U.S. patent application number 17/494455 was filed with the patent office on 2022-04-21 for pharmaceutical formulations.
The applicant listed for this patent is THERACOS SUB, LLC. Invention is credited to Qiuhua CAI, Joseph Ho-Lun CHAU, Chunfeng DAI, Vipan DHALL, Fuxia DONG, Michael J. HADD, Vinay PATIL, Brian SEED, Rina SHAH, Ankit SHRIVASTAVA, Feng WANG.
Application Number | 20220117898 17/494455 |
Document ID | / |
Family ID | 1000006088900 |
Filed Date | 2022-04-21 |
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United States Patent
Application |
20220117898 |
Kind Code |
A1 |
WANG; Feng ; et al. |
April 21, 2022 |
PHARMACEUTICAL FORMULATIONS
Abstract
The pharmacokinetic profile of the SGLT2 inhibitor bexagliflozin
can be improved by formulating it as an extended release tablet.
Compared with standard immediate-release dosage forms these tablets
can permit a lower peak plasma concentration, C.sub.max, while
maintaining plasma concentrations at therapeutic levels for a
desired period. This can be used, for instance, to administer lower
doses while still providing the same pharmacological effect.
Inventors: |
WANG; Feng; (Shanghai,
CN) ; SHRIVASTAVA; Ankit; (Bina, IN) ; SHAH;
Rina; (Ahmedabad, IN) ; SEED; Brian; (Boston,
MA) ; PATIL; Vinay; (Pune, IN) ; HADD; Michael
J.; (San Jose, CA) ; DONG; Fuxia; (Shanghai,
CN) ; DHALL; Vipan; (Brampton, CA) ; DAI;
Chunfeng; (Shanghai, CN) ; CHAU; Joseph Ho-Lun;
(Whistler, CA) ; CAI; Qiuhua; (Shanghai,
CN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
THERACOS SUB, LLC |
Marlborough |
MA |
US |
|
|
Family ID: |
1000006088900 |
Appl. No.: |
17/494455 |
Filed: |
October 5, 2021 |
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/2013 20130101;
A61K 9/284 20130101; A61K 9/006 20130101; A61K 9/2054 20130101;
A61K 31/70 20130101 |
International
Class: |
A61K 9/20 20060101
A61K009/20; A61K 9/00 20060101 A61K009/00; A61K 31/70 20060101
A61K031/70; A61K 9/28 20060101 A61K009/28 |
Foreign Application Data
Date |
Code |
Application Number |
Oct 5, 2020 |
CN |
PCT/CN2020/119816 |
Claims
1. An extended-release tablet comprising bexagliflozin.
2. The extended-release tablet of claim 1, further comprising a
mucoadhesive.
3. The extended-release tablet of claim 1, wherein an in vitro
dissolution test in simulated gastric fluid, releases .ltoreq.17%
of its bexagliflozin after 1 hour and releases .gtoreq.80% after 8
hours.
4.-5. (canceled)
6. The extended-release tablet of claim 3, wherein the in vitro
dissolution test is performed with a United States Pharmacopoeia
(USP) Apparatus 1 at 50 rpm with 900 mL of 0.1 N HCl at
37.+-.0.5.degree. C.
7. (canceled)
8. The extended-release tablet of claim 1, wherein said tablet
provides a plasma bexagliflozin C.sub.max of .ltoreq.8 ng/mL per mg
of bexagliflozin in the tablet in a fasted subject having a body
mass greater than 60 kg.
9.-18. (canceled)
19. The extended-release tablet of claim 1, comprising 20 mg
bexagliflozin, wherein and an in vitro dissolution test performed
with a United States Pharmacopoeia (USP) Apparatus 1 at 50 rpm with
900 mL of 0.1 N HCl at 37.+-.0.5.degree. C., releases .ltoreq.17%
of its bexagliflozin after 1 hour, releases between 20-45% of its
bexagliflozin after 3 hours, releases between 45-75% of its
bexagliflozin after 5 hours, and releases .gtoreq.80% of its
bexagliflozin after 8 hours.
20.-24. (canceled)
25. The extended-release tablet of claim 1, wherein bexagliflozin
is in the form of a crystalline solid.
26. The extended-release tablet of claim 1, comprising a monolithic
matrix in which bexagliflozin is dispersed within solid
excipient(s) which comprise a water-insoluble substance.
27. The extended-release tablet of claim 26, wherein the
water-insoluble substance is glyceryl dibehenate.
28. The extended-release tablet of claim 27, including 30-35% by
weight glyceryl dibehenate.
29. The extended-release tablet of claim 1, wherein the tablet has
a density below 1.04 g/cm.sup.3 and can float in simulated gastric
fluid.
30. The extended-release tablet of claim 1, wherein the tablet
further comprises a solubilizer.
31. The extended-release tablet of claim 30, wherein the
solubilizer comprises a poloxamer, such as poloxamer 188.
32. The extended-release tablet of claim 31, including 10-12% by
weight poloxamer 188.
33. The extended-release tablet of claim 1, wherein the tablet
further comprises a filler.
34. The extended-release tablet of claim 33, wherein the tablet
further comprises lactose and/or microcrystalline cellulose.
35. The extended-release tablet of claim 34, including 11-13% by
weight lactose and/or 18-20% by weight microcrystalline
cellulose.
36. The extended-release tablet of claim 1, wherein the tablet
further comprises a glidant and/or a lubricant.
37. The extended-release tablet of claim 36, wherein the tablet
further comprises magnesium stearate and/or colloidal silicon
dioxide.
38. The extended-release tablet of claim 37, including 1.5-2.5% by
weight magnesium stearate and/or 1.0-1.5% by weight colloidal
silicon dioxide.
39. The extended-release tablet of claim 1, wherein the tablet
further comprises a mucoadhesive.
40. The extended-release tablet of claim 39, wherein the
mucoadhesive is a polyethylene oxide.
41. The extended-release tablet of claim 40, including 16-20% by
weight polyethylene oxide having an average molecular weight of
approximately 900,000 or greater.
42. The extended-release tablet of claim 1, wherein the tablet has
a coating surrounding a core.
43. The extended-release tablet of claim 42, wherein the coating
(i) comprises polyvinyl alcohol and (ii) is present at between
2.5-3.5% of the core's weight.
44. The extended-release tablet of claim 1, wherein the tablet has
a hardness between 20-100 N and/or a friability of .ltoreq.1% by
weight.
45. A extended-release tablet of claim 1, further comprising
glyceryl dibehenate; polyethylene oxide; lactose; poloxamer 188;
microcrystalline cellulose; colloidal silicon dioxide; and
magnesium stearate; and optionally having a coating comprising
polyvinyl alcohol.
46. The extended-release tablet of claim 45, having the following
composition per tablet: bexagliflozin, between 5-50 mg; glyceryl
dibehenate, between 100-140 mg; polyethylene oxide, between 50-75
mg; lactose, between 40-50 mg; poloxamer 188, between 40-45 mg;
microcrystalline cellulose, between 60-80 mg; colloidal silicon
dioxide, between 4-5 mg; and magnesium stearate, between 6-9 mg;
optionally also having 10-12 mg of the coating.
47. A batch of tablets which include an amount of bexagliflozin
between 5-50 mg wherein, when tablets are assessed in an in vitro
dissolution assay conducted in USP Apparatus 1 charged with 900 mL
of 0.1 N HCl and stirred at a rate of 50 rpm with the temperature
maintained at 37.+-.0.5.degree. C., from which 10 mL is extracted
at 1, 3, 5 and 8 hours after being added to the HCl, at least one
of the following criteria is satisfied: (i) six tablets of the
batch are analyzed and all six tablets release .ltoreq.17% of their
bexagliflozin after 1 hour, release between 20-45% of their
bexagliflozin after 3 hours, release between 45-75% of their
bexagliflozin after 5 hours, and release .ltoreq.80% of their
bexagliflozin after 8 hours; (ii) six tablets did not satisfy
criteria (i), but the average bexagliflozin release for those six
tablets and six further tablets is .ltoreq.17% after 1 hour,
between 20-45% after 3 hours, between 45-75% after 5 hours, and
.gtoreq.80% after 8 hours, and the bexagliflozin release seen by
all twelve tablets falls no more than 2 mg outside these release
criteria; or (iii) twelve tablets did not satisfy criteria (ii),
but the average bexagliflozin release for those twelve tablets and
twelve further tablets is .ltoreq.17% after 1 hour, between 20-45%
after 3 hours, between 45-75% after 5 hours, and .gtoreq.80% after
8 hours; not more than 2 of the 24 tablets are more than 10%
outside each of the ranges of .ltoreq.17% after 1 hour, between
20-45% after 3 hours, between 45-75% after 5 hours, and .gtoreq.80%
after 8 hours; and none of the tablets is more than 20% outside
each of the ranges of .ltoreq.17% after 1 hour, between 20-45%
after 3 hours, between 45-75% after 5 hours, and .gtoreq.80% after
8 hours.
48. The batch of claim 47, wherein the tablets release (a) between
45-72% of its bexagliflozin after 5 hours (b) between 50-70% of its
bexagliflozin after 5 hours (c) between 49-69% of its bexagliflozin
after 5 hours or (d) between 48-68% of its bexagliflozin after 5
hours.
49. A batch of extended release bexagliflozin tablets which include
an amount of bexagliflozin between 5-50 mg wherein: (a) upon
administration to an appropriately constituted cohort of healthy
fasted subjects, a first representative sample set of tablets from
the batch provides on one occasion a first mean logarithm of the
C.sub.max and a first mean logarithm of the AUC.sub.0-t, and a
second representative sample of tablets from the batch produces on
a different occasion a second mean logarithm of the C.sub.max and a
second mean logarithm of the AUC.sub.0-t, and wherein the
differences between the first and second mean logarithms of the
C.sub.max and between the first and second mean logarithms of the
AUC.sub.0-t both exhibit 90% confidence intervals, the endpoints of
which lie between -0.22314 and +0.22314. (b) upon administration to
an appropriately constituted cohort of healthy subjects each
provided on one occasion a single tablet from a first
representative tablet sample set in the fasted state, and on a
different occasion a single tablet from a second representative
tablet sample set in the fed state, the mean differences in
ln(C.sub.max) and ln(AUC.sub.0-t) both exhibit a 90% confidence
interval, the endpoints of which lie between -0.22314 and +0.58779;
(c) upon administration to an appropriately constituted cohort of
fasted healthy subjects each provided on one occasion a single
tablet from a first representative tablet sample set without any
prior dosage of a parenteral GLP-1 receptor agonist, and on a
different occasion, a single tablet from a second representative
tablet sample set 30 minutes following an approved dosage of a
parenteral GLP-1 receptor agonist, the mean differences in
ln(C.sub.max) and ln(AUC.sub.0-t) both exhibit a 90% confidence
interval wherein the upper bound of the interval is less than
0.69315; and/or (d) upon administration to an appropriately
constituted cohort of healthy subjects each provided on one
occasion a single tablet from a first representative tablet sample
set in the fasted state, and on a different occasion, a single
tablet from a second representative tablet sample set in the fed
state, the differences created by subtracting the values for the
T.sub.max for the fasted state from the values for the T.sub.max
for the fed state exhibit a median that is less than or equal to
3.5 hours.
50.-55. (canceled)
56. A method for treating a subject suffering from diabetes or its
symptoms, comprising a step of administering to the subject the
tablet of claim 1.
Description
CROSS-REFERENCES TO RELATED APPLICATIONS
[0001] This application claims priority to International
Application No. PCT/CN2020/119816, filed on Oct. 5, 2020, the
entirety of which is incorporated herein by reference for all
purposes.
TECHNICAL FIELD
[0002] The invention provides pharmaceutical formulations of SGLT2
inhibitors useful for treating diabetes mellitus and other
conditions, and in particular oral formulations of bexagliflozin
with improved pharmacokinetic properties.
BACKGROUND OF THE INVENTION
[0003] Bexagliflozin (EGT0001442, EGT1442, THR1442, THR0001442) is
an inhibitor of SGLT2 (renal Na.sup.+/glucose transporter) that is
useful for the treatment and management of various conditions,
including diabetes (see: Zhang et al. (2011) Pharmacol Res
63(4):284-93; Allegretti et al. (2019) Am J Kidney Dis. 74:328 doi:
10.1053/j.ajkd.2019.03.417; Zhang et al. (2019) Xenobiotica doi:
10.1080/00498254.2019.1654634). It has been tested in humans in the
form of oral solid dosage forms (e.g. see NCT01377844 or
NCT01029704) as well as oral solutions, and has been shown to be
well-tolerated and to provide a durable, clinically meaningful
improvement in glycemic control, as well as a reduction in body
mass and blood pressure in diabetic adults (Halvorsen et al. (2019)
Diabetes Obes Metab doi: 10.1111/dom.13833, Halvorsen et al. (2019)
Diabetes Obes Metab 21:2248 doi: 10.1111/dom.13801).
SUMMARY OF THE INVENTION
[0004] Studies of human subjects who have been administered
bexagliflozin in the form of oral capsules or oral solutions have
shown that the plasma concentration of bexagliflozin displays a
high peak/trough ratio (both C.sub.max to C.sub.min and C.sub.max
to C.sub.24h), with a steep decline during the alpha phase. The
inventors have found that a better pharmacokinetic profile can be
achieved by formulating bexagliflozin as an extended release
tablet. Compared with standard immediate-release dosage forms,
these tablets can permit lower doses to be administered while still
providing the same pharmacological effect (a lower peak plasma
concentration, C.sub.max, while maintaining plasma concentrations
at therapeutic levels), and can reduce the likelihood of side
effects for any given dose. It is well known in the art that
adverse drug reactions, especially poorly predictable idiosyncratic
reactions (which frequently are not detected during the
pre-approval testing of new drugs but, once discovered, can lead to
restriction or withdrawal of the approved medication) are more
likely to occur in drugs that must be administered in large doses,
and that the likelihood of adverse reactions often increases as the
C.sub.max increases. Thus, in a first aspect, the invention
provides an extended release tablet of bexagliflozin.
[0005] A particularly preferred tablet of the first aspect releases
bexagliflozin in vivo to provide a plasma C.sub.max in fasted
subjects which is at least 125,000.times. lower per milliliter than
the tablet's total bexagliflozin content. Thus, for example, a
tablet containing 20 mg bexagliflozin would provide a fasted
C.sub.max of .ltoreq.160 ng/mL. Ideally the plasma C.sub.max is at
least 135,000.times. lower than the bexagliflozin content (i.e.
.ltoreq.148 ng/mL for a tablet containing 20 mg bexagliflozin), or
even at least 145,000.times. lower (i.e. .ltoreq.138 ng/mL for a 20
mg tablet).
[0006] According to a second aspect, the invention provides an
extended release tablet that contains between 10 mg and 20 mg of
bexagliflozin and that provides an in vivo plasma C.sub.max of
.ltoreq.160 ng/mL in fasted subjects. Ideally the C.sub.max is
.ltoreq.133 ng/mL. In one embodiment, the tablet contains 10 mg
bexagliflozin and the C.sub.max is .ltoreq.80 ng/mL; in another
embodiment, the tablet contains 20 mg bexagliflozin and the
C.sub.max is .ltoreq.160 ng/mL.
[0007] According to a third aspect, the invention provides an
extended release tablet that contains between 30 mg and 60 mg of
bexagliflozin and that provides an in vivo plasma C.sub.max of
<400 ng/mL in fasted subjects. In one embodiment, the tablet
contains 40 mg bexagliflozin and the plasma C.sub.max is <320
ng/mL; in another embodiment, the tablet contains 50 mg
bexagliflozin and the plasma C.sub.max is <400 ng/mL.
[0008] For both the first and second aspects, a preferred tablet
contains 20 mg bexagliflozin and provides an AUC.sub.0-t between
600 and 1200 ng h mL.sup.-1 in fasted subjects. Similarly, a
preferred tablet contains 20 mg bexagliflozin and provides an
AUC.sub.0-.infin. between 675 and 1275 ng h mL.sup.-1 in fasted
subjects.
[0009] For both the first and second aspects, a preferred tablet
contains 20 mg bexagliflozin and provides a plasma C.sub.max
between 80 and 150 ng/mL in fasted subjects.
[0010] For the first, second and third aspects, a preferred tablet
provides a bexagliflozin plasma concentration 24 hours after
administration (i.e. C.sub.24h) of .gtoreq.5 ng/mL, and ideally
.gtoreq.10 ng/mL.
[0011] For the first, second and third aspects, a preferred tablet
provides a time to maximum bexagliflozin plasma concentration (i.e.
T.sub.max) that is between 2 and 6 hours in fasted subjects, and
ideally between 2 and 4.5 hours.
[0012] As explained in more detail below, the properties defined
for a tablet will typically be measured after administration of
representative specimens of a batch of which that tablet is an
exemplar, and an appropriate average (e.g. geometric mean) of the
results will be calculated. With this in mind, a batch of tablets
according to the first aspect may release bexagliflozin in vivo to
provide a geometric mean plasma C.sub.max in fasted subjects which
is at least 125,000.times. lower per milliliter than each tablet's
total bexagliflozin content. Similarly, a batch of tablets
according to the second aspect may provide, an in vivo geometric
mean plasma C.sub.max of .ltoreq.160 ng/mL (e.g. a geometric mean
C.sub.max.ltoreq.133 ng/mL) in fasted subjects; for instance,
tablets may contain 10 mg bexagliflozin and provide a geometric
mean C.sub.max.ltoreq.80 ng/mL, or they may contain 20 mg
bexagliflozin and provide a geometric mean C.sub.max.ltoreq.160
ng/mL. Similarly, a batch of tablets according to the third aspect
may provide an in vivo geometric mean plasma C.sub.max of <400
ng/mL in fasted subjects; for instance, tablets may contain 40 mg
bexagliflozin and provide a geometric mean plasma C.sub.max<320
ng/mL, or may contain 50 mg bexagliflozin and provide a geometric
mean plasma C.sub.max<400 ng/mL. Furthermore, a batch of tablets
of the first and second aspects containing 20 mg bexagliflozin may
provide in fasted subjects (i) a geometric mean AUC.sub.0-t between
600 and 1200 ng h mL.sup.-1 and/or (ii) a geometric mean
AUG.sub.0-.infin. between 675 and 1275 ng h mL.sup.-1 and/or (iii)
a geometric mean plasma C.sub.max between 80 and 150 ng/mL.
Similarly, for the first, second and third aspects, a batch of
tablets may provide a geometric mean C.sub.24h of .gtoreq.5 ng/mL,
and ideally .gtoreq.10 ng/mL.
[0013] For a batch of tablets according to the first, second and
third aspects, the ratio of the median bexagliflozin plasma
C.sub.max and C.sub.min values may be less than 10 e.g. between
5-10, between 6-8, or between 7-8. The high peak/trough ratio seen
in the prior art can thus be avoided. A median C.sub.min of at
least 10 ng/mL is preferred. As shown below, these pharmacokinetic
parameters represent robust statistical estimates based on
measurements from over 800 subjects from various regions in the
world, using various different extended release bexagliflozin
tablets.
[0014] The inventors have also observed that bexagliflozin is a
P-gp substrate, and that absorption of bexagliflozin from the large
intestine is minimal Because P-gp expression increases with
distance along the small intestine, absorption is likely greater in
the duodenum than the ileum, and quantitative mass balance studies
using [.sup.14C]-bexagliflozin have shown that colonic absorption
is minimal (Zhang et al. Xenobiotica. 2019 Aug. 27:1-11. doi:
10.1080/00498254.2019.1654634). Because of the potential practical
incompatibility of using an extended release tablet while aiming
for most drug release to occur high in the small intestine, tablets
of the invention advantageously include an adaptation that can help
to retain them in the stomach. A large part of the extended release
of bexagliflozin can thus occur in the stomach, permitting
absorption of the drug to occur at the desired location in the
small intestine, thereby providing an advantageous pharmacokinetic
profile. Tablets with gastric retention adaptations have been shown
to function well in vivo even though bexagliflozin is unstable in
the prolonged presence of acid, and is susceptible to acidic
decomposition.
[0015] Various adaptations can be used to help retain a tablet of
the invention in the stomach, including but not limited to: (i)
inclusion of an effervescent excipient, which can provide buoyancy
during gaseous release in stomach acid; (ii) rapid gastric
dispersal into multiple granules or pellets, thereby avoiding
expulsion of the complete tablet from the stomach in a single
event; (iii) the use of low density excipients to provide a buoyant
or floating tablet; and/or (iv) the inclusion of a mucoadhesive in
the tablet. These four approaches can be used individually or
together to provide advantageous tablets for delivery of
bexagliflozin.
[0016] According to a fourth aspect, the invention provides an
extended release tablet that contains bexagliflozin and a
mucoadhesive. Ideally, this tablet has a density below that of
gastric contents. It can also be effervescent (particularly when in
contact with gastric acid) and/or it can disperse into multiple
granules or pellets when it comes into contact with gastric
acid.
[0017] According to a fifth aspect, the invention provides a solid
oral dosage form, typically an extended release tablet, that
contains bexagliflozin and that in an in vitro dissolution test in
simulated gastric fluid (see below) releases .ltoreq.17% of its
bexagliflozin after 1 hour and releases .gtoreq.80% after 8 hours.
In one embodiment, it releases between 20-45% (inclusive) of its
bexagliflozin after 3 hours, and/or between 45-75% (inclusive) of
its bexagliflozin after 5 hours. This tablet can be from a
manufacturing batch of tablets which pass the formal dissolution
acceptance criteria discussed below.
[0018] According to a sixth aspect, the invention provides a solid
oral dosage form, typically an extended release tablet, that
contains bexagliflozin and that in an in vitro dissolution test in
simulated gastric fluid (see below) has a f.sub.2 value of >50
when compared to a reference tablet, wherein f.sub.2 is
proportional to the decimal logarithm of one plus the mean squared
error:
f 2 = 100 - 25 .times. log 10 .function. ( 1 + n - 1 .times. i = 1
n .times. ( R i - T i ) 2 ) ##EQU00001##
[0019] where: n is number of time points at which dissolution is
measured; R.sub.i is the dissolution percentage of a reference
tablet at the i-th timepoint; and T.sub.i is the dissolution
percentage of the solid oral dosage form at the i-th timepoint;
[0020] and where the reference tablet is an extended release tablet
that contains bexagliflozin and that, in an in vitro dissolution
test in simulated gastric fluid, releases .ltoreq.17% of its
bexagliflozin at 1 hour, releases .gtoreq.80% at 8 hours and,
optionally, releases between 20-45% (inclusive) of its
bexagliflozin at 3 hours and/or 45-75% (inclusive) of its
bexagliflozin at 5 hours. Three suitable reference tablets are
disclosed in more detail below as reference tablets (a) to (c),
where tablet (c) is preferred. The value of n is preferably at
least 3 e.g. between 4-8.
[0021] According to a seventh aspect, the invention provides a
batch of extended release bexagliflozin tablets wherein, upon
administration to a cohort of healthy fasted subjects, a first
representative sample set of tablets from the batch provides on one
occasion a first mean logarithm of C.sub.max and a first mean
logarithm of AUC.sub.0-t, and a second representative sample of
tablets from the batch produces on a different occasion a second
mean logarithm of C.sub.max and a second mean logarithm of
AUC.sub.0-t, and wherein the differences between the first and
second mean logarithms of C.sub.max and between the first and
second mean logarithms of AUC.sub.0-t both exhibit 90% confidence
intervals having endpoints which lie between -0.22314 and +0.22314.
Details on assessing these parameters are given in the section
`Bioequivalence` below e.g. the use of a random crossover study in
a suitable test population, etc. Ideally each tablet in the batch
contains 5 mg, 10 mg, or 20 mg of bexagliflozin.
[0022] According to an eighth aspect, the invention provides a
batch of extended release bexagliflozin tablets wherein, upon
administration to a cohort of healthy subjects each provided on one
occasion a single tablet from a first representative tablet sample
set in the fasted state, and on a different occasion a single
tablet from a second representative tablet sample set in the fed
state (e.g., 30 minutes following a standard high fat, high calorie
meal, as described in the section `Bioequivalence` below and
references therein), the mean differences in ln(C.sub.max) and
ln(AUC.sub.0-t) (created by subtracting the values for the
logarithms of C.sub.max and the logarithms of AUC.sub.0-t for the
fasted state from the values for the logarithms of C.sub.max and
the logarithms of AUC.sub.0-t for the fed state) both exhibit a 90%
confidence interval with endpoints which lie between -0.22314 and
+0.58779. Ideally each tablet in the batch contains 5 mg, 10 mg, or
20 mg of bexagliflozin.
[0023] According to a ninth aspect, the invention provides a batch
of extended release bexagliflozin tablets wherein, upon
administration to a cohort of fasted healthy subjects each provided
on one occasion a single tablet from a first representative tablet
sample set without any prior dosage of a parenteral GLP-1 receptor
agonist, and on a different occasion a single tablet from a second
representative tablet sample set 30 minutes following an approved
dosage of a parenteral GLP-1 receptor agonist, the mean differences
in ln(C.sub.max) and ln(AUC.sub.0-t) (created by subtracting the
values of the logarithms of C.sub.max and the logarithms of
AUC.sub.0-t for the first sample set from the values of the
logarithms for the second sample set) both exhibit a 90% confidence
interval with an upper bound of less than 0.69315. Ideally each
tablet in the batch contains 5 mg, 10 mg, or 20 mg of
bexagliflozin.
[0024] According to a tenth aspect, the invention provides a batch
of extended release bexagliflozin tablets wherein, upon
administration to a cohort of healthy subjects each provided on one
occasion a single tablet from a first representative tablet sample
set in the fasted state, and on a different occasion, a single
tablet from a second representative tablet sample set in the fed
state (e.g., 30 minutes following a standard high fat, high calorie
meal as described in the section `Bioequivalence` below), the
differences created by subtracting the values for the T.sub.max for
the fasted state from the values for the T.sub.max for the fed
state exhibit a median that is less than or equal to 3.5 hours. The
median difference is the difference for which 50% of the subjects
have values above the median and 50% of subjects have values below
the median; for example in an ordered listing of the differences,
for an odd number of subjects (e.g., 2n+1 subjects), the median is
the difference for the subject in the list midpoint, (subject n+1),
and for an even number of subjects (e.g., 2n subjects), the median
is the arithmetic average of the differences for the two subjects
flanking the midpoint (subjects n and n+1). Ideally each tablet in
the batch contains 5 mg, 10 mg, or 20 mg of bexagliflozin.
[0025] According to an eleventh aspect, the invention provides a
solid oral dosage form, typically an extended release tablet, that
contains bexagliflozin and that provides a first plasma C.sub.max,
a first AUC.sub.0-t and a first T.sub.max in fasted subjects, and
provides a second plasma C.sub.max, a second AUC.sub.0-t and a
second Tm.sub.ax in fed subjects, wherein (i) the ratio of the
second divided by the first C.sub.max is between 0.8 and 1.8; (ii)
the ratio of second divided by the first AUC.sub.0-t is between 0.8
and 1.8; or (iii) the ratio of second divided by the first
T.sub.max is between 0.8 and 3.0.
[0026] As explained below, the properties defined for such a tablet
will typically be measured after administration of representative
specimens of a batch of which that tablet is an exemplar. Thus a
batch of tablets of the eleventh aspect can provide a first
geometric mean plasma C.sub.max, a first geometric mean AUC.sub.0-t
and a first median T.sub.max in fasted subjects, and provides a
second geometric mean plasma C.sub.max, a second geometric mean
AUC.sub.0-t and a second median T.sub.max in fed subjects, wherein
(i) the ratio of the second divided by the first geometric mean
C.sub.max is between 0.8 and 1.8; (ii) the ratio of second divided
by the first geometric mean AUC.sub.0-t is between 0.8 and 1.8; or
(iii) the ratio of second divided by the first median T.sub.max is
between 0.8 and 3.0.
[0027] According to a twelfth aspect, the invention provides a
solid oral dosage form, typically an extended release tablet, that
contains bexagliflozin and that provides a first plasma C.sub.max,
a first AUC.sub.0-t and a first T.sub.max in subjects not
previously administered a parenteral GLP-1 receptor agonist, and
provides a second plasma C.sub.max, a second AUC.sub.0-t and a
second T.sub.max in subjects previously administered a parenteral
GLP-1 receptor agonist, wherein (i) the ratio of the second divided
by the first C.sub.max is between 0.8 and 2.0; (ii) the ratio of
second divided by the first AUC.sub.0-t is between 0.8 and 2.0; or
(iii) the ratio of second divided by the first T.sub.max is between
0.8 and 3.0.
[0028] As explained below, the properties defined for such a tablet
will typically be measured after administration of representative
specimens of a batch of which that tablet is an exemplar. Thus a
batch of tablets of the twelfth aspect can provide a first
geometric mean plasma C.sub.max, a first geometric mean AUC.sub.0-t
and a first median T.sub.max in subjects not previously
administered a parenteral GLP-1 receptor agonist, and provides a
second geometric mean plasma C.sub.max, a second geometric mean
AUC.sub.0-t and a second median T.sub.max in subjects previously
administered a parenteral GLP-1 receptor agonist, wherein (i) the
ratio of the second divided by the first geometric mean C.sub.max
is between 0.8 and 2.0; (ii) the ratio of second divided by the
first geometric mean AUC.sub.0-t is between 0.8 and 2.0; or (iii)
the ratio of second divided by the first median T.sub.max is
between 0.8 and 3.0.
[0029] The invention also provides methods for treating patients as
discussed in more detail below.
BRIEF DESCRIPTION OF DRAWINGS
[0030] FIG. 1 shows the geometric mean plasma concentration (ng/mL)
of bexagliflozin in fasted subjects as a function of time post-dose
(hours). Closed circles (.circle-solid.) show data for 20 mg
capsules, whereas the other symbols are for 15 mg tablets XR5 (),
XR8 (.DELTA.), or XR11 (.largecircle.).
[0031] FIG. 2 shows the geometric mean plasma concentration (ng/mL)
of bexagliflozin in fasted subjects who received 10 mg
(.circle-solid.), 15 mg (.largecircle.), or 30 mg () tablets.
[0032] FIG. 3A and FIG. 3B show the % of bexagliflozin released
(ordinate) after 1 hour (.diamond-solid.), 3 hours (.box-solid.), 5
hours (.tangle-solidup.), or 8 hours (X) in an in vitro dissolution
test. The tablets had been stored for up to 60 months (abscissa) at
25.degree. C. (FIG. 3A) or 30.degree. C. (FIG. 3B). The graph shows
measured means with a line of regression.
DETAILED DESCRIPTION OF THE INVENTION
[0033] The invention provides extended release tablet formulations
that provide improved pharmacokinetic properties for bexagliflozin
when compared to capsule formulations.
[0034] Bexagliflozin
[0035] Bexagliflozin is a SGLT2 inhibitor in the C-aryl glucoside
class and has formula (I):
##STR00001##
[0036] Its IUPAC name is
(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-(2-cyclopropoxyethoxy)benzyl)phenyl)-6--
(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol. Its CAS registry
number is 1118567-05-7.
[0037] Tablets of the invention include bexagliflozin, usually in
the form of a crystalline solid (e.g. see WO2011/153953). In some
embodiments bexagliflozin may be present in the form of an ester
(mono-, di-, tri-, or tetra-) but usually bexagliflozin will be
used as the tetraol of formula (I) as shown above. Furthermore, in
some embodiments bexagliflozin may be present in the form of a
co-crystal e.g. a co-crystal with proline, such as `THR1474`
(bexagliflozin:proline at a 1:2 molar ratio) as disclosed in
WO2010/022313. These forms of bexagliflozin may optionally be
present in tablets of the invention as a solvate. The invention
encompasses all such forms of bexagliflozin.
[0038] The amount of bexagliflozin in a tablet of the invention
will generally range from 1 mg to 100 mg, and is preferably within
the range of 5 mg to 50 mg (e.g. 10-20 mg for the second aspect of
the invention). Tablets containing 5 mg, 10 mg, or 20 mg are
particularly preferred. These values are expressed in terms of the
tetraol of formula (I). Extended release tablets of these strengths
(and in particular 20 mg) offer good therapeutic effects.
[0039] References to a particular content of bexagliflozin in a
tablet will be understood in the normal context of pharmaceutical
formulation. Thus, content may be measured, for instance, in line
with USP General Chapter <905>, Ph. Eur. 2.9.40 Uniformity of
Dosage Units, or JP 6.02 Uniformity of Dosage Units. Where a tablet
is licensed for medicinal use in a particular territory then the
relevant licence, marketing authorization, prescribing information,
summary of product characteristics, product information, patient
literature, etc., will specifically mention the amount of
bexagliflozin therein e.g. a tablet dosage form with a strength of
5 mg, 10 mg, 20 mg, 40 mg, or 50 mg.
[0040] It is possible that tablets of the invention may include
bexagliflozin-related impurities and/or degradation products. If
so, these should be present at .ltoreq.1.0% of the total mass of
bexagliflozin in the tablet, and any particular impurity or
degradation product should be present at .ltoreq.0.20% of the total
mass of bexagliflozin.
[0041] General
[0042] The term "comprising" encompasses "including" as well as
"consisting" e.g. a composition "comprising" X may consist
exclusively of X or may include something additional e.g. X+Y.
[0043] The term "about" in relation to a numerical value x is
optional and means, for example, x.+-.10%.
[0044] The word "substantially" does not exclude "completely" e.g.
a composition which is "substantially free" from Y may be
completely free from Y. Where necessary, the word "substantially"
may be omitted when defining the invention.
[0045] The term "between" with reference to two values includes
those two values e.g. the range "between" 10 mg and 20 mg
encompasses inter alia 10, 15, and 20 mg.
[0046] The inferred pharmacokinetic parameters of a
noncompartmental analysis are here defined as most frequently
employed in the art and summarized in the following:
[0047] "T.sub.max" is the time at which the greatest observed
plasma concentration is recorded and, when presented for a
population, is, unless otherwise described, given as the population
median.
[0048] "C.sub.max" is the greatest observed plasma
concentration.
[0049] "C.sub.min" is the lowest observed plasma concentration,
typically obtained as the value prior to a repeat dosing in a
regularly scheduled dosing regimen. For example, for daily dosing
C.sub.min is often recorded 24 hours after the previous dose.
[0050] "AUC" is the "area under the curve" of the plasma
concentration as a function of time, constructed by the linear
trapezoidal rule, according to which the AUC is given by the
summation of the arithmetic mean of the concentration at two
adjacent sampling points in time, multiplied by the difference in
time between those sampling points:
(C(t.sub.i)+C(t.sub.i+1))(t.sub.i+1-t.sub.i)/2.
[0051] "AUC.sub.0-t" represents the AUC from time 0 (e.g. the time
of ingestion) to the last quantifiable concentration.
[0052] "AUC.sub.0-.infin." represents the AUC from time 0 to
infinity, as produced by extrapolation of a simple (monophasic)
exponential decay.
AUC.sub.0-.infin.=AUC.sub.0-t+C.sub.last/k.sub.el, where C.sub.last
is the last quantifiable concentration and k.sub.el is the terminal
elimination rate constant.
[0053] "t.sub.1/2" is the terminal half-life, also referred to as
the elimination half-life. If the empirically determined terminal
elimination kinetics are not first-order in time, t.sub.1/2 cannot
be defined.
T 1 / 2 = - ln .function. ( 2 ) / k el .apprxeq. 0.693 / k el .
##EQU00002##
[0054] The terms "d(0.1)", "d(0.5)" and "d(0.9)" describe the
threshold diameters for particles falling in the smallest 10%, 50%
and 90% of the total volume of all particles. Thus at d(0.9), 90%
of the volume of the sample can be found in particles of smaller
diameter than d(0.9).
[0055] The "logarithm" as used herein refers by default to the
natural logarithm, often written as a function of argument x as
ln(x), where for avoidance of doubt, x=e.sup.ln(x). If the base of
the logarithm is 10, the logarithm is referred to as the decimal
logarithm, and written as a function of argument y as
log.sub.10(y), where, for avoidance of doubt,
y=10.sup.log.sup.10.sup.(y).
[0056] A "solid oral dosage form" herein can be any solid (or
semi-solid) dosage form which can be administered orally. It can
take the form of a tablet, a solid pill, a capsule, a caplet, an
encapsulated gel or encapsulated liquid, or combinations or
concretions of such as may be present in layers or subcomponents
such as beads, droplets or particles of various shapes and of
differing properties embedded in a matrix or contained in a capsule
or caplet.
[0057] A "batch" of tablets can range in size from 100 tablets up
to a complete manufacturing batch (e.g. all of the tablets that are
made from the same initial quantity of material and have undergone
the same series of manufacturing operations, or any aggregate
quantity of tablets that have undergone similar manufacturing
operations and are pooled for testing or distribution purposes).
The definition of "manufacturing batch" includes that provided by
21 USC 201.3 i.e. a "specific quantity of a drug or other material
that is intended to have uniform character and quality, within
specified limits, and is produced according to a single
manufacturing order during the same cycle of manufacture."
[0058] The word "representative", when applied to a unit or sample
of a batch, means a unit or sample that is not pre-selected for any
particular character, such as weight, density, hardness or hue of
coating, that is free from manufacturing defects and that is drawn
substantially at random from the batch.
[0059] The phrase "substantially at random" means either completely
at random, such that every unit in the batch has an equal
probability of being selected, or chosen by a process that aims to
achieve a practical balanced representation of the batch being
sampled. For example, representative units may be drawn at regular
intervals during production or coating to avoid a sampling
imbalance in which units with slightly different properties, e.g.
as produced from the beginning or end of a run, are
overrepresented. Such units would be said to be drawn substantially
at random from the batch.
[0060] A "sample set" as used herein refers to a collection of
units or samples that can be individually or collectively analyzed
to estimate the properties of a batch or population as a whole.
When used in connection with in vitro or in vivo testing of tablet
properties, the sample set refers to a collection that is
individually tested, and from which the properties of the batch of
tablets as a whole are estimated.
[0061] The properties defined for any particular unit (e.g. a
tablet) are to be understood as being the properties of a
representative unit drawn from a manufacturing batch, the members
of which impart or exhibit the referenced properties in an
appropriate test typically consuming multiple units from the
manufacturing batch. Thus, when a unit is said to produce a
particular pharmacokinetic parameter, it will be understood that
this parameter will typically be measured after administration of
representative specimens of a manufacturing batch of which that
unit is an exemplar, and an appropriate statistical
characterization of the results will be calculated. Parameters
based on plasma bexagliflozin concentrations (e.g. C.sub.max and
AUC) will typically be characterized as geometric means, whereas
the T.sub.max will typically be characterized by the population
median. Furthermore, when a pharmacokinetic parameter is defined as
having a certain range of values, it is to be understood that
administration of representative specimens of a manufacturing batch
of which that unit is an exemplar would produce, in an
appropriately constituted experimental cohort, the characterized
parameter (e.g., the geometric mean or the median) falling within
the stated range of values.
[0062] For instance, when tablets are said to produce a statistical
measure (e.g., a geometric mean C.sub.max) falling within a certain
range of values, it is to be understood that administration of
representative specimens of a manufacturing batch of which that
tablet is an exemplar would produce, in an appropriately
constituted cohort, the statistical measure (e.g., the geometric
mean C.sub.max) falling within the stated range of values.
[0063] An "appropriately constituted cohort" refers to a collection
of test subjects that typically consists of healthy individuals of
both sexes in a sample size that provides appropriate power to
estimate the desired pharmacokinetic parameter. A sample size that
provides appropriate power can be calculated as described below. In
routine practice, for example to demonstrate bioequivalence for
regulatory purposes, twelve or more subjects of each sex are often
employed, or a total sample size of 24 subjects if sex is not
balanced. It is typical to request that the participants in a test
of this sort abstain from consumption of alcohol and avoid
ingestion of foods known to substantially influence the metabolism
of drugs. Although it is not, for example, a regulatory
requirement, it is to be understood that for the purposes of
determining whether or not a sample set represents tablets of the
present invention, the experimental cohort should be constituted
from individuals near the midpoint of the healthy population of
young adults as a whole, so that for example the cohort would not
contain a preponderance of individuals of high or low body mass, or
exceptionally lean or obese habitus, or of elderly individuals or
individuals with unusual dietary habits or consumptions of
medications, herbal preparations or supplements that might confound
the measurements.
[0064] A "sample size that provides appropriate power" to estimate
a pharmacokinetic parameter is the number of individuals in the
cohort needed to achieve a discrimination of a particular degree
between groups subjected to two experimental conditions, for
example, having consumed tablets from one source or tablets from
another. Methods of calculating statistical power are well-known in
the art. In its simplest form, statistical power describes the
probability of obtaining a statistically significant result in a
study when the predicted difference actually exists between two
populations. A power calculation is often cast as the determination
of the minimum sample size to detect a true intergroup difference
with a specified likelihood of failure due to randomness. For
example a 90% power means that in 9 out of ten studies a
statistically significant result will emerge, but in 1 out of 10,
significance will not be achieved even though the difference is
present. Hence 100% minus the power is the probability of a false
negative. Typical power values in testing pharmacokinetic
parameters are 90% or greater and for definiteness "appropriate
power" will be defined here as 95% or greater. To perform a power
calculation, the variability in the measure to be taken, usually
expressed as a standard deviation, and the difference to be
detected (the difference in the values of the measure from the two
groups to be detected) must be input. If there is substantial
uncertainty about the standard deviation of a measure in a
population, it can be empirically determined. When used in the
setting of noninferiority determinations, power calculations are
used to estimate the sample size needed to confirm that the
difference between two groups is less than a certain quantity. For
example bioequivalence studies are two-sided noninferiority tests
that aim to demonstrate that the difference between two
preparations falls within certain bounds.
[0065] When the prandial state, e.g., fasted or fed, is specified,
the fasted state is to be achieved by each subject by refraining
from consumption of food or beverages other than water for at least
ten hours prior to ingestion of a tablet and the fed state is to be
achieved by each subject by consumption of a standard high fat,
high caloric content meal as provided by regulatory guidance (e.g.,
FDA Guidance for Industry: Bioavailability and Bioequivalence
Studies Submitted in NDAs or INDs--General Considerations, March
2014), with ingestion of the tablet 30 minutes after consumption of
the meal is initiated. Further information on how these specific
prandial states are to be achieved is provided below in the section
Bioequivalence.
[0066] Extended Release Tablets
[0067] Bexagliflozin has been administered to human subjects in
several dosage forms. A 50 mg dose of bexagliflozin delivered as an
aqueous solution to healthy male volunteers in a radiolabeled
tracer mass balance study has been found to produce a C.sub.max of
692 ng mL.sup.-1, an AUC.sub.0-t of 2523 ng h mL.sup.-1 and an
AUC.sub.0-.infin. of 2604 ng h mL.sup.-1; the T.sub.max was 0.5 h
and the t.sub.1/2 5.6 h (Zhang et al. (2019), op. cit.). The
dose-normalized C.sub.max was 13.84 ng mL.sup.-1 per mg
bexagliflozin.
[0068] Oral administration of a capsule formulation of
bexagliflozin has been well tolerated by healthy and diabetic
subjects at single and repeated doses of up to 100 mg. Capsules
provide relatively rapid in vivo release of bexagliflozin, but
subsequent plasma concentrations display a high peak/trough ratio.
Capsules containing 6.7, 16.7 and 34 mg bexagliflozin have produced
a dose-normalized C.sub.max following ingestion in the fasted state
of 12.6, 11.3 and 11.5 ng mL.sup.- mg.sup.-1 bexagliflozin,
respectively, with median T.sub.max values of 1, 2 and 1 h,
respectively. Based on these values a capsule containing 20 mg of
bexagliflozin, for instance, displays a C.sub.max of between 226
and 252 ng/mL in fasted subjects, occurring about 1 to 2 hours
after administration (i.e. T.sub.max of about 1 to 2 hours). The
rate of absorption is most rapid for an oral solution, which shows
the smallest T.sub.max and the greatest dose-normalized C.sub.max.
Capsules containing 34 mg produced a C.sub.24h of greater than 10
ng/mL. The plasma concentration displays a steep decline during the
alpha phase (i.e. the distribution phase of a standard
two-compartment model).
[0069] Compared with an immediate release capsule, the inventors
have found that the pharmacokinetic profile of bexagliflozin can be
improved by formulating bexagliflozin as an extended release
tablet. These tablets can provide a lower C.sub.max (e.g. 8 ng/mL
per mg bexagliflozin or below) while still maintaining a C.sub.24h
of about 10 ng/mL for a 20 mg tablet. The reduced C.sub.max reduces
the risk of side effects, but the medicine remains efficacious
because near-maximal urinary glucose excretion is seen in dosage
forms which are able to provide a plasma concentration 24 hours
after dosing (i.e. C.sub.24h) of 10 ng/mL or more.
[0070] The first aspect of the invention therefore provides an
extended release tablet of bexagliflozin.
[0071] An extended release (also referred to as prolonged or
sustained release) tablet releases its contents in vivo over an
extended period of time following ingestion. Ideally release should
begin promptly after ingestion (e.g. as soon as the tablet enters
the stomach), and should not be delayed. Thus, a tablet of the
invention will in general not have an enteric coating, as this
would give a delayed release profile.
[0072] Tablets of the invention should provide a unimodal plasma
concentration of bexagliflozin as a function of time (in most
subjects). Thus, after a single tablet is administered to a
subject, the subsequent plasma concentration of bexagliflozin
should show only one peak (e.g. see FIG. 1 and FIG. 2).
[0073] Tablets of the invention can display substantially
zero-order release of bexagliflozin in vitro.
[0074] The plasma concentration of bexagliflozin can decrease in a
biphasic manner after reaching C.sub.max.
[0075] As mentioned above, a capsule containing 20 mg of
bexagliflozin displays a plasma C.sub.max of about 226 to 252 ng/mL
in fasted subjects i.e. the C.sub.max per milliliter of plasma is
80,000 to 90,000.times. lower than the capsule's total
bexagliflozin content. In preferred tablets of the invention,
however, C.sub.max in fasted subjects should be at least
125,000.times. lower than the tablet's bexagliflozin content. Thus,
a 20 mg tablet would provide C.sub.max.ltoreq.160 ng/mL. Ideally,
the ratio of C.sub.max to bexagliflozin content is even higher than
125,000.times., for example .gtoreq.135,000.times. or
.gtoreq.145,000.times..
[0076] Thus, the invention in particular provides an extended
release tablet which provides an in vivo geometric mean plasma
C.sub.max of .ltoreq.8 ng/mL per mg of bexagliflozin in the tablet
(ideally .ltoreq.6 ng/mL per mg bexagliflozin) in fasted healthy
subjects (e.g. in a cohort of not less than 6 fasted subjects
having a body mass greater than 60 kg). In one embodiment the
tablet contains 10 mg bexagliflozin and provides a C.sub.max of
.ltoreq.80 ng/mL; in another embodiment, the tablet contains 20 mg
bexagliflozin and provides a C.sub.max of .ltoreq.160 ng/mL.
[0077] Where a tablet of the invention provides a C.sub.max of
.ltoreq.160 ng/mL, this is preferably .ltoreq.150 ng/mL, and is
ideally between 80-150 ng/mL (particularly for a 20 mg
bexagliflozin dose). A preferred 20 mg tablet provides a C.sub.max
between 85-145 ng/mL, and more preferably a C.sub.max between
95-140 ng/mL.
[0078] An extended release tablet of the invention should provide a
bexagliflozin plasma C.sub.24h in fasted subjects of .gtoreq.3
ng/mL. As mentioned above, near-maximal urinary glucose excretion
is seen with a plasma C.sub.24h of .gtoreq.10 ng/mL, so a preferred
tablet of the invention can provide a plasma C.sub.24h of
.gtoreq.10 ng/mL e.g. within the range of 10-25 ng/mL. In one
embodiment the tablet contains 10 mg bexagliflozin and provides a
C.sub.24h of .gtoreq.3 ng/mL; in another embodiment, the tablet
contains 20 mg bexagliflozin and provides a C.sub.24h of .gtoreq.6
ng/mL.
[0079] As mentioned above, a capsule formulation of bexagliflozin
displays a plasma T.sub.max of about 1 hour in a fasted subject. In
contrast, preferred tablets of the invention can provide a
T.sub.max in a fasted subject that is typically between 2 and 6
hours. Thus, tablets of the invention can delay bexagliflozin's
T.sub.max when compared to immediate release capsules.
[0080] Preferred tablets of the invention provide a plasma
AUC.sub.0-t between 15-60 ng h mL.sup.-1 per mg of bexagliflozin in
the tablet in a fasted subject. In one embodiment the tablet
contains 10 mg bexagliflozin and provides AUC.sub.0-t of between
150-600 ng h mL.sup.-1 e.g. between 350-450 ng h mL.sup.-1; in
another embodiment, the tablet contains 20 mg bexagliflozin and
provides an AUC.sub.0-t of between 600-1200 ng h mL.sup.-1 e.g.
between 650-1150 ng h mL.sup.-1.
[0081] Preferred tablets of the invention provide a plasma
AUC.sub.0-.infin. between 17.5-65 ng h mL.sup.-1 per mg of
bexagliflozin in the tablet in a fasted subject. In one embodiment
the tablet contains 10 mg bexagliflozin and provides
AUC.sub.0-.infin. of between 410-510 ng h mL.sup.-1; in another
embodiment, the tablet contains 20 mg bexagliflozin and provides
AUC.sub.0-.infin. of between 675-1275 ng h mL.sup.-1 e.g. between
750-1200 ng h mL.sup.-1.
[0082] Preferred tablets of the invention provide a t.sub.1/2z
(terminal elimination half-life) in a fasted subject that is
between 7 and 14 hours e.g. between 8 and 13 hours.
[0083] C.sub.max, T.sub.max, t.sub.1/2z, C.sub.24h, AUC.sub.0-t,
and AUC.sub.0-.infin., are standard pharmacokinetic parameters.
They can be estimated manually or by using modelling software well
known in the art, such as the Phoenix WinNonlin package using a
non-compartmental model. The general basis for calculation of these
quantities is well-known (e.g. see Rowland & Tozer (2019)
Clinical Pharmacokinetics and Pharmacodynamics: Concepts and
Applications ISBN 978-1496385048, or Jambhekar & Breen (2012)
Basic Pharmacokinetics ISBN 978-0853699804). Typically, the
parameters will be assessed as the average (e.g. geometric mean)
from within a group of at least 12 (and normally between 24 and 36)
healthy human adults. Parameters should be measured in accordance
with standards and practices which would be acceptable to a
pharmaceutical regulatory agency such as FDA, EMEA, MHLW, or WHO.
The values may be based on measurements taken at appropriate
intervals following the time of tablet ingestion, such as every
hour, or at increasingly sparse sampling intervals, such as 1, 3,
5, 7, 9, 11, 13, 15, 20, and 24 hours after ingestion.
[0084] The pharmacokinetic parameters mentioned above were defined
for the plasma of fasted human subjects i.e. subjects who have had
a minimum of a 10-hour overnight fast. These parameters of
bexagliflozin differ in fasted and fed subjects, and if the tablet
is taken after eating (e.g. 30 minutes after starting a meal) then
typically C.sub.max, C.sub.24h, AUC.sub.0-t, and AUC.sub.0-.infin.
are all higher. The fasted subjects in whom the parameters as
defined herein have been assessed, and should be measured, are
fasted healthy (i.e. non-diabetic, and not medicated for other
conditions) human adult Caucasian subjects (male and female) having
a body mass between 60-100 kg e.g. a body mass about 75 kg. The
same behavior may be seen in other subjects as well (e.g. in Asian
subjects, or in patients with a lower body mass), but populations
in whom the parameters are assessed should meet these criteria.
Testing in a cohort of at least 6 subjects is typical.
[0085] Extended release tablets having the desired C.sub.max,
T.sub.max, C.sub.24h, AUC.sub.0-t, and/or AUC.sub.0-.infin.
properties can be prepared by following the guidance given below,
in conjunction with common general knowledge about the preparation
of extended release tablets e.g. as described in Collett &
Moreton (2007) chapter 32 of Pharmaceutics: The Science of Dosage
Form Design (3.sup.rd edition), in Lordi (1986) chapter in Theory
and Practice of Industrial Pharmacy (3.sup.rd edition), in Timmins
et al. (2014) Hydrophilic Matrix Tablets for Oral Controlled
Release ISBN 978-1493915187, in Sushma et al. (2014) Matrix
Tablets: An Approach Towards Sustained Release Drug Delivery ISBN
978-3659579110, in Rasul et al. (2011) Sustained Release Tablets
ISBN 978-3844323719, and in Eyjolfsson (2014) Design and
Manufacture of Pharmaceutical Tablets ISBN 978-0128021828. Patel
(2013) Extended Release Tablet of Antidiabetic Drug: Development,
Optimization and Evaluation, ISBN 978-3659448140, describes how an
extended release tablet of glipizide was developed using
hydroxyethyl- and hydroxypropyl-cellulose.
[0086] The principles of extended release tablet manufacture are
thus well known in the art. Compared to an immediate release
capsule of any particular dose, the use of extended release tablet
technology reduces C.sub.max of bexagliflozin, in accordance with
the desirable pharmacokinetic profile of the invention. The degree
of the decrease can be controlled by modifying the characteristics
of the extended release tablet, in line with known design
principles.
[0087] There are three main ways in which extended release from a
tablet is achieved: (i) by using a monolithic matrix, with drug
particles dispersed in either a soluble matrix or an insoluble
matrix; (ii) reservoir or membrane-controlled systems; or (iii)
osmotic pump systems. A tablet based on a soluble matrix includes a
compressed mixture of bexagliflozin and a water-swellable
hydrophilic polymer, and on entering the GI tract the tablet starts
to dissolve and release bexagliflozin over an extended period of
time. A tablet based on an insoluble matrix includes a mixture of
bexagliflozin and a wax or a water-insoluble substance, such as a
fat or polymer, into which water can diffuse and dissolve the
bexagliflozin to permit its release. The paths for water diffusion
can be part of the tablet when it is swallowed, or they can emerge
after ingestion as channeling agents leach from the tablet. A
tablet based on a reservoir system includes a membrane through
which bexagliflozin must diffuse, and hydration of the membrane
permits this diffusion to occur. The membranes are generally made
from polymers which remain intact during the period of release,
such as acrylic copolymers, ethylcelluloses, shellac, and zein. The
osmotic pump system is similar to the reservoir system, but
hydration of the tablet core builds up a hydrostatic pressure which
forces dissolved bexagliflozin through a hole in the core's
semi-permeable coating. Details of suitable release-controlling
agents for use in these tablets are given below.
[0088] These general approaches are well known and a person skilled
in the art of tablet formulation will be able to make and test
tablets utilizing any of these approaches and to adapt them
according to the tablet's desired pharmacokinetic properties. A
tablet's properties can be modified according to the
characteristics of the formulation approach which is used. For
instance: with a soluble matrix, the chemical nature, physical
nature, and quantity of the water-swellable hydrophilic polymer can
be chosen to control release; with a water-insoluble (such as a
wax) matrix, the quantity of the water-insoluble substance and the
nature and quantity of the channeling agent can be chosen to
control release; with an insoluble polymeric matrix, the pore
structure of the matrix is the key parameter, and a more rigid and
less porous matrix will generally lead to slower release; with a
reservoir system the choice of membrane is the key, and in
particular the choice and quantity of membrane plasticizer, but
addition of water-soluble components to the membrane can also be
used to increase the rate of release;
[0089] and with an osmotic pump system the rates at which water can
enter the core, and at which bexagliflozin can leave the coating's
hole, govern the tablet's release characteristics. The ingredients
and design principles for controlling a tablet's release
characteristics while providing a physically stable tablet are thus
well known, and a person skilled in the art of tablet formulation
can make and test (both in vitro and in vivo) tablets utilizing any
of these approaches to give a product whose release characteristics
provide the desired C.sub.max, T.sub.max, C.sub.24h, AUC.sub.0-t,
and AUC.sub.0-.infin. for any particular quantity of
bexagliflozin.
[0090] Preferred tablets of the invention include bexagliflozin
dispersed in a water-insoluble (e.g. wax) matrix (e.g. based on
glyceryl dibehenate, as discussed below).
[0091] In addition to employing these techniques for providing
extended release from the tablet, it is also desirable to adapt the
tablet for gastric retention (as discussed below) to increase the
proportion of the extended release which occurs in the duodenum,
thereby further refining the in vivo pharmacokinetic behavior by
delaying progress of bexagliflozin through the small intestine.
[0092] Before in vivo testing to determine C.sub.max, T.sub.max,
C.sub.24h, AUC.sub.0-t, and/or AUC.sub.0-.infin. in humans it can
be useful to subject a tablet to in vitro dissolution testing to
give some preliminary predictions and to facilitate design
modifications. These in vitro tests are used in a regulatory
setting to ensure that a tablet can reliably and safely deliver the
required therapeutic amount of a drug into the bloodstream, and
involve applying formal dissolution acceptance testing to tablets
sampled from manufacturing batches intended to be delivered to
human patients. Such formal acceptance testing ensures that the
desired amount of bexagliflozin can be delivered in vivo over the
desired time interval.
[0093] The invention therefore provides a solid oral dosage form
(most typically an extended release tablet) that contains
bexagliflozin and that, in an in vitro dissolution test in
simulated gastric fluid (see below), releases .ltoreq.17% of its
bexagliflozin after 1 hour and releases .gtoreq.80% after 8 hours.
Thus, at least 83% of the bexagliflozin remains in the dosage form
1 hour into the in vitro dissolution test, but at least 80% has
been released 8 hours into the test (which includes embodiments in
which 100% has already been released at the 8-hour point). The
amount of bexagliflozin released by this tablet after 1 hour in the
dissolution test is less than with an immediate release capsule
containing the same amount of bexagliflozin. In one embodiment,
this dosage form releases between 20-45% (inclusive) of its
bexagliflozin after 3 hours and between 45-75% (inclusive) of its
bexagliflozin after 5 hours.
[0094] In embodiments of the invention where a dosage form (such as
an extended release tablet) releases between 20-45% of its
bexagliflozin after 3 hours in an in vitro dissolution test, the
dosage form can be prepared such that it releases between 23-43% of
its bexagliflozin after 3 hours.
[0095] In embodiments of the invention where a dosage form (such as
an extended release tablet) releases between 45-75% of its
bexagliflozin after 5 hours in an in vitro dissolution test, the
dosage form can be prepared such that it releases (a) between
45-72% of its bexagliflozin after 5 hours (b) between 50-70% of its
bexagliflozin after 5 hours (c) between 49-69% of its bexagliflozin
after 5 hours or (d) between 48-68% of its bexagliflozin after 5
hours. More generally, the dosage form may release between x-y% of
its bexagliflozin after 5 hours, where: x is selected from 45, 47,
48, 49, or 50; and y is selected from 68, 69, 70, 72 or 75.
[0096] In one embodiment, an extended release tablet may release in
an in vitro dissolution test (1) between 23-43% of its
bexagliflozin after 3 hours and (2) between 45-72%, between 50-70%,
between 49-69%, or between 48-68%, of its bexagliflozin after 5
hours. These percentages may therefore be the criteria used at 3
hours and 5 hours in the in vitro dissolution testing disclosed
herein.
[0097] Because determining these release characteristics is
necessarily destructive, these parameters need not be determined
directly for a particular tablet of interest, but rather for a
tablet made by the same manufacturing process with the same
components. Thus, a manufacturing batch of tablets can be made by a
particular process, and in vitro dissolution testing is performed
on a sample set of representative tablets from the manufacturing
batch. If the results for this testing meet the requirements noted
above then tablets made by the manufacturing process in question
are tablets of the present invention. Thus the invention also
provides the tablets from any such manufacturing batch.
[0098] The in vitro dissolution test which is used for these
determinations is one of several that are standard in the art,
particularly for extended release tablets e.g. see USP <711>
Dissolution or Ph. Eur. 2.9.3. Further details are given below.
[0099] Studies of particular types of tablet formulations enable
provision of an IVIVC (in vitro-in vivo correlation) that describes
the relationship between an in vitro attribute of a tablet (e.g.
the rate or extent of drug release) and a relevant in vivo response
(e.g. C.sub.max or AUC.sub.0-t). Models of this type facilitate the
rational development, evaluation and modification of
extended-release dosage tablets of the invention.
[0100] Ideally, an extended release preparation exhibits no
dependence on prandial state, but if such an influence is
unavoidable (for example, if the extended release mechanism depends
on the mechanics of content release from the stomach as in the case
of several embodiments of the present invention), then it is
desirable that the consequences of prior food consumption be
predictable and circumscribed, in any case not to present a risk to
the patient of either an adverse side effect or an inadequate
therapeutic effect. These criteria are met by tablets of the
present invention.
[0101] Various medications are known to affect gastrointestinal
mobility either as a side effect or as a mechanism of therapeutic
action. Among the agents that influence gastric emptying and that
are frequently co-delivered with oral antidiabetic drugs are
agonists of the glucagon-like peptide-1 (GLP-1) receptor. GLP-1
receptor agonists suppress gastric emptying and have the potential
to mimic the fed prandial state, thereby elevating exposure to
bexagliflozin if delivered in advance of the bexagliflozin dose. At
present, most GLP-1 receptor agonists are delivered by subcutaneous
injection, but a preparation of semaglutide for oral delivery has
been recently approved and more such agonist preparations or
synthetic agonists may be approved in the future. As in the case of
prandial state, it is desirable that the consequences of GLP-1
receptor agonist administration be predictable and circumscribed.
These criteria are met by tablets of the present invention.
[0102] Gastric Retention
[0103] Extended release tablets having the desired C.sub.max,
T.sub.max, C.sub.24h, AUC.sub.0-t, and/or AUC.sub.0-.infin.
properties can be prepared by following the guidance given above,
in conjunction with common general knowledge about the preparation
of extended release tablets. A further way to modify the tablets to
achieve the desired parameters is to incorporate into the tablet a
gastric retention adaptation, and in particular one or more of the
four adaptations discussed below. The overall goal of gastric
retention as discussed herein is to delay progress of bexagliflozin
through the small intestine, thereby encouraging a large part of
the extended release of bexagliflozin to occur in the stomach or
high in the small intestine (see Hou et al. (2003) Crit Rev Ther
Drug Carrier Syst 20:459-97). Compared to immediate release
capsules these adaptations have all been shown to decrease in vivo
plasma C.sub.max while still providing a therapeutically useful
C.sub.24h, and also with T.sub.max, AUC.sub.0-t, and
AUC.sub.0-.infin. within the desired ranges.
[0104] A first approach for achieving the desired in vivo
pharmacokinetic behavior is to include an effervescent excipient in
the tablet, and in particular an excipient that will effervesce on
contact with gastric acid e.g. a carbonate or a bicarbonate or
hydrogen carbonate salt, such as sodium bicarbonate. As the tablet
effervesces it tends to float due to the release of gas, and thus
the tablet's progress towards the pyloric sphincter at the base of
the stomach is delayed (e.g. see Wei et al. (2001) Drug Dev Ind
Pharm 27:469-74, Ray & Prusty (2010) Int J Appl Pharmaceutics
2:12-16). A bicarbonate-containing tablet matrix provides the
additional advantage of protecting bexagliflozin against acid
degradation. As shown in the examples, the inclusion of an
effervescent excipient reduces C.sub.max, thereby contributing to
the desired pharmacokinetic profile.
[0105] A second approach for achieving the desired in vivo
pharmacokinetic behavior is to construct the tablet so that on
contact with gastric contents it disperses into a large number of
granules or pellets, which in turn provide extended release. In
general, it takes longer for the stomach to expel multiple small
granules/pellets than one large tablet. A similar approach was
disclosed by Aburahma & Hamza Yel (2011) Pharm Dev Technol
16(4):316-30, who compressed extended-release beads with a
fast-disintegrating component.
[0106] A third approach for achieving the desired in vivo
pharmacokinetic behavior is to use low density excipients that
thereby provide a buoyant or floating tablet. By using adequate
amounts of low density excipients, it is possible to provide a
tablet with an overall density below that of gastric contents,
thereby permitting it to float in the stomach and thus delay its
transit to the pyloric sphincter without needing effervescence
(e.g. Srikanth Meka et al. (2014) Acta Pharm 64:485-494). As shown
in the examples, this approach provides a useful decrease in
C.sub.max. Gastric contents have a density of about 1.004-1.010
g/cm.sup.3 and so the tablet should have a density below this,
ideally such that it can float.
[0107] Buoyancy, and the length of time that a tablet remains
buoyant as it degrades, can be assessed in vitro in simulated
gastric fluids maintained at 37.degree. C. In some embodiments,
tablets of the invention may remain buoyant (i.e. persist on the
surface) until they have released 90% of their bexagliflozin. In
some embodiments, tablets of the invention may remain buoyant for 5
hours or more e.g. for 8 hours or more. In practice, the tablets
can be studied using the same technique as discussed below for the
in vitro dissolution test e.g. in an apparatus containing 900 mL of
0.1 N HCl at 37.+-.0.5.degree. C. (simulated gastric fluid). The
density of a tablet can be determined by the displacement method
using analytical grade benzene as a displacing medium.
[0108] A fourth approach for achieving the desired in vivo
pharmacokinetic behavior is to include a mucoadhesive excipient in
the tablet. Mucoadhesives permit the tablet to interact with the
mucosal surfaces of the gastrointestinal tract, for example of the
stomach wall, thereby retarding the tablet's progress. This
approach is discussed in, for instance, Jha & Nanda (2013)
Asian J Biomed Pharm Sci 3:44-49. Various mucoadhesive excipients
suitable for inclusion in tablets are known in the art, and these
are often hydrophilic polymers. In general, good mucoadhesives have
strong hydrogen bonding groups (--OH, --COOH), strong anionic
charges, sufficient flexibility to penetrate the extended glycan
network of the cell glycocalyx, surface tension characteristics
suitable for wetting mucus/mucosal tissue surface, and/or a high
molecular weight (see Yadav et al. (2010) J Chem Pharm Res
2:418-32). Examples of mucoadhesive excipients are given below.
Some mucoadhesives are known to provide tablets with extended
release characteristics (e.g. HPMC, polyethylene oxides) and so can
usefully fulfill both roles in a tablet of the invention. A useful
amount of mucoadhesive in a tablet of the invention can be between
10-25% by weight of the total tablet.
[0109] Thus, the fourth aspect of the invention provides an
extended release tablet that contains bexagliflozin and a
mucoadhesive. The mucoadhesive is included in the tablet at an
amount that retards its progress in vivo through the stomach and/or
the duodenum when compared to an equivalent tablet that has the
same composition except for the absence of the mucoadhesive. A
preferred mucoadhesive for inclusion in tablets of the invention is
a nonionic polyethylene oxide polymer, particularly with an average
molecular weight of 800,000 or more e.g. from 900,000-5,000,000.
These hydrophilic polymer powders are available in pharmacopoeial
grade under the trade name POLYOX.TM. from Dow Chemical, with
molecular weights ranging from 100,000-7,000,000. They are known as
both mucoadhesives and for providing extended release
characteristics and so they can usefully fulfill both roles in a
tablet of the invention. Suitable quantities of mucoadhesive are
discussed above.
[0110] The four approaches discussed above can be used individually
to provide extended release tablets for delivery of bexagliflozin
that display the desired pharmacokinetic parameters. In particular,
each approach can decrease C.sub.max when compared to an immediate
release formulation. The degree of the decrease can be controlled
to a certain extent, in particular by increasing the particular
adaptation, to provide a desired C.sub.max for any particular
amount of bexagliflozin in the tablet. For instance, increasing
amounts of an effervescent excipient or increasing the number of
individual granules/pellets will, up to a point, increase gastric
retention and thus decrease C.sub.max accordingly. Similarly,
increases in buoyancy will increase gastric retention, although
there are practical limits on how far buoyancy can be increased
Finally, increased levels of mucoadhesive, or the use of a stronger
mucoadhesive, will increase gastric retention although, again,
there are practical limits on a tablet's capacity for mucoadhesive
content. Overall, however, a person skilled in the art of tablet
formulation will be able to make and test tablets utilizing these
approaches and to adapt them according to the desired
pharmacokinetic properties.
[0111] Although the four approaches can be used individually,
advantageously the various approaches can be combined.
[0112] The inventors have found that the first approach on its own
can decrease C.sub.max as desired, but that these tablets can
display significant inter-patient variability (in particular for
T.sub.max). Without wishing to be bound by theory, this behavior
could arise if the tablet exits the stomach earlier than desired in
some patients, after which it no longer experiences the acid-driven
disintegrating forces of effervescence and so drug release and thus
bioavailability decreases. To alleviate this problem, the first and
second approaches can be combined e.g. by compressing multiple
effervescent granules into a single tablet, with the individual
effervescent granules being released as the tablet disperses in the
stomach.
[0113] The second approach is technically difficult to implement
consistently and, although it decreases C.sub.max, the effect is
not so great (e.g. not as much as the first approach). Furthermore,
the granules can have a relatively short commercial shelf-life, so
the second approach is not preferred, either on its own or in
combination with any of the other approaches.
[0114] When more than one approach is used for improving the
pharmacokinetic behavior, one option is to combine the third and
fourth approaches to give a low-density tablet that includes a
mucoadhesive. As shown in the examples, this combination of
approaches provides tablets having advantageous properties for
delivery of bexagliflozin in humans. Thus, the invention provides
an extended release tablet that contains bexagliflozin and a
mucoadhesive, wherein the tablet has a density below that of human
gastric acid. Further details of suitable mucoadhesives and their
content, and also of suitable densities, are discussed above.
[0115] Gastric retention can be measured by including a
radionuclide in the formulation and directly recording the fraction
of the formulation that remains in the stomach as a function of
time following dosing using an appropriate scintillation camera.
Although this approach has relatively high precision, it has two
principal drawbacks: (i) the radionuclide itself is typically not
found in the commercial article and hence the formulation departs
in its constitution from the intended commercial form, and (ii) the
conduct of such experiments is difficult and expensive and subjects
the participants to the additional risk of exposure to
radioactivity. Thus, gastric retention can instead be determined by
inference from other properties of a formulation e.g. by comparison
of the T.sub.max produced by the formulation to the T.sub.max
produced by an immediate release formulation, or by comparison of
the T.sub.max in the fasted state to the T.sub.max in the fed
state. As mentioned above, studies using [.sup.14C]-bexagliflozin
have shown that colonic absorption is minimal, and the majority of
absorption takes place in the small bowel. The effect of prandial
state is also consistent with this description. For example,
bexagliflozin capsules in strengths from 6.7 to 34 mg produced a
T.sub.max from 1 to 2 h in the fasted state, but 5 h in the fed
state, which is explicable if release of the gastric contents were
to be required for a maximal rate of absorption. Bexagliflozin
extended release tablets of the U20 formulation (see below)
produced a T.sub.max of 3.5 h in the fasted state and 5 h in the
fed state, consistent with the view that they are retained in the
stomach for a longer period of time than extended release
formulations.
[0116] Tablet Components
[0117] As discussed above, a tablet of the invention will generally
or optionally include, in addition to bexagliflozin: one or more
release-controlling agents (such as ingredients for forming a
matrix or a membrane); one or more matrix or membrane modifiers
(such as channeling agents or wicking agents); one or more
solubilizers; one or more glidants, lubricants and/or flow aids;
one or more disintegrants; one or more fillers; one or more
binders; one or more density modifiers and/or effervescent
components; one or more colorings; one or more flavorings; one or
more anti-oxidants; and/or one or more mucoadhesives. Such
components will generally be present in admixture within the
tablet, but may also be present in differing proportion in layers
or discrete geometric structures, such as particles or spheres of
one composition embedded in another, or in sheets or blocks of
material of differing bulk composition.
[0118] It is common to create tablets that have a core of one
composition surrounded by a coating or exterior layer of another.
Tablets of the invention will typically include a coating.
[0119] Examples of release-controlling agents for forming a matrix
include, but are not limited to, the water-swellable hydrophilic
polymers (such as hydroxypropyl-celluloses or -methylcelluloses,
sodium carboxymethylcelluloses, alginates, alginic acid, gelatin,
xanthan gums (with or without locust bean gum), carbopols,
polyethylene oxides, galactomannoses, etc.), waxes (such as
hydrogenated vegetable oils, microcrystalline wax, carnauba wax,
etc.), and insoluble polymers (e.g. ethylcelluloses). These
components can make 15-40% by weight of the tablet.
[0120] A particularly useful release-controlling agent for forming
a tablet matrix of the present invention is glyceryl dibehenate, as
this advantageously has a density lower than gastric fluid and is
resistant to gastric lipase. Glyceryl dibehenate is known for use
as a sustained-release agent (e.g. as described by Opota et al.
(2013) Int J Pharm Tech Res 5:622-8). A preferred tablet includes
30-35% by weight of glyceryl dibehenate. The term "glyceryl
dibehenate" is the current preferred pharmaceutical description for
commercial mixtures of glyceryl esters (including mono-, di- and
tri-behenic esters) that are predominantly in the form of the
diester. There are two regioisomers of glyceryl monobehenic ester
and two regioisomers of glyceryl dibehenic ester. Previously the
term "glyceryl behenate" had been used to describe the commercial
mixture of esters, but this terminology had the disadvantage of
suggesting that the composition was principally in the form of the
monobehenic ester, which is inaccurate. Commercial preparations of
glyceryl dibehenate contain 40-60% by weight of the diester within
the mixture. Any reference to "glyceryl dibehenate" herein should
be understood to refer to products comprising a mixture of glyceryl
esters of behenic acid, and not to the amount of glyceryl dibehenic
ester contained therein.
[0121] Commercial preparations of glyceryl dibehenate may have been
formulated to improve their performance in drug manufacturing
processes, for example to improve blending or flow characteristics,
and the inventors have found that formulations which have been
micronized or atomized (such as Compritol 888 ATO.TM.) can have
favorable properties for preparing tablets of the present
invention.
[0122] Examples of release-controlling agents for forming a
membrane include, but are not limited to, ethylcellulose, acrylic
polymers (e.g. Eudragit RL & RS.TM.), shellac, and zein. These
can be combined with plasticizers such as dibutyl phthalate,
diethyl phthalate, dibutyl sebecate, or citric acid esters. A
plasticizer will generally be included at about 10-25% by weight of
the membrane polymer, giving enough for complete coalescence of the
membrane to form a film without making it too elastic, plastic,
soft or permeable.
[0123] Examples of matrix modifiers include, but are not limited
to, sugars, polyols and soluble salts. These can modify the
diffusional characteristics of the matrix, and also the rate and
extent of its hydration, and thus modify bexagliflozin release.
Channeling agents include sodium chloride, sugars, and polyols
(e.g. lactose), and these agents can make 10-30% by weight of the
tablet.
[0124] Examples of solubilizers include, but are not limited to,
surfactants (including ionic and non-ionic surfactants) such as
sodium lauryl sulfate, cetyltrimethylammonium bromide, polysorbates
(such as polysorbate 20 or 80), poloxamers (such as poloxamer 188
or 207), and macrogols. A preferred tablet includes a poloxamer,
which is ideally micronized e.g. in micro-prilled form
(EP-A-1661558). An average poloxamer particle size of between
10-200 .mu.m is useful. The most preferred poloxamer is poloxamer
188 micronized. A preferred amount of poloxamer 188 in a tablet of
the invention is 10-12% by weight. Higher levels of poloxamer can
favor faster release from a tablet.
[0125] In some embodiments, a surfactant can be combined with
amorphous bexagliflozin in the manner disclosed in WO2018/167589,
with the aim of providing tablets having extended stability and
good bioavailability (and, optionally, being bioequivalent to a
reference tablet as disclosed herein). Useful surfactants for such
embodiments are available under the trade names SEPITRAP.TM. 80 and
Dubcare.TM. GPE810. SEPITRAP.TM. 80 is a micro-encapsulated form of
polysorbate 80 in powder form, in which polysorbate 80 is adsorbed
onto a porous magnesium aluminometasilicate carrier. Dubcare.TM.
GPE810 is a mixture of PEG-8 caprylic/capric glycerides.
[0126] Examples of lubricants, glidants and flow aids include, but
are not limited to, magnesium stearate, calcium stearate, stearic
acid, hydrogenated vegetable oil, glyceryl palmitostearate,
glyceryl dibehenate, sodium stearyl fumarate, colloidal silicon
dioxide, and talc. The amount of lubricant in a tablet can
generally be between 1-5% by weight. Preferred tablets of the
invention include magnesium stearate and/or colloidal silicon
dioxide (e.g. an amorphous anhydrous form). A preferred tablet
includes 1.5-2.5% by weight magnesium stearate and/or 1.0-1.5% by
weight colloidal silicon dioxide.
[0127] Examples of disintegrants include, but are not limited to,
starches, celluloses, cross-linked PVP, sodium starch glycolate,
croscarmellose sodium, etc.
[0128] Examples of fillers (also known as bulking agents or
diluents) include, but are not limited to, starches, maltodextrins,
polyols (such as lactose), and celluloses. Preferred tablets of the
invention include lactose and/or microcrystalline cellulose (e.g.
the Avicel range of products; see Doelker et al. (1995) Drug Dev
Ind Pharmacy 21:643-61). Lactose can be used in anhydrous or
hydrated form (e.g. monohydrate), and is typically prepared by
spray drying, fluid bed granulation, or roller drying. Preferred
microcrystalline celluloses have a particle size between about
150-200 .mu.m. A preferred tablet includes 11-13% by weight lactose
and/or 18-20% by weight microcrystalline cellulose. Spray-dried
lactose monohydrate is preferred.
[0129] Examples of binders include, but are not limited to,
cross-linked PVP, HPMC, microcrystalline cellulose, sucrose,
starches, etc.
[0130] Examples of effervescent components include, but are not
limited to, carbonate or bicarbonate (hydrogen carbonate) salts,
such as sodium bicarbonate.
[0131] Examples of antioxidants include, but are not limited to,
butylated hydroxyanisole, butylated hydroxytoluene, sodium
metabisulfite, propyl gallate, and cysteine. Preferred tablets
include butylhydroxytoluene as an anti-oxidant.
[0132] Examples of mucoadhesives include, but are not limited to,
carbopols (polymers of acrylic acid cross-linked with polyalkenyl
ethers or divinyl glycol), cross-linked carboxy-polymethylenes,
carboxy-methylcelluloses (such as sodium carboxy methylcellulose),
hydroxy-ethylcellulose, hydroxypropyl-methylcellulose,
polycarbophils, gum tragacanth, poly(acrylic acid/divinyl benzene),
alginates (such as sodium alginate), gum karaya, and
polyoxyethylenes (also known as polyethylene oxides or polyethylene
glycols). As mentioned above, a useful amount of mucoadhesive in a
tablet of the invention can be between 10-25% by weight of the
total tablet. A preferred mucoadhesive component for inclusion in a
tablet of the invention is a nonionic polyethylene oxide polymer,
particularly with an average molecular weight (e.g. number average)
of at least 800,000 (based on rheological measurements). A
preferred tablet includes 16-20% by weight of polyethylene
oxide.
[0133] Although uncoated tablets may be used, it is more usual to
provide a coated tablet, in which case a conventional non-enteric
coating may be used. The coating may be white or colored e.g. blue.
Suitable coatings include, but are not limited to, polymeric film
coatings such as those comprising polyvinyl alcohol e.g. `Opadry
II`.TM. (which includes part-hydrolyzed PVA, titanium dioxide,
macrogol 3350 and talc, with optional coloring such as indigo
carmine or iron oxide yellow or FD&C yellow #6). The amount of
coating will generally be between 2.5-3.5% of the core's
weight.
[0134] Some components can play multiple roles in tableting e.g.
glyceryl dibehenate can be used as a release-controlling agent in a
tablet matrix or as a gastroretentive excipient (by virtue of its
density), or as a lubricant, and polyethylene oxide can be used as
a release-controlling agent or it can be used as a mucoadhesive.
Thus, a single component can play multiple roles within a single
tablet, but often a component will be included with a single aim
and so its quantity and location (in the tablet and/or in the
manufacturing process) will be selected accordingly.
[0135] Tablets of the invention will generally have a hardness
within the range 20 to 100 N, and more typically between 20-60 N,
30-40 N, or 60-90 N. Hardness can conveniently be assessed using
the Dr. Schleuniger Pharmatron tester which drives an anvil to
compress a tablet at a constant rate until it fractures, operating
in accordance with USP <1217>.
[0136] Tablets of the invention will generally have a friability of
.ltoreq.1% by weight. Friability can be assessed according to USP
<1216>.
[0137] Tablets of the invention will generally have a water content
of .ltoreq.5% by weight. Water content can be assessed according to
USP <921>.
[0138] Tablets of the invention can conveniently be prepared by
direct compression (followed, if required, by coating).
[0139] Preferred Tablets
[0140] Preferred tablets of the invention comprise: bexagliflozin;
glyceryl dibehenate; polyethylene oxide; lactose (anhydrous or,
preferably, monohydrate); poloxamer 188 (preferably micronized);
microcrystalline cellulose; colloidal silicon dioxide; and
magnesium stearate; optionally also having a coating comprising
polyvinyl alcohol.
[0141] Examples of such tablets have the following composition per
tablet: bexagliflozin, between 3-60 mg; glyceryl dibehenate,
between 100-140 mg; polyethylene oxide, between 50-75 mg; lactose,
between 40-50 mg; poloxamer 188, between 40-45 mg; microcrystalline
cellulose, between 60-80 mg; colloidal silicon dioxide, between 4-5
mg; and magnesium stearate, between 6-9 mg; optionally also having
10-12 mg of a coating which comprises polyvinyl alcohol.
[0142] Three preferred tablets of the invention comprise one of the
following cores, for which further details of the excipients are
well known, and can also be found in Handbook of Pharmaceutical
Excipients (eds. Sheskey, Cook & Cable; 8.sup.th edition
2016):
TABLE-US-00001 (i) (ii) (iii) Bexagliflozin 5 mg 10 mg 20 mg
Polyethylene oxide, average 65 mg 65 mg 65 mg molecular weight
900,000 Glyceryl dibehenate 120 mg 120 mg 120 mg Lactose (either
anhydrous or 45 mg 45 mg 45 mg monohydrate e.g. spray-dried)
Poloxamer 188 42 mg 42 mg 42 mg Microcrystalline cellulose 70 mg 70
mg 70 mg Colloidal silicon dioxide 4.5 mg 4.5 mg 4.5 mg Magnesium
stearate 7.5 mg 7.5 mg 7.5 mg
[0143] The core preferably has a hardness of between 40-60 N or
60-90 N, and a friability of .ltoreq.1% by weight.
[0144] The invention also provides a tablet comprising one of these
three cores coated with a polymeric film coating comprising
polyvinyl alcohol, titanium dioxide, and macrogol 3350. The amount
of coating can be 3% of the core's weight.
[0145] In these preferred tablets: the poloxamer 188 should be
micronized; the lactose can be anhydrous but is preferably a
monohydrate; and the optional coating can comprise polyvinyl
alcohol, titanium dioxide, macrogol 3350, talc, brilliant blue FCF
and indigo carmine, such as an Opadry II blue product.
[0146] The invention also provides an oral dosage form (and in
particular a solid oral dosage form, such as a tablet) that
produces in a cohort of healthy subjects a geometric mean C.sub.max
and geometric mean AUC.sub.0-t for which the 90% confidence
intervals of the log-transformed C.sub.max and log-transformed
AUC.sub.0-t fall, upon exponentiation, completely within the range
80.00-125.00% of the geometric mean C.sub.max and geometric mean
AUC.sub.0-t, respectively, of the values produced in the same
cohort by a reference tablet having one of the following
compositions (see also tablets U5, U10 and U20 below): [0147] (a) A
tablet having: a core consisting of an admixture of 5 mg
bexagliflozin, 65 mg non-ionic polyethylene oxide having an average
molecular weight of approximately 900,000, 120 mg glyceryl
dibehenate powder, 45 mg spray-dried lactose monohydrate, 42 mg
micronized poloxamer 188, 70 mg microcrystalline cellulose, 4.5 mg
amorphous anhydrous colloidal silicon dioxide, and 7.5 mg magnesium
stearate; and a film coating consisting of 10.77 mg of a mixture of
PVA, titanium dioxide, macrogol 3350, talc, brilliant blue FCF and
indigo carmine (such as Opadry II.TM. blue 85F99153); where the
core has a tablet hardness of between 40-60 N and is formed by
compression using a 14.8.times.6.5 mm caplet-shaped tablet punch.
[0148] (b) A tablet having: a core consisting of an admixture of 10
mg bexagliflozin, 65 mg non-ionic polyethylene oxide having an
average molecular weight of approximately 900,000, 120 mg glyceryl
dibehenate powder, 45 mg spray-dried lactose monohydrate, 42 mg
micronized poloxamer 188, 70 mg microcrystalline cellulose, 4.5 mg
amorphous anhydrous colloidal silicon dioxide, and 7.5 mg magnesium
stearate; and a film coating consisting of 10.92 mg of a mixture of
PVA, titanium dioxide, macrogol 3350, talc, brilliant blue FCF and
indigo carmine (such as Opadry II.TM. blue 85F99153); where the
core has a tablet hardness of between 40-60 N and is formed by
compression using a 14.8.times.6.5 mm caplet-shaped tablet punch.
[0149] (c) A tablet having: a core consisting of an admixture of 20
mg bexagliflozin, 65 mg non-ionic polyethylene oxide having an
average molecular weight of approximately 900,000, 120 mg glyceryl
dibehenate powder, 45 mg spray-dried lactose monohydrate, 42 mg
micronized poloxamer 188, 70 mg microcrystalline cellulose, 4.5 mg
amorphous anhydrous colloidal silicon dioxide, and 7.5 mg magnesium
stearate; and a film coating consisting of 11.22 mg of a mixture of
PVA, titanium dioxide, macrogol 3350, talc, brilliant blue FCF and
indigo carmine (such as Opadry II.TM. blue 85F99153); where the
core has a tablet hardness of between 40-60 N and is formed by
compression using a 14.8.times.6.5 mm caplet-shaped tablet
punch.
[0150] These reference tablets (a), (b) and (c) can be manufactured
as follows: (i) blending the bexagliflozin, colloidal silicon
dioxide and 80% of the MCC and then sifting the mixture; (ii) add
the remaining MCC to give mixture `A`; (iii) sifting the
polyethylene oxide, glyceryl dibehenate and lactose to give mixture
`B`; (iv) blending mixtures `A` and `B` together; (v) adding sifted
magnesium stearate, followed by further blending; (vi) compressing
this material into tablet cores e.g. using 14.8.times.6.5 mm
caplet-shaped punches and appropriate dies; (vii) de-dusting; and
(viii) coating e.g. using a 12% or 18% w/w suspension of the
coating material to achieve a coating that results in an
approximate increase in tablet mass of 3%. The bexagliflozin
preparations used to manufacture these reference tablets should
have the solid crystalline form disclosed in WO2011/153953.
Preferred embodiments of such preparations have a particle size
distribution having a d(0.9).ltoreq.700 .mu.m.
[0151] Further details for assessing whether the 90% confidence
intervals of log-transformed C.sub.max and AUC.sub.0-t values fall
within the 80.00-125.00% range of values achieved with the
reference tablets are given in the next section e.g. the use of a
random crossover study in a suitable test population, etc.
[0152] Bioequivalence
[0153] The invention thus provides oral dosage forms which are
bioequivalent to reference tablets (a) to (c). The oral dosage form
will include the same molar amount of bexagliflozin as the relevant
reference tablet i.e. the same amount as 5 mg, 10 mg, or 20 mg of
bexagliflozin of formula (I).
[0154] It is well known in the bioavailability and bioequivalence
arts how to determine whether any particular tablet meets
regulatory requirements for equivalent bioavailability and
pharmacokinetic bioequivalence e.g. see: Niazi (2014) Handbook of
Bioequivalence Testing, 2.sup.nd Edition, ISBN 978-1482226379; FDA
Guidance for Industry: Bioequivalence Studies with Pharmacokinetic
Endpoints for Drugs Submitted Under an ANDA, December 2013; FDA
Guidance for Industry: Bioavailability and Bioequivalence Studies
Submitted in NDAs or INDs--General Considerations, March 2014; FDA
Guidance for Industry: Bioanalytical Method Validation, May 2018;
Guideline On The Investigation Of Bioequivalence, EMA January 2010
(CPMP/EWP/QWP/1401/98 Rev. 1/ Corr **); and Guideline on the
pharmacokinetic and clinical evaluation of modified release dosage
forms, EMA November 2014 (EMA/CPMP/EWP/280/96 Corr1).
[0155] Many factors that vary from individual to individual can
affect the concentration of a drug in plasma. It is therefore
common to take into account the mass of the subject, whether the
drug is administered in the fasted or fed state, the degree of
impairment of hepatic and/or renal function of the subject, the
subject's concomitant medications, diet, alcohol or tobacco
consumption, and sex, racial, genetic and cultural influences. As
such, drug concentrations can vary substantially from individual to
individual, even under optimally controlled conditions. The
specification of the properties of an extended release formulation
are most precisely made by reference to attributes that can be
measured in vitro, such as the percent dissolution as a function of
time (see elsewhere herein). When reference is made to properties
that are measured in vivo, it is appropriate to adjust or normalize
the effects to the expected behavior in a well-characterized
prototypical subject.
[0156] From a practical perspective, though, even the specification
of a prototypical subject cannot capture all of the variation
between individuals, and for this reason, comparisons between
formulations are typically performed by administering to the same
individual each of the formulations to be compared, for example the
reference formulation on one day and the comparator formulation on
another, and vice versa. Usually a substantial period of time (at
least ten half-lives of the drug from the preceding formulation) is
allowed to elapse so that prior administration of one formulation
has little likelihood of affecting measurements made after the
administration of the subsequent formulation. Because substantial
inter-individual variation is nearly always present, the
comparisons are usually made on groups of individuals, typically no
fewer than 12. When certain criteria are met for the comparison of
the pharmacokinetic measurements between the subjects who had
received each of the two formulations, the formulations are said to
be bioequivalent.
[0157] There are in principle many ways to define bioequivalence
between formulations but a prevalent standard for regulatory
purposes that is adopted herein is that two preparations can be
considered bioequivalent for a particular pharmacokinetic parameter
if the lower bound of the 90% confidence interval for the logarithm
of the geometric mean for the parameter for a test formulation
yields a value upon exponentiation that is .gtoreq.80.00% of the
geometric mean for the same parameter for the reference formulation
and if the upper bound of the 90% confidence interval for the
logarithm of the geometric mean of the parameter for the test
formulation yields a value upon exponentiation that is
.ltoreq.125.00% of the geometric mean for the parameter for the
reference formulation. The typical parameters that must be found to
be meet this test are the observed maximum drug concentration
(C.sub.max), the area under the curve for the concentration as a
function of time from the beginning of dosing to the last
accurately measurable value (AUC.sub.0-t) and the area under the
curve for the concentration as a function of time from the
beginning of dosing, extrapolated to infinite time
(AUC.sub.0-.infin.). Geometric means and logarithms are used in
these calculations because most physiological variables, including
drug plasma concentrations, typically show a log-normal
distribution on repeated sampling of the same individual, and on
sampling from different individuals within a population.
[0158] The invention therefore provides an extended-release tablet
comprising bexagliflozin, wherein the tablet is bioequivalent by
C.sub.max and AUC.sub.0-t with any one of reference tablets (a) to
(c).
[0159] To ensure statistical power a study to measure the C.sub.max
and AUC.sub.0-t values will be performed in multiple subjects e.g.
in a group of at least 12 (and normally between 24 and 36) healthy
human adults.
[0160] For establishing bioequivalence a two-period, two-sequence,
two-treatment, single-dose, crossover study design can be used, a
single-dose parallel study design, or a replicate study design. The
preferred design is a two-period, two-sequence, two-treatment,
single-dose, crossover study using healthy subjects. Each study
subject should receive each treatment (test and reference drug) in
random order. The most accurate, sensitive and reproducible method
of measuring the drug concentration in plasma should be used. For
bexagliflozin the preferred method is a validated high performance
or ultra high performance liquid chromatographic separation with
detection of the analyte by a tandem mass spectrometry method. For
an extended release bexagliflozin tablet, both a fasting
bioequivalence study and a fed bioequivalence study should be
conducted. In each case the highest dosage strength formulation
should be tested. Multiple dose (e.g., steady state) studies are
not recommended.
[0161] A minimum of 12 subjects with evaluable data are generally
required to support a determination of bioequivalence. For a study
conducted in the fasted prandial state, a minimum fast of 10 h
before dosing is required and water should be withheld from 1 h
before to 1 h after dosing. Food should not be provided for at
least 4 h following dosing. The investigational product can be
provided with 240 mL of water.
[0162] For a study conducted in the fed prandial state, a minimum
fast of 10 h should precede a standard high fat, high calorie meal
of 800 to 1000 kcal, with approximately 150, 250, and 500-600 kcal
from protein, carbohydrate and fat, respectively (see e.g., FDA
Guidance for Industry: Bioequivalence Studies with Pharmacokinetic
Endpoints for Drugs Submitted Under an ANDA (2013) and Guideline on
the pharmacokinetic and clinical evaluation of modified release
dosage forms (EMA/CPMP/EWP/280/96 Corr1) section 5.1.4.1.) The meal
should be consumed in 30 minutes or less, and drug administration
should be performed 30 min after the beginning of the meal. No
additional food should be provided for a minimum of 4 h.
[0163] For testing in either prandial state venous blood specimens
should be drawn at appropriate intervals, generally consisting of
12 to 18 specimens in total, and covering at least three terminal
elimination half-lives of the drug. Dense sampling around the
expected T.sub.max is recommended to provide the most accurate
C.sub.max.
[0164] Because determining the C.sub.max and AUC.sub.0-t values
necessarily consumes each tablet tested, and because variation
would be present from one test to the next, even if the tablets
were identical in all respects and the same subject were used, the
pharmacokinetic parameters are determined for an average of the
C.sub.max and AUC values of a collection of subjects dosed with a
representative sample set of tablets from a manufacturing batch.
The average is composed geometrically instead of arithmetically. To
take the C.sub.max as an example in this and the following, for a
cohort of six subjects, the geometric mean C.sub.max is calculated
as the sixth root of the product of the six C.sub.max values for
the subjects. The same result will be obtained if the arithmetic
average of the logarithms of the C.sub.max values is exponentiated.
The values for the logarithms of the C.sub.max for each subject
will collectively create a distribution of individual logarithms of
C.sub.max values.
[0165] To compare a second manufacturing batch to the first, the
measurement process can be repeated with the same subjects but with
tablets from the second manufacturing batch. (In actual practice,
the order of administration would typically be randomly chosen for
each subject, so that some would receive tablets from the second
manufacturing batch first and some from the first manufacturing
batch first.) For each subject a difference is calculated by
subtracting the logarithm of the C.sub.max for the tablet from the
first manufacturing batch from the logarithm of the C.sub.max for
the tablet from the second manufacturing batch. The exponential of
this difference is the ratio of the C.sub.max for the second tablet
to the C.sub.max for the first tablet, which is unity if the
difference is zero (e.sup.0=1). Following the usual statistical
methods for analyzing differences between two collections of values
(analysis of variance), the endpoints of the 90% confidence
interval for the differences of the logarithms are determined. For
the two distributions to be considered bioequivalent, the endpoints
of the 90% confidence interval for the differences of the
logarithms must fall between -0.22314 and +0.22314. If these values
are exponentiated they give 80.00% and 125.00% respectively (e.g.,
e.sup.-0.22314=0.8000).
[0166] Although it is considered advantageous to dose each subject
with tablets from each manufacturing batch to minimize variation
between the measured values, if different cohorts of subjects are
used for evaluating the tablets from the two manufacturing batches
a similar approach can be used in which the mean difference in the
logarithms for the two cohorts is calculated and a 90% confidence
interval for the differences of the logarithms is constructed.
[0167] This type of test can be applied to establish whether
tablets in question are tablets as defined herein. If a batch of
tablets made by an unknown manufacturing process is compared by the
methodology described above to a batch of tablets of the present
invention defined by reference to C.sub.max and AUC.sub.0-t, and
for both the C.sub.max and the AUC.sub.0-t the endpoints of the 90%
confidence interval for the differences of the logarithms of the
values for the two batches falls between -0.22314 and +0.22314, the
batch of tablets made by the unknown process are tablets which meet
the relevant C.sub.max and AUC.sub.0-t requirements.
[0168] A corollary of the above is that if a cohort of subjects is
dosed twice with tablets of the present invention from the same
manufacturing batch, and defined by reference to C.sub.max and
AUC.sub.0-t, the endpoints of the 90% confidence interval for the
differences of the logarithms between the values for the first and
second dosings for both the C.sub.max and the AUC.sub.0-t will fall
between -0.22314 and +0.22314.
[0169] This can be expressed more formally to state that two
representative sample sets from the same batch will produce in a
cohort of healthy subjects an inter-set mean difference in the
logarithm of the C.sub.max and the logarithm of the AUC.sub.0-t for
which the endpoints of the 90% confidence interval for the
inter-set differences of the logarithms falls between -0.22314 and
+0.22314. The distinction from the preceding paragraph is that the
order of testing from the two sample sets may be randomly assigned
among the subjects of the cohort, as for example is recommended in
bioequivalence testing regulatory guidance documents.
[0170] In Vitro Dissolution Testing
[0171] Methods for the testing of extended release solid oral
dosage forms are well known in the art and include USP <711>,
which specifies the types of apparatus as well as the methods for
use for immediate and extended release solid oral dosage forms.
[0172] Testing for bexagliflozin extended release tablets is
conducted in USP Apparatus 1 (a basket apparatus e.g. with a
nominal capacity of 1 liter), charged with 900 mL of 0.1 N HCl
(i.e. simulated gastric fluid) and stirred at a rate of 50 rpm with
the temperature maintained at 37.+-.0.5.degree. C. Individual
tablets are placed in the apparatus and sampling conducted at the
specified times (e.g. 1, 3, 5 and 8 h) by withdrawal of 10 mL of
fluid without replacement. At each timepoint the concentration of
bexagliflozin in the fluid sample is determined (e.g. by a
validated HPLC method), thereby permitting calculation of the
amount which has been released from a tablet. Where such a method
involves filtering the withdrawn fluid before HPLC analysis, to
avoid variation caused by possible interaction of bexagliflozin
with the filter (e.g. with a PVDF material) it can be useful to
filter a first fraction of the fluid (e.g. 3.5 mL of a 10 mL
sample) and then to perform analysis on a subsequent fraction (e.g.
on the remaining 6.5 mL of the 10 mL sample).
[0173] Testing can proceed in up to three stages, referred to as
levels. In the first stage (level one testing), six tablets are
analyzed. A success is recorded if no individual value lies outside
each of the stated ranges and no individual value is less than the
stated amount at the final test time. If this criterion is not met,
an additional 6 tablets are analyzed (level two testing). A success
is recorded if the average value of all 12 units lies within each
of the stated ranges (i.e. for 1, 3, 5 and 8 h) and is not less
than the stated amount at the final test time AND if none is more
than 10% of the labelled amount (i.e. 2 mg for a 20 mg tablet)
outside each of the stated ranges and none is more than 10% of the
labelled amount below the stated amount at the final test time. If
the level two criteria are not met, level three testing must be
undertaken. An additional 12 tablets are tested. The average of all
24 tablets must lie within each of the stated ranges and not be
less than the stated amount at the final test time. Not more than 2
of the 24 units are more than 10% of labelled content outside each
of the stated ranges; not more than 2 of the 24 units are more than
10% of labelled content below the stated amount at the final test
time; and none of the units is more than 20% of labelled content
(i.e. 4 mg for a 20 mg tablet) outside each of the stated ranges or
more than 20% of labelled content below the stated amount at the
final test time.
[0174] A manufacturing batch of bexagliflozin extended release
tablets is said to have passed formal dissolution acceptance
testing if the criteria for success for at least one of the three
testing levels is satisfied. Representative units of the
manufacturing batch will meet these criteria, as defined in
Acceptance Table 2 of USP <711>. In practical terms, testing
is terminated once a success has been achieved. Additional testing,
for example repeat testing to begin anew at level one if testing
fails at level three, should not be performed.
[0175] The invention thus provides an extended-release tablet
comprising bexagliflozin, wherein the tablet is from a
manufacturing batch having a composition or method of testing or
manufacture that falls within the formal acceptable ranges for
process, testing or ingredient variation of the U5, U10, U20 or U40
formulations (see below). Of these four formulations, U20 is the
most preferred for use in diabetes therapy.
[0176] The invention also provides an extended-release tablet
comprising bexagliflozin, wherein the tablet is from a
manufacturing batch having the composition of the U5, U10, U20 or
U40 formulations (see below).
[0177] Similarly, the invention provides a solid oral dosage form
(and in particular a tablet, such as an extended release tablet)
that contains bexagliflozin and that in an in vitro dissolution
test in simulated gastric fluid has a f.sub.2 value of >50 when
compared to one of reference tablets (a), (b) or (c) as defined
above, wherein f.sub.2 is the decimal logarithmic reciprocal square
root transformation of the sum of the squared error: f.sub.2=100-25
log.sub.10 (1+n.sup.-1.SIGMA..sub.i=1.sup.n(R.sub.i-T.sub.i).sup.2)
where: n is number of time points at which dissolution is measured;
R.sub.i is the dissolution percentage of the reference tablet at
the i-th timepoint; and T.sub.i is the dissolution percentage of
the solid oral dosage form at the i-th timepoint.
[0178] The invention provides an extended release tablet that
contains bexagliflozin and that, in an in vitro dissolution test in
simulated gastric fluid, releases .ltoreq.17% of its bexagliflozin
after 1 hour and releases .gtoreq.80% after 8 hours. Preferably,
this tablet releases between 20-45% of its bexagliflozin after 3
hours, and/or between 45-75% of its bexagliflozin after 5 hours. As
mentioned above, within the 45-75% range after 5 hours it is
possible for a tablet to release (a) between 45-72% of its
bexagliflozin (b) between 50-70% of its bexagliflozin (c) between
49-69% of its bexagliflozin or (d) between 48-68% of its
bexagliflozin. Furthermore, within the 20-45% range after 3 hours,
it is possible for a tablet to release between 23-43% of its
bexagliflozin.
[0179] The invention also provides a solid oral dosage form,
typically an extended release tablet, that contains bexagliflozin
and that passes formal dissolution acceptance testing (see above)
in simulated gastric fluid with criterion standards for release of
.ltoreq.17% of the bexagliflozin dosage after 1 hour and
.gtoreq.80% of the bexagliflozin after 8 hours. Preferably, the
criterion standard for dissolution acceptance testing requires that
between 20-45% of the bexagliflozin be released after 3 hours (e.g.
between 23-43%) and/or between 45-75% of the bexagliflozin be
released after 5 hours (e.g. between 45-72%, 50-70%, 49-69%, or
48-68%, as mentioned above). In the formal dissolution acceptance
testing, these dosage forms pass at least one level of a formal
three level testing protocol as defined by USP <711>
Acceptance Table 2.
[0180] Therapeutic Methods
[0181] Tablets of the invention may be used to treat diabetes and
its symptoms, and in particular type 2 diabetes. More specifically,
tablets of the invention may be used as an adjunct to diet and
exercise to improve glycemic control in adults with type 2 diabetes
mellitus.
[0182] The invention provides methods for treating subjects
suffering from diabetes or its symptoms. The methods involve
administering a tablet of the invention to the subject, and will
generally involve repeated administrations (e.g. once daily),
either indefinitely or until a desired therapeutic result is
achieved. A dose of 5 mg, 10 mg, 20 mg or 40 mg bexagliflozin once
daily is typical.
[0183] Similarly, the invention provides a tablet of the invention
for use in such treatment methods.
[0184] The invention also provides the use of bexagliflozin and at
least one pharmaceutically acceptable excipient in the manufacture
of a medicament for treating diabetes, wherein the medicament is a
tablet of the invention as discussed above. The pharmaceutically
acceptable excipient(s) can be selected as discussed herein to
provide an extended release tablet of the invention.
[0185] As discussed above, a single tablet of the invention
preferably includes 5 mg, 10 mg, 20 mg, or 40 mg of bexagliflozin.
Thus, methods and uses of the invention will generally involve
administering to the subject 5 mg, 10 mg, 20 mg, or 40 mg (or an
integer multiple thereof) of bexagliflozin e.g. 5 mg, 10 mg, 20 mg,
or 40 mg once daily.
[0186] These therapeutic methods and uses may be performed on a
diabetic subject who is also receiving a second diabetes therapy,
such as a GLP-1 receptor agonist (e.g. exenatide, lixisenatide,
dulaglutide, liraglutide, albiglutide or semaglutide). As discussed
elsewhere herein, tablets of the invention can be safely
administered to such subjects, without requiring a change in
prescribing pattern.
[0187] Among the existing GLP-1 receptor agonists can be counted
exenatide, lixisenatide, liraglutide, albiglutide, dulaglutide and
semaglutide (reviewed by Gentilella et al., (2019) Diabetes Metab
Res Rev 35:e3070 doi: 10.1002/dmrr.3070). The first two are analogs
of exendin-4, a peptide isolated from the saliva of Gila monsters
that facilitates predation by causing severe hypoglycemia in bitten
prey. The latter four are analogs of human GLP-1 with modifications
that extend plasma half-life. Approved dosages of these agonists
are as follows: exenatide is delivered in 5 .mu.g or 10 .mu.g
subcutaneous injections, twice daily, or by once weekly injection
of an extended release depot preparation; lixisenatide is delivered
by 20 .mu.g once daily subcutaneous injection; in maintenance
therapy liraglutide is delivered once daily by subcutaneous
injection of 1.2 or 1.8 mg; the others are delivered by weekly
subcutaneous injection, albiglutide in 30 or 50 mg dosage,
dulaglutide in 0.75 or 1.5 mg dosage, and semaglutide in 0.5 or 1.0
mg dosage.
MODES FOR CARRYING OUT THE INVENTION
Example 1
Effervescent Tablets
[0188] Effervescent tablets containing 10, 15, or 20 mg
bexagliflozin were developed. Early tablets were formed by direct
compression and were composed of hydroxypropyl-methyl-cellulose
(HPMC; low and medium viscosity), lactose monohydrate, sodium
bicarbonate, and magnesium stearate. Each of these excipients had
first been shown to be compatible with bexagliflozin during
stability studies (whereas, for instance, breakdown was observed
when citric acid monohydrate was tested as an effervescence agent).
Bexagliflozin and the lactose monohydrate (diluent) were mixed and
sieved, and then HPMC, sodium bicarbonate and silicon dioxide were
added in a blender. Finally, the magnesium stearate was added as a
lubricant and the tablets were formed.
[0189] Two target release profiles were initially proposed, to
release .gtoreq.80% of bexagliflozin either at 12 hours or at 18
hours, as assessed by an in vitro dissolution test of the tablets
(USP Apparatus 2, 50 rpm at 37.+-.0.5.degree. C., with sinkers) in
900 mL of 0.1 N HCl. The tablet compositions were as follows:
TABLE-US-00002 Mass % Mass % Component (mg) wt (mg) wt
Bexagliflozin 10 6.67% 10 6.67%.sup. HPMC (low viscosity) 35 23.33%
37.5 25% HPMC (medium viscosity) 10 6.67% -- -- Lactose monohydrate
78.5 52.33% 86 57.33% Sodium bicarbonate 15 .sup. 10% 15 10%
Magnesium stearate 1.5 1% 1.5 1% Total 150 100% 150 100%
[0190] The tablet with a mixture of HPMCs showed 68% release at 10
hours and 82% at 14 hours. In contrast, the tablet with a single
HPMC showed 62% release at 10 hours, 75% at 12 hours, and 89% at 16
hours.
[0191] Two further batches were prepared:
TABLE-US-00003 Mass % Mass % Component (mg) wt (mg) wt
Bexagliflozin 10 6.67%.sup. 10 6.67% HPMC (low) 40.5 27% 28.125
18.75% HPMC (medium) -- -- 9.375 6.25% Lactose monohydrate 83
55.33% 86 57.33% Sodium bicarbonate 15 10% 15 .sup. 10% Magnesium
stearate 1.5 1% 1.5 1% Total 150 100% 150 100%
[0192] These two tablets had similar release profiles until 12
hours (75%), but thereafter release was slightly quicker using the
mixture of HPMCs (91% vs. 87% at 18 hours).
[0193] Various further tablets were prepared, and a final tablet
composition was selected as follows:
TABLE-US-00004 Component Mass (mg) % wt Bexagliflozin 10 6.67%.sup.
HPMC (low) 37.5 25% Lactose monohydrate 86 57.33% Sodium
bicarbonate 15 10% Magnesium stearate 1.5 1% Total 150 100%
[0194] Different formulations were initially tested for 20 mg
tablets:
TABLE-US-00005 Mass % Mass % Component (mg) wt (mg) wt
Bexagliflozin 20 13.33% 20 13.33% HPMC (low) 45 30% 30 20% HPMC
(medium) -- -- 15 10% Lactose monohydrate 67.75 45.17% 67.75 45.17%
Sodium bicarbonate 15 10% 15 10% Colloidal silicon 0.75 0.5% 0.75
0.5% dioxide Magnesium stearate 1.5 1% 1.5 1% Total 150 .sup. 100%
150 100%
[0195] These tablets had a slower release profile than desired
(less than 75% after 12 hours in both cases), so modifications were
made. Final tablet compositions for 15 mg and 20 mg tablets were
selected as follows:
TABLE-US-00006 Mass % Mass % Component (mg) wt (mg) wt
Bexagliflozin 20 13.33% 15 10% HPMC (low) 37.5 25% 37.5 25% Lactose
monohydrate 76 50.67% 81 54% Sodium bicarbonate 15 10% 15 10%
Colloidal silicon 0.75 0.5% 0.75 0.5% dioxide Magnesium stearate
0.75 0.5% 0.75 0.5% Total 150 .sup. 100% 150 100%
[0196] Data from various further in vitro studies indicated that
low viscosity HPMC (19-24% methoxyl, 7-12% hydroxypropyl, apparent
viscosity of 2% aqueous solution at 20.degree. C. around 3000 mPas)
could be used as the sole release-controlling polymer while giving
the desired release profile. Sticking was avoided using 1%
magnesium stearate. Thus, final batches for clinical studies were
prepared with the following compositions (masses in mg) and release
profiles:
TABLE-US-00007 Component Mass % wt Mass % wt Mass % wt
Bexagliflozin 10 6.67%.sup. 15 10% 20 13.33% HPMC (low viscosity)
37.5 25% 40 26.67% 40 26.67% Lactose monohydrate 86 57.33% 77.75
51.83% 72.75 48.5% Sodium bicarbonate 15 10% 15 10% 15 10%
Colloidal silicon dioxide -- -- 0.75 0.5% 0.75 0.5% Magnesium
stearate 1.5 1% 1.5 1% 1.5 1% Total 150 100% 150 .sup. 100% 150
.sup. 100% Release: 1 hour 15% 13% 12% after 6 hours 55% 53% 50% 12
hours 90% 87% 85%
[0197] These three tablets were made by mixing the lactose
monohydrate and bexagliflozin, then adding HPMC, sodium bicarbonate
and silicon dioxide, and finally magnesium stearate. This mixture
was tableted by direct compression with a 7 mm punch. The tablets
were stable for 1 month at 40.degree. C., 75% relative
humidity.
[0198] These three extended release (XR) tablets were tested in
human clinical trials to evaluate pharmacokinetics and
pharmacodynamics, along with a 20 mg immediate release (IR) tablet.
Tablets were administered once-daily for 5 days under fasted (days
1 & 2) or fed (day 3) conditions. Mean PK parameters.+-.SD
derived from the trials in the fasted condition were:
TABLE-US-00008 20 mg IR 10 mg XR 15 mg XR 20 mg XR C.sub.max
(ng/mL) 238 .+-. 85.1 54.6 .+-. 22.9 75.9 .+-. 23.1 99.9 .+-. 77.9
T.sub.max (h) 1.0 3.0 5.0 4.0 AUC.sub.0-24 h 961 .+-. 252 341 .+-.
123 525 .+-. 169 632 .+-. 334 (ng h mL.sup.-1) AUC.sub.0-.infin.
1024 .+-. 263 391 .+-. 133 615 .+-. 170 746 .+-. 321 (ng h
mL.sup.-1) t.sub.1/2z (h) 7.14 .+-. 3.88 8.15 .+-. 2.30 8.17 .+-.
2.85 9.42 .+-. 3.45
[0199] Thus, compared to the 20 mg immediate release tablet, the 20
mg extended release tablet's C.sub.max was about 40% and it showed
a longer half-life, but with an apparent reduction of
bioavailability of around 30%. Absorption and clearance were
consistent across the three extended release doses, and C.sub.max
and AUC values increased with increasing dose.
[0200] For the 20 mg IR formulation, food decreased the amount of
and delayed the absorption of bexagliflozin, as demonstrated by
lower C.sub.max and longer T.sub.max. Although food decreased the
rate of absorption of the 20 mg IR formulation, it had little
impact on the overall bioavailability.
[0201] For the 10 mg XR formulation, food appeared to have little
impact on the PK profile except for shortening of mean T.sub.max.
However, examination of the PK parameters revealed that the median
T.sub.max values were the same under both fed and fasted
conditions.
[0202] For the 15 mg and 20 mg XR formulations, food reduced
T.sub.max but mean C.sub.max and AUC.sub.0-.infin. were similar
under fed and fasted conditions for both dose levels. These
observations indicate that food may have accelerated but did not
increase the magnitude of absorption of bexagliflozin following
administration of the 15 mg and 20 mg XR formulations.
[0203] In terms of pharmacodynamics, all tablets were associated
with significant dose-dependent glucosuria in healthy subjects.
Glucose excretion occurred later with the XR formulations compared
to the IR formulation, but the total daily glucose excretion was
comparable. In general, urinary glucose excretion was highest in
the first 12 hours post-dose and on day 2 under fasted and fed
conditions for all tablets. Food appeared to have minimal effects
on glucose excretion over 24 hours for all tablets as excretion
under the fed state fell within ranges observed during the fasted
conditions.
[0204] Although these XR formulations succeeded in reducing
C.sub.max of bexagliflozin, the bioavailability and
pharmacokinetics were more variable than desired. In particular,
the T.sub.max was unacceptably variable, perhaps because of a
failure to retain the tablet in the stomach. Early exit from the
stomach could also explain the sporadic lower bioavailability, due
in part to negation of the disruptive stresses which arise from
acid-driven effervescence. Thus, further XR formulations were
developed in order to reduce this variability.
Example 2
Pellet-Releasing Capsules
[0205] A capsule which disperses into many small pellets or
granules in the stomach would reduce the chances that the total
dose of bexagliflozin would be expelled from the stomach in a
single event. Two approaches were thus proposed, both relying on
capsules which release multiple bexagliflozin pellets. The first
releases low density pellets which float in gastric acid; the
second releases coated pellets.
[0206] Five formulations with floating pellets (`floater` capsules)
were prepared and assessed as before by in vitro dissolution tests
in 0.1 N HCl. The contents of these capsules were as follows (mg
per capsule), along with the % of bexagliflozin which had been
released after 12 hours:
TABLE-US-00009 A B C D E Bexagliflozin 15 15 15 15 15 Glyceryl
dibehenate 150 25 87.5 -- -- Cetostearyl alcohol -- -- -- 150 --
Stearic acid 50 -- -- -- -- 150 Eudragit RS PO* 90 180 135 90 90
Eudragit RS 30D* -- 50 25 -- -- Triethyl citrate (TEC) -- 10 10 --
-- Microcrystalline cellulose (MCC) 75 50 67.5 75 75
Polyvinylpolypyrrolidone (PVPP) 30 40 30 30 30 Total 360 mg
Dissolution % (12 hours) 89.8 68.9 79.4 88.4 90.2 *Poly(ethyl
acrylate-co-methyl methacrylate-co-trimethylammonioethyl
methacrylate chloride) 1:2:0.1
[0207] Twenty-one formulations with coated pellets were tested,
with seven types of pellet each with three different coatings.
Compositions and 12 hour dissolution % were as follows:
TABLE-US-00010 A B C Core pellet Bexagliflozin 15 15 15 MCC 170 170
170 PVPP 15 15 15 Poloxamer 188 -- -- -- XR coating 1 2 3 1 2 3 1
Eudragit RS 30D 6 14 18 3 5 7 -- Eudragit RL 30D* 6 14 13 9 15 21
12 Lactose -- -- -- -- -- -- -- TEC 2.4 5.6 7.2 2.4 4.0 5.6 2.4
Talc 6 14 18 6 10 14 6 Total 220.4 247.6 261.2 220.4 234.0 247.6
220.4 Dissolution % 71.2 56.2 53.4 75.4 69.8 65.9 81.4 C D E Core
pellet Bexagliflozin 15 15 15 MCC 170 170 155 PVPP 15 15 15
Poloxamer 188 -- -- 45 XR coating 2 3 1 2 3 1 2 Eudragit RS 30D --
-- -- -- -- -- -- Eudragit RL 30D 16 24 12 16 24 13.8 18.4 Lactose
-- -- 1.2 1.6 2.4 -- -- TEC 3.2 4.8 2.4 3.2 4.8 2.8 3.7 Talc 8 12 6
8 12 6.9 9.2 Total 227.2 240.8 221.6 228.8 243.2 253.5 261.3
Dissolution % 77.4 75.7 84.1 74.9 79.2 98.3 90.5 E F G Core pellet
Bexagliflozin 15 15 15 MCC 155 155 225 PVPP 15 15 15 Poloxamer 188
45 45 45 XR coating 3 1 2 3 1 2 3 Eudragit RS 30D -- 23.0 32.2 31.4
27.0 31.5 36.0 Eudragit RL 30D -- -- -- -- -- -- -- Lactose -- --
-- -- -- -- -- TEC 5.5 4.6 6.4 8.3 7.2 8.4 9.6 Talc 13.8 11.5 16.1
20.7 18.0 21.0 24.0 Total 276.9 269.1 284.7 300.4 361.2 371.4 381.6
Dissolution % 99.0 50.5 27.2 27.3 50.5 27.2 27.3 *Poly(ethyl
acrylate-co-methyl methacrylate-co-trimethylammonioethyl
methacrylate chloride) 1:2:0.2
[0208] Based on the in vitro dissolution tests, formulations were
chosen as follows:
TABLE-US-00011 Floater A Coated G mg per % mg per % capsule wt
capsule wt Bexagliflozin 15 4.2 15 3.9 Glyceryl dibehenate 150 41.7
-- -- Eudragit RS PO 90 25.0 -- -- Microcrystalline cellulose 75
20.8 225 58.6 Polyvinylpolypyrrolidone 30 8.3 15 3.9 Poloxamer 188
-- -- 45 11.7 Pellet core weight 360 100% 300 Eudragit RS 30D -- --
36 9.4% Eudragit RL 30D -- -- 13.4 3.5% Triethyl citrate -- -- 9.9
2.6% Talc -- -- 24.7 6.4% Total pellet weight 360 100% 384 100%
Capsule 0#, green
[0209] To make the pellets: bexagliflozin, glyceryl dibehenate
(retardant and floating agent), ethyl acrylate/methyl methacrylate
copolymer (Eudragit RS PO; matrix material), microcrystalline
cellulose (MCC; filler) and polyvinylpolypyrrolidone (binder and
disintegrant) were mixed; and then water was added to provide wet
granules. Extrusion and spheronisation gave wet pellets, which were
then dried to give the floating pellets, which were then filled
into capsules.
[0210] To make the coated granules bexagliflozin, microcrystalline
cellulose (filler), poloxamer 188 (solubilizer) and
polyvinylpolypyrrolidone (binder and disintegrant) were mixed, and
then water was added to provide wet granules. Extrusion and
spheronisation gave wet pellets which were then dried. A coating
composition was then formed by mixing talc (lubricant), TEC
(plasticizer) and water to give a suspension which was then mixed
with the two Eudragit copolymer components (extended release
coatings). This was used to coat the dry pellets and the coated
pellets were filled into capsules.
[0211] Accelerated stability studies showed that the compositions
were stable for 8 weeks at 40.degree. C. with 75% RH, but their
dissolution profiles changed significantly (slower for the coated
pellets, faster for the floaters). Thus, these formulations succeed
in altering the pharmacokinetic profile of bexagliflozin, but their
shelf-life is not optimal for commercial purposes.
Example 3
Floating Tablets
[0212] A tablet which floats in gastric contents could delay
transit from the stomach and thus avoid rapid premature expulsion
from the stomach as discussed in Example 1 above.
[0213] Two prototype formulations were prepared, with compositions
as follows (mg per tablet):
TABLE-US-00012 H I Bexagliflozin 15 15 Nonionic polyethylene oxide
105 60 Glyceryl dibehenate 100 120 Lactose (filler) -- 25
Microcrystalline cellulose (MCC) (filler) 77 77 Colloidal silicon
dioxide 1.5 1.5 Magnesium stearate 1.5 1.5 Total 300 300
[0214] These tablets were compressed to a hardness of 40 N or 50 N
and then subjected to in vitro dissolution tests as in Examples 1
& 2. The percentage of bexagliflozin released at 8 and 12 hours
was as follows:
TABLE-US-00013 H, 40 N H, 50 N I, 40 N I, 50 N 8 hours 59.8 67.9
82.7 51.4 12 hours 95.6 95.2 100 76.9
[0215] Based on these results the final tablet formulation was
selected as follows:
TABLE-US-00014 mg per % tablet wt Function Bexagliflozin 15 5
Active ingredient Polyethylene oxide (PEO) 105 35 Mucoadhesive
matrix Glyceryl dibehenate 100 33.3 Retardant and floating agent
Microcrystalline cellulose 77 25.7 Filler Colloidal silicon dioxide
1.5 0.5 Glidant Magnesium stearate 1.5 0.5 Lubricant Total 300
100%
[0216] These tablets are made by (a) combining bexagliflozin, MCC,
glyceryl dibehenate and PEO and (b) combining the silicon dioxide
and magnesium stearate, and then combining (a) & (b) for direct
compression to form tablets.
[0217] Accelerated stability studies showed that the tablets were
stable for 8 weeks at 40.degree. C. with 75% RH, with minimal
differences in dissolution profile.
Example 4
Tablets with More Rapid Extended Release
[0218] Further work was performed to obtain faster release from the
mucoadhesive tablets of Example 3 (aiming for complete release with
4-6 hours), while maintaining a similar tablet composition and the
direct compression manufacturing technique. Thus, the tablet
composition was modified and investigations led to two further
formulations:
TABLE-US-00015 J J K K (mg) (% wt) (mg) (% wt) Bexagliflozin 15 4.3
15 4.3 Polyethylene oxide 65 18.8 50 14.3 Glyceryl dibehenate 120
34.7 120 34.4 Lactose 45 13.0 -- -- Poloxamer 188 42 12.1 87 24.9
Microcrystalline cellulose (MCC) 50 14.5 50 14.3
Polyvinylpolypyrrolidone -- -- 15 4.3 Colloidal silicon dioxide 4.5
1.3 6 1.7 Magnesium stearate 4.5 1.3 6 1.7 Total 346 mg 100% 349 mg
100%
[0219] These tablets were manufactured in the same manner as
Example 3 i.e. all components except the lubricant and glidant are
combined, and then these are mixed with the combined
lubricant/glidant and pressed into tablets by direct compression to
a hardness of 30 N.
[0220] The tablets' dissolution profiles over 8 hours were as
follows:
TABLE-US-00016 Hours 0 1 2 3 4 5 6 8 J % 0.0 10.7 23.6 38.3 59.5
85.7 94.7 94.2 K % 0.0 7.4 20.8 46.8 83.9 95.4 94.2 92.0
[0221] The tablets were stable at 40.degree. C. at 75% RH for at
least 8 weeks. After this storage tablet J's dissolution profile
showed negligible differences, but tablet K's release profile was
slightly faster. Furthermore, both tablets became slightly harder
after storage.
[0222] Thus, faster release than in Example 3 was successfully
achieved.
Example 5
Lactose-Free Extended Release Tablets
[0223] Tablet J from Example 4 includes lactose. As this is an
animal-derived material, alternative fillers were tested aiming at
tablets having a similar release profile. In particular, mannitol,
sorbitol, xylitol and maltodextrin were tested as alternatives (45
mg in each case).
[0224] All four of these ingredients were first shown to be
compatible with bexagliflozin.
[0225] Using mannitol in place of lactose gave tablets with a
similar release behaviour, with both formulations reaching >90%
released in 5 hours in vitro. Higher tablet hardness was tried
(45-55N), which resulted in a shorter floating time and thus
slightly faster dissolution.
[0226] Maltodextrin, sorbitol and xylitol resulted in slightly
faster release profiles than lactose and mannitol, possibly due to
their higher solubility.
[0227] Overall, it was feasible to achieve comparable dissolution
behavior by replacing lactose with alternative excipients.
Example 6
Extended Release Tablets for Clinical Trials
[0228] Five floating mucoadhesive tablets were prepared for
clinical testing, including the final formulation from Example 3
and tablets J & K from Example 4. Their compositions and
properties were:
TABLE-US-00017 L M N O P Bexagliflozin 15 15 15 15 15 Polyethylene
oxide 105 85 65 65 50 Glyceryl dibehenate 100 100 120 120 120
Lactose anhydrous -- 45 45 45 -- Poloxamer 188, micronized -- -- 42
42 87 MCC 77 77 50 50 50 PVPP -- -- -- -- 15 Colloidal silicon
dioxide 1.5 1.5 1.5 4.5 6 Magnesium stearate 1.5 1.5 1.5 4.5 6
Total 300 325 340 346 349 Hardness range 40 N 40-50 N 20-30 N 30 N
30 N
[0229] In general, these were manufactured by combining (a) a
mixture of bexagliflozin and MCC (b) a mixture of the lubricant and
glidant (c) a mixture of the remaining ingredients. This mixture
was then compressed to a desired hardness using a rotary
compression machine with a 14.times.6 mm caplet shaped punch.
Friability was no more than 1% w/w.
[0230] Some sticking was seen using formulation N and so the amount
of magnesium stearate was increased to 4.5 mg and this resolved the
issue. A further increase in the amount of silicon dioxide then
provided formulation O.
[0231] Formulations L, M and O were found to have the best overall
properties in dissolution, stability, etc. These three tablets were
selected for further study of the impact of dissolution times:
tablet L transitioned from 80% to 90% release between the 10 and 12
hour samples; for tablet M this occurred between 8 and 10 hours;
and for tablet O it occurred between 5 and 6 hours. Thus, these
tablets were named XR11, XR8 and XR5 to reflect their dissolution
profiles, and they were taken forwards to clinical trial
testing.
Example 7
Alternative Doses in Tablets for Clinical Trials
[0232] Based on the XR5 results in Example 6 (tablet O) further
floating mucoadhesive tablets were prepared in the same way, but
containing 10 mg or 30 mg bexagliflozin. Additionally, these
tablets had a film coating made from Opdary II white. The final
tablets had the following compositions (mg per tablet):
TABLE-US-00018 Q10 Q15 Q30 Bexagliflozin 10 15 30 Polyethylene
oxide 65 65 65 Glyceryl dibehenate 120 120 120 Lactose anhydrous 45
45 45 Poloxamer 188, micronized 42 42 42 MCC 50 50 50 Colloidal
silicon dioxide 4.5 4.5 4.5 Magnesium stearate 4.5 4.5 4.5 Total
341 346 361 Hardness range 30-40 N 30-40 N 30-40 N Coating (Opadry
II white) 10.23 10.38 10.83 Coated tablet weight 351.23 356.38
371.83 Friability .ltoreq.1% by weight
[0233] Coated tablets were cured for up to 24 hours at 50.degree.
C. to study the effect on hardness. The tablets' dissolution
release profile and hardness were not affected by curing and so
this treatment was not used in further studies.
[0234] Accelerated stability studies showed no effect on
dissolution properties for the tablets.
[0235] Release of bexagliflozin in in vitro dissolution tests
(performed as above) were as follows:
TABLE-US-00019 Time (hours) Q10 Q15 Q30 1 9% 9% 8% 3 47% 44% 44% 5
85% 82% 80% 8 96% 96% 94%
[0236] The stability and release profiles of these tablets were in
accordance with the intended properties and so they were taken
forwards into human clinical testing, along with the XR5, XR8 and
XR11 tablets from Example 6.
Example 8
Particle Size Distribution
[0237] The effect of crystalline bexagliflozin particle size
distribution on tablet dissolution in an in vitro dissolution test
was assessed in XR5-type tablets having 20 mg or 30 mg total
bexagliflozin dose. Various particle size distributions were
tested, with d(0.9) values ranging from about 10 .mu.m up to around
700 .mu.m (i.e. particle size distributions in which 90% of the
cumulative volume of the crystalline bexagliflozin particles had a
diameter no more than 10 .mu.m up to 700 .mu.m) e.g. with d(0.9) of
220 .mu.m or 325 .mu.m. No significant variations in tablet
dissolution profile were observed with these different d(0.9)
values, so particle size distribution of crystalline bexagliflozin
is not seen as an important parameter for tablet dissolution.
Example 9
Clinical Trials
[0238] A 2-part Phase 1 open-labeled study was conducted to assess
the pharmacokinetics of multiple oral doses of these floating
tablets in healthy male subjects. Part 1 assessed the PK profiles
in XR5, XR8 or XR11 tablets (Example 6). Part 2 assessed three
dosage strengths (10 mg, 15 mg, and 30 mg) of tablets with a 5-hour
release profile (Example 7). Secondary objectives were to assess
the safety and tolerability of bexagliflozin and to evaluate the
effect of food on PK parameters.
[0239] Part 1 used a crossover design. 20 subjects were dosed with
each of the three 15 mg tablets, or with a 20 mg capsule (size 2
white opaque gelatin capsules containing 20 mg bexagliflozin, and
microcrystalline cellulose, silicified). There were 4 dosing
periods with no washout in between. The first dosing period
consisted of 2 days of once-daily dosing in the fasted state,
followed by 1 day of dosing in the fed state. The second to fourth
dosing periods consisted of 1 day of dosing in the fasted state and
1 day of dosing in the fed state. Subjects were randomized to
receive 1 of the 4 formulations in 1 of the 24 permutations
possible for a 4-period crossover study with a single constraint
that the first dosing period incorporated each formulation 5
times.
[0240] Part 2 used a parallel design in 30 subjects. Tablets were
administered once daily for 2 days in the fasted state and for 1
day in the fed state.
[0241] Tablets (or capsules) were administered with approximately
200 mL of water, while subjects were in an upright position, to be
swallowed without chewing. Dosing while fasting occurred following
a minimum of a 10-hour overnight fast. For doses in the fasted
state, breakfast was provided 1 hour after dosing. Dosing in the
fed state occurred 30 minutes after the start of a standard meal.
Bexagliflozin plasma concentrations were determined by a validated
HPLC MS/MS method from samples of whole venous blood anticoagulated
with K.sub.2EDTA (see below).
[0242] FIG. 1 shows the geometric mean plasma concentration of
bexagliflozin in fasted subjects in part 1 of the trial. The
capsule shows a high C.sub.max, but this was successfully decreased
using the XR5, XR8 or XR11 tablets, providing an extended
absorption phase with a median T.sub.max of 3 hours for all three
XR tablets in fasted subjects (compared to 1 hour with the
capsules). Taking account of their lower dose (15 mg vs. 20 mg),
the normalized C.sub.max of the tablets was reduced to <5
ng/mL/mg compared to 10.2 ng/mL/mg. C.sub.max was also reduced in
the fed state, although to a lesser extent; XR11 gave the greatest
decrease. After reaching C.sub.max, plasma concentrations decreased
in a biphasic manner for the tablets and also for the capsules.
Overall, specific pharmacokinetic parameters were as follows:
TABLE-US-00020 XR11 XR8 XR5 Capsule Fasted Fed Fasted Fed Fasted
Fed Fasted Fed C.sub.max (ng/mL) 44.2 85.0 48.5 95.6 68.9 118 204
174 AUC.sub.0-24 (ng h mL.sup.-1) 409 609 497 633 562 723 1019 1025
AUC.sub.0-t (ng h mL.sup.-1) 410 600 467 634 562 720 1018 1023
AUC.sub.0-.infin. (ng h mL.sup.-1) 497 720 628 741 700 822 1111
1118 T.sub.max (h) 3.0 5.0 3.0 5.0 3.0 5.0 1.0 3.0
[0243] FIG. 2 shows the geometric mean plasma concentration of
bexagliflozin in fasted subjects in part 2 of the trial. All three
doses (10, 15, and 30 mg) showed an extended absorption phase with
a median T.sub.max of 3 hours for all doses in fasted subjects.
After reaching C.sub.max, plasma concentrations decreased in a
biphasic manner for all three tablets. Exposure (AUC.sub.24h and
C.sub.max) generally appeared to increase in a dose-proportional
manner for the 10-30 mg range, but clearance and volume of
distribution were dose-independent. Overall, specific
pharmacokinetic parameters were as follows:
TABLE-US-00021 Q10 Q15 Q30 Fasted Fed Fasted Fed Fasted Fed
C.sub.max (ng/mL) 41.0 85.9 56.7 106 102 236 AUC.sub.0-24 411 523
445 704 1090 1461 (ng h mL.sup.-1) AUC.sub.0-t 386 523 455 704 939
1461 (ng h mL.sup.-1) AUC.sub.0-.infin. 465 606 583 783 1246 1572
(ng h mL.sup.-1) T.sub.max (h) 3.0 3.0 3.0 5.0 3.0 5.0
[0244] In summary of the pharmacokinetic study, administration of
XR11, XR8, and XR5 tablets resulted in a prolonged absorption
relative to the capsule formulation. Mean exposure was higher
following administration of 20 mg of the capsule formulation than
15 mg of the XR formulations following administration in either
dietary state. Among the XR formulations XR5 produced the greatest
exposure. Administration of the XR formulations in the fed state
resulted in an increase in exposure of 27% to 49% and 71% to 97%,
for AUC.sub.0-24 and C.sub.max, respectively, compared to
administration in the fasted state. Administration of 10, 15, and
30 mg of the XR5 formulation resulted in a dose proportional
increase in exposure.
[0245] Analytical Methods for Human Plasma Samples
[0246] As noted above, bexagliflozin concentrations have been
determined in human plasma samples by a validated HPLC MS/MS
method. One example of a suitable method is provided as
follows.
[0247] The internal standard `IS` was bexagliflozin in which the 6
hexose carbons are substituted with .sup.13C. Other internal
standards, for example tolbutamide, can be used, but an
isotopically labeled internal standard is preferred.
[0248] For each run, a "Blank+IS" and a "Blank+Drug" sample are
included to monitor any contribution from the IS to the analyte or
vice versa. The solvent for all standards and reconstitution is
methanol. The matrix is human plasma anticoagulated with
K.sub.2EDTA.
[0249] The analytical method proceeds as follows: thaw standards,
QCs, blank matrix and study samples (as applicable) and vortex for
3 minutes before pipetting; add 100 .mu.L of blank plasma into
Blank, Blank+IS, Blank+Drug, Test, and Calibration Standards; spike
Blank+Drug with 5 .mu.L of 16000 ng/mL bexagliflozin spiking
solution; spike Test with 5 .mu.L of 80 ng/mL spiking solution; to
Calibration Standards, add 5 .mu.L of spiking solutions at each
concentration; to QC tubes, add 100 .mu.L of QC samples at the
appropriate concentrations and number of replicates; if applicable,
add 100 .mu.L of each Study Sample to the appropriate tubes; add 5
.mu.L of MeOH into Blank, Blank+IS, QCs and Study Samples tubes, as
applicable; add 50 .mu.L of IS into Test, Blank+IS, Calibration
Standard, and QC (and Study Sample, if applicable) tubes; add 50
.mu.L of MeOH into Blank and Blank+Drug tubes; vortex for
approximately 2 minutes at high speed.
[0250] The protein precipitation extraction procedure is as
follows: add 500 .mu.L acetonitrile (ACN) into all tubes; vortex
tubes for approximately 3 minutes at high speed, then centrifuge
for 10 minutes at 3000 rpm; transfer the supernatant into
16.times.100 mm labeled tubes; evaporate to dryness in a 40.degree.
C. bath under nitrogen stream for .apprxeq.10 minutes; reconstitute
all samples with 200 .mu.L of MeOH to each tube and vortex for
.apprxeq.1 minute at high speed; transfer to autosampler vials for
LC-MS/MS analysis; centrifuge vials for .apprxeq.5 minutes at 3000
rpm.
[0251] Equipment used was: Vacuum Degasser, DGU 14A, Shimadzu
Corp.; Solvent Delivery System, LC-10ADvp, SCL-10Avp, Shimadzu
Corp.; Autoinjector, HTC PAL, CTC Analytics; Column Heater at
35.degree. C., TS-130, Phenomenex.TM.; Mass Spectrometer, Triple
Quadrupole MS (API 4000), Sciex.
TABLE-US-00022 Human Plasma Analytical Method Analyte Bexagliflozin
Matrix K.sub.2 EDTA Human Plasma Calibration Standard
concentrations 1, 2, 8, 48, 150, 500, 800, and 1000 ng/mL Quality
Control concentrations 1, 3, 80, and 800 ng/mL Internal Standard
[.sup.13C]-bexagliflozin at 500 ng/mL Regression type Linear
analysis with 1/x.sup.2 weighting Sample volume 100 .mu.L
Extraction procedure summary Protein precipitation extraction of
the analyte and internal standard from K.sub.2EDTA human plasma
using acetonitrile (ACN) Reconstitution solvent 200 .mu.L of
ACN:H.sub.2O:1M NH.sub.4OAc/25:75:0.5 (v:v:v) Chromatography
Settings Column type Synergi Hydro-RP, 80 A, 50 .times. 2.00 mm, 4
.mu.m, Phenomenex Column switching 1.1-2.5 min to mass spec Mobile
phase composition A: Water: 1M NH.sub.4OAc:HCOOH/1000:0.5:1 (V:V:V)
B: ACN:HCOOH/1000:1 (V:V) Program Gradient Time (min) 0.5 2.0 2.2
4.2 4.3 5.3 % B 30 70 95 95 30 Stop Flow Rate (mL/min) 0.4 0.4 0.4
0.4 0.4 -- Autoinjector temperature 10.degree. C. Autoinjector wash
solvent 1 ACN:HCOOH/100:2 (V:V) Autoinjector wash solvent 2
MeOH:H.sub.2O:HCOOH/30:70:2 (V:V:V) Flow rate .apprxeq.400
.mu.L/min Analysis time .apprxeq.5.8 min Injection volume 10 .mu.L
Retention time bexagliflozin .apprxeq. 1.80 min
[.sup.13C]-bexagliflozin .apprxeq. 1.80 min Mass Spectrometer
Settings (Recommended Values) Source Temperature (TEM): 500.degree.
C. Collision Gas (CAD): 12 psig N.sub.2 (82737 Pa) Curtain Gas
(CUR): 20 psig N.sub.2 (137895 Pa) Ion Source Gas 1 (GS1): 70 psig
N.sub.2 (482633 Pa) Ion Source Gas 2 (GS2): 50 psig N.sub.2 (344737
Pa) Ion Spray Voltage (IS): 5500 V Entrance Potential (EP): 10 V
Scan duration: 3.5 min Dwell Declustering Collision Collision Exit
Ionization Time Potential Energy Potential Transition Compound Mode
(msec) (V) (eV) (V) (m/z) bexagliflozin TIS+ 200 50 37 14 482.2
.fwdarw. 167.3 [.sup.13C]-bexagliflozin TIS+ 200 80 36 30 488.2
.fwdarw. (IS) 168.9
Example 10
Additional Tablet Strengths
[0252] To supplement Example 9, tablets of 3 and 90 mg
bexagliflozin were prepared. The 3 mg tablets were similar to the
tablets of Example 9, but excipients were removed from the 90 mg
tablets and these lost their floating characteristics. Placebo
tablets were also prepared to observe floating properties.
Mucoadhesive was retained in all tablets. The new tablets had these
compositions:
TABLE-US-00023 R S Placebo Bexagliflozin 3 90 -- Polyethylene oxide
65 65 65 Glyceryl dibehenate 120 120 120 Lactose anhydrous 45 45 45
Poloxamer 188, micronized 42 42 42 MCC 50 -- 70 Colloidal silicon
dioxide 4.5 4.5 4.5 Magnesium stearate 4.5 4.5 4.5 Total 334 371
361 Hardness range 30-40N 30-40N 30-40N Coating (Opadry II white)
10.02 11.13 10.83 Coated tablet weight 344.02 382.13 371.83
Friability <1.0% w/w
[0253] The absence of MCC in tablet S was found to affect
compressibility, with severe lamination observed. Thus, further 90
mg tablets with 25 or 50 mg MCC were prepared, or with a
combination of 20 mg lactose and 25 mg MCC. Furthermore, the
lubricant and glidant were co-sifted with the bexagliflozin to
reduce lamination. Based on observed dissolution and floating
profiles the following tablets were prepared for clinical use:
TABLE-US-00024 T3 T10 T30 T90 Bexagliflozin 3 10 30 90 Polyethylene
oxide 65 65 65 65 Glyceryl dibehenate 120 120 120 120 Lactose
anhydrous 45 45 45 -- Poloxamer 188, micronized 42 42 42 42 MCC 50
50 50 50 Colloidal silicon dioxide 4.5 4.5 4.5 4.5 Magnesium
stearate 4.5 4.5 4.5 4.5 Total 334 341 361 376 Hardness range
30-40N 30-40N 30-40N >50N Coating (Opadry II white) 10.02 10.23
10.83 11.28 Coated tablet weight 344.02 352.13 371.83 387.28
Friability <1.0% w/w
[0254] These were made as before, by mixing (a) bexagliflozin plus
MCC by co-sifting with (b) polyethylene oxide, poloxamer, lactose,
and glyceryl dibehenate, followed by addition of a mixture of (c)
magnesium stearate and silicon dioxide. This material was
compressed to the desired hardness in a 14.times.6 mm caplet-shaped
punch, and the tablets were then coated.
[0255] Release of bexagliflozin from these tablets was assessed by
in vitro dissolution tests according to USP <711> as
discussed above (USP Apparatus 1, charged with 900 mL of 0.1 N HCl,
stirred at 50 rpm, 37.degree. C., sampling without replacement).
The following table presents appropriate chromatographic conditions
for the detection of bexagliflozin in 0.1 N HCl. The 10 mL samples
from Apparatus 1 are passed through a 10 .mu.m PVDF filter and 50
.mu.L injected onto the chromatography column.
TABLE-US-00025 Column Waters Sunfire C.sub.18, 50 .times. 4.6 mm,
3.5 .mu.m Mobile Phase 0.1% H.sub.3PO.sub.4 (aq.):Acetonitrile
(59:41) Isocratic Column temperature 40.degree. C. Injection volume
50 .mu.L Flow rate 1.0 mL/minute Detection wavelength 225 nm Auto
sampler temperature 20.degree. C. Run time 6 minutes Diluent
Methanol:Water (90:10 v/v) Needle wash Methanol Bexagliflozin
elution time .apprxeq.2.26 minutes
[0256] Results from these in vitro dissolution tests were as
follows:
TABLE-US-00026 Time (hours) T3 T10 T30 T90 1 8% 8% 6% 5% 3 35% 31%
29% 24% 5 62% 57% 51% 44% 8 90% 84% 78% 72%
[0257] Specific pharmacokinetic parameters for the T10 and T30
tablets in a clinical study in fed and fasted patients were as
follows:
TABLE-US-00027 T10 T30 Fasted Fed Fasted Fed C.sub.max (ng/mL) 62.4
99.3 203 283 AUC.sub.0-t (ng h mL.sup.-1) 437 517 1639 1656
AUC.sub.0-.infin. (ng h mL.sup.-1) 461 539 1733 1697 T.sub.max (h)
3.0 4.0 4.0 4.0
Example 11
Further Mucoadhesive Clinical Tablets
[0258] Based on the preceding examples, tablets were prepared for
clinical studies as follows:
TABLE-US-00028 U5 U10 U20 Placebo Bexagliflozin 5 10 20 0
Polyethylene oxide 65 65 65 65 Glyceryl dibehenate 120 120 120 120
Lactose monohydrate 45 45 45 45 Poloxamer 188, micronized 42 42 42
42 MCC 70 70 70 70 Colloidal silicon dioxide 4.5 4.5 4.5 4.5
Magnesium stearate 7.5 7.5 7.5 7.5 Core total 359 364 374 354
Coating (Opadry II blue) 10.77 10.92 11.22 10.62 Coated tablet
weight 369.77 374.92 385.22 364.62 Target hardness (up to 70N)
45-55N 45-55N 45-55N 45-55N
[0259] The tablets were manufactured as follows: (i) co-sifting the
bexagliflozin, colloidal silicon dioxide and 80% of the MCC using a
vibrational sifter with a #20 sieve; (ii) blending the sifted
material for 6 minutes in a container tumbler at 14 rpm (U5) or 18
rpm (U10 & U20); optionally (iii) sifting this material with
the remaining MCC through a conical screen mill with a 813 .mu.m
screen at 1000 rpm, to give mixture `A`; (iv) sifting the
polyethylene oxide, glyceryl dibehenate and lactose using a
vibrational sifter with a #20 sieve, to give mixture `B`; (v)
blending mixtures `A` and `B` in a container tumbler at 14 rpm;
(vi) adding magnesium stearate which has been sifted through a #30
sieve and blending in a container tumbler at 14 rpm; (vii)
compressing this material into tablet cores using 14.8.times.6.5 mm
bevelled caplet-shaped punches and appropriate dies with a Korsch
XL100 press, using 10 punch sets with 20-50 rpm force feeder and
55-70 rpm turret, or with a Killian T-300 press with 32 punch sets
and a minimal force feeder; (viii) de-dusting; and (ix) coating
using a 18% w/w suspension of the coating material in a 600 mm (U5)
or 800 mm (U10 & U20) pan.
[0260] Release of bexagliflozin in in vitro dissolution tests were
as follows, measured in a USP Apparatus 1 with 900 mL of 0.1 N HCl
maintained at 37.+-.0.5.degree. C. and stirred at 50 rpm:
TABLE-US-00029 Time (hours) U5 U10 U20 1 10% 9% 6% 3 40% 34% 27% 5
66% 58% 48% 8 93% 88% 80% 10 95% 96% 94%
[0261] The tablets were confirmed to be stable. The U20 tablet was
selected for clinical uses requiring a 20 mg dose of
bexagliflozin.
[0262] Further batches of tablets were prepared in a similar way,
with minor variations. For instance, step (vii) was modified to use
a Killian T-200 press with 19 heads. Furthermore, the concentration
of coating material in step (ix) was reduced from 18% to 12%.
Tablets made by these modified processes had the desired
properties.
[0263] A reference batch of U20 tablets was prepared, and in vitro
dissolution tests on a sample of tablets showed release of 7%, 27%,
50% and 86% of bexagliflozin after 1, 3, 5 and 8 hours,
respectively. Tests were performed on nine further manufacturing
batches (all tested at 1, 5 and 8 hours; five also tested at 3
hours) and f.sub.2 values were within the range of 54 to 94
compared to the reference tablets.
Example 12
Stability Testing
[0264] U20 tablets were stored for up to 5 years at either
25.degree. C./60% relative humidity or 30.degree. C./75% relative
humidity and their dissolution profiles were tested at various
points (3, 6, 9, 12, 18, 24, 36, 48 and 60 months) in an in vitro
dissolution test in simulated gastric fluid, in accordance with USP
<711>.
[0265] FIG. 3A and FIG. 3B show the mean % of bexagliflozin release
from six representative stored tablets per test after 1, 3 5, and 8
hours in simulated gastric fluid. Under both storage conditions,
and over the full 5 year period, the % released in the dissolution
test after 1 hour stays well below 17%, after 3 hours stays well
within the range 20-45% (even between 23-43%), after 5 hours stays
well within the range of 45-75% (even between 48-68%), and after 8
hours stays well above 80%.
[0266] For samples stored at 25.degree. C., linear regression shows
a very slight positive slope for the mean % released after 1 and 8
hours, and a very slight negative slope for the mean % released
after 3 and 5 hours. For samples stored at 30.degree. C., linear
regression shows a very slight positive slope for the mean %
released after 8 hours, and a very slight negative slope for the
mean % released after 1, 3 and 5 hours. Under both storage
conditions, however, the upper and lower 95% confidence bounds for
all four dissolution time-points are greater than and less than
zero, respectively, indicating that the slope is not significantly
different from zero. Moreover the small magnitude of the changes
with time are consistent with the interpretation that the release
profile of tablets does not meaningfully vary with storage for up
to 5 years.
Example 13
Effectiveness of the U20 Formulation in Randomized Controlled
Trials
[0267] To support late stage clinical development, seven batches of
U20 tablets were prepared, including five batches of
.apprxeq.800,000 tablets. Trials were performed as follows, with
between 200-1700 subjects each:
TABLE-US-00030 Duration Design Comparator (wks) bexagliflozin
monotherapy vs. placebo Placebo 24 bexagliflozin vs. placebo in
subjects with renal Placebo 24 impairment bexagliflozin vs.
sitagliptin added to Sitagliptin 24 metformin bexagliflozin vs.
placebo added to metformin Placebo 24 bexagliflozin vs. glimepiride
added to Glimepiride 96 metformin bexagliflozin vs. placebo in
subjects with Placebo .apprxeq.66 to 197 diabetes and increased
cardiovascular risks bexagliflozin vs. placebo in subjects with
Placebo 36 hypertension
Example 14
Clinical Pharmacology and Food Effect Studies with U20
[0268] Additional characterization of the U20 formulation by in
vivo experimentation was provided in the course of five clinical
pharmacology studies investigating the effects of prior food
consumption on the pharmacokinetics of bexagliflozin delivered by
the formulation, and of the effects of co-administration of other
medications on the pharmacokinetics. Only results from those arms
of the latter studies in which an additional medication was not
co-administered (i.e., the control arms) are provided in the
compilation below.
[0269] The U20 tablets were provided following an overnight fast of
at least 10 h, with no food or nutrients provided for 4 h following
dosing. Tablets were ingested with 240 mL of water but no water was
otherwise provided for the hour preceding or the hour following
ingestion. No additional medications were permitted to be
co-administered.
[0270] Geometric mean values for the indicated numbers of subjects
(n) were as follows:
TABLE-US-00031 Mass (n) C.sub.max (n) AUC.sub.0-t (n)
AUC.sub.0-.infin. (n) t.sub.1/2 (n) Study (kg) ng mL.sup.-1 ng h
mL.sup.-1 ng h mL.sup.-1 h A 77.1 (18) 125 (18) 1101 (18) 1154 (18)
10.3 (18) B 77.3 (18) 117 (18) 958 (18) 1012 (17*) 12.6 (17*) C
72.4 (16) 98 (16) 698 (16) 761 (16) 12.2 (16) D 77.1 (20) 96 (20)
703 (20) 776 (17*) 12.4 (17*) E 72.6 (24) 134 (24) 1074 (24) 1149
(24) 11.7 (24) Total 75.2 (96) 114 (96) 900 (96) 972 (92) 11.8 (92)
*a terminal elimination phase could not be accurately estimated for
some subjects
[0271] These data show the generally expected variation in
pharmacokinetic parameters that result from in vivo analysis of a
formulation in cohorts of experimental subjects. The data also
illustrate the importance of performing testing in a crossover
design, so that each individual serves as his/her own control. The
mean value for the dose-normalized C.sub.max was 5.7 ng mL.sup.-1
mg.sup.-1 bexagliflozin, whereas the corresponding values for the
dose-normalized C.sub.max for immediate release capsules
administered in the fasted state were 12.6, 11.3 and 11.5 ng
mL.sup.-1 mg.sup.-1 bexagliflozin for capsules containing 6.7, 16.7
and 34 mg bexagliflozin, respectively. The dose-normalized
C.sub.max for a 50 mg oral solution dosage administered in the
fasted state was 13.8 ng mL.sup.-1 mg.sup.-1 bexagliflozin. The
AUC.sub.0-t for a 50 mg oral solution, 2523 ng h mL.sup.-1, is
equivalent to 1009 ng h mL.sup.-1 for a 20 mg dosage strength. Thus
the U20 formulation provides a substantially lower dose-normalized
C.sub.max while decreasing the dose-normalized AUC.sub.0-t only
slightly compared to a rapidly absorbed oral solution.
[0272] The effects of prior consumption of food have been largely
consistent across multiple studies. In a dedicated food effect
study with a random sequence subject assignment, the geometric mean
C.sub.max following ingestion in the fed state was 175.7 ng
mL.sup.-1, compared to 133.7 ng mL.sup.-1 in the fasted state, or
131.4% of the fasted geometric mean C.sub.max. The AUC.sub.0-t and
AUC.sub.0-.infin. were also increased in the fed state, but by a
smaller proportion, 13.9% and 11.1%, respectively. The median
T.sub.max was 3.5 h following dosing in the fasted state and 5 h
following dosing in the fed state. In other studies in which a
comparison of pharmacokinetics was made following dosing in
different prandial states the median T.sub.max in the fasted state
was typically 3 h and the median T.sub.max in the fed state was
typically 5 h. Thus it is a benefit of the formulation of the
present invention that the effects of prior consumption of a high
fat, high calorie meal are relatively modest and that the
pharmacokinetic parameters measured after dosing in either prandial
state are not highly variable.
[0273] In some clinical pharmacology studies subjects were dosed in
the fed state, according to a protocol whereby the subjects fasted
for a minimum of 10 hours, then consumed a high calorie, high fat
meal within 30 minutes. They ingested U20 tablets 30 minutes after
the start of the meal, after which they did not consume additional
food for at least 4 h. The results from several studies of this
type are shown in the following table, presented as geometric mean
values.
TABLE-US-00032 Mass (n) C.sub.max (n) AUC.sub.0-t (n)
AUC.sub.0-.infin. (n) t.sub.1/2 (n) Study kg ng mL.sup.-1 ng h
mL.sup.-1 ng h mL.sup.-1 h F 76.1 (18) 159 (17) 1142 (18) 1205
(17*) 8.0 (17*) G 79.9 (16) 162 (15) 1056 (16) 1047 (15*) 12.2
(15*) H 77.1 (16) 159 (16) 969 (16) 1035 (16) 10.5 (16) I 71.7 (25)
176 (23) 1223 (23) 1276 (23*) 10.9 (23*) Total 75.6 (75) 165 (71)
1106 (71) 1165 (71) 10.1 (71) *a terminal elimination phase could
not be accurately estimated for some subjects
[0274] In a drug-drug interaction clinical pharmacology study the
effects of the GLP-1 receptor agonist exenatide on the
pharmacokinetics of bexagliflozin were studied in a randomized
crossover study. It is known that GLP-1 receptor agonists retard
gastric emptying and because the bexagliflozin dosage form has a
gastroretentive mechanism, the possibility that the retardation
would adversely affect bexagliflozin delivery was considered
important to address (see e.g., Guideline on the pharmacokinetic
and clinical evaluation of modified release dosage forms
(EMA/CPMP/EWP/280/96 Corr1) section 5.1.4.2.). In the study,
participants were assigned to either receive bexagliflozin alone
first, or combined treatment with bexagliflozin and exenatide
first. Each group received both treatments alternately, in a
crossover fashion (two-period, two-treatment crossover design),
with the two treatment periods separated by a 7-day washout period.
Systemic exposure, as measured by AUC.sub.0-t, AUC.sub.0-.infin.,
and C.sub.max of bexagliflozin following administration 30 min
after 10 .mu.g of exenatide were delivered by subcutaneous
injection, was increased by approximately 48%, 38%, and 25%,
respectively compared to bexagliflozin administration alone. The
ratio [with 90% confidence interval] of geometric least square
means for AUC.sub.0-t, AUC.sub.0-.infin., and C.sub.max of
bexagliflozin with exenatide to those of bexagliflozin alone were
147.50% [130.23%, 167.07%], 137.56% [122.28%, 154.75%], and 125.27%
[104.45%, 150.24%], respectively. Although the endpoints of the
confidence intervals fell outside of the range 80-125%, indicating
an interaction leading to a change in exposure when bexagliflozin
was administered following exenatide, the effect of exenatide on
bexagliflozin pharmacokinetics was not so large as to jeopardize
patient safety or to provoke a recommendation for a change in
prescribing pattern. Intra-subject variability for the comparison
of bexagliflozin with exenatide to bexagliflozin alone was <22%
for the primary PK parameters AUC.sub.0-t and AUC.sub.0-.infin.,
and approximately 32% for C.sub.max. Absorption was delayed when
bexagliflozin was administered 30 minutes after exenatide
injection, with a median T.sub.max of 5.00 hours post-dose compared
to 2.00 hours post-dose following administration of bexagliflozin
alone.
Example 15
Population Pharmacokinetic Modeling
[0275] Sparse sampling of the plasma drug concentrations obtained
from large diverse populations, combined with pharmacokinetic
modeling (population PK modeling), is a tool for exploring
potential influences (covariates) on the pharmacokinetics of a
drug. Samples for bexagliflozin population PK analysis were
obtained from healthy volunteers or diabetic subjects enrolled in
studies evaluating pharmacokinetics, from diabetic subjects
participating in a sparse sampling program to obtain specimens from
multicenter, international clinical trials, from subjects with
moderate hepatic impairment and from hypertensive subjects
participating in an open label run-in phase (a phase during which
all subjects received bexagliflozin). Participants were recruited
from North America, Europe and East Asia. The database for analysis
contained 884 subjects with 6247 concentration records. The
analysis included participants exposed to the T3, T10, T30 and T90
formulations as well as the U5, U10 and U20 formulations. Most of
the subjects were exposed to the U20 formulation. Subjects who
consented to participate in the sparse sampling program contributed
3 blood samples drawn at variable numbers of hours after dosing,
typically six to eight weeks after dosing had begun. Study data
included dosing histories (dosage strength, dates and times of
dosing), plasma concentrations with corresponding sample collection
dates and times, demographic descriptors, laboratory values and
concomitant medication records. The model initially contained terms
for prandial state, age, weight, body mass index (BMI), body
surface area, albumin, alanine transaminase, aspartate
transaminase, bilirubin, creatinine clearance, dose, sex, race,
disease status, nation and concomitant medications.
[0276] The data were well fit by a transit compartment model for
the absorption phase coupled with a typical central and peripheral
two compartment model for the elimination phase. The
inter-individual variations in the absorption rate constant,
clearance and central compartment volume were taken to be
log-normally distributed, although the actual distributions had
fatter tails. Overall, the final PPK model described the observed
data very well. Body mass, creatinine clearance, prandial state and
Asian race were significant in the PPK model. Heavier patients were
found to have lower exposure, whereas reduced creatinine clearance
was associated with higher exposure. The fed state was found to
lower the C.sub.max, but AUC and C.sub.min were similar to those
observed after ingestion in the fasted state. The population PK
estimate of the food effect was opposite to that of the definitive
food effect study, and by-study analysis of data from the
population PK study indicated that the food effect study data
appeared to deviate from that of the population as a whole. Asian
race was associated with higher C.sub.max and clearance.
[0277] The population PK simulations for the reference population,
consisting of healthy Caucasians, produced a median C.sub.max of
112 ng mL.sup.-1 and a median C.sub.min of 14 ng mL.sup.-1, for a
C.sub.max to C.sub.min ratio of 7.67 and a median 24 h AUC at
steady state of 1023 ng h mL.sup.-1. Simulation values for a
diabetic Caucasian population produced median values approximately
10% lower with a C.sub.max to C.sub.min ratio of 7.66. The first
and third quartiles for C.sub.min for the latter population were
10.6 and 20.2 ng mL.sup.-1, above the target concentration of 10 ng
mL.sup.-1 (approximately 10.times. the in vitro IC.sub.50). A
C.sub.min.gtoreq.10 ng mL.sup.-1 and a C.sub.max to C.sub.min ratio
of less than 10 were design objectives for the prolonged release
formulation development program.
Example 16
Clinically Acceptable Solid Dosage Forms
[0278] The inventors have provided tablet compositions and methods
of manufacture that ensure that the extended release formulations
of the invention consistently behave according to rigorous and
well-accepted standards for in vitro dissolution testing. Not all
aspects of a formulation's in vivo behavior can be captured by in
vitro testing, however. If a different formulation is designed to
impart similar characteristics to the formulation through a
materially different composition, or by a different principle or
principles for achieving extended release, the in vivo properties
can be confirmed to be similar by formal bioequivalence testing.
Such testing ensures that the rate and extent of absorption are not
significantly or objectionably altered by the new composition.
[0279] Gastroretentive tablets of the U5, U10 and U20 formulations
have been tested and found to produce statistically significant
treatment effects in large scale randomized controlled trials in
human diabetes patients. To ensure that further formulations
provide similar therapeutic benefits, to be clinically acceptable
each batch of tablets destined for human consumption should pass
formal dissolution acceptance testing by the three-level process
described above (i.e., as documented in USP <711> Acceptance
Table 2) with not more than 17% bexagliflozin release by 1 h,
between 23% and 43% bexagliflozin release by 3 h, between 45% and
75% bexagliflozin release by 5 h, and not less than 80%
bexagliflozin release by 8 h in a test method based on USP
Apparatus 1 initially charged with 900 mL of 0.1 N HCl and
maintained at 37.+-.0.5.degree. C. with a stirring rate of 50
rpm.
[0280] If any substantial change in the formulation is made, in
addition to passing these formal dissolution acceptance testing
criteria, the tablets must be shown to exhibit in vivo
bioequivalence with a reference batch of clinically acceptable
tablets for at least the C.sub.max and AUC.sub.0-t parameters.
[0281] A formulation is clinically acceptable if it either (i) has
been shown to be clinically effective for the treatment of a
disease or condition and is produced in a well-controlled and
pre-specified manner by adhering to acceptable ranges for
ingredients and processes of manufacture and that passes formal
dissolution acceptance testing or (ii) deviates from the original
manufacturing ranges for ingredients and/or process of manufacture
but that passes formal dissolution acceptance testing and, in
addition, is shown to be bioequivalent with the original
formulation. The invention encompasses all such clinically
acceptable oral solid dosage forms.
[0282] The following criteria (from FDA's March 2014 Guidance for
Industry: CMC Postapproval Manufacturing Changes To Be Documented
in Annual Reports, Appendix B) illustrate the degree of
modification to the formulations which, under ordinary
circumstances, would not require a documentation of bioequivalence.
In addition, certain other changes may be acceptable as provided in
Appendix A of the Guidance. [0283] 1. Any change made to comply
with the official compendium for the U20 formulation, once
specified, except relaxation of an acceptance criterion or deletion
of a test. [0284] 2. Complete or partial deletion of an ingredient
intended to affect only the color, flavor, or fragrance of the
formulation without change in other approved specification. [0285]
3. Change in nonrelease controlling excipients, expressed as
percentage (w/w) of total formulation approved in the original
application, less than or equal to the following percent ranges:
Filler (lactose monohydrate, MCC).+-.5%, Lubricant (magnesium
stearate).+-.0.25%, Glidant (colloidal silicon dioxide).+-.0.1%,
and Film Coat (Opadry II blue).+-.1%. [0286] 4. Change in the
supplier of an excipient, if the technical grade and specification
for the excipient remain the same. [0287] 5. Changes in
release-controlling excipients (polyethylene oxide, poloxamer 188,
glyceryl dibehenate) less than or equal to 5% expressed as a
percentage (w/w) of total release-controlling excipients in U20.
After the change, the total weight of the dosage form and its
specification should remain the same as U20.
[0288] It will be understood that the invention is described above
by way of example only and modifications may be made while
remaining within the scope and spirit of the invention.
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