U.S. patent application number 14/486014 was filed with the patent office on 2015-01-01 for pharmaceutical formulations.
The applicant listed for this patent is Janssen Pharmaceutica NV. Invention is credited to Thomas C. Joseph, Todd Outwin, Wenhua Wang.
Application Number | 20150005244 14/486014 |
Document ID | / |
Family ID | 44260412 |
Filed Date | 2015-01-01 |
United States Patent
Application |
20150005244 |
Kind Code |
A1 |
Wang; Wenhua ; et
al. |
January 1, 2015 |
PHARMACEUTICAL FORMULATIONS
Abstract
The present invention relates to formulations including
compounds of Formula (I), ##STR00001## or prodrug, or a
pharmaceutically acceptable salt thereof.
Inventors: |
Wang; Wenhua; (Newtown,
PA) ; Outwin; Todd; (Chalfont, PA) ; Joseph;
Thomas C.; (Oakford, PA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Janssen Pharmaceutica NV |
Beerse |
|
BE |
|
|
Family ID: |
44260412 |
Appl. No.: |
14/486014 |
Filed: |
September 15, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13968496 |
Aug 16, 2013 |
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14486014 |
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13105008 |
May 11, 2011 |
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13968496 |
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61333495 |
May 11, 2010 |
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Current U.S.
Class: |
514/23 |
Current CPC
Class: |
A61K 9/2866 20130101;
A61P 43/00 20180101; A61P 3/00 20180101; A61P 25/16 20180101; A61P
3/06 20180101; A61P 5/50 20180101; A61P 3/10 20180101; A61P 13/00
20180101; A61K 9/2013 20130101; A61K 9/2054 20130101; A61K 31/7004
20130101; A61P 9/10 20180101; C07D 409/10 20130101; A61K 47/26
20130101; A61K 47/38 20130101; A61P 13/12 20180101; A61K 31/381
20130101; A61P 3/04 20180101; A61P 27/02 20180101; A61P 9/12
20180101; A61K 9/2018 20130101; A61P 25/00 20180101; A61K 31/7042
20130101 |
Class at
Publication: |
514/23 |
International
Class: |
C07D 409/10 20060101
C07D409/10; A61K 47/26 20060101 A61K047/26; A61K 31/381 20060101
A61K031/381; A61K 47/38 20060101 A61K047/38 |
Goverment Interests
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
[0002] The research and development of the invention described
below was not federally sponsored.
Claims
1-3. (canceled)
4. The pharmaceutical tablet of claim 14, wherein the compound is
present in an amount of about 25 mg to about 600 mg.
5. The pharmaceutical tablet of claim 14, wherein the compound is
present in an amount of about 50 mg to about 300 mg.
6. The pharmaceutical tablet of claim 14, wherein the compound is
present in an amount of about 100 mg.
7. The pharmaceutical tablet of claim 14, wherein the compound is
present in an amount of about 300 mg.
8-9. (canceled)
10. A method for treating a sodium-dependent glucose transporter
mediated disorder, said method comprising administering to a
patient in need thereof, the pharmaceutical tablet of claim 14.
11. The method of claim 10 wherein the compound is administered at
a dose of from about 50 mg to about 300 mg once daily.
12. The method of claim 10 wherein the compound is administered at
a dose of about 100 mg per day.
13. The method of claim 10 wherein the compound is administered at
a dose of about 300 mg per day.
14. An orally administrable pharmaceutical tablet comprising (a) a
compound of Formula (I-S) ##STR00004## or a prodrug or
pharmaceutically acceptable salt thereof present in an amount
within the range of from about 40% to about 60% by weight; (b) a
diluent or filler comprising a combination of microcrystalline
cellulose and lactose present in an amount within the range of from
about 30% to about 50% by weight; (c) at least one disintegrant in
an amount within the range of from about 3% to about 10% by weight;
(d) at least one binder present in an amount within the range of
from about 0.5% to about 5% by weight; and (e) at least one
lubricant present in an amount within the range of from about 0.5%
to about 2% by weight; wherein the % by weight is based on the
weight of the tablet.
15. The pharmaceutical tablet of claim 14, wherein the compound is
1-(.beta.-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethy-
l]benzene)hemihydrate.
16-17. (canceled)
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional
Application 61/333,495 filed on May 11, 2010, which is incorporated
by reference herein in its entirety.
FIELD OF THE INVENTION
[0003] This invention relates to novel pharmaceutical compositions
comprising a compound of Formula (I), a prodrug thereof, or a
pharmaceutically acceptable salt thereof, disclosed herein, that
can be used in the treatment of diabetes mellitus, obesity,
diabetic complications, and related diseases.
BACKGROUND
[0004] WO 2005/012326, the disclosure of which is hereby
incorporated by reference in its entirety, discloses a class of
compounds that are inhibitors of sodium-dependent glucose
transporter (SGLT) and therapeutic uses for such compounds such as
the treatment of diabetes, obesity, diabetic complications, and the
like. WO 2005/012326 discloses the compound
1-(.beta.-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thi-
enylmethyl]benzene).
1-(.beta.-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethy-
l]benzene)hemihydrate and certain crystal form thereof are
disclosed in WO 2008/069327, the disclosure of which is also hereby
incorporated by reference in its entirety.
SUMMARY OF THE INVENTION
[0005] In its many embodiments, the present invention provides a
novel pharmaceutical composition of compounds of Formula (I), a
prodrug thereof, or a pharmaceutically acceptable salt thereof, and
methods of treatment, prevention, inhibition or amelioration of one
or more diseases associated with sodium-dependent glucose
transporter using such pharmaceutical compositions.
[0006] One aspect of the present invention features an orally
administrable pharmaceutical formulation comprising
(a) compound of Formula (I)
##STR00002##
wherein
[0007] R.sub.1 is halo, cyano, optionally substituted lower alkyl,
or optionally substituted lower alkoxyl; and
[0008] R.sub.2 is optionally substituted aryl, or optionally
substituted heterocyclyl;
[0009] or a prodrug, or pharmaceutically acceptable salt
thereof;
(b) at least one diluent or filler; (c) optionally at least one
disintegrant; (d) optionally at least one binder; and (e)
optionally at least one lubricant; wherein the compound of formula
(I) is present in an amount within the range of from about 1% to
about 80% by weight; the diluent or filler is present in an amount
within the range of from about 10% to about 95% by weight; the
disintegrant, if present, is present in an amount within the range
of from about 0.1% to about 20% by weight; the binder, if present,
is present in an amount within the range of from about 0.1% to
about 20% by weight; and the lubricant, if present, is present in
an amount within the range of from about 0.1% to about 5% by
weight, all of the above % by weight being based on the weight of
the formulation.
[0010] In certain embodiments, the compound of Formula (I) is a
compound of Formula (I-S) as described herein.
[0011] In certain embodiments, the present invention is directed to
an orally administrable pharmaceutical formulation comprising a
compound of Formula (I) as described herein in combination with a
bioavailability-promoting agent.
[0012] In certain embodiments, the bioavailability-promoting agent
increases the bioavailability of the compound and includes
excipients known in the formulation of pharmaceuticals. Preferably
formulating a compound of Formula (I) with the
bioavailability-promoting agent results in improved measurable
bioavailability of the compound upon administration of the
formulation.
[0013] Preferably, the present invention is further directed to a
bioavailability-promoting agent that includes a composition of
excipients, such as binders, fillers, disintegrants, lubricants or
combinations thereof.
[0014] In certain embodiments, the formulation of the present
invention is a solid oral dosage form that provides for an
increased bioavailability of the compound included therein as
compared to an oral suspension including the compound in the same
amount as the solid oral dosage form.
[0015] Additional embodiments and advantages of the invention will
become apparent from the detailed discussion, schemes, examples,
and claims below.
BRIEF DESCRIPTION OF THE FIGURES
[0016] FIGS. 1A and B provides linear and logarithmic plasma
concentration profiles of compound of Formula (I-S) following oral
administration of various formulations of compound of Formula (I-S)
in dogs.
[0017] FIG. 2 provides plasma concentration profiles of compound
(I-S) following oral administration of various formulations of
compound of Formula (I-S) in human subjects.
DETAILED DESCRIPTION OF THE INVENTION
[0018] The present invention is directed in part to an orally
administrable pharmaceutical formulation comprising
[0019] (a) a compound of Formula (I-S):
##STR00003##
[0020] or a prodrug or pharmaceutically acceptable salt
thereof;
[0021] (b) at least one diluent or filler;
[0022] (c) optionally at least one disintegrant;
[0023] (d) optionally at least one binder; and
[0024] (e) optionally at least one lubricant;
[0025] wherein [0026] the compound of formula (I-S) is present in
an amount within the range of from about 1% to about 80% by weight;
[0027] the diluent or filler is present in an amount within the
range of from about 10% to about 95% by weight; [0028] the
disintegrant, if present, is present in an amount within the range
of from about 0.1% to about 20% by weight; [0029] the binder, if
present, is present in an amount within the range of from about
0.1% to about 20% by weight; and [0030] the lubricant, if present,
is present in an amount within the range of from about 0.1% to
about 5% by weight, all of the above % by weight being based on the
weight of the formulation.
[0031] In certain embodiments, the present invention is directed to
an orally administrable pharmaceutical formulation comprising
[0032] (a) a compound of Formula (I-S), or a prodrug or
pharmaceutically acceptable salt thereof present in an amount
within the range of from about 40% to about 60% by weight;
[0033] (b) at least one diluent or filler present in an amount
within the range of from about 30% to about 50% by weight;
[0034] (c) at least one disintegrant in an amount within the range
of from about 3% to about 10% by weight;
[0035] (d) at least one binder present in an amount within the
range of from about 0.5% to about 5% by weight; and
[0036] (e) at least one lubricant present in an amount within the
range of from about 0.5% to about 2% by weight;
[0037] wherein the % by weight is based on the weight of the
formulation.
[0038] The compound of Formula (I-S) may also be referred to as
1-(.beta.-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethy-
l]benzene).
[0039] In certain preferred embodiments, the compound of formula
(I-S) is the hemihydrate of the compound of Formula (I-S), also
referred to as
1-(.beta.-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethy-
l]benzene)hemihydrate.
[0040] In certain embodiments, the invention is directed to a
pharmaceutical composition as described herein for use in the
manufacture of a pharmaceutical dosage form for oral administration
to a mammal in need of treatment, characterized in that said dosage
form can be administered at any time of the day independently of
the food taken in by said mammal.
[0041] In certain embodiments, the invention is directed to a
method of therapy of the human or non-human animal body that
comprises administering to said body a therapeutically effective
dose of a pharmaceutical composition described herein.
[0042] In certain embodiments, the invention is directed to a
pharmaceutical package suitable for commercial sale comprising a
container, an oral dosage form as described herein, and associated
with said package written matter non-limited as to whether the
dosage form can be administered with or without food.
A) Terms
[0043] Some terms are defined below and by their usage throughout
this disclosure.
[0044] "Administering" or "administration" means providing a drug
to a patient in a manner that is pharmacologically useful.
[0045] "Patient" or "subject" means an animal, preferably a mammal,
more preferably a human, in need of therapeutic intervention.
[0046] "Dosage form" means one or more compounds in a medium,
carrier, vehicle, or device suitable for administration to a
patient. "Oral dosage form" means a dosage form suitable for oral
administration.
[0047] "Dose" means a unit of drug. Conventionally, a dose is
provided as a dosage form. Doses may be administered to patients
according to a variety of dosing regimens. Common dosing regimens
include once daily orally (qd), twice daily orally (bid), and
thrice daily orally (tid).
[0048] "Terminal half-life" (t.sub.1/2) is calculated as 0.693/k,
wherein "k" means the apparent elimination rate constant, estimated
by linear regression of the log-transformed plasma concentration
during the terminal log-linear elimination phase. The plasma
half-life of a drug (t.sub.1/2) is the time necessary to halve the
plasma concentration, for example to decrease from 100 to 50 mg/L.
The knowledge of the half-life is useful for the determination of
the frequency of administration of a drug (the number of intakes
per day) for obtaining the desired plasma concentration. Generally,
the half-life of a particular drug is independent of the dose
administered. In certain exceptional cases, it varies with the
dose: it can increase or decrease according to, for example, the
saturation of a mechanism (elimination, catabolism, binding to
plasma proteins etc).
[0049] "Area under the curve" or "AUC" is the area as measured
under a plasma drug concentration curve, also termed plasma
concentration profile. Often, the AUC is specified in terms of the
time interval across which the plasma drug concentration curve is
being integrated, for instance AUC.sub.start-finish. Thus,
AUC.sub.0-48 h refers to the AUC obtained from integrating the
plasma concentration curve over a period of zero to 48 hours, where
zero is conventionally the time of administration of the drug or
dosage form comprising the drug to a patient. AUC.sub.t refers to
area under the plasma concentration curve from hour 0 to the last
detectable concentration at time t, calculated by the trapezoidal
rule. AUC.sub.inf refers to the AUC value extrapolated to infinity,
calculated as the sum of AUC.sub.t and the area extrapolated to
infinity, calculated by the concentration at time t (C.sub.t)
divided by k. (If the t.sub.1/2 value was not estimable for a
subject, the mean t.sub.1/2 value of that treatment was used to
calculate AUC.sub.inf.).
[0050] "Mean area under a plasma concentration profile" means the
mean AUC.sub.inf obtained over several patients or multiple
administrations to the same patient on different occasions with
sufficient washout in between dosings to allow drug levels to
subside to pre-dose levels, etc., following a single administration
of a dosage form to each patient.
[0051] "C" means the concentration of drug in blood plasma, or
serum, of a subject, generally expressed as mass per unit volume,
typically nanograms per milliliter. For convenience, this
concentration may be referred to herein as "drug plasma
concentration", "plasma drug concentration" or "plasma
concentration". The plasma drug concentration at any time following
drug administration is referenced as C.sub.time, as in C.sub.9 h or
C.sub.24 h, etc. A maximum plasma concentration obtained following
administration of a dosage form obtained directly from the
experimental data without interpolation is referred to as
C.sub.max. The average or mean plasma concentration obtained during
a period of interest is referred to as C.sub.avg or C.sub.mean.
"Mean, single dose, maximum plasma concentration C.sub.max" means
the mean C.sub.max obtained over several patients or multiple
administrations to the same patient with sufficient washout in
between dosing to allow drug levels to subside to pre-dose levels,
etc., etc., following a single administration of a dosage form to
each patient.
[0052] "Plasma concentration profile" refers to the curve obtained
by plotting plasma concentration of the drug compound versus time.
Usually, the convention is that the zero point on the time scale
(conventionally on the x axis) is the time of administration of the
drug compound or dosage form comprising the drug compound to a
patient.
[0053] "Mean time to maximum plasma concentration" is the mean time
elapsed from administration to a patient of a dosage form
comprising a drug to the time at which the C.sub.max for that drug
is obtained over several patients or multiple administrations to
the same patient with sufficient washout in between dosing to allow
drug levels to subside to pre-dose levels, etc., following a single
administration of the dosage form to each patient, and obtained
directly from the experimental data without interpolation.
[0054] The bioavailability indicates the percentage of the
administered drug, which arrives in the central compartment. It is
generally measured by comparing the AUC obtained after intravenous
administration and after oral administration, for example. After
intravenous administration, the AUC obtained corresponds to a
bioavailability, which, by definition, is 100%; after oral
administration, the AUC corresponds at best to an identical
bioavailability. It is generally lower, sometimes null. In
contrast, in this application bioavailability is indicated by the
maximum plasma concentration C.sub.max reached after administration
of the drug. A higher C.sub.max of a drug dosage form is indicative
of better drug bioavailability via administrating this dosage
form.
[0055] The compartment indicates the fictitious volume in which a
drug would be distributed. It can correspond or not to a real
volume, for example the volume of blood called first or central
compartment, or the whole body except blood, called second
compartment. The central compartment typically includes the plasma
and in addition those tissues or parts in tissues in which drug
concentrations rapidly come to equilibrium with the plasma. The
real anatomical sectors in which the drug is distributed at
different concentrations are represented by one, two, rarely three
virtual compartments where the concentration of the drug is
regarded as homogeneous. The concept of compartment thus makes it
possible to model the fate of a drug.
[0056] The term "halo" means chlorine, bromine, iodine, and
fluorine, and chlorine and fluorine are preferable.
[0057] The term "alkyl" or "alkyl group" means a straight or
branched saturated monovalent hydrocarbon chain having 1 to 12
carbon atoms. The straight chain or branched chain alkyl group
having 1 to 6 carbon atoms is preferable, and the straight chain or
branched chain alkyl group having 1 to 4 carbon atoms is more
preferable. Examples thereof are methyl group, ethyl group, propyl
group, isopropyl group, butyl group, t-butyl group, isobutyl group,
pentyl group, hexyl group, isohexyl group, heptyl group,
4,4-dimethylpentyl group, octyl group, 2,2,4-trimethylpentyl group,
nonyl group, decyl group, and various branched chain isomers
thereof. Further, the alkyl group may optionally and independently
be substituted by one to five substituents as listed below, if
necessary.
[0058] "Alkoxy" radicals are oxygen ethers formed from the
previously described straight or branched chain alkyl groups. In
some embodiments, the alkoxy may be optionally and independently be
substituted with one to five, preferably one to three substituents
defined below.
[0059] The term "alkylene group" or "alkylene group" means a
straight or branched divalent saturated hydrocarbon chain having 1
to 12 carbon atoms. The straight chain or branched chain alkylene
group having 1 to 6 carbon atoms is preferable, and the straight
chain or branched chain alkylene group having 1 to 4 carbon atoms
is more preferable. Examples thereof are methylene group, ethylene
group, propylene group, trimethylene group, etc. If necessary, the
alkylene group may optionally be substituted in the same manner as
the above-mentioned "alkyl group". Where alkylene groups as defined
above attach at two different carbon atoms of the benzene ring,
they form an annelated five, six or seven membered carbocycle
together with the carbon atoms to which they are attached, and may
optionally be substituted by one or more substituents defined
below.
[0060] The term "alkenyl group" means a straight or branched
monovalent hydrocarbon chain having 2 to 12 carbon atoms and having
at least one double bond. Preferable alkenyl group is a straight
chain or branched chain alkenyl group having 2 to 6 carbon atoms,
and the straight chain or branched chain alkenyl group having 2 to
4 carbon atoms is more preferable. Examples thereof are vinyl
group, 2-propenyl group, 3-butenyl group, 2-butenyl group,
4-pentenyl group, 3-pentenyl group, 2-hexenyl group, 3-hexenyl
group, 2-heptenyl group, 3-heptenyl group, 4-heptenyl group,
3-octenyl group, 3-nonenyl group, 4-decenyl group, 3-undecenyl
group, 4-dodecenyl group, 4,8,12-tetradecatrienyl group, etc. The
alkenyl group may optionally and independently be substituted by 1
to 4 substituents as mentioned below, if necessary.
[0061] The term "alkenylene group" means a straight or branched
divalent hydrocarbon chain having 2 to 12 carbon atoms and having
at least one double bond. The straight chain or branched chain
alkenylene group having 2 to 6 carbon atoms is preferable, and the
straight chain or branched chain alkenylene group having 2 to 4
carbon atoms is more preferable. Examples thereof are vinylene
group, propenylene group, butadienylene group, etc. If necessary,
the alkylene group may optionally be substituted by 1 to 4
substituents as mentioned below, if necessary. Where alkenylene
groups as defined above attach at two different carbon atoms of the
benzene ring, they form an annelated five, six or seven membered
carbocycle (e.g., a fused benzene ring) together with the carbon
atoms to which they are attached, and may optionally be substituted
by one or more substituents defined below.
[0062] The term "alkynyl group" means a straight or branched
monovalent hydrocarbon chain having at least one triple bond. The
preferable alkynyl group is a straight chain or branched chain
alkynyl group having 2 to 6 carbon atoms, and the straight chain or
branched chain alkynyl group having 2 to 4 carbon atoms is more
preferable. Examples thereof are 2-propynyl group, 3-butynyl group,
2-butynyl group, 4-pentynyl group, 3-pentynyl group, 2-hexynyl
group, 3-hexynyl group, 2-heptynyl group, 3-heptynyl group,
4-heptynyl group, 3-octynyl group, 3-nonynyl group, 4-decynyl
group, 3-undecynyl group, 4-dodecynyl group, etc. The alkynyl group
may optionally and independently be substituted by 1 to 4
substituents as mentioned below, if necessary.
[0063] The term "cycloalkyl group" means a monocyclic or bicyclic
monovalent saturated hydrocarbon ring having 3 to 12 carbon atoms,
and the monocyclic saturated hydrocarbon group having 3 to 7 carbon
atoms is more preferable. Examples thereof are a monocyclic alkyl
group and a bicyclic alkyl group such as cyclopropyl group,
cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl
group, cyclooctyl group, cyclodecyl group, etc. These groups may
optionally and independently be substituted by 1 to 4 substituents
as mentioned below, if necessary. The cycloalkyl group may
optionally be condensed with a saturated hydrocarbon ring or an
unsaturated hydrocarbon ring (said saturated hydrocarbon ring and
unsaturated hydrocarbon ring may optionally contain an oxygen atom,
a nitrogen atom, a sulfur atom, SO or SO.sub.2 within the ring, if
necessary), and the condensed saturated hydrocarbon ring and the
condensed unsaturated hydrocarbon ring may be optionally and
independently be substituted by 1 to 4 substituents as mentioned
below.
[0064] The term "cycloalkylidene group" means a monocyclic or
bicyclic divalent saturated hydrocarbon ring having 3 to 12 carbon
atoms, and the monocyclic saturated hydrocarbon group having 3 to 6
carbon atoms is preferable. Examples thereof are a monocyclic
alkylidene group and a bicyclic alkylidene group such as
cyclopropylidene group, cyclobutylidene group, cyclopentylidine
group, cyclohexylidene group, etc. These groups may optionally and
independently be substituted by 1 to 4 substituents as mentioned
below, if necessary. Besides, the cycloalkylidene group may
optionally be condensed with a saturated hydrocarbon ring or an
unsaturated hydrocarbon ring (said saturated hydrocarbon ring and
unsaturated hydrocarbon ring may optionally contain an oxygen atom,
a nitrogen atom, a sulfur atom, SO or SO.sub.2 within the ring, if
necessary), and the condensed saturated hydrocarbon ring and the
unsaturated hydrocarbon ring may be optionally and independently be
substituted by 1 to 4 substituents as mentioned below.
[0065] The term "cycloalkenyl group" means a monocyclic or bicyclic
monovalent unsaturated hydrocarbon ring having 4 to 12 carbon atoms
and having at least one double bond. The preferable cycloalkenyl
group is a monocyclic unsaturated hydrocarbon group having 4 to 7
carbon atoms. Examples thereof are monocyclic alkenyl groups such
as cyclopentenyl group, cyclopentadienyl group, cyclohexenyl group,
etc. These groups may optionally and independently be substituted
by 1 to 4 substituents as mentioned below, if necessary. Besides,
the cycloalkenyl group may optionally be condensed with a saturated
hydrocarbon ring or an unsaturated hydrocarbon ring (said saturated
hydrocarbon ring and unsaturated hydrocarbon ring may optionally
contain an oxygen atom, a nitrogen atom, a sulfur atom, SO or
SO.sub.2 within the ring, if necessary), and the condensed
saturated hydrocarbon ring and the unsaturated hydrocarbon ring may
be optionally and independently be substituted by 1 to 4
substituents as mentioned below.
[0066] The term "cycloalkynyl group" means a monocyclic or bicyclic
unsaturated hydrocarbon ring having 6 to 12 carbon atoms, and
having at least one triple bond. The preferable cycloalkynyl group
is a monocyclic unsaturated hydrocarbon group having 6 to 8 carbon
atoms. Examples thereof are monocyclic alkynyl groups such as
cyclooctynyl group, cyclodecynyl group. These groups may optionally
be substituted by 1 to 4 substituents as mentioned below, if
necessary. Besides, the cycloalkynyl group may optionally and
independently be condensed with a saturated hydrocarbon ring or an
unsaturated hydrocarbon ring (said saturated hydrocarbon ring and
unsaturated hydrocarbon ring may optionally contain an oxygen atom,
a nitrogen atom, a sulfur atom, SO or SO.sub.2 within the ring, if
necessary), and the condensed saturated hydrocarbon ring or the
unsaturated hydrocarbon ring may be optionally and independently be
substituted by 1 to 4 substituents as mentioned below.
[0067] The term "aryl group" means a monocyclic or bicyclic
monovalent aromatic hydrocarbon group having 6 to 10 carbon atoms.
Examples thereof are phenyl group, naphthyl group (including
1-naphthyl group and 2-naphthyl group). These groups may optionally
and independently be substituted by 1 to 4 substituents as
mentioned below, if necessary. Besides, the aryl group may
optionally be condensed with a saturated hydrocarbon ring or an
unsaturated hydrocarbon ring (said saturated hydrocarbon ring and
unsaturated hydrocarbon ring may optionally contain an oxygen atom,
a nitrogen atom, a sulfur atom, SO or SO.sub.2 within the ring, if
necessary), and the condensed saturated hydrocarbon ring or the
unsaturated hydrocarbon ring may be optionally and independently be
substituted by 1 to 4 substituents as mentioned below.
[0068] The term "unsaturated monocyclic heterocyclic ring" means an
unsaturated hydrocarbon ring containing 1-4 heteroatoms
independently selected from a nitrogen atom, an oxygen atom and a
sulfur atom, and the preferable one is a 4- to 7-membered saturated
or unsaturated hydrocarbon ring containing 1-4 heteroatoms
independently selected from a nitrogen atom, an oxygen atom and a
sulfur atom. Examples thereof are pyridine, pyrimidine, pyrazine,
furan, thiophene, pyrrole, imidazole, pyrazole, oxazole, isoxazole,
4,5-dihydrooxazole, thiazole, isothiazole, thiadiazole, triazole,
tetrazole, etc. Among them, pyridine, pyrimidine, pyrazine, furan,
thiophene, pyrrole, imidazole, oxazole, and thiazole can be
preferably used. The "unsaturated monocyclic heterocyclic ring" may
optionally and independently be substituted by 1-4 substituents as
mentioned below, if necessary.
[0069] The term "unsaturated fused heterobicyclic ring" means
hydrocarbon ring comprised of a saturated or a unsaturated
hydrocarbon ring condensed with the above mentioned unsaturated
monocyclic heterocyclic ring where said saturated hydrocarbon ring
and said unsaturated hydrocarbon ring may optionally contain an
oxygen atom, a nitrogen atom, a sulfur atom, SO, or SO.sub.2 within
the ring, if necessary. The "unsaturated fused heterobicyclic ring"
includes, for example, benzothiophene, indole,
tetrahydrobenzothiophene, benzofuran, isoquinoline,
thienothiophene, thienopyridine, quinoline, indoline, isoindoline,
benzothiazole, benzoxazole, indazole, dihydroisoquinoline, etc.
Further, the "heterocyclic ring" also includes possible N- or
S-oxides thereof.
[0070] The term "heterocyclyl" means a monovalent group of the
above-mentioned unsaturated monocyclic heterocyclic ring or
unsaturated fused heterobicyclic ring and a monovalent group of the
saturated version of the above-mentioned unsaturated monocyclic
heterocyclic or unsaturated fused heterobicyclic ring. If
necessary, the heterocyclyl may optionally and independently be
substituted by 1 to 4 substituents as mentioned below.
[0071] The term "alkanoyl group" means a formyl group and ones
formed by binding an "alkyl group" to a carbonyl group.
[0072] The term "substituted" refers to a radical in which one or
more hydrogen atoms are each independently replaced with the same
or different substituent(s).
[0073] With reference to substituents, the term "independently"
means that when more than one of such substituent is possible, such
substituents may be the same or different from each other.
[0074] It is intended that the definition of any substituent or
variable at a particular location in a molecule be independent of
its definitions elsewhere in that molecule. It is understood that
substituents and substitution patterns on the compounds of this
invention can be selected by one of ordinary skill in the art to
provide compounds that are chemically stable and that can be
readily synthesized by techniques known in the art as well as those
methods set forth herein.
[0075] The substituent for the above each group includes, for
example, a halogen atom (fluorine, chlorine, bromine), a nitro
group, a cyano group, an oxo group, a hydroxy group, a mercapto
group, a carboxyl group, a sulfo group, an alkyl group, an alkenyl
group, an alkynyl group, a cycloalkyl group, a
cycloalkylidenemethyl group, a cycloalkenyl group, a cycloalkynyl
group, an aryl group, a heterocyclyl group, an alkoxy group, an
alkenyloxy group, an alkynyloxy group, a cycloalkyloxy group, a
cycloalkenyloxy group, a cycloalkynyloxy group, an aryloxy group, a
heterocyclyloxy group, an alkanoyl group, an alkenylcarbonyl group,
an alkynylcarbonyl group, a cycloalkylcarbonyl group, a
cycloalkenylcarbonyl group, a cycloalkynylcarbonyl group, an
arylcarbonyl group, a hetero-cyclylcarbonyl group, an
alkoxy-carbonyl group, an alkenyloxy-carbonyl group, an
alkynyloxy-carbonyl group, a cycloalkyloxy-carbonyl group, a
cycloalkenyl-oxy-carbonyl group, a cyclo-alkynyl-oxycarbonyl group,
an aryloxycarbonyl group, a hetero-cyclyloxycarbonyl group, an
alkanoyloxy group, an alkenyl-carbonyloxy group, an
alkynyl-carbonyloxy group, a cycloalkyl-carbonyloxy group, a
cycloalkenyl-carbonyloxy group, a cycloalkynyl-carbonyloxy group,
an arylcarbonyloxy group, a hetero-cyclylcarbonyloxy group, an
alkylthio group, an alkenyl-thio group, an alkynylthio group, a
cycloalkylthio group, a cycloalkenyl-thio group, a cycloalkynylthio
group, an arylthio group, a heterocyclylthio group, an amino group,
a mono- or di-alkyl-amino group, a mono- or di-alkanoylamino group,
a mono- or di-alkoxy-carbonyl-amino group, a mono- or
di-arylcarbonyl-amino group, an alkylsulfinylamino group, an
alkyl-sulfonyl-amino group, an arylsulfinylamino group, an
arylsulfonylamino group, a carbamoyl group, a mono- or
di-alkyl-carbamoyl group, a mono- or di-arylcarbamoyl group, an
alkylsulfinyl group, an alkenyl-sulfinyl group, an alkynylsulfinyl
group, a cycloalkyl-sulfinyl group, a cycloalkenylsulfinyl group, a
cycloalkynyl-sulfinyl group, an arylsulfinyl group, a
heterocyclyl-sulfinyl group, an alkyl-sulfonyl group, an
alkenylsulfonyl group, an alkynylsulfonyl group, a
cycloalkylsulfonyl group, a cycloalkenyl-sulfonyl group, a
cycloalkynylsulfonyl group, an aryl-sulfonyl group, and a
heterocyclylsulfonyl group. Each group as mentioned above may
optionally be substituted by these substituents.
[0076] Further, the terms such as a haloalkyl group, a halo-lower
alkyl group, a haloalkoxy group, a halo-lower alkoxy group, a
halophenyl group, or a haloheterocyclyl group mean an alkyl group,
a lower alkyl group, an alkoxy group, a lower alkoxy group, a
phenyl group or a heterocyclyl group (hereinafter, referred to as
an alkyl group, etc.) being substituted by one or more halogen
atoms, respectively. Preferable ones are an alkyl group, etc. being
substituted by 1 to 7 halogen atoms, and more preferable ones are
an alkyl group, etc. being substituted by 1 to 5 halogen atoms.
Similarly, the terms such as a hydroxyalkyl group, a hydroxy-lower
alkyl group, a hydroxyalkoxy group, a hydroxy-lower alkoxy group
and a hydroxyphenyl group mean an alkyl group, etc., being
substituted by one or more hydroxy groups. Preferable ones are an
alkyl group, etc., being substituted by 1 to 4 hydroxy groups, and
more preferable ones are an alkyl group, etc., being substituted by
1 to 2 hydroxy groups. Further, the terms such as an alkoxyalkyl
group, a lower alkoxyalkyl group, an alkoxy-lower alkyl group, a
lower alkoxy-lower alkyl group, an alkoxyalkoxy group, a lower
alkoxyalkoxy group, an alkoxy-lower alkoxy group, a lower
alkoxy-lower alkoxy group, an alkoxyphenyl group, and a lower
alkoxyphenyl group means an alkyl group, etc., being substituted by
one or more alkoxy groups. Preferable ones are an alkyl group,
etc., being substituted by 1 to 4 alkoxy groups, and more
preferable ones are an alkyl group, etc., being substituted by 1 to
2 alkoxy groups.
[0077] The terms "arylalkyl" and "arylalkoxy" as used alone or as
part of another group refer to alkyl and alkoxy groups as described
above having an aryl substituent.
[0078] The term "lower" used in the definitions for the formulae in
the present specification means a straight or branched carbon chain
having 1 to 6 carbon atoms, unless defined otherwise. More
preferably, it means a straight or branched carbon chain having 1
to 4 carbon atoms.
[0079] The term "composition" is intended to encompass a product
comprising the specified ingredients in the specified amounts, as
well as any product which results, directly or indirectly, from
combinations of the specified ingredients in the specified
amounts.
[0080] The term "prodrug" means an ester or carbonate, which is
formed by reacting one or more hydroxy groups of the compound of
the Formula (I) with an acylating agent substituted by an alkyl, an
alkoxy or an aryl by a conventional method to produce acetate,
pivalate, methylcarbonate, benzoate, etc. Further, the prodrug
includes also an ester or amide, which is similarly formed by
reacting one or more hydroxy groups of the compound of the Formula
(I) with an .alpha.-amino acid or a .beta.-amino acid, etc. using a
condensing agent by a conventional method. In addition, the prodrug
includes also ether, which is similarly formed by reacting one or
more hydroxy groups of the compound of the Formula (I) with a
condensing agent via a conventional method.
[0081] "Pharmaceutically acceptable" means molecular entities and
compositions that are of sufficient purity and quality for use in
the formulation of a composition or medicament of the present
invention. Since both human use (clinical and over-the-counter) and
veterinary use are equally included within the scope of the present
invention, a formulation would include a composition or medicament
for either human or veterinary use.
[0082] The term "pharmaceutically acceptable salt" refers includes,
for example, a salt with an alkali metal such as lithium, sodium,
potassium, etc.; a salt with an alkaline earth metal such as
calcium, magnesium, etc.; a salt with zinc or aluminum; a salt with
an organic base such as ammonium, choline, diethanolamine, lysine,
ethylenediamine, t-butylamine, t-octylamine,
tris(hydroxymethyl)aminomethane, N-methyl glucosamine,
triethanolamine and dehydroabietylamine; a salt with an inorganic
acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid,
sulfuric acid, nitric acid, phosphoric acid, etc.; or a salt with
an organic acid such as formic acid, acetic acid, propionic acid,
oxalic acid, malonic acid, succinic acid, fumaric acid, maleic
acid, lactic acid, malic acid, tartaric acid, citric acid,
methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid,
etc.; or a salt with an acidic amino acid such as aspartic acid,
glutamic acid, etc.
[0083] The compound of Formula (I) of the present invention also
includes a mixture of stereoisomers, or each pure or substantially
pure isomer. For example, the present compound may optionally have
one or more asymmetric centers at a carbon atom containing any one
of substituents. Therefore, the compound of the Formula (I) may
exist in the form of enantiomer or diastereomer, or a mixture
thereof. When the present compound of Formula (I) contains a double
bond, the present compound may exist in the form of geometric
isomerism (cis-compound, trans-compound), and when the present
compound of Formula (I) contains an unsaturated bond such as
carbonyl, then the present compound may exist in the form of a
tautomer, and the present compound also includes these isomers or a
mixture thereof. The starting compound in the form of a racemic
mixture, enantiomer or diastereomer may be used in the processes
for preparing the present compound. When the present compound is
obtained in the form of a diastereomer or enantiomer, they can be
separated by a conventional method such as chromatography or
fractional crystallization.
[0084] In addition, the present compound of Formula (I) includes an
intramolecular salt, hydrate, solvate or polymorphism thereof.
[0085] To provide a more concise description, some of the
quantitative expressions given herein are not qualified with the
term "about". It is understood that whether the term "about" is
used explicitly or not, every quantity given herein is meant to
refer to the actual given value, and it is also meant to refer to
the approximation to such given value that would reasonably be
inferred based on the ordinary skill in the art, including
approximations due to the experimental and/or measurement
conditions for such given value.
[0086] To provide a more concise description, some of the
quantitative expressions herein are recited as a range from about
amount X to about amount Y. It is understood that wherein a range
is recited, the range is not limited to the recited upper and lower
bounds, but rather includes the full range from about amount X
through about amount Y, or any amount or range therein.
B) Compounds
[0087] Compounds of Formula (I) exhibit an excellent inhibitory
activity against sodium-dependent glucose transporter, and an
excellent glucose lowering effect. Therefore, the formulation of
the present invention is useful for treating or delaying the
progression or onset of a sodium-dependent glucose transporter
mediated disorder. In particular, the formulation of the present
invention is useful for treating or delaying the progression or
onset of diabetes mellitus, diabetic retinopathy, diabetic
neuropathy, diabetic nephropathy, delayed wound healing, insulin
resistance, hyperglycemia, hyperinsulinemia, elevated blood levels
of fatty acids, elevated blood levels of glycerol, hyperlipidemia,
obesity, hypertriglyceridemia, Syndrome X, diabetic complications,
atherosclerosis, or hypertension. In particular, the formulation of
the present invention is useful in the treatment or the prophylaxis
of diabetes mellitus (type 1 and type 2 diabetes mellitus, etc.),
diabetic complications (such as diabetic retinopathy, diabetic
neuropathy, diabetic nephropathy) or obesity, or is useful in the
treatment of postprandial hyperglycemia.
[0088] In certain preferred embodiments, R.sub.1 as shown in
Formula (I) is a halogen atom, or a lower alkyl group; and R.sub.2
as shown in Formula (I) phenyl is optionally substituted by 1 to 3
substituents selected from the group consisting of a halogen atom,
a cyano group, a lower alkyl group, a halo-lower alkyl group, a
lower alkoxy group, a halo-lower alkoxy group, a methylenedioxy
group, an ethyleneoxy group, a mono- or di-lower alkylamino group,
a carbamoyl group, and a mono- or di-lower alkylcarbamoyl
group.
[0089] Preferably drug compounds of Formula (I) used in the
disclosed formulation typically possess slight to poor water
solubility in their crystalline or amorphous form and hence poor
bioavailability, but the present invention is not necessarily
limited to compounds with little to no water solubility.
[0090] Preferred representative compounds for use in the
formulations of the present invention include
1-(.beta.-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethy-
l]benzene), or a prodrug or a pharmaceutically acceptable salt
thereof. In certain further preferred embodiments, the compound for
use in the formulations of the present invention is
1-(.beta.-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethy-
l]benzene)hemihydrate.
[0091] Preferably the
1-(.beta.-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethy-
l]benzene), or a prodrug or a pharmaceutically acceptable salt
thereof is included in the formulation of the present invention in
an amount of from about 25 mg to about 600 mg, preferably from
about 50 mg to about 400 mg.
[0092] In certain further preferred embodiments, the
1-(.beta.-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethy-
l]benzene), or a prodrug or a pharmaceutically acceptable salt
thereof is included in the formulation of the present invention in
an amount of about 25 mg, about 50 mg, about 75 mg, about 100 mg,
about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350
mg, or about 400 mg. In certain further preferred embodiments, the
1-(.beta.-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethy-
l]benzene), or a prodrug or a pharmaceutically acceptable salt
thereof is included in the formulation of the present invention in
an amount of about 100 mg or about 300 mg. In certain embodiments,
wherein the
1-(.beta.-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethy-
l]benzene) is in the hemihydrate form the
1-(.beta.-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethy-
l]benzene)hemihydrate is preferably included in the formulation in
an amount of about 25.5 mg, about 51 mg, about 102 mg, about 204
mg, or about 306 mg, preferably in an amount of about 102 mg or
about 306 mg.
C) Formulation
[0093] In embodiments of the present invention, the compound is
formulated into oral dosage forms suitable for administration to
patients in need thereof.
[0094] The oral dosage form may be provided in any pharmaceutically
acceptable solid dosage form. Preferably, the solid dosage form
includes, for example, solid preparation such as tablets, pills,
granules, capsules, powders and others. More preferably, the solid
dosage form is an oral tablet or capsule formulation. Most
preferably the solid dosage form is an oral tablet.
[0095] In certain embodiments of the present invention the
formulation includes a filler or diluent in the amount of about 10%
to about 95% by weight of the formulation, preferably from about
25% to about 90% by weight of the formulation, more preferably from
about 30% to about 50% by weight of the formulation or from about
35% to about 45% by weight of the formulation.
[0096] In certain embodiments of the present invention the
formulation includes a disintegrant in the amount of about 0.1% to
about 20% by weight of the formulation, preferably from about 0.25%
to about 10% by weight of the formulation, more preferably from
about 3% to about 10% by weight of the formulation or from about 5%
to about 7% by weight of the formulation.
[0097] In certain embodiments of the present invention the
formulation includes a binder in the amount of about 0.1% to about
20% by weight of the formulation, preferably from about 0.1% to
about 10% by weight of the formulation, more preferably from about
0.5% to about 5% by weight of the formulation or from about 1% to
about 4% by weight of the formulation.
[0098] In certain embodiments of the present invention the
formulation includes a lubricant in the amount of about 0.1% to
about 5% by weight of the formulation, preferably from about 0.1%
to about 2% by weight of the formulation, more preferably from
about 0.5% to 2% by weight of the formulation or 0.5% to 1.5% by
weight of the formulation.
[0099] In certain embodiments of the present invention the
formulation optionally includes a surfactant in the amount of about
0% to about 10% by weight of the formulation, preferably from about
0% to about 5% by weight of the formulation.
[0100] The solid dosage forms may comprise the compound in
combination with various pharmaceutically acceptable excipients,
and preferably the dosage form is adapted to provide increased
bioavailability of the compound in a manner to obtain the desired
clinical effect through oral administration to the patient.
[0101] The bioavailability promoting agent of the present invention
includes any combination of the excipients described herein such
that the formulation provides for the increase bioavailability of
the compound included the formulation. In certain preferred
embodiments, the bioavailability promoting agent includes two or
more excipients described herein.
[0102] Pharmaceutically acceptable excipients are known in the art
and can be provided according to considerations of desired
functionality and process ability. Roles for the excipients in the
oral dosage form include but are not limited to fillers, binders,
disintegrants, release controlling agents, glidants, lubricants,
coatings and the like.
[0103] For example, in one embodiment of the invention, it is
desired to have an immediate release profile for the dosage form.
To help achieve this profile in a solid dosage form, the dosage
form preferably comprises a disintegrant in an amount as noted
herein. In another embodiment of the invention, wherein a
controlled or sustained release formulation of the compound is
desired. Such a formulation can be achieved by varying the amounts,
concentrations and ratios of certain release controlling
polymers.
[0104] In one embodiment, the formulation of the present invention
includes the compound in an amount of about 1% to about 80%,
preferably from about 5% to about 60% by weight of the formulation,
more preferably from about 40% to about 60% by weight of the
formulation or about 45% to about 55% by weight of the formulation.
Depending on the desired dose of the compound, one or more of the
dosage forms can be administered.
[0105] For example, in one preferred embodiment of the invention,
an oral release formulation is provided in tablet form comprising
about 100 mg of
1-(.beta.-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethy-
l]benzene), microcrystalline cellulose, hydroxypropyl cellulose,
croscarmellose sodium, lactose anhydrous, and magnesium
stearate.
[0106] In another preferred embodiment of the invention, an oral
release formulation is provided in tablet form comprising about 300
mg of
1-(.beta.-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethy-
l]benzene), microcrystalline cellulose, hydroxypropyl cellulose,
croscarmellose sodium, lactose anhydrous, and magnesium
stearate.
[0107] In another preferred embodiment of the invention, an oral
release formulation is provided in tablet form comprising about 102
mg of
1-(.beta.-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethy-
l]benzene) hemihydrate, microcrystalline cellulose, hydroxypropyl
cellulose, croscarmellose sodium, lactose anhydrous, and magnesium
stearate.
[0108] In another preferred embodiment of the invention, an oral
release formulation is provided in tablet form comprising about 306
mg of
1-(.beta.-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethy-
l]benzene) hemihydrate, microcrystalline cellulose, hydroxypropyl
cellulose, croscarmellose sodium, lactose anhydrous, and magnesium
stearate.
[0109] Fillers or diluents for use in the formulations of the
present invention include fillers or diluents typically used in the
formulation of pharmaceuticals. Examples of fillers or diluents for
use in accordance with the present invention include but are not
limited to sugars such as lactose, dextrose, glucose, sucrose,
cellulose, starches and carbohydrate derivatives, polysaccharides
(including dextrates and maltodextrin), polyols (including
mannitol, xylitol, and sorbitol), cycludextrins, calcium
carbonates, magnesium carbonates, microcrystalline cellulose,
combinations thereof, and the like. In certain preferred
embodiments the filler or diluent is lactose, microcrystalline
cellulose, or combination thereof. Several types of
microcrystalline cellulose are suitable for use in the formulations
described herein, for example, microcrystalline cellulose selected
from the group consisting of Avicel.RTM. types: PH101, PH102,
PH103, PH105, PH 112, PH113, PH200, PH301, and other types of
microcrystalline cellulose, such as silicified microcrystalline
cellulose. Several types of lactose are suitable for use in the
formulations described herein, for example, lactose selected from
the group consisting of anhydrous lactose, lactose monohydrate,
lactose fast flo, directly compressible anhydrous lactose, and
modified lactose monohydrate. In one embodiment of the invention,
the filler or diluent is a combination of microcrystalline
cellulose and lactose.
[0110] Binders for use in the formulations of the present invention
include binders commonly used in the formulation of
pharmaceuticals. Examples of binders for use in accordance with the
present invention include but are not limited to cellulose
derivatives (including hydroxypropyl cellulose, hydroxypropyl
methylcellulose, methylcellulose, and sodium carboxymethyl
cellulose), glycol, sucrose, dextrose, corn syrup, polysaccharides
(including acacia, targacanth, guar, alginates and starch), corn
starch, pregelatinized starch, modified corn starch, gelatin,
polyvinylpyrrolidone, polyethylene, polyethylene glycol,
combinations thereof and the like. Preferably, the binding agent,
if present, is hydroxypropyl cellulose.
[0111] Disintegrants for use in the formulations of the present
invention include disintegrants commonly used in the formulation of
pharmaceuticals. Examples of disintegrants for use in accordance
with the present invention include but are not limited to starches,
clays, celluloses, alginates and gums and crosslinked starches,
celluloses and polymers, combinations thereof and the like.
Representative disintegrants include microcrystalline cellulose,
croscarmellose sodium, alginic acid, sodium alginate,
crosprovidone, cellulose, agar and related gums, sodium starch
glycolate, corn starch, potato starch, sodiumstarch glycolate,
Veegum HV, methylcellulose, agar, bentonite,
carboxymethylcellulose, alginic acid, guar gum combinations
thereof, and the like. Preferably, the disintegrant, if present, is
a cross-linked cellulose, more preferably cross-linked sodium
carboxymethylcellulose or croscarmellose sodium.
[0112] Lubricants for use in the formulations of the present
invention include lubricants commonly used in the formulation of
pharmaceuticals. Examples of lubricants for use in accordance with
the present invention include but are not limited to magnesium
carbonate, magnesium laurylsulphate, calcium silicate, talc, fumed
silicon dioxide, combinations thereof, and the like. Other useful
lubricants include but are not limited to magnesium stearate,
calcium stearate, stearic acid, sodium stearyl fumarate,
polyethylene glycol, sodium lauryl sulphate, magnesium lauryl
sulphate, sodium benzoate, colloidal silicon dioxide, magnesium
oxide, microcrystalline cellulose, starches, mineral oil, waxes,
glyceryl behenate, polyethylene glycol, sodium acetate, sodium
chloride, combinations thereof, and the like. Preferably, the
lubricant, if present, is magnesium stearate or stearic acid, more
preferably magnesium stearate.
[0113] Surfactants for use in the formulations of the present
invention include surfactants commonly used in the formulation of
pharmaceuticals. Examples of surfactants for use in accordance with
the present invention include but are not limited to ionic- and
nonionic surfactants or wetting agents commonly used in the
formulation of pharmaceuticals, such as ethoxylated castor oil,
polyglycolyzed glycerides, acetylated monoglycerides, sorbitan
fatty acid esters, poloxamers, polyoxyethylene sorbitan fatty acid
esters, polyoxyethylene derivatives, monoglycerides or ethoxylated
derivatives thereof, diglycerides or polyoxyethylene derivatives
thereof, sodium docusate, sodium laurylsulfate, cholic acid or
derivatives thereof, lecithins, phospholipids, combinations
thereof, and the like.
[0114] Other polymers commonly used as excipients include but are
not limited to methylcellulose (MC), ethylcellulose (EC),
hydroxyethylcellulose (HEC), methyl hydroxyethylcellulose (MHEC),
hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose
(HPMC), sodium carboxymethylcellulose (NaCMC), and the like. These
polymers, either alone or in various combinations, may serve
multiple purposes including but not limited to controlling release
of the compound of the formulations of the present invention.
[0115] In any case, the appropriate excipients should be selected
such that they are compatible with other excipients and do not bind
with the drug compound or cause drug degradation.
[0116] The pharmaceutical formulations disclosed herein can further
comprise antioxidants and chelating agents. For example, the
pharmaceutical formulations can comprise butylated hydroxyanisole
(BHA), butylated hydroxytoluene (BHT), propyl gallate (PG), sodium
metabisulfite, ascorbyl palmitate, potassium metabisulfite,
disodium EDTA (ethylenediamine tetraacetic acid; also known as
disodium edentate), EDTA, tartaric acid, citric acid, citric acid
monohydrate, and sodium sulfite.
[0117] In another embodiment, the tablet or capsule of the
invention has a protective outer layer. The protective outer layer
of the tablet or capsule, where present, can include from about 10%
to about 95% of polymer based on the weight of the coating layer,
and can be prepared employing conventional procedures. In one
embodiment, the outer layer of the tablet or capsule includes from
about 20% to about 90% of polymer based on the weight of the
coating layer. The formulation can contain at least one coating
layer polymer and a coating solvent, for example, water, which is
used for processing and removed by drying. Suitable examples of
polymer for the coating layer include, but are not limited to,
hydroxypropyl methylcellulose, polyvinyl alcohol (PVA), ethyl
cellulose, methacrylic polymers, hydroxypropyl cellulose, and
starch. In one embodiment, the coating layer polymer is PVA. In
another embodiment, the coating layer polymer is hydroxypropyl
cellulose.
[0118] The coating can also optionally include a plasticizer of
from about 0% to about 30% by weight, based on the weight of the
coating layer. In one embodiment, the plasticizer is from about 15%
to about 25% by weight of the coating layer. Suitable plasticizers
include, but are not limited to, triacetin, diethyl phthalate,
tributyl sebacate, polyethylene glycol (PEG), glycerin, triacetin,
and triaethyl citrate, for example.
[0119] In another embodiment, the coating can also optionally
include an anti-adherent or glidant such as talc, fumed silica, or
magnesium stearate, for example.
[0120] In another embodiment, the coating can also optionally
include an opacifying agent, such as titanium dioxide, for
example.
[0121] In yet another embodiment, wherein the formulation is a
tablet, the tablet may be further coated with a coating layer that
provides cosmetic benefits to the dosage form. In certain
embodiments, such a coating helps to protect the tablets. In
certain embodiments such coating comprises hydroxypropyl
methylcellulose, polyethylene glycol, polydextrose, titanium
dioxide, and triacetin. In certain other embodiments such coating
comprises hydroxypropyl methylcellulose 2910, polyethylene glycol
400, polydextrose, titanium dioxide, carnuba wax, and iron oxide
yellow. In at least one embodiment such a coating layer comprises
Opadry.RTM. II (white) in an amount of from about 0% to about 10%
by weight of the tablet; in certain other embodiments in an amount
of from about 0% to about 6% by weight of the tablet; and in still
other embodiments in an amount of from about, 0% to about 3% by
weight of the tablet; and in other embodiments from about 2 to
about 4% by weight of the tablet.
D) Additional Therapeutic Agents
[0122] In another embodiment the formulations of the present
invention further include one or more additional therapeutic agents
to provide the desired therapeutic effect.
[0123] Other therapeutic agent(s) suitable for combination with the
formulations of the present invention include, but are not limited
to, known therapeutic agents useful in the treatment of the
aforementioned disorders associated with SGLT2 activity including:
anti-diabetic agents; anti-hyperglycemic agents; hypolipidemic or
lipid lowering agents; anti-obesity agents; anti-hypertensive
agents and appetite suppressants.
[0124] The invention further provides a method for treating or
delaying the progression or onset of diseases or disorders
associated with SGLT2 activity comprising administering to a
mammalian species in need of such treatment a therapeutically
effective amount of the pharmaceutical formulation of the invention
and one or more of the following: anti-diabetic agent(s),
anti-hyperglycemic agent(s); hypolipidemic or lipid lowering
agent(s); anti-obesity agent(s); anti-hypertensive agent(s) and
appetite suppressant(s).
[0125] In one embodiment, the invention provides a method for
treating type II diabetes comprising administering to a mammalian
species in need of such treatment a therapeutically effective
amount of the pharmaceutical formulation of the invention and one
or more anti-diabetic agent(s). In another embodiment, the
invention provides a method for delaying the progression or onset
of type II diabetes comprising administering to a mammalian species
in need of such treatment a therapeutically effective amount of the
pharmaceutical formulation of the invention and one or more
anti-diabetic agent(s).
[0126] In another embodiment, the invention provides a method for
treating or delaying the progression or onset of type II diabetes
comprising administering to a mammalian species in need of such
treatment a therapeutically effective amount of the pharmaceutical
formulation of the invention and one or more of the following:
anti-hyperglycemic agent(s); hypolipidemic or lipid lowering
agent(s); anti-obesity agent(s); anti-hypertensive agent(s) and
appetite suppressant(s). For example, the invention provides a
method for treating or delaying the progression or onset of type II
diabetes comprising administering to a mammalian species in need of
such treatment a therapeutically effective amount of a
pharmaceutical formulation of the invention and an
anti-hyperglycemic agent(s). In another embodiment, the invention
provides a method for treating or delaying the progression or onset
of type II diabetes comprising administering to a mammalian species
in need of such treatment a therapeutically effective amount of a
pharmaceutical formulation of the invention and a hypolipidemic
agent(s). In another embodiment, the invention provides a method
for treating or delaying the progression or onset of type II
diabetes comprising administering to a mammalian species in need of
such treatment a therapeutically effective amount of a
pharmaceutical formulation of the invention and an anti-obesity
agent(s). In another embodiment, the invention provides a method
for treating or delaying the progression or onset of type II
diabetes comprising administering to a mammalian species in need of
such treatment a therapeutically effective amount of a
pharmaceutical formulation of the invention and an
anti-hypertensive agent(s). In another embodiment, the invention
provides a method for treating or delaying the progression or onset
of type II diabetes comprising administering to a mammalian species
in need of such treatment a therapeutically effective amount of a
pharmaceutical formulation of the invention and an appetite
suppressant(s).
[0127] Examples of suitable anti-diabetic agents for use in
combination with the formulations of the present invention include,
but are not limited to, biguanides (e.g., metformin or phenformin),
glucosidase inhibitors (e.g., acarbose or miglitol), insulins
(including insulin secretagogues or insulin sensitizers),
meglitinides (e.g., repaglinide), sulfonylureas (e.g., glimepiride,
glyburide, gliclazide, chlorpropamide and glipizide),
biguanide/glyburide combinations (e.g., Glucovance.RTM.),
thiazolidinediones (e.g., troglitazone, rosiglitazone and
pioglitazone), PPAR-alpha agonists, PPAR-gamma agonists, PPAR
alpha/gamma dual agonists, glycogen phosphorylase inhibitors,
inhibitors of fatty acid binding protein (aP2), glucagon-like
peptide-1 (GLP-1) and other agonists of the GLP-1 receptor, and
dipeptidyl peptidase IV (DPP4) inhibitors.
[0128] Other suitable thiazolidinediones include, but are not
limited to, MCC-555, faraglitazar, englitazone or darglitazone;
isaglitazone, reglitazar, rivoglitazone, liraglutide, and
(Z)-1,4-bis-4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl-methyl)]phenoxybut-2-e-
ne.
[0129] Examples of PPAR-alpha agonists, PPAR-gamma agonists and
PPAR alpha/gamma dual agonists include, but are not limited to,
muraglitazar, peliglitazar, tesaglitazar AR-H039242, GW-501516, and
IRP297.
[0130] Suitable DPP4 inhibitors include, but are not limited to,
sitigliptin and saxagliptin.
[0131] Examples of suitable anti-hyperglycemic agents for use in
combination with the formulations of the present invention include,
but are not limited to, glucagon-like peptide-1 (GLP-1) such as
GLP-1 (1-36) amide, GLP-1 (7-36) amide, GLP-1 (7-37), exenatide,
LY-315902, MK-0431, liraglutide, ZP-10, and CJC-1131.
[0132] Examples of suitable hypolipidemic/lipid lowering agents for
use in combination with the formulations of the present invention
include one or more MTP inhibitors, HMG CoA reductase inhibitors
(such as e.g., mevastatin, lovastatin, pravastatin, simvastatin,
fluvastatin, cerivastatin, atorvastatin, atavastatin,
rosuvastatin), squalene synthetase inhibitors, fibric acid
derivatives (such as e.g., fenofibrate, gemfibrozil, clofibrate,
bezafibrate, ciprofibrate, clinofibrate and the like, probucol,
bile acid sequestrants, such as cholestyramine, colestipol and
DEAE-Sephadex, as well as lipostabil), ACAT inhibitors,
lipoxygenase inhibitors, cholesterol absorption inhibitors, ileal
Na.sup.+/bile acid co-transporter inhibitors, up-regulators of LDL
receptor activity, bile acid sequestrants, cholesterol ester
transfer protein (e.g., CETP inhibitors, such as torcetrapib and
JTT-705, PPAR agonists (as described above) and/or nicotinic acid
and derivatives thereof. Preferred hypolipidemic agents include
pravastatin, lovastatin, simvastatin, atorvastatin, fluvastatin,
cerivastatin, atavastatin and rosuvastatin, for example.
[0133] Examples of suitable anti-hypertensive agents for use in
combination with the formulations of the present invention include,
but are not limited to, beta adrenergic blockers, calcium channel
blockers (L-type and T-type; e.g. diltiazem, verapamil, nifedipine,
amlodipine and mybefradil), diuretics (e.g., chlorothiazide,
hydrochlorothiazide, flumethiazide, hydroflumethiazide,
bendroflumethiazide, methylchlorothiazide, trichloromethiazide,
polythiazide, benzthiazide, ethacrynic acid tricrynafen,
chlorthalidone, furosemide, musolimine, bumetanide, triamtrenene,
amiloride, spironolactone), renin inhibitors, ACE inhibitors (e.g.,
captopril, zofenopril, fosinopril, enalapril, ceranopril,
cilazopril, delapril, pentopril, quinapril, ramipril, lisinopril),
AT-1 receptor antagonists (e.g., losartan, irbesartan, valsartan),
and ET receptor antagonists (e.g., sitaxsentan, and atrsentan).
Examples of suitable anti-obesity agents for use in combination
with the formulations of the present invention include, but are not
limited to, beta 3 adrenergic agonists, lipase inhibitors,
serotonin (and dopamine) reuptake inhibitors, thyroid receptor beta
drugs, 5HT2C agonists; MCHR1 antagonists, such as Synaptic
SNAP-7941 and Takeda T-226926, melanocortin receptor (MC4R)
agonists, melanin-concentrating hormone receptor (MCHR)
antagonists, galanin receptor modulators, orexin antagonists, CCK
agonists, NPY1 or NPY5 antagonist, NPY2 and NPY4 modulators,
corticotropin releasing factor agonists, histamine receptor-3 (H3)
modulators, 11-beta-HSD-1 inhibitors, adinopectin receptor
modulators, monoamine reuptake inhibitors or releasing agents,
ciliary neurotrophic factors, BDNF (brain-derived neurotrophic
factor), leptin and leptin receptor modulators, cannabinoid-1
receptor antagonists, and anorectic agents.
[0134] Examples of lipase inhibitors that can be employed in
combination with formulations of the present invention include, but
are not limited to, orlistat and ATL-962 (Alizyme).
[0135] Serotonin (and dopamine) reuptake inhibitors (or serotonin
receptor agonists) that can be employed in combination with the
formulations of the present invention include, but are not limited
to, BVT-933, sibutramine, topiramate and axokine.
[0136] Examples of monoamine reuptake inhibitors that can be
employed in combination with the formulations of the present
invention include, but are not limited to, fenfluramine,
dexfenfluramine, fluvoxamine, fluoxetine, paroxetine, sertraline,
chlorphentermine, cloforex, clortermine, picilorex, sibutramine,
dexamphetamine, phentermine, phenylpropanolamine and mazindol.
[0137] Anorectic agents that can be employed in combination with
the formulations of the present invention include, but are not
limited to, topiramate, dexamphetamine, phentermine,
phenylpropanolamine and mazindol.
[0138] Where any of the formulations of the invention are used in
combination with other therapeutic agent(s), the other therapeutic
agent(s) can be used, for example, in the amounts indicated in the
Physician's Desk Reference, or as otherwise known and used by one
of ordinary skill in the art.
[0139] Where any of the formulations of the invention are used in
combination with other therapeutic agent(s), each of the compounds
of the combination can be administered simultaneously or
sequentially and in any order, and the components can be
administered separately or as a fixed combination, in jointly
therapeutically effective amounts, for example, in daily dosages as
described herein. In one embodiment of the invention, a fixed
combination of the invention can be prepared by mixing a dry
granulation of the compound of Formula (I) or (I-S) or formulation
of the invention and a dry granulation of the other therapeutic
agent(s) and filling the mixture into capsules of desired size,
shape, color, or other characteristics, or compressing to form
tablets.
E) Manufacturing of Formulation
[0140] In certain embodiments, the formulations of the invention
are prepared by making an admixture of the drug compound, and a
bioavailability-promoting agent. Dissolving these components in a
liquid solvent therefore and subsequently removing the solvent may
affect this most straightforwardly. Thus viewed from a further
aspect the invention provides a process for the preparation of a
pharmaceutical composition, said process comprising: dissolving a
drug compound, and the pharmaceutically acceptable excipients in a
solvent; removing solvent from the resultant solution; optionally
forming the resultant product into desired shapes; and optionally
coating the resulting product with a physiologically tolerable
coating material.
[0141] Preferably, dosage forms in accordance with the embodiments
depicted herein are manufactured by standard techniques. For
example, the dosage form may be manufactured by the wet granulation
technique. In the wet granulation technique, the drug and carrier
are blended using an aqueous or organic solvent, such as denatured
anhydrous ethanol, as the granulation fluid. The remaining
ingredients can be dissolved in a portion of the granulation fluid,
such as the solvent described above, and this latter prepared wet
blend is slowly added to the drug blend with continual mixing in
the blender. The granulating fluid is added until a wet blend is
produced, which wet mass blend is then forced through a
predetermined screen and dried in a fluid bed dryer. The dried
granules are then sized. Next, magnesium stearate, or another
suitable lubricant and other excipient materials are added to the
drug granulation, and the granulation is put into milling jar sand
mixed on a jar mill for 10 minutes. The composition is pressed into
a layer, for example, in a Manesty.RTM. press or a Korsch LCT
press. For a trilayered core, granules or powders of the drug layer
compositions and push layer composition are sequentially placed in
an appropriately-sized die with intermediate compression steps
being applied to each of the first two layers, followed by a final
compression step after the last layer is added to the die to form
the trilayered core. The intermediate compression typically takes
place under a force of about 50-100 Newtons. Final stage
compression typically takes place at a force of 3500 Newtons or
greater, often 3500-5000 Newtons. The compressed cores are fed to a
dry coater press, e.g., Kilian.RTM. Dry Coaterpress, and
subsequently coated with the wall materials as described
herein.
[0142] Pan coating may be conveniently used to provide the
completed dosage form. In the pan coating system, the wall-forming
composition for the inner wall or the outer wall, as the case may
be, is deposited by successive spraying of the appropriate wall
composition onto the compressed core accompanied by tumbling in a
rotating pan. A pan coater is used because of its availability at
commercial scale. Other techniques can be used for coating the
compressed core. Once coated, the wall is dried in a forced-air
oven or in a temperature and humidity controlled oven to free the
dosage form of solvent(s) used in the manufacturing. Drying
conditions will be conventionally chosen on the basis of available
equipment, ambient conditions, solvents, coatings, coating
thickness, and the like.
[0143] Other coating techniques can also be employed. For example,
one alternative technique uses an air-suspension procedure. This
procedure consists of suspending and tumbling the compressed core
in a current of air, until a coating is applied to the core. The
air-suspension procedure is described in U.S. Pat. No. 2,799,241;
in J. Am. Pharm. Assoc., Vol. 48, pp. 451-459 (1959); and, ibid.,
Vol. 49, pp. 82-84 (1960). The dosage form also can be coated with
a Wurster.RTM. air-suspension coater using, for example, methylene
dichloride methanol as a cosolvent for the wall forming material.
An Aeromatic.RTM. air-suspension coater can be used employing a
cosolvent.
[0144] In another embodiment, the drug and other ingredients
comprising the drug layer are blended and pressed into a solid
layer. The layer possesses dimensions that correspond to the
internal dimensions of the area the layer is to occupy in the
dosage form, and it also possesses dimensions corresponding to the
push layer, if included, for forming a contacting arrangement
therewith. The drug and other ingredients can also be blended with
a solvent and mixed into a solid or semisolid form by conventional
methods, such as ballmilling, calendering, stirring or rollmilling,
and then pressed into a preselected shape. The compressed cores
then may be coated with the inner wall material and the
semipermeable wall material as described herein.
[0145] Another manufacturing process that can be used comprises
blending the powdered ingredients in a fluid bed granulator. After
the powdered ingredients are dry blended in the granulator, a
granulating fluid, for example, polyvinylpyrrolidone in water, is
sprayed onto the powders. The coated powders are then dried in the
granulator. This process granulates all the ingredients present
therein while adding the granulating fluid. After the granules are
dried, a lubricant, such as stearic acid or magnesium stearate, is
mixed into the granulation using a blender e.g., V-blender or tote
blender. The granules are then pressed and coated in the manner
described above.
[0146] Exemplary solvents suitable for manufacturing the dosage
form components comprise aqueous or inert organic solvents that do
not adversely harm the materials used in the system. The solvents
broadly include members selected from the group consisting of
aqueous solvents, alcohols, ketones, esters, ethers, aliphatic
hydrocarbons, halogenated solvents, cycloaliphatics, aromatics,
heterocyclic solvents and mixtures thereof. Typical solvents
include acetone, diacetone alcohol, methanol, ethanol, isopropyl
alcohol, butyl alcohol, methyl acetate, ethylacetate, isopropyl
acetate, n-butyl acetate, methyl isobutyl ketone, methyl propyl
ketone, nhexane, n-heptane, ethylene glycol monoethyl ether,
ethylene glycol monoethyl acetate, methylene dichloride, ethylene
dichloride, propylene dichloride, carbon tetrachloridenitroethane,
nitropropane tetrachloroethane, ethyl ether, isopropyl ether,
cyclohexane, cyclooctane, benzene, toluene, naphtha, 1,4-dioxane,
tetrahydrofuran, diglyme, water, aqueous solvents containing
inorganic salts such as sodium chloride, calcium chloride, and the
like, and mixtures thereof such as acetone and water, acetone and
methanol, acetone and ethyl alcohol, methylene dichloride and
methanol, and ethylene dichloride and methanol.
[0147] Exemplary liquid carriers for the present invention include
lipophilic solvents (e.g., oils and lipids), surfactants, and
hydrophilic solvents. Exemplary lipophilic solvents, for example,
include, but are not limited to, Capmul PG-8, Caprol MPGO, Capryol
90, Plurol Oleique CC497, Capmul MCM, Labrafac PG, N-Decyl Alcohol,
Caprol 10G10O, Oleic Acid, Vitamin E, Maisine 35-1, Gelucire 33/01,
Gelucire 44/14, Lauryl Alcohol, Captex 355EP, Captex 500,
Capylic/Caplic Triglyceride, Peceol, Caprol ET, Labrafil M2125 CS,
Labrafac CC, Labrafil M20 1944 CS, Captex 8277, Myvacet 9-45,
Isopropyl Nyristate, Caprol PGE 860, Olive Oil, Plurol Oleique,
Peanut Oil, Captex 300 Low C6, and Capric Acid.
[0148] Exemplary surfactants for example, include, but are not
limited to, Vitamin E TPGS, Cremophor (grades EL, EL-P, and RH40),
Labrasol, Tween (grades 20, 60, 80), Pluronic (gradesL-31, L-35,
L-42, L-64, and L-121), Acconon S-35, Solutol HS-15, and Span
(grades 20, and 80).
[0149] Exemplary hydrophilic solvents for example, include, but are
not limited to, Isosorbide Dimethyl Ether, Polyethylene Glycol (PEG
grades 300, 400, 600, 3000, 4000, 6000, and 8000) and Propylene
Glycol (PG).
[0150] In general, essentially complete solvent removal will be
preferred as the resultant product can then readily be shaped.
Shaping may be effected by spray-drying the solution (to provide
the product in particulate form), by evaporation of solvent from
solution disposed in molds, by molding (e.g. injection molding), by
extrusion and the like. In general the product can be formed when
hot and allowed to solidify on cooling. The shaped product may
likewise be produced in film or sheet form by evaporation or by
pouring a heated mass onto a plate and evaporating off the
solvent.
F) Formulation Examples
[0151] The following formulation examples are illustrative only and
are not intended to limit the scope of the inventions in any way.
Tablets were prepared using the ingredients listed in Tables
1.1-1.6 and the following procedure.
[0152] In the following examples in Table 1.1-1.6, the exemplified
compound, lactose anhydrous, microcrystalline cellulose, and
croscarmellose sodium were screened and placed into a fluid
bed.
[0153] Hydroxypropyl cellulose and purified water were mixed to
prepare the granulating solution.
[0154] The granulating solution was sprayed into the fluid bed to
granulate the dry ingredients.
[0155] When the granulating solution was exhausted, the granulation
was dried within the fluid bed.
[0156] The dried granules were passed through a suitable mill
fitted with an appropriate screen.
[0157] The milled granulation was placed in an appropriate blender
and combined with screened magnesium stearate.
[0158] The mixture was blended for an appropriate period of
time.
[0159] A suitable rotary tablet press was employed to compress the
final blend into tablets.
[0160] Where a filmcoating was utilized (e.g., Opadry II), the
filmcoating powder was mixed with purified water to obtain the
film-coating suspension.
[0161] The tablets were filmcoated in a suitable coating pan and
dried.
TABLE-US-00001 TABLE 1.1 100 mg Tablet Formulation Ingredient
Weight (mg/tablet) % Weight/tablet 1-(.beta.-D-glucopyranosyl)-4-
102.00 51.00% methy1-3-[5-(4- fluorophenyl)-2-
thienylmethyl]penzene) hemihydrate.sup.1 Silicified
Microcystralline 39.26 19.63% Cellulose Lactose Anhydrous 39.26
19.63% Hydroxypropyl Cellulose 6.00 3.00% Croscarmellose Sodium
12.00 6.00% Magnesium Stearate 1.48 0.74% Total 200.00 100%
.sup.1amount of hemihydrate equivalent to 100 mg of
1-(.beta.-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethy-
l]benzene)
TABLE-US-00002 TABLE 1.2 25 mg Tablet Formulation Ingredient Weight
(mg/tablet) % Weight/tablet 1-(.beta.-D-glucopyranosyl)-4- 25.50
12.75% methyl-3-[5-(4- fluorophenyl)-2- thienylmethyl]benzene)
hemihydrate.sup.1 Silicified Microcystralline 81.76 40.88%
Cellulose Lactose Anhydrous 81.76 40.88% Hydroxypropyl Cellulose
1.50 0.75% Croscarmellose Sodium 8.00 4.00% Magnesium Stearate 1.48
0.74% Total 200.00 100% .sup.1amount of hemihydrate equivalent to
25 mg of
1-(.beta.-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethy-
l]benzene)
TABLE-US-00003 TABLE 1.3 200 mg Tablet Formulation Ingredient
Weight (mg/tablet) % Weight/tablet 1-(.beta.-D-glucopyranosyl)-4-
204.00 51.00% methyl-3-[5-(4- fluorophenyl)-2-
thienylmethyl]benzene) hemihydrate.sup.1 Silicified
Microcystralline 78.52 19.63% Cellulose Lactose Anhydrous 78.52
19.63% Hydroxypropyl Cellulose 12.00 3.00% Croscarmellose Sodium
24.00 6.00% Magnesium Stearate 2.96 0.74% Total 400.00 100%
.sup.1amount of hemihydrate equivalent to 200 mg of
1-(.beta.-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethy-
l]benzene)
TABLE-US-00004 TABLE 1.4 50 mg Tablet Formulation Ingredient Weight
(mg/tablet) % Weight/tablet 1-(.beta.-D-glucopyranosyl)-4- 51.00
51.00% methyl-3-[5-(4- fluorophenyl)-2- thienylmethyl]benzene)
hemihydrate.sup.1 Silicified Microcystralline 19.63 19.63%
Cellulose Lactose Anhydrous 19.63 19.63% Hydroxypropyl Cellulose
3.00 3.00% Croscarmellose Sodium 6.00 6.00% Magnesium Stearate 0.74
0.74% Total 100.00 100% .sup.1amount of hemihydrate equivalent to
50 mg of
1-(.beta.-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethy-
l]benzene)
TABLE-US-00005 TABLE 1.5 300 mg coated Tablet Formulation
Ingredient Weight (mg/tablet) % Weight/tablet
1-(.beta.-D-glucopyranosyl)-4- 306.00 51.50% methy1-3-[5-(4-
fluoropheny1)-2- thienylmethyl]benzene) hemihydrate.sup.1
Microcystralline Cellulose 117.78 19.63% Lactose Anhydrous 117.78
19.63% Hydroxypropyl Cellulose 18.00 3.00% Croscarmellose Sodium
36.00 6.00% Magnesium Stearate 4.44 0.74% Total 600.00 100% Opadry
II.sup.2 18.00 3.00% .sup.1amount of hemihydrate equivalent to 300
mg of
1-(.beta.-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethy-
l]benzene) .sup.2Tablets are coated to a 3% weight gain with Opadry
II
TABLE-US-00006 TABLE 1.6 100 mg coated Tablet Formulation
Ingredient Weight (mg/tablet) % Weight/tablet
1-(.beta.-D-glucopyranosyl)-4- 102.00 51.00% methy1-3-[5-(4-
fluoropheny1)-2- thienylmethylbenzene) hemihydrate.sup.1
Microcystralline Cellulose 39.26 19.63% Lactose Anhydrous 39.26
19.63% Hydroxypropyl Cellulose 6.00 3.00% Croscarmellose Sodium
12.00 6.00% Magnesium Stearate 1.48 0.74% Total 200.00 100% Opadry
II.sup.2 8.00 4.00% .sup.1amount of hemihydrate equivalent to 100
mg of
1-((3-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]be-
nzene) .sup.2Tablets are coated to a 4% weight gain with Opadry
II
G) Biological Examples
In Vivo Pharmacokinetic Data from Dog Studies
[0162] Exposure of
1-(.beta.-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethy-
l]benzene) in dogs was compared using various orally administrable
formulations. Eleven male beagle dogs weighing from 8.0 to 10.0 kg
at dose administration and exhibiting good general health were
chosen for this study. The dogs were placed into 3 groups according
to their weight. Following an overnight fast each dog received
either a single oral suspension dosage or tablet dosage form. In
total, three dosage forms of drug compound
1-(.beta.-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethy-
l]benzene) were administered: a 5 mg/mL nanosuspension, the 100 mg
Tablet Formulation and 25 mg Tablet Formulation. Three fasted dogs
in Group 1 received 20 mL of a 5 mg/mL nanosuspension; 4 fasted
dogs assigned to Group 2 received the 100 mg Tablet Formulation (1
tablet per dog; ingredients listed in Table 1.1); and the 4 fasted
dogs assigned to Group 3 received the 25 mg Tablet Formulation (4
tablets per dog; ingredients listed in Table 1.2).
[0163] Following each dose, the dogs received 10 mL of tap water to
ensure delivery of the entire dose. Blood samples of about 3 mL
were collected via jugular venipuncture, or other suitable site,
into K.sub.2 EDTA tubes and placed on wet ice, at times of 0, 0.5,
1, 2, 4, 8, 24, and 48 hours post initial dosing. Plasma was
harvested by centrifugation, and frozen at -20.degree. C. All
samples were placed in amber vials for protection from white light
and were processed within two hours of collection.
[0164] Plasma samples were analyzed for plasma concentrations of
drug compound
I-(.beta.-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thi-
enylmethyl]benzene) by using a liquid chromatographic-triple
quadruple mass spectrometric (LC-MS/MS) assay procedure with a
lower limit of quantification of 50 ng/mL. Plasma concentration
data were electronically transferred to a Watson.TM. LIMS computer
system. The Watson.TM. system assigns a value of 0.00 to those
concentrations below the lower limit of quantification.
TABLE-US-00007 TABLE 2 Body Subject Weight C.sub.max t.sub.max
AUC.sub.0-48 h AUC.sub.inf t.sub.1/2 CL/F Dosage/Formulation ID
(kg) (ng/mL) (h) (ng h/mL) (ng h/mL) (h) (mL/h) 20 mL of 5 mg/mL 1
9.10 6480 2.00 114000 119000 10.4 763 nanosuspension 2 8.10 7760
0.500 105000 107000 8.01 759 3 9.90 4210 1.00 64300 66000 9.24 1500
Mean 9.03 6150 1.17 94600 97300 9.23 1008 SD 0.902 1800 0.764 26700
27900 1.22 427 1 .times. 100 mg tablet 4 10.0 9670 2.00 147000
153000 10.5 656 5 8.00 6440 2.00 95800 97300 7.95 1030 6 8.30 7910
1.00 116000 118000 8.49 847 7 9.80 7230 4.00 137000 142000 9.63 705
Mean 9.03 7810 2.25 124000 127000 9.13 809 SD 1.02 1380 1.26 22700
24700 1.13 167 4 .times. 25 mg tablets 8 8.60 11100 4.00 180000
188000 10.8 532 9 9.30 9640 4.00 155000 161000 9.83 621 10 8.30
7460 4.00 157000 163000 10.4 612 11 8.80 9360 2.00 109000 112000
8.86 895 Mean 8.75 9390 3.50 150000 156000 9.97 665 SD 0.420 1500
1.00 29600 32000 0.845 159
[0165] The nanosuspension used as a control in the study included a
0.5% Methocel.RTM. suspension measured in weight percentage.
Methocel.RTM. is a hydroxypropyl methylcellulose (HPMC) polymer
exhibiting high viscosity and used as a thickener of the
suspension. The drug concentration was 5 mg of drug per 1 mL of
suspension volume. A total of 20 mL suspension was administered to
each dog in the nanosuspension group.
[0166] Pharmacokinetic analysis of the plasma concentrations of
drug compound
1-(.beta.-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thi-
enylmethyl]benzene) was performed to determine the maximum plasma
concentration (C.sub.max), the time to maximum plasma concentration
(t.sub.max), the area under the plasma concentration versus time
curve extrapolated to infinity (AUC.sub.inf and AUC.sub.0-48 h),
the terminal half-life (t.sub.1/2), and the plasma clearance (CL/F)
using the WinNonlin Version 4.0.1 (Pharsight) validated computer
program.
TABLE-US-00008 TABLE 3 Body Weight C.sub.max t.sub.max t.sub.1/2
AUC.sub.0-48 h AUC.sub.inf Bio- CL/F Formulation (kg) (ng/mL) (h)
(h) (ng h/mL) (ng h/mL) availability (mL/h) 20 mL of 5 mg/mL Mean
9.03 6150 1.17 9.23 94600 97300 Reference 1008 nanosuspension SD
(0.902) (1800) (0.764) (1.22) (26700) (27900) (427) 1 .times. 100
mg Tablet Mean 9.03 7810 2.25 9.13 124000 127000 127 809 SD (1.020)
(1380) (1.26) (1.13) (22700) (24700) (167) 4 .times. 25 mg Tablet
Mean 8.75 9390 3.50 9.97 150000 156000 153 665 SD (0.420) (1500)
(1.00) (0.845) (29600) (32000) (159)
[0167] Following a single 20 mL oral dose of a 5 mg/mL
nanosuspension of the compound to male beagle dogs, absorption of
the compound was rapid based on a mean t.sub.max value of 1.17
hours and its elimination was slow based on a mean t.sub.1/2 value
of 9.23 hours. Administration of the single oral dose of 100 mg
Tablet Formulation or four doses of the 25 mg Tablet Formulation of
the compound showed delayed absorption of the compound as indicated
by mean t.sub.max values of 2.25 and 3.50 hours, respectively.
[0168] Yet, the elimination of the compound after administration of
both Tablet Formulations remained slow with mean t.sub.1/2 values
9.13 and 9.97 hours, respectively. Based on mean plasma
pharmacokinetic parameters that were normalized to 1 mg/kg, the
maximum plasma concentration (C.sub.max) of the compound following
oral administration of one dose of the 100 mg Tablet Formulation
and four doses of the 25 mg Tablet Formulation was higher as
compared to the 5 mg/mL nanosuspension (FIGS. 1A & B).
[0169] Furthermore, bioavailability, as indicated by AUC.sub.inf,
following administration of the compound of the 100 mg Tablet
Formulation or the 25 mg Tablet Formulation was higher than after
the administration of the 5 mg/mL nanosuspension.
[0170] In Vivo Pharmacokinetic Data from Human Studies
[0171] Healthy human subjects received single oral doses of a
liquid nanosuspension or tablet formulation under fed and/or fasted
conditions at three different dose levels of the drug compound
1-(.beta.-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethy-
l]benzene). The three dose levels included 25 mg (representative
formulation listed in Table 1.2), 200 mg (representative
formulation listed in Table 1.3) and 400 mg of the drug compound.
In particular, the 400 mg tablet dose was achieved by administering
two doses of the 200 mg Tablet Formulation.
[0172] The mean plasma concentration profiles of the compound
following oral administration of the 200 mg Tablet Formulation
under fasted and fed condition and 40 mL of the 5 mg/mL liquid
nanosuspension (fed condition) are shown in FIG. 2. Similar
profiles for the Tablet Formulation versus the nanosuspension were
obtained at doses of 25 mg and 400 mg.
[0173] Following 25 and 200 mg doses under fed conditions as shown
in Table 4, the median time to maximum plasma concentration
(t.sub.max) of the compound was approximately 1 to 1.5 hours for
Tablet Formulations versus 4 hours in case of the nanosuspension.
At the 400 mg dose level, median t.sub.max was approximately 1.75
hours for 2 doses of the 200 mg Tablet Formulation versus 2.25
hours in case of the nanosuspension.
[0174] For all doses (25 mg, 200 mg, 400 mg), under fed conditions,
the mean C.sub.max was lower for the nanosuspension formulation
compared to the Tablet Formulations.
[0175] Following administration of 25 and 200 mg doses of the
Tablet Formulation, the mean C.sub.max was higher under fasted
conditions than under fed conditions. For all doses (25 mg, 200 mg
and 400 mg), under fed or fasting (25 mg and 200 mg Tablet
Formulation only) conditions, mean AUC.sub.inf values of the
compound were comparable.
TABLE-US-00009 TABLE 4 Nanosuspension Tablet Tablet 25 mg Dose Food
Intake Fed Fasted Fed Number of 17 17 18 subjects C.sub.max (ng/mL)
130.6 (38.6) 217.1 (52.0) 183.9 (46.1) t.sub.max.sup.a (hr) 4.0
(1-6) 1.5 (1-4) 1.0 (1-3) t.sub.1/2(hr) 7.9 (1.6) 8.1 (1.9) 7.6
(1.2) AUC.sub.inf 1,476 (368) 1,441 (347) 1,462 (421) (ng .times.
h/mL) Bioavailability Reference 166.2 140.8 200 mg Dose Food Intake
Fed Fasted Fed Number of 15 17 16 subjects C.sub.max (ng/mL) 985.9
(273.4) 1,411.7 (319.8) 1,284.3 (320.5) t.sub.max.sup.a (hr) 4.0
(3-6) 1.5 (1-3) 1.5 (1-4) t.sub.1/2 (hr) 12.4 (4.2) 12.1 (2.4) 11.9
(2.6) AUC.sub.inf 13,007 (2881) 12,291 (2579) 12,846 (2489) (ng
.times. h/mL) Bioavailability Reference 143.2 130.3 400 mg Dose 30
Min. Prior to With Food Intake Fed Breakfast Breakfast Number of 12
12 12 subjects C.sub.max (ng/mL) 1,683.3 (310.1) 2,412.5 (727.6)
2,315.0 (474.9) t.sub.max.sup.a (hr) 2.25 (0.5-6) 1.5 (1-4) 1.75
(1-2.5) t.sub.1/2 (hr) 11.8 (3.7) 11.0 (3.9) 10.1 (4.0) AUC.sub.inf
24,520 (4599) 26,158 (11263) 23,667 (2259) (ng .times. h/mL)
Bioavailability Reference 143.3 137.5 .sup.aData represents mean
(SD) values
[0176] These data suggest that food had no significant effect on
the extent of bioavailability to the drug compound, but it
decreased the rate of absorption as evidenced by a decrease in
C.sub.max and delay in t.sub.max.
[0177] Following tablet administration at the 400 mg dose
(2.times.200 mg tablets), altering meal-timing (dosing 30 minutes
prior to breakfast versus dosing 10 minutes prior to breakfast) did
not appear to influence t.sub.max, t.sub.1/2, C.sub.max, or
AUC.sub..infin..
[0178] For all treatment regimens regardless of formulation and
food intake, the mean t.sub.1/2 of the drug compound ranged from
about 8 to about 12 h.
* * * * *