U.S. patent application number 14/010308 was filed with the patent office on 2014-03-06 for methods for compositions for the treatment of irritable bowel syndrome.
This patent application is currently assigned to MediciNova, Inc.. The applicant listed for this patent is MediciNova, Inc.. Invention is credited to Yuichi Iwaki, Kazuko MATSUDA, Kale Ruby.
Application Number | 20140066513 14/010308 |
Document ID | / |
Family ID | 44763232 |
Filed Date | 2014-03-06 |
United States Patent
Application |
20140066513 |
Kind Code |
A1 |
MATSUDA; Kazuko ; et
al. |
March 6, 2014 |
METHODS FOR COMPOSITIONS FOR THE TREATMENT OF IRRITABLE BOWEL
SYNDROME
Abstract
A method for a prevention and/or treatment of irritable bowel
syndrome or amelioration of a symptom thereof in a subject,
comprises administering to said subject an effective amount of a
compound of formula I: ##STR00001##
Inventors: |
MATSUDA; Kazuko; (Beverly
Hills, CA) ; Iwaki; Yuichi; (Palos Verdes Estates,
CA) ; Ruby; Kale; (Encinitas, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
MediciNova, Inc. |
San Diego |
CA |
US |
|
|
Assignee: |
MediciNova, Inc.
San Diego
CA
|
Family ID: |
44763232 |
Appl. No.: |
14/010308 |
Filed: |
August 26, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13079566 |
Apr 4, 2011 |
8518995 |
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14010308 |
|
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61322201 |
Apr 8, 2010 |
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Current U.S.
Class: |
514/567 ;
514/619 |
Current CPC
Class: |
Y02A 50/491 20180101;
A61P 43/00 20180101; A61P 29/00 20180101; A61P 23/02 20180101; A61P
1/10 20180101; A61P 1/14 20180101; A61K 31/165 20130101; A61P 1/12
20180101; C07C 2602/10 20170501; A61P 31/00 20180101; A61P 13/06
20180101; A61P 25/24 20180101; Y02A 50/30 20180101; C07C 235/20
20130101; A61K 31/192 20130101; A61K 45/06 20130101; A61P 1/00
20180101; A61K 31/165 20130101; A61K 2300/00 20130101; A61K 31/192
20130101; A61K 2300/00 20130101 |
Class at
Publication: |
514/567 ;
514/619 |
International
Class: |
A61K 31/165 20060101
A61K031/165; A61K 45/06 20060101 A61K045/06 |
Claims
1. A method for a prevention and/or treatment of irritable bowel
syndrome or amelioration of a symptom thereof in a subject,
comprising administering to said subject an effective amount of a
compound of formula I: ##STR00015## wherein n is an integer
selected from 1 or 2; X is a C.sub.1-C.sub.6 alkylene group; Y is
--N(R).sub.2 wherein each R is independently selected from hydrogen
or C.sub.1-C.sub.6 alkyl, or two R along with the nitrogen bound
thereto join together to form a 3 to 7 membered heterocyclic ring
optionally containing an oxygen atom; and * represents a carbon
atom in an R configuration, an S configuration, or a mixture
thereof, a metabolite thereof, a prodrug thereof, or a
pharmaceutically acceptable salt of any of the foregoing.
2. The method of claim 1, wherein the compound is of formula II:
##STR00016## wherein n is an integer selected from 1 or 2; X is a
C.sub.1-C.sub.6 alkylene group; and Y is --N(R).sub.2 wherein each
R is independently selected from hydrogen or C.sub.1-C.sub.6 alkyl,
or two R along with the nitrogen bound thereto join together to
form a 3 to 7 membered heterocyclic ring optionally containing an
oxygen atom; a metabolite thereof, a prodrug thereof, or a
pharmaceutically acceptable salt of any of the foregoing.
3. The method of claim 1, wherein the compound is of formula III:
##STR00017## a metabolite thereof, a prodrug thereof, or a
pharmaceutically acceptable salt of any of the foregoing.
4. The method of claim 1, wherein the metabolite is of formula IV:
##STR00018## wherein n is an integer selected from 1 or 2; X is a
C.sub.1-C.sub.6 alkylene group; and * represents a carbon atom in
an R configuration, an S configuration, or a mixture thereof, or a
pharmaceutically acceptable salt thereof.
5. A method for a prevention and/or treatment of irritable bowel
syndrome or amelioration of a symptom thereof in a subject,
comprising administering to said subject an effective amount of a
compound of formula V: ##STR00019##
6. The method of claim 1, wherein the subject is a female or male
mammal.
7. The method of claim 1, further comprising administering to the
subject one or more of a drug selected from the group consisting of
non-steroidal anti-inflammatory drug, antibiotic, probiotics,
anti-prostaglandin, COX-2 inhibitor, local anesthetic, laxative,
anti-diarrhea medicine, anti-spasmodic, and anti-depressant.
8. The method of claim 7, wherein the drug is administered
concomitantly or sequentially to said composition.
9. The method of claim 1, wherein the administration is oral.
10. The method of claim 9, wherein the compound is in a form of a
tablet, capsule, gel or solution.
11. The method of claim 1, wherein the administration is parenteral
selected from intravenous, intramuscular, intraarterial,
percutaneous, or subcutaneous.
12. The method of claim 1, wherein the administration is
transdermal.
13. The method of claim 1, wherein the prodrug is selected from the
group consisting of compounds wherein hydroxyl or amine groups are
bonded to a group that, when administered to a subject, cleaves to
form a free hydroxyl or amine group, respectively.
14. The method of claim 1, wherein the prodrug is selected from the
group consisting of acetate, formate, benzoate and phosphate ester
derivatives of hydroxyl functional group, and acetyl and benzoyl
derivatives of amine functional group.
15. The method of claim 1, wherein the pharmaceutically acceptable
salt is an acid addition salt wherein the acid is selected from the
group consisting of hydrochloric, sulfuric, phosphoric, acetic,
citric, oxalic, malonic, salicyclic, malic, gluconic, fumaric,
succinic, ascorbic, maleic, and methanesulfonic acid.
16. The method of claim 1, wherein the compound is in a composition
comprising a pharmaceutically acceptable carrier.
17. The method of claim 1, wherein the compound is administered in
a dose of about 0.0001 to about 500 mg per kilogram of body weight
per day.
18. The method of claim 1, wherein the administration of the
compound reduces the incidence of one or more adverse side effects
in the subject.
19. The method of claim 18, wherein the number of incidences of the
one or more of adverse side effects in the subject is reduced
compared to the number of such incidences, which would have been
observed in the subject with the administration of terbutaline,
ritodrine, or meluadrine.
20. The method of claim 18, wherein the one or more adverse side
effects are selected from palpitations; peripheral tremors;
increased heart rate; decreased blood pressure; pulmonary edema;
hypoglycemia; aggravation of preexisting diabetes; aggravation of
preexisting keto acidosis; tremors; nervousness; dizziness;
headaches; drowsiness; vomiting; nausea; sweating; muscle cramps;
and electrocardiogram (ECG) changes.
21. The method of claim 18, wherein the number of incidences of
increased heart rate, increased tremors, decrease in mean blood
pressure, or all in the subject is reduced compared to the number
of such incidences, which would have been observed in the subject
with the administration of terbutaline.
Description
RELATED APPLICATIONS
[0001] This application claims priority to U.S. provisional
application No. 61/322,201 filed on Apr. 8, 2010, which is
incorporated herein by reference.
FIELD OF THE INVENTION
[0002] The present technology relates to compositions, devices and
methods for the treatment of irritable bowel syndrome and is
generally related to the field of medicine, pharmacology, molecular
biology, and chemistry.
BACKGROUND OF THE INVENTION
[0003] Irritable bowel syndrome (IBS) is one of the common ailments
of the bowel (intestines) and affects an estimated 15% of people in
the US. Other names for IBS include, but are not limited to,
spastic colon, spastic colitis, and mucous colitis.
[0004] IBS may be due to the abnormal function of the muscles of
the organs of the gastrointestinal tract or the nerves controlling
the organs. The abnormal function of the nervous system in IBS may
occur in a gastrointestinal muscular organ, the spinal cord, or the
brain. The abnormalities may occur in the sensory nerves, the motor
nerves, or at processing centers in the intestine, spinal cord, or
brain. Normal activities, such as stretching of the small intestine
by food, may give rise to abnormal sensory signals that are sent to
the spinal cord and brain, where they are perceived as pain.
Abnormal commands through the motor nerves may also produce a
painful spasm (contraction) of the muscles. Therefore, IBS may be
due to sensory dysfunction, motor dysfunction, or both sensory and
motor dysfunction.
[0005] IBS normally causes cramping, abdominal pain, bloating,
constipation, diarrhea, etc. IBS may not lead to more serious
conditions in most patients, but it is a source of chronic pain,
fatigue and other symptoms. It increases a patient's medical cost
and may contribute to work absenteeism. The high prevalence of IBS
in conjunction with increased costs may produce a disease with a
high societal cost. It is also regarded as a chronic illness and
can dramatically affect the quality of a sufferer's life.
[0006] Thus, there exists a need for an effective and safe
treatment of irritable bowel syndrome.
SUMMARY OF THE INVENTION
[0007] Disclosed herein are methods, compositions, and devices for
the treatment of irritable bowel syndrome.
[0008] In one aspect, there is provided a method for a prevention
and/or treatment of irritable bowel syndrome or amelioration of a
symptom thereof in a subject, comprising administering to said
subject an effective amount of a compound of formula I:
##STR00002##
wherein [0009] n is an integer selected from 1 or 2; [0010] X is a
C.sub.1-C.sub.6 alkylene group; [0011] Y is --N(R).sub.2 wherein
each R is independently selected from hydrogen or C.sub.1-C.sub.6
alkyl, or two R along with the nitrogen bound thereto join together
to form a 3 to 7 membered heterocyclic ring optionally containing
an oxygen atom; and [0012] * represents a carbon atom in an R
configuration, an S configuration, or a mixture thereof, a
metabolite thereof, a prodrug thereof, or a pharmaceutically
acceptable salt of any of the foregoing.
[0013] In one aspect, there is provided a method for a prevention
and/or treatment of irritable bowel syndrome or amelioration of a
symptom thereof in a subject, comprising administering to said
subject an effective amount of a compound of formula V:
##STR00003##
DETAILED DESCRIPTION OF THE INVENTION
1. Definitions
[0014] It must be noted that as used herein, and in the appended
claims, the singular forms "a," "an" and "the" include plural
references unless the context clearly dictates otherwise.
[0015] 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 materials similar or equivalent to those
described herein can be used in the practice or testing of the
present invention, the preferred methods, devices, and materials
are now described. All publications cited herein are incorporated
herein by reference in their entirety for the purpose of describing
and disclosing the methodologies, reagents, and tools reported in
the publications that 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.
[0016] The practice of the present invention will employ, unless
otherwise indicated, conventional methods of chemistry,
biochemistry, molecular biology, cell biology, genetics,
immunology, and pharmacology, within the skill of the art. Such
techniques are explained fully in the literature. (See, e.g.,
Gennaro, A. R., ed. (1990) Remington's Pharmaceutical Sciences,
18.sup.th ed., Mack Publishing Co.; Colowick, S. et al., eds.,
Methods In Enzymology, Academic Press, Inc.; D. M. Weir, and C. C.
Blackwell, eds. (1986) Handbook of Experimental Immunology, Vols.
I-IV, Blackwell Scientific Publications; Maniatis, T. et al., eds.
(1989) Molecular Cloning: A Laboratory Manual, 2.sup.nd edition,
Vols. I-III, Cold Spring Harbor Laboratory Press; Ausubel, F. M. et
al., eds. (1999) Short Protocols in Molecular Biology, 4.sup.th
edition, John Wiley & Sons; Ream et al., eds. (1998) Molecular
Biology Techniques: An Intensive Laboratory Course, Academic Press;
Newton & Graham eds. (1997) PCR (Introduction to Biotechniques
Series), 2nd ed., Springer Verlag).
[0017] An "administration" or "administering," refers to the
delivery of a medication, such as the composition of the invention
to an appropriate location of the subject or in vitro, where a
desired effect is achieved. Non-limiting examples include topical,
oral, parenteral, direct application to target area or proximal
areas on the skin, or applied transdermally such as a patch.
Various physical and/or mechanical technologies are available to
permit the sustained or immediate release of the composition after
administration.
[0018] A "C.sub.1-C.sub.6 alkyl" refers to saturated monovalent
hydrocarbyl groups having from 1 to 6 carbon atoms, more
particularly from 1 to 5 carbon atoms, and even more particularly 1
to 3 carbon atoms. This term is exemplified by groups such as
methyl, ethyl, n-propyl, iso-propyl, n-butyl, t-butyl, n-pentyl and
the like.
[0019] A "C.sub.1-C.sub.6 alkylene" refers to divalent saturated
aliphatic hydrocarbyl groups having from 1 to 6 carbon atoms and,
in some embodiments, from 1 to 3 carbon atoms. The alkylene groups
include branched and straight chain hydrocarbyl groups. Examples
include methylene (--CH.sub.2--), ethylene, propylene,
2-methypropylene, pentylene and the like.
[0020] A "compound" herein refers to a compound utilized according
to the invention, a pharmaceutically acceptable salt thereof, a
metabolite thereof, a prodrug thereof, a pharmaceutically
acceptable salt of the metabolite thereof, or a pharmaceutically
acceptable salt of the prodrug thereof. The compounds include
stereoisomeric forms and the tautomeric forms of the compounds.
[0021] A "comprising" is intended to mean that the compositions and
methods include the recited elements, but not excluding others.
"Consisting essentially of" when used to define compositions and
methods, shall mean excluding other elements of any essential
significance to the combination for the stated purpose. Thus, a
composition consisting essentially of the elements as defined
herein would not exclude trace contaminants from the isolation and
purification method and pharmaceutically acceptable carriers, such
as phosphate buffered saline, preservatives and the like.
"Consisting of" shall mean excluding more than trace elements of
other ingredients and substantial method steps for administering
the compositions of this invention or process steps to produce a
composition or achieve an intended result. Embodiments defined by
each of these transition terms are within the scope of this
invention.
[0022] An "effective amount" or a "therapeutically effective
amount" is an amount sufficient to effect beneficial or desired
results, e.g., alleviation, amelioration, palliation or elimination
of one or more manifestations of IBS in the subject. The full
therapeutic effect may occur in one dose; may not necessarily occur
by administration of one dose (or dosage); and may occur only after
administration of a series of doses. Thus, a therapeutically
effective amount may be administered in one or more
administrations, applications or dosages.
[0023] A "heterocycle" or "heterocyclic" refers to a saturated or
unsaturated (but not aromatic) group having a single ring or
multiple condensed rings, from 3 to 6 carbon atoms, and from 1 to 4
hetero atoms selected from the group consisting of nitrogen or
oxygen within the ring wherein, in fused ring systems, one or more
of the rings can be aryl or heteroaryl provided that the point of
attachment is at the heterocycle. The nitrogen ring atoms can
optionally be oxidized to provide for the N-oxide derivatives.
Examples of heterocycles include, but are not limited to,
azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine,
pyrimidine, pyridazine, etc.
[0024] A "metabolite" refers to any substance that is produced as
an intermediate or a product after the metabolism of the compound
utilized according to the invention. Examples of metabolites
include, but are not limited to, acid metabolized from the amide
moiety, amine metabolized from the substituted amide moiety,
alcohol metabolized from alkoxy moiety, and the like. A
representative carboxylic acid metabolite, is described in U.S.
Pat. No. 6,136,852, the disclosure of which is incorporated herein
by reference in its entirety.
[0025] A "subject" or "patient" is a female or male mammal,
including a human. Non-human animals subject to diagnosis or
treatment include, for example, murine, such as rats, mice, canine,
such as dogs, leporids, such as rabbits, livestock, sport animals,
and pets.
[0026] A "pharmaceutically acceptable carrier" encompasses any of
the standard pharmaceutical carriers, such as a phosphate buffered
saline solution, water, and emulsions, such as an oil/water or
water/oil emulsion, and various types of wetting agents. The
compositions also can include stabilizers and preservatives. For
examples of carriers, stabilizers and adjuvants, see Martin,
Remington's Pharm. Sci., 15th Ed. (Mack Publ. Co., Easton (1975)).
The term includes carriers that facilitate controlled release of
the active agent as well as immediate release.
[0027] A "pharmaceutically acceptable salt" refers to
pharmaceutically acceptable salts of a compound, which salts are
derived from a variety of organic, and inorganic counter ions well
known in the art. When the molecule contains a basic functionality,
salts include, by way of example only, sodium, potassium, calcium,
magnesium, ammonium, tetraalkylammonium, and the like. When the
molecule contains a basic functionality, salts of organic or
inorganic acids include, such as hydrochloric, sulfuric,
phosphoric, acetic, citric, oxalic, malonic, salicyclic, malic,
gluconic, fumaric, succinic, ascorbic, maleic, methanesulfonic
acid, etc.
[0028] A "prodrug", as used herein, refers to any covalently bonded
carrier which releases the active parent drug in vivo when such
prodrug is administered to a subject. Prodrugs of a compound are
prepared by modifying functional groups present in the compounds in
such a way that the bonds are cleaved, either in routine
manipulation or in vivo, to the parent compounds. Prodrugs include,
but are not limited to, compounds wherein hydroxyl or amine groups
are bonded to any group that, when administered to a subject,
cleave to form a free hydroxyl or amino, group, respectively.
Examples of prodrugs include, but are not limited to, acetate,
formate, benzoate and phosphate ester derivatives of hydroxyl
functional groups, especially the hydroxyl group on the phenyl ring
of formula I, and acetyl and benzoyl derivatives of amine
functional groups in the compounds utilized according to the
invention and the like.
[0029] A "treating," "treatment" and the like refer to obtaining a
desired pharmacologic and/or physiologic effect. The effect can be
prophylactic in terms of completely or partially preventing a
disease or disorder or sign or symptom thereof, and/or can be
therapeutic in terms of a partial or complete cure for a disorder
and/or adverse effect attributable to the disorder. Examples of
"treatment" include but are not limited to: preventing a disease
from occurring in a subject that may be predisposed or at risk of a
disease, but has not yet been diagnosed as having it; inhibiting a
disease, i.e., arresting its development; and/or relieving or
ameliorating the symptoms of disease or reducing the likelihood of
recurrence of the disease, such as IBS. As is understood by those
skilled in the art, "treatment" can include systemic amelioration
of the symptoms associated with the pathology and/or a delay in
onset of symptoms.
2. Methods of the Invention
[0030] In one aspect, there is provided a method for a prevention
and/or treatment of irritable bowel syndrome or amelioration of a
symptom thereof in a subject, comprising administering to the
subject an effective amount of a compound, as provided herein.
[0031] Irritable bowel syndrome (IBS or spastic colon) may be a
functional bowel disorder characterized by chronic abdominal pain,
discomfort, bloating, and alteration of bowel habits. In some
cases, the symptoms are relieved by bowel movements. Diarrhea or
constipation may be a predominant symptom of IBS that may alternate
in the patient, i.e., an incidence of diarrhea may be followed by
an incidence of constipation which may be followed by an incidence
of diarrhea. IBS may begin after an infection, a stressful life
event, or onset of maturity without any other medical
indicators.
[0032] IBS may be classified as either diarrhea-predominant
(IBS-D), constipation-predominant (IBS-C) or IBS with alternating
stool pattern (IBS-A or pain-predominant). In some subjects, IBS
may have an acute onset and develop after an infectious illness
characterized by two or more of the following: fever, vomiting,
diarrhea, or positive stool culture. This post-infective syndrome
is called "post-infectious IBS" (IBS-PI). Several other conditions
may be related to IBS including, but are not limited to, celiac
disease, mild infections, parasitic infections like giardiasis,
inflammatory bowel disease, functional chronic constipation, and
chronic functional abdominal pain. It is to be understood that the
treatment of IBS disclosed herein, includes the treatment of
various types of IBS, symptoms of IBS, and other secondary diseases
caused by or related to IBS.
[0033] The common symptoms of IBS resemble symptoms of other
conditions or medical problems, such as, but are not limited to,
nausea, vomiting, diarrhea, constipation, abdominal bloating (the
sensation of abdominal fullness), flatulence, abdominal distention
(enlargement), and pain. The symptom of rapid transportation of
food may be diarrhea and slow transportation of food may be
constipation. In addition, there may be increased amounts of mucus
coating the stool or a sense of incomplete evacuation after a bowel
movement.
[0034] IBS may be diagnosed based on the symptoms, including the
frequency of the abdominal pain or discomfort during the past year
or month or week; the beginning and the end of the pain in relation
to bowel function; and the change in the bowel frequency and stool
consistency. Several diagnostic tests may be performed to diagnose
IBS. These tests include, but are not limited to, stool sample
testing, blood tests, x-rays, endoscopy such as, sigmoidoscopy,
colonoscopy, etc., abdominal ultrasonography (US), computerized
tomography (CT or CAT scans), or magnetic resonance imaging
(MRI).
[0035] The dosage and the regimen for the treatment for IBS using
the compositions and methods of the invention can depend on age,
overall health, and medical history; extent of the condition; cause
of the condition (primary or secondary); and tolerance for specific
medications, procedures, or therapies.
[0036] Accordingly, in some embodiments, there is provided a method
for a prevention and/or treatment of irritable bowel syndrome or
amelioration of a symptom thereof in a subject, comprising
administering to said subject an effective amount of a compound of
formula I:
##STR00004##
wherein [0037] n is an integer selected from 1 or 2; [0038] X is a
C.sub.1-C.sub.6 alkylene group; [0039] Y is --N(R).sub.2 wherein
each R is independently selected from hydrogen or C.sub.1-C.sub.6
alkyl, or two R along with the nitrogen bound thereto join together
to form a 3 to 7 membered heterocyclic ring optionally containing
an oxygen atom; and [0040] * represents a carbon atom in an R
configuration, an S configuration, or a mixture thereof, [0041] a
metabolite thereof, a prodrug thereof, or a pharmaceutically
acceptable salt of any of the foregoing.
[0042] In some embodiments, there is provided a method for a
prevention and/or treatment of irritable bowel syndrome or
amelioration of a symptom thereof in a subject, comprising
administering to said subject an effective amount of a compound of
formula II:
##STR00005##
wherein [0043] n is an integer selected from 1 or 2; [0044] X is a
C.sub.1-C.sub.6 alkylene group; and [0045] Y is --N(R).sub.2
wherein each R is independently selected from hydrogen or
C.sub.1-C.sub.6 alkyl, or two R along with the nitrogen bound
thereto join together to form a 3 to 7 membered heterocyclic ring
optionally containing an oxygen atom; [0046] a metabolite thereof,
a prodrug thereof, or a pharmaceutically acceptable salt of any of
the foregoing.
[0047] In some embodiments, there is provided a method for a
prevention and/or treatment of irritable bowel syndrome or
amelioration of a symptom thereof in a subject, comprising
administering to said subject an effective amount of a compound of
formula III:
##STR00006## [0048] a metabolite thereof, a prodrug thereof, or a
pharmaceutically acceptable salt of any of the foregoing.
[0049] In some embodiments, there is provided a method for a
prevention and/or treatment of irritable bowel syndrome or
amelioration of a symptom thereof in a subject, comprising
administering to said subject an effective amount of a metabolite
of formula IV:
##STR00007##
wherein [0050] n is an integer selected from 1 or 2; [0051] X is a
C.sub.1-C.sub.6 alkylene group; and [0052] * represents a carbon
atom in an R configuration, an S configuration, or a mixture
thereof, [0053] or a pharmaceutically acceptable salt thereof.
[0054] In some embodiments, there is provided a method for a
prevention and/or treatment of irritable bowel syndrome or
amelioration of a symptom thereof in a subject, comprising
administering to said subject an effective amount of a compound of
formula V:
##STR00008##
[0055] In one aspect, the present invention provides a method for
treating a human subject suffering from irritable bowel syndrome.
In some embodiments, the human subject is female. In some
embodiments, the human subject is male.
[0056] The treatments that may be used in conjunction with the
methods of the invention to relieve symptoms of IBS, include, but
are not limited to, dietary adjustments, drugs and psychological
interventions. The drugs include, but are not limited to, such as
laxatives, anti-diarrhea medicines, anti-spasmodics, or
anti-depressants.
[0057] In some embodiments, the methods provided herein further
comprise administering to the subject one or more of a drug
selected from the group consisting of non-steroidal
anti-inflammatory drug, antibiotic, probiotics, anti-prostaglandin,
COX-2 inhibitor, local anesthetic, laxative, anti-diarrhea
medicine, anti-spasmodic, and anti-depressant. The methods of the
invention may be accompanied with life style changes such as,
reduced stress, exercise, and change in the diet.
[0058] Non-limiting examples of non-steroidal anti-inflammatory
drugs suitable for use in the method of the invention include, but
are not limited to, aspirin, ibuprofen, indomethacin,
phenylbutazone, bromfenac, fenamate, sulindac, nabumetone,
ketorolac, and naproxen. Examples of antibiotics include, but are
not limited to, rifaximin and neomycin. Examples of probiotics
include, but are not limited to, VSL#3, Flora-Q or bifidobacterium
infantis 35624. Examples of local anesthetics include, but are not
limited to, lidocaine, mepivacaine, etidocaine, bupivacaine,
2-chloroprocaine hydrochloride, procaine, and tetracaine
hydrochloride. Examples of COX-2 inhibitors include, but are not
limited to, celecoxib, meloxicam and flosulide. Examples of
laxatives include, but are not limited to, dietary fiber and
osmotic laxatives such as polyethylene glycol, sorbitol, and
lactulose. Examples of anti-diarrheal medicines include, but are
not limited to, opiate, opioid or opioid analogs such as
loperamide, codeine, diphenoxylate. Examples of anti-spasmodic
include, but are not limited to, anticholinergics such as
hyoscyamine or dicyclomine. Examples of anti-depressants include,
but are not limited to, selective serotonin reuptake inhibitor
anti-depressants (SSRIs). A synergistic effect may be achieved by
using a combination of the compound utilized according to the
invention with the drugs recited above.
[0059] In some embodiments, the compound utilized according to the
invention and optionally the above recited drug is in combination
with a biocompatible excipient provided herein. In some
embodiments, the compound utilized according to the invention is
present in an amount sufficient to attain a therapeutically
effective amount of the compound in the intestinal muscle of the
subject upon administration.
[0060] In some embodiments, the administration of the compound
utilized according to the invention to the subject results in
reduced, negligible, or no adverse side effects. Typically, the
side effects of common .beta.-adrenergic agonists include, but are
not limited to, cardiovascular such as palpitations, peripheral
tremors, increased heart rate, decreased blood pressure; pulmonary
edema and hypoglycemia; aggravation of preexisting diabetes and
keto acidosis; tremors; nervousness; palpitations; dizziness;
headaches; drowsiness; vomiting; nausea; sweating; muscle cramps;
and ECG changes. In some embodiments, the use of the compounds
utilized according to the invention reduces or eliminates one or
more of the above-noted side effects. It is important to note that
such reduced, negligible, or lack of adverse side effects may be
especially manifest when comparing the outcomes using the compounds
of the invention with outcomes using other .beta.-adrenergic
agonists, including but not limited to one or more of HSR-81,
terbutaline, ritodrine, isoproterenol, or pharmaceutically
acceptable salts thereof.
[0061] Accordingly, in the methods provided herein, the
administration of the compound reduces the incidence of one or more
adverse side effects in the subject. In some embodiments, the
number of incidences of the one or more of adverse side effects in
the subject is reduced with the administration of the compound
utilized according to the invention as compared to the number of
such incidences, which would have been observed in the subject with
the administration of terbutaline, ritodrine, or meluadrine. In
some embodiments, the .beta.-adrenergic agonist is terbutaline
sulfate, ritodrine hydrochloride, or HSR-81. In some embodiments,
the administration of the compound utilized according to the
invention reduces the incidence of one or more adverse side effects
in the subject as compared to terbutaline. In some embodiments, the
number of incidences of increased heart rate, increased tremors,
decrease in mean blood pressure, or all in the subject after the
administration of the compound utilized according to the invention
is reduced compared to the number of such incidences, which would
have been observed in the subject with the administration of
terbutaline. See Lyrenas et al. Scand J Gastroenterol 20:1163-1168
(1985); Lyrenas et al. Scand J Gastroenterol 28:907-910 (1993).
[0062] The reduction of one or more of the adverse side effects by
the compound utilized according to the invention is more than 10%
reduction; or alternatively more than 20% reduction; or
alternatively more than 30% reduction; or alternatively more than
40% reduction; or alternatively more than 50% reduction; or
alternatively more than 60% reduction; or alternatively more than
70% reduction; or alternatively more than 80% reduction; or
alternatively more than 90% reduction; or alternatively more than
99% reduction; or alternatively complete reduction of the adverse
side effect. In some embodiments, the above recited reduction in
the one or more of the adverse side effects is as compared to the
adverse side effects of other .beta.-adrenergic agonists. In some
embodiments, the above recited reduction in the one or more of the
adverse side effects is as compared to the adverse side effects of
terbutaline.
[0063] Typically, the .beta.-adrenergic agonists suffer from a
short half life or low bioavailability. In some embodiments, the
compounds of the invention have a longer half life or higher
bioavailability as compared to other .beta.-adrenergic agonists,
such as but not limited to, terbutaline.
3. Compounds Used in the Invention
[0064] The compounds that are used in the methods, compositions,
and devices of the invention are as follows.
[0065] In one aspect, the compound is of formula I:
##STR00009##
wherein [0066] n is an integer selected from 1 or 2; [0067] X is a
C.sub.1-C.sub.6 alkylene group; [0068] Y is --N(R).sub.2 wherein
each R is independently selected from hydrogen or C.sub.1-C.sub.6
alkyl, or two R along with the nitrogen bound thereto join together
to form a 3 to 7 membered heterocyclic ring optionally containing
an oxygen atom; and [0069] * represents a carbon atom in an R
configuration, an S configuration, or a mixture thereof, [0070] a
metabolite thereof, a prodrug thereof, or a pharmaceutically
acceptable salt of any of the foregoing.
[0071] In one aspect, the compound is of formula II:
##STR00010##
wherein [0072] n is an integer selected from 1 or 2; [0073] X is a
C.sub.1-C.sub.6 alkylene group; and [0074] Y is --N(R).sub.2
wherein each R is independently selected from hydrogen or
C.sub.1-C.sub.6 alkyl, or two R along with the nitrogen bound
thereto join together to form a 3 to 7 membered heterocyclic ring
optionally containing an oxygen atom; [0075] a metabolite thereof,
a prodrug thereof, or a pharmaceutically acceptable salt of any of
the foregoing.
[0076] In one aspect, the compound is of formula III:
##STR00011##
a metabolite thereof, a prodrug thereof, or a pharmaceutically
acceptable salt of any of the foregoing.
[0077] In one aspect, the metabolite is of formula IV:
##STR00012##
wherein [0078] n is an integer selected from 1 or 2; [0079] X is a
C.sub.1-C.sub.6 alkylene group; and [0080] * represents a carbon
atom in an R configuration, an S configuration, or a mixture
thereof, [0081] or a pharmaceutically acceptable salt thereof.
[0082] In some embodiments, the compound is of formula V:
##STR00013##
[0083] In some embodiments of the above recited aspects, X is a
C.sub.1-C.sub.3 alkylene group. In some embodiments of the above
recited aspects, X is a --CH.sub.2-- group.
[0084] In some embodiments of the above recited aspects, Y is
--N(R).sub.2 wherein each R is hydrogen.
[0085] In some embodiments of the above recited aspects, Y is
--N(R).sub.2 wherein each R is C.sub.1-C.sub.6 alkyl. In some
embodiments of the above recited aspects, Y is --N(R).sub.2 wherein
each R is C.sub.1-C.sub.2 alkyl. In some embodiments of the above
recited aspects, Y is --N(R).sub.2 wherein each R is methyl. In
some embodiments of the above recited aspects, Y is --NHR wherein R
is C.sub.1-C.sub.2 alkyl.
[0086] In some embodiments of the above recited aspects, Y is
--N(R).sub.2 wherein two R along with the nitrogen bound thereto
join together to form a 3 to 7 membered heterocyclic ring
optionally containing an oxygen atom.
[0087] In some embodiments of the above recited aspects, *
represents a carbon atom in R configuration. In some embodiments of
the above recited aspects, * represents a carbon atom in S
configuration. In some embodiments of the above recited aspects, *
represents a carbon atom which is a mixture of R and S
configuration.
[0088] In some embodiments of the above recited aspects, n is 1. In
some embodiments of the above recited aspects, n is 2.
[0089] The compounds utilized according to the invention can exist
in unsolvated as well as solvated forms, including hydrated forms.
In general, the solvated forms, including hydrated forms and the
like are equivalent to the unsolvated forms for purposes of the
invention.
[0090] In some embodiments, the compound is in a form of a prodrug
wherein the prodrug is selected from the group consisting of
compounds wherein hydroxyl or amine groups are bonded to a group
that, when administered to a subject, cleaves to form a free
hydroxyl or amine group, respectively. In some embodiments, the
prodrug is selected from the group consisting of acetate, formate,
benzoate and phosphate ester derivatives of hydroxyl functional
group, and acetyl and benzoyl derivatives of amine functional
group.
[0091] In some embodiments, the compound or the prodrug thereof is
in a form of a pharmaceutically acceptable salt thereof wherein the
pharmaceutically acceptable salt thereof is an acid addition salt
wherein the acid is selected from the group consisting of
hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic,
malonic, salicyclic, malic, gluconic, fumaric, succinic, ascorbic,
maleic, and methanesulfonic acid. In some embodiments, the
pharmaceutically acceptable salt thereof is sulfuric acid.
[0092] In some embodiments, the compound is a metabolite of a
compound of formula I, II, III, IV, or V, where metabolites are as
described herein. In some embodiments, the compound is a
pharmaceutically acceptable salt of the metabolite of the compound,
where pharmaceutically acceptable salts are as described
herein.
[0093] The compounds of the invention can be synthesized using
routine synthetic chemistry known to one skilled in the art. For
example, the syntheses of the compounds of the invention and their
experimental data are described in U.S. Pat. No. 6,133,266 and U.S.
Pat. No. 6,136,852, which are incorporated herein by reference in
their entirety.
4. Pharmaceutical Compositions, Devices and Dosages
[0094] In one aspect, the compound utilized according to present
invention are administered as a composition comprising the compound
and a pharmaceutically acceptable carrier. The compounds utilized
according to the invention can be administered in admixture with
conventional excipients, such as, pharmaceutically acceptable
liquid, semi-liquid or solid organic or inorganic carriers, which
do not deleteriously react with the active compound in admixture
therewith. Suitable pharmaceutically acceptable carriers include
but are not limited to water, salt solutions, alcohols, vegetable
oils, polyethylene glycols, gelatin, lactose, amylose, magnesium
stearate, talc, silicic acid, viscous paraffin, perfume oil, fatty
acid monoglycerides and diglycerides, pentaerythritol fatty acid
esters, hydroxy methylcellulose, polyvinyl pyrrolidone, etc.
[0095] The pharmaceutical preparations can be sterilized and if
desired mixed with auxiliary agents, e.g., lubricants,
preservatives, stabilizers, wetting agents, emulsifiers, salts for
influencing osmotic pressure, buffers, coloring, flavoring, and/or
aromatic substances and the like which do not deleteriously react
with the active compounds.
[0096] Various delivery systems are known and can be used to
administer the compounds or compositions of the invention,
including, for example, encapsulation in liposomes, microbubbles,
emulsions, microparticles, microcapsules and the like. The required
dosage can be administered as a single unit or in a sustained
release form.
[0097] In some embodiments, the composition is administered as a
formulation suitable for parenteral routes of administration, such
as intravenous, intramuscular, percutaneous, and subcutaneous
administration. For parenteral application, particularly suitable
are solutions, preferably oily or aqueous solutions, as well as
suspensions, emulsions, or implants, including suppositories.
[0098] In a related embodiment, the intravenous formulation
comprises approximately 0.20 mg to about 20 mg; or alternatively
about 0.20 mg to about 10 mg; or alternatively about 0.20 mg to
about 5 mg; or alternatively about 0.20 mg to about 3 mg; or
alternatively about 0.20 mg to about 2 mg; or alternatively about
0.20 mg to about 1 mg; of the compound utilized according to the
invention in an aqueous delivery system. The aqueous delivery
system may comprise about 0.02% to about 0.5% (w/v) of an acetate,
phosphate, or citrate buffer. In another aspect, the formulation
has a pH of about 3.0 to about 7.0. In a related aspect, the
concentration of the compound in the intravenous formulation falls
in the range of about 0.15 .mu.mol/mL to about 0.25 .mu.mol/mL.
[0099] In some embodiments, the subject is administered an amount
of the compound in the range of about 3 .mu.g/kg patient (or about
200 .mu.g per patient) to about 60 .mu.g/kg patient (or about 4 mg
per patient). The dosage may be administered intravenously as a
single bolus injection to the subject, or as single bolus injection
followed by a constant infusion for up to 24, 36, 48, or 72 hours,
or as a constant infusion for up to 24, 36, 48, or 72 hours. The
dosage may be administered subcutaneously or intravenously at
intervals not less than 4 hours and for up to 24, 36, 48, or 72
hours. In some embodiments, the subject is administered
intravenously for 15 minutes at about 40 .mu.g/min and then about
45 minutes at about 13 .mu.g/min. In yet another embodiment, the
subjects are those who have been admitted to an emergency room.
[0100] In some embodiments, the intravenous formulation is
reconstituted from a freeze-dried drug product comprising the
compound. In another embodiment, the freeze-dried drug product
further comprises carbohydrate and/or polyhydric alcohols. The
carbohydrate may be mannose, ribose, trehalose, maltose, inositol,
lactose, or the like. The polyhydric alcohols may be sorbitol,
mannitol, or the like.
[0101] In certain embodiments within the various aspects and
embodiments of the present invention, the compound is administered
by infusion. In one embodiment, the infusion is performed at a rate
of about 3 .mu.g (.mu.gm or .mu.g)/minute to about 60 .mu.g/min;
about 6 .mu.g/minute to about 30 .mu.g/minute; about 12
.mu.g/minute to about 15 .mu.g/minute; about 7 .mu.g/minute to
about 18 .mu.g/minute; about 9 .mu.g/minute; about 13 .mu.g/minute;
and about 16 .mu.g/minute.
[0102] The compound is formulated as a liquid formulation for
administration in accordance with the various aspects and
embodiments of the present invention. In some embodiments, the
liquid formulation comprises the compound in an amount of about 3
.mu.g/mL to about 60 .mu.g/mL, about 6 .mu.g/mL to about 30
.mu.g/mL, and about 12 .mu.g/mL to about 30 .mu.g/mL, and about 15
.mu.g/mL to about 20 .mu.g/mL. In another embodiment, the liquid
formulation further comprises dextrose. In another embodiment, the
liquid formulation is an aqueous formulation. In another
embodiment, the liquid formulation is suitable for intravenous
injection or infusion.
[0103] In the various aspects and embodiments of the present
invention, the compound is used as a 2 mg, unit dose, lyophilized
drug product. Other unit dose forms in the range of about 0.2 mg to
about 20 mg are also contemplated. In one embodiment, the
lyophilized drug product further comprises lactose.
[0104] In one aspect, the compositions of the invention are
delivered topically. Topical administration can involve the use of
transdermal administration such as transdermal patches or
iontophoresis devices. Dosage forms for topical administration of
the compounds and compositions can include creams, sprays, lotions,
gels, ointments, and the like. In such dosage forms, the
compositions of the invention can be mixed to form white, smooth,
homogeneous, opaque cream or lotion with, for example, benzyl
alcohol 1% or 2% (wt/wt) as a preservative, emulsifying wax,
glycerin, isopropyl palmitate, lactic acid, purified water and
sorbitol solution. In addition, the compositions can contain
polyethylene glycol 400. They can be mixed to form ointments with,
for example, benzyl alcohol 2% (wt/wt) as preservative, white
petrolatum, emulsifying wax, and tenox II (butylated
hydroxyanisole, propyl gallate, citric acid, propylene glycol).
[0105] The compositions can also be applied topically using a
transdermal system, such as one of an acrylic-based polymer
adhesive with a resinous cross-linking agent impregnated with the
composition and laminated to an impermeable backing. In some
embodiments, the compositions utilized according to the present
invention are administered in the form of a transdermal patch, such
as in the form of a sustained-release transdermal patch. In some
embodiments, the compositions utilized according to the present
invention are administered in a form of a five day transdermal
patch.
[0106] The transdermal patches utilized according to the present
invention can include any conventional form such as, for example,
adhesive matrix, polymeric matrix, reservoir patch, matrix or
monolithic-type laminated structure, and are generally comprised of
one or more backing layers, adhesives, penetration enhancers, an
optional rate controlling membrane and a release liner which is
removed to expose the adhesives prior to application. Polymeric
matrix patches also comprise a polymeric-matrix forming
material.
[0107] In some embodiments, the transdermal patches comprise a
therapeutically effective amount of the composition of the
invention and optionally an antioxidant. Examples of antioxidants
include, but are not limited to, hydralazine compounds,
glutathione, vitamin C, vitamin E, cysteine, N-acetyl-cysteine,
.beta.-carotene, ubiquinone, ubiquinol-10, tocopherols, coenzyme Q,
and the like. Suitable antioxidant enzymes include, but are not
limited to, superoxide dismutase, catalase, glutathione peroxidase,
and the like. Suitable antioxidants are described more fully in the
literature, such as in Goodman and Gilman, The Pharmacological
Basis of Therapeutics (9th Edition), McGraw-Hill, 1995; and the
Merck Index on CD-ROM, Twelfth Edition, Version 12:1, 1996).
[0108] In some embodiments, the composition, the transdermal patch,
or the delivery device can be a controlled release composition.
Non-limiting examples of a suitable biocompatible excipient for
applying the compound include a lipophilic carrier or a hydrophilic
carrier. Non-limiting examples of a lipophilic carrier include
semi-synthetic glycerides of saturated fatty acids. Non-limiting
examples of a hydrophilic carrier include polyethylene glycol
having an average molecular weight of 6000, polyethylene glycol
having an average molecular weight of 1500, polyethylene glycol
having an average molecular weight of 400 or mixtures thereof. The
biocompatible excipient can also include a muco-adhesive agent such
as alginate, pectin, or cellulose derivative. The biocompatible
excipient can also include a penetration enhancer such as bile
salts, organic solvents, ethoxydiglycol, or interesterified stone
oil.
[0109] In one embodiment of the invention, the excipient comprises
between about 60 to 90% by weight lipophilic carrier, between about
5 to 25% mucoadhesive agent, and between about 5 to 20% penetration
enhancer. In another embodiment of the invention, the excipient
comprises between about 60 to 90% by weight hydrophilic carrier,
between about 5 to 25% muco-adhesive agent, and between about 5 to
20% penetration enhancer. In another embodiment of the invention,
the patch or the drug delivery device comprises a standard
fragrance free lotion formulation. In another embodiment, the
biocompatible excipient can include glycerin, mineral oil,
polycarbophil, carbomer 934P, hydrogenated palm oil, glyceride,
sodium hydroxide, sorbic acid, and purified water.
[0110] In some embodiments, the transdermal patch contains, about
5-5000 mg; or alternatively about 5-4000 mg; or alternatively about
5-3000 mg; or alternatively about 5-2000 mg; or alternatively about
5-1000 mg; or alternatively about 5-500 mg; or alternatively about
5-100 mg; or alternatively about 5-50 mg, of the compound utilized
according to the invention. In some embodiments, the transdermal
patch administers a sustained release of the compound utilized
according to the invention over a period of from about few months
to about few weeks; or from about few weeks to about few days; or 6
days; or 5 days; or 4 days; or 3 days; or 2 days; or 1 day. The
transdermal patch may be replaced once a day, once a week, or once
a month for effective treatment.
[0111] For enteral application, particularly suitable are unit
dosage forms, e.g., tablets, dragees or capsules having talc and/or
a carbohydrate carrier or binder or the like, the carrier
preferably being lactose and/or corn starch and/or potato starch;
particulate solids, e.g., granules; and liquids and semi-liquids,
e.g., syrups and elixirs or the like, wherein the active compound
is protected with differentially degradable coatings, e.g., by
microencapsulation, multiple coatings, etc. Suitable for oral
administration are, inter alia, tablets, dragees, capsules, pills,
granules, suspensions and solutions. Each unit dose, e.g., each
tablespoon of liquid or each tablet, or dragee contains, for
example, 5-5000 mg of each active agent or the compound utilized
according to the invention.
[0112] In some embodiments, the pharmaceutically acceptable carrier
is a bioadhesive carrier. In some aspects, the bioadhesive carrier
is a cross-linked water-insoluble but water-swellable
polycarboxylic acid polymer. The cross-linked polycarboxylic acid
polymer formulation, is generally described in U.S. Pat. No.
4,615,697 (hereinafter "the '697 patent"), which is incorporated
herein by reference. In general, at least about eighty percent of
the monomers of the polymer in such a formulation may contain at
least one carboxyl functionality. The cross-linking agent may be
present at such an amount as to provide enough bioadhesion to allow
the system to remain attached to the target epithelial surfaces for
a sufficient time to allow the desired dosing to take place. This
preferred level of bioadhesion can be attained when the
cross-linking agent is present at about 0.1 to 6.0 weight percent
of the polymer, with about 1.0 to 2.0 weight percent being most
preferred, as long as the appropriate level of bioadhesion results.
Bioadhesion can also be measured by commercially available surface
tensiometers utilized to measure adhesive strength.
[0113] The polymer formulation can be adjusted to control the
release rate of the compounds of the invention, by varying the
amount of cross-linking agent in the polymer. Suitable
cross-linking agents include divinyl glycol, divinylbenzene,
N,N-diallylacrylamide, 3,4-dihydroxy-1,5-hexadiene,
2,5-dimethyl-1,5-hexadiene and similar agents. A preferred polymer
for use in such a formulation is Polycarbophil, U.S.P., which is
commercially available from B.F. Goodrich Speciality Polymers of
Cleveland, Ohio under the trade name NOVEON.RTM.-M1. The United
States Pharmacopeia, 1995 edition, United States Pharmacopeial
Convention, Inc., Rockville, Md., at pages 1240-41, indicates that
polycarbophil is a polyacrylic acid, cross-linked with divinyl
glycol. It has also been used as a base for compositions with other
active substances such as progesterone (Crinone.RTM.) (see U.S.
Pat. No. 5,543,150) and Nonoxynol-9 (Advantage-S) (see U.S. Pat.
No. 5,667,492). Other useful bioadhesive polymers that may be used
in such a drug delivery system formulation are mentioned in the
'697 patent. For example, these include polyacrylic acid polymers
cross-linked with, for example, 3,4-dihydroxy-1,5-hexadiene, and
polymethacrylic acid polymers cross-linked with, for example,
divinyl benzene.
[0114] Typically, these polymers may not be used in their salt
form, because this would decrease their bioadhesive capability.
Such bioadhesive polymers may be prepared by conventional free
radical polymerization techniques utilizing initiators such as
benzoyl peroxide, azobisisobutyronitrile, and the like. Exemplary
preparations of useful bioadhesives are provided in the '697
patent.
[0115] The bioadhesive formulation may be in the form of a gel,
cream, tablet, pill, capsule, suppository, film, or any other
pharmaceutically acceptable form that adheres to the mucosa and
does not wash away easily. Different formulations are further
described in the '697 patent, which is incorporated herein by
reference.
[0116] Additionally, the additives taught in the '697 patent may be
mixed in with the cross-linked polymer in the formulation for
maximum or desired efficacy of the delivery system or for the
comfort of the patient. Such additives include, for example,
lubricants, plasticizing agents, preservatives, gel formers, tablet
formers, pill formers, suppository formers, film formers, cream
formers, disintegrating agents, coatings, binders, vehicles,
coloring agents, taste and/or odor controlling agents, humectants,
viscosity controlling agents, pH-adjusting agents, and similar
agents.
[0117] The compound utilized according to the invention or the
other optional drug can be administered as an admixture or as a
separate unit dosage form, either simultaneously therewith or at
different times during the day from each other. The compound and
the optional drug are preferably administered at least once daily
(unless administered in a dosage form which delivers the active
agents continuously) and more preferable several times daily, e.g.,
in 2 to 6 divided doses. The typical dose is about 0.5 to 1000 mg
of each active agent.
[0118] A lower dosage regimen can be initiated and the dosage can
be increased until a positive effect is achieved or a higher dosage
regimen can initially be utilized, e.g., in a crisis situation, and
the dosages regulated downward as relief from the symptoms is
achieved.
[0119] In some embodiments, the method of the invention comprises
rectal insertion of a device comprising a compound utilized
according to the invention for treatment of IBS in a
pharmaceutically acceptable, non-toxic carrier. The composition is
combined with a suitable delivery device or system which permits
the rectal delivery of the drug. Examples of the drug delivery
system include, but are not limited to, pessary, tablet,
suppository, sponge, bioadhesive tablet, bioadhesive microparticle,
cream, lotion, foam, ointment, solution and gel. Alternatively, it
can be a coating on a suppository wall or a sponge or other
absorbent material impregnated with a liquid drug containing
solution, lotion, or suspension of bioadhesive particles. Any form
of drug delivery system which will effectively deliver the
treatment agent to the rectal epithelium is intended to be included
within the scope of this invention.
[0120] In some embodiments, the compound and an optional drug are
in the form of a microsphere for enhancing uptake of the compound
and the drug. The microparticles have a diameter of 10-100 pm and
can be prepared from starch, gelatin, albumin, collagen, or
dextran.
[0121] The compound can also be incorporated into creams, lotions,
foams, paste, ointments, and gels which can be applied to the
vagina using an applicator. Processes for preparing pharmaceuticals
in cream, lotion, foam, paste, ointment and gel formats can be
found throughout the literature. An example of a suitable system is
a standard fragrance free lotion formulation containing glycerol,
ceramides, mineral oil, petrolatum, parabens, fragrance and water.
Suitable nontoxic pharmaceutically acceptable systems for use in
the compositions of the present invention will be apparent to those
skilled in the art of pharmaceutical formulations and examples are
described in REMINGTON'S Pharmaceutical Sciences, 19th Edition, A.
R. Gennaro, ed., 1995. The choice of suitable carriers will depend
on the exact nature of the particular dosage form desired, e.g.,
whether the active ingredient(s) is/are to be formulated into a
cream, lotion, foam, ointment, paste, solution, or gel, as well as
on the compound.
[0122] The excipient can be an inert or inactive substance used in
the production of pharmaceutical products or other tablets,
including without limitation any substance used as a binder,
disintegrant, coating, compression/encapsulation aid, cream or
lotion, lubricant, parenteral, sweetener or flavoring,
suspending/gelling agent, or wet granulation agent. Binders
include, e.g., carbopol, povidone, xanthan gum, etc.; coatings
include, e.g., cellulose acetate phthalate, ethylcellulose, gellan
gum, maltodextrin, etc.; compression/encapsulation aids include,
e.g., calcium carbonate, dextrose, fructose dc, honey dc, lactose
(anhydrate or monohydrate; optionally in combination with
aspartame, cellulose, or microcrystalline cellulose), starch dc,
sucrose, etc.; disintegrants include, e.g., croscarmellose sodium,
gellan gum, sodium starch glycolate, etc.; creams and lotions
include, e.g., maltodextrin, carrageenans, etc.; lubricants
include, e.g., magnesium stearate, stearic acid, sodium stearyl
fumarate, etc.; materials for chewable tablets include, e.g.,
dextrose, fructose dc, lactose (monohydrate, optionally in
combination with aspartame or cellulose), etc.; parenterals
include, e.g., mannitol, povidone, etc.; plasticizers include,
e.g., dibutyl sebacate, polyvinylacetate phthalate, etc.;
suspending/gelling agents include, e.g., carrageenan, sodium starch
glycolate, xanthan gum, etc.; sweeteners include, e.g., aspartame,
dextrose, fructose dc, sorbitol, sucrose dc, etc.; and wet
granulation agents include, e.g., calcium carbonate, maltodextrin,
microcrystalline cellulose, etc.
[0123] In certain embodiments within the various aspects and
embodiments of the present invention, the compound is administered
in an amount of about 2000 .mu.g (or 2 mg), about 1200 .mu.g, about
1000 .mu.g, about 800 .mu.g, about 600 .mu.g, about 450 .mu.g,
about 400 .mu.g, about 250 .mu.g, and about 200 .mu.g (or 0.2 mg).
In other embodiments, the compound is administered in an amount of
about 200 .mu.g to about 2000 .mu.g.
[0124] In certain embodiments within the various aspects and
embodiments of the present invention, the compound is administered
once a day, twice a day or thrice a day up to a period of days,
months or years, until relief from symptoms is achieved. The
compound may be administered at various rates of administration,
for various periods of time.
[0125] The following examples are provided to illustrate select
embodiments of the invention as disclosed and claimed herein.
EXAMPLES
[0126] The compound MN-221 in the examples provided herein, refers
to the sulfate salt of formula:
(-)-bis(2-{[(2S)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(2-hydroxyethyl)phenyl-
]ethyl}amino)-1,2,3,4-tetrahydronaphthalen-7-yl]oxy}-N,N-dimethyl-acetamid-
e)monosulfate.
##STR00014##
[0127] MN-221 can be synthesized according to methods reported in
literature. See, e.g., U.S. Pat. No. 6,133,266, which is
incorporated herein by reference in its entirety.
Example 1
Effects of MN-221 on Rectosigmoid Motility
[0128] In this study, subjects with the irritable bowel syndrome
(IBS) are studied with regard to the effects of MN-221 on
rectosigmoid motility.
Materials and Methods
Subjects
[0129] Men and women aged 24-52 years are included in the study.
The diagnosis of IBS is made on the basis of the following
criteria: 1) symptoms lasting more than few months; 2) abdominal
pain with or without relation to meals; 3) constipation or a
combination of diarrhea and constipation; 4) normal colonic barium
enema and sigmoidoscopy; 5) negative test for lactose intolerance;
and 6) negative finding on stool culture.
[0130] The subjects are all symptomatic at the time of the study.
The subjects are taking no medications of significant importance
for intestinal motility. Informed consent is obtained from each
subject.
Experimental Design
[0131] After a 12 hours fast, all subjects undergo sigmoidoscopy
without air insufflations. A probe with one to three polyethylene
catheters is inserted through the sigmoidoscope so that the
proximal catheter is about 18-20 centimeter (cm) from the anal
margin, the tip of the second catheter about 5 cm below, and the
third catheter is positioned just inside the internal sphincter. An
about 5-cm-long balloon surrounds each of the two distal catheters.
The distal balloon is inflated with about 20 milliliter (mL) of air
to prevent the device from moving in the distal direction. The
balloon in the upper rectum, connected to the middle catheter, is
kept inflated with about 80 ml of air in 10 of the subjects and
with about 60 mL in the other 2 subjects throughout the recording
sessions. Each subject has the same balloon volume during the three
examinations.
[0132] Intra-luminal pressure is measured from the proximal rectal
balloon and the sigmoid catheter (inside diameter, about 1.67
millimeter (mm)), which is open tipped with a side orifice of about
1.5 mm diameter.
[0133] The catheter is continuously perfused with body-temperature
water at 3.5 mL/h by means of an infusion pump. Pressure is
transmitted to transducers (e.g., Statham P 23 Db, Statham
Instruments, Hato Ray, Puerto Rico) and recorded on a Grass RPS 7C
polygraph (e.g., Grass Instrument Co., Quincy, Mass.). To determine
motility, the area under the pressure curves is continuously
determined by integrators (such as, e.g., Grass 7P 10). As an index
of contractile activity, the total area minus the area under an
estimated basal pressure line is used. The principle for motility
calculation is described in detail in Abrahamsson et al. Dig Dis
Sci 1983, 28, 590-594.
[0134] Motility index is expressed as kPa.times.min (1
kPa.times.min=7.5 mm Hg.times.min). The study is randomized and
double blinded. Each subject is investigated on 3 different days
with not less than 5 days between each investigation to avoid any
possible influence of an earlier drug infusion. After an initial
rest period of 30 minutes (min), pressure is quantified for three
periods of 25 min. The first period, designated the control period,
is preceded by saline infusion, 1 mL/min, for 5 min. The following
two test periods are each preceded by an infusion of 0.25 mg MN-221
intravenously to a total amount of 0.50 mg on the 1st day, 1.0 mg
on the 2nd day, and 5 ml placebo (plus 5 mL saline) on the 3rd
day.
[0135] The blood pressure and heart rate are measured by a
sphygmomanometer 10 and 25 min after the end of each drug infusion.
Blood samples are drawn from a venous cannula at the same time for
determination of the plasma concentrations of the drugs. The code
for the drug is not broken until calculations of motility indices
are completed.
Statistical Analysis
[0136] Results are expressed as the mean.+-.SEM. Differences
between control and test periods are tested with Wilcoxon's rank
sign test for paired data.
Analytical Methods
[0137] The plasma concentration of MN-221 is determined by liquid
chromatography and mass spectrometry.
Results
Sigmoid Motility
[0138] Basal Conditions and Effects of Placebo.
[0139] The sigmoid motility index varies considerably between the
subjects and in the same subject on the different days. The motor
activity consists mainly of three different types of motor waves.
The commonest form is pressure waves with a frequency of 2-3/min.
The amplitude is generally between 1 and 4 kPa, and the duration of
each wave 10-25 seconds (sec). Between these prominent waves, other
waves with low amplitude and a frequency of 6-8/min may occur. In
periods with high motor activity, the base-line pressure may often
increase, with clusters of 3/min waves and superimposed small 7/min
waves. After placebo infusion, contractile activity has a tendency
to increase in wave frequency, duration, and amplitude. Results
show that sigmoid motility increases in subjects.
[0140] Effects of MN-221.
[0141] During the control period before MN-221 infusion the
motility index is calculated. After 0.50 milligram (mg) of MN-221
administered intravenously, the mean motility index decreases by
more than about 50% compared with the control period. After MN-221
in a total dose of 1.0 mg is administered intravenously, the
motility index decreases further. Results show that sigmoid
motility decreases in subjects.
Rectal Motility
[0142] Rectal motility, as registered with the proximal rectal
balloon, shows substantial individual variations in motility
between each day of registration. One third of all control periods
had a motility close to zero. This pattern is not changed after
infusion of MN-221.
Systemic Effects
[0143] Placebo infusion is not followed by any significant changes
in heart rate or in blood pressure compared with the preceding
control period. After MN-221 infusion to a total of 0.50 mg
intravenously, no significant increase in the systolic blood
pressure; decrease in the diastolic blood pressure; and/or increase
in the heart rate is observed. MN-221 infusion to a total of 1.0 mg
intravenously results in no significant increase in systolic blood
pressure; decrease in diastolic blood pressure; and/or increase in
heart rate. No major complaints or discomfort are noted among the
subjects after infusion of MN-221. These results show that the use
of MN-221 is associated with little to no adverse side effects
compared with the use of terbutaline, which is associated with an
undesirable incidence of significant adverse side effects,
including increase in systolic blood pressure and the heart
rate.
Plasma Concentrations of the Drugs
[0144] The drug infusions are followed by a dose-dependent increase
in plasma levels of the drugs.
Discussion
[0145] The present study shows that administration of MN-221
significantly decreases sigmoid colonic motility in subjects with
the IBS. After placebo infusion, motility has a tendency to
increase during the test period, further emphasizing the inhibitory
effect of MN-221. The plasma concentrations of MN-221 are observed
to be within the therapeutic levels used in clinical practice.
[0146] Rectal motility is registered from an air inflated balloon.
The inflated volume used in the study is chosen so as not to reach
the low pain threshold for rectal distention. None of the subjects
complains of pain during balloon inflation. Thus, variation in
distention-induced discomfort is not likely to have influenced the
response to the drugs. Statistical comparison between the test and
control periods do not show any change after each drug.
[0147] This study suggests an inhibitory influence on motility
along the whole gut by MN-221.
Example 2
Effects of MN-221 on Human Esophageal Peristalsis
[0148] Subjects with irritable bowel syndrome may complain of upper
gastrointestinal symptoms, including heartburn and dysphagia.
MN-221 inhibits esophageal peristalsis and tone of the lower
esophageal sphincter in subjects suffering from IBS.
[0149] This study investigates the inhibitory influence of
beta-2-adrenergic stimulation by MN-221 on esophageal motility with
little to no incidence of significant adverse side effects. In the
study, esophageal peristalsis is studied in subjects suffering from
IBS. The subjects have no history of gastrointestinal or
cardiovascular disease. Subjects are considered to have the
irritable bowel syndrome if they have an abdominal pain with or
without diarrhea or constipation. Relief of pain by defecation,
abdominal distension, a feeling of incomplete evacuation, and/or a
response to a high-residue diet are taken as useful additional
symptoms. The blood picture, erythrocyte sedimentation rate, and
results of sigmoidoscopy, rectal biopsy, and barium enema are
normal in all subjects. The symptoms of the subjects, including
dysphagia and heartburn, are recorded on data sheets for
correlation with manometric findings.
[0150] Each subject is orally given MN-221, 5 mg three times daily,
for 10 days. The subjects are studied before medication (basal), on
days 3 and 10 during the medication, and 1 week after withdrawal of
the drug. At each session esophageal peristaltic pressure, heart
rate, and finger tremor are assessed.
Esophageal Measurements
[0151] Manometric studies are performed with a triple-lumen tube
with each channel perfused with water, 0.5 ml/min, via a
low-compliance capillary system. The channels are connected to
pressure transducers with recording on a Grass polygraph. The
pressure recording sites are about 8 cm apart. After an overnight
fast, the subjects are examined seated in a standardized position
with the manometric probe inserted via the nasal route. The probe
is placed with the distal recording point about 2 cm proximal to
the lower esophageal sphincter (LES). Thus, pressure is recorded
about 18 cm proximal to the LES (proximal esophagus), about 10 cm
proximal to the LES (middle esophagus), and about 2 cm proximal to
the LES (distal esophagus).
[0152] After a resting period of 20 min., esophageal peristalsis in
response to 20 wet swallows (water bolus of 5 ml, room temperature)
is recorded. At least 30 sec are allowed between each bolus. Each
recording curve is coded and read by one investigator who is not
aware of the subject's study day. The amplitude of the peristaltic
pressure waves is measured at each recording point, and an
individual mean value for the 20 swallows is calculated for each
examination.
Extra Intestinal Recordings
[0153] At each session, heart rate is recorded in the resting
subject and calculated as a mean value for 2 min. Finger tremor are
assessed with an optical method (e.g., Opto-Tremor Graph, Draco),
and the middle finger of the right hand is chosen for measurement.
Tremor values are displayed as digital data and given as the sum of
the length of movements in millimeters per minute.
MN-221 Analyses
[0154] At each session, venous blood samples are taken immediately
after the last test swallow. After centrifugation, samples are
stored at -20.degree. C. until analysis. The plasma concentration
of MN-22 1 is determined by liquid chromatography plus mass
spectrometry.
Adverse Reactions
[0155] Tachycardia and tremor are classified in accordance with a
four-degree scale: absent, slight (not disturbing), moderate
(disturbing, but not disabling), and severe (disabling).
Results
Esophageal Peristalsis
[0156] Oral administration of MN-221 results in a significant
decrease of esophageal peristaltic pressure. The decrease is
evident in proximal, middle and/or distal esophagus. One week
later, there is still a trend towards decreased peristaltic
pressure.
Heart Rate and Tremor
[0157] The extraintestinal variables, heart rate and finger tremor,
do not change during MN-221 medication. Thus, both heart rate and
tremor stay substantially the same as before medication. At the end
of the medication period, such as on day 10, no significant changes
in the heart rate or finger tremor are seen. There is no
substantial indication of the tolerance of the subjects toward
MN-221.
[0158] It is concluded that oral medication with MN-221 inhibits
esophageal peristalsis in subjects with IBS. These results show
that the use of MN-221 is associated with little to no adverse side
effects compared with the use of terbutaline, which is associated
with an undesirable incidence of significant adverse side effects,
including increase in the heart rate and finger tremors. The
results also indicate no significant development of esophageal
tolerance to MN-221 as compared to terbutaline which is associated
with the development of esophageal tolerance with continued
medication.
Example 3
Treatment of Irritable Bowel Syndrome Using MN-221
[0159] A 35-year-old male patient complains of symptoms associated
with IBS, including diarrhea with discharge of mucus and blood,
cramping abdominal pain, and/or inflammation and edema of the
mucous membrane with patches of ulceration. The patient is treated
with tablets containing 5 mg of MN-221, three times per day, for at
least two months. After this time period, the patient reports
positive effects, including a reduction in the symptoms. Similar
positive results are observed for other male or female patients
complaining of one or more of the similar symptoms attributable to
IBS.
Example 4
Treatment of Irritable Bowel Syndrome Using MN-221
[0160] Previous reports have demonstrated that intravesical
instillation of ovalbumin in sensitized guinea pigs increases
bladder contractions. See, Ahluwalia et al. "Ovalbumin-induced
neurogenic inflammation in the bladder of sensitized rats" Br. J.
Pharmacol. (1998) 124:190-6. In this study, MN-221 is shown to be
beneficial in suppressing ovalbumin-induced bladder contractions in
a rat model of inflammation-induced bladder hyperactivity. This rat
model serves as an animal model for irritable bowel syndrome.
Methods:
A. Sensitization of Rats:
[0161] Sprague-Dawley rats (n=50; 200.+-.250 g) are utilized for
this study. The animals are divided into 5 groups (n=10). The first
group serves as a control and second group is sensitized with
ovalbumin (OA). The third, fourth, and fifth groups are also
sensitized as described but are subjected to oral gavaging with
MN-221 prior to acute ovalbumin challenge.
[0162] Sensitization of the animals is accomplished with an
intraperitoneal injection of a mixture of 1 mg OA and 100 mg
aluminum hydroxide suspended in 1 mL of saline. Fourteen days
later, these sensitized rats are anaesthetized with a subcutaneous
injection of urethane (1.2 g/kg) for intravesical OA (10 mg/mL)
administration and evaluation of bladder hyperactivity. The animals
in group 1 receive saline (control), group 2 animals receive about
2 mL of OA (10 mg/mL OA in sterile saline) and groups 3-5 animals
receive oral MN-221 (10, 30, 50 mg/kg in gum acacia suspension) 60
minutes prior to acute OA challenge (2 mL of 10 mg/mL OA).
B. Evaluation of Bladder Overactivity:
[0163] All animals are subjected to evaluation of bladder
hyperactivity. Briefly, a 1 cm incision is made along the
centerline of the lower ventral abdomen. The bladder is
exteriorized, and catheterized by means of a polyethylene tube
(e.g., PE 50, Clay Adams) inserted into the bladder dome and
sutured in place using a 2-0 braided silk suture. The bladder is
returned to the abdomen, with the catheter line escaping through
the incision. The catheter is then connected to a pressure
transducer (e.g., UFI, Morro Bay, Calif.) and in turn, connected to
an infusion pump (e.g., Harvard Apparatus, MA). During the
continuous filling bladder cystometry, the pressure is recorded
with the transducer using the program LabVIEW (National
Instruments, TX).
[0164] For cystometry (See, Chuang et al. "Intravesical protamine
sulfate and potassium chloride as a model for bladder
hyperactivity" Urology (2003) 61:664-70), the bladder is first
infused with warm 0.9% saline (37.degree. C.) at 40 .mu.L/min (2.4
mL/hr) and at least 20 minutes of stable voiding cycles are
recorded during infusion. This process is followed by intravesical
infusion of OA (10 mg/mL) and bladder contractions are recorded.
Frequency of contractions (voids), inter-contractile interval
(ICI), and non-voiding contractions (NVC) are calculated from these
recordings.
Results:
[0165] Tracings of bladder cystometrograms (CMGs) of treatment
groups are compared. Infusion of intact rat bladder with 0.9%
saline results in normal and comparable numbers of voids and NVC.
In OA sensitized rats, intravesical OA (10 mg/mL) infusion results
in an increase in NVC relative to non-sensitized saline infusion
values. Pre-treatment with MN-221 results in dose-dependent
inhibition of OA-induced changes in NVC and ICI. No significant
differences are observed in voiding frequency between control
(group 1) and different treatment groups (2-5).
[0166] These studies indicate that acute intravesical challenge of
OA-sensitized rats causes contractions of bladder smooth muscle
leading to a significant increase in NVC and a decrease in ICI.
Pre-treatment with MN-221 produces a significant protection against
these OA-induced changes. Similar outcomes are expected for the
pre-treatment with the metabolite of MN-221.
[0167] It is to be understood that while the invention has been
described in conjunction with the above embodiments, that the
foregoing description and examples are intended to illustrate and
not limit the scope of the invention. Other aspects, advantages and
modifications within the scope of the invention will be apparent to
those skilled in the art to which the invention pertains.
* * * * *