U.S. patent application number 14/834411 was filed with the patent office on 2016-05-05 for compositions and methods for the treatment of inflammatory bowel disease.
The applicant listed for this patent is Cellix Bio Private Limited. Invention is credited to Mahesh Kandula.
Application Number | 20160120839 14/834411 |
Document ID | / |
Family ID | 55851449 |
Filed Date | 2016-05-05 |
United States Patent
Application |
20160120839 |
Kind Code |
A1 |
Kandula; Mahesh |
May 5, 2016 |
COMPOSITIONS AND METHODS FOR THE TREATMENT OF INFLAMMATORY BOWEL
DISEASE
Abstract
The invention relates to the compounds of formula I and formula
II or its pharmaceutical acceptable salts, as well as polymorphs,
solvates, enantiomers, stereoisomers and hydrates thereof. The
pharmaceutical compositions comprising an effective amount of
compounds of formula I or formula II; and methods for treating or
preventing inflammatory bowel disease may be formulated for oral,
buccal, rectal, topical, transdermal, transmucosal, intravenous,
parenteral administration, syrup, or injection. Such compositions
may be used to treatment of gastrointestinal diseases and
inflammation such as inflammatory bowel disease, ulcerative
colitis, mild-to-moderate Crohn's disease, rheumatoid arthritis,
inflammatory arthritis, psoriatic arthritis, liver cirrhosis and
idiopathic urticaria.
Inventors: |
Kandula; Mahesh; (Andhra
Pradesh, IN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Cellix Bio Private Limited |
Hyderabad |
|
IN |
|
|
Family ID: |
55851449 |
Appl. No.: |
14/834411 |
Filed: |
August 24, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
14533111 |
Nov 5, 2014 |
|
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14834411 |
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Current U.S.
Class: |
514/150 ;
514/533; 514/535; 554/106; 554/111 |
Current CPC
Class: |
C07C 251/86 20130101;
A61K 31/655 20130101; A61K 31/606 20130101; C07C 243/22 20130101;
A61K 31/202 20130101; A61K 45/06 20130101; A61K 31/606 20130101;
A61K 2300/00 20130101; A61K 2300/00 20130101; A61K 2300/00
20130101; A61K 2300/00 20130101; C07C 233/55 20130101; A61K 31/245
20130101; A61K 31/245 20130101; A61K 31/235 20130101; A61K 31/235
20130101; C07C 235/74 20130101; C07C 233/54 20130101; C07C 2601/16
20170501; A61K 31/202 20130101 |
International
Class: |
A61K 31/245 20060101
A61K031/245; C07C 243/22 20060101 C07C243/22; A61K 31/655 20060101
A61K031/655; C07C 235/74 20060101 C07C235/74 |
Claims
1. A compound of Formula I: ##STR00043## or a pharmaceutically
acceptable salt, hydrate, solvate, enantiomer, or stereoisomer
thereof, wherein: R.sub.1 independently represents ##STR00044##
##STR00045## R.sub.2 and R.sub.4 each independently represent
##STR00046## ##STR00047## ##STR00048## a is 2, 3 or 7; each b is
independently 3, 5 or 6; e is 1, 2 or 6; and c and d are each
independently H, D, --OH, --OD, C.sub.1-C.sub.6-alkyl, --NH.sub.2
or --COCH.sub.3.
2. (canceled)
3. A pharmaceutical composition comprising a compound of claim 1
and a pharmaceutically acceptable carrier.
4. (canceled)
5. The pharmaceutical composition of claim 3, wherein said
pharmaceutical composition is formulated to treat an underlying
etiology with an effective amount administering the patient in need
by oral administration, delayed release or sustained release,
transmucosal, syrup, topical, parenteral administration, injection,
subdermal, oral solution, rectal administration, buccal
administration or transdermal administration.
6. (canceled)
7. Compounds and compositions of claim 5, wherein said compounds
and compositions are formulated for the treatment of
gastrointestinal diseases and inflammation such as inflammatory
bowel disease, ulcerative colitis, mild-to-moderate Crohn's
disease, rheumatoid arthritis, inflammatory arthritis, psoriatic
arthritis, liver cirrhosis and idiopathic urticaria.
8. (canceled)
9. A pharmaceutical composition of claim 3, further comprising a
molecular conjugate of mesalazine, caprylic acid and carboxylic
compounds selected form a group consisting of eicosapentaenoic acid
and docosahexaenoic acid.
10. The molecular conjugate of claim 9, wherein the carboxylic acid
compound is eicosapentaenoic acid.
11. The molecular conjugate of claim 9, wherein the carboxylic acid
compound is docosahexaenoic acid.
12. (canceled)
13. (canceled)
14. (canceled)
Description
PRIORITY
[0001] This application is a Continuation application of and claims
priority to the U.S. non-provisional application Ser. No.
14/533,111 filed on Nov. 5, 2014. The U.S. non-provisional
application Ser. No. 14/533,111 further claims the priority of the
Patent Cooperation Treaty (PCT) application # PCT/IB2013/053982
titled "COMPOSITIONS AND METHODS FOR THE TREATMENT OF INFLAMMATORY
BOWEL DISEASE" filed on May 15, 2013 Published with WIPO
Publication # WO/2013/175357, which further claims priority to
parent application 2062/CHE/2012 filed on May 23, 2012 in the
country of India. The entire disclosure of the priority
applications are relied on for all purposes and is incorporated
into this application by reference.
FIELD OF THE INVENTION
[0002] This disclosure generally relates to compounds and
compositions for the treatment of Inflammatory Bowel Disease. More
particularly, this invention relates to treating subjects with a
pharmaceutically acceptable dose of compounds, stereoisomers,
enantiomers, crystals, esters, salts, hydrates, prodrugs, or
mixtures thereof.
BACKGROUND OF THE INVENTION
[0003] Inflammatory bowel disease (IBD) encompasses several chronic
inflammatory conditions, most significantly ulcerative colitis (UC)
and Crohn's disease (CD). While these two conditions share many
common features--diarrhea, bloody stools, weight loss, abdominal
pain, fever, and fatigue--each has unique features. A complete
discussion of Crohn's disease will be addressed in a future
article. Ulcerative colitis and associated risk factors,
pathogenesis, nutrient deficiencies, conventional treatment
approaches, natural treatment approaches, and extra-intestinal
manifestations of the disease.
[0004] Ulcerative colitis affects the colon and rectum and
typically involves only the innermost lining or mucosa, manifesting
as continuous areas of inflammation and ulceration, with no
segments of normal tissue. The Crohn's and Colitis Foundation of
America defines several varieties of UC. Disease involving only the
most distal part of the colon and the rectum is termed ulcerative
proctitis; disease from the descending colon down is referred to as
limited or distal colitis; and disease involving the entire colon
is called pancolitis. UC may be insidious, with gradual onset of
symptoms, or the first attack may be acute and fulminate.
[0005] More mild symptoms include a progressive loosening of the
stool, abdominal cramping, and diarrhea. As the disease progresses
from mild to more severe, the patient may also experience weight
loss, fatigue, loss of appetite that may result in nutrient
deficiencies, mucus in the stool, severe rectal bleeding, fever,
and anemia. It is estimated that 1-2 million Americans suffer from
IBD; approximately half of these have ulcerative colitis. UC can
occur anytime in life, but is usually diagnosed prior to age 30.
The disease appears to affect men and women equally. Approximately
20 percent of people with UC have a close relative with IBD.
Caucasians have a higher incidence of UC, with Jewish people of
European descent 3-6 times more likely to develop the disease.
Regions with a low incidence of UC include Asia, Japan, Africa, and
South America.
[0006] Differing cytokine and other inflammatory-mediator profiles
have been identified for UC and CD. The classic lesions of UC,
involving the mucosal layer with extensive epithelial damage,
abundant neutrophils, and crypt abscesses have led to a search for
an immune mechanism to explain the epithelial damage. Signs of
increased oxidative stress are in evidence in the intestinal mucosa
of patients with ulcerative colitis and may be secondary to
inflammation. One study examined signs of oxidative stress and
plasma antioxidant levels in controls compared to patients with UC
and CD. Oxidative DNA damage was noted in both IBD groups compared
to controls, measured by production of 8-hydroxy-deoxyguanosine
(8-OHdG). UC patients were found to have significantly lower plasma
levels of vitamins A and E and several carotenoids compared to
controls; there were no differences between UC and CD groups.
[0007] Mucosal biopsies of UC patients were analyzed and shown to
have increased reactive oxygen intermediates, DNA oxidation
products (8-OHdG), and iron in inflamed tissue compared to
controls. Decreased levels of copper and zinc, cofactors for the
endogenous antioxidant superoxide dismutase, were also
observed.
[0008] Managing acute pathology of often relies on the addressing
underlying pathology and symptoms of the disease. There is
currently a need in the art for new compositions to treatment or
delay of the onset of Inflammatory Bowel Disease and its associated
complications progression.
SUMMARY OF THE INVENTION
[0009] The present invention provides compounds, compositions
containing these compounds and methods for using the same to treat,
prevent and/or ameliorate the effects of the conditions such as
Inflammatory Bowel Disease.
[0010] The invention herein provides compositions comprising of
formula I or pharmaceutical acceptable salts thereof. The invention
also provides pharmaceutical compositions comprising one or more
compounds of formula I or intermediates thereof and one or more of
pharmaceutically acceptable carriers, vehicles or diluents. These
compositions may be used in the treatment of Inflammatory Bowel
Disease and its associated complications.
##STR00001##
[0011] In certain embodiments, the present invention relates to the
compounds and compositions of formula I, or pharmaceutically
acceptable salts thereof,
##STR00002##
[0012] Wherein,
[0013] R.sup.1, R.sup.3 each independently represents
--CH.sub.3CO--, acetyl, D, H, CD.sub.3CO--,
##STR00003## ##STR00004##
[0014] R.sup.2, R.sup.4 each independently represents H, D,
##STR00005## ##STR00006##
[0015] a is independently 2, 3 or 7;
[0016] each b is independently 3, 5 or 6;
[0017] e is independently 1, 2 or 6;
[0018] c and d are each independently H, D, --OH, --OD,
C.sub.1-C.sub.6-alkyl, --NH.sub.2 or --COCH.sub.3.
[0019] The invention herein also provides compositions comprising
of formula II or pharmaceutical acceptable salts thereof. The
invention also provides pharmaceutical compositions comprising one
or more compounds of formula II or intermediates thereof and one or
more of pharmaceutically acceptable carriers, vehicles or diluents.
These compositions may be used in the treatment of Inflammatory
Bowel Disease and its associated complications.
##STR00007##
[0020] Accordingly, in certain embodiments, the present invention
relates to the compounds and compositions of formula II, or
pharmaceutically acceptable salts thereof,
##STR00008##
[0021] Wherein
[0022] R.sup.1, R.sup.3 each independently represents H, D,
##STR00009## ##STR00010##
[0023] R.sup.2, R.sup.4 each independently represents D,
CH.sub.3CO, CD.sub.3CO,
##STR00011## ##STR00012##
[0024] a is independently 2, 3 or 7;
[0025] each b is independently 3, 5 or 6;
[0026] e is independently 1, 2 or 6;
[0027] c and d are each independently H, D, --OH, --OD,
C.sub.1-C.sub.6-alkyl, --NH.sub.2 or --COCH.sub.3.
[0028] In the illustrative embodiments, examples of compounds of
formula I are as set forth below:
##STR00013##
[0029] In the illustrative embodiments, examples of compounds of
formula II are as set forth below:
##STR00014##
[0030] Herein the application also provides a kit comprising any of
the pharmaceutical compositions disclosed herein. The kit may
comprise instructions for use in the treatment of Inflammatory
Bowel Disease or its related complications.
[0031] The application also discloses a pharmaceutical composition
comprising a pharmaceutically acceptable carrier and any of the
compositions herein. In some aspects, the pharmaceutical
composition is formulated for systemic administration, oral
administration, sustained release, parenteral administration,
injection, subdermal administration, or transdermal
administration.
[0032] Herein, the application additionally provides kits
comprising the pharmaceutical compositions described herein. The
kits may further comprise instructions for use in the treatment of
Inflammatory Bowel Disease or its related complications.
[0033] The compositions described herein have several uses. The
present application provides, for example, methods of treating a
patient suffering from Inflammatory Bowel Disease or its related
complications manifested from Inflammation, metabolic conditions or
disorders, metabolic syndrome, chronic diseases or disorders;
Hyperinsulinemia, Insulin resistance, Glucose intolerance,
Hepatology, Cancer, Respiratory, Hematological, Orthopedic,
Cardiovascular, Renal, Skin, Nephrological, or Ocular
complications.
BRIEF DESCRIPTION OF FIGURE
[0034] Example embodiments are illustrated by way of example and
not limitation in the FIGURE of the accompanying drawing, in which
like references indicate similar elements and in which:
[0035] FIG. 1 shows the 1H-NMR results for Formula I.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
[0036] As used herein, the following terms and phrases shall have
the meanings set forth below. Unless defined otherwise, all
technical and scientific terms used herein have the same meaning as
commonly understood to one of ordinary skill in the art.
[0037] The compounds of the present invention can be present in the
form of pharmaceutically acceptable salts. The compounds of the
present invention can also be present in the form of
pharmaceutically acceptable esters (i.e., the methyl and ethyl
esters of the acids of formula I and formula II to be used as
prodrugs). The compounds of the present invention can also be
solvated, i.e. hydrated. The solvation can be affected in the
course of the manufacturing process or can take place i.e. as a
consequence of hygroscopic properties of an initially anhydrous
compound of formula I and formula II (hydration).
[0038] Compounds that have the same molecular formula but differ in
the nature or sequence of bonding of their atoms or the arrangement
of their atoms in space are termed "isomers." Isomers that differ
in the arrangement of their atoms in space are termed
"stereoisomers." Diastereomers are stereoisomers with opposite
configuration at one or more chiral centers which are not
enantiomers. Stereoisomers bearing one or more asymmetric centers
that are non-superimposable mirror images of each other are termed
"enantiomers." When a compound has an asymmetric center, for
example, if a carbon atom is bonded to four different groups, a
pair of enantiomers is possible. An enantiomer can be characterized
by the absolute configuration of its asymmetric center or centers
and is described by the R- and S-sequencing rules of Cahn, Ingold
and Prelog, or by the manner in which the molecule rotates the
plane of polarized light and designated as dextrorotatory or
levorotatory (i.e., as (+) or (-)-isomers respectively). A chiral
compound can exist as either individual enantiomer or as a mixture
thereof. A mixture containing equal proportions of the enantiomers
is called a "racemic mixture".
[0039] As used herein, the term "metabolic condition" refers to an
Inborn errors of metabolism (or genetic metabolic conditions) are
genetic disorders that result from a defect in one or more
metabolic pathways; specifically, the function of an enzyme is
affected and is either deficient or completely absent.
[0040] The term "polymorph" as used herein is art-recognized and
refers to one crystal structure of a given compound.
[0041] The phrases "parenteral administration" and "administered
parenterally" as used herein refer to modes of administration other
than enteral and topical administration, such as injections, and
include without limitation intravenous, intramuscular,
intrapleural, intravascular, intrapericardial, intraarterial,
intrathecal, intracapsular, intraorbital, intracardiac,
intradennal, intraperitoneal, transtracheal, subcutaneous,
subcuticular, intra-articular, subcapsular, subarachnoid,
intraspinal and intrastemal injection and infusion.
[0042] A "patient," "subject," or "host" to be treated by the
subject method may mean either a human or non-human animal, such as
primates, mammals, and vertebrates.
[0043] The phrase "pharmaceutically acceptable" is art-recognized.
In certain embodiments, the term includes compositions, polymers
and other materials and/or dosage forms which are, within the scope
of sound medical judgment, suitable for use in contact with the
tissues of mammals, human beings and animals without excessive
toxicity, irritation, allergic response, or other problem or
complication, commensurate with a reasonable benefit/risk
ratio.
[0044] The phrase "pharmaceutically acceptable carrier" is
art-recognized, and includes, for example, pharmaceutically
acceptable materials, compositions or vehicles, such as a liquid or
solid filler, diluent, solvent or encapsulating material involved
in carrying or transporting any subject composition, from one
organ, or portion of the body, to another organ, or portion of the
body. Each carrier must be "acceptable" in the sense of being
compatible with the other ingredients of a subject composition and
not injurious to the patient. In certain embodiments, a
pharmaceutically acceptable carrier is non-pyrogenic. Some examples
of materials which may 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) cocoa butter and suppository waxes; (9)
oils, such as peanut oil, cottonseed oil, sunflower 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.
[0045] The term "prodrug" is intended to encompass compounds that,
under physiological conditions, are converted into the
therapeutically active agents of the present invention. A common
method for making a prodrug is to include selected moieties that
are hydrolyzed under physiological conditions to reveal the desired
molecule. In other embodiments, the prodrug is converted by an
enzymatic activity of the host animal.
[0046] The term "prophylactic or therapeutic" treatment is
art-recognized and includes administration to the host of one or
more of the subject compositions. If it is administered prior to
clinical manifestation of the unwanted condition (e.g., disease or
other unwanted state of the host animal) then the treatment is
prophylactic, i.e., it protects the host against developing the
unwanted condition, whereas if it is administered after
manifestation of the unwanted condition, the treatment is
therapeutic, (i.e., it is intended to diminish, ameliorate, or
stabilize the existing unwanted condition or side effects
thereof).
[0047] The term "predicting" as used herein refers to assessing the
probability related diseases patient will suffer from abnormalities
or complication and/or terminal platelet aggregation or failure
and/or death (i.e. mortality) within a defined time window
(predictive window) in the future. The mortality may be caused by
the central nervous system or complication. The predictive window
is an interval in which the subject will develop one or more of the
said complications according to the predicted probability. The
predictive window may be the entire remaining lifespan of the
subject upon analysis by the method of the present invention.
[0048] The term "treating" is art--recognized and includes
preventing a disease, disorder or condition from occurring in an
animal which may be predisposed to the disease, disorder and/or
condition but has not yet been diagnosed as having it; inhibiting
the disease, disorder or condition, e.g., impeding its progress;
and relieving the disease, disorder, or condition, e.g., causing
regression of the disease, disorder and/or condition. Treating the
disease or condition includes ameliorating at least one symptom of
the particular disease or condition, even if the underlying
pathophysiology is not affected, such as treating the
gastrointestinal disorders such as inflammatory bowel disease,
ulcerative colitis and mild-to-moderate Crohn's disease of a
subject by administration of an agent even though such agent does
not treat the cause of the condition. The term "treating", "treat"
or "treatment" as used herein includes curative, preventative
(e.g., prophylactic), adjunct and palliative treatment.
[0049] The phrase "therapeutically effective amount" is an
art-recognized term. In certain embodiments, the term refers to an
amount of a salt or composition disclosed herein that produces some
desired effect at a reasonable benefit/risk ratio applicable to any
medical treatment. In certain embodiments, the term refers to that
amount necessary or sufficient to eliminate or reduce medical
symptoms for a period of time. The effective amount may vary
depending on such factors as the disease or condition being
treated, the particular targeted constructs being administered, the
size of the subject, or the severity of the disease or condition.
One of ordinary skill in the art may empirically determine the
effective amount of a particular composition without necessitating
undue experimentation.
[0050] In certain embodiments, the pharmaceutical compositions
described herein are formulated in a manner such that said
compositions will be delivered to a patient in a therapeutically
effective amount, as part of a prophylactic or therapeutic
treatment. The desired amount of the composition to be administered
to a patient will depend on absorption, inactivation, and excretion
rates of the drug as well as the delivery rate of the salts and
compositions from the subject compositions. It is to be noted that
dosage values may also vary with the severity of the condition to
be alleviated. It is to be further understood that for any
particular subject, specific dosage regimens should be adjusted
over time according to the individual need and the professional
judgment of the person administering or supervising the
administration of the compositions. Typically, dosing will be
determined using techniques known to one skilled in the art.
[0051] Additionally, the optimal concentration and/or quantities or
amounts of any particular salt or composition may be adjusted to
accommodate variations in the treatment parameters. Such treatment
parameters include the clinical use to which the preparation is
put, e.g., the site treated, the type of patient, e.g., human or
non-human, adult or child, and the nature of the disease or
condition.
[0052] In certain embodiments, the dosage of the subject
compositions provided herein may be determined by reference to the
plasma concentrations of the therapeutic composition or other
encapsulated materials. For example, the maximum plasma
concentration (Cmax) and the area under the plasma
concentration-time curve from time 0 to infinity may be used.
[0053] When used with respect to a pharmaceutical composition or
other material, the term "sustained release" is art-recognized. For
example, a subject composition which releases a substance over time
may exhibit sustained release characteristics, in contrast to a
bolus type administration in which the entire amount of the
substance is made biologically available at one time. For example,
in particular embodiments, upon contact with body fluids including
blood, spinal fluid, mucus secretions, lymph or the like, one or
more of the pharmaceutically acceptable excipients may undergo
gradual or delayed degradation (e.g., through hydrolysis) with
concomitant release of any material incorporated therein, e.g., an
therapeutic and/or biologically active salt and/or composition, for
a sustained or extended period (as compared to the release from a
bolus). This release may result in prolonged delivery of
therapeutically effective amounts of any of the therapeutic agents
disclosed herein.
[0054] The phrases "systemic administration," "administered
systemically," "peripheral administration" and "administered
peripherally" are art-recognized, and include the administration of
a subject composition, therapeutic or other material at a site
remote from the disease being treated. Administration of an agent
for the disease being treated, even if the agent is subsequently
distributed systemically, may be termed "local" or "topical" or
"regional" administration, other than directly into the central
nervous system, e.g., by subcutaneous administration, such that it
enters the patient's system and, thus, is subject to metabolism and
other like processes.
[0055] The phrase "therapeutically effective amount" is an
art-recognized term. In certain embodiments, the term refers to an
amount of a salt or composition disclosed herein that produces some
desired effect at a reasonable benefit/risk ratio applicable to any
medical treatment. In certain embodiments, the term refers to that
amount necessary or sufficient to eliminate or reduce medical
symptoms for a period of time. The effective amount may vary
depending on such factors as the disease or condition being
treated, the particular targeted constructs being administered, the
size of the subject, or the severity of the disease or condition.
One of ordinary skill in the art may empirically determine the
effective amount of a particular composition without necessitating
undue experimentation.
[0056] The present disclosure also contemplates prodrugs of the
compositions disclosed herein, as well as pharmaceutically
acceptable salts of said prodrugs.
[0057] This application also discloses a pharmaceutical composition
comprising a pharmaceutically acceptable carrier and the
composition of a compound of Formula I and formula II may be
formulated for systemic or topical or oral administration. The
pharmaceutical composition may be also formulated for oral
administration, oral solution, injection, subdermal administration,
or transdermal administration. The pharmaceutical composition may
further comprise at least one of a pharmaceutically acceptable
stabilizer, diluent, surfactant, filler, binder, and lubricant.
[0058] In many embodiments, the pharmaceutical compositions
described herein will incorporate the disclosed compounds and
compositions (Formula I and Formula II) to be delivered in an
amount sufficient to deliver to a patient a therapeutically
effective amount of a compound of formula I and formula II or
composition as part of a prophylactic or therapeutic treatment. The
desired concentration of formula I and formula II or its
pharmaceutical acceptable salts will depend on absorption,
inactivation, and excretion rates of the drug as well as the
delivery rate of the salts and compositions from the subject
compositions. It is to be noted that dosage values may also vary
with the severity of the condition to be alleviated. It is to be
further understood that for any particular subject, specific dosage
regimens should be adjusted over time according to the individual
need and the professional judgment of the person administering or
supervising the administration of the compositions. Typically,
dosing will be determined using techniques known to one skilled in
the art.
[0059] Additionally, the optimal concentration and/or quantities or
amounts of any particular compound of formula I and formula II may
be adjusted to accommodate variations in the treatment parameters.
Such treatment parameters include the clinical use to which the
preparation is put, e.g., the site treated, the type of patient,
e.g., human or non-human, adult or child, and the nature of the
disease or condition.
[0060] The concentration and/or amount of any compound of formula I
and formula II may be readily identified by routine screening in
animals, e.g., rats, by screening a range of concentration and/or
amounts of the material in question using appropriate assays. Known
methods are also available to assay local tissue concentrations,
diffusion rates of the salts or compositions, and local blood flow
before and after administration of therapeutic formulations
disclosed herein. One such method is microdialysis, as reviewed by
T. E. Robinson et al., 1991, microdialysis in the neurosciences,
Techniques, volume 7, Chapter 1. The methods reviewed by Robinson
may be applied, in brief, as follows. A microdialysis loop is
placed in situ in a test animal. Dialysis fluid is pumped through
the loop. When compounds with formula I and formula II such as
those disclosed herein are injected adjacent to the loop, released
drugs are collected in the dialysate in proportion to their local
tissue concentrations. The progress of diffusion of the salts or
compositions may be determined thereby with suitable calibration
procedures using known concentrations of salts or compositions.
[0061] In certain embodiments, the dosage of the subject compounds
of formula I and formula II provided herein may be determined by
reference to the plasma concentrations of the therapeutic
composition or other encapsulated materials. For example, the
maximum plasma concentration (Cmax) and the area under the plasma
concentration-time curve from time 0 to infinity may be used.
[0062] Generally, in carrying out the methods detailed in this
application, an effective dosage for the compounds of Formulas I is
in the range of about 0.01 mg/kg/day to about 100 mg/kg/day in
single or divided doses, for instance 0.01 mg/kg/day to about 50
mg/kg/day in single or divided doses. The compounds of Formulas I
may be administered at a dose of, for example, less than 0.2
mg/kg/day, 0.5 mg/kg/day, 1.0 mg/kg/day, 5 mg/kg/day, 10 mg/kg/day,
20 mg/kg/day, 30 mg/kg/day, or 40 mg/kg/day. Compounds of Formula I
and formula II may also be administered to a human patient at a
dose of, for example, between 0.1 mg and 1000 mg, between 5 mg and
80 mg, or less than 1.0, 9.0, 12.0, 20.0, 50.0, 75.0, 100, 300,
400, 500, 800, 1000, 2000, 5000 mg per day. In certain embodiments,
the compositions herein are administered at an amount that is less
than 95%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, or 10% of the
compound of formula I and formula II required for the same
therapeutic benefit.
[0063] An effective amount of the compounds of formula I and
formula II described herein refers to the amount of one of said
salts or compositions which is capable of inhibiting or preventing
a disease.
[0064] An effective amount may be sufficient to prohibit, treat,
alleviate, ameliorate, halt, restrain, slow or reverse the
progression, or reduce the severity of a complication resulting
from nerve damage or demyelization and/or elevated reactive
oxidative-nitrosative species and/or abnormalities in
neurotransmitter homeostasis's, in patients who are at risk for
such complications. As such, these methods include both medical
therapeutic (acute) and/or prophylactic (prevention) administration
as appropriate. The amount and timing of compositions administered
will, of course, be dependent on the subject being treated, on the
severity of the affliction, on the manner of administration and on
the judgment of the prescribing physician. Thus, because of
patient-to-patient variability, the dosages given above are a
guideline and the physician may titrate doses of the drug to
achieve the treatment that the physician considers appropriate for
the patient. In considering the degree of treatment desired, the
physician must balance a variety of factors such as age of the
patient, presence of preexisting disease, as well as presence of
other diseases.
[0065] The compositions provided by this application may be
administered to a subject in need of treatment by a variety of
conventional routes of administration, including orally, topically,
parenterally, e.g., intravenously, subcutaneously or
intramedullary. Further, the compositions may be administered
intranasally, as a rectal suppository, or using a "flash"
formulation, i.e., allowing the medication to dissolve in the mouth
without the need to use water. Furthermore, the compositions may be
administered to a subject in need of treatment by controlled
release dosage forms, site specific drug delivery, transdermal drug
delivery, patch (active/passive) mediated drug delivery, by
stereotactic injection, or in nanoparticles.
[0066] The compositions may be administered alone or in combination
with pharmaceutically acceptable carriers, vehicles or diluents, in
either single or multiple doses. Suitable pharmaceutical carriers,
vehicles and diluents include inert solid diluents or fillers,
sterile aqueous solutions and various organic solvents. The
pharmaceutical compositions formed by combining the compositions
and the pharmaceutically acceptable carriers, vehicles or diluents
are then readily administered in a variety of dosage forms such as
tablets, powders, lozenges, syrups, injectable solutions and the
like. These pharmaceutical compositions can, if desired, contain
additional ingredients such as flavorings, binders, excipients and
the like. Thus, for purposes of oral administration, tablets
containing various excipients such as L-arginine, sodium citrate,
calcium carbonate and calcium phosphate may be employed along with
various disintegrates such as starch, alginic acid and certain
complex silicates, together with binding agents such as
polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally,
lubricating agents such as magnesium stearate, sodium lauryl
sulfate and talc are often useful for tabletting purposes. Solid
compositions of a similar type may also be employed as fillers in
soft and hard filled gelatin capsules. Appropriate materials for
this include lactose or milk sugar and high molecular weight
polyethylene glycols. When aqueous suspensions or elixirs are
desired for oral administration, the essential active ingredient
therein may be combined with various sweetening or flavoring
agents, coloring matter or dyes and, if desired, emulsifying or
suspending agents, together with diluents such as water, ethanol,
propylene glycol, glycerin and combinations thereof. The compounds
of formula I and formula II may also comprise enterically coated
comprising of various excipients, as is well known in the
pharmaceutical art.
[0067] For parenteral administration, solutions of the compositions
may be prepared in (for example) sesame or peanut oil, aqueous
propylene glycol, or in sterile aqueous solutions may be employed.
Such aqueous solutions should be suitably buffered if necessary and
the liquid diluent first rendered isotonic with sufficient saline
or glucose. These particular aqueous solutions are especially
suitable for intravenous, intramuscular, subcutaneous and
intraperitoneal administration. In this connection, the sterile
aqueous media employed are all readily available by standard
techniques known to those skilled in the art.
[0068] The formulations, for instance tablets, may contain e.g. 10
to 100, 50 to 250, 150 to 500 mg, or 350 to 800 mg e.g. 10, 50,
100, 300, 500, 700, 800 mg of the compounds of formula I and
formula II disclosed herein, for instance, compounds of formula I
and formula II or pharmaceutical acceptable salts of a compounds of
Formula I.
[0069] Generally, a composition as described herein may be
administered orally, or parenterally (e.g., intravenous,
intramuscular, subcutaneous or intramedullary). Topical
administration may also be indicated, for example, where the
patient is suffering from gastrointestinal disorder that prevent
oral administration, or whenever the medication is best applied to
the surface of a tissue or organ as determined by the attending
physician. Localized administration may also be indicated, for
example, when a high dose is desired at the target tissue or organ.
For buccal administration the active composition may take the form
of tablets or lozenges formulated in a conventional manner.
[0070] The dosage administered will be dependent upon the identity
of the inflammatory bowel disease; the type of host involved,
including its age, health and weight; the kind of concurrent
treatment, if any; the frequency of treatment and therapeutic
ratio.
[0071] Illustratively, dosage levels of the administered active
ingredients are: intravenous, 0.1 to about 200 mg/kg;
intramuscular, 1 to about 500 mg/kg; orally, 5 to about 1000 mg/kg;
intranasal instillation, 5 to about 1000 mg/kg; and aerosol, 5 to
about 1000 mg/kg of host body weight.
[0072] Expressed in terms of concentration, an active ingredient
can be present in the compositions of the present invention for
localized use about the cutis, intranasally, pharyngolaryngeally,
bronchially, intravaginally, rectally, or ocularly in a
concentration of from about 0.01 to about 50% w/w of the
composition; preferably about 1 to about 20% w/w of the
composition; and for parenteral use in a concentration of from
about 0.05 to about 50% w/v of the composition and preferably from
about 5 to about 20% w/v.
[0073] The compositions of the present invention are preferably
presented for administration to humans and animals in unit dosage
forms, such as tablets, capsules, pills, powders, granules,
suppositories, sterile parenteral solutions or suspensions, sterile
non-parenteral solutions of suspensions, and oral solutions or
suspensions and the like, containing suitable quantities of an
active ingredient. For oral administration either solid or fluid
unit dosage forms can be prepared.
[0074] As discussed above, the tablet core contains one or more
hydrophilic polymers. Suitable hydrophilic polymers include, but
are not limited to, water swellable cellulose derivatives,
polyalkylene glycols, thermoplastic polyalkylene oxides, acrylic
polymers, hydrocolloids, clays, gelling starches, swelling
cross-linked polymers, and mixtures thereof. Examples of suitable
water swellable cellulose derivatives include, but are not limited
to, sodium carboxymethylcellulose, cross-linked
hydroxypropylcellulose, hydroxypropyl cellulose (HPC),
hydroxypropylmethylcellulose (HPMC), hydroxyisopropylcellulose,
hydroxybutylcellulose, hydroxyphenylcellulose,
hydroxyethylcellulose (HEC), hydroxypentylcellulose,
hydroxypropylethylcellulose, hydroxypropylbutylcellulose, and
hydroxypropylethylcellulose, and mixtures thereof. Examples of
suitable polyalkylene glycols include, but are not limited to,
polyethylene glycol. Examples of suitable thermoplastic
polyalkylene oxides include, but are not limited to, poly(ethylene
oxide). Examples of suitable acrylic polymers include, but are not
limited to, potassium methacrylatedivinylbenzene copolymer,
polymethylmethacrylate, high-molecular weight crosslinked acrylic
acid homopolymers and copolymers such as those commercially
available from Noveon Chemicals under the tradename CARBOPOL.TM..
Examples of suitable hydrocolloids include, but are not limited to,
alginates, agar, guar gum, locust bean gum, kappa carrageenan, iota
carrageenan, tara, gum arabic, tragacanth, pectin, xanthan gum,
gellan gum, maltodextrin, galactomannan, pusstulan, laminarin,
scleroglucan, gum arabic, inulin, pectin, gelatin, whelan, rhamsan,
zooglan, methylan, chitin, cyclodextrin, chitosan, and mixtures
thereof. Examples of suitable clays include, but are not limited
to, smectites such as bentonite, kaolin, and laponite; magnesium
trisilicate; magnesium aluminum silicate; and mixtures thereof.
Examples of suitable gelling starches include, but are not limited
to, acid hydrolyzed starches, swelling starches such as sodium
starch glycolate and derivatives thereof, and mixtures thereof.
Examples of suitable swelling cross-linked polymers include, but
are not limited to, cross-linked polyvinyl pyrrolidone,
cross-linked agar, and cross-linked carboxymethylcellulose sodium,
and mixtures thereof.
[0075] The carrier may contain one or more suitable excipients for
the formulation of tablets. Examples of suitable excipients
include, but are not limited to, fillers, adsorbents, binders,
disintegrants, lubricants, glidants, release-modifying excipients,
superdisintegrants, antioxidants, and mixtures thereof.
[0076] Suitable binders include, but are not limited to, dry
binders such as polyvinyl pyrrolidone and
hydroxypropylmethylcellulose; wet binders such as water-soluble
polymers, including hydrocolloids such as acacia, alginates, agar,
guar gum, locust bean, carrageenan, carboxymethylcellulose, tara,
gum arabic, tragacanth, pectin, xanthan, gellan, gelatin,
maltodextrin, galactomannan, pusstulan, laminarin, scleroglucan,
inulin, whelan, rhamsan, zooglan, methylan, chitin, cyclodextrin,
chitosan, polyvinyl pyrrolidone, cellulosics, sucrose, and
starches; and mixtures thereof. Suitable disintegrants include, but
are not limited to, sodium starch glycolate, cross-linked
polyvinylpyrrolidone, cross-linked carboxymethylcellulose,
starches, microcrystalline cellulose, and mixtures thereof.
[0077] Suitable lubricants include, but are not limited to, long
chain fatty acids and their salts, such as magnesium stearate and
stearic acid, talc, glycerides waxes, and mixtures thereof.
Suitable glidants include, but are not limited to, colloidal
silicon dioxide. Suitable release-modifying excipients include, but
are not limited to, insoluble edible materials, pH-dependent
polymers, and mixtures thereof.
[0078] Suitable insoluble edible materials for use as
release-modifying excipients include, but are not limited to,
water-insoluble polymers and low-melting hydrophobic materials,
copolymers thereof, and mixtures thereof. Examples of suitable
water-insoluble polymers include, but are not limited to,
ethylcellulose, polyvinyl alcohols, polyvinyl acetate,
polycaprolactones, cellulose acetate and its derivatives,
acrylates, methacrylates, acrylic acid copolymers, copolymers
thereof, and mixtures thereof. Suitable low-melting hydrophobic
materials include, but are not limited to, fats, fatty acid esters,
phospholipids, waxes, and mixtures thereof. Examples of suitable
fats include, but are not limited to, hydrogenated vegetable oils
such as for example cocoa butter, hydrogenated palm kernel oil,
hydrogenated cottonseed oil, hydrogenated sunflower oil, and
hydrogenated soybean oil, free fatty acids and their salts, and
mixtures thereof. Examples of suitable fatty acid esters include,
but are not limited to, sucrose fatty acid esters, mono-, di-, and
triglycerides, glyceryl behenate, glyceryl palmitostearate,
glyceryl monostearate, glyceryl tristearate, glyceryl trilaurylate,
glyceryl myristate, GlycoWax-932, lauroyl macrogol-32 glycerides,
stearoyl macrogol-32 glycerides, and mixtures thereof. Examples of
suitable phospholipids include phosphotidyl choline, phosphotidyl
serene, phosphotidyl enositol, phosphotidic acid, and mixtures
thereof. Examples of suitable waxes include, but are not limited
to, carnauba wax, spermaceti wax, beeswax, candelilla wax, shellac
wax, microcrystalline wax, and paraffin wax; fat-containing
mixtures such as chocolate, and mixtures thereof. Examples of super
disintegrants include, but are not limited to, croscarmellose
sodium, sodium starch glycolate and cross-linked povidone
(crospovidone). In one embodiment the tablet core contains up to
about 5 percent by weight of such super disintegrant.
[0079] Examples of antioxidants include, but are not limited to,
tocopherols, ascorbic acid, sodium pyrosulfite,
butylhydroxytoluene, butylated hydroxyanisole, edetic acid, and
edetate salts, and mixtures thereof. Examples of preservatives
include, but are not limited to, citric acid, tartaric acid, lactic
acid, malic acid, acetic acid, benzoic acid, and sorbic acid, and
mixtures thereof.
[0080] In one embodiment, the immediate release coating has an
average thickness of at least 50 microns, such as from about 50
microns to about 2500 microns; e.g., from about 250 microns to
about 1000 microns. In embodiment, the immediate release coating is
typically compressed at a density of more than about 0.9 g/cc, as
measured by the weight and volume of that specific layer.
[0081] In one embodiment, the immediate release coating contains a
first portion and a second portion, wherein at least one of the
portions contains the second pharmaceutically active agent. In one
embodiment, the portions contact each other at a center axis of the
tablet. In one embodiment, the first portion includes the first
pharmaceutically active agent and the second portion includes the
second pharmaceutically active agent.
[0082] In one embodiment, the first portion contains the first
pharmaceutically active agent and the second portion contains the
second pharmaceutically active agent. In one embodiment, one of the
portions contains a third pharmaceutically active agent. In one
embodiment one of the portions contains a second immediate release
portion of the same pharmaceutically active agent as that contained
in the tablet core.
[0083] In one embodiment, the outer coating portion is prepared as
a dry blend of materials prior to addition to the coated tablet
core. In another embodiment the outer coating portion is included
of a dried granulation including the pharmaceutically active
agent.
[0084] Formulations with different drug release mechanisms
described above could be combined in a final dosage form containing
single or multiple units. Examples of multiple units include
multilayer tablets, capsules containing tablets, beads, or granules
in a solid or liquid form. Typical, immediate release formulations
include compressed tablets, gels, films, coatings, liquids and
particles that can be encapsulated, for example, in a gelatin
capsule. Many methods for preparing coatings, covering or
incorporating drugs, are known in the art.
[0085] The immediate release dosage, unit of the dosage form, i.e.,
a tablet, a plurality of drug-containing beads, granules or
particles, or an outer layer of a coated core dosage form, contains
a therapeutically effective quantity of the active agent with
conventional pharmaceutical excipients. The immediate release
dosage unit may or may not be coated, and may or may not be admixed
with the delayed release dosage unit or units (as in an
encapsulated mixture of immediate release drug-containing granules,
particles or beads and delayed release drug-containing granules or
beads).
[0086] Extended release formulations are generally prepared as
diffusion or osmotic systems, for example, as described in
"Remington--The Science and Practice of Pharmacy", 20th. Ed.,
Lippincott Williams & Wilkins, Baltimore, Md., 2000). A
diffusion system typically consists of one of two types of devices,
reservoir and matrix, which are wellknown and described in die art.
The matrix devices are generally prepared by compressing the drug
with a slowly dissolving polymer carrier into a tablet form.
[0087] An immediate release portion can be added to the extended
release system by means of either applying an immediate release
layer on top of the extended release core; using coating or
compression processes or in a multiple unit system such as a
capsule containing extended and immediate release beads.
[0088] Delayed release dosage formulations are created by coating a
solid dosage form with a film of a polymer which is insoluble in
the acid environment of the stomach, but soluble in the neutral
environment of small intestines. The delayed release dosage units
can be prepared, for example, by coating a drug or a
drug-containing composition with a selected coating material. The
drug-containing composition may be a tablet for incorporation into
a capsule, a tablet for use as an inner core in a "coated core"
dosage form, or a plurality of drug-containing beads, particles or
granules, for incorporation into either a tablet or capsule.
[0089] A pulsed release dosage form is one that mimics a multiple
dosing profile without repeated dosing and typically allows at
least a twofold reduction in dosing frequency as compared to the
drug presented as a conventional dosage form (e.g., as a solution
or prompt drug-releasing, conventional solid dosage form). A pulsed
release profile is characterized by a time period of no release
(lag time) or reduced release followed by rapid drug release.
[0090] Each dosage form contains a therapeutically effective amount
of active agent. In one embodiment of dosage forms that mimic a
twice daily dosing profile, approximately 30 wt. % to 70 wt. %,
preferably 40 wt. % to 60 wt. %, of the total amount of active
agent in the dosage form is released in the initial pulse, and,
correspondingly approximately 70 wt. % to 3.0 wt. %, preferably 60
wt. % to 40 wt. %, of the total amount of active agent in the
dosage form is released in the second pulse. For dosage forms
mimicking the twice daily dosing profile, the second pulse is
preferably released approximately 3 hours to less than 14 hours,
and more preferably approximately 5 hours to 12 hours, following
administration.
[0091] Another dosage form contains a compressed tablet or a
capsule having a drug-containing immediate release dosage unit, a
delayed release dosage unit and an optional second delayed release
dosage unit. In this dosage form, the immediate release dosage unit
contains a plurality of beads, granules particles that release drug
substantially immediately following oral administration to provide
an initial dose. The delayed release dosage unit contains a
plurality of coated beads or granules, which release drug
approximately 3 hours to 14 hours following oral administration to
provide a second dose.
[0092] For purposes of transdermal (e.g., topical) administration,
dilute sterile, aqueous or partially aqueous solutions (usually in
about 0.1% to 5% concentration), otherwise similar to the above
parenteral solutions, may be prepared.
[0093] Methods of preparing various pharmaceutical compositions
with a certain amount of one or more compounds of formula I and
formula II or other active agents are known, or will be apparent in
light of this disclosure, to those skilled in this art. For
examples of methods of preparing pharmaceutical compositions, see
Remington's Pharmaceutical Sciences, Mack Publishing Company,
Easton, Pa., 19th Edition (1995).
[0094] In addition, in certain embodiments, subject compositions of
the present application maybe lyophilized or subjected to another
appropriate drying technique such as spray drying. The subject
compositions may be administered once, or may be divided into a
number of smaller doses to be administered at varying intervals of
time, depending in part on the release rate of the compositions and
the desired dosage.
[0095] Formulations useful in the methods provided herein include
those suitable for oral, nasal, topical (including buccal and
sublingual), rectal, vaginal, aerosol and/or parenteral
administration. The formulations 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 a subject composition which may
be combined with a carrier material to produce a single dose may
vary depending upon the subject being treated, and the particular
mode of administration.
[0096] Methods of preparing these formulations or compositions
include the step of bringing into association subject compositions
with the carrier and, optionally, one or more accessory
ingredients. In general, the formulations are prepared by uniformly
and intimately bringing into association a subject composition with
liquid carriers, or finely divided solid carriers, or both, and
then, if necessary, shaping the product.
[0097] The compounds of formula I and formula II described herein
may be administered in inhalant or aerosol formulations. The
inhalant or aerosol formulations may comprise one or more agents,
such as adjuvants, diagnostic agents, imaging agents, or
therapeutic agents useful in inhalation therapy. The final aerosol
formulation may for example contain 0.005-90% w/w, for instance
0.005-50%, 0.005-5% w/w, or 0.01-1.0% w/w, of medicament relative
to the total weight of the formulation.
[0098] In solid dosage forms for oral administration (capsules,
tablets, pills, dragees, powders, granules and the like), the
subject composition is mixed with one or more pharmaceutically
acceptable carriers and/or any of the following: (1) fillers or
extenders, such as starches, lactose, sucrose, glucose, mannitol,
and/or silicic acid; (2) binders, such as, for example,
carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone,
sucrose and/or acacia; (3) humectants, such as glycerol; (4)
disintegrating agents, such as agar-agar, calcium carbonate, potato
or tapioca starch, alginic acid, certain silicates, and sodium
carbonate; (5) solution retarding agents, such as paraffin; (6)
absorption accelerators, such as quaternary ammonium compounds; (7)
wetting agents, such as, for example, acetyl alcohol and glycerol
monostearate; (8) absorbents, such as kaolin and bentonite clay;
(9) lubricants, such a talc, calcium stearate, magnesium stearate,
solid polyethylene glycols, sodium lauryl sulfate, and mixtures
thereof; and (10) coloring agents. In the case of capsules, tablets
and pills, the pharmaceutical compositions may also comprise
buffering agents. Solid compositions of a similar type may also be
employed as fillers in soft and hard-filled gelatin capsules using
lactose or milk sugars, as well as high molecular weight
polyethylene glycols and the like.
[0099] Liquid dosage forms for oral administration include
pharmaceutically acceptable emulsions, microemulsions, solutions,
suspensions, syrups and elixirs. In addition to the subject
compositions, 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, corn, peanut, sunflower, soybean,
olive, castor, and sesame oils), glycerol, tetrahydrofuryl alcohol,
polyethylene glycols and fatty acid esters of sorbitan, and
mixtures thereof.
[0100] Suspensions, in addition to the subject compositions, may
contain suspending agents such as, for example, ethoxylated
isostearyl alcohols, polyoxyethylene sorbitol, and sorbitan esters,
microcrystalline cellulose, aluminum metahydroxide, bentonite,
agar-agar and tragacanth, and mixtures thereof.
[0101] Formulations for rectal or vaginal administration may be
presented as a suppository, which may be prepared by mixing a
subject composition with one or more suitable non-irritating
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 appropriate body cavity and release the
encapsulated compound(s) and composition(s). Formulations which are
suitable for vaginal administration also include pessaries,
tampons, creams, gels, pastes, foams, or spray formulations
containing such carriers as are known in the art to be
appropriate.
[0102] Dosage forms for transdermal administration include powders,
sprays, ointments, pastes, creams, lotions, gels, solutions,
patches, and inhalants. A subject composition may be mixed under
sterile conditions with a pharmaceutically acceptable carrier, and
with any preservatives, buffers, or propellants that may be
required. For transdermal administration, the complexes may include
lipophilic and hydrophilic groups to achieve the desired water
solubility and transport properties.
[0103] The ointments, pastes, creams and gels may contain, in
addition to subject compositions, other carriers, such as animal
and vegetable fats, oils, waxes, paraffins, starch, tragacanth,
cellulose derivatives, polyethylene glycols, silicones, bentonites,
silicic acid, talc and zinc oxide, or mixtures thereof. Powders and
sprays may contain, in addition to a subject composition,
excipients such as lactose, talc, silicic acid, aluminum hydroxide,
calcium silicates and polyamide powder, or mixtures of such
substances. Sprays may additionally contain customary propellants,
such as chlorofluorohydrocarbons and volatile unsubstituted
hydrocarbons, such as butane and propane.
[0104] Methods of delivering a composition or compositions via a
transdermal patch are known in the art. Exemplary patches and
methods of patch delivery are described in U.S. Pat. Nos.
6,974,588, 6,564,093, 6,312,716, 6,440,454, 6,267,983, 6,239,180,
and 6,103,275.
[0105] In another embodiment, a transdermal patch may comprise: a
substrate sheet comprising a composite film formed of a resin
composition comprising 100 parts by weight of a polyvinyl
chloride-polyurethane composite and 2-10 parts by weight of a
styrene-ethylene-butylene-styrene copolymer, a first adhesive layer
on the one side of the composite film, and a polyalkylene
terephthalate film adhered to the one side of the composite film by
means of the first adhesive layer, a primer layer which comprises a
saturated polyester resin and is formed on the surface of the
polyalkylene terephthalate film; and a second adhesive layer
comprising a styrene-diene-styrene block copolymer containing a
pharmaceutical agent layered on the primer layer. A method for the
manufacture of the above-mentioned substrate sheet comprises
preparing the above resin composition molding the resin composition
into a composite film by a calendar process, and then adhering a
polyalkylene terephthalate film on one side of the composite film
by means of an adhesive layer thereby forming the substrate sheet,
and forming a primer layer comprising a saturated polyester resin
on the outer surface of the polyalkylene terephthalate film.
[0106] Another type of patch comprises incorporating the drug
directly in a pharmaceutically acceptable adhesive and laminating
the drug-containing adhesive onto a suitable backing member, e.g. a
polyester backing membrane. The drug should be present at a
concentration which will not affect the adhesive properties, and at
the same time deliver the required clinical dose.
[0107] Transdermal patches may be passive or active. Passive
transdermal drug delivery systems currently available, such as the
nicotine, estrogen and nitroglycerine patches, deliver
small-molecule drugs. Many of the newly developed proteins and
peptide drugs are too large to be delivered through passive
transdermal patches and may be delivered using technology such as
electrical assist (iontophoresis) for large-molecule drugs.
[0108] Iontophoresis is a technique employed for enhancing the flux
of ionized substances through membranes by application of electric
current. One example of an iontophoretic membrane is given in U.S.
Pat. No. 5,080,646 to Theeuwes. The principal mechanisms by which
iontophoresis enhances molecular transport across the skin are (a)
repelling a charged ion from an electrode of the same charge, (b)
electroosmosis, the convective movement of solvent that occurs
through a charged pore in response the preferential passage of
counter-ions when an electric field is applied or (c) increase skin
permeability due to application of electrical current.
[0109] In some cases, it may be desirable to administer in the form
of a kit, it may comprise a container for containing the separate
compositions such as a divided bottle or a divided foil packet.
Typically the kit comprises directions for the administration of
the separate components. The kit form is particularly advantageous
when the separate components are preferably administered in
different dosage forms (e.g., oral and parenteral), are
administered at different dosage intervals, or when titration of
the individual components of the combination is desired by the
prescribing physician.
[0110] An example of such a kit is a so-called blister pack.
Blister packs are well known in the packaging industry and are
widely used for the packaging of pharmaceutical unit dosage forms
(tablets, capsules, and the like). Blister packs generally consist
of a sheet of relatively stiff material covered with a foil of a
plastic material that may be transparent.
[0111] Methods and compositions for the treatment of Inflammatory
Bowel Disease. Among other things, herein is provided a method of
treating Inflammatory Bowel Disease, comprising administering to a
patient in need thereof a therapeutically effective amount of
compound of Formula I:
##STR00015##
[0112] Wherein,
[0113] R.sup.1, R.sup.3 each independently represents
--CH.sub.3CO--, acetyl, D, H, CD.sub.3CO--,
##STR00016##
[0114] R.sup.2, R.sup.4 each independently represents H, D,
##STR00017## ##STR00018##
[0115] a is independently 2, 3 or 7;
[0116] each b is independently 3, 5 or 6;
[0117] e is independently 1, 2 or 6;
[0118] c and d are each independently H, D, --OH, --OD,
C.sub.1-C.sub.6-alkyl, --NH.sub.2 or --COCH.sub.3;
[0119] Accordingly, in another aspect the methods and compositions
for the treatment of Inflammatory Bowel Disease. Among other
things, herein is provided a method of treating Inflammatory Bowel
Disease, comprising administering to a patient in need thereof a
therapeutically effective amount of compound of Formula II:
##STR00019##
[0120] Wherein
[0121] R.sup.1, R.sup.3 each independently represents H, D,
##STR00020##
[0122] R.sup.2, R.sup.4 each independently represents D,
CH.sub.3CO, CD.sub.3CO,
##STR00021## ##STR00022##
[0123] a is independently 2, 3 or 7;
[0124] each b is independently 3, 5 or 6;
[0125] e is independently 1, 2 or 6;
[0126] c and d are each independently H, D, --OH, --OD,
C.sub.1-C.sub.6-alkyl, --NH.sub.2 or --COCH.sub.3.
Methods for Using Compounds of Formula I and Formula II:
[0127] The invention also includes methods for treating
gastrointestinal diseases and inflammation such as inflammatory
bowel disease, ulcerative colitis, mild-to-moderate Crohn's
disease, rheumatoid arthritis, inflammatory arthritis, psoriatic
arthritis, liver cirrhosis and idiopathic urticaria.
Methods of Making
[0128] Examples of synthetic pathways useful for making compounds
of formula I and formula II are set forth in example below and
generalized in scheme 1, scheme 2 and scheme 3:
##STR00023##
Step-1: Synthesis of Compound 2
##STR00024##
[0130] To a stirred solution of potassium hydroxide (70 kg, 1250
mol) and water (250 L) was added 2 (50 kg, 248 mol) over a period
of 20 minutes between 25 and 30.degree. C. in an autoclave. The
reaction mixture was heated to 125-130.degree. C., stirred at the
same temperature for 5 hours under 2.5 kg/cm2. The reaction mass
was cooled to 25.degree. C. and acidified to pH 1.0-2.0 using
hydrochloric acid (85 L), stirred for 1 hour. The precipitated
solid was filtered and washed with water (150 L), and the cake was
slurried in water (300 L) at 30.degree. C. for 1 hour, filtered,
washed with water (150 L) and dried at 65.degree. C. for 10 hours
to afford 3 43.5 kg Yield: 43.5 kg (96%) (Purity: 99.87%).
Step-2: Synthesis of Compound 3
##STR00025##
[0132] Compound 2 (40 kg, 218 mol) was added slowly to a stirred
mixture of water (320 L) and sodium carbonate (16.3 kg, 153 mol),
stirred for 30 minutes and the mass pH maintained between 8.0 and
9.5. 10% Raney Nickel (8 L) along with water (80 L) was added to
the above solution. The resultant mixture was hydrogenated at
atmospheric pressure at 60.degree. C. for 6 hours. 5% sodium
hydroxide (130 L) was added to the mass at 25.degree. C., stirred
for 30 minutes. The catalyst was filtered through celite, and
washed with water (80 L). The solution was acidified to pH 2.5-3.0
with hydrochloric acid (33 L) and stirred for 1 hour. The obtained
compound was filtered, washed with water (40 L). To the solution of
wet cake and water (560 L) and hydrochloric acid (41 L), active
charcoal (2.8 kg) was added, and the contents were heated to
70.degree. C., maintained at the same temperature for 2 hours.
Filtered the total solution through celite, washed with water (28
L). Active charcoal (2.8 kg) was added to the filtrate, stirred at
a temperature of 70.degree. C. for 2 hours, filtered through celite
and washed with water (28 L). To the obtained filtrate, pH was
adjusted to 3.0-3.5 with aq. sodium bicarbonate solution (15 L),
stirred for 1 hour, filtered the solid and washed with water (42
L), dried the solid at 80.degree. C. for 9 hours to give the title
compound 3 as a off white colored powder. Yield: 27.5 kg (82%)
(Purity: 99.9%).
Step-3: Synthesis of Compound 4
##STR00026##
[0134] Compound 3 (10 mmol) was kept in a RB, added thionyl
chloride 10 ml and refluxed the reaction mixture. After completion
of the reaction, excess thionyl chloride was distilled off and the
crude acid chloride (4) was used for next step without further
purification.
Step-4: Synthesis of Compound 6
##STR00027##
[0136] To a solution of compound 5 (1.0 mmol) in dry DCM (1.8 ml)
was added N, N-diisopropylethylamine (2.0 mmol) at -10.degree. C.,
followed by drop wise addition of 4 (1.2 mmol) for 30 min at the
same temperature and the reaction mixture was allowed to stir for 1
h at 0.degree. C. On completion of the reaction (monitored by TLC),
the reaction mixture the solvent was evaporated and the crude was
purified through column to obtain compound 6.
Step-5: Synthesis of Compound 8
##STR00028##
[0138] A 50 mL vial was charged with a magnetic spin bar, compound
6 (0.38 mmol), acid 7 (0.57 mmol), DMF (1.912 ml), and
diisopropylethylamine (0.334 ml, 1.91 mmol). With stirring, HATU
(0.291 g, 0.76 mmol) was added and the reaction was warmed to
50.degree. C. for 3 h. The reaction was then diluted with water and
extracted with ethyl acetate (3.times.50 mL). The combined organic
extract was dried with MgSO4, filtered through a bed of Celite, and
cone, in vacuo to yield the product which was purified via silica
gel to get compound 8. M.F: C35H49NO5; Mol. Wt.: 563.36; Elemental
Analysis: C, 74.57; H, 8.76; N, 2.48; O, 14.19.
##STR00029##
Step-1: Synthesis of Compound 2
##STR00030##
[0140] Compound 1 (10 mmol) was kept in a RB, added thionyl
chloride 10 ml and refluxed the reaction mixture. After completion
of the reaction, excess thionyl chloride 2 was distilled off and
the crude acid chloride was used for next step without further
purification.
Step-2: Synthesis of Compound 4
##STR00031##
[0142] To a solution of compound 3 (1.0 mmol) in dry DCM (1.8 ml)
was added N, N-diisopropylethylamine (2.0 mmol) at -10.degree. C.,
followed by drop wise addition of 2 (1.2 mmol) for 30 min at the
same temperature and the reaction mixture was allowed to stir for 1
h at 0.degree. C. On completion of the reaction (monitored by TLC),
the reaction mixture the solvent was evaporated and the crude was
purified through column to get compound 4.
Step-3: Synthesis of Compound 6
##STR00032##
[0144] Compound 5 (10 mmol) was kept in a RB, added thionyl
chloride 10 ml and refluxed the reaction mixture. After completion
of the reaction, excess thionyl chloride 6 was distilled off and
the crude acid chloride was used for next step without further
purification.
Step-4: Synthesis of Compound 8
##STR00033##
[0146] To a solution of compound 7 (1.0 mmol) in dry DCM (1.8 ml)
was added N, N-diisopropylethylamine (2.0 mmol) at -10.degree. C.,
followed by drop wise addition of 6 (1.2 mmol) for 30 min at the
same temperature and the reaction mixture was allowed to stir for 1
h at 0.degree. C. On completion of the reaction (monitored by TLC),
the reaction mixture the solvent was evaporated and the crude was
purified through column to get compound 8.
Step-5: Synthesis of Compound 9
##STR00034##
[0148] NaH (15 mmol) was taken in a RB, added DMF, cooled to
0.degree. C. and added Compound 8 in DMF (10 mmol) dropwise with
stirring. The stirring was continued for 20 min and then added
CH3I, stirred the reaction mixture at room temperature for 4 h.
After completion of the reaction the mixture was cooled to
0.degree. C. and added ice cold water dropwise. The reaction
mixture was extracted with diethyl ether and the organic layer was
dried over Na2SO4 and evaporated to get the crude product which was
purified through column to get compound 9.
Step-6: Synthesis of Compound 10
##STR00035##
[0150] Compound 9 (0.56 mmol) was dissolved in a mixture of 5 mL of
concentrated HCl and 2.5 mL of water and diazotized with a solution
of sodium nitrite (0.56 mmol). In the meantime compound 4 (0.56
mmol), potassium hydroxide (1.12 mmol) and sodium carbonate are
dissolved in water. The diazo suspension is added in portions to
the alkaline solution of salicylic acid and the alkalinity
maintained at a sufficiently high level during the whole reaction
by means of addition of further quantities of potassium hydroxide
solution. After 2 days the reaction mixture is heated for 30 min at
50.degree. C. The azo compound 10 was precipitated by means of HCl
and filtered off (yield 85%), to yield the compound 10.
Step-7: Synthesis of Compound 11
##STR00036##
[0152] Compound 10 (1 mmol) was dissolved in dry DCM (5 ml) and
added boron tribromide (BBr3) (1.0 M, 2 mmol) at 0.degree. C. and
stirred the reaction mixture at rt for 5 h. After completion of
reaction the mixture was cooled to 0.degree. C. and added saturated
aqueous NaHCO3 dropwise to neutralize the reaction mixture. The two
layers were separated and the organic layer was dried over and
evaporated to get the crude material which on purification through
column to yielded compound 11. M.F: C.sub.42H.sub.52N.sub.2O.sub.8;
Mol. Wt.: 712.37; Elemental Analysis: C, 70.76; H, 7.35; N, 3.93;
O, 17.95.
##STR00037##
Step-1: Synthesis of Compound 2
##STR00038##
[0154] (5Z,8Z,11Z,14Z,17Z)-ethyl icosa-5,8,11,14,17-pentaenoate (1,
50 g, 0.151 mol) was dissolved in Methanol (1000 ml) and added NaOH
aqueous solution (60.5 g, 1.513 moles, 200 ml of H.sub.2O). Then
the Reaction Mixture was stirred for 2 h at room temperature. After
completion of the reaction, volatiles were evaporated under reduced
pressure on rotavap. The obtained crude material was diluted with
water (200 ml) and acidified with 3N HCl, extracted with ethyl
acetate (2.times.300 ml). The combined organic extracts were washed
with brine (2.times.100 mL), dried over anhydrous sodium sulfate,
filtered and concentrated to dryness. Purification on silica gel
(20% EtOAc in hexane) yielded compound 2 (38 g, 83.12% yield); Mass
(m/z): 301 (M-H).
Step-2: Synthesis of Compound 3
##STR00039##
[0156] To a solution of compound 2 (10 g, 0.033 mol) in DCM (40 ml)
was added oxallyl chloride (4.32 ml, 0.049 mol) at 0.degree. C.,
added 1 drop of DMF. Then the reaction mixture was stirred for 1 h
at room temperature. After completion of the reaction, mixture was
concentrated under N.sub.2 atmosphere. The obtained crude 3 (10 g)
was taken up in the next step without any further purification.
Step-3: Synthesis of Compound 5
##STR00040##
[0158] To a solution of 5-amino-2-hydroxybenzoic acid (4, 5.06 g,
0.033 mol) in CH.sub.2Cl.sub.2 (20 ml) was added Triethyl amine
(13.8 ml, 0.099 mol) and compound 3 at 0.degree. C. The mixture was
continued to stir for 1 h at the same temperature. After completion
of the reaction, acidified with 2N HCl and separated the organic
layer, dried over anhydrous sodium sulfate, filtered and
concentrated to dryness. Purification by recrystallization in
hexane gave compound 5 (5 g, 34.7% yield); Mass (m/z): 438.5
(M+H).
Step-4: Synthesis of Compound 6
##STR00041##
[0160] Part-A:
[0161] To a stirred solution of octanoic acid (10 g, 0.069 mol) in
dichloromethane (60 mL), 1-2 drops of DMF followed by oxallyl
chloride (9.0 mL, 0.103 mol, 1.5 eq.) were added drop wise at
0.degree. C. under N.sub.2 atmosphere for 20 min and stirred at
room temperature. After being stirred for 2 h volatiles were
concentrated under nitrogen atmosphere to gave octonoyl chloride
[crude].
[0162] Part-B:
[0163] To a stirred solution of sodium iodide (10.3 g, 0.069 mol, 1
eq.) in acetonitrile (70 mL) at 0.degree. C. was added acetaldehyde
(3.88 ml, 0.069 mol) then added the above acid chloride [Part-A] to
it and stirred the mixture for another 2 h at 0-5.degree. C. After
completion of the reaction (monitored by TLC) mixture was poured in
to ice water (100 mL) and extracted with hexane (2.times.200 mL).
The combined organic extracts were washed with 5% aqueous
sodiumthiosulfate solution (2.times.50 ml), 5% sodium bicarbonate
solution (50 mL) and finally with brine solution (2.times.50 ml),
dried over anhydrous sodium sulfate, filtered and concentrated to
dryness to afford crude compound-6 as oil (10 g, 48.5%). Used in
the next step without any further purification.
Step-5: Synthesis of Compound 7
##STR00042##
[0165] To a stirred solution of compound 5 (5 g, 0.011 mol, 1 eq.)
in ethyl acetate (110 mL) was added triethylamine (1.98 mL, 0.0133
mol, 2 eq.) drop wise at room temperature under N.sub.2 atmosphere
for 2 min, followed by sodium iodide (0.342 g, 0.002 mol) and
compound-6 (5.09 g, 0.011 mol). Then reaction mixture temperature
was raised to 50.degree. C. and continued to stir it for overnight.
After completion of the reaction (monitored by TLC) it was diluted
with ethyl acetate and water. The organic layer was separated and
dried over anhydrous sodium sulfate, filtered and concentrated to
dryness. Purification on silica gel (10% EtOAc in hexane) yielded
compound 7 (5.2 g, 75.3% yield with 98.18% purity by LC-MS) as a
light yellow liquid. .sup.1H-NMR (CDCl3): .delta. 10.4 (s, 1H),
8.00 (S, 1H), 7.50 (d, 1H), 7.18-7.05 (m, 2H), 6.88 (d, 1H), 5.40
(m, 10H), 2.82 (m, 8H), 2.38 (m, 4H), 2.20 (m, 2H), 2.10 (m, 2H),
1.82 (m, 2H), 1.40-1.20 (m, 12H), 1.00 (t, 3H), 0.9 (m, 6H); Mass:
608.5 [M+H].
EQUIVALENTS
[0166] The present disclosure provides among other things
compositions and methods for treating epilepsy and their
complications. While specific embodiments of the subject disclosure
have been discussed, the above specification is illustrative and
not restrictive. Many variations of the systems and methods herein
will become apparent to those skilled in the art upon review of
this specification. The full scope of the claimed systems and
methods should be determined by reference to the claims, along with
their full scope of equivalents, and the specification, along with
such variations.
INCORPORATION BY REFERENCE
[0167] All publications and patents mentioned herein, including
those items listed above, are hereby incorporated by reference in
their entirety as if each individual publication or patent was
specifically and individually indicated to be incorporated by
reference. In case of conflict, the present application, including
any definitions herein, will control.
* * * * *