in sterile water, or some other sterile injectable
medium immediately before use. These compositions may also
optionally contain opacifying agents and may be of a composition
that they release the active ingredient(s) only, or preferentially,
in a certain portion of the gastrointestinal tract, optionally, in
a delayed manner. Examples of embedding compositions which can be
used include polymeric substances and waxes. The active ingredient
can also be in micro-encapsulated form, if appropriate, with one or
more of the above-described excipients.
[0082] Liquid dosage forms for oral administration of balsalazide
include pharmaceutically-acceptable emulsions, microemulsions,
solutions, suspensions, syrups and elixirs. In addition to the
active ingredient, the liquid dosage forms may contain inert
diluents commonly used in the art, such as, for example, water or
other solvents, solubilizing agents and emulsifiers, such as ethyl
alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl
alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol,
oils (in particular, cottonseed, groundnut, corn, germ, olive,
castor and sesame oils), glycerol, tetrahydrofuryl alcohol,
polyethylene glycols and fatty acid esters of sorbitan, and
mixtures thereof.
[0083] Pharmaceutical compositions of the invention for rectal
administration may be presented as a suppository, which may be
prepared by mixing balsalazide with one or more suitable
nonirritating excipients or carriers comprising, for example, cocoa
butter, polyethylene glycol, a suppository wax or a salicylate, and
which is solid at room temperature, but liquid at body temperature
and, therefore, will melt in the rectum and release the active
agent.
[0084] Dosage forms for the topical or transdermal administration
of balsalazide include powders, sprays, ointments, pastes, creams,
lotions, gels, solutions, patches and inhalants. Balsalazide may be
mixed under sterile conditions with a pharmaceutically-acceptable
carrier, and with any preservatives, buffers, or propellants which
may be required.
[0085] Examples of suitable aqueous and nonaqueous carriers, which
may be employed in the pharmaceutical compositions of the invention
include water, ethanol, polyols (such as glycerol, propylene
glycol, polyethylene glycol, and the like), and suitable mixtures
thereof, vegetable oils, such as olive oil, and injectable organic
esters, such as ethyl oleate. Proper fluidity can be maintained,
for example, by the use of coating materials, such as lecithin, by
the maintenance of the required particle size in the case of
dispersions, and by the use of surfactants.
[0086] These compositions may also contain adjuvants such as
preservatives, wetting agents, emulsifying agents and dispersing
agents. Prevention of the action of microorganisms may be ensured
by the inclusion of various antibacterial and antifungal agents,
for example, paraben, chlorobutanol, phenol sorbic acid, and the
like. It may also be desirable to include isotonic agents, such as
sugars, sodium chloride, and the like into the compositions. In
addition, prolonged absorption of the injectable pharmaceutical
form may be brought about by the inclusion of agents that delay
absorption such as aluminum monostearate and gelatin.
[0087] In some cases, in order to prolong the effect of a drug, it
is desirable to slow the absorption of the drug from subcutaneous
or intramuscular injection. This may be accomplished by the use of
a liquid suspension of crystalline or amorphous material having
poor water solubility. The rate of absorption of the drug then
depends upon its rate of dissolution that in turn may depend upon
crystal size and crystalline form. Alternatively, delayed
absorption of a parenterally-administered drug form is accomplished
by dissolving or suspending the drug in an oil vehicle.
[0088] Injectable depot forms are made by forming microencapsule
matrices of balsalazide in biodegradable polymers such as
polylactide-polyglycolide. Depending on the ratio of drug to
polymer, and the nature of the particular polymer employed, the
rate of drug release can be controlled. Examples of other
biodegradable polymers include poly(orthoesters) and
poly(anhydrides). Depot injectable formulations are also prepared
by entrapping the drug in liposomes or microemulsions which are
compatible with body tissue.
[0089] When balsalazide are administered as pharmaceuticals, to
humans and animals, they can be given per se or as a pharmaceutical
composition containing, for example, 0.1 to 99.5% (more preferably,
0.5 to 90%) of active ingredient in combination with a
pharmaceutically-acceptable carrier.
[0090] In some cases, to ameliorate, for example, simultaneously,
conditions associated with the condition for which balsalazide is
administered, such as pain, candida, dysphagia, odynophagia,
mucositis, esophagitis, pneumonitis, stomatitis, or xerostomia,
balsalazide may be formulated as a combination with other
appropriate agents including but not limited to nystatin,
ketoconazole, fluconazole, lidocaine, benzocaine, diphenhydramine,
dimenhydrinate, azelastine, cetirizine, hydrocortisone, prednisone,
prednisolone, dexamethasone, triamcinolone, beclomethosone,
budesonide, mometasone, or other steroid, local anesthetic,
anti-fungal, or antihistamine agents. This formulation may take the
form of a viscous or non-viscous liquid, a topically applied
compound, an aerosol, or an injectable.
[0091] Regardless of the route of administration selected,
balsalazide, which may be used in a suitable hydrated form, and/or
the pharmaceutical compositions of the present invention, are
formulated into pharmaceutically-acceptable dosage forms by
conventional methods known to those of skill in the art.
[0092] Actual dosage levels and time course of administration of
the active ingredients in the pharmaceutical compositions of the
invention may be varied so as to obtain an amount of the active
ingredient which is effective to achieve the desired therapeutic
response for a particular subject, composition, and mode of
administration, without being toxic to the subject. Exemplary
dosage forms are disclosed infra.
[0093] Packaged compositions are also provided, and may comprise a
therapeutically effective amount of balsalazide. Balsalazide and a
pharmaceutically acceptable carrier or diluent, wherein the
composition is formulated for treating a subject suffering from or
susceptible to a bowel disorder, and packaged with instructions to
treat a subject suffering from or susceptible to a bowel
disorder.
Prescribing Information A subject being administered balsalazide
may be informed of one or more of the following:
[0094] GIAZO, film-coated tablets containing 1.1 g balsalazide, is
indicated for the treatment of mildly to moderately active
ulcerative colitis in male patients 18 years of age and older;
effectiveness in female patients was not demonstrated in clinical
studies. Safety and effectiveness of GIAZO therapy beyond 8 weeks
have not been established.
[0095] For treatment of active ulcerative colitis in adult male
patients, the usual dose is three 1.1 g GIAZO tablets to be taken 2
times a day with food (6.6 g per day) for up to 8 weeks.
[0096] GIAZO is available as yellow, oval, film-coated tablets
containing 1.1 g balsalazide disodium, with BZT debossed on one
side of the tablet.
[0097] GIAZO is contraindicated in patients with hypersensitivity
to salicylates, balsalazide, or their metabolites, or to any of the
components of GIAZO tablets. Hypersensitivity reactions may
include, but are not limited to the following: anaphylaxis,
bronchospasm, and skin reaction.
[0098] Mesalamine has been associated with an acute intolerance
syndrome that may be difficult to distinguish from an exacerbation
of ulcerative colitis. In controlled clinical studies with GIAZO in
adults with ulcerative colitis, 7% of male patients reported
exacerbation of the symptoms of ulcerative colitis. Symptoms
include cramping, acute abdominal pain and bloody diarrhea,
sometimes fever, headache, and rash. Observe patients closely for
worsening of these symptoms while on treatment. If acute
intolerance syndrome is suspected, promptly discontinue treatment
with GIAZO.
[0099] Renal impairment, including minimal change nephropathy,
acute and chronic interstitial nephritis, and, rarely, renal
failure, has been reported in patients given products that release
mesalamine in the gastrointestinal tract. It is recommended that
patients have an evaluation of renal function prior to initiation
of GIAZO therapy and periodically while on therapy. Exercise
caution when using GIAZO in patients with known renal dysfunction
or a history of renal disease.
[0100] There have been reports of hepatic failure in patients with
pre-existing liver disease who have been administered mesalamine.
Because balsalazide is converted to mesalamine, caution should be
exercised when administering GIAZO to patients with liver
disease.
[0101] Patients with pyloric stenosis may have prolonged gastric
retention of GIAZO tablets, which may delay delivery of GIAZO to
the colon.
[0102] Because clinical studies are conducted under widely varying
conditions, adverse reaction rates observed in the clinical studies
of a drug cannot be directly compared to rates in the clinical
studies of another drug and may not reflect the rates observed in
practice.
[0103] In an in vitro study using human liver microsomes,
balsalazide and its metabolites [5-aminosalicylic acid (5-ASA),
N-acetyl-5-aminosalyicylic acid (N-Ac-5-ASA),
4-aminobenzoyl-.beta.-alanine (4-ABA), and
N-acetyl-4-aminobenzoyl-.beta.-alanine (N-Ac-4-ABA)] were not shown
to inhibit the major CYP enzymes evaluated (CYP1A2, CYP2C9,
CYP2C19, CYP2D6, and CYP3A4/5). Therefore, balsalazide and its
metabolites are not expected to inhibit the metabolism of other
drugs that are substrates of CYP1A2, CYP2C9, CYP2C19, CYP2D6, or
CYP3A4/5.
[0104] Pregnancy Category B. Reproduction studies were performed in
rats and rabbits at oral doses up to 2 g/kg/day, 2.5 and 4.9 times
the recommended human dose based on body surface area for the rat
and rabbit, respectively, and revealed no evidence of impaired
fertility or harm to the fetus due to balsalazide disodium. There
are, however, no adequate and well-controlled studies in pregnant
women. Because animal reproduction studies are not always
predictive of human response, this drug should be used during
pregnancy only if clearly needed.
[0105] Mesalamine is known to cross the placental barrier.
[0106] It is not known whether balsalazide disodium or its
metabolites are excreted in human milk. Because many drugs are
excreted in human milk, caution should be exercised when GIAZO is
administered to a nursing woman.
[0107] This invention is further illustrated by the following
examples which should not be construed as limiting. The contents of
all references, patents and published patent applications cited
throughout this application are hereby incorporated by
reference.
EXAMPLES
Example 1
Clinical Studies
[0108] The data described below reflect exposure of GIAZO in 565
ulcerative colitis patients with mildly to moderately active
disease. GIAZO was evaluated in one placebo-controlled study (168
treated with GIAZO), one active-controlled study (210 treated with
GIAZO); a subset of these patients also participated in an
uncontrolled, open-label, extension study (additional 187 treated
with GIAZO). The population studied had a mean age of 43.1 (range:
18-80) years; approximately 94% of patients were <65 years old,
49% were male, and 84% were white.
Adverse Reactions/Contraindications
[0109] In the placebo-controlled study, a greater proportion of
patients experienced an adverse reaction in the placebo group (68%)
compared with the GIAZO group (55%). The most common adverse
reactions with GIAZO in male patients were headache,
nasopharyngitis, anemia, diarrhea, fatigue, pharyngolaryngeal pain,
and urinary tract infection. A lower proportion of GIAZO (10%)
patients discontinued treatment due to an adverse reaction compared
to the placebo group (13%). The majority of adverse reactions were
mild to moderate in severity. The percentage of patients who
experienced a serious adverse reaction was greater in the placebo
group (5.1%) than the GIAZO group (2.4%). The most common serious
adverse reactions were gastrointestinal disorders, which were
mainly associated with symptoms of ulcerative colitis.
[0110] Adverse reactions occurring in at least 2% of male patients
in the placebo-controlled study are listed in Table 1.
TABLE-US-00001 TABLE 1 Adverse Reactions Experienced by at Least 2%
of GIAZO -Treated Male Patients and at a Rate Greater than Placebo
in a Placebo-Controlled Phase 3 Study GIAZO 6.6 g/day PLACEBO
Adverse Reaction N = 82 N = 37 Anemia 3.7% 0% Diarrhea 3.7% 0%
Pharyngolaryngeal Pain 3.7% 0% Urinary Tract Infection 3.7% 0%
Arthralgia 2.4% 0% Insomnia 2.4% 0% Pain 2.4% 0%
[0111] Data collected from all three studies (placebo-controlled,
active-controlled, and open-label) showed that female patients
reported adverse reactions more frequently than did male patients
(76% and 66%, respectively).
[0112] The following adverse reactions, presented by body system,
were reported infrequently (less than 1%) by GIAZO-treated
ulcerative colitis patients in controlled studies.
[0113] Cardiovascular and Vascular: increased blood pressure,
increased heart rate
[0114] Dermatological: erythema nodosum, rash
[0115] Gastrointestinal Disorders: abdominal pain, constipation,
defecation urgency, diarrhea, dry mouth, hard feces, flatulence,
gastroesophageal reflux disease, vomiting
[0116] Hepatobiliary Disorders: increased aspartate
aminotransferase
[0117] Infections and Infestations: gastroenteritis, upper
respiratory infection
[0118] Musculoskeletal and Connective Tissue Disorders: arthralgia,
back pain, myalgia
[0119] Nervous System Disorders: dizziness, lethargy
[0120] Respiratory, Thoracic and Mediastinal Disorders: dyspnea
[0121] General Disorders and Administrative Site Disorders: face
edema, fatigue, malaise, pain, pyrexia, swelling
[0122] Because these reactions are reported voluntarily from a
population of unknown size, it is not always possible to reliably
estimate their frequency or establish a causal relationship to drug
exposure. These adverse reactions have been chosen for inclusion
due to a combination of seriousness, frequency of reporting, or
potential causal connection to mesalamine.
[0123] The following adverse reactions have been identified during
use of balsalazide-containing products in clinical practice:
[0124] Cardiovascular and Vascular: myocarditis, pericarditis,
vasculitis
[0125] Dermatological: alopecia, pruritus
[0126] Gastrointestinal: pancreatitis
[0127] Respiratory: alveolitis, pleural effusion, pneumonia (with
and without eosinophilia)
[0128] Renal: interstitial nephritis, renal failure
[0129] The following additional adverse reactions have been
identified during post-approval use in clinical practice of
products which contain (or are metabolized to) mesalamine:
[0130] Hepatobiliary Disorders: elevated liver enzymes (AST, ALT,
GGT, LDH, alkaline phosphatase), elevated bilirubin, jaundice,
cholestatic jaundice, cirrhosis, hepatocellular damage including
liver necrosis and liver failure, Kawasaki-like syndrome including
hepatic dysfunction. Some of these cases were fatal.
Absorption
[0131] After single-dose administration of 3.3 g GIAZO in 18
healthy subjects, the median time of peak plasma concentration
(T.sub.max) was 0.5 hr for balsalazide, while the median T.sub.max
was 12 hr for both 5-ASA and N-Ac-5-ASA (Table 2). Pharmacokinetic
parameters exhibited high variability, with % CV ranging from 31%
to 67% for AUC and from 27% to 68% for C.sub.max.
[0132] After repeated doses of 3.3 g GIAZO tablets every 12 hours,
steady-state was achieved after about 3 days for balsalazide and
all metabolites. The AUC and C.sub.max were the highest for
N-Ac-5-ASA, followed by 5-ASA and balsalazide. There was minimal
accumulation of balsalazide, as suggested by a 1.2-fold increase in
AUC. On the other hand, a larger increase in the systemic exposure
to metabolites was observed at steady-state. The accumulation
ratios based on AUC for the metabolites were 6.1 for 5-ASA, 3.6 for
N-Ac-5-ASA, 4.8 for 4-ABA, and 3.6 for N-Ac-4-ABA.
TABLE-US-00002 TABLE 2 Pharmacokinetic Parameters for Balsalazide
and Metabolites (5-ASA and N-Ac-5-ASA) Following Single- and
Repeated-Doses (Q12) of 3.3 g Balsalazide Disodium as GIAZO (N =
18) Single Dose Repeated Dose Parameter Mean SD Mean SD C.sub.max
(mcg/mL) Balsalazide 0.3 0.2 0.3 0.2 5-ASA 0.5 0.3 1.5 0.6
N-Ac-5-ASA 1.2 0.4 2.2 0.6 T.sub.max.sup.a (hours) Balsalazide 0.5
(0.5-2) 0.5 (0.5-2) 5-ASA 12 (8-16) 12 (1.5-16) N-Ac-5-ASA 12
(8-16) 10 (1-16) AUC.sub.tau (mcg h/mL) Balsalazide 1.3 0.7 1.6 0.9
5-ASA 2.2 1.6 13.4 6.3 N-Ac-5-ASA 5.9 2.9 21 6.4 AUC.sub.0-.infin.
(mcg h/mL) Balsalazide 1.4 0.8 NA NA 5-ASA 8.5 3.9 NA NA N-Ac-5-ASA
33.5 14.1 NA NA T.sub.1/2.sup.b (hour) Balsalazide 1.9 0.7 8.4 12.4
5-ASA 9.5.sup.b 10.1 9.0 8.6 N-Ac-5-ASA 10.4.sup.b 17.6 7.2 6.8
.sup.aExpressed as median and range. .sup.bN = 17.
[0133] Food Effect
[0134] After administration of single dose of 3.3 g (3.times.1.1 g
tablets) of GIAZO with a high-fat meal, the AUC of balsalazide was
unaffected compared to fasted administration, but the presence of
food reduced both peak concentrations and AUC of the metabolites
5-ASA and N-Ac-5-ASA. A high fat meal increased the median
T.sub.max for balsalazide from 0.5 to 2 hours; for 5-ASA from 12 to
24 hours; and for N-Ac-S-ASA from 12 to 24 hours. Under fed
conditions, the mean C.sub.max was reduced by 44% for balsalazide,
65% for 5-ASA, and 48% for N-Ac-S-ASA. No significant changes were
observed for AUC.sub.0-.infin. for balsalazide; however,
AUC.sub.0-.infin. was reduced for 5-ASA by 46% and for N-Ac-S-ASA
by 17%.
[0135] The binding of balsalazide to human plasma proteins was
.gtoreq.99%; 5-ASA and N-Ac-5-ASA were 43% and 78% bound,
respectively, to plasma proteins.
[0136] Following oral administration, balsalazide is cleaved by
bacterial azoreduction to release equimolar quantities of 5-ASA,
the active moiety, and 4-ABA, a carrier moiety. Mesalamine (5-ASA)
and 4-ABA are further acetylated to N-Ac-S-ASA and N-Ac-4-ABA,
respectively in the intestinal mucosa and liver. The terminal
half-life was 1.9 h for balsalazide, 9.5 h for 5-ASA, and 10.5 h
for N-Ac-5-ASA.
[0137] At steady-state following administration of repeated doses
of 3.3 g GIAZO every 12 hours in healthy volunteers, the combined %
of dose excreted in urine for balsalazide and its metabolites over
12 hours was 23%. The mean % of dose excreted in urine over 12
hours was 0.16% for balsalazide, 4.6% for 5-ASA, 15.6% for
N-Ac-5-ASA, 0.40% for 4-ABA, and 1.8% for N-Ac-4-ABA.
Example 2
Carcinogenicity Studies
[0138] In a 24-month rat (Sprague Dawley) carcinogenicity study,
oral (dietary) balsalazide disodium at doses up to 2 g/kg/day was
not tumorigenic. For a 50 kg person of average height this dose
represents 2.5 times the recommended human dose on a body surface
area basis. Balsalazide disodium was not genotoxic in the following
in vitro or in vivo tests: Ames test, human lymphocyte chromosomal
aberration test, and mouse lymphoma cell (L5178Y/TK+/-) forward
mutation test, or mouse micronucleus test. However, it was
genotoxic in the in vitro Chinese hamster lung cell (CH V79/HGPRT)
forward mutation test.
[0139] The compound 4-aminobenzoyl-.beta.-alanine, a metabolite of
balsalazide disodium, was not genotoxic in the Ames test and the
mouse lymphoma cell (L5178Y/TK+/-) forward mutation test but was
positive in the human lymphocyte chromosomal aberration test.
N-acetyl-4-aminobenzoyl-.beta.-alanine, a conjugated metabolite of
balsalazide disodium, was not genotoxic in Ames test, the mouse
lymphoma cell (L5178Y/TK+/-) forward mutation test, or the human
lymphocyte chromosomal aberration test. Balsalazide disodium at
oral doses up to 2 g/kg/day, 2.5 times the recommended human dose
based on body surface area, was found to have no effect on
fertility and reproductive performance in rats.
Example 3
Placebo-Controlled Study
[0140] A double-blind, placebo-controlled, multi-center study was
conducted in 250 adult patients with mildly to moderately active
ulcerative colitis. The study population was primarily white (84%),
had a mean age of 44 years (7% age 65 years or older), and 49% were
men. Disease activity was assessed using a modified Mayo Disease
Activity Index.sup.1 (MMDAI), which was a sum of four subscores
(bowel frequency, rectal bleeding, endoscopic appearance, and
physician's global assessment), each ranging from 0 to 3, with
higher scores indicating worse disease. The median baseline MMDAI
score was 8. Patients were randomized 2:1 to receive 8 weeks of
treatment with either GIAZO 3.3 g twice daily or placebo.
[0141] The primary efficacy endpoint was to compare the proportion
of patients that achieved clinical improvement and improvement in
the rectal bleeding subscale of the MMDAI at the end of 8 weeks of
treatment for GIAZO vs. placebo. Clinical Improvement was defined
as having both a .gtoreq.3 point improvement from baseline in the
MMDAI score and a .gtoreq.1 point improvement from baseline in the
rectal bleeding subscore. Two key secondary efficacy endpoints
compared the proportion of patients with Clinical Remission and
Mucosal Healing at the end of 8 weeks of treatment for GIAZO vs.
placebo. Clinical Remission was defined as a score of 0 for rectal
bleeding and a combined score of .ltoreq.2 for bowel frequency and
physician's assessment using the MMDAI subscale; the endoscopic
sub-score was not considered in this definition. Mucosal Healing
was defined as an endoscopy/sigmoidoscopy score of 0 or 1, where a
score of 1 could include signs of erythema or decreased vascular
pattern; by definition, the presence of friability indicated a
score of 2 or 3.
[0142] After 8 weeks of treatment, the proportion of patients
showing Clinical Improvement was greater for the GIAZO-treated
group compared to the placebo group (Table 3).
TABLE-US-00003 TABLE 3 Proportion of Patients with Clinical
Improvement* at Week 8 for the Total Population and by Gender
Subgroups GIAZO Placebo p-value Total Population 55% 40% 0.0237
Males 57% 20% Females 54% 58% *Clinical Improvement: .gtoreq.3
improvement in MMDAI score and .gtoreq.1 point improvement in
rectal bleeding.
[0143] These differences were statistically significant in the
overall population; however, these effects were entirely driven by
the results in the male subpopulation. With adjustment for
multiplicity, statistically significant differences were also seen
in the male patients for
[0144] Clinical Remission (35% with GIAZO vs. 13% for placebo) and
for Mucosal Healing (52% with GIAZO vs. 20% for placebo).
Effectiveness of GIAZO was not demonstrated in the female
subpopulation in the clinical trial.
CONCLUSIONS
[0145] Instruct patients not to take GIAZO if they have a
hypersensitivity to salicylates (e.g., aspirin).
[0146] Instruct patients to take GIAZO with food.
[0147] Instruct patients to contact their health care provider if
they experience a worsening of their ulcerative colitis symptoms,
because it could be due to a reaction to GIAZO.
[0148] Instruct patients to make sure they let their health care
provider know:
[0149] if they have or are later diagnosed with renal dysfunction.
Damage to the kidney has been observed in some people given
medications similar to GIAZO.
[0150] if they have or are later diagnosed with liver disease.
Worsening liver disease has been observed in some people given
medications similar to GIAZO.
[0151] if they have or are later diagnosed with pyloric stenosis,
because GIAZO tablets may be slow to pass through their digestive
tract.
INCORPORATION BY REFERENCE
[0152] The contents of all references, patents, pending patent
applications and published patents, cited throughout this
application are hereby expressly incorporated by reference.
EQUIVALENTS
[0153] Those skilled in the art will recognize, or be able to
ascertain using no more than routine experimentation, many
equivalents to the specific embodiments of the invention described
herein. Such equivalents are intended to be encompassed by the
following claims.
* * * * *