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`US009326945B2
`
`c12) United States Patent
`Patel et al.
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 9,326,945 B2
`May 3, 2016
`
`(54) APIXABAN FORMULATIONS
`
`(75)
`
`Inventors: Jatin Patel, West Windsor, NJ (US);
`Charles Frost, Yardley, PA (US);
`Jingpin Jia, Belle Mead, NJ (US);
`Chandra Vemavarapu, Hillsborough,
`NJ (US)
`
`(73) Assignees: Bristol-Myers Squibb Company,
`Princeton, NJ (US); Pfizer Inc., New
`York, NY (US)
`
`( *) Notice:
`
`Subject to any disclaimer, the term ofthis
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`(21)
`
`Appl. No.:
`
`13/579,796
`
`(22)
`
`PCT Filed:
`
`Feb.24,2011
`
`(86)
`
`PCT No.:
`
`PCT/US2011/025994
`
`§ 371 (c)(l),
`(2), ( 4) Date: Oct. 10, 2012
`
`(87)
`
`PCT Pub. No.: W02011/106478
`
`PCT Pub. Date: Sep. 1, 2011
`
`(65)
`
`Prior Publication Data
`
`US 2013/0045245 Al
`
`Feb. 21, 2013
`
`Related U.S. Application Data
`
`(60)
`
`Provisional application No. 61/308,056, filed on Feb.
`25, 2010.
`
`(51)
`
`Int. Cl.
`A61K9/20
`A61K 3114545
`A61K 311437
`A61K 3114412
`
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`
`(52) U.S. Cl.
`CPC ............. A61K 912018 (2013.01); A61K 912013
`(2013.01); A61K 912054 (2013.01); A61K
`912095 (2013.01); A61K 3114545 (2013.01);
`A61K 311437 (2013.01); A61K 3114412
`(2013.01)
`
`(58) Field of Classification Search
`None
`See application file for complete search history.
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`6,150,366 A
`6,967,208 B2
`7,396,932 B2
`2006/0069258 Al
`
`1112000 Arenson et al.
`1112005 Pinto et al.
`7 /2008 Shapiro et al.
`3/2006 Shapiro et al.
`(Continued)
`
`FOREIGN PATENT DOCUMENTS
`
`CN
`CN
`
`1578660 A
`212005
`8/2009
`101516355 A
`(Continued)
`OTHER PUBLICATIONS
`
`Official Action in Mexican Application No. MX/2012/060772
`(issued Jun. 14, 2013).
`
`(Continued)
`
`Primary Examiner - Bethany Barham
`Assistant Examiner - Barbara Frazier
`(74) Attorney, Agent, or Firm - Fitzpatrick, Cella, Harper&
`Scinto
`
`ABSTRACT
`(57)
`Compositions comprising crystalline apixaban particles hav(cid:173)
`ing a D90 equal to or less than 89 µm, and a pharmaceutically
`acceptable carrier, are substantially bioequivalent and can be
`used to for the treatment and/or prophylaxis ofthromboem(cid:173)
`bolic disorders.
`38 Claims, 4 Drawing Sheets
`
`Dissolution Rates of2.5-mg Apixaban Tablets Using Drug Substance
`
`of Different Particle Size
`
`105
`
`115
`
`.E 35
`E
`~ 75
`.5
`"' !: r.; 65
`"' a .,,, 55
`
`45
`
`35
`
`0
`
`20
`
`60
`BO
`40
`100
`Drug Substance Particle Size 090 ( Micron)
`
`120
`
`14D
`
`MYLAN EXHIBIT 1001
`
`

`

`US 9,326,945 B2
`Page 2
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`2006/0160841 Al
`2008/0279845 Al *
`2009/0123390 Al*
`2009/0285887 Al *
`2012/0087978 Al
`2013/0072512 Al*
`
`712006
`1112008
`512009
`1112009
`412012
`3/2013
`
`Wei eta!.
`Conley et al. .............. 424/130.l
`Hill ................................. 424/45
`Abu-Baker et al ............ 424/469
`Nause
`J ahagirdar et al.
`
`514/279
`
`FOREIGN PATENT DOCUMENTS
`
`JP
`JP
`JP
`JP
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`
`2005-507889 A
`2008-514712 A
`2008-537750 A
`2010-502762 A
`00/39131 Al
`2006/108643 A2
`2007/022165 A2
`2008/031782 Al
`2009/135947 A2
`2010/003811 Al
`2010/147978 Al
`
`3/2005
`5/2008
`9/2008
`1/2010
`712000
`10/2006
`212007
`3/2008
`1112009
`1/2010
`12/2010
`
`OTHER PUBLICATIONS
`
`First Office Action in Chinese Application No. 201180011229.X
`(issued Aug. 9, 2013).
`First Examination Report in New Zealand Application No. 601738
`(Apr. 29, 2013).
`Office Action in Colombian Application No. 12.152.138 (issued Nov.
`5, 2013).
`Communication pursuant to Article 94(3) EPC in European Appli(cid:173)
`cation No. 11707284.3 (issued Jun. 28, 2013).
`Amidon et al., "A Theoretical Basis for a Biopharmaceutic Drug
`Classification: The Correlation of in Vitro Drug Product Dissolution
`and in Vivo Bioavailability", Pharmaceutical Research, vol. 12, pp.
`413-420, 1995.
`Office Action in Mexican Application No. MX/a/2012/009244
`(issued Jun. 6, 2014).
`J. Thompson, Practica Contemporanea En Farmacia (2nd edition), p.
`287 (2006).
`Alfonso R. Gennaro, Remington, Farmacia. Medica Panamericana
`(20th edition), Chapter I, p. 1005 (2000).
`Summons to attend oral proceedings pursuant to Rule 115( 1) EPC in
`European Application No. 11707284.3 (dated Nov. 14, 2014).
`Official Action in Mexican Application No. MX/a/2012/009244
`(dated Feb. 10, 2015).
`Notification of Reasons for Refusal in Japanese Patent Application
`No. 2012-555127 (notified Feb. 24, 2015).
`Hiroshi Nakagawa et al., "Formulation of Insoluble Drug," 24(11)
`JJSHP 15-22 (1988).
`Hideo Yamada, Pharmaceutics I: Drug Compounding/Formulation,
`Chapter 2: Pharmaceutical Preparation Method, pp. 62-76 (Asakura
`Publishing Co., Ltd., 1995).
`Heiichirou Toubata, Granulation Handbook, Application of Pel(cid:173)
`letization, pp. 438-439 (Japan Powder Industry Association, 1975).
`Akinobu Ohtsuka et al., Pharmaceutics, Chapter4 : Unit Operation of
`Powder Preparation, pp. 104-105 (Hirokawa Publishing Co., Ltd.,
`1976).
`
`Office Action in Russian Application No. 2012140690 (dated Feb.
`12, 2015).
`Dressman et al., "The BCS: Where Do We Go from Here?" Pharma(cid:173)
`ceutical Technology, pp. 68-76 (Jul. 2001).
`Third Party Observations in European Application No. 11707284.3
`(dated May 19, 2015).
`Notification Concerning the Date of Oral Proceedings in European
`Application No. 11707284.3 (dated May 12, 2015).
`Notification Concerning the Date of Oral Proceedings in European
`Application No. 11707284.3 (dated May 27, 2015).
`Official Action in Israeli Application No. 221064 (dated May 10,
`2015).
`Technical Report No. EDM 36/2015 in Peruvian Application No.
`001362-2012 (dated Jul. 9, 2015).
`Opposition to Peruvian Application No. 001362-2012 (dated Jun. 20,
`2013).
`Third Party Observations in European Application No. 11707284.3
`(dated Jul. 30, 2014).
`Third Party Observations in European Application No. 11707284.3
`(dated Jul. 15, 2014).
`Third Party Observations in European Application No. 11707284.3
`(dated Aug. 18, 2014).
`European Pharmacopoeia 6.0; Section 2.9 .31-"Particle Size Analy(cid:173)
`sis by Laser Light Diffraction", pp. 311-314 (Jul. 2007).
`European Pharmacopoeia 7 .O; Section 2.9 .31-"Particle Size Analy(cid:173)
`sis by Laser Light Diffraction", pp. 295-299 (Jul. 2010).
`Resolution N° 61405 in Colombian Application No. 12.152.138
`(dated Oct. 14, 2014).
`Peng Chen et al., "Enhancement for Dissolution of Poorly Water
`Soluble Drug by Micronization," 10 Chemistry Bulletin 766-771
`(2007).
`Second Office Action in Chinese Application No. 201180011229 .X
`(issued Oct. 31, 2014).
`Third Party Observations in European Application No. 11707284.3
`(filed Jan. 16, 2015).
`International Standard-ISO 13320-1, First Edition, Particle Size
`Analysis-Laser Diffraction Methods, pp. 1-34 (Nov. 1999).
`Nor Hafizah Hj Annuar et al., "Effects of Sample Conditions on
`Multi-Particle Size Analysis Using Laser Diffraction Technique,"
`Scientia Bruneiana, pp. 19-26 (2010).
`Zoran Stojanovic et al., "Determination of Particle Size Distributions
`by Laser Diffraction," 21 Technics-New Materials 11-20 (2012).
`Third Party Observations on European Application No. 11707284.3
`(dated Jul. 24, 2015).
`U.S. Pharmacopoeia(USP) 38, Chapter429, "Light Diffraction Mea(cid:173)
`surement of Particle Size," pp. 294-299 (May 2015) (Annex 1).
`Third Office Action in Chinese Application No. 201180011229X
`(notified Dec. 11, 2015).
`Resolution No. 39058 in Colombian Application No. 12.152.138
`(published Aug. 4, 2015).
`Resolution No. 64634 in Colombian Application No. 14.268.266
`(published Sep. 22, 2015).
`Office Action in Russian Application No. 2012140690 (dated Dec.
`18, 2015).
`Extended European Search Report in European Application No.
`15190823.3 (Feb. 3, 2016).
`Technical Report No. EDM 008-2016/ A in Peruvian Application No.
`001362-2012 (Mar. 7, 2016).
`* cited by examiner
`
`

`

`U.S. Patent
`
`May 3, 2016
`
`Sheet 1of4
`
`US 9,326,945 B2
`
`Scatter Plot oflndividual Dose-Normalized AUC(INF) Values for
`Figure 1:
`Solutions (CV185001, CV185006, and CV185007) and Tablets (CV185001 and
`CV185024)
`
`800
`
`700
`
`ti)
`
`600
`
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`Cl
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`t
`
`0.5 mg 1 mg 2.5 mg 20 mg 2.5 mg 5 mg 5 mg A 5 mg B 5 mg C
`
`Solution
`CV185001
`
`Tablet
`Solution
`CV185006 CV185001
`CV185007
`
`Tablet
`CV185024
`
`Source: CV185001, CV185006, CV185007, and CV185024 Clinical Study Reports
`The solid line represents the geometric mean of AUC(INF) and the solid square represents the
`average %in-vitro dissolved at 30 minutes (using QC method in Table l.2C). The X-axis represents
`the dose administered.
`For CV185024, 5 mg A = Apixaban Phase 2 tablet (86% dissolution) 2x2.5 mg (reference
`formulation), 5 mg B = Apixaban Phase 2 tablet (77% dissolution) 2x2.5 mg, 5 mg C = Apixaban
`Phase 3 tablet (89% dissolution) 2x2.5 mg.
`
`

`

`U.S. Patent
`
`May 3, 2016
`
`Sheet 2 of 4
`
`US 9,326,945 B2
`
`Scatter Plot oflndividual Dose Nonnalized Cmax Values for Solutions
`Figure 2:
`(CV185001, CV185006, and CV185007) and Tablets (CV185001 and CV185024)
`
`50
`
`40
`
`al
`(fl
`0 c
`Cl 30
`E
`::i
`E
`Ci .s 20
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`
`0.5 mg 1 mg 2.5 mg 20 mg 2.5 mg 5 mg 5 mgA 5 mg B 5 mg C
`
`Solution
`CV185001
`
`Solution
`CV185006
`CV185007
`
`Tablet
`CV185001
`
`Tablet
`CV185024
`
`Source: CV185001, CV185006, CV185007, and CV185024 Clinical Study Reports
`The solid line represents the geometric mean of Cmax and the solid square represents the average
`%in-vitro dissolved at 30 minutes (using QC method in Table l.2C). The X-axis represents the dose
`administered.
`For CV185024, 5 mg A = Apixaban Phase 2 tablet (86% dissolution) 2x2.5 mg (reference
`formulation), 5 mg B = Apixaban Phase 2 tablet (77% dissolution) 2x2.5 mg, 5 mg C = Apixaban
`Phase 3 tablet (89% dissolution) 2x2.5 mg.
`
`

`

`U.S. Patent
`
`May 3, 2016
`
`Sheet 3 of 4
`
`US 9,326,945 B2
`
`Figure 3:
`
`Dissolution Rates of2.5-mg Apixaban Tablets Using Drug Substance
`
`of Different Particle Size
`
`95
`
`0
`
`s 75 ··················t··················································
`•
`
`minimum dissolution requireme11t
`
`45
`
`35+-~~~..--~~--,~~~---..~~~-y-~~~.....-~~~.....-~~--1
`so
`40
`60
`0
`100
`120
`20
`140
`Omg Substance Particle Size 090 ( Micron}
`
`

`

`U.S. Patent
`
`May 3, 2016
`
`Sheet 4 of 4
`
`US 9,326,945 B2
`
`Figure 4:
`
`Dissolution Rates of5-mg Apixaban Tablets Using Drug Substance of
`
`Different Particle Size
`
`95
`
`!::: e 85
`.!: 75
`
`0
`M
`
`"O
`ii)
`>
`0
`
`0)
`{/)
`
`0
`,;e
`"'
`
`135
`
`55
`
`45
`
`35
`
`••
`
`t
`
`minimum dissolution requirement
`
`I}
`
`20
`
`40
`80
`60
`Drug Substance Particle Size 090 ( Micron)
`
`100
`
`120
`
`140
`
`

`

`1
`APIXABAN FORMULATIONS
`
`US 9,326,945 B2
`
`2
`physiologic pH), hence, consistent exposure and consistent
`Factor Xa inhibition that will lead to consistency in therapeu(cid:173)
`tic effect. Consistent exposure is defined as that where in-vivo
`exposure from tablets is similar to that from a solution and not
`affected by the differences in dissolution rates. The compo(cid:173)
`sitions were prepared using a dry granulation process.
`Accordingly, the invention provides a pharmaceutical com(cid:173)
`position comprising crystalline apixaban particles having a
`D90 equal to or less than about 89 µm as measured by laser
`10 light scattering method, and a pharmaceutically acceptable
`diluent or carrier. It is preferred that the apixaban particles in
`the composition have a D90 not exceeding 89 µm. It is noted
`the notation Dx means that X % of the volume of particles
`15 have a diameter less than a specified diameter D. Thus a D90
`of 89 µm means that 90% of the volume of particles in an
`apixaban composition have a diameter less than 89 µm.
`The range of particle sizes preferred for use in the invention
`is D90 less than 89 µm, more preferably D90 less than 50 µm,
`20 even more preferably D90 less than 30 µm, and most prefer(cid:173)
`ably 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.
`The invention further provides the pharmaceutical compo-
`25 sition further comprising a surfactant from 0.25% to 2% by
`weight, preferably from 1 % to 2% by weight. As regards the
`surfactant, it is generally used to aid in wetting of a hydro(cid:173)
`phobic drug in a tablet formulation to ensure efficient disso(cid:173)
`lution of the drug, for example, sodium lauryl sulfate, sodium
`30 stearate, polysorbate 80 and poloxamers, preferably sodium
`lauryl sulfate.
`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 pro-
`35 phylaxis a therapeutically effective amount of a composition
`comprising crystalline apixaban particles having a D90 equal
`to or less than about 89 µmas measured by laser light scat(cid:173)
`tering, and a pharmaceutically acceptable carrier.
`The present invention also provides a dry granulation pro-
`40 cess for preparing a composition comprising crystalline
`apixaban particles having a D90 equal to or less than about 89
`µmas measured by laser light scattering, and a pharmaceuti(cid:173)
`cally acceptable carrier.
`The formulations of this invention are advantageous
`45 because, inter alia, as noted above, they lead to consistent
`human in-vivo dissolution. The invention is surprising in this
`respect, however, in that exposures are variable even though
`apixaban has adequate aqueous solubility that would allow
`the drug to dissolve rapidly. That is, one would expect disso-
`50 lution rate for a drug that has high solubility (as defined by the
`Biopharmaceutical Classification System) would not be lim(cid:173)
`ited by the particle size. It has surprisingly been found, how(cid:173)
`ever, that the particle size that impacts apixaban absorption
`rate is about a D90 of89 µm. Thus apixaban can be formulated
`55 in a composition having a reasonable particle size using dry
`granulation process, to achieve and maintain relatively fine
`particles to facilitate consistent in vivo dissolution.
`In a relative bioavailabiltiy study where various apixaban
`formulations were evaluated, it was determined that formu-
`60 lations 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 89 µm) had lower exposures compared to
`tablets made using the same process but with particle size of
`65 D90 of 50 µm. In a dry granulation process, water is not used
`during manufacturing to develop granules containing apixa(cid:173)
`ban and the excipients.
`
`This application is the National Stage of International
`Application No. PCT/US2011/025994, filed Feb. 24, 2011,
`which claims the benefit of U.S. Provisional Application No. 5
`61/308,056, filed Feb. 25, 2010.
`
`FIELD OF THE INVENTION
`
`This invention relates to apixaban pharmaceutical formu(cid:173)
`lations comprising crystalline apixaban particles having a
`maximum size cutoff; and methods of using them, for
`example, for the treatment and/ or prophy !axis of thromboem(cid:173)
`bolic disorders.
`
`BACKGROUND OF THE INVENTION
`
`Apixaban is a known compound having the structure:
`
`The chemical name for apixaban is 4,5,6,7-tetrahydro-l(cid:173)
`( 4-methoxyphenyl)-7-oxo-6-[ 4-(2-oxo-l-piperidinyl)phe(cid:173)
`nyl]-1H-pyrazolo[3,4-c ]pyridine-3-carboxamide
`(CAS
`name) or 1-( 4-methoxyphenyl)-7-oxo-6-[ 4-(2-oxo-l-pip(cid:173)
`eridinyl)phenyl]-4,5,6, 7-tetrahydro- l H-pyrazolo[3,4-c ]pyri(cid:173)
`dine-3-carboxamide (IUPAC name).
`Apixaban is disclosed in U.S. Pat. No. 6,967 ,208 (based on
`U.S. application Ser. No. 10/245,122 filed Sep. 17, 2002),
`which is herein incorporated by reference in its entirety, has
`utility as a Factor Xa inhibitor, and is being developed for oral
`administration in a variety of indications that require the use
`of an antithrombotic agent.
`The aqueous solubility ( 40 µg/mL at all physiological pH)
`of apixaban suggests that the tablets with less than 10 mg
`apixaban (dose/solubility ratio=250 mL) should not demon(cid:173)
`strate dissolution rate limited absorption since dissolution
`rate limitations are only expected when the dose/solubility
`ratio is greater than 250 mL. Based on this dose and solubility
`consideration, the particle size of the compound should not be
`critical for achieving consistent plasma profiles, according to
`the prediction based on the Biopharmaceutics Classification
`System (BCS; Amidon, G. L. et al., Pharmaceutical
`Research, 12: 413-420 (1995)). However, it was determined
`that formulations that were made using a wet granulation
`process as well as those using large particles of apixaban drug
`substance resulted in less than optimal exposures, which can
`present quality control challenges.
`
`SUMMARY OF THE INVENTION
`
`Surprisingly and unexpectedly, it has been found that com(cid:173)
`positions for tablets comprising up to 5 mg, apixaban par(cid:173)
`ticles having a D90 (90% of the volume) less than 89 microns
`(µm) lead to consistent in-vivo dissolution in humans (at
`
`

`

`US 9,326,945 B2
`
`4
`thereto (i.e., in terms of excipients 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.
`The present invention may be embodied in other specific
`forms without departing from the spirit or essential attributes
`thereof. Thus, the above embodiments should not be consid(cid:173)
`ered limiting. Any and all embodiments of the present inven(cid:173)
`tion may be taken in conjunction with any other embodiment
`or embodiments to describe additional embodiments. Each
`individual element of the embodiments is its own indepen(cid:173)
`dent embodiment. Furthermore, any element of an embodi(cid:173)
`ment is meant to be combined with any and all other elements
`from any embodiment to describe an additional embodiment.
`In addition, the present invention encompasses combinations
`of different embodiment, parts of embodiments, definitions,
`descriptions, and examples of the invention noted herein.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`FIG. 1 is a scatter plot of individual dose-normalizedAUC
`(INF) values for solutions (CV! 85001, CV! 85006, and
`CV185007) and tablets (CV185001 and CV185024).
`FIG. 2 is scatter plot of individual dose-normalized Cm=
`values for solutions (CV! 85001, CV! 85006, and CV! 85007)
`and tablets (CV185001 and CV185024).
`FIG. 3 is a plot of dissolution rates of 2.5 mg apixaban
`tablets using drug substance of different particle size.
`FIG. 4 is a plot of dissolution rates of5 mg apixaban tablets
`using drug substance of different particle size.
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`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.
`40 6,967,208 and/or US20060069258Al (based on U.S. appli(cid:173)
`cation Ser. No. 11/235,510 filed Sep. 26, 2005), herein incor(cid:173)
`porated by reference.
`FormN-1 (neat) andFormH2-2 (hydrate) ofapixabanmay
`be characterized by unit cell parameters substantially equal to
`45 the following shown in Table 1.
`
`3
`Formulations according to this invention, when dissolution
`tested in vitro preferably exhibit the following dissolution
`criteria. That is, the formulation exhibits dissolution proper(cid:173)
`ties such that, when an amount of the drug equivalent to 77%
`therein dissolves within 30 minutes. Usually the test result is
`established as an average for a pre-determined number of
`dosages (e.g., tablets, capsules, suspensions, or other dosage
`form), usually 6. The dissolution test is typically performed in
`an aqueous media buff erred to a pH range (1 to 7.4) observed
`in the gastrointestinal tract and controlled at 37° C. (±1° C.), 10
`together maintaining a physilogical relevance. 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 HPLC, as hereinafter described. The dis- 15
`solution (in-vitro) test is developed to serve as a quality con(cid:173)
`trol tool, and more preferably to predict the biological (in(cid:173)
`vivo) performance of the tablet, where invivo-invitro
`relationships (IVIVR) are established.
`The term "particles" refers to individual drug substance 20
`particles whether the particles exist singly or are agglomer(cid:173)
`ated. Thus, a composition comprising particulate apixaban
`may contain agglomerates that are well beyond the size limit
`of about 89 µm specified herein. However, if the mean size of
`the primary drug substance particles (i.e., apixaban) compris- 25
`ing the agglomerate are less than about 89 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.
`Reference to apixaban particles having "a mean particle 30
`size" (herein also used interchangeably with "VMD" for
`"volume mean diameter") equal to or less than a given diam(cid:173)
`eter or being within a given particle size range means that the
`average of all apixaban particles in the sample have an esti(cid:173)
`mated volume, based on an assumption of spherical shape, 35
`less than or equal to the volume calculated for a spherical
`particle with a diameter equal to the given diameter. Particle
`size distribution can be measured by laser light scattering
`technique as known to those skilled in the art and as further
`disclosed and discussed below.
`"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 Cm= for each cross(cid:173)
`over group is at least 80% of the (corresponding) meanAUC
`and/or cmax 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 89 µm. The 30 µm particle
`size is, in effect, a standard against which other different 50
`formulations can be compared. AUCs are plots of serum
`concentration of apixaban along the ordinate (Y-axis) against
`time for the abscissa (X-axis). Generally, the values for AUC
`represent a number of values taken from all the subjects in a
`patient population and are, therefore, mean values averaged 55
`over the entire test population. C.sub.max, the observed maxi(cid:173)
`mum in a plot of serum level concentration of apixaban
`(Y-axis) versus time (X-axis) is likewise an average value.
`Use of AUCs, Cm=' and crossover studies is, of course
`otherwise well understood in the art. The invention can 60
`indeed be viewed in alternative terms as a composition com(cid:173)
`prising crystalline apixaban particles having a mean particle
`size equal to or less than about 89 µm, as measured by Mal(cid:173)
`vern light scattering, and a pharmaceutically acceptable car(cid:173)
`rier, said composition exhibiting a mean AUC and/or mean 65
`Cmax which are at least 80% of the corresponding meanAUC
`and/or cmax values exhibited by a composition equivalent
`
`Form
`
`Solvate
`T
`a(A)
`b(A)
`c(A)
`a,c
`13,c
`y, c
`V(A3
`Z'
`Vm
`SG
`Deale
`R
`Sol. sites
`
`)
`
`TABLE 1
`
`N-1
`
`None
`+22
`10.233(1)
`13.852(1)
`15.806(1)
`90
`92.98(1)
`90
`2237.4(5)
`1
`559
`P2/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
`P2/n
`1.335
`0.09
`2H2 0
`
`Z' is the number of molecules per asymmetric unit.
`T(0 C.) is the temperature for the crystallographic data.
`Vm = V(unit cell)/(ZZ')
`
`Characteristic X-ray diffraction peak positions (degrees
`28±0.1) at room temperature, based on a high quality pattern
`
`

`

`US 9,326,945 B2
`
`5
`collected with a diffractometer (CuKa) with a spinning cap(cid:173)
`illary with 28 calibrated with a NIST suitable standard are
`shown in Table 2 below.
`
`TABLE2
`
`Form N-1
`
`Form H2-2
`
`10.0
`10.6
`12.3
`12.9
`18.5
`27.1
`
`5.8
`7.4
`16.0
`20.2
`23.5
`25.2
`
`35
`
`40
`
`6
`bic apixaban drug substance (contact angle=54 ° with water),
`further exacerbated as part of air-jet milling process that is
`used to reduce apixaban particle size to the desired size.
`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
`10 therapy as well. As previously mentioned, such dosage forms
`are useful, inter alia, in the prevention and/or treatment of
`thromboembolic disorders, for example, deep vein thrombo(cid:173)
`sis, acute coronary syndrome, stroke, and pulmonary embo-
`lism, as disclosed in U.S. Pat. No. 6,967,208.
`As noted, average particle size can be determined by Mal(cid:173)
`vern light scattering, a laser light scattering technique. In the
`examples below, the particle size for apixaban drug substance
`was measured using a Malvern particle size analyzer.
`Upon measurement completion, the sample cell was emp(cid:173)
`tied and cleaned, refilled with suspending medium, and the
`sampling procedure repeated for a total of three measure-
`ments.
`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 development.
`While both methods serve the purposes as quality control
`tests (with adequate discrimination ability), and in establish(cid:173)
`ing IVIVR, the latter was preferred from the standpoint of
`method robustness. A role of SDS (surfactant) in the latter
`dissolution medium is as a wetting aid to facilitate complete
`dissolution ofhydrophobic apixaban from tablets, rather than
`to increase the solubility of apixaban. Dissolution data from
`both the tests are included in this invention record and unless
`otherwise specified, the results reported were averages of
`values from six tablets.
`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 phar(cid:173)
`macokinetic parameters (eg, Cmax, AUC, T-HALF) are
`derived by non-compartmental methods using Kinetica®
`software from the time-concentration profiles.
`The invention is further exemplified and disclosed by the
`following non-limiting examples:
`Table 3 shows apixaban tablet compositions prepared
`using the drygranulation process that were evaluated in
`bioequivalence (BE) study.
`
`It will be appreciated by those skilled in the art of manu- 15
`facturing and granulation processes that there are numerous
`known methods which can be applied to producing apixaban
`solid dosage forms. The feature of this invention, however,
`involves processes that produce apixaban dosage forms with
`an ability to produce primary particles at the site of dissolu- 20
`ti on with a d90<89 µm. Examples of such methods include as
`well as dry granulation or wet-granulation by low or high(cid:173)
`shear techniques
`The dry granulation process that produces crystalline
`apixaban particles having a mean particle size equal to or less 25
`than about 89 µm, is believed to be novel, and is accordingly
`provided as a further feature of the invention. Thus, the inven(cid:173)
`tion provides a drug product manufacturing process, compris(cid:173)
`ing the steps:
`(1) Blend the raw materials required prior to granulation; 30
`(2) Granulate the raw materials from Step 1 using a dry or
`wet granulation process;
`(3) Blend the sized granules from step 3 with extra granular
`raw materials;
`(4) Compress the blend from Step 3 into tablets; and
`(5) Film coat the tablets from step 4.
`In another embodiment, the invention provides a drug
`product manufacturing process, comprising the steps:
`(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 45
`lubricant using a suitable screen or mill. Add the
`lubricant to the blend from step (2) and blend. Com(cid:173)
`pact the lubricated blend to ribbons of density in the
`range of 1.0 to 1.2 glee and size the compacted rib(cid:173)
`bons using a roller compactor; or
`(3b) WET GRANULATION: Wet granulate the compo(cid:173)
`sition from step
`(2) using water to a target end point and optionally, size
`the wet-granules by passing through a screen/mill.
`Remove water for granulation by drying in a convec- 55
`tion 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 extra(cid:173)
`granular 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).
`In a preferred embodiment, a dry granulation process is
`employed.
`In a preferred embodiment, the surfactant (SLS) in the
`composition serves as a wetting aid for inherently hydropho-
`
`50
`
`TABLE3
`
`Dry Granulation
`
`5%w/wDrug
`Loaded Granulation
`(%w/w)
`
`20mg
`Tablet
`(mg/tablet)
`
`Intragranular
`
`Ingredients
`
`Apixaban
`Lactose Anhydrous
`Microcrystalline Cellulose
`
`5.00
`49.25
`39.50
`
`20.00
`197.00
`158.00
`
`60
`
`65
`
`

`

`US 9,326,945 B2
`
`7
`TABLE 3-continued
`
`Dry Granulation
`
`5%w/wDrug
`Loaded Granulation
`(%w/w)
`
`20mg
`Tablet
`(mg/tablet)
`
`2.00
`0.50
`1.00
`Extragranular
`
`2.00
`0.75
`
`100.00 mg
`3.5
`
`103.5 mg
`
`8.00
`2.00
`4.00
`
`8.00
`3.00
`
`400mg
`14.0
`
`414mg
`
`10
`
`15
`
`Ingredients
`
`Croscarmellose Sodiwn
`Magnesium Stearate
`Sodium Laury! Sulfate
`
`Croscarmellose Sodiwn
`Magnesium Stearate
`
`Total
`Film Coat
`
`Total
`
`Table 4 shows apixaban tablet compos1t10ns prepared
`using the wet granulation process that were evaluated in BE
`study.
`
`20
`
`TABLE4
`
`Wet Granulation
`
`25
`
`8
`TABLE S-continued
`
`% apixaban dissolved (USP II, 75 rpm,
`0.05% SLS in 50 mM phosphate, pH 6.8)
`
`Time
`(minutes)
`
`Wet Granulation
`20 mg Tablets
`
`Dry Granulation
`20 mg Tablets
`
`45
`60
`AP! Particle Size
`Dgo (µrn)
`
`71
`76
`83.8
`
`86
`90
`83.8
`
`TABLE Sa
`
`% apixaban dissolved (USP II, 75 rpm, O.lN HCl)
`
`Time
`(minutes)
`
`Wet Granulation
`20 mg Tablets
`
`Dry Granulation
`20 mg Tablets
`
`10
`20
`30
`45
`60
`90
`AP! Particle Size
`Dgo (µrn)
`
`30
`39
`45
`51
`56
`64
`83.8
`
`41
`52
`58
`64
`68
`74
`83.8
`
`Ingredients
`
`5%w/wDrug
`Loaded Granulation
`(%w/w)
`
`20mg
`Tablet
`(mg/tablet)
`
`Apixaban
`Lactose Monohydrate
`Microcrystalline Cellulose
`Croscarmellose Sodiwn
`Povidone
`Purified Water
`
`Croscarmellose Sodiwn
`Magnesium Stearate
`Microcrystalline Cellulose
`Total
`Film Coat
`
`Total
`
`Intragranular
`
`5.00
`70.00
`5.00
`2.50
`4.50
`17.40
`Extragranular
`
`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
`
`Table S and Table Sa show the dissolution data that indi- 45
`cates that having a dry granulation process will result in faster
`dissolution compared to that from