(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property Organization
`International Bureau
`
`(43) International Publication Date
`23 December 2010 (23.12.2010)
`
`PCT
`
`I lllll llllllll II llllll lllll lllll lllll llll I II Ill lllll lllll lllll 111111111111111111111111111111111
`
`(10) International Publication Number
`WO 2010/147978 Al
`
`(51) International Patent Classification:
`A61K 9100 (2006.01)
`A61K 311437 (2006.01)
`A61K 9116 (2006.01)
`A61P 7102 (2006.01)
`A61K 9128 (2006.01)
`
`(72) Inventor; and
`(75) Inventor/Applicant (for US only): NAUSE, Richard, G.
`[US/US]; Clo Pfizer Inc., Easton Point Rd., Ms 8156-21,
`Groton, CT 06340 (US).
`
`(21) International Application Number:
`PCT /US20 l 0/038660
`
`(74) Agents: OKUN, Janson, M. et al.; Fitzpatrick, Cella,
`Harper & Scinto, 1290 Avenue Of The Americas, New
`York, NY 10104-3801 (US).
`
`(22) International Filing Date:
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`15 June 2010 (15.06.2010)
`
`(81)
`
`English
`
`English
`
`Designated States (unless otherwise indicated, for every
`kind of national protection available): AE, AG, AL, AM,
`AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ,
`CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO,
`DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT,
`HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP,
`KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD,
`ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI,
`NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD,
`SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR,
`TT, TZ, VA, VG, US, UZ, VC, VN, ZA, ZM, ZW.
`
`(84) Designated States (unless otherwise indicated, for every
`kind of regional protection available): ARIPO (BW, GH,
`GM, KE, LR, LS, MW, MZ, NA, SD, SL, SZ, TZ, VG,
`
`(30) Priority Data:
`61/187,442
`
`(71)
`
`16 June 2009 (16.06.2009)
`
`us
`Applicants (for all designated States except US): PFIZ(cid:173)
`ER INC. [US/US]; 235 East 42nd Street, New York, NY
`lOOl 7 (US). BRISTOL-MYERS SQUIBB COMPANY
`[US/US]; Rt. 206 & Province Line Road, Princeton, NJ
`08543-4000 (US).
`
`=
`---- ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
`------------
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`;;;;;;;;;;;;;;; (54) Title: DOSAGE FORMS OF APIXABAN
`
`FIG. 1
`
`[Continued on next page]
`
`(57) Abstract: The present invention relates
`to a Factor Xa inhibitor dosage form compris(cid:173)
`ing apixaban in a solubility-improved form
`wherein the dosage form provides controlled
`release of apixaban and methods for prevent(cid:173)
`ing or treating venous thromboembolisms,
`deep vein thrombosis and acute coronary syn(cid:173)
`drome with said dosage form.
`
`- 12
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`3
`~
`
`II
`I
`
`I
`I
`
`\
`\
`15
`
`MYLAN EXHIBIT 1006
`
`6
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`;;;;;;;;;;;;;;;
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`;;;;;;;;;;;;;;;
`;;;;;;;;;;;;;;;
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`;;;;;;;;;;;;;;;
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`;;;;;;;;;;;;;;;
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`j
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`.
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`---- l~
`----
`----
`------------ 9~
`----
`----
`----
`--------
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`

`

`W 0 2010 /14 7 97 8 A 1 I lllll llllllll II llllll lllll lllll lllll llll I II Ill lllll lllll lllll 111111111111111111111111111111111
`
`ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, Published:
`TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK,
`-
`with international search report (Art. 21 (3))
`EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU,
`LV, MC, MK, MT, NL, NO, PL, PT, RO, SE, SI, SK,
`SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ,
`GW, ML, MR, NE, SN, TD, TG).
`
`

`

`WO 2010/147978
`
`PCT /US2010/038660
`
`DOSAGE FORMS OF APIXABAN
`
`BACKGROUND OF THE INVENTION
`
`The present invention relates to a Factor Xa inhibitor dosage form comprising
`
`5 Apixaban in a solubility-improved form wherein the dosage form provides controlled
`
`release of Apixaban and methods for preventing or treating venous thromboembolisms,
`
`deep vein thrombosis and acute coronary syndrome with said dosage form.
`
`Activated Factor Xa, whose major practical role is the generation of thrombin by
`
`the limited proteolysis of prothrombin, holds a central position that links the intrinsic and
`
`1 O extrinsic activation mechanisms in the final common pathway of blood coagulation. The
`
`generation of thrombin, the final serine protease in the pathway to generate a fibrin clot,
`
`from its precursor is amplified by formation of prothrombinase complex (Factor Xa, Factor
`
`V, Ca 2+ and phospholipid). Since it is calculated that one molecule of Factor Xa can
`
`generate 138 molecules of thrombin inhibition, Factor Xa may be more efficient than
`
`15
`
`inactivation of thrombin in interrupting the blood coagulation system. Accordingly, Factor
`
`Xa inhibitors are a class of compounds that are efficacious for the treatment of
`
`thromboembolic disorders.
`
`U.S. Patent No. 6,967,208 (hereby incorporated by reference) discloses a series of
`
`Factor Xa inhibitors including 1H-Pyrazolo[3,4-c]pyridine-3-carboxamide,4,5,6,7-
`
`20
`
`tetrahydro-1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-1-piperidinyl)phenyl]-; alternatively
`
`named as 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5,6, 7-
`
`tetrahydro-1 H-pyrazolo[3.4-c]pyridine-3-carboxamide (hereinafter referred to as
`
`apixaban). The structure of apixaban is
`NH2
`
`0
`
`0
`
`25
`
`

`

`WO 2010/147978
`
`PCT /US2010/038660
`
`U.S. Pat. No. 6,967,208 discloses that the compounds of the invention may be
`
`administered in the form of a pharmaceutical composition comprising at least one of the
`
`compounds, together with a pharmaceutically acceptable vehicle, diluent, or carrier. For
`
`oral administration a pharmaceutical composition can take the form of solutions,
`
`5
`
`suspensions, tablets, pills, capsules, powders and the like. Apixaban has been provided
`
`as a twice daily administration. WO 2007/022165 discloses an injectable Factor Xa (e.g.,
`
`apixaban) formulation. WO 2006079474 and W02008066102 disclose sustained release
`
`Factor Xa inhibitor formulations. W02008031782 discloses modified release
`
`Formulations of Factor Xa inhibitors. Further pharmaceutical dosage forms are described
`
`10
`
`in EP 1653926.
`
`There is a continuing need to find safe, effective methods of delivering Factor Xa
`
`inhibitors including abixaban.
`
`SUMMARY OF INVENTION
`The present invention is directed to a solubility-improved form of apixaban
`
`15 wherein the dosage form provides controlled release of apixaban, designated the A
`
`dosage form.
`
`A preferred aspect of the A dosage form is a controlled release dosage form that
`
`releases in vivo or in vitro 70 wt% of apixaban over 2 hours or more after administration
`
`of the dosage form to an aqueous environment of use.
`
`20
`
`Another preferred aspect of the A dosage form, designated the B dosage form, is
`
`an osmotic controlled release dosage form.
`
`A preferred aspect of the B dosage form, designated the C dosage form, is a
`
`bilayer osmotic controlled release dosage form.
`
`Another preferred aspect of the A dosage form is a dosage form wherein following
`
`25
`
`administration to an in vivo use environment, the dosage form provides a plasma
`
`concentration of apixaban of about 70 ng/ml or more for a period of about 12 hours or
`
`more.
`
`Yet another preferred aspect of the A dosage form is a dosage form wherein the
`
`solubility-improved form is selected from the group consisting of a solid amorphous
`
`30
`
`dispersion, lipid vehicle comprising apixaban, a solid adsorbate comprising apixaban
`
`adsorbed onto a substrate, nanoparticles, adsorbates of apixaban in a crosslinked
`
`polymer, a nanosuspension, a supercooled form, an apixaban/cyclodextrin drug form, a
`
`softgel form, a self-emulsifying form, a three-phase apixaban form, a crystalline highly
`
`-2-
`
`

`

`WO 2010/147978
`
`PCT /US2010/038660
`
`soluble form, a high-energy crystalline form, a hydrate or solvate crystalline form, an
`
`amorphous form, a mixture of apixaban and a solubilizing agent, and a solution of
`
`apixaban dissolved in a liquid.
`
`Yet another preferred aspect of the A dosage form, designated the D dosage form
`
`5
`
`is a dosage form wherein said solubility-improved form is a solid amorphous dispersion
`
`comprising apixaban and a polymer.
`
`A preferred aspect of the D dosage form is a dosage form wherein the solid
`
`amorphous dispersion is a spray-dried dispersion.
`
`A preferred aspect form of the C dosage form, designated the E dosage form, is
`1 o a dosage form wherein the osmotic controlled release dosage form comprises a solid
`amorphous dispersion comprising apixaban and a polymer.
`
`A preferred aspect of the E dosage form, designated the F dosage form, is a
`
`dosage form wherein the solid amorphous dispersion comprising apixaban and a
`
`polymer is a spray-dried dispersion.
`
`15
`
`A preferred aspect of the F dosage form, designated the G dosage form, is a
`
`dosage form wherein the osmotic controlled release dosage form comprises a bilayer
`
`tablet comprising an orifice.
`
`A preferred aspect of the G dosage form is a dosage form wherein following
`
`administration to an in vivo use environment, the dosage form provides a plasma
`
`20
`
`concentration of apixaban of about 70 ng/ml or more for a period of about 12 hours or
`
`more.
`
`Yet another preferred aspect of the A dosage form, designated the H dosage
`
`form, is a dosage form wherein the controlled release dosage form is a matrix controlled
`
`release dosage form.
`
`25
`
`A preferred aspect of the H dosage form is a dosage form wherein the matrix
`
`controlled release dosage form comprises a solid amorphous dispersion comprising
`
`apixaban and a polymer and the solid amorphous dispersion is a spray-dried dispersion.
`
`A preferred aspect of the A dosage form is a dosage form having an in-vitro
`
`dissolution rate, wherein the in-vitro dissolution rate is wherein less than about 10 wt%
`
`30
`
`apixaban is released by one hour, about 20 wt% apixaban to about 40 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 ten hours.
`
`

`

`WO 2010/147978
`
`PCT /US2010/038660
`
`A preferred aspect of the A dosage form is a dosage form having an in-vitro
`
`dissolution rate, wherein the in-vitro dissolution rate is wherein less than about 20 wt%
`
`apixaban is released by one hour, about 20 wt% apixaban to about 40 wt% apixaban is
`
`released by two hours, about 50 wt% apixaban to about 75 wt% apixaban is released at
`
`5
`
`about four hours, and more than about 70 wt% apixaban is released at six hours.
`
`Yet another preferred aspect of the A dosage form is a dosage form having an
`
`average release rate, wherein the average release rate of apixaban is from about 7
`
`wto/o/hr to about 10 wto/o/hr.
`
`Yet another preferred aspect of the A dosage form is a dosage form having an
`
`1 O
`
`average release rate, wherein the average release rate of apixaban is from about 11
`
`wto/o/hr to about 18 wto/o/hr.
`
`Yet another aspect of this invention is a method for treating thromboembolic
`
`disorders comprising administering to a mammal in need of treatment any of the above
`
`dosage forms.
`
`15
`
`Preferred thromboembolic disorders are venous thromboembolism, deep vein
`
`thrombosis, acute coronary syndrome and arterial thrombosis.
`
`By controlled release is meant broadly that apixaban is released at a rate that is
`
`slower than immediate release. Controlled release is intended to embrace sustained
`
`release, delayed release and immediate release followed by sustained release.
`
`20 Controlled release of apixaban may be accomplished by any means known in the
`
`pharmaceutical arts, including use of osmotic controlled-release devices, matrix
`
`controlled-release devices, and multiparticulate controlled-release devices.
`
`The solubility-improved form of apixaban is any form that is capable of
`
`supersaturating, at least temporarily, in an aqueous use environment by a factor of
`
`25
`
`about 1.25-fold or more, relative to the solubility of crystalline apixaban. That is, the
`
`solubility-improved form provides a maximum dissolved drug concentration (MDC) of
`
`apixaban in a use environment that is at least 1.25-fold the equilibrium drug
`
`concentration provided by the crystalline form of apixaban alone.
`
`The foregoing and other objectives, features, and advantages of the invention will
`
`30
`
`be more readily understood upon consideration of the following detailed description of
`
`the invention, taken in conjunction with the accompanying drawings.
`
`-4-
`
`

`

`WO 2010/147978
`
`PCT /US2010/038660
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`FIGS. 1 - 7 are schematic drawings of cross sections of exemplary embodiments
`
`of dosage forms of the present invention.
`
`Figure 8 is a graph of median plasma apixaban concentration-time profiles
`
`5
`
`following single oral doses for different formulations of apixaban.
`
`Figure 9 is a graph of individual and geometric mean plasma Apixaban AUCinf
`
`values following administration of different formulations of apixaban.
`
`Figure 10 is a graph of individual and geometric mean plasma Cmax values
`
`following administration of different formulations of apixaban.
`
`10
`
`DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
`
`The present invention provides a controlled release dosage form comprising
`
`apixaban in a solubility-improved form. As used herein, by "immediate release" is
`
`meant that at least 70 wt% of a compound initially present in the dosage form is
`
`15
`
`released within one hour or less following introduction to a use environment. By
`
`"controlled release" is meant that apixaban is released at a rate that is slower than
`
`immediate release i.e., less than 70 wt% of apixaban is released by (within) one hour
`
`following introduction to a use environment. Specific embodiments can be in the form of
`
`a sustained release oral dosage form, or, alternatively, in the form of a delayed release
`
`20
`
`dosage form, or alternatively, in the form of an oral dosage form which exhibits a
`
`combination of sustained and delayed release characteristics. The term "controlled" is
`
`generic to "sustained" and "delayed." Thus, "controlled release" is intended to embrace
`
`sustained release and sustained release after a lag time of immediate release apixaban.
`
`Sustained release characteristics include dosage forms that release apixaban
`
`25
`
`according to zero-order, first-order, mixed-order or other kinetics.
`
`Reference to a "use environment" can either mean in vivo fluids, such as the GI
`
`tract, subdermal, intranasal, buccal, intrathecal, ocular, intraaural, subcutaneous spaces,
`
`vaginal tract, arterial and venous blood vessels, pulmonary tract or intramuscular tissue of
`
`an animal, such as a mammal and particularly a human, or the in vitro environment of a
`
`30
`
`test solution, such as phosphate buffered saline (PBS), simulated intestinal buffer without
`
`enzymes (SIN), or a Model Fasted Duodenal (MFD) solution. An appropriate PBS
`
`solution is an aqueous solution comprising 20 mN sodium phosphate (Na2HP04), 47 mM
`potassium phosphate (KH2P04), 87 mM NaCl, and 0.2 mM KCI, adjusted to pH 6.5 with
`- 5 -
`
`

`

`WO 2010/147978
`
`PCT /US2010/038660
`
`NaOH. An appropriate simulated intestinal fluid -no enzyme (SIN) solution is 50 mM
`KH2P04 adjusted to pH 7.4 or 200 mM sodium phosphate (Na2HP04) adjusted to pH 6.8.
`An appropriate MFD solution is the same PBS solution wherein additionally is present
`
`7.3 mM sodium taurocholic acid and 1.4 mM of 1-palmitoyl-2-oleyl-sn-glycero-3-
`
`5
`
`phosphocholine.
`
`"Administration" to a use environment means, where the in vivo use environment is
`
`the GI tract, delivery by ingestion or swallowing or other such means to deliver the drugs.
`
`One skilled in the art will understand that "administration" to other in vivo use
`
`environments means contacting the use environment with the composition of the
`
`1 o
`
`invention using methods known in the art. See for example, Remington: The Science and
`
`Practice of Pharmacy, 20th Edition (2000). Where the use environment is in vitro,
`
`"administration" refers to placement or delivery of the dosage form to the in vitro test
`
`medium.
`
`Release rates, suitable dosage forms, apixaban and solubility-improved forms
`
`15
`
`are discussed in more detail below.
`
`RELEASE RA TES
`
`The dosage forms of the present invention provide controlled-release of apixaban
`
`in a solubility-improved form. As previously stated, "controlled release" is meant that
`
`20
`
`apixaban is released at a rate that is slower than immediate release i.e., less than 70
`
`wt% of apixaban is released within one hour following introduction to a use
`
`environment. As used herein, the rate of release of apixaban from a dosage form is
`
`characterized by the percentage of apixaban initially present in the dosage form that is
`
`released within one hour subsequent to administering the dosage form to a use
`
`25
`
`environment.
`
`The release of apixaban from the dosage forms of the present invention may be
`
`characterized in terms of the time duration between introducing the dosage form to an
`
`environment of use and the time at which 70% of apixaban has left the dosage form.
`
`Description of apixaban release rate is complicated by the fact that such dosage forms
`
`30 may have initial delay periods during which little or no release occurs, and may release
`
`apixaban according to zero-order, first-order, mixed-order or other kinetics. To avoid
`
`confusion, release rates are described in terms of the time duration between dosing the
`
`dosage form to an environment of use and the time at which 70% of apixaban has left
`
`-6-
`
`

`

`WO 2010/147978
`
`PCT /US2010/038660
`
`the dosage form. This description applies to all dosage forms that release apixaban,
`
`regardless of the shape of the percent released vs. time curve and is intended to
`
`embrace sustained release dosage forms as well as dosage forms that exhibit
`
`sustained release after an initial lag time. Thus, by "controlled release" of apixaban is
`
`5 meant a dosage form that releases less than 70 wt% of apixaban initially present in the
`
`dosage form at 1 hour following introduction to a use environment. By "sustained
`
`release" is meant a dosage form wherein apixaban is released slowly over time after
`
`administration to the use environment. A dosage form that releases 70 wt% of
`
`apixaban initially present in the dosage form over any 1 hour period following
`
`1 o
`
`introduction to the use environment is not considered to be a sustained release dosage
`
`form.
`
`In one embodiment, the time to release 70% of apixaban initially present in the
`
`dosage form is at least about 2 hours, preferably at least about 3 hours, more preferably
`
`at least about 4 hours.
`
`15
`
`However, the release of apixaban from the dosage form should not be too slow.
`
`Thus, it is also preferred that the time to release 70% of apixaban initially present in the
`
`dosage form be about 24 hours or less, more preferably about 20 hours or less, and
`
`most preferably about 18 hours or less.
`
`The release of apixaban from the dosage form may also be characterized by an
`
`20
`
`average rate of release of apixaban per hour for a time period, defined as the wt% of
`
`apixaban present in the dosage form released during the time period divided by the
`
`duration (in hours) of the time period. For example, if the dosage form releases 70 wt%
`
`of apixaban initially present in the dosage form within 16 hours, the average rate of
`
`release of apixaban is 4.4 wto/o/hr (70 wto/o/16 hours). While the average rate of release
`
`25 may be calculated at any time period following introduction to the use environment,
`
`conventionally the time used is the time required to release 70 wt% of apixaban initially
`
`present in the dosage form.
`
`Thus, the dosage forms of this invention have an average rate of release of
`
`apixaban of less than about 70 wto/o/hr. Preferably, the dosage forms of the present
`
`30
`
`invention release apixaban at an average rate that is about 35 wto/o/hr or less, more
`
`preferably about 23 wto/o/hr or less, and even more preferably about 17.5 wto/o/hr or less.
`
`It is also preferred that the dosage forms of the present invention release apixaban at an
`
`-7-
`
`

`

`WO 2010/147978
`
`PCT /US2010/038660
`
`average rate that is about 2.9 wt%/hr or more, preferably about 3.5 wt%/hr or more, more
`
`preferably about 3.9 wt%/hr or more.
`
`The dosage form of the present invention provides controlled release of apixaban
`
`relative to an immediate release control dosage form consisting of an equivalent amount
`
`5
`
`of apixaban in the same solubility-improved form dosed as an oral powder for constitution.
`
`In one embodiment, when the use environment is the GI tract of a mammal, the dosage
`
`form provides a time to reach maximum drug concentration (T max) in the blood of the
`
`mammal following administration that is longer than the immediate release control dosage
`
`form. Preferably, the T max in the blood is at least about 1.25-fold longer than the
`
`1 O
`
`immediate release control dosage form, preferably at least about 1.5-fold longer, and
`
`more preferably at least about 2-fold longer. In addition, the maximum concentration of
`
`drug (Cmax) in the blood is less than or equal to 80%, and may be less than or equal to
`
`65%, or even less than or equal to 50% of the Cmax provided by the immediate release
`
`control dosage form. Both T max and Cmax may be compared in either the fed or fasted
`
`15
`
`state, and the dosage form meets the above criteria for at least one of, and preferably
`
`both, the fed and fasted state.
`
`In another aspect, the dosage forms of the present invention provide controlled
`
`release of apixaban which, after oral dosing, elicit the following effects: a decrease of
`
`20% or more in mean plasma Cmax relative to a dosage form that provides immediate
`
`20
`
`release of the same amount of the solubility-improved form of apixaban after dosing for 8
`
`weeks. In other words, the dosage form, following administration to an in vivo use
`
`environment, provides a maximum drug concentration in the blood that is less than or
`
`equal to 80% of the maximum drug concentration in the blood provided by a dosage
`
`form that provides immediate release of the same amount of the solubility-improved
`
`25
`
`form of said apixaban.
`
`The dosage forms of the present invention may be dosed to a human subject in
`
`the fasted or fed state. It is preferred that they be dosed in the fed state.
`
`Preferred apixaban doses and apixaban release rates from the dosage forms of
`
`this invention may be determined by pharmacokinetic (PK) modeling for apixaban, or by
`
`30
`
`clinical experimentation (i.e. in human subjects or patients) as familiar to those
`
`experienced in the art. PK modeling may also be used to predict Cmax for various
`
`apixaban doses and release rates, in order to identify those doses and release rates that
`
`- 8 -
`
`

`

`WO 2010/147978
`
`PCT /US2010/038660
`
`will decrease Cmax by 20% or more, relative to an immediate release dosage form at the
`
`same dose.
`
`In one aspect, when apixaban in the dosage forms of the present invention, after
`
`oral dosing, elicit one or more of the following effects: (a) plasma concentrations of
`
`5
`
`apixaban which exceed about 70 ng/ml, preferably about 110 ng/ml, more preferably
`
`about 160 ng/ml, even more preferably about 325 ng/ml for a period of around 12 hr or
`
`greater, preferably 16 hr or greater, more preferably about 24 hours or greater and (b)
`
`a decrease of 20% or more in mean plasma Cmax relative to a dosage form that provides
`
`immediate release of the same amount of the solubility-improved form of apixaban.
`
`1 o
`
`Expressed as release rate profiles, exemplary release rates are wherein the in-
`
`vitro dissolution rate of a dosage form is measured by the direct dissolution tests
`
`provided below.
`
`In one embodiment, an exemplary dosage form has the release rate profile
`
`wherein less than about 10 wt% apixaban is released by one hour, about 60 wt%
`
`15
`
`apixaban to about 80 wt% apixaban is released at about eight hours, and more than
`
`about 70 wt% apixaban is released at ten hours.
`
`Analogously, in another embodiment, an exemplary dosage form has the release
`
`rate profile wherein less than about 10 wt% apixaban is released by one hour, about 20
`
`wt% apixaban to about 40 wt% apixaban is released by four hours, about 60 wt%
`
`20
`
`apixaban to about 80 wt% apixaban is released at about eight hours, and more than
`
`about 70 wt% apixaban is released at ten hours.
`
`Analogously, in another embodiment, an exemplary dosage form has the release
`
`rate profile wherein less than about 20 wt% apixaban is released by one hour, about 50
`
`wt% apixaban to about 75 wt% apixaban is released by four hours, and more than
`
`25
`
`about 70 wt% apixaban is released at six hours.
`
`Analogously, in another embodiment, an exemplary dosage form has the release
`
`rate profile wherein less than about 20 wt% apixaban is released by one hour, about 20
`
`wt% apixaban to about 40 wt% apixaban is released by two hours, about 50 wt%
`
`apixaban to about 75 wt% apixaban is released at about four hours, and more than
`
`30
`
`about 70 wt% apixaban is released at six hours.
`
`In terms of average release rate, in one embodiment, an exemplary dosage form
`
`provides an average rate of release of apixaban that is at least about 8 wto/o/hr. In
`
`another embodiment, an exemplary dosage form provides an average rate of release of
`
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`apixaban that is from about 7 wt%/hr to about 10 wt%/hr. In yet another embodiment,
`
`an exemplary dosage form provides an average rate of release of apixaban that is from
`
`about 6 wt%/hr to about 13 wt%/hr.
`
`In still another embodiment, an exemplary dosage form provides an average rate
`
`5
`
`of release of apixaban that is at least about 13 wt%/hr. In another embodiment, an
`
`exemplary dosage form provides an average rate of release of apixaban that is from
`
`about 11 wt%/hr to about 18 wt%/hr.
`
`The dosage forms of the present invention are dosed preferably once daily
`
`("QD"). The achievement of this aspect depends upon apixaban dose and apixaban
`
`1 o
`
`release rate from the dosage form.
`
`An in vitro test is used to determine whether a dosage form provides a release
`
`profile within the scope of the present invention. In vitro tests are well known in the art.
`
`The in vitro tests are designed to mimic the behavior of the dosage form in vivo. One
`
`skilled in the art will understand that in such tests the dissolution medium need not act as
`
`15
`
`a sink for the drug in the dosage form. This is particularly true of osmotic dosage forms
`
`where the rate at which undissolved drug extrudes from the osmotic dosage form is not
`
`substantially affected by the solubility of the drug in the dissolution medium. However, for
`
`dosage forms that deliver the drug in the dissolved state, it is preferred that a dissolution
`
`medium be chosen in which the solubility of the drug in the medium times the volume of
`
`20
`
`the media exceeds the total mass of drug dosed; that is, the media should act as a sink
`
`for the drug. By "sink" is meant that the composition and volume of the dissolution
`
`medium is sufficient such that a quantity of drug alone equivalent to that in the dosage
`
`form will dissolve into the dissolution medium. Preferably, the composition and volume of
`
`dissolution medium is sufficient that a quantity of drug equivalent to at least about 2-fold
`
`25
`
`that in the dosage form will dissolve in the dissolution medium. In most cases apixaban is
`
`sufficiently insoluble in aqueous media that a surfactant, such as sodium lauryl sulfate or
`
`other excipients may be added to the dissolution medium to raise the solubility of the drug
`
`and ensure the dissolution medium acts as a sink for the drug(s).
`
`Thus, the following test (in vitro dosage form dissolution test) is that test (by
`
`30
`
`definition) which is used to determine whether a dosage form provides a release profile
`
`within the scope of the present invention. In this test, a so-called "direct" test, the dosage
`
`form is placed into a dissolution medium at 37°C simulating the contents of the intestine,
`
`and specifically 50 mM KH2P04 at pH 7.4 or 200mM NaH2P04 at pH 6.8 with 0.5%
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`sodium laurel sulfate (SlS). The medium is stirred using paddles that rotate at a rate of
`
`75 rpm. When the dosage form is in the form of a tablet, capsule or other solid dosage
`
`form, the dosage form may be placed in a wire support to keep the dosage form off of the
`
`bottom of the flask, so that all of its surfaces are exposed to the dissolution media.
`
`5 Samples of the dissolution medium are taken at periodic intervals using a VanKel VK8000
`
`autosampling dissoette with automatic receptor solution replacement. The concentration
`
`of dissolved drug in the dissolution medium is then determined by High Performance
`
`Liquid Chromatography (HPlC), by comparing UV absorbance of samples to the
`
`absorbance of drug standards. The mass of dissolved drug in the dissolution medium is
`
`1 O
`
`then calculated from the concentration of drug in the medium and the volume of the
`
`medium, which value is used to calculate the actual amount of drug released from the
`
`dosage form, taking into consideration the mass of drug originally present in the dosage
`
`form.
`
`While the above test is that test which is used to determine a release rate profile of
`
`15
`
`a dosage form of the present invention, the dosage forms of the present invention may
`
`also be evaluated using a "residual test," which is performed as follows. A plurality of
`
`dosage forms are each placed into separate stirred USP type 2 dissoette flasks
`
`containing 900 ml of a buffer solution at 37°C simulating a gastric or intestinal
`
`environment. After a given time interval, a dosage form is removed from a flask, released
`
`20 material is removed from the surface of the dosage form, and the dosage form cut in half
`
`and placed in 100 ml of a recovery solution as follows. For the first two hours, the
`
`dosage form is stirred in 25 ml acetone or other solvent suitable to dissolve any coating
`
`on the dosage form. Next, 125 ml of methanol is added and stirring continued overnight
`
`at ambient temperature to dissolve the drug remaining in the dosage form. Approximately
`
`25
`
`2 ml of the recovery solution is removed and centrifuged, and 250 ml of supernatant
`
`added to an HPlC vial and diluted with 750 ml methanol. Residual drug is then
`
`analyzed by HPlC. The amount of drug remaining in the dosage form is subtracted from
`
`the total drug initially present in the dosage form to obtain the amount released at each
`
`time interval.
`
`30
`
`Alternatively, an in vivo test may be used to determine whether a dosage form
`
`provides a drug release profile within the scope of the present invention. However, due to
`
`the inherent difficulties and complexity of the in vivo procedure, it is preferred that in vitro
`
`procedures be used to evaluate dosage forms even though the ultimate use environment
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`is often the human GI tract. The in vitro tests described above are expected to
`
`approximate in vivo behavior, and a dosage form that meets the in vitro release rates
`
`described herein are within the scope of the invention. Dosage forms are dosed to a
`
`group of test subjects, such as humans, and drug release and drug absorption is
`
`5 monitored either by (1) periodically withdrawing blood and measuring the serum or
`
`plasma concentration of drug or (2) measuring the amount of drug remaining in the
`
`dosage form following its exit from the anus (residual drug) or (3) both (1) and (2). In 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 drug remaining in the dosage
`
`1 o
`
`form using the same procedure described above for the in vitro residual test. The
`
`difference between the amount of drug in the original dosage form and the amount of
`
`residual drug is a measure of the amount of drug released during the mouth-to-anus
`
`transit time. This test has limited utility since it provides only a single drug release time
`
`point but is useful in demonstrating the correlation between in vitro and in vivo release.
`
`15
`
`In one in vivo method of monitoring drug release and absorption, the serum or
`
`plasma drug concentration is plotted along the ordinate (y-axis) against the blood sample
`
`time along the abscissa (x-axis). The data may then be analyzed to determine drug
`
`release rates using any conventional analysis, such as the Wagner-Nelson or Loo(cid:173)
`
`Riegelman analysis. See also Welling, "Pharmacokinetics: Processes and Mathematics"
`
`20
`
`(ACS Monograph 185, Amer. Chem. Soc., Washington, D.C., 1986). Treatment of the
`
`data in this man