Note: Descriptions are shown in the official language in which they were submitted.
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COMPOSITIONS AND METHODS FOR THE
TREATMENT OF .HYPERGLYCEMIA
PRIORITY
10001] The present application claims the benefit of Indian Provisional Patent
Application. No. 181 IICHEI2012 filed on 08-May-2012, the entire disclosure of
which is
relied on for all purposes and is incorporated into this application by
reference.
HELD OF THE INVENTION
100021 This disclosure generally relates to compounds and. compositions for
the treatment.
of hyperglycemia, diabetes and insulin resistance. More particularly, this
invention
relates to treating subjects with a pharmaceutically acceptable dose of
compounds,
crystals, esters, stereoisomersõ enamiomers, salts, hydrates, prodrug,s, or
mixtures thereof
BACKGROUND OF THE INVENTION
100031 The multifaceted metabolic syndrome is defined as a number of major
metabolic
disorders that enhances the risk of cardiovascular disease (CVD) ¨ still the
most
important cause of death in the Western world ----- and type 2 diabetes
mellitus. It is also
known as the insulin resistance syndrome, syndrome X, dysmetabolic syndrome,
or the
deadly quartet, and is characterized by aberrations in a wide variety of
metabolic risk.
markers such as hyperinsuline.mia, impaired glucose metabolism, elevated
plasma levels
of triglycerides, decreased levels of high-density lipoprotein cholesterol
(l'IDI,C), raised
blood pressure, centrally distributed obesityõ impaired endothelial and
haemostatic
function, and a low-grade inflammatoly state.
(00041 Type 2 Diabetes Mellitus (T2DM) is characterized by fasting and
postprandial
hyperglycemia and relative insulin insufficiency. If left untreated, then
hyperglycemia
may cause long term microvascular and .macrovaseular complications, such as
nephropathy, neuropathy, retinopathy, and atherosclerosis. This disease causes
significant
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.morbidity and mortality at considerable expense to patients, their families
and society.
The incidence of T2DM worldwide is now increasing at. more rapid rates in
Africa, .Asia
and South America than in Europe or the U.S, Thus, T2DM is now considered
worldwide
epidemic.
100051 Oxidative stress has long been associated with the late complications
of diabetes,
and has been implicated in their etiology. The reactive oxygen intermediates,
produced in
mitochondria, peroxisomes, and the cytosol, are scavenged by cellular
defending systems,
including enzymatic (ex. superoxide dismutase, glutathione peroxidase (IPx,
glutathione.
reductase and catalase) and nonenzy Matic antioxidants (ex. glutathione
thioredoxin, lipoic acid, ubiquinol, albumin, uric acid, flavonoids, vitamins
A, C and E.
etc.). Some are located in cell membranes, others in the cytosol, and others
in the blood
plasma, in hyperglycemia, an altered oxidative metabolism is a consequence
either of the
chronic exposure to hyperglycaemia or of the absolute or relative insulin
deficit; insulin
regulates several reactions involved in ox i do-red u ct v e metabolism.
Despite strong
experimental evidence indicating that oxidative stress may determine the onset
and
progression of late-diabetic complications controversy exists about whether
the increased
oxidative stress is merely associative rather than causal in hyperglycemia.
[00061 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 diabetes related hyperglycemia and its
associated.
complications progression
_SUMMARY OF THE INVENTION
100071 The present invention provides corn pounds. compositions containing
these
compounds and methods for using the same to treat, prevent and/or ameliorate
the.
effects of the conditions such as hyperglycemia..
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[00081 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 hyperglycemia and its associated
corn ph i cat i on s
R4
R2
R5
R6
R7
Formula I
100091 In certain embodim en ts the present invention relates to the compounds
and
compositions of formula I. or pharmaceutically acceptable salts thereof,
R4
R3
R2
R5
136 R7
Formula t
Wherein,
RI independently represents D, H. methyl, ethyl. CH3C0 or
-
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each n is independently 0,1, 2, or 3;
R2 independently represents
0 0
0
--ss.,,,,0 O'V,
NH )?-2-'")55*".
, ,
0 0 4------%
)
F s, ¨
0 0
\
0
0 0 0 0
v
NH2 NH2
,
H H
--..css ...,..õ---......õ..õN A
,(N....., N ,,,,õ/ hoA
---. ---
H .
H H
N
,
0
H H
0
,
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0 FIN 0
c-C
112, 0 0AsSS OH
0
0
Or
R3 independently represents
0
H SH
H2N"
0
0
1 HS
0
0
c5SSN,õ
0
I 9
4 7 10 13 16
0
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0
s / g 11 14 20
0
0
U 14 7 20
t132-4,
r.sS5
9
4 7 10 13 16
0
N CH3
NH NH
= OH
0
H2N
N CH3
HO
OH
0
HS
0
0
N
4177_
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N CH3
-...,,...
HO
OH 0 0
H
N OH
NH2
, 7
N CH1
"N....,
11.-... OH 1
'.% H
' IllottHN711N;i55:HNN:"Fir H ' s:' --..''
HO
0 0
0
. 0 H
HN
S
\ 0
NHCOCH3
1101 0 0
= . CO2 H 011 css, 0 coN,,2
OH A OCOCH3
,
OH 0
.., 0 11110
0 riiil,
WI
0 CH3 H3C¨Nt.....õ77N.ZIV io
s4 \ 0
HC 4
CH3
CH3 6- Zc't CH3 OH !..Z? 0
, . ,
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OH
0
HO
NH2
:
a
b
a is independently 2,3 or 7:
each b is independently 3, 5 or
e is independently I, 2 or 6;
c and d are each independently H. 0, -0.H., -OD, CI-C6-alkyl, -NH. a or -
COCH:.;:
R4, R. R. R7 each independently are selected from the groups consisting of ft
D, -OH,
-OD, methyl, ethyl, -OCH.3, -0CD3 or acetyl.
E00101 In the illustrative embodiments, examples of compounds of formula 1 are
as set
forth below:
0
OH
N 0
HO
HO OH
(1-1)
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0 0
OH
N
HO = - - HN y
HO OH NH
(: 1 -2)
OH
= . ¨ ¨
HO...-6;4:144.\0 = :1 14 17 20
HO OH
(1 -3)
10011i 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 hyperglycemia or its related complicati On S
[00121 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, par en teral administration, inj ecti on,
subdemial
administration, or trait sdermal administration.
100131 'Herein, the application additionally provides kits comprising the
pharmaceutical
compositions described herein. The kits may further comprise instructions for
use in the
treatment of hyperglycemia or its related complications.
[00141 The compositions described herein have several uses. 'The present
application
provides, for example, methods of treating a patient suffering from
hyperglycemia or its
related complications manifested from metabolic conditions or disorders,
metabolic
syndrome, chronic diseases or disorders; Hyperinsulineinia., Insulin
resistance, Glucose
intolerance, Hepatology, Cancer, Respi ratory, Hem atol ogi cal
, Orthopedic,
Cardiovascular, Renal, Skin, Vascular or Ocular complications.
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.DETAILED DESCRIPTION OF THE INVENTION
=i)efini ti ons
100151 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.
(00161 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 to be used as prodrugq 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 he. as a consequence of hygroscopic
properties
of an initially anhydrous compound of formula I (hydration).
1001.7] 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
"stereoisome.rs." 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
enamiomer
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, lngold and Prelog, or
by the
manner in which the molecule rotates the plane of polarized light, and
designated. as
dextrorotatoly 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 ig called a "racetnie mixture".
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100181 .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.
[001.91 In some embodi men ts, a M. ol ecu ar conjugate comprise& of COM pou
11 d S Se ected
from the group consisting of R-lipoic, acid (CAS No, I 200-22-2), salsalate
(CAS No,
552-94-3)õ acetylcysteine (CAS No. 616-91-1), iti:icosapentaenoic acid (CAS
No. 10417-
94-4), ,Docosahexaenoic acid (CAS No. 6217-54-5).
100201 The term "polymorph÷ as used herein is art-recognized and refers to one
crystal
structure of a given compound,
10021.1 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, imraarterial, intrathecal, intracapsular,
intraorbital,
intracardiac, intradennal, intraperitoneal, transtracheal, subcutaneous,
subcuticular, Ultra
-
articular, subcapsular, subarachnoid, intraspinal and intrastemal injection
and infusion.
10022] .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,
(00251 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. irntaton, aHegic. response, or other problem or complication:,
commensurate
with a reasonable benefit/risk ratio,
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100241 The phrase "pharmaceutically acceptable carrier" is art-recognized, and
includes,
for example, pharmaceutically acceptable materials, compositions or vehicles,
such as a
liquid or solid tiller, 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 earlier is non -
pyrogenie
Some examples of materials which may serve as pharmaceutically acceptable
carriers.
include: (I) 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 traaacanth; (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, coin 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.
100251 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 prodnag 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.
100261 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
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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 conthtion or side
effects
thereof).
100271 The term "predicting" as used herein refers to assessing the
probability related
diseases patient will sufTe.r from abnormalities or complication andlor
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,
100281 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 hyperglycemia, insulin resistance, diabetes mellitus,
diabetes
insipidus, type I diabetes, type 2 diabetes, microvascular complications,
macrovascular
complications, lipid, disorders, hypertriglyceridemi a, cardiovascular
complications, and
post prandial hyperglycemia 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.
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100291 The phrase "therapeutically effective amount" is an art-recognized
ternr in
certain embodiments, the term refers to an amount of a salt or composition
disclosed
herein that produces some desired effect at a reasonable benefithisk 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.
100301 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.
[00311 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.
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[00321 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.
10033" 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 }Ti 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.
190341 The phrases "systemic administration," "administered systen-nically,"
"peripheral
administration" and "administered peripherally" are art-recognized, and
include the
administration of a subject composition, therapeutic o.r other material at a
site remote
from the disease being treated. Administratioi 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.
[00351 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
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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.
[0036] The present disclosure also contemplates prodruas of the compositions
disclosed
hereinõ as well as pharmaceutically acceptable salts of said pmdrugs,
[0037] This application also discloses a pharmaceutical composition comprising
a
pharmaceutically acceptable carrier and -the composition of a compound of
Formula. I
may be formulated for systemic or topical or oral administration. The
pharmaceutical
composition may be also tbrinulated 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.
100381 In many embodiments, the pharmaceutical compositions described herein
will
incorporate the disclosed compounds and. compositions (Formula 1) to be
delivered in an
amount sufficient to deliver to a patient a therapeutically effective amount
of a compound
of formula 1 or composition as part of a prophylactic or therapeutic
treatment. The
desired concentration of formula I 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 .f10111 the subject compositions, h 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.
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administering or supervising the administration of the compositions.
Typically, dosing
will be determined using techniques known to one skilled in the art.
10039] .Additionallyõ .the optimal concentration and/or quantities or amounts
of any
particular compound of formula 1 may be adjusted to accommodate variations in
the
treatment parameters. Such treatment parameters include the clinical use to
which the
preparation is put, es., the site treated, the type of patient, es.õ human or
non-human,
adult or child, and the nature of the disease or condition.
100401 The concentration and/or amount of any compound of formula I 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 microdialyMs, as
reviewed by T. E. Robinson et at. 1991, microdialysis in the neuroscience.s,
Techniques,
volume 7, Chapter I. The methods reviewed by :Robinson may be applied, in
brief, ag
foilows. A microdialysis loop is placed in situ in a test animal, Dialysis
fluid is pumped
through the loop, When compounds with ,formula 1 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.
[00411 hi certain embodiments, the dosage of the subject compounds of formula
1
provided herein may be determined by reference to the pla,sma 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.
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100421 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
niglk.gldity to about.
100 .mg/kg/day in single or divided doses, for instance 0,01 mg/kg/day to
about 50
m.g/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
mgikg/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 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 required for the same therapeutic benefit.,
100431 An effective amount of the compounds of formula 1 described herein
refers to the
amount of one of said salts or compositions which is capable of inhibiting or
preventing a
disease.
100441 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 physiological 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 ti
trate 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
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factors such as age of the patient, presence of preexisting disease, as well
as presence of
other diseases.
100451 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.õ intravenously, subcutaneously or
intramedullary.
Further, the compositions may be administered intranasallyõ as a rectal
suppository, or
using a "flash" formuiation, 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,
transderm.al drug del iveryõ patch (active/passive) mediated drug delivery, by
stereota.ctic
injection, or in nanoparticles,
100461 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
flavotings, 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, lubricafing
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
tillers 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.
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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 may
also comprise enterically coated comprising of various excipients, as is well
known in the
pharmaceutical art.
100471 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.
100481 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 disclosed herein, for instance, compounds of formula 1 or
pharmaceutical
acceptable salts of a compounds of Formula.!.
100491 Generally, a composition as described herein may he 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.
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21
100501 The dosage administered will be dependent upon the identity of the
metabolic
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.
10051] 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 1.000 mg/kg; intranasal instillation, 5 to about 1000 mg/kg, and
aerosol, 5 to about.
1000 mag of host body weight.
100521 Expressed in terms of concentration, an active ingredient can be
present in the:
compositions of the present invention I'm .localized use about the cutis,
intranasally,
pharyngolaryngeallyõ 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%
wfv.
[00531 The compositions of the present invention are preferably presented for
administration to humans and animals in unit dosage fonns, 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.
[00541 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 swell able cellulose derivatives include,
but are not
limited to, sodium carboxy methylcell ulose, cross-linked hydro.xypropyl
cellulose,
hydroxypropyl cellulose (H.PC),
h:ydroxypropylm ethyl cell ul ose (11PMC),
hydroxyisopropylcellul use, hydrox.ybutylcellul use,
hydroxyphenyl cellulose,
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22
hydroxyethyl cellulose (HEC), hydroxypentylcellulose, hydroxypropylethylcell
tdose,
hydroxypropylbutylcellulose, and hydroxypropylethylcellulose, and mixtures
thereof
Examples of suitable polyalkylene glycols include, but are not limited to,
polyethylene
glycol. Examples of suitable thermoplastic polyalkyl en e oxides include, but
are not
limited to, poly(ethylene oxide). Examples of suitable acrylic polymers
include, but are
not I united to, potassium meth
acrylated i viny Iheuzene copolymer,
polymethylM ethac ry I ate, high-molecular weight cross] inked acrylic acid
homopolymers
and copolymers such as those commercially available from Noveon Chemicals
under the
tradename C.,`ARTIOPOLIm. Examples of suitable hydrocolloids include, but are
not:
I imited 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, selerogluean, gum arabic, inulin, pectin,
gelatin,
whelan, rhamsan, zooglan, methylanõ 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 glyeolate 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 carboxymethyleellulose sodium, and mixtures thereof
10055] The carrier may contain one or more suitable excipients for the
formulation of
tablets. Examples of suitable excipients include, but are not limited to,
tillers, adsorbents,
binders, di si ntegrants, lubricants, gl
idants, release-modifying excipients,
superdisintegrants, antioxidants, and mixtures thereof
100561 Suitable binders include, but are not limited to, dry binders such as
polyvinyl
pyrroli done and hydroxypropylmethylcellulose; wet binders such as water-
soluble
polymers, including hydrocolloids such as acacia, alginates, agar, guar gum,
locust bean,
carrageenan, carboxymethyleellulose, tara, gum arable, traQacanth, pectin,
xantlaan,
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gellanõ gelatin, maltodextrinõ galactom.annan, pusstulan, laminarin,
scleroglucan, inulin,
whelanõ rhamsan, zooglan, methylan, chitin, cyclodextrin, chitoskm, polyvinyl
pyrrolidone, cellulosics, sucrose, and starches; and mixtures thereof.
Suitable
disintegrants include, but are not limited to, sodium starch glycol ate, cross-
linked
polyvinyl pyTrol.idone, cross-linked carbon/ methylc el 1 ulose, starches,
microcrystalline
cellulose, and mixtures thereof.
[0057] 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 &Wants 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,
[0058] 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, etb.ylcellulose,
polyvinyl alcohols,
polyvinyl acetate, polycaprolactonesõ cellulose acetate and its derivatives,
a.crylafes,
methacrylates, acrylic acid copolymers, copolymers thereof, and mixtures
thereof.
Suitable low-melting hydrophobic materials include, but are not limited to,
fats, fatty acid
esters, phosphoiipids, 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
palmitosteara.te, glyceryl
monostearate, glyceryl tn stearate, glyceryl trilaurylate, gl ycery I my
ristate, GlycoWax-
932, lauroyl macrogo1-32 glycerides, steamy( .macrogo1-32 glycerides, and
mixtures
thereof Examples of suitable phospholipi.ds include phosphotidyl choline,
phosphotidyl
serene, phosphotidyl .enositol, phosphotidic acid, and mixtures thereof
Examples of
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24
suitable waxes include, but are not limited to, earnauba vax, spermaceti wax,
beeswax.,
candelilla wax, shellac wax, microcrystalli ne 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
percent by weight of such super disintegrant,
[00591 Examples of' antioxidants hid ude, 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.
10060j 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 gicc, as measured by
the weight
and volume of that specific layer,
[00611 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
phanna,ceutically active
agent and the second portion includes the second pharmaceutically active agent
100621 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
pharmaceuticallv active agent as that contained in the tablet core,
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100631 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 ph art/I
aceutically active
agent,
100641 Formulations with different drug release mechanisms described above
could be.
combined in a final dosage form containing single or multiple units. :Examples
of
MUI ti.ple units include MUlti layer .tablets, capsules containing tablets,
beads, or granules in
a solid or liquid form. Typical, immediate release formulations include
compressed
tablets, ,4e1s, films, coatings, liquids and particles that can be
encapsulated, for example,
in a gelatin capsule. :Many methods tbr preparing coatings., covering or
incorporating
drugs, are known in the art.
100651 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 excipieats. The immediate release dosage unit may or may not be
coated,
and may or may not be admixed with the delayed. release dosage U1-fit or units
(as in an
encapsulated mixture of immediate rel.ease ddig-containing granules, particles
or beads
and delayed release drug-containing granules or beads).
100661 Extended release formulations are generally prepared as diffusion or
osmotic
systems, for example, as described in "Re.mington¨The Science and Practice of
Ph arm a.cy ", 20th. Ed . õ Lippincott Williams & Wilkins, B all i in ore,
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 carder into a tablet
form.
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[00671 .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,
[00681 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.
10069" 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 dnig 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,
10070] Each dosage form contains a therapeutically effective amount. of active
agent. in
one embodiment of dosage forms that mimic a twice daily closing 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 Wi t,''() to 40 wt. %, of the total amount
of active agent in
the dosag.e 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
admi ni strati on.
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100711 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 followim,t oral administration to provide a
second
dose.
1007211 For purposes of tran sdermal, (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,
100731 .Methods of preparing various pharmaceutical compositions with a
certain.
amount of one .or more compounds of formula I 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).
100741 In addition, in certain embodiments, subject compositions of the
present,
application maybe lyophilized or subjected to another appropriate drying
technique such
as spray diying. 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.
100751 -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.
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28
produce a single dose may vary depending upon the subject being treated, and
the
particular mode of administration
10076] 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.
(00771 The compounds of formula I 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.linal aerosol formulation may for example contain
0.005-90%
wiw, for instance 0.005-50%, 0.005-5% why, or 0.01-1.0% .w/w, of medicament
relative
to the total weight of the formulati ,
[00781 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: (I) fillers
or extenders,
such as starches, lactose, sucrose, glucose, mannitol, and/or silleic acid;
(2) binders, such
as, for example, carboKymethylcellulose, alginates, gelatin, polyvinyl
pyrrolidone,
sucrose andlor 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 mmostearate; (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.
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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.
100791 Liquid dosage forms for oral admi istration include pharmaceutically
acceptable
emul si ons, mi croemul si ons, solutions, suspensions, syrups and el ixirs In
addition to the
subject COM positions, the liquid dosage fonns 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,
10080j Suspensions, in addition to the subject compositions, may contain
suspending,
agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene
sorbitol,
and sorbitan esters, rnicrocrystalline cellulose, altmlinum metahydroxide,
bentonite, agar-
agar and tragacanth, and mixtures thereof.
100811
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 co.mpfising, 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.
[0082] Dosage forms for transdermal administration include powders, sprays,
ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. A
subject
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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,
[00831 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,. SiTICOneS,
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, silicie
acid, aluminum
hydroxide, calcium silicates and poiyamide powder, or mixtures of such
substances.
Sprays .may additionally contain customary propellants, such as
chlorofluorohydrocarbons and .volatile unsubstituted hydrocarbons, such as
butane and
propane.
100841 Methods of delivering a composition or compositions via a transderm.al
patch are
known in the art. Exemplary patches and methods of patch delivery are
described in US
Patent Nos. 6,974,588, 6,564,093, 6,312,716, 6,440,454, 6,267,983, 6,239,180,
and
6,103,275,
[00851 Itn 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 polyalkyl:ene
.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
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31
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
terephthal ate film,
10086" 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.
10087" Transdemal 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.
00881 lontophoresis 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 Theeuwe.s. 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.
10089" In some Cases, it may be desirable to administer in the t7orm of a kit,
it may.
comprise a container for containing the separate compositions such as a.
divided bottle or
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a divided foil packet. Typically the kit comprises directions for the
administration of the
separate components. The kit .tbrin 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.
[00901 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.
[00911 Methods and compositions for the treatment of hyperglycemia. Among
other
things, herein is provided a method of treating hyperglycemia, comprising
administering
to a patient in need thereof a therapeutically effective amount of compound of
Formula I:
R4
.R3
= N R2
R5
R.
Ry
Formula
RI independently represents D, H, methyl, ethyl, CF1,1C0 or
-
-=
0
,n
=
each n is independently 0,1, 2, or 3;
R2 independently represents .E.1, D,
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33
0 0
;3
0 40 ')C
0 1
NH 2
:A,. ,sss, õ
0 ,
0 0
I-0-+..----42 1
,
0
µ0---- __________ H< \ 1SSC
0
N tzaz., i
0
0 0 0 0
=-.,
cssS
N H 2 NH 2
, .
H H
N i \iN ,,,,,...õ....õ"..õ. /
Nt;\ -----C)-1
H .
H H
N
,
0
H H
/11\
- 0)1)
N
).1?: ' ' ' -. , õ , , , , ", ' ''''' "N ' -,, ., õ = - - '''''
NN",,,,...,,,,FN `1, ,,, , , ,
0
,
0 0
A, 5.,...
/-
(7--e-,,
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0
H
-,
1
S ,
or H ,
R3 inciependettly represents
0
0
SH
H2N1,õ
D
,.....õ----------A,
0 .
H
..A.Ann
I HS...."-"- S- s
......õ
, ,
. .
0
co
s.........õ0
0 ,
õx.0\
_________________________________________________________ _
_ _______________________
4 7 10 ii J6 19
0 ,
0
8 11 14 17 20
0 .
0
5 S' 11 14 17 20
\_.
,
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,..s.s5
_
4 7 10 13 16 19
0 -
N CH3
N....,..õ
NH
--,sio ----- OH
\ V
H2N
. .
N CHA
OH
0
õ.."3------ o HS N
H
4-)----- 0 \--------s's.õ,._ t.ty
h
N -1-
, H
N OH3
',..õ....
HO 7,,
OF-1
0 0
1.---N
H .51\5S,3\'N OH
H
NH2
, ,
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36
N CH3
H 1 ..- OH
'.1.:
if\11 HO .,-="''
OH
''N'''F-µ\=='µT
HO
=c,sys.,..
N
00 H
1 ,
it 11 : H
,
Hurl\ NH
H k
,
'go/4
\3 0 0 ,
NHCOCH3
4011 0
co2H 0 all CONH2
0-..
OH 0(77 OCOCH3 IP 0"1/.
, ,
OH
-sse 0
cH3 CH
0 0
0
Si CH 3 H,,,c_Nl-
vs-C\C 0 0
F1,0 0 .
,, CH3
C1-13 t= 0 CH3 OH ..-1.7 0
,
OH
H
111101 o
NS
;s
',..
A
FIN 1101 N
\
1\11-1, ,
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37
0
(2.
a
or
a is independently 2,3 or 7;
each b is independently 3, 5 or 6;
e is independently I, 2 or 6;
c and d are each independently H, D, -OH., -OD, Cr-C6-alkyl, or -COCH3;
R4, R. R, R7 each independently are selected from the groups consisting of ft
D, -OH,
-OD,. methyl, ethyl, -OCH.3õ -0CD3 or acetyl.
Aleihoth for using COMpOlinthi offormula
100921 The invention also includes methods for treating hyperglycemia, insulin
resistance, diabetes mellitus, diabetes insipidusõ type I diabetes, type 2
diabetes,
microvascular complications, macrovascular complications, lipid disorders,
prediabetes,
obesity, arrhythmia, myocardial infarction, stroke, neuropathy, renal
complications,
hypertriglyceridetnia, cardiovascular complications, and post prandial
hyperglycemia.
METHODS OF :MAKING
100931 Examples of synthetic pathways useful for making compounds of formula I
are
set forth in example below and generalized in scheme I :
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Scheme-1:
1) (coci),
- NaBH3CN
Er10 Bn0...õ. DMSO i3n0
Br) , .1
L LiAIH4
_________________ as.
a (NsOH -73 ''C 7h en , 0 NH4HCO2
(excess)
).
Bn 0 i oH THF Bh01.----N.OH 2) Et3N Eln0
. 'No Na2S0 4
Oen 20 h oBn 5Bn CH3OH
-78 QC- 0 ut: . 2h -
1 2 3
0 (t-rt, 20 h
Bn0. HO HO
I 10% Fd/C-H2
BnOk NH 1M aqõ HO
_________________ is HO:....)
NH 4. a ..--...õ..-Ncl K2003 HO
il^ 6,, ...1 N.,-..õ..,"==,c1
DOH DMF
Br10 Y HO ,
a. 90 QC, 5h
oBn rt, 20 h OH OH
4 5 6 7
K2C0.3
+ HO _ ¨ ---- ¨ ---- *
DMF
0 8 -10"C
HO)
0
OH g
0
OH
HO N-----'0
-\-,..õ.....\
HO OH
100941 Step-1: Synthesis of compound 2:
en0,4 Bh0..õ1
BnO,õ. Ao LiAll-i4
r- OH
_______________________________ 4,
Fincye's,---LoH THF Bn01..)-""=,-------'0H
E
OBn 20h OBn
1 2
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100951 iLiAlftl. (3.5 eq) was added in portions to a cooled (0 'C) and thy
.solution of
compound I in THF (0,15 M). The reaction mixture was stirred for :20 hours,
allowing it
to warm to .rt, The excess Li,A.11-14 .was quenched with water at 0 T. The
mixture was
diluted with Et0Ac and washed with sat aq NIT4C1 (3x). The organic phase was
dried
(MgS0.4) and concentrated. The resulting product (2) was used crude in the
next reaction.
A small sample was purified by silica gel column chromatography (20%--450%
Et0Ae in
PE) for characterization purposes to provide 2 as a colorless oil.
100961 Step-2: Synthesis of compound 41
(C0C)2 NaBHsCN
BnO DMS-0 BrIO
Bh0 .
QH
DCM NH4HCO2
-78 C,2h Bn0
0 (excess)
BnOOH
NH
2) Et3N BnOQ Na2SO4 en
6-*Bn
OBn CH3OH
06n
-78 C- 0 C , 2h ----
2 3 0 C-rt, 20 h 4
100971 A solution of oxalylchloride (4 eq) in .DCM. (1 M) was cooled to -78
'C. After
dropwise addition of a solution of ,DMS0 (5 eq) in DC.N1 (2 M) over 10
minutes, the.
reaction mixture was stirred for 40 minutes while being, kept below -70 C.
Next, a dry
solution of the glucitol 2 intermediate from above reaction in DCM ((15 M) was
added
dropwise to the reaction mixture over a 15 minutes period, while keeping the
reaction
mixture below -70 C. After stirring the reaction mixture for :2 hours below -
65 C, Et3N
(12 eq) was added dropwise over a 10 minute period, while keeping the reaction
mixture
below -65 "C. After addition, the reaction mixture was allowed to warm to -5
("C over 2
hours.
100981 The Swem reaction mixture was concentrated at a moderate temperature (-
30 C.)
with simultaneous coevaporation with tolu.erie (3>f). The residue was
dissolved in Me01-1
(0.05 'M relative to .starting compound') and NE4HCO2 (20 eq) was added. The
mixture
was cooled to 0 C and stirred until all N.H4HCO::, had dissolvedõ Activated
3A mdsi eves
(10 tilinmol) were added and reaction mixture was stirred for 20 minutes,
after which
NaBH3CN (4 eq) was added. The reaction mixture was kept at 0 'C for one hour
after
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which the cooling source was removed and the reaction was stirred for an
additional 20
hours. After removal of the mol sieves over a glass microlibre filter, the -
filtrate was
concentrated, dissolved in 'Et0Ac and washed with sat aq Nal-ICO. The aqueous
phase
was back-extracted with Et0Ac (3x) and the combined organic layers were dried
(MgS0.4) and concentrated. The resulting residue was purified by silica gel
column
chromatography (20%-475% Et0Ac in PE) to provide 4 (9.932 g, 18.98 maid.) as a
light
yellow crystalline solid.
100991 Step-3: Synthesis of compound 5:
Bn0õ,_ HO
10% Pd/C-H2
Bn0:0 1M aq. HCI H04.06
NH _______________________________________ NH
J.--
Bn0 Et0H
HO
OBn tt, 20 h OH
4 5
1.001001 A solution of 4 (.1.06 g, 1.91 nunol) in Et01-1 (50 ad..) was
acidified to pH. -2
with 1M aq 'HO. and purged of oxygen by bubbling argon through the solution
for 15
minutes. Pd/C (10 wt%, 100 mg) was added and the mixture was exposed to 4 bar
of
hydrogen for 20 hours. The reaction mixture was filtered over a glass
microfiber filter
and the filter cake was rinsed successively with Me01-1 (4x20 nit) and 1.120
(2.x20 Mt).
The combined filtrate was concentrated and coevaporated with Ma-YU (3A50
trt.1). The,
residue was purified by column chromatography with aluminum oxide (isocratic
16:3.7:0.3, n-propano1:11 ONE14014) to provide 5 (290 mg, 1.78 mmol) in 93%
yield as a
white foam.
1001011 Step-4: Synthesis of compound 7:
HO HO
HONH
K2 C 03 HO,,
CI
"OH s:-) DMF
90 GC, 5h HO
OH
6
5 7
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1001021 A dry suspension of potassium carbonate (7.2 mmol), 5 (4.8 mmol) and
1,3-
dichloropropane (53 mmolin DIVF was heated to 90 'C. for 5 h. The reaction
mixture
was filtered over a Oas microfibre filter and the filtrate was concentrated.
The residue
was purified by silicagel column chromatography (Me0111 in C.1-10-3 4- 1% NI-
140E1) to
obtain the intermediate 7.
1001031 Step-5: Synthesis of compound 9:
HO
K2CO3
H 0+ HO - = = - = _______ = = -- =
yOMF
HO 0
8 -10 C
OH
7
HO
HO
HO 0
H 9
10010411n a RE flask the acid 8 (1.2 mmol) & anhydrous K2CO3 (1.1 mmol) was
taken
in dry DMF (10 vol) stir at room temperature for 30 min and then cooled to -10
compound 7 was added slowly drop wise & then allowed to stir at room
temperature for
12 h. Reaction was monitored by TLC. On completion of the reaction, the
reaction
mixture was poured into water (10 ml-) and extracted with ethyl acetate (2x5
ml). The
combined organic layers were washed with water (2 x 5mL) followed by brine
solution
(10 in L.), dried over anhydrous Na,SO4and evaporated under reduced pressure.
The crude
was purified by column chromatography over 100-200 mesh silica gel to obtain
the final
product 9.
EXAMPLES
1001051 The Solubility of the Compound of Formula 1 (1-3) in Water was
Compared
with that of eicosapentaenoic acid (EPA)
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1001061 Measurement of the water solubility of the test compounds is
accomplished by
using methods well known to those skilled in the art. Specifically, to a
weighed amount
of the test. compound of the example compound Formula I (1-3) distilled water
was added
in .small proportions until a clear solution was obtained. The total volume of
the solution
is measured.. The water solubility is calculated by dividing the weight of the
salt, in
milligrams (mg), by the volume of the solution, in mI.,. The water solubility
of the.
compound of formula 1(1-3) when measured using the above technique, was
determined
to be 68.6 mg/ml, 'Likewise, the water solubility of EPA was found to be <0.2
inglmiL.
The compound of Formula. 1 (1-3) is therefore, at least 260 times more soluble
in water
than EPA itself. This is a. clear indication of an unexpectedly high degree of
bioayailability of the compositions of the invention. Highly water soluble
m.edicinal
preparations, when administered .orally, result in efficient absorption from
the
gastrointestinal tract in to systemic circulation. Furthermore, water soluble
preparations
are especially suitable for parenteral administration.
1001071 The term "sample" refers to a sample of a body fluid, to a sample of
separated
cells or to a sample from a tissue 0.1' an organ. Samples of body fluids can
he obtained, by
well known techniques and include, preferably, samples of blood, plasma,
serum, or
urine, more preferably, samples of blood, plasma or serum.
EQUIVALENTS
1001081 The present disclo.sure provides among other things com.positions and
methods
for treating hyperglycemia and their complicatims. While specific embodiments
of the
subject disclosure have been discussed, the above specification is
illustrative and not
restrictive.
INCORPORATION BY REFERENCE
1001091 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,