03822.000060.PV
`
`APIXABAN FORMULATIONS
`
`FIELD OF THE INVENTION
`
`[0001]
`
`This invention relates to apixaban pharmaceutical formulations comprising
`
`5
`
`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
`
`[0002]
`
`Apixaban is a known compound having the structure:
`
`H2NOC
`
`~I
`
`OMe
`
`10
`
`[0003]
`
`The chemical name for apixaban is 4,5,6,7-tetrahydro-1-(4-
`
`methoxyphenyl)-7-oxo-6-[ 4-(2-oxo-1-piperidinyl)phenyl]-1H-pyrazolo[3,4-
`
`c ]pyridine-3-carboxamide (CAS name) or 1-( 4-methoxyphenyl)-7-oxo-6-[ 4-(2-oxo-1-
`
`piperidiny 1 )phenyl ]-4,5, 6, 7 -tetrahydro- lH-pyrazolo[ 3 ,4-c ]pyridine-3-carboxamide
`
`15
`
`(IUPAC name).
`
`[0004]
`
`Apixaban is disclosed in U.S. Patent No. 6,967,208 (based on U.S.
`
`Application Serial No. 10/245, 122 filed September 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
`
`20
`
`of an antithrombotic agent.
`
`[0005]
`
`The aqueous solubility (40 µg/mL) 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
`
`25
`
`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.,
`
`- 1 -
`
`MYLAN EXHIBIT 1017
`
`

`

`03822.000060.PV
`
`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
`
`apixaban with large particles resulted in less than optimal exposures, which can
`
`present quality control challenges.
`
`5
`
`SUMMARY OF THE INVENTION
`
`[0006]
`
`Surprisingly and unexpectedly, it has been found that compositions for
`
`tablets comprising up to 5 mg apixaban particles having a D90 (90% of the volume)
`
`less than 85 microns (µm) exhibit consistent in-vivo dissolution in humans (at
`
`10
`
`physiologic pH), hence, consistent exposure and consistent Factor Xa inhibition that
`
`will lead to consistency in therapeutic effect. The compositions were prepared using a
`
`dry granulation process. Accordingly, the invention provides a pharmaceutical
`
`composition comprising crystalline apixaban particles having a D90 equal to or less
`
`than about 85 µmas measured by laser light distribution, and a pharmaceutically
`
`15
`
`acceptable diluent or carrier. It is preferred that the apixaban particles in the
`
`composition have a D90 not exceeding 85 µm. It is noted the notation Dx means that
`
`X% of the volume of particles have a diameter less than a specified diameter D. Thus
`
`a D90 of 85 µm means that 90% of the volume of particles in an apixaban composition
`
`have a diameter less than 85 µm.
`The range of particle sizes preferred for use in the invention is D90 less
`
`[0007]
`
`20
`
`than 85 µm, more preferably D 90 less than 50 µm, even more preferably D 90 less than
`
`30 µm, and most preferably D90 less than 25 µm. The particle sizes stipulated herein
`
`and in the claims refer to particle sizes were determined using a laser light scattering
`
`technique.
`
`25
`
`[0008]
`
`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 D90 equal to or less than about 85
`
`µm as measured by laser light scattering, and a pharmaceutically acceptable carrier.
`
`30
`
`[0009]
`
`The present invention also provides a dry granulation process for preparing
`
`a composition comprising crystalline apixaban particles having a D90 equal to or less
`
`- 2 -
`
`

`

`03822.000060.PV
`
`than about 85 µm as measured by laser light scattering, and a pharmaceutically
`
`acceptable carrier.
`
`[0010]
`
`The formulations of this invention are advantageous because, inter alia, as
`
`noted above, they exhibit consistent human in-vivo dissolution. The invention is
`
`5
`
`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
`
`10
`
`impacts apixaban absorption rate is about 85 µm. Thus apixaban can be formulated in
`
`a composition having a reasonable particle size using dry granulation process, to
`
`achieve and maintain relatively tiny particles to facilitate consistent in vivo
`
`dissolution.
`
`[0011]
`
`In a relative bioavailabiltiy study where various apixaban formulations
`
`15 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 (D90 of 85 µm)
`
`had lower exposures compared to tablets made using the same process but with
`
`particle size of D90 of 50 µm. In a dry granulation process, water is not used during
`
`20 manufacturing to develop granules containing apixaban and the excipients.
`
`[0012]
`
`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
`
`25
`
`average for a pre-determined number of dosages (e.g., tablets, capsules, suspensions,
`
`or other dosage form), usually 6. The dissolution media is typically maintained at
`
`37° C during the test. It is noted that if the dosage form being tested is a tablet,
`
`typically paddles rotating at 50 -7 5 rpm are used to test the dissolution rate of the
`
`tablets. The amount of dissolved apixaban can be determined conventionally by
`
`30 HPLC, as hereinafter described.
`
`- 3 -
`
`

`

`03822.000060.PV
`
`[0013]
`
`The term "particles" refers to individual 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 85 µm
`
`specified herein. However, if the mean size of the primary drug substance particles
`
`5
`
`(i.e., apixaban) comprising the agglomerate are less than about 85 µm 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.
`
`[0014]
`
`Reference to apixaban particles having "a mean particle size" (herein also
`
`used interchangeably with "VMD" for "volume mean diameter") equal to or less than
`
`10
`
`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
`
`15
`
`skilled in the art and as further disclosed and discussed below.
`
`[0015]
`
`"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 Cmax for each
`
`crossover group is at least 80% of the (corresponding) mean AUC and/or Cmax
`
`20
`
`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 D90 in the range from 30 to 85 µm. The 30 µm particle size is, in effect, a standard
`
`against which other different formulations can be compared. AU Cs are plots of serum
`
`concentration of apixaban along the ordinate (Y-axis) against time for the abscissa (X-
`
`25
`
`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.
`
`[0016]
`
`Use of AUCs, Cmax, and crossover studies is, of course otherwise well
`
`30
`
`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
`
`- 4 -
`
`

`

`03822.000060.PV
`
`equal to or less than about 85 µm, as measured by Malvern light scattering, and a
`
`pharmaceutically acceptable carrier, said composition exhibiting a mean AUC and/or
`
`mean Cmax which are at least 80% of the corresponding mean AUC and/or Cmax
`
`values exhibited by a composition equivalent thereto (i.e., in terms of excipients
`
`5
`
`employed and the amount of apixaban) but having an apixaban mean particle size of
`
`30 µm. 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 µm particle size composition.
`
`[0017]
`
`The present invention may be embodied in other specific forms without
`
`10
`
`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
`
`15
`
`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.
`
`20
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`[0018]
`
`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 US20060069258Al (based on U.S. Application
`
`Serial No. 11/235,510 filed September 26, 2005), herein incorporated by reference.
`
`25
`
`[0019]
`
`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.
`
`- 5 -
`
`

`

`Table 1
`
`03822.000060.PV
`
`Form
`Solvate
`T
`a(A)
`b(A)
`c(A)
`a,o
`B,o
`'Y,o
`V(A3
`Z'
`Vm
`SG
`Deale
`R
`Sol.sites
`
`)
`
`N-1
`None
`+22
`10.233(1)
`13.852(1)
`15.806(1)
`90
`92.98(1)
`90
`2237.4(5)
`1
`559
`P21/n
`1.364
`0.05
`None
`
`H2-2
`Dihydrate
`+22
`6.193(1)
`30.523(1)
`13.046(1)
`90
`90.95(1)
`90
`2466.0(5)
`1
`617
`P21/n
`1.335
`0.09
`2H20
`
`Z' is the number of molecules per asymmetric unit.
`
`T(°C) is the temperature for the crystallographic data.
`5 Vm = V(unit cell)/ (ZZ')
`
`[0020]
`
`Characteristic X-ray diffraction peak positions (degrees 20±0.1) at room
`
`temperature, based on a high quality pattern collected with a diffractometer (CuKa)
`
`with a spinning capillary with 20 calibrated with a NIST suitable standard are shown
`
`10
`
`in Table 2 below.
`
`Table 2
`
`Form N-1
`10.0
`10.6
`12.3
`12.9
`18.5
`27.1
`
`Form H2-2
`5.8
`7.4
`16.0
`20.2
`23.5
`25.2
`
`[0021]
`
`It will be appreciated by those skilled in the art of manufacturing and
`
`15
`
`granulation processes that there are numerous known methods which can be applied
`
`- 6 -
`
`

`

`03822.000060.PV
`
`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 d90<85 µm. Examples of such
`
`methods include as well as dry granulation or wet-granulation by low or high-shear
`
`5
`
`techniques
`
`10
`
`15
`
`20
`
`[0022]
`
`The dry granulation process that produces crystalline apixaban particles
`
`having a mean particle size equal to or less than about 85 µm, 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 steps:
`
`(1)
`
`(2)
`
`(3)
`
`(4)
`
`(5)
`
`Blend the raw materials required prior to granulation;
`
`Granulate the raw materials from Step 1 using a dry or wet granulation
`
`process;
`
`Blend the sized granules from step 3 with extragranular raw materials;
`
`Compress the blend from Step 3 into tablets; and
`
`Film coat the tablets from step 4.
`
`[0023]
`
`In another embodiment, the invention provides a drug product
`
`manufacturing process, comprising the steps:
`
`(1)
`
`(2)
`
`Blend the raw materials, with apixaban of controlled particle size;
`
`Include intragranular portions of binder, disintegrant and other fillers
`
`in the mix from step ( 1);
`
`(3)
`
`Granulate the materials from step (2) using process (3a) or (3b):
`
`(3a) DRY GRANULATION: Delump the intragranular lubricant using
`
`a suitable screen or mill. Add the lubricant to the blend from step (2)
`
`25
`
`and blend. Compact the lubricated blend to ribbons of density in the
`
`range of 1.1 to 1.2 glee and size the compacted ribbons using a roller
`
`compactor; or
`
`(3b) WET GRANULATION: Wet granulate the composition from step
`
`(2) using water to a target end point and optionally, size the wet(cid:173)
`
`30
`
`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;
`
`- 7 -
`
`

`

`03822.000060.PV
`
`(4)
`
`Blend the sized granules from step (3) and the extragranular
`
`disintegrant in a suitable blender;
`
`(5)
`
`Delump the extragranular lubricant using a suitable screen/mill and
`
`5
`
`blend with granules from step (4);
`
`(6)
`
`(7)
`
`Compress the blend from (5) into tablets;
`
`Film coat the tablets from step (6).
`
`[0024]
`
`In a preferred embodiment, a dry granulation process is employed.
`
`10
`
`[0025]
`
`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
`
`15
`
`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.
`
`[0026]
`
`As noted, average particle size can be determined by Malvern light
`
`20
`
`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.
`
`[0027]
`
`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.
`
`25
`
`[0028]
`
`The dissolution test is performed in 900 mL of dissolution medium at 37
`
`~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
`
`30
`
`development. Unless otherwise specified, the results reported were averages of values
`
`from six tablets.
`
`- 8 -
`
`

`

`03822.000060.PV
`
`[0029]
`
`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 (eg,
`
`5
`
`Cmax, AUC, T-HALF) are derived by non-compartmental methods using Kinetica®
`
`software from the time-concentration profiles.
`
`[0030]
`
`The invention is further exemplified and disclosed by the following non-
`
`limiting examples:
`
`10
`
`[0031]
`
`Table 3 shows apixaban tablet compositions prepared using the dry
`
`granulation process that were evaluated in bioequivalence (BE) study.
`
`Table 3
`
`Ingredients
`
`Intragranular
`Apixaban
`Lactose Anhydrous
`Microcrystalline Cellulose
`Croscarmellose Sodium
`Magnesium Stearate
`Sodium Lauryl Salfate
`Extragranular
`Croscarmellose Sodium
`Magnesium Stearate
`Total
`
`Film Coat
`
`Total
`
`Dry Granulation
`5% w/w Drug Loaded
`20 mg Tablet
`(mg/tablet)
`Granulation
`(%w/w)
`
`5.00
`49.25
`39.50
`2.00
`0.50
`1.00
`
`2.00
`0.75
`100.00 mg
`3.5
`103.5 mg
`
`20.00
`197.00
`158.00
`8.00
`2.00
`4.00
`
`8.00
`3.00
`400mg
`14.0
`414mg
`
`[0032]
`
`Table 4 shows apixaban tablet compositions prepared using the wet
`
`granulation process that were evaluated in BE study.
`
`15
`
`20
`
`- 9 -
`
`

`

`Table 4
`
`Ingredients
`
`Intragranular
`Apixaban
`Lactose Monohydrate
`Microcrystalline Cellulose
`Croscarmellose Sodium
`Povidone
`Purified Water
`Extragranular
`Croscarmellose Sodium
`Magnesium Stearate
`Microcrystalline Cellulose
`Total
`
`Film Coat
`
`Total
`
`03822.000060.PV
`
`Wet Granulation
`5% w/w Drug Loaded
`20 mg Tablet
`(mg/tablet)
`Granulation
`(%w/w)
`
`5.00
`70.00
`5.00
`2.50
`4.50
`17.40
`
`2.50
`0.50
`10.00
`100.00
`3.5
`103.5 mg
`
`20.00
`280.00
`60.00
`10.00
`18.00
`69.60
`
`10.00
`2.09
`10.09
`400.00
`14.0
`414.0
`
`[0033]
`
`Table 5 shows the dissolution data that indicates that having a dry
`
`5
`
`granulation process will result in faster dissolution compared to that from a wet
`
`granulation process. As shown in Table 5, the 20 mg tablets made using a dry
`
`granulation process had 58% apixaban dissolved in 30 minutes versus 45% apixaban
`
`dissolved at 30 minutes for the 20 mg tablets made using a wet granulation process.
`
`10
`
`Table 5
`
`Time (minutes)
`
`10
`20
`30
`45
`60
`90
`API Particle Size
`D90 (µm)
`
`% apixaban dissolved (USP II, 75 rpm, O. lN HCl)
`Wet Granulation
`Dry Granulation
`20 mg Tablets
`20 mg Tablets
`41
`30
`52
`39
`45
`58
`51
`64
`56
`68
`64
`74
`
`83.8
`
`83.8
`
`- 10 -
`
`

`

`03822.000060.PV
`
`[0034]
`
`Table 6 illustrates the dissolution data that indicates that that having
`
`particles less than 84 µm will result in consistent exposures. As shown Table 6,
`
`apixaban tablets that had 54% dissolved in 30 minutes or 72% dissolved in 30
`
`minutes both had AUC values that met bioequivalence criteria (Confidence Interval
`
`5
`
`between 80% to 125%) when compared to the tablets that had 79% dissolved at 30
`
`minutes.
`
`Table 6
`
`% apixaban dissolved (USP II, 75 nm, O. lN HCl)
`Dry Granulation
`Time (minutes) Wet Granulation Wet Granulation
`2 x 2.5 mg Tablets 2 x 2.5 mg Tablets
`2 x 2.5 mg Tablets
`(A)
`(C)
`(B)
`44
`25
`56
`62
`43
`71
`72
`54
`79
`80
`66
`85
`84
`74
`88
`
`10
`20
`30
`45
`60
`API Particle
`Size
`D90 (µm)
`Cmax (ng/mL)
`AUC(INF)
`(ng*hr/mL)
`Geomean (CV%) are presented for Cmax and AUC(INF)
`
`83.3
`
`53.1
`
`101.8 (21)
`
`1088 (32)
`
`87.8 (24)
`
`1030 (25)
`
`30.9
`
`108.3 (24)
`
`1153 (26)
`
`10
`
`[0035]
`
`The results of clinical studies demonstrated that, for tablets with similar
`
`dissolution rates (79% and 72% at 30 min in O. lN HCl), Cmax and AUC of the
`
`coated Phase 3 tablet (C) relative to the uncoated Phase 2 tablet (A), met
`
`15
`
`bioequivalence criteria. Tablets with different dissolution rates (59% and 72% at 30
`
`min in O. lN HCl) had similar AUCs, but did not meet equivalence criteria for Cmax.
`
`The lower boundary of the 90% confidence interval of ratio of geometric mean Cmax
`
`was 0.788, indicating the rate of absorption, as defined by Cmax, was lower for the
`
`slower dissolving tablet (59% at 30 min in O. lN HCl). However, the exposure (AUC
`
`20
`
`and Cmax) for the tablets with slow dissolution rate are similar to those following
`
`administration of solution from single ascending dose study, ADME study, and site of
`
`absorption study, respectively.
`
`- 11 -
`
`

`

`03822.000060.PV
`
`[0036]
`
`Table 7 illustrates the dissolution data that shows that while particle size
`
`impacts dissolution, controlling the particle size to less than 85 microns will result in
`
`a dissolution rate that will ensure consistent in-vivo exposures. As indicated in Table
`
`7, consistent exposures are expected once apixaban tablets have greater than 54%
`
`5
`
`apixaban dissolved in 30 minutes. Since the tablets with 83.8 microns have 69%
`
`dissolved at 30 minutes, these tablets will also exposures that are equivalent to the
`
`exposures from tablets made with smaller particles (such as the tablets with 12.8
`
`micron particles shown below).
`
`10
`
`Table 7
`
`% apixaban dissolved (USP II, 75 rpm, O. lN HCl)
`Dry Granulation
`Dry Granulation
`12.8 micron particles
`84 micron particles
`10 mg Tablets
`2 x 5 mg Tablets
`46
`72
`61
`86
`91
`69
`76
`95
`97
`81
`98
`88
`
`12.8
`
`83.8
`
`Time (minutes)
`
`10
`20
`30
`45
`60
`90
`API Particle
`Size
`D90 (µm)
`
`- 12 -
`
`

`

`03822.000060.PV
`
`WHAT IS CLAIMED IS:
`
`1. A composition comprising crystalline apixaban particles having a mean particle
`
`size equal to or less than about 85 µm and a pharmaceutically acceptable diluent or
`
`carrier.
`
`5
`
`2. A composition as defined in claim 1, wherein said composition comprises Form N-
`
`1 of apixaban.
`
`3. A composition as defined in claim 1, wherein particles with a D90 equal to or less
`
`10
`
`than 85 µm.
`
`4. A composition as defined in claim 1, wherein particles with a D90 equal to or less
`
`than 50 µm.
`
`15
`
`5. A composition as defined in claim 1, wherein particles with a D90 equal to or less
`
`than 30 µm.
`
`6. A composition as defined in claim 1, wherein particles with a D90 equal to or less
`
`than 25 µm.
`
`20
`
`7. A composition as defined in claim 1 which exhibits an AUC and/or Cmax that is at
`
`least 80% of the mean AUC and/or Cmax observed for an equivalent formulation
`
`differing only in that the apixaban mean particle size is 85 µm.
`
`25
`
`8. A method of the treatment of a thromboembolic disorder, comprising administering
`
`to a patient in need of such treatment an effective amount of a composition as defined
`
`in claim 1.
`
`9. A process of manufacturing apixaban tablets having a composition as defined in
`
`30
`
`claim 1, comprising the steps of:
`
`(1)
`
`Blend the raw materials required prior to granulation;
`
`- 13 -
`
`

`

`03822.000060.PV
`
`(2)
`
`Granulate the raw materials from step (1) using a wet or dry
`
`granulation process;
`
`(3)
`
`Blend the sized granules from step (2) with extragranular raw
`
`materials;
`
`5
`
`(4)
`
`(5)
`
`Compress the blend from step (3) into tablets; and
`
`Film coat the tablets from step (4).
`
`10. A process of manufacturing apixaban tablets having a composition as defined in
`
`claim 1, comprising the steps of:
`
`10
`
`(1) Blend the raw materials, with apixaban of controlled particle size;
`
`(2) Include intragranular portions of binder, disintegrant and other fillers
`
`in the mix from step ( 1);
`
`(3) Granulate the materials from step (2) using process (3a) or (3b):
`
`(3a) DRY GRANULATION: Delump the intragranular lubricant using
`
`15
`
`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 1.1 to 1.2 glee and size the compacted ribbons using a roller
`
`compactor; or
`
`(3b) WET GRANULATION: Wet granulate the composition from step
`
`20
`
`(2) using water to a target end point and optionally, size the wet(cid:173)
`
`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;
`
`(4) Blend the sized granules from step (3) and the extragranular
`
`25
`
`disintegrant in a suitable blender;
`
`(5) Delump the extragranular lubricant using a suitable screen/mill and
`
`blend with granules from step (4);
`
`(6) Compress the blend from (5) into tablets;
`
`(7) Film coat the tablets from step (6).
`
`30
`
`11. A process of manufacturing apixaban tablets according to claim 10, wherein
`
`process (3a) is used.
`
`- 14 -
`
`

`

`03822.000060.PV
`
`ABSTRACT
`
`Compositions comprising crystalline apixaban particles having a D90 equal to or less
`
`than 85 µm, and a pharmaceutically acceptable carrier, are substantially bioequivalent
`
`and can be used to for the treatment and/or prophylaxis of thromboembolic disorders.
`
`5
`
`- 15 -
`
`

`

`Doc Code: TR.PROV
`Document Description: Provisional Cover Sheet (SB16)
`
`PTO/SB/16 (04-07)
`Approved for use through 06/30/2010 0MB 0651-0032
`U.S. Patent and Trademark Office: U.S. DEPARTMENT OF COMMERCE
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`Provisional Application for Patent Cover Sheet
`This is a request for filing a PROVISIONAL APPLICATION FOR PATENT under 37 CFR 1.53(c)
`
`lnventor(s)
`
`Inventor 1
`
`Given Name
`
`Middle Name
`
`Family Name
`
`City
`
`State
`
`Jatin
`
`Inventor 2
`
`Patel
`
`West Windsor
`
`NJ
`
`Given Name
`
`Middle Name
`
`Family Name
`
`City
`
`State
`
`I Remove I
`Country
`
`us
`
`I Remove I
`Country
`
`Frost
`
`Yardley
`
`PA
`
`us
`
`Charles
`
`Inventor 3
`
`Given Name
`
`Middle Name
`
`Family Name
`
`City
`
`State
`
`Jingpin
`
`Inventor 4
`
`Jia
`
`Belle Mead
`
`NJ
`
`Given Name
`
`Middle Name
`
`Family Name
`
`City
`
`State
`
`Chandra
`
`Vema-Varapu
`
`Hillsborough
`
`NJ
`
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`generated within this form by selecting the Add button.
`
`Title of Invention
`
`APIXABAN FORMULATIONS
`
`Attorney Docket Number (if applicable)
`
`03822.000060.PV
`
`Correspondence Address
`
`Direct all correspondence to (select one):
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`0 Firm or Individual Name
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`Customer Number
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`75296
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`i
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`i
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`i
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`i
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`I Remove I
`Country
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`us
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`I Remove I
`Country
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`us
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`I Add
`
`I
`
`The invention was made by an agency of the United States Government or under a contract with an agency of the United
`States Government.
`0 No.
`0 Yes, the name of the U.S. Government agency and the Government contract number are:
`
`EFS - Web 1.0.1
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`

`

`Doc Code: TR.PROV
`Document Description: Provisional Cover Sheet (SB16)
`
`PTO/SB/16 (04-07)
`Approved for use through 06/30/2010 0MB 0651-0032
`U.S. Patent and Trademark Office: U.S. DEPARTMENT OF COMMERCE
`Under the Paperwork Reduction Act of 1995, no persons are required to respond to a collection of information unless it displays a valid 0MB control number
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`Entity Status
`Applicant claims small entity status under 37 CFR 1.27
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`Signature
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`Please see 37 CFR 1.4(d} for the form of the signature.
`
`Signature
`
`/Jason M. Okun/
`
`Date (YYYY-MM-DD}
`
`2010-02-25
`
`First Name
`
`Jason
`
`Last Name
`
`Okun
`
`Registration Number
`(If appropriate)
`
`48512
`
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