U.S. patent application number 15/474236 was filed with the patent office on 2017-07-20 for apixaban formulations.
The applicant listed for this patent is Bristol-Myers Squibb Company, Pfizer Inc.. Invention is credited to Charles Frost, Jingpin Jia, Jatin Patel, Chandra Vemavarapu.
Application Number | 20170202824 15/474236 |
Document ID | / |
Family ID | 43901603 |
Filed Date | 2017-07-20 |
United States Patent
Application |
20170202824 |
Kind Code |
A1 |
Patel; Jatin ; et
al. |
July 20, 2017 |
APIXABAN FORMULATIONS
Abstract
Compositions comprising crystalline apixaban particles having a
D.sub.90 equal to or less than 89 .mu.m, and a pharmaceutically
acceptable carrier, are substantially bioequivalent and can be used
to for the treatment and/or prophylaxis of thromboembolic
disorders.
Inventors: |
Patel; Jatin; (West Windsor,
NJ) ; Frost; Charles; (Yardley, PA) ; Jia;
Jingpin; (Belle Mead, NJ) ; Vemavarapu; Chandra;
(Hillsborough, NJ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Bristol-Myers Squibb Company
Pfizer Inc. |
Princeton
New York |
NJ
NY |
US
US |
|
|
Family ID: |
43901603 |
Appl. No.: |
15/474236 |
Filed: |
March 30, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15086447 |
Mar 31, 2016 |
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15474236 |
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13579796 |
Oct 10, 2012 |
9326945 |
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PCT/US2011/025994 |
Feb 24, 2011 |
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15086447 |
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61308056 |
Feb 25, 2010 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/2054 20130101;
A61K 9/2095 20130101; A61K 31/4412 20130101; A61K 9/2018 20130101;
A61P 7/02 20180101; A61K 31/437 20130101; A61K 31/4545 20130101;
A61K 9/20 20130101; A61K 9/14 20130101; A61K 9/2013 20130101; A61K
9/48 20130101; A61K 31/4162 20130101; A61K 9/16 20130101; A61K
9/4833 20130101 |
International
Class: |
A61K 31/4545 20060101
A61K031/4545; A61K 9/48 20060101 A61K009/48; A61K 9/20 20060101
A61K009/20 |
Claims
1-9. (canceled)
10. A solid pharmaceutical composition comprising about 2.5 mg to
about 5 mg of apixaban and a pharmaceutically acceptable diluent or
carrier, wherein apixaban comprises crystalline apixaban, and
wherein, as measured using a USP Apparatus 2 at a paddle rotation
speed of 75 rpm in 900 mL of a dissolution medium at 37.degree. C.,
at least 77 wt % of apixaban in the solid pharmaceutical
composition dissolves within 30 minutes in the dissolution medium,
and the dissolution medium is 0.05 M sodium phosphate at a pH 6.8
containing 0.05% sodium lauryl sulfate.
11. The composition as defined in claim 10, wherein the crystalline
apixaban comprises Form N-1 of apixaban.
12. The composition as defined in claim 10, wherein apixaban is
granulated during preparation of the solid pharmaceutical
composition.
13. The composition as defined in claim 12, wherein apixaban is
granulated by dry granulation.
14. The composition as defined in claim 10, wherein the
pharmaceutical composition comprises 2.5 mg of apixaban.
15. The composition as defined in claim 10, wherein the
pharmaceutical composition comprises 5 mg of apixaban.
16. The composition as defined in claim 10, which is a tablet.
17. The composition as defined in claim 10, which is a capsule.
18. The composition as defined in claim 14, which is a tablet.
19. The composition as defined in claim 14, which is a capsule.
20. The composition as defined in claim 15, which is a tablet.
21. The composition as defined in claim 15, which is a capsule.
22. A solid pharmaceutical composition comprising about 2.5 mg to
about 5 mg of apixaban and a pharmaceutically acceptable diluent or
carrier, wherein, as measured using a USP Apparatus 2 at a paddle
rotation speed of 75 rpm in 900 mL of a dissolution medium at
37.degree. C., at least 77 wt % of apixaban in the solid
pharmaceutical composition dissolves within 30 minutes in the
dissolution medium, and the dissolution medium is 0.05 M sodium
phosphate at a pH 6.8 containing 0.05% sodium lauryl sulfate.
23. The composition as defined in claim 22, wherein apixaban is
granulated during preparation of the solid pharmaceutical
composition.
24. The composition as defined in claim 23, wherein apixaban is
granulated by dry granulation.
25. The composition as defined in claim 22, wherein the
pharmaceutical composition comprises 2.5 mg of apixaban.
26. The composition as defined in claim 22, wherein the
pharmaceutical composition comprises 5 mg of apixaban.
27. The composition as defined in claim 22, which is a tablet.
28. The composition as defined in claim 22, which is a capsule.
29. The composition as defined in claim 25, which is a tablet.
30. The composition as defined in claim 25, which is a capsule.
31. The composition as defined in claim 26, which is a tablet.
32. The composition as defined in claim 26, which is a capsule.
33. A tablet comprising about 2.5 mg to about 5 of apixaban and a
pharmaceutically acceptable diluent or carrier, wherein the tablet
exhibits a mean C.sub.max and/or AUC for apixaban upon
administration that is from 80% to 125% of a mean C.sub.max and/or
AUC, respectively, of a reference tablet comprising an equivalent
amount of apixaban and the pharmaceutically acceptable diluent or
carrier, and wherein the reference tablet is prepared using
crystalline apixaban particles having a D.sub.90 equal to about 30
.mu.m as a raw material.
34. The tablet as defined in claim 33, wherein, as measured using a
USP Apparatus 2 at a paddle rotation speed of 75 rpm in 900 mL of a
dissolution medium at 37.degree. C., at least 77 wt % of apixaban
in the tablet dissolves within 30 minutes in the dissolution
medium, and the dissolution medium is 0.05 M sodium phosphate at a
pH 6.8 containing 0.05% sodium lauryl sulfate.
35. The tablet as defined in claim 33, wherein the reference tablet
is prepared using dry granulation.
36. The tablet as defined in claim 33, wherein the crystalline
apixaban particles used in preparing the reference tablet comprise
Form N-1 of apixaban.
37. The tablet as defined in claim 33, wherein the tablet comprises
2.5 mg of apixaban.
38. The tablet as defined in claim 33, wherein the tablet comprises
5 mg of apixaban.
39. A capsule comprising about 2.5 mg to about 5 of apixaban and a
pharmaceutically acceptable diluent or carrier, wherein the capsule
exhibits a mean C.sub.max and/or AUC for apixaban upon
administration that is from 80% to 125% of a mean C.sub.max and/or
AUC, respectively, of a reference capsule comprising an equivalent
amount of apixaban and the pharmaceutically acceptable diluent or
carrier, and wherein the reference capsule is prepared using
crystalline apixaban particles having a D.sub.90 equal to about 30
.mu.m as a raw material.
40. The capsule as defined in claim 39, wherein, as measured using
a USP Apparatus 2 at a paddle rotation speed of 75 rpm in 900 mL of
a dissolution medium at 37.degree. C., at least 77 wt % of apixaban
in the capsule dissolves within 30 minutes in the dissolution
medium, and the dissolution medium is 0.05 M sodium phosphate at a
pH 6.8 containing 0.05% sodium lauryl sulfate.
41. The capsule as defined in claim 39, wherein the crystalline
apixaban particles used in preparing the reference capsule comprise
Form N-1 of apixaban.
42. The capsule as defined in claim 39, wherein the capsule
comprises 2.5 mg of apixaban.
43. The capsule as defined in claim 39, wherein the capsule
comprises 5 mg of apixaban.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 15/086,447, filed Mar. 31, 2016, which is a
continuation of U.S. patent application Ser. No. 13/579,796, now
U.S. Pat. No. 9,326,945, which was the National Stage of
International Application No. PCT/US2011/025994, filed Feb. 24,
2011, which claims the benefit of U.S. Provisional Application No.
61/308,056, filed Feb. 25, 2010. U.S. patent application Ser. Nos.
13/579,796 and 15/086,447 are incorporated herein by reference in
their entirety.
FIELD OF THE INVENTION
[0002] This invention relates to apixaban pharmaceutical
formulations comprising crystalline apixaban particles having a
maximum size cutoff, and methods of using them, for example, for
the treatment and/or prophylaxis of thromboembolic disorders.
BACKGROUND OF THE INVENTION
[0003] Apixaban is a known compound having the structure:
##STR00001##
[0004] The chemical name for apixaban is
4,5,6,7-tetrahydro-1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-1-piperidinyl)ph-
enyl]-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (CAS name) or
1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-1-piperidinyl)phenyl]-4,5,6,7-tetra-
hydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (IUPAC name).
[0005] Apixaban is disclosed in U.S. Pat. No. 6,967,208 (based on
U.S. application Ser. No. 10/245,122, filed Sep. 17, 2002), which
is herein incorporated by reference in its entirety, has utility as
a Factor Xa inhibitor, and is being developed for oral
administration in a variety of indications that require the use of
an antithrombotic agent.
[0006] The aqueous solubility (40 .mu.g/mL at all physiological pH)
of apixaban suggests that the tablets with less than 10 mg apixaban
(dose/solubility ratio=250 mL) should not demonstrate dissolution
rate limited absorption since dissolution rate limitations are only
expected when the dose/solubility ratio is greater than 250 mL.
Based on this dose and solubility consideration, the particle size
of the compound should not be critical for achieving consistent
plasma profiles, according to the prediction based on the
Biopharmaceutics Classification System (BCS; Amidon, G. L. et al.,
Pharmaceutical Research, 12: 413-420 (1995)). However, it was
determined that formulations that were made using a wet granulation
process as well as those using large particles of apixaban drug
substance resulted in less than optimal exposures, which can
present quality control challenges.
SUMMARY OF THE INVENTION
[0007] Surprisingly and unexpectedly, it has been found that
compositions for tablets comprising up to 5 mg, apixaban particles
having a D.sub.90 (90% of the volume) less than 89 microns (.mu.m)
lead to consistent in vivo dissolution in humans (at physiologic
pH), hence, consistent exposure and consistent Factor Xa inhibition
that will lead to consistency in therapeutic effect. Consistent
exposure is defined as that where in vivo exposure from tablets is
similar to that from a solution and not affected by the differences
in dissolution rates. The compositions were prepared using a dry
granulation process. Accordingly, the invention provides a
pharmaceutical composition comprising crystalline apixaban
particles having a D.sub.90 equal to or less than about 89 .mu.m,
as measured by laser light scattering method, and a
pharmaceutically acceptable diluent or carrier. It is preferred
that the apixaban particles in the composition have a D.sub.90 not
exceeding 89 .mu.m. It is noted the notation D.sub.x means that X %
of the volume of particles have a diameter less than a specified
diameter D. Thus, a D.sub.90 of 89 .mu.m means that 90% of the
volume of particles in an apixaban composition have a diameter less
than 89 .mu.m.
[0008] The range of particle sizes preferred for use in the
invention is D.sub.90 less than 89 .mu.m, more preferably D.sub.90
less than 50 .mu.m, even more preferably D.sub.90 less than 30
.mu.m, and most preferably D.sub.90 less than 25 .mu.m. The
particle sizes stipulated herein and in the claims refer to
particle sizes determined using a laser light scattering
technique.
[0009] The invention further provides the pharmaceutical
composition further comprising a surfactant from 0.25% to 2% by
weight, preferably from 1% to 2% by weight. As regards the
surfactant, it is generally used to aid in wetting of a hydrophobic
drug in a tablet formulation to ensure efficient dissolution of the
drug, for example, sodium lauryl sulfate, sodium stearate,
polysorbate 80 and poloxamers, preferably sodium lauryl
sulfate.
[0010] The invention further provides a method for the treatment or
prophylaxis of thromboembolic disorders, comprising administering
to a patient in need of such treatment or prophylaxis a
therapeutically effective amount of a composition comprising
crystalline apixaban particles having a D.sub.90 equal to or less
than about 89 .mu.m as measured by laser light scattering, and a
pharmaceutically acceptable carrier.
[0011] The present invention also provides a dry granulation
process for preparing a composition comprising crystalline apixaban
particles having a D.sub.90 equal to or less than about 89 .mu.m as
measured by laser light scattering, and a pharmaceutically
acceptable carrier.
[0012] The formulations of this invention are advantageous because,
inter alia, as noted above, they lead to consistent human in-vivo
dissolution. The invention is surprising in this respect, however,
in that exposures are variable even though apixaban has adequate
aqueous solubility that would allow the drug to dissolve rapidly.
That is, one would expect dissolution rate for a drug that has high
solubility (as defined by the Biopharmaceutical Classification
System) would not be limited by the particle size. It has
surprisingly been found, however, that the particle size that
impacts apixaban absorption rate is about a D.sub.90 of 89 .mu.m.
Thus, apixaban can be formulated in a composition having a
reasonable particle size using dry granulation process, to achieve
and maintain relatively fine particles to facilitate consistent in
vivo dissolution.
[0013] In a relative bioavailability study where various apixaban
formulations were evaluated, it was determined that formulations
made using a wet granulation process resulted in lower exposures
compared to the exposures obtained from a dry granulation process.
Additionally, tablets made using larger particles (D.sub.90 of 89
.mu.m) had lower exposures compared to tablets made using the same
process but with particle size of D.sub.90 of 50 .mu.m. In a dry
granulation process, water is not used during manufacturing to
develop granules containing apixaban and the excipients.
[0014] Formulations according to this invention, when dissolution
tested in vitro preferably exhibit the following dissolution
criteria. That is, the formulation exhibits dissolution properties
such that, when an amount of the drug equivalent to 77% therein
dissolves within 30 minutes. Usually the test result is established
as an average for a pre-determined number of dosages (e.g.,
tablets, capsules, suspensions, or other dosage form), usually 6.
The dissolution test is typically performed in an aqueous media
buffered to a pH range (1 to 7.4) observed in the gastrointestinal
tract and controlled at 37.degree. C. (.+-.1.degree. C.), together
maintaining a physiological relevance. It is noted that if the
dosage form being tested is a tablet, typically paddles rotating at
50-75 rpm are used to test the dissolution rate of the tablets. The
amount of dissolved apixaban can be determined conventionally by
HPLC, as hereinafter described. The dissolution (in vitro) test is
developed to serve as a quality control tool, and more preferably
to predict the biological (in vivo) performance of the tablet,
where in vivo-in vitro relationships (IVIVR) are established.
[0015] The term "particles" refers to individual drug substance
particles whether the particles exist singly or are agglomerated.
Thus, a composition comprising particulate apixaban may contain
agglomerates that are well beyond the size limit of about 89 .mu.m
specified herein. However, if the mean size of the primary drug
substance particles (i.e., apixaban) comprising the agglomerate are
less than about 89 .mu.m individually, then the agglomerate itself
is considered to satisfy the particle size constraints defined
herein and the composition is within the scope of the
invention.
[0016] Reference to apixaban particles having "a mean particle
size" (herein also used interchangeably with "VMD" for "volume mean
diameter") equal to or less than a given diameter or being within a
given particle size range means that the average of all apixaban
particles in the sample have an estimated volume, based on an
assumption of spherical shape, less than or equal to the volume
calculated for a spherical particle with a diameter equal to the
given diameter. Particle size distribution can be measured by laser
light scattering technique as known to those skilled in the art and
as further disclosed and discussed below.
[0017] "Bioequivalent" as employed herein means that if a dosage
form is tested in a crossover study (usually comprising a cohort of
at least 10 or more human subjects), the average Area under the
Curve (AUC) and/or the C.sub.max for each crossover group is at
least 80% of the (corresponding) mean AUC and/or C.sub.max observed
when the same cohort of subjects is dosed with an equivalent
formulation and that formulation differs only in that the apixaban
has a preferred particle size with a D.sub.90 in the range from 30
to 89 .mu.m. The 30 .mu.m particle size is, in effect, a standard
against which other different formulations can be compared. AUCs
are plots of serum concentration of apixaban along the ordinate
(Y-axis) against time for the abscissa (X-axis). Generally, the
values for AUC represent a number of values taken from all the
subjects in a patient population and are, therefore, mean values
averaged over the entire test population. C.sub.max, the observed
maximum in a plot of serum level concentration of apixaban (Y-axis)
versus time (X-axis) is likewise an average value.
[0018] Use of AUCs, C.sub.max, and crossover studies is, of course,
otherwise well understood in the art. The invention can indeed be
viewed in alternative terms as a composition comprising crystalline
apixaban particles having a mean particle size equal to or less
than about 89 .mu.m, as measured by Malvern light scattering, and a
pharmaceutically acceptable carrier, said composition exhibiting a
mean AUC and/or mean C.sub.max which are at least 80% of the
corresponding mean AUC and/or C.sub.max values exhibited by a
composition equivalent thereto (i.e., in terms of excipients
employed and the amount of apixaban) but having an apixaban mean
particle size of 30 .mu.m. Use of the term "AUC" for purposes of
this invention implies crossover testing within a cohort of at
least 10 healthy subjects for all compositions tested, including
the "standard" 30 .mu.m particle size composition.
[0019] The present invention may be embodied in other specific
forms without departing from the spirit or essential attributes
thereof. Thus, the above embodiments should not be considered
limiting. Any and all embodiments of the present invention may be
taken in conjunction with any other embodiment or embodiments to
describe additional embodiments. Each individual element of the
embodiments is its own independent embodiment. Furthermore, any
element of an embodiment is meant to be combined with any and all
other elements from any embodiment to describe an additional
embodiment. In addition, the present invention encompasses
combinations of different embodiment, parts of embodiments,
definitions, descriptions, and examples of the invention noted
herein.
BRIEF DESCRIPTION OF THE DRAWINGS
[0020] FIG. 1 is a scatter plot of individual dose-normalized
AUC(INF) values for solutions (CV185001, CV185006, and CV185007)
and tablets (CV185001 and CV185024) from CV185001, CV185006,
CV185007, and CV185024 Clinical Study Reports. The solid line
represents the geometric mean of AUC(INF) and the solid square
represents the average % in vitro dissolved at 30 minutes (using QC
method in Table 1.2C). The X-axis represents the dose administered.
For CV185024, 5 mg A=Apixaban Phase 2 tablet (86% dissolution)
2.times.2.5 mg (reference formulation), 5 mg B=Apixaban Phase 2
tablet (77% dissolution) 2.times.2.5 mg, 5 mg C=Apixaban Phase 3
tablet (89% dissolution) 2.times.2.5 mg.
[0021] FIG. 2 is scatter plot of individual dose-normalized
C.sub.max values for solutions (CV185001, CV185006, and CV185007)
and tablets (CV185001 and CV185024) from CV185001, CV185006,
CV185007, and CV185024 Clinical Study Reports. The solid line
represents the geometric mean of C.sub.max and the solid square
represents the average % in vitro dissolved at 30 minutes (using QC
method in Table 1.2C). The X-axis represents the dose administered.
For CV185024, 5 mg A=Apixaban Phase 2 tablet (86% dissolution)
2.times.2.5 mg (reference formulation), 5 mg B=Apixaban Phase 2
tablet (77% dissolution) 2.times.2.5 mg, 5 mg C=Apixaban Phase 3
tablet (89% dissolution) 2.times.2.5 mg.
[0022] FIG. 3 is a plot of dissolution rates of 2.5 mg apixaban
tablets using drug substance of different particle size.
[0023] FIG. 4 is a plot of dissolution rates of 5 mg apixaban
tablets using drug substance of different particle size.
DETAILED DESCRIPTION OF THE INVENTION
[0024] As previously stated, apixaban in any form which will
crystallize can be used in this invention. Apixaban may be obtained
directly via the synthesis described in U.S. Pat. No. 6,967,208
and/or US 2006/0069258 A1 (based on U.S. application Ser. No.
11/235,510, filed Sep. 26, 2005), herein incorporated by
reference.
[0025] Form N-1 (neat) and Form H2-2 (hydrate) of apixaban may be
characterized by unit cell parameters substantially equal to the
following shown in Table 1.
TABLE-US-00001 TABLE 1 Form N-1 H2-2 Solvate None Dihydrate T +22
+22 a (.ANG.) 10.233(1) 6.193(1) b (.ANG.) 13.852(1) 30.523(1) c
(.ANG.) 15.806(1) 13.046(1) .alpha., .degree. 90 90 .beta.,
.degree. 92.98(1) 90.95(1) .gamma., .degree. 90 90 V (.ANG..sup.3)
2237.4(5) 2466.0(5) Z' 1 1 Vm 559 617 SG P2.sub.1/n P2.sub.1/n
Dcalc 1.364 1.335 R 0.05 0.09 Sol. sites None 2 H.sub.2O Z'is the
number of molecules per asymmetric unit. T (.degree.C.) is the
temperature for the cryallographic data. Vm + V(unit
cell)/(ZZ')
Z' is the number of molecules per asymmetric unit. [0026]
T(.degree. C.) is the temperature for the crystallographic data.
[0027] Vm=V(unit cell)/(ZZ')
[0028] Characteristic X-ray diffraction peak positions (degrees
2.theta..+-.0.1) at room temperature, based on a high quality
pattern collected with a diffractometer (CuK.alpha.) with a
spinning capillary with 2.theta. calibrated with a NIST suitable
standard are shown in Table 2 below.
TABLE-US-00002 TABLE 2 Form N-1 Form H2-2 10.0 5.8 10.6 7.4 12.3
16.0 12.9 20.2 18.5 23.5 27.1 25.2
[0029] It will be appreciated by those skilled in the art of
manufacturing and granulation processes that there are numerous
known methods which can be applied to producing apixaban solid
dosage forms. The feature of this invention, however, involves
processes that produce apixaban dosage forms with an ability to
produce primary particles at the site of dissolution with a
D.sub.90<89 .mu.m. Examples of such methods include dry
granulation or wet granulation by low or high-shear techniques.
[0030] The dry granulation process that produces crystalline
apixaban particles having a mean particle size equal to or less
than about 89 .mu.m is believed to be novel, and is accordingly
provided as a further feature of the invention. Thus, the invention
provides a drug product manufacturing process, comprising the
following steps: [0031] (1) Blend the raw materials required prior
to granulation; [0032] (2) Granulate the raw materials from Step 1
using a dry or wet granulation process; [0033] (3) Blend the sized
granules from step 3 with extragranular raw materials; [0034] (4)
Compress the blend from Step 3 into tablets; and [0035] (5) Film
coat the tablets from step 4.
[0036] In another embodiment, the invention provides a drug product
manufacturing process, comprising the following steps: [0037] (1)
Blend the raw materials, with apixaban of controlled particle size;
[0038] (2) Include intragranular portions of binder, disintegrant
and other fillers in the mix from step (1); [0039] (3) Granulate
the materials from step (2) using process (3a) or (3b): [0040] (3a)
DRY GRANULATION: Delump the intragranular lubricant using a
suitable screen or mill. Add the lubricant to the blend from step
(2) and blend. Compact the lubricated blend to ribbons of density
in the range of 1.0 to 1.2 g/cc and size the compacted ribbons
using a roller compactor; or [0041] (3b) WET GRANULATION: Wet
granulate the composition from step (2) using water to a target end
point and optionally, size the wet-granules by passing through a
screen/mill. Remove water for granulation by drying in a convection
oven or a fluid-bed dryer. Size the dried granules by passing
through a screen/mill; [0042] (4) Blend the sized granules from
step (3) and the extragranular disintegrant in a suitable blender;
[0043] (5) Delump the extragranular lubricant using a suitable
screen/mill and blend with granules from step (4); [0044] (6)
Compress the blend from (5) into tablets; [0045] (7) Film coat the
tablets from step (6).
[0046] In a preferred embodiment, a dry granulation process is
employed.
[0047] In a preferred embodiment, the surfactant (SLS) in the
composition serves as a wetting aid for inherently hydrophobic
apixaban drug substance (contact angle=54.degree. with water),
further exacerbated as part of air-jet milling process that is used
to reduce apixaban particle size to the desired size.
[0048] The amount of apixaban contained in a tablet, capsule, or
other dosage form containing a composition of this invention will
usually be between 2.5 and 5 mg, usually administered orally twice
a day, although amounts outside this range and different
frequencies of administration are feasible for use in therapy as
well. As previously mentioned, such dosage forms are useful, inter
alia, in the prevention and/or treatment of thromboembolic
disorders, for example, deep vein thrombosis, acute coronary
syndrome, stroke, and pulmonary embolism, as disclosed in U.S. Pat.
No. 6,967,208.
[0049] As noted, average particle size can be determined by Malvern
light scattering, a laser light scattering technique. In the
examples below, the particle size for apixaban drug substance was
measured using a Malvern particle size analyzer.
[0050] Upon measurement completion, the sample cell was emptied and
cleaned, refilled with suspending medium, and the sampling
procedure repeated for a total of three measurements.
[0051] The dissolution test is performed in 900 mL of dissolution
medium at 37.degree. C., using USP Apparatus 2 (paddles) method at
a rotation speed of 75 rpm. Samples are removed after 10, 20, 30,
45, and 60 minutes from test initiation and analyzed for apixaban
by HPLC at 280 nm. 0.1 N HCl or 0.05 M sodium phosphate pH 6.8 with
0.05% SDS solution has been used as dissolution medium during
formulation development. While both methods serve the purposes as
quality control tests (with adequate discrimination ability), and
in establishing IVIVR, the latter was preferred from the standpoint
of method robustness. A role of SDS (surfactant) in the latter
dissolution medium is as a wetting aid to facilitate complete
dissolution of hydrophobic apixaban from tablets, rather than to
increase the solubility of apixaban. Dissolution data from both the
tests are included in this invention record and unless otherwise
specified, the results reported were averages of values from six
tablets.
[0052] Blood samples are drawn at predetermined time points
following drug administration as specified in the clinical study
protocol. Concentrations of the samples are measured using a
validated analytical method (Liquid Chromatography with Tandem Mass
Spectrometry). Individual subject pharmacokinetic parameters (e.g.,
C.sub.max, AUC, T-HALF) are derived by non-compartmental methods
using Kinetica.RTM. software from the time-concentration
profiles.
[0053] The invention is further exemplified and disclosed by the
following non-limiting examples:
[0054] Table 3 shows apixaban tablet compositions prepared using
the dry granulation process that were evaluated in the
bioequivalence (BE) study.
TABLE-US-00003 TABLE 3 Dry Granulation 5% w/w Drug Loaded
Granulation 20 mg Tablet Ingredients (% w/w) (mg/tablet)
Intragranular Apixaban 5.00 20.00 Lactose Anhydrous 49.25 197.00
Microcrystalline Cellulose 39.50 158.00 Croscarmellose Sodium 2.00
8.00 Magnesium Stearate 0.50 2.00 Sodium Lauryl Sulfate 1.00 4.00
Extragranular Croscarmellose Sodium 2.00 8.00 Magnesium Stearate
0.75 3.00 Total 100.00 mg 400 mg Film Coat 3.5 14.0 Total 103.5 mg
414 mg
[0055] Table 4 shows apixaban tablet compositions prepared using
the wet granulation process that were evaluated in the BE
study.
TABLE-US-00004 TABLE 4 Wet Granulation 5% w/w Drug Loaded
Granulation 20 mg Tablet Ingredients (% w/w) (mg/tablet)
Intragranular Apixaban 5.00 20.00 Lactose Monohydrate 70.00 280.00
Microcrystalline Cellulose 5.00 60.00 Croscarmellose Sodium 2.50
10.00 Povidone 4.50 18.00 Purified Water 17.40 69.60 Extragranular
Croscarmellose Sodium 2.50 10.00 Magnesium Stearate 0.50 2.09
Microcrystalline Cellulose 10.00 10.09 Total 100.00 400.00 Film
Coat 3.5 14.0 Total 103.5 mg 414.0
[0056] Table 5 and Table 5a show the dissolution data that
indicates that using a dry granulation process will result in
faster dissolution compared to that using a wet granulation
process. As shown in Table 5, the 20 mg tablets made using a dry
granulation process had 79% apixaban dissolved in 30 minutes versus
62% apixaban dissolved at 30 minutes for the 20 mg tablets made
using a wet granulation process. Dissolution test in 0.1 N HCl also
indicated a similar behavior of faster dissolution from tablets
made using dry granulation process (58% in 30 min), compared to wet
granulation process (45% in 30 min).
TABLE-US-00005 TABLE 5 % apixaban dissolved (USP II, 75 rpm, 0.05%
SLS in 50 mM phosphate, pH 6.8) Wet Granulation Dry Granulation
Time (minutes) 20 mg Tablets 20 mg Tablets 10 38 47 20 54 70 30 62
79 45 71 86 60 76 90 API Particle Size 83.8 83.8 D.sub.90
(.mu.m)
TABLE-US-00006 TABLE 5a % apixaban dissolved (USP II, 75 rpm, 0.1N
HCl) Wet Granulation Dry Granulation Time (minutes) 20 mg Tablets
20 mg Tablets 10 30 41 20 39 52 30 45 58 45 51 64 60 56 68 90 64 74
API Particle Size 83.8 83.8 D.sub.90 (.mu.m)
[0057] Table 6 and Table 6a provide the dissolution data from
tablets made with different manufacturing processes (wet and dry
granulation) and drug substance different particle sizes. As shown
Table 6, apixaban tablets that had 77% dissolved in 30 minutes or
86% dissolved in 30 minutes both had AUC values that met
bioequivalence criteria (Confidence Interval between 80% to 125%)
when compared to the tablets that had 89% dissolved at 30 minutes.
Similar rank order of the dissolution rates were observed for these
tablets (A, B & C) when tested in 0.1 N HCl.
TABLE-US-00007 TABLE 6 % apixaban dissolved (USP II, 75 rpm, 0.05%
SLS in 50 mM phosphate, pH 6.8) Wet Granulation Wet Granulation Dry
Granulation 2 .times. 2.5 2 .times. 2.5 mg 2 .times. 2.5 mg mg
Tablets Tablets Tablets Time (minutes) (A) (B) (C) 10 63 42 70 20
79 64 84 30 86 77 89 45 91 87 94 60 94 93 96 C.sub.max (ng/mL)
101.8 (21) 87.8 (24) 108.3 (24) AUC (INF) 1088 (32) 1030 (25) 1153
(26) (ng * hr/mL) Geomean (CV %) are presented for C.sub.max and
AUC (INF)
TABLE-US-00008 TABLE 6A % apixaban dissolved (USP II, 75 rpm, 0.1N
HCl) Wet Granulation Wet Granulation Dry Granulation 2 .times. 2.5
mg 2 .times. 2.5 mg 2 .times. 2.5 mg Tablets Tablets Tablets Time
(minutes) (A) (B) (C) 10 44 25 56 20 62 43 71 30 72 54 79 45 80 66
85 60 84 74 88 AUC (INF) 1088 (32) 1030 (25) 1153 (26) (ng * hr/mL)
Geomean (CV %) are presented for C.sub.max and AUC (INF)
[0058] The results of clinical studies demonstrated that, for
tablets with similar dissolution rates (89% and 86% at 30 min in pH
6.8 phosphate buffer containing 0.05% SLS), C.sub.max and AUC of
the coated Phase 3 tablet (C) relative to the uncoated Phase 2
tablet (A) met bioequivalence criteria. Tablets with different
dissolution rates (77% and 86% at 30 min) had similar AUCs, but did
not meet equivalence criteria for C.sub.max. The lower boundary of
the 90% confidence interval of the ratio of geometric mean
C.sub.max was 0.788, indicating the rate of absorption, as defined
by C.sub.max, was lower for the slower dissolving tablet (77% at 30
min). Since the oral bioavailability from these tablets is shown to
be comparable to that from solution (see FIGS. 1 and 2), this
dissolution rate (77% in 30 min) is defined as the threshold for
achieving consistent exposure.
[0059] FIGS. 3 and 4 illustrate the dissolution data that shows
that while particle size impacts dissolution, controlling the
particle size to less than 89 microns will result in a dissolution
rate that will ensure consistent in vivo exposures. As indicated in
FIGS. 3 and 4, consistent exposures are expected once apixaban
tablets have greater than 77% apixaban dissolved in 30 minutes.
Since the tablets with 89 microns have >77% dissolved at 30
minutes, these tablets will also exhibit exposures that are
equivalent to the exposures from tablets made with smaller
particles (such as the tablets with 10 micron particles shown
below). Whilst dissolution rate at an apixaban particle size of 119
microns is marginally greater than 77% in 30-min for the 5-mg
apixaban tablets (FIG. 4), the particle size threshold claimed is
less than 89 microns. This allows for the typical variability
(RSD=2 to 3%) in the dissolution results, such that the oral
bioavailability from tablets consistently matches that from
solution.
* * * * *