`c19) United States
`
`c12) Patent Application Publication
`
`US 2012/0087978 Al
`c10) Pub. No.:
`(43) Pub. Date: Apr. 12, 2012
`Nause
`
`
`
`US 20120087978Al
`
`
`
`I IIIII IIIIIIII II llllll lllll lllll lllll lllll lllll lllll lllll lllll lllll lllll 111111111111111111
`
`(54)DOSAGE FORMS OF APIXABAN
`
`
`
`Publication Classification
`
`(51)Int. Cl.
`
`
`(75)Inventor:Richard G. Nause, Morristown, NJ
`A61K 31/437
`(US)
`
`C07D 471/04
`
`(73)Assignees:BRISTOL-MYERS SQUIBB
`
`
`COMPANY, Princeton, NJ (US);
`PFIZER INC., New York, NY (US)
`
`A61K 9/28
`
`A61P 7102
`
`B82Y 5100
`
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2011.01)
`
`(21)Appl. No.:13/378,236
`
`(22)PCT Filed:Jun. 15, 2010
`
`(52)U.S. Cl.... 424/465; 514/303; 424/400; 546/120;
`
`
`
`977/773; 977/915
`
`(86)PCT No.: P CT /US2010/038660
`(57)
`
`ABSTRACT
`
`§371 (c)(l),
`
`(2), ( 4) Date:Dec. 14, 2011
`
`The present invention relates to a Factor Xa inhibitor dosage
`
`
`
`
`
`
`
`
`form comprising apixaban in a solubility-improved form
`
`
`
`
`wherein the dosage form provides controlled release of apixa­
`
`
`
`ban and methods for preventing or treating venous throm­
`
`
`
`boembolisms, deep vein thrombosis and acute coronary syn­
`
`
`(60) Provisional application No. 61/187,442, filed on Jun.
`drome with said dosage form.
`16, 2009.
`
`
`
`
`
`Related U.S. Application Data
`
`BMS 2011
`MYLAN v. BMS
`IPR2018-00892
`
`

`

`Apr. 12, 2012 Sheet 1 of 9
`
`Patent Application Publication
`
`
`
`
`
`US 2012/0087978 Al
`
`FIG� 1
`
`

`

`Apr. 12, 2012 Sheet 2 of 9
`
`
`Patent Application Publication
`
`US 2012/0087978 Al
`
`
`
`20
`
`30
`\
`
`\ :I
`
`l
`i
`
`FilG .. 3
`
`""-., ...,
`
`,
`·�33
`
`.32
`
`

`

`Apr. 12, 2012 Sheet 3 of 9
`
`Patent Application Publication
`
`
`
`
`
`US 2012/0087978 Al
`
`FIG» 4
`
`42
`
`

`

`
`
`Patent Application Publication
`
`Apr. 12, 2012 Sheet 4 of 9 US 2012/0087978 Al
`
`
`
`52
`
`

`

`Apr. 12, 2012 Sheet 5 of 9
`
`
`Patent Application Publication
`
`US 2012/0087978 Al
`
`
`
`F ........ , .. 1·,·G· ... ·· a.··.
`
`. : . .
`.
`
`. . .
`
`: (_. _·::·: � ;_: _:··-.
`
`a:o .. •· \J>._.·_
`
`t
`
`) ' . .,l,
`
`i
`
`�"""'
`�%
`
`

`

`Apr. 12, 2012 Sheet 6 of 9
`
`Patent Application Publication
`
`
`
`
`
`US 2012/0087978 Al
`
`FIG, 7
`
`11
`
`l .-...:�,
`
`74
`
`

`

`
`
`Patent Application Publication
`
`Apr. 12, 2012 Sheet 7 of 9 US 2012/0087978 Al
`
`
`
`

`

`
`
`Patent Application Publication
`
`Apr. 12, 2012 Sheet 8 of 9 US 2012/0087978 Al
`
`
`
`0�----
`
`� --------
`
`� --------
`
`� ---�
`1 ::Jm�: Mtt) ·r .::t�;�t
`
`(�
`
`

`

`
`Apr. 12, 2012 Sheet 9 of 9
`
`Patent Application Publication
`
`US 2012/0087978 Al
`
`
`
`t300
`r
`
`f
`r
`r
`r
`r
`r
`r
`�2(.(,i
`r
`
`r
`r
`r
`r
`
`rr r
`
`f
`r· H'.t!
`
`r
`r
`r
`r
`
`f'·· ..........................................................................................
`;························································· ... ······························:.,(�
`
`
`*
`if i
`[!J
`
`r
`
`.. t.. [
`
`

`

`
`
`US 2012/0087978 Al
`
`Apr. 12, 2012
`
`1
`
`DOSAGE FORMS OF APIXABAN
`
`BACKGROUND OF THE INVENTION
`
`[0004] There is a continuing need to find safe, effective
`
`
`
`
`
`
`methods of delivering Factor Xa inhibitors including abixa­
`ban.
`
`SUMMARY OF INVENTION
`
`Xa inhibi­to a Factor [0001] The present invention relates
`
`
`
`
`to a solubility­[0005] The present invention is directed
`
`
`
`
`
`tor dosage form comprising Apixaban in a solubility-im­
`
`
`
`improved form of apixaban wherein the dosage form provides
`
`
`proved form wherein the dosage form provides controlled
`design ated the A dosage form.
`
`
`controlled release of apixaban,
`
`
`
`
`release of Apixaban and methods for preventing or treating
`
`
`[0006] A preferred aspect of the A dosage form is a con­
`
`
`venous thromboembolisms, deep vein thrombosis and acute
`
`
`
`trolled release dosage form that releases in vivo or in vitro 70
`
`
`coronary syndrome with said dosage form.
`
`
`wt% of apixaban over 2 hours or more after administration of
`
`
`
`role is [0002] Activated Factor Xa, whose major practical
`
`
`the dosage form to an aqueous environment of use.
`
`
`
`
`the generation of thrombin by the limited proteolysis of pro­
`
`
`
`of the A dosage form, des­[0007] Another preferred aspect
`
`
`
`
`thrombin, holds a central position that links the intrinsic and
`
`
`
`ignated the B dosage form, is an osmotic controlled release
`
`
`
`extrinsic activation mechanisms in the final common pathway
`dosage form.
`
`
`
`of blood coagulation. The generation of thrombin, the final
`[0008] A preferred aspect of the B dosage form, designated
`
`
`
`
`
`
`
`serine protease in the pathway to generate a fibrin clot, from
`
`
`
`the C dosage form, is a bilayer osmotic controlled release
`
`
`
`its precursor is amplified by formation of prothrombinase
`dosage form.
`
`complex (Factor Xa, Factor V, Ca 2+ and phospholipid).
`of the A dosage form is a [0009] Another preferred aspect
`
`
`
`
`
`
`
`
`
`Since it is calculated that one molecule of Factor Xa can dosage form wherein following administration to an in vivo
`
`
`use environment, the dosage form provides a plasma concen­
`
`
`
`
`generate 138 molecules of thrombin inhibition, Factor Xa
`
`
`
`tration of apixaban of about 70 ng/mL or more for a period of
`
`
`
`may be more efficient than inactivation ofthrombin in inter­
`about 12 hours or more.
`
`
`
`
`
`rupting the blood coagulation system. Accordingly, Factor Xa
`of the A dosage form is [001 OJ Yet another preferred aspect
`
`
`
`
`
`
`inhibitors are a class of compounds that are efficacious for the
`
`
`a dosage form wherein the solubility-improved form is
`
`
`treatment ofthromboembolic disorders.
`
`
`selected from the group consisting of a solid amorphous
`by [0003] U.S. Pat. No. 6,967,208 (hereby incorporated
`
`
`
`
`
`
`
`dispersion, lipid vehicle comprising apixaban, a solid adsor­
`
`
`
`
`
`reference) discloses a series of Factor Xa inhibitors including
`
`
`
`
`bate comprising apixaban adsorbed onto a substrate, nano­
`
`
`
`1 H-Pyrazolo[3,4-c ]pyridine-3-carboxamide,4,5,6, 7-tetrahy­
`
`
`
`
`
`particles, adsorbates of apixaban in a crosslinked polymer, a
`
`
`
`
`dro-1-( 4-methoxyphenyl)-7-oxo-6-[ 4-(2-oxo-l-piperidinyl)
`
`
`nanosuspension, a supercooled form, an apixaban/cyclodex­
`
`
`phenyl]-; alternatively named as 1-(4-methoxyphenyl)-7-
`
`
`trin drug form, a softgel form, a self-emulsifying form, a
`
`
`
`oxo-6-[ 4-(2-oxopiperidin-l-yl)phenyl]-4,5,6, 7-tetrahydro-
`
`
`
`
`
`three-phase apixaban form, a crystalline highly soluble form,
`
`
`l H-pyrazolo[3 .4-c ]pyridine-3-carboxamide (hereinafter
`
`
`
`
`a high-energy crystalline form, a hydrate or solvate crystal­
`
`
`
`
`referred to as apixaban). The structure of apixaban is
`
`
`line form, an amorphous form, a mixture of apixaban and a
`
`
`
`
`
`solubilizing agent, and a solution of apixaban dissolved in a
`liquid.
`of the A dosage form, [0011] Yet another preferred aspect
`
`
`
`
`
`designated the D dosage form is a dosage form wherein said
`
`solubility-improved form is a solid amorphous dispersion
`
`
`comprising apixaban and a polymer.
`
`
`[0012] A preferred aspect of the D dosage form is a dosage
`
`
`
`form wherein the solid amorphous dispersion is a spray-dried
`dispersion.
`
`[0013] A preferred aspect form of the C dosage form, des­
`
`
`
`ignated the E dosage form, is a dosage form wherein the
`
`
`
`
`osmotic controlled release dosage form comprises a solid
`
`
`
`
`amorphous dispersion comprising apixaban and a polymer.
`
`
`[0014] A preferred aspect of the E dosage form, designated
`
`the F dosage form, is a dosage form wherein the solid amor­
`
`
`
`
`phous dispersion comprising apixaban and a polymer is a
`
`
`
`U.S. Pat. No. 6,967,208 discloses that the compounds of the
`
`spray-dried dispersion.
`
`
`invention may be administered in the form of a pharmaceu­
`
`
`[0015] A preferred aspect of the F dosage form, designated
`
`
`tical composition comprising at least one of the compounds,
`
`the G dosage form, is a dosage form wherein the osmotic
`
`
`
`
`
`together with a pharmaceutically acceptable vehicle, diluent,
`
`
`
`
`controlled release dosage form comprises a bilayer tablet
`
`
`
`
`
`or carrier. For oral administration a pharmaceutical compo­comprising an orifice.
`
`
`
`
`
`
`aspect of the G dosage form is a dosage sition can take the form of solutions, suspensions, tablets, [0016] A preferred
`
`
`
`form wherein following administration to an in vivo use envi­
`
`
`
`pills, capsules, powders and the like. Apixaban has been
`
`
`
`ronment, the dosage form provides a plasma concentration of
`
`
`provided as a twice daily administration. WO 2007/022165
`
`
`apixaban of about 70 ng/mL or more for a period of about 12
`
`
`
`
`discloses an injectable Factor Xa (e.g., apixaban) formula­
`hours or more.
`
`
`
`tion. WO 2006079474 and W02008066102 disclose sus­
`of the A dosage form, preferred aspect tained release Factor Xa inhibitor formulations. [0017] Yet another
`
`
`
`
`
`
`
`
`
`
`
`
`
`W02008031782 discloses modified release Formulations of designated the H dosage form, is a dosage form wherein the
`
`
`
`
`
`
`
`Factor Xa inhibitors. Further pharmaceutical dosage forms controlled release dosage form is a matrix controlled release
`
`are described in EP 1653926.
`dosage form.
`
`

`

`
`
`US 2012/0087978 Al
`
`Apr. 12, 2012
`
`2
`
`con­[0018] A preferred aspect of the H dosage form is a dosage [0029] FIG. 8 is a graph of median plasma apixaban
`
`
`
`
`
`
`
`
`form wherein the matrix controlled release dosage form com­
`
`
`
`
`centration-time profiles following single oral doses for dif­
`
`
`
`
`
`prises a solid amorphous dispersion comprising apixaban and
`
`
`ferent formulations of apixaban.
`
`
`
`a polymer and the solid amorphous dispersion is a spray-dried
`[0030] FIG. 9 is a graph of individual and geometric mean
`
`
`dispersion.
`
`
`
`plasma Apixaban AUCinf values following administration of
`
`[0019] A preferred aspect of the A dosage form is a dosage
`
`
`
`different formulations of apixaban.
`
`
`
`form having an in-vitro dissolution rate, wherein the in-vitro
`[0031] FIG.10 is a graph ofindividual and geometric mean
`
`
`
`
`dissolution rate is wherein less than about 10 wt % apixaban
`
`
`plasma Cmax values following administration of different
`
`
`is released by one hour, about 20 wt % apixaban to about 40
`
`formulations of apixaban.
`
`
`wt % apixaban is released by four hours, about 60 wt %
`
`
`
`apixaban to about 80 wt% apixaban is released at about eight
`
`
`
`hours, and more than about 70 wt % apixaban is released at
`DETAILED DESCRIPTION OF THE PREFERRED
`
`ten hours.
`EMBODIMENTS
`[0020] A preferred aspect of the A dosage form is a dosage
`
`
`
`
`
`form having an in-vitro dissolution rate, wherein the in-vitro
`release a controlled [0032] The present invention provides
`
`
`
`
`
`
`dissolution rate is wherein less than about 20 wt % apixaban
`
`dosage form comprising apixaban in a solubility-improved
`
`
`is released by one hour, about 20 wt % apixaban to about 40
`
`
`
`form. As used herein, by "immediate release" is meant that at
`
`
`wt % apixaban is released by two hours, about 50 wt %
`
`
`
`least 70 wt % of a compound initially present in the dosage
`
`
`
`apixaban to about 7 5 wt % apixaban is released at about four
`
`
`
`form is released within one hour or less following introduc­
`
`
`
`hours, and more than about 70 wt % apixaban is released at six
`
`
`
`tion to a use environment. By "controlled release" is meant
`hours.
`
`
`that apixaban is released at a rate that is slower than imme­
`of the A dosage form is [ 0021] Yet another preferred aspect
`
`
`
`
`
`
`
`diate release i.e., less than 70 wt% of apixaban is released by
`
`
`
`a dosage form having an average release rate, wherein the
`
`
`
`(within) one hour following introduction to a use environ­
`
`
`
`average release rate of apixaban is from about 7 wt %/hr to
`
`
`ment. Specific embodiments can be in the form of a sustained
`about 10 wt %/hr.
`
`
`release oral dosage form, or, alternatively, in the form of a
`
`
`
`of the A dosage form is [0022] Yet another preferred aspect
`
`
`
`delayed release dosage form, or alternatively, in the form of
`
`
`
`a dosage form having an average release rate, wherein the
`
`
`an oral dosage form which exhibits a combination of sus­
`
`
`
`average release rate of apixaban is from about 11 wt %/hr to
`
`
`
`
`tained and delayed release characteristics. The term "con­
`about 18 wt %/hr.
`
`
`
`
`trolled" is generic to "sustained" and "delayed." Thus, "con­
`
`
`
`
`is a method for invention [0023] Yet another aspect ofthis
`
`
`
`
`
`
`trolled release" is intended to embrace sustained release and
`
`
`
`
`treating thromboembolic disorders comprising administering
`
`
`
`
`sustained release after a lag time of immediate release apixa­
`
`to a mammal in need of treatment any of the above dosage
`
`
`
`
`ban. Sustained release characteristics include dosage forms
`forms.
`
`
`
`
`that release apixaban according to zero-order, first-order,
`
`
`
`disorders are venous [0024] Preferred thromboembolic
`
`mixed-order or other kinetics.
`
`
`thromboembolism, deep vein thrombosis, acute coronary
`can either mean in [0033] Reference to a "use environment"
`
`
`syndrome and arterial thrombosis.
`
`
`
`
`
`
`
`vivo fluids, such as the GI tract, subdermal, intranasal, buccal,
`
`
`
`that apixaban [ 0025] By controlled release is meant broadly
`
`
`
`
`
`intrathecal, ocular, intraaural, subcutaneous spaces, vaginal
`
`
`is released at a rate that is slower than immediate release.
`
`
`
`
`tract, arterial and venous blood vessels, pulmonary tract or
`
`
`
`
`
`Controlled release is intended to embrace sustained release,
`
`
`
`intramuscular tissue of an animal, such as a mammal and
`
`
`
`
`
`delayed release and immediate release followed by sustained
`
`
`particularly a human, or the in vitro environment of a test
`
`
`
`
`release. Controlled release of apixaban may be accomplished
`
`
`
`solution, such as phosphate buffered saline (PBS), simulated
`
`
`by any means known in the pharmaceutical arts, including use
`
`
`
`
`intestinal buffer without enzymes (SIN), or a Model Fasted
`
`
`
`of osmotic controlled-release devices, matrix controlled-re­
`
`
`
`
`Duodenal (MFD) solution. An appropriate PBS solution is an
`
`
`lease devices, and multiparticulate controlled-release
`
`
`aqueous solution comprising 20 mN sodium phosphate
`devices.
`
`
`(Na2HP04), 47 mM potassium phosphate (KH2P04), 87 mM
`
`
`[0026] The solubility-improved form of apixaban is any
`
`NaCl, and 0.2 mM KC!, adjusted to pH 6.5 with NaOH. An
`
`
`
`form that is capable of supersaturating, at least temporarily, in
`
`
`
`
`appropriate simulated intestinal fluid-no enzyme (SIN)
`
`
`
`
`an aqueous use environment by a factor of about 1.25-fold or
`
`
`to pH 7.4 or 200 mM solution is 50 mM KH2P04 adjusted
`
`
`
`
`more, relative to the solubility of crystalline apixaban. That is,
`
`
`to pH 6.8. An appro­sodium phosphate (Na2HP04) adjusted
`
`
`the solubility-improved form provides a maximum dissolved
`
`
`
`priate MFD solution is the same PBS solution wherein addi­
`
`
`drug concentration (MDC) of apixaban in a use environment
`
`
`
`tionally is present 7 .3 mM sodium taurocholic acid and 1.4
`
`
`that is at least 1.25-fold the equilibrium drug concentration
`
`mM of l -palmitoyl-2-oleyl-sn-glycero-3-phosphocholine.
`
`
`
`provided by the crystalline form of apixaban alone.
`
`
`means, [0034] "Administration" to a use environment
`
`
`
`features, and [0027] The foregoing and other objectives,
`
`
`
`where the in vivo use environment is the GI tract, delivery by
`
`
`
`advantages of the invention will be more readily understood
`
`
`
`ingestion or swallowing or other such means to deliver the
`
`
`
`
`upon consideration of the following detailed description of
`
`
`drugs. One skilled in the art will understand that "adminis­
`
`
`the invention, taken in conjunction with the accompanying
`
`
`tration" to other in vivo use environments means contacting
`drawings.
`
`
`the use environment with the composition of the invention
`
`using methods known in the art. See for example,
`Remington:
`
`20'h Edition (2000).
`
`
`The Science and Practice of Pharmacy,
`
`
`
`
`
`
`refers is in vitro, "administration" Where the use environment [0028] FIGS. 1-7 are schematic drawings of cross sections
`
`
`
`
`
`of exemplary embodiments of dosage forms of the present to placement or delivery of the dosage form to the in vitro test
`invention.
`medium.
`
`
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`

`

`
`
`US 2012/0087978 Al
`
`
`
`Apr. 12, 2012
`
`3
`
`
`
`Release Rates
`
`[0041] Thus, the dosage forms of this invention have an
`
`and apixaban dosage forms, [0035] Release rates, suitable
`
`
`
`
`
`
`
`
`average rate of release of apixaban of less than about 70 wt
`
`
`solubility-improved forms are discussed in more detail
`
`
`%/hr. Preferably, the dosage forms of the present invention
`below.
`
`
`
`
`release apixaban at an average rate that is about 35 wt %/hr or
`
`
`less, more preferably about 23 wt %/hr or less, and even more
`
`
`
`preferably about 17 .5 wt %/hr or less. 1t is also preferred that
`
`
`
`
`the dosage forms of the present invention release apixaban at
`
`
`
`provide [0036] The dosage forms of the present invention
`
`
`
`an average rate that is about 2.9 wt %/hr or more, preferably
`
`
`
`controlled-release of apixaban in a solubility-improved form.
`
`about 3.5 wt %/hror more, more preferably about 3.9 wt %/hr
`
`
`
`
`As previously stated, "controlled release" is meant that apixa­
`or more.
`
`
`ban is released at a rate that is slower than immediate release
`
`
`
`
`
`
`i.e., less than 70 wt % of apixaban is released within one hour
`provides [0042] The dosage form of the present invention
`
`
`
`
`
`following introduction to a use enviromnent. As used herein,
`
`
`
`
`controlled release of apixaban relative to an immediate
`
`
`the rate of release of apixaban from a dosage form is charac­
`
`
`
`release control dosage form consisting of an equivalent
`
`
`
`
`
`terized by the percentage of apixaban initially present in the
`
`
`
`amount of apixaban in the same solubility-improved form
`
`
`
`
`dosage form that is released within one hour subsequent to
`
`
`dosed as an oral powder for constitution. ln one embodiment,
`
`administering the dosage form to a use enviromnent.
`
`
`when the use enviromnent is the Gl tract of a mammal, the
`
`dosage form provides a time to reach maximum drug concen­
`
`
`from the dosage forms of [0037] The release of apixaban
`
`
`
`admin­blood of the mammal following tration (Tm=) in the
`
`
`
`the present invention may be characterized in terms of the
`
`
`
`istration that is longer than the immediate release control
`
`
`
`time duration between introducing the dosage form to an
`
`
`dosage form. Preferably, the T blood is at least about max in the
`
`
`enviromnent of use and the time at which 70% of apixaban
`
`
`
`
`1 .25-fold longer than the immediate release control dosage
`
`
`
`
`has left the dosage form. Description of apixaban release rate
`
`
`
`form, preferably at least about 1.5-fold longer, and more
`
`is complicated by the fact that such dosage forms may have
`
`
`
`preferably at least about 2-fold longer. ln addition, the maxi­
`
`
`
`
`initial delay periods during which little or no release occurs,
`
`mum concentration of drug (Cmax) in the blood is less than or
`
`
`
`
`and may release apixaban according to zero-order, first-order,
`equal to 80%, and may be less than or equal to 65%, or even
`
`
`
`mixed-order or other kinetics. To avoid confusion, release
`
`
`imme­less than or equal to 50% of the Cby the max provided
`
`
`
`
`rates are described in terms of the time duration between
`dosage form. Both T max and Cmax may be
`
`diate release control
`
`
`dosing the dosage form to an enviromnent of use and the time
`
`
`
`compared in either the fed or fasted state, and the dosage form
`
`at which 70% of apixaban has left the dosage form. This
`
`meets the above criteria for at least one of, and preferably
`
`
`
`description applies to all dosage forms that release apixaban,
`
`both, the fed and fasted state.
`
`
`
`
`regardless of the shape of the percent released vs. time curve
`
`
`
`
`and is intended to embrace sustained release dosage forms as
`[0043] ln another aspect, the dosage forms of the present
`
`
`
`
`
`
`well as dosage forms that exhibit sustained release after an
`
`
`
`
`
`invention provide controlled release of apixaban which, after
`
`
`
`
`
`initial lag time. Thus, by "controlled release" of apixaban is
`
`
`
`
`
`oral dosing, elicit the following effects: a decrease of 20% or
`
`meant a dosage form that releases less than 70 wt % of
`
`more in mean plasma Cmax relative to a dosage form that
`
`
`
`apixaban initially present in the dosage form at 1 hour fol­
`
`
`
`provides immediate release of the same amount of the solu­
`
`
`lowing introduction to a use enviromnent. By "sustained
`
`
`bility-improved form ofapixaban after dosing for 8 weeks. In
`
`
`
`release" is meant a dosage form wherein apixaban is released
`
`
`other words, the dosage form, following administration to an
`
`
`slowly over time after administration to the use enviromnent.
`
`
`
`in vivo use enviromnent, provides a maximum drug concen­
`
`
`
`A dosage form that releases 70 wt % of apixaban initially
`
`tration in the blood that is less than or equal to 80% of the
`
`
`present in the dosage form over any 1 hour period following
`
`
`
`maximum drug concentration in the blood provided by a
`
`
`
`
`introduction to the use enviromnent is not considered to be a
`
`
`
`
`dosage form that provides immediate release of the same
`
`
`sustained release dosage form.
`
`amount of the solubility-improved form of said apixaban.
`
`
`[0044] The dosage forms of the present invention may be
`
`
`70% of [0038] ln one embodiment, the time to release
`
`
`
`dosed to a human subject in the fasted or fed state. 1t is
`
`
`
`
`apixaban initially present in the dosage form is at least about
`
`preferred that they be dosed in the fed state.
`
`
`
`
`2 hours, preferably at least about 3 hours, more preferably at
`least about 4 hours.
`release rates [0045] Preferred apixaban doses and apixaban
`
`
`
`
`
`
`from the dosage forms of this invention may be determined by
`
`
`
`from the dosage of apixaban [0039] However, the release
`
`
`
`pharmacokinetic (PK) modeling for apixaban, or by clinical
`
`
`form should not be too slow. Thus, it is also preferred that the
`
`
`
`
`experimentation (i.e. in human subjects or patients) as famil­
`
`
`
`
`time to release 70% of apixaban initially present in the dosage
`
`
`
`iar to those experienced in the art. PK modeling may also be
`
`form be about 24 hours or less, more preferably about 20
`
`
`apixaban doses and release used to predict Cmax for various
`
`
`hours or less, and most preferably about 18 hours or less.
`
`
`
`rates, in order to identify those doses and release rates that
`
`from the dosage form may [0040] The release of apixaban
`
`C
`
`
`will decrease by 20% or more, relative to an immediate
`
`
`
`
`also be characterized by an average rate of release of apixaban
`
`release dosage form at the same dose.
`
`
`per hour for a time period, defined as the wt % of apixaban
`
`
`in the dosage forms of [0046] ln one aspect, when apixaban
`
`
`present in the dosage form released during the time period
`
`
`
`
`the present invention, after oral dosing, elicit one or more of
`
`
`
`divided by the duration (in hours) of the time period. For
`
`
`the following effects: (a) plasma concentrations of apixaban
`
`
`
`
`example, if the dosage form releases 70 wt % of apixaban
`
`
`which exceed about 70 ng/ml, preferably about 1 1 0 ng/ml,
`
`
`initially present in the dosage form within 16 hours, the
`
`
`
`more preferably about 160 ng/ml, even more preferably about
`
`
`
`average rate of release of apixaban is 4.4 wt %/hr (70 wt %/16
`
`
`325 ng/ml for a period of around 12 hr or greater, preferably
`
`
`
`
`hours). While the average rate ofrelease may be calculated at
`
`
`
`16 hr or greater, more preferably about 24 hours or greater and
`
`
`
`any time period following introduction to the use environ­
`
`
`to(b) a decrease of20% or more in mean plasma Cmax relative
`
`
`ment, conventionally the time used is the time required to
`
`
`
`a dosage form that provides immediate release of the same
`
`
`
`
`
`release 70 wt % of apixaban initially present in the dosage
`
`amount of the solubility-improved form of apixaban.
`form.
`
`max
`
`

`

`
`
`US 2012/0087978 Al
`
`
`
`Apr. 12, 2012
`
`4
`
`medium is sufficient that a quantity of drug equivalent to at
`
`
`
`
`
`
`
`
`exemplary release [0047] Expressed as release rate profiles,
`
`
`
`least about 2-fold that in the dosage form will dissolve in the
`
`
`
`rates are wherein the in-vitro dissolution rate of a dosage form
`
`
`dissolution medium. In most cases apixaban is sufficiently
`
`
`
`
`is measured by the direct dissolution tests provided below.
`
`
`
`insoluble in aqueous media that a surfactant, such as sodium
`
`
`[0048] In one embodiment, an exemplary dosage form has
`
`
`
`lauryl sulfate or other excipients may be added to the disso­
`
`
`
`the release rate profile wherein less than about 10 wt %
`
`
`lution medium to raise the solubility of the drug and ensure
`
`
`
`apixaban is released by one hour, about 60 wt % apixaban to
`
`the dissolution medium acts as a sink for the drug(s).
`
`
`
`about 80 wt % apixaban is released at about eight hours, and
`
`
`
`more than about 70 wt% apixaban is released at ten hours.
`
`[0056] Thus, the following test (in vitro dosage form dis­
`
`
`
`[0049] Analogously, in another embodiment, an exemplary
`
`
`
`
`solution test) is that test (by definition) which is used to
`
`
`
`dosage form has the release rate profile wherein less than
`
`
`
`
`determine whether a dosage form provides a release profile
`
`
`about 10 wt% apixaban is released by one hour, about 20 wt
`
`
`
`within the scope of the present invention. In this test, a so­
`
`
`
`% apixaban to about 40 wt % apixaban is released by four
`
`
`
`
`called "direct" test, the dosage form is placed into a dissolu­
`
`
`
`tion medium at 3 7° C. simulating the contents of the intestine,
`
`
`
`hours, about 60 wt % apixaban to about 80 wt % apixaban is
`
`
`
`released at about eight hours, and more than about 70 wt %
`
`and specifically 50 mM KH2P04 at pH 7.4 or 200 mM
`
`
`apixaban is released at ten hours.
`
`
`NaH2P04 at pH 6.8 with 0.5% sodium laurel sulfate (SLS).
`[0050] Analogously, in another embodiment, an exemplary
`
`
`
`
`
`
`The medium is stirred using paddles that rotate at a rate of75
`
`
`
`dosage form has the release rate profile wherein less than
`
`rpm. When the dosage form is in the form of a tablet, capsule
`
`
`about 20 wt % apixaban is released by one hour, about 50 wt
`
`or other solid dosage form, the dosage form may be placed in
`
`
`
`% apixaban to about 75 wt% apixaban is released by four
`
`a wire support to keep the dosage form off of the bottom of the
`
`
`
`
`hours, and more than about 70 wt % apixaban is released at six
`
`
`
`flask, so that all of its surfaces are exposed to the dissolution
`hours.
`
`
`media. Samples of the dissolution medium are taken at peri­
`
`
`odic intervals using a VanKel V K8000 autosampling disso­
`[0051] Analogously, in another embodiment, an exemplary
`
`
`
`
`
`
`
`ette with automatic receptor solution replacement. The con­
`
`
`
`dosage form has the release rate profile wherein less than
`
`
`
`centration of dissolved drug in the dissolution medium is then
`
`
`about 20 wt % apixaban is released by one hour, about 20 wt
`
`
`determined by High Performance Liquid Chromatography
`
`
`
`% apixaban to about 40 wt % apixaban is released by two
`
`
`
`(HPLC), by comparing UV absorbance of samples to the
`
`
`
`hours, about 50 wt% apixaban to about 75 wt% apixaban is
`
`
`
`absorbance of drug standards. The mass of dissolved drug in
`
`
`
`released at about four hours, and more than about 70 wt %
`
`
`the dissolution medium is then calculated from the concen­
`
`
`apixaban is released at six hours.
`
`tration of drug in the medium and the volume of the medium,
`
`
`[0052] In terms of average release rate, in one embodiment,
`
`
`which value is used to calculate the actual amount of drug
`
`
`an exemplary dosage form provides an average rate of release
`
`
`released from the dosage form, taking into consideration the
`
`
`
`of apixaban that is at least about 8 wt %/hr. In another embodi­
`
`
`mass of drug originally present in the dosage form.
`
`
`
`ment, an exemplary dosage form provides an average rate of
`
`
`release ofapixaban that is from about 7 wt %/hr to about 10 wt
`
`[0057] While the above test is that test which is used to
`
`
`
`%/hr. In yet another embodiment, an exemplary dosage form
`
`
`
`determine a release rate profile of a dosage form of the present
`
`
`
`
`
`provides an average rate of release of apixaban that is from
`
`
`
`invention, the dosage forms of the present invention may also
`about 6 wt %/hr to about 13 wt %/hr.
`
`
`
`
`be evaluated using a "residual test," which is performed as
`
`
`follows. A plurality of dosage forms are each placed into
`
`
`
`
`an exemplary dosage [0053] In still another embodiment,
`
`
`
`
`
`
`separate stirred USP type 2 dissoette flasks containing 900
`
`
`
`
`
`form provides an average rate of release of apixaban that is at
`
`
`mL of a buffer solution at 37° C. simulating a gastric or
`
`
`
`least about 13 wt %/hr. In another embodiment, an exemplary
`
`
`
`intestinal environment. After a given time interval, a dosage
`
`
`
`dosage form provides an average rate of release of apixaban
`
`
`
`
`form is removed from a flask, released material is removed
`
`that is from about 11 wt %/hr to about 18 wt %/hr.
`
`from the surface of the dosage form, and the dosage form cut
`
`
`
`are dosed [0054] The dosage forms of the present invention
`
`
`
`
`in halfand placed in 100 mL ofa recovery solution as follows.
`
`
`
`
`preferably once daily ("QD"). The achievement ofthis aspect
`
`
`
`For the first two hours, the dosage form is stirred in 25 mL
`
`
`depends upon apixaban dose and apixaban release rate from
`
`
`
`
`
`acetone or other solvent suitable to dissolve any coating on
`the dosage form.
`
`
`the dosage form. Next, 125 mL of methanol is added and
`
`[0055] An in vitro test is used to determine whether a dos­
`
`
`
`
`
`stirring continued overnight at ambient temperature to dis­
`
`
`
`
`age form provides a release profile within the scope of the
`
`solve the drug remaining in the dosage form. Approximately
`
`
`present invention. In vitro tests are well known in the art. The
`
`
`
`
`2 mL of the recovery solution is removed and centrifuged, and
`
`
`in vitro tests are designed to mimic the behavior of the dosage
`
`
`250 mL of supernatant added to an HPLC vial and diluted
`
`
`form in vivo. One skilled in the art will understand that in such
`
`
`
`with 750 mL methanol. Residual drug is then analyzed by
`
`
`tests the dissolution medium need not act as a sink for the drug
`
`HPLC. The amount of drug remaining in the dosage form is
`
`
`
`in the dosage form. This is particularly true of osmotic dosage
`
`
`
`subtracted from the total drug initially present in the dosage
`
`
`forms where the rate at which undissolved drug extrudes from
`
`
`form to obtain the amount released at each time interval.
`
`
`
`
`the osmotic dosage form is not substantially affected by the
`
`[0058] Alternatively, an in vivo test may be used to deter­
`
`
`
`
`
`solubility of the drug in the dissolution medium. However, for
`
`
`
`mine whether a dosage form provides a drug release profile
`
`
`
`
`dosage forms that deliver the drug in the dissolved state, it is
`
`
`
`
`within the scope of the present invention. However, due to the
`
`
`preferred that a dissolution medium be chosen in which the
`
`
`
`inherent difficulties and complexity of the in vivo procedure,
`
`solubility of the drug in the medium times the volume of the
`
`
`it is preferred that in vitro procedures be used to evaluate
`
`
`media exceeds the total mass of drug dosed; that is, the media
`
`
`dosage forms even though the ultimate use environment is
`
`should act as a sink for the drug. By "sink" is meant that the
`
`
`often the human GI tract. The in vitro tests described above
`
`
`composition and volume of the dissolution medium is suffi­
`
`
`
`are expected to approximate in vivo behavior, and a dosage
`
`
`cient such that a quantity of drug alone equivalent to that in
`
`
`
`form that meets the in vitro release rates described herein are
`
`
`the dosage form will dissolve into the dissolution medium.
`
`
`within the scope of the invention. Dosage forms are dosed to
`
`
`Preferably, the composition and volume of dissolution
`
`

`

`
`
`US 2012/0087978 Al
`
`Apr. 12, 2012
`
`5
`
`
`
`
`
`Osmotic Controlled Release Devices
`
`
`
`a group oftest subjects, such as humans, and drug release and collection of devices known in the pharmaceutical arts that
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`drug absorption is monitored either by (1) periodically with­allow delivery of a drug in a controlled manner. Exemplary
`
`
`
`
`
`
`
`drawing blood and measuring the serum or plasma concen­devices include erodible and non-erodible matrix controlled­
`
`
`
`
`
`
`
`
`tration of drug or (2) measuring the amount of drug remaining release devices, osmotic controlled-release devices, and mul­
`
`
`
`in the dosage form following its exit from the anus (residual ti particulate controlled-release devices.
`
`drug) or (3) both (1) and (2). ln the second method, residual
`
`
`drug is measured by recovering the dosage form upon exit
`
`
`from the anus of the test subject and measuring the amount of
`form may be [0063] Apixaban in solubility-improved
`
`
`
`drug remaining in the dosage form using the same procedure
`
`
`
`
`
`incorporated into an osmotic controlled release device. Such
`
`
`
`described above for the in vitro residual test. The difference
`
`
`devices have at least t