111111111111111111111111111111111111111111111111111111111111111111111111111
`US009555027B2
`
`c12) United States Patent
`Fujihara
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 9,555,027 B2
`*Jan. 31, 2017
`
`(54) PHARMACEUTICAL COMPOSITION
`(71) Applicant: SUMITOMO DAINIPPON PHARMA
`CO., LTD, Osaka (JP)
`Inventor: Kazuyuki Fujihara, Suzuka (JP)
`(72)
`(73) Assignee: SUMITOMO DAINIPPON PHARMA
`CO., LTD., Osaka (JP)
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`( *) Notice:
`
`This patent is subject to a terminal dis(cid:173)
`claimer.
`(21) Appl. No.: 14/512,189
`Oct. 10, 2014
`(22) Filed:
`Prior Publication Data
`(65)
`
`US 2015/0056284 Al
`
`Feb. 26, 2015
`
`Related U.S. Application Data
`
`(63) Continuation of application No. 14/183,283, filed on
`Feb. 18, 2014, now Pat. No. 8,883,794, which is a
`continuation of application No. 11/919,678, filed as
`application No. PCT/JP2006/310571 on May 26,
`2006, now Pat. No. 8,729,085.
`Foreign Application Priority Data
`
`(30)
`
`(JP) ................................. 2005-153508
`
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`
`May 26, 2005
`Int. Cl.
`(51)
`A61K 311496
`A61K 9100
`A61K 9120
`C07D 417112
`(52) U.S. Cl.
`CPC ........... A61K 311496 (2013.01); A61K 910053
`(2013.01); A61K 912009 (2013.01); A61K
`912018 (2013.01); A61K 912027 (2013.01);
`A61K 912031 (2013.01); A61K 912054
`(2013.01); A61K 912059 (2013.01); A61K
`912095 (2013.01); C07D 417112 (2013.01)
`(58) Field of Classification Search
`CPC .. A61K 31/496; A61K 9/0053; A61K 9/2009;
`A61K 9/2018; A61K 9/2027; A61K
`9/2031; A61K 9/2054; A61K
`9/2059; A61K 9/2095; C07D 417/12
`See application file for complete search history.
`References Cited
`
`(56)
`
`U.S. PATENT DOCUMENTS
`
`4,600,579 A
`5,532,372 A
`6,150,366 A
`2003/0203020 A1
`2004/0028741 A1
`2004/0186105 A1
`2005/0147669 A1
`
`7/1986 Salpekar et al.
`7/1996 Saji eta!.
`1112000 Arenson et a!.
`10/2003 Ortyl et a!.
`2/2004 Fujihara
`9/2004 Allenspach et a!.
`7/2005 Lawrence eta!.
`
`FOREIGN PATENT DOCUMENTS
`
`EP
`JP
`JP
`
`1327440 A1
`08-325146
`2000-26292
`
`7/2003
`12/1996
`1/2000
`
`wo
`wo
`wo
`wo
`
`10/2001
`WO 01/76557 A1
`3/2002
`WO 02/24166 A1
`WO 2004017973 A1 * 3/2004
`WO 2004/078173 A1
`9/2004
`
`........... A61K 31/496
`
`OTHER PUBLICATIONS
`
`Ghosh, Tapash K. et a!., "Theory and Practice of. Contemporary
`Pharmaceutics," CRC Press, Chapter 10, p. 279-331 (2005).
`Gennaro, Alfonso R., "Remington: The Science and Practice of
`
`Pharmacy," 191h Edition, Mack Publishing Co., Chapter 92, vol. II,
`pp. 1615-1620, [1995].
`Request for Invalidation from invalidity proceedings in correspond(cid:173)
`ing Chinese Application No. 200680018223.4 (original Chinese
`version and English-language translation), Aug. 5, 2012.
`Bi Dianzhou, Pharmaceutics, Edition 4, Beijing: People's Medical
`Publishing House, Feb. 2003.
`"Application and Effect of Pregelatinized Starch in Tablets," Chi(cid:173)
`nese Pharmaceutical Information, vol. 16, Issue 7, 2000, published
`in 2000.
`"Use of Pregelatinized Starch in Tablet Manufacturing," Chinese
`Pharmaceutical Journal, vol. 29, Issue 4, Apr. 1994, published in
`Apr. 1994.
`"Application of the Pregelatinized Starch in Capsules," Chinese
`Journal of Modern Applied Pharmacy, vol. 8, Issue 1, Feb. 1991,
`published in Feb. 1991.
`"In Vitro Dissolution and Bioavailability of Acyclovir Capsules
`Formulated with Pregelatinized Starch," Chinese Journal of Phar(cid:173)
`maceuticals, 1998, 29(5), published on May 20, 1998.
`Dissolution of Drug Solid Preparation, "Factors Influencing Disso(cid:173)
`lution Rates," Wu Guangchen, Yue Zhiwei, People's Medical Pub(cid:173)
`lishing House, published in Oct. 1994.
`Reply Brief from invalidity proceedings in corresponding Chinese
`Application No. 200680018223.4 (original Chinese version and
`English-language translation), 2012 Oct. 25, 2012
`Examination Decision on the Request for Invalidation in corre(cid:173)
`sponding Chinese Application No. 200680018223.4 (original Chi(cid:173)
`nese version and English-language translation), Apr. 26, 2013.
`EPO Communication dated Feb. 1, 2012, with enclosed Supple(cid:173)
`mental Search Report, in EPO Appln. 11181100.6.
`Kibbe, Handbook of Pharmaceutical Excipients, Chapter 7, pp.
`528-530 (2000).
`Handbook of Pharmaceutical Excipients, 2nd edition, vol. 491, The
`Pharmaceutical Press, 1994.
`Chueshov, V. 1., et a!., "Manufacturing Technologies of Drugs,"
`Promyshlennaya Technologiya Lekarstv, vol. 2, pp. 10-11 (1999).
`Russian Official Action (2009).
`Makino, T., et a!., "Importance of Gelatinization Degree of Starch
`Past Binder in Hardness and Disintegration Time of Tablets," Chern.
`Pharm. Bull., vol. 43, No.3, pp. 514-116 (1995).
`Gohil, U sha C. et a!., "Investigations into the use of pregelatinised
`starch to deveop powder-filled hard capsules," International Journal
`of Pharmaceutics 285 (2004) pp. 51-63.
`* cited by examiner
`Primary Examiner- Sarah Pihonak
`(74) Attorney, Agent, or Firm- Obion, McClelland,
`Maier & Neustadt, L.L.P.
`ABSTRACT
`(57)
`A preparation for oral administration comprising: a prege(cid:173)
`latinized starch comprising N-[ 4-[ 4-(1 ,2-benzisothiazol-3-
`yl)-1-piperazinyl]-(2R,3R)-2,3-tetramethylene-butyl]-(1 'R,
`2'S,3'R,4 'S )-2,3-bicyclo [2,2, 1]-heptanedicarboxyimide
`hydrochloride (lurasidone) represented by the formula (1) as
`an active ingredient: a water-soluble excipient; and a water(cid:173)
`soluble polymeric binder, the preparation exhibiting an
`invariant level of elution behavior even when the content of
`its active ingredient is varied.
`
`34 Claims, 3 Drawing Sheets
`
`Par Pharm., Inc.
`Exhibit 1001
`Page 001
`
`

`

`U.S. Patent
`
`Jan.31,2017
`
`Sheet 1 of 3
`
`US 9,555,027 B2
`
`Figure 1
`
`100
`
`........
`
`!
`I
`
`f2 = 77
`
`'''""""! l
`
`····----1
`
`.. __ __;___, ________ _j
`
`80
`
`60
`
`40
`
`~ ~
`¢)
`......
`<U
`M
`s::
`0
`:;::;
`.2
`0
`ell
`ell
`
`0 20
`
`0
`
`0
`
`15
`
`30
`
`45
`
`Time (min)
`
`__.._ 10 mg tablet (4 tablets)
`
`~40 mg tablet
`
`Par Pharm., Inc.
`Exhibit 1001
`Page 002
`
`

`

`U.S. Patent
`
`Jan.31,2017
`
`Sheet 2 of 3
`
`US 9,555,027 B2
`
`Figure 2
`
`100
`
`80
`
`7
`
`1-+
`
`!2._.
`<l>
`~ 60
`c .s
`_.....,
`;::i
`0
`ffl
`Cll
`6
`
`40
`
`20
`
`0
`
`~~ ·(""":===:=~-----~
`i ........... . ........ --~-;;g:~~1
`
`f2 = 37
`
`l,,·_-_-_1_7·_·_· __ ·_·_·_·_·_·_·_
`
`f ~~ ····················!
`. 1
`l
`........... !
`v ······························!
`
`! __________________ , ____________________ .._ __________________ __!
`30
`45
`15
`0
`
`Time (min)
`
`-+- 40 mg tablet (2 tablets)
`
`~so mg tablet
`
`Par Pharm., Inc.
`Exhibit 1001
`Page 003
`
`

`

`U.S. Patent
`
`Jan.31,2017
`
`Sheet 3 of 3
`
`US 9,555,027 B2
`
`Figure 3
`
`100
`
`80
`
`,o
`S'::.
`...,
`<D 60
`crl
`....
`t::
`0
`·_p 40
`E
`0 "' rJ')
`i5 20
`
`r
`l
`t·
`l l
`r--"'·--
`!··
`~
`~
`
`! ~·. I
`
`'
`
`f2 = 88
`(2 tablets of 40 mg tablet for 80 mg tablet)
`
`f2 ~ 97
`(4 tablets of 20 mg tablet for 80 mg tablet}
`
`............. """'"1
`l
`~
`l
`""Vl: ' l
`
`0
`
`15
`
`30
`
`45
`
`Time (min)
`
`--+- 80 mg tablet
`
`~ 40 mg tablet
`(2 tablets)
`----..&- 20 m g tablet
`(4 tablets)
`
`Par Pharm., Inc.
`Exhibit 1001
`Page 004
`
`

`

`US 9,555,027 B2
`
`1
`PHARMACEUTICAL COMPOSITION
`
`This is a continuation of prior application Ser. No. 14/183,
`283, filed Feb. 18, 2014, which is a continuation of appli(cid:173)
`cation Ser. No. 11/919,678, filed Oct. 31, 2007, which issued
`on May 20, 2014, as U.S. Pat. No. 8,729,085, which is a
`National Stage Entry of International Application No. PCT/
`JP2006/310571, filed May 26, 2006, which claims priority
`to Japanese Patent Application No. 2005-153508, filed May
`26, 2005.
`
`TECHNICAL FIELD
`
`The present invention relates to an oral preparation with
`a good disintegration which comprises as an active ingre(cid:173)
`dient N -[ 4-[ 4-(1 ,2-benzisothiazol-3-yl)-1-piperazinyl]-(2R,
`3R)-2,3-tetramethylene-butyl]-(1 'R,2'S,3'R,4'S)-2,3-bicyclo
`[2,2, 1]heptanedicarboxyimide hydrochloride (lurasidone ).
`More particularly, the present invention relates to a prepa(cid:173)
`ration for oral administration, particularly a tablet, compris(cid:173)
`ing lurasidone as an active ingredient, which has an equiva(cid:173)
`lent dissolution profile of the active ingredient even though
`contents of the active ingredient therein are varied.
`
`BACKGROUND ART
`
`Patent Document 1 discloses that a compound such as
`lurasidone can be orally administered and an oral prepara(cid:173)
`tion can be prepared by blending an active ingredient with
`a conventional carrier, excipient, binder, stabilizer and the
`like, but there is no disclosure of an oral preparation which
`shows a rapid dissolution and has an equivalent dissolution
`profile of the active ingredient even though contents of the
`active ingredient therein are varied in the wide range,
`particularly an oral preparation with increased contents of 35
`the active ingredient which has a similar dissolution profile
`to that of multiple tablets with a lower content of the active
`ingredient per tablet.
`For the purpose of securing the bioequivalence when
`pharmaceutical preparations with different contents of the 40
`active ingredient were administered so as to be the same
`dose to each other, a guideline has been issued, i.e., "Guide(cid:173)
`line for Bioequivalence Studies of Oral Solid Dosage Forms
`with Different Content" (Notification No. 64 of the Evalu(cid:173)
`ation and Licensing Division, Pharmaceutical and Food 45
`Safety Bureau, promulgated on Feb. 14, 2000) by which it
`has been required that pharmaceutical preparations with
`different contents should have an equivalent dissolution
`profile in each test solution such as buffers of pH1.2, 3.0 to
`5.0 and 6.8 (which correspond to the pH values of stomach, 50
`intestine and oral cavity, respectively), water, and saline.
`Patent Document 2 discloses an oral preparation compris(cid:173)
`ing lurasidone as an active ingredient, which shows a rapid
`dissolution and has an equivalent dissolution profile even
`though contents of the active ingredient therein are varied, 55
`particularly an oral preparation with increased contents of
`the active ingredient which has an equivalent dissolution
`profile to that of multiple tablets with a lower content of the
`active ingredient per tablet and can release a slightly water(cid:173)
`soluble active ingredient therefrom at a desired concentra- 60
`tion.
`Patent Document 2 further discloses an oral preparation,
`particularly a tablet, which shows a rapid dissolution of the
`active ingredient even though contents of the active ingre(cid:173)
`dient therein are varied in the range of several mg to several 65
`tens of mg (e.g. in the range of 5 mg to 20 mg or in the range
`of 5 mg to 40 mg), and further has an equivalent dissolution
`
`2
`profile in the same componential ratio. An oral preparation
`has been frequently required to be a preparation with higher
`contents of the active ingredient in order to get higher
`clinical effects, or a preparation which has an equivalent
`dissolution profile to that of multiple tablets and can release
`the active ingredient therefrom at a desired concentration in
`wider ranges of contents in order to adjust clinical effects
`depending on conditions of patients. The art disclosed in
`Patent Document 2 may provide an oral preparation which
`10 has an equivalent dissolution profile in the range of 5 mg to
`40 mg oflurasidone per tablet, as shown in FIG. 1. However,
`as shown in FIG. 2, when the content of the active ingredient
`per tablet was increased to double, i.e., 80 mg tablet, it could
`not have an equivalent dissolution profile. Hence, it remains
`15 in a state of administering multiple tablets at one time or
`using a tablet having a big size which is difficult to admin(cid:173)
`ister. Therefore, for such a slightly water-soluble active
`ingredient as lurasidone, it has been difficult to provide an
`oral preparation having an equivalent dissolution profile
`20 even in high content or in wider ranges of contents of the
`active ingredient.
`In Patent Document 2, a water-soluble polymer binder
`includes starch, but there is no description about a pregela(cid:173)
`tinized starch therein. The pregelatinized starch is known to
`25 remarkably improve a disintegration and a dissolution of a
`pharmaceutical composition as described, for example, in
`Patent Document 3, but it is often used, typically, in 10% or
`less of contents as also described in Non-patent Document
`1.
`30 Patent Document 1: JP2800953
`Patent Document 2: W02002/024166
`Patent Document 3: JP2000-26292
`Non-patent Document 1: Handbook of Pharmaceutical
`Excipients, 2nd edition, 491, 1994, The Pharmaceutical
`Press
`
`DISCLOSURE OF INVENTION
`
`Problems to be Resolved by the Invention
`
`The present invention is directed to provide an oral
`preparation comprising lurasidone as an active ingredient
`which shows a rapid dissolution and has an equivalent
`dissolution profile even though contents of the active ingre(cid:173)
`dient therein are varied in the wide range, particularly an
`oral preparation with increased contents of the active ingre(cid:173)
`dient which has a similar dissolution profile to that of
`multiple tablets with a lower content of the active ingredient
`per tablet and can release the active ingredient therefrom at
`a desired concentration.
`The present invention is directed to provide a preparation
`for oral administration which comprises as an active ingre(cid:173)
`dient N-[ 4-[ 4-(1 ,2-benzisothiazol-3-yl)-1-piperazinyl]-(2R,
`3R)-2,3-tetramethylene-butyl]-(1 'R,2'S,3'R,4'S)-2,3-bicyclo
`[2,2, 1]heptanedicarboxyimide hydrochloride (hereinafter
`referred to as lurasidone), which has an equivalent dissolu(cid:173)
`tion profile of the active ingredient even though contents of
`the active ingredient therein are varied.
`
`Means of Solving the Problems
`
`The present inventors have intensively studied in order to
`solve the above problems and found to solve said problems
`by means of the following methods.
`
`Par Pharm., Inc.
`Exhibit 1001
`Page 005
`
`

`

`US 9,555,027 B2
`
`3
`The present invention includes the following embodi(cid:173)
`ments:
`(1) An oral preparation which comprises N-[4-[4-(1,2-ben(cid:173)
`zisothiazol-3-yl)-1-piperazinyl]-(2R,3R)-2,3-tetramethyl(cid:173)
`ene-butyl]-(1 'R,2'S,3'R,4'S)-2,3-bicyclo[2,2, 1]heptanedicar-
`boxyimide hydrochloride (lurasidone) of the formula (1 ):
`
`(1)
`
`5
`
`15
`
`4
`50% (wt/wt) based on the weight of the preparation and a
`content oflurasidone in the preparation is 25 to 40% (wt/wt).
`(18) The oral preparation of any one of (1) to ( 4) wherein the
`water-soluble excipient is mannitol or lactose, the pregela(cid:173)
`tinized starch is incorporated in an amount of 10 to 50%
`(wt/wt) based on the weight of the preparation and a content
`of lurasidone in the preparation is 25 to 40% (wt/wt).
`(19) The oral preparation of any one of (1) to ( 4) wherein the
`10 water-soluble excipient is mannitol or lactose, the pregela(cid:173)
`tinized starch is incorporated in an amount of 20 to 30%
`(wt/wt) based on the weight of the preparation and a content
`of lurasidone in the preparation is 25 to 40% (wt/wt).
`(20) The oral preparation of any one of (1) to ( 4) wherein the
`water-soluble excipient is mannitol or lactose, the pregela(cid:173)
`tinized starch is incorporated in an amount of 20 to 30%
`(wt/wt) based on the weight of the preparation and a content
`of lurasidone per tablet is 40 to 120 mg.
`(21) The oral preparation of any one of (1) to ( 4) wherein a
`pregelatinizing ratio of the pregelatinized starch is 50 to
`95%.
`(22) The oral preparation of any one of (1) to ( 4) wherein an
`average particle size of lurasidone is 0.1 to 8 f.tm.
`(23) The oral preparation of any one of (1) to ( 4) wherein the
`pregelatinized starch contains water soluble matter of 30%
`or less.
`(24) The oral preparation of any one of (1) to ( 4) wherein the
`water-soluble excipient is mannitol or lactose, the pregela(cid:173)
`tinized starch is incorporated in an amount of 20 to 30%
`(wt/wt) based on the weight of the preparation, a content of
`lurasidone in the preparation is 25 to 40% (wt/wt) and a
`35 content of lurasidone per tablet is 20 to 120 mg.
`
`a pregelatinized starch, a water-soluble excipient and a 20
`water-soluble polymer binder.
`(2) An oral preparation which is prepared by granulating a
`powder mixture comprising lurasidone, a pregelatinized
`starch and a water-soluble excipient by using a solution of
`a water-soluble polymer binder.
`(3) An oral preparation which is prepared by granulating a
`powder mixture comprising a pregelatinized starch and a
`water-soluble excipient by a solution or dispersion of lur(cid:173)
`asidone and a water-soluble polymer binder.
`( 4) The oral preparation of any one of (1) to (3) wherein the 30
`water-soluble excipient is mannitol or lactose.
`(5) A method of granulation of a powder mixture which
`comprises granulating a powder mixture comprising lurasi(cid:173)
`done, a pregelatinized starch and a water-soluble excipient
`by using a solution of a water-soluble polymer binder.
`(6) A method of granulation of a powder mixture which
`comprises granulating a powder mixture comprising a
`pregelatinized starch and a water-soluble excipient by using
`a solution or dispersion of lurasidone and a water-soluble
`polymer binder.
`(7) The method of granulation of (5) wherein the water(cid:173)
`soluble excipient is mannitol or lactose.
`(8) The oral preparation of any one of (1) to ( 4) wherein the
`pregelatinized starch is incorporated in an amount of 10 to
`50% (wt/wt) based on the weight of the preparation.
`(9) The oral preparation of any one of (1) to ( 4) wherein the
`pregelatinized starch is incorporated in an amount of 20 to
`30% (wt/wt) based on the weight of the preparation.
`(10) The oral preparation of any one of (1) to (4) wherein a
`content oflurasidone in the preparation is 20 to 45% (wt/wt). 50
`(11) The oral preparation of any one of (1) to ( 4) wherein a
`content oflurasidone in the preparation is 25 to 40% (wt/wt).
`(12) The oral preparation of any one of (1) to (4) wherein a
`content of lurasidone per tablet is 10 to 160 mg.
`(13) The oral preparation of any one of (1) to (4) wherein a 55
`content of lurasidone per tablet is 20 to 120 mg.
`(14) The oral preparation of any one of (1) to (4) wherein a
`content of lurasidone per tablet is 40 to 120 mg.
`(15) The oral preparation of any one of(1) to ( 4) wherein the
`water-soluble excipient is mannitol or lactose and the prege- 60
`latinized starch is incorporated in an amount of 10 to 50%
`(wt/wt) based on the weight of the preparation.
`(16) The oral preparation of any one of(1) to ( 4) wherein the
`water-soluble excipient is mannitol or lactose and a content
`of lurasidone in the preparation is 25 to 40% (wt/wt).
`(17) The oral preparation of any one of(1) to ( 4) wherein the
`pregelatinized starch is incorporated in an amount of 10 to
`
`25
`
`Effects of Invention
`
`40
`
`It has been confirmed in the art disclosed in Patent
`Document 2 that a pharmaceutical preparation with low
`contents of lurasidone up to 40 mg per tablet could provide
`an oral preparation having an equivalent dissolution profile.
`However, a pharmaceutical preparation with higher contents
`45 of lurasidone could not have an equivalent dissolution
`profile. Therefore, double amounts or more of the prepara(cid:173)
`tion with low contents should have been administered to a
`patient in need of high doses of lurasidone, which imposed
`increased burdens on the patient, and hence an improvement
`thereon has been required. The preparation of the present
`invention which comprises a pregelatinized starch can pro-
`vide an oral preparation with higher contents of lurasidone
`which imposes less of burdens on a patient. Additionally, the
`present invention can provide an oral preparation with high
`contents of lurasidone, and a preparation for oral adminis(cid:173)
`tration which has an equivalent dissolution profile even
`though contents of lurasidone therein are varied. Moreover,
`the preparations are excellent for a long-term conservation.
`
`BEST MODE FOR CARRYING OUT THE
`INVENTION
`
`N -[ 4-[ 4-(1 ,2-benzisothiazol-3-yl)-1-piperazinyl]-(2R,
`65 3R)-2,3-tetramethylene-butyl]-(1 'R,2'S,3'R,4'S)-2,3-bicyclo
`[2,2, 1]heptanedicarboxyimide hydrochloride (lurasidone)
`refers to a compound of the following formula:
`
`Par Pharm., Inc.
`Exhibit 1001
`Page 006
`
`

`

`US 9,555,027 B2
`
`5
`
`(1)
`
`HCl
`
`6
`includes hydroxypropylcellulose,
`More preferable one
`hydroxypropyl methylcellulose, polyvinylpyrrolidone or
`polyvinyl alcohol. Said water-soluble polymer binder may
`be used alone, or two or more thereof may be used together.
`5 The water-soluble polymer binder is incorporated in an
`amount of, for example, the range of0.5 to 10% by weight,
`preferably the range of 1 to 5% by weight on the basis of the
`total weight of a tablet.
`The oral preparation in the form of a pharmaceutical
`10 composition of the present invention refers to a pharmaceu(cid:173)
`tical preparation which is formulated into tablet, capsule,
`granule or fine granule. Said preparation may be formulated
`by a conventional method into tablet, capsule, granule or
`fine granule by using water-soluble excipient as well as
`15 water-insoluble excipient, binder, disintegrant, lubricant,
`etc. The following agents may be added thereto.
`The "water-insoluble excipient" includes, for example,
`corn starch, crystalline cellulose, etc. Said water-insoluble
`excipient may be used alone, or two or more thereof may be
`20 used together.
`The "disintegrant" includes, for example, corn starch,
`crystalline cellulose, low substituted hydroxypropylcellu(cid:173)
`lose, carmellose, carmellose calcium, carmellose sodium,
`croscarmellose sodium, carboxymethyl starch sodium,
`25 crospovidone, etc. Said disintegrant may be used alone, or
`two or more thereof may be used together. The disintegrant
`is used in an amount of, for example, the range of 0 to 10%
`by weight, preferably the range of 0.5 to 5% by weight on
`the basis of the total weight of a tablet.
`The "lubricant" includes, for example, magnesium stear(cid:173)
`ate, talc, polyethylene glycol, silica, hydrogenated vegetable
`oil, etc.
`The oral preparation of the present invention may be
`prepared according to a conventional method depending on
`35 a desired dosage form.
`(1) Preparation of an Aqueous Solution of Water-Soluble
`Polymer Binder:
`A water-soluble polymer binder is dissolved in purified
`water. The amount of the water-soluble polymer binder is,
`40 for example, in the range of 1 to 20% by weight, preferably
`in the range of 2 to 8% by weight of purified water.
`(2) Preparation of Granule Comprising Lurasidone:
`To a fluid bed granulator are charged excipient including
`lurasidone, mannitol and partly pregelatinized starch, and
`45 disintegrant, and thereto is sprayed the water-soluble poly(cid:173)
`mer binder prepared in the above process (1) to be granu(cid:173)
`lated.
`The apparatus for granulation includes, for example, one
`classified into fluid bed granulation, high share granulation,
`rota fluid bed granulation, etc., but it is not limited thereto.
`(3) Drying of Granule:
`The above-obtained granule is dried either under reduced
`pressure or atmospheric pressure. The drying is carried out
`so that the loss on dry measured by infrared moisture meter
`is, for example, within 3% by weight, preferably 1 to 2% by
`weight.
`(4) Blending of Lubricant:
`To the granule dried in the above (3) is added lubricant to
`be mixed. For mixing, for example, a blending machine
`classified into diffusion mixers [Tumble] is used. Specifi(cid:173)
`cally, tumble blender, V blenders, double cone, bin tumble,
`etc. are used, but it is not limited thereto.
`(5) Compression:
`The above mixture is compressed to give a tablet.
`The apparatus for compression includes, for example, one
`classified into tablet press, etc. The compression hardness is
`selected, for example, from the range of 30 to 200N.
`
`(see, for example, JP2800953). Lurasidone is known to
`exhibit a psychotropic effect, and it is useful as a therapeutic
`agent for schizophrenia, etc. Said compound is incorporated
`into the preparation, for example, in the range of 10 to 50%
`by weight, preferably in the range of 20 to 45% by weight,
`particularly in the range of 20 to 45% by weight on the basis
`of the total weight of a tablet. Additionally, the compound is
`preferably finely milled, for example, 90% by volume or
`more of particles have 27 f.Ull or less of particle size, and
`average particle size in a volume ratio (i.e. 50% by volume
`particle size) includes, for example, in the range of0.1 to 8
`f.tm, preferably in the range of 1 to 4 f.tm. The contents of
`lurasidone are 10 to 160 mg, preferably 20 to 120 mg, more
`preferably 40 to 120 mg per tablet.
`The "pregelatinized starch" refers to those prepared by
`pregelatinizing various kinds of starch (e.g. com starch,
`potato starch, wheat starch, rice starch, tapioca starch, etc.),
`and may include pregelatinized starch or partly pregelati- 30
`nized starch described in Japanese Pharmaceutical Excipi(cid:173)
`ents. The pregelatinized starch has a pregelatinizing ratio,
`for example, in the range of 50 to 100%, preferably in the
`range of 50 to 95%, more preferably in the range of 80 to
`95%. Additionally, the pregelatinized starch contains water
`soluble matter of, for example, 40% or less, more preferably
`30% or less. Such a pregelatinized starch is typically used in
`a powder which average particle size is in the range of 1 to
`1000 f.Ull, preferably in the range of 1 to 500 f.tm, more
`preferably in the range of 10 to 100 f.tm. A commercially
`available pregelatinized starch suitable for the present inven(cid:173)
`tion includes, for example, partly pregelatinized starch such
`as PCS (brand name, manufactured by Asahi Kasei Corpo(cid:173)
`ration) or Starch 1500 (brand name, manufactured by Col(cid:173)
`orcon, Inc.), etc. Among the above pregelatinized starch,
`partly pregelatinized starch such as PCS (brand name,
`manufactured by Asahi Kasei Corporation) is preferably
`used. A pregelatinizing ratio of partly pregelatinized starch
`is preferably in the range of 50 to 95%, more preferably in
`the range of 80 to 95%. The pregelatinized starch used in the 50
`present invention is in the range of 10% to 50%, preferably
`in the range of 10% to 40%, particularly in the range of 20%
`to 30% by weight of the preparation.
`The "water-soluble excipient" includes, for example,
`mannitol, lactose, saccharose, sorbitol, D-sorbitol, erythri- 55
`to!, xylitol, etc. More preferable one includes mannitol and
`lactose. Further preferable one may include mannitol. Also,
`said water-soluble excipient may be used alone, or two or
`more thereof may be used together. The water-soluble
`excipient is incorporated in an amount of, for example, the 60
`range of 30 to 80% by weight, preferably the range of 40 to
`60% by weight on the basis of the total weight of a tablet.
`The average particle size of mannitol is, for example, in the
`range of 1 0 to 200 f.tm.
`for 65
`includes,
`The "water-soluble polymer binder"
`example, hydroxypropylcellulose, hydroxypropyl methyl(cid:173)
`cellulose, polyvinylpyrrolidone, polyvinyl alcohol, etc.
`
`Par Pharm., Inc.
`Exhibit 1001
`Page 007
`
`

`

`US 9,555,027 B2
`
`7
`(6) Film-Coating is Optionally Carried Out:
`The above-obtained tablet may be optionally subjected to
`if necessary. The apparatus for coating
`film-coating,
`includes, for example, one classified into a coating pan.
`Preferable one includes one classified by perforated coating
`system.
`The coating agent includes, for example, a mixture of
`base material (e.g. hydroxypropyl methylcellulose, hydro(cid:173)
`propylcellulose, polyvinylpyrrolidone, polyvinyl alcohol,
`etc.) and plasticizer (e.g. polyethylene glycol, propylene 10
`glycol, triacetin, triethyl citrate, glycerin, glycerin fatty acid
`ester, polyethylene glycol, etc.). If necessary, an additive
`such as titanium oxide may be also added therein. After
`film-coating, carnauba wax, etc. may be also added as
`polishing agent therein.
`(7) Drying:
`The above-obtained tablet is dried. The drying is carried
`out either under reduced pressure or atmospheric pressure so
`that the loss on dry measured by infrared moisture meter is,
`for example, within 3% by weight, preferably 1 to 2% by
`weight.
`Examples of the present invention are illustrated below.
`Said examples are intended to exemplifY the present inven(cid:173)
`tion but not to limit the present invention thereto.
`
`20
`
`15
`
`8
`
`(3) Compression:
`The granule for compression prepared in the above (2)
`was compressed by HT-AP12SS-II (manufactured by Hata
`Iron Works Co., Ltd.) to give a tablet.
`Pestle size: <jl10 mm 14R
`Thickness: 4.20 to 4.30 mm
`Compression pressure: 10 KN
`(4) Coating:
`The uncoated tablet prepared in the above (3) were coated
`by using High Coater HCT30N (manufactured by Freund
`Industrial Co., Ltd.) under the following conditions so as to
`control amounts of the coat to 5 mg, and thereto was added
`carnauba wax after coating to give a film-coated tablet.
`FC Conditions
`Temperature for supplying air: 80° C.
`Airflow: 0.6 m 3/min
`Rotation rate of pan: 25 rpm
`Spray pressure: 0.15 MPa
`Liquid flow rate: 5 g/min
`The preparation obtained in the above method was evalu(cid:173)
`ated a quality thereof according to the following methods,
`and the present invention has been achieved on the basis of
`the knowledge obtained therein.
`
`C. Quality Evaluation
`
`EXAMPLES
`
`Example 1
`
`A. A Film-Coated Tablet Comprising 80 mg of
`Lurasidone (Example 1)
`
`Granules, uncoated tablets and FC tablets comprising the
`following components are sequentially prepared. The charg(cid:173)
`ing amounts shown in parentheses in the following descrip(cid:173)
`tion are an example for preparing the formulation shown in
`Example 1.
`According to the preparation method, other examples may
`be also prepared in principle, provided that the charging
`amounts are needed to be changed depending on formula(cid:173)
`tions.
`
`B. Preparation Method
`
`30
`
`25 (1) Dissolution Test
`A manufactured preparation was subjected to the disso(cid:173)
`lution test according to the Japanese Pharmacopoeia, Dis(cid:173)
`solution test, Method 2. Measuring conditions are shown
`below.
`Test solution: Diluted Mcilvaine buffer, pH4.0
`Rotation rate of paddle: 50 rpm
`Test fluid: 900 ml
`(2) Similarity of Dissolution Profiles
`A similarity factor f2 shown in Scale-Up and Past-
`35 Approval Changes for Intermediate Release Products (SU(cid:173)
`PAC-IR) was used as an indicative for evaluating a similar(cid:173)
`ity of dissolution profiles. The f2 value is calculated by the
`following equation. It was determined that each manufac(cid:173)
`tured preparation had a similar dissolution profile in case
`that the f2 value calculated from dissolution ratio of each
`40 preparation by SUPAC-IR was in the range of 50sf2s00.
`Dissolution ratios at three time points such as 15 min, 30 min
`and 45 min after starting the test were used for a calculation
`of the f2 value.
`
`(1) Preparation of Binding Solution (5% Aqueous Hydroxy(cid:173)
`propyl Methylcellulose Solution):
`Hydroxypropyl methylcellulose (32 g) as water-soluble
`polymer binder was dissolved in purified water (608 g) to
`give binding solution.
`(2) Granulation:
`Lurasidone (320 g), mannitol (576 g), partly pregelati- 50
`nized starch (320 g) and croscarmellose sodium (16 g) were
`charged to a fluid bed granulator (Multiplex MP-01/manu(cid:173)
`factured by Powrex Corporation), and the mixture was
`granulated by spray granulation under the following condi(cid:173)
`tions using the binding solution prepared in the above (1) to 55
`give granule powder. To the obtained granule powder was
`added magnesium stearate to give a granule for compression
`having a formulation (b) after mixing (40 rpm, 5 minutes).
`Magnesium stearate was mixed in amounts calculated from
`a formulation on the basis of yields of granule powder.
`Conditions for Granulation
`Temperature for supplying air: 60° C.
`Airflow: 50 to 65 m 3/hr
`Spray speed: 13 g/min
`Diameter of spray nozzle: 1.2 mm
`Spray pressure: 0.12 MPa
`Gun position: the middle stand
`
`45
`
`100
`
`L (Ti-Ri) 2
`1 + :___;~!::____ _ _
`
`Ti and Ri are the percent dissolved at each point.
`n is the number of points to be compared.
`(3) Size Distribution
`A size distribution of lurasidone was measured according
`to a dry-spray method by Laser Diffraction Particle Size
`Analyzer (SLAD-3000/Shimadzu Corporation). Measuring
`conditions are shown below.
`
`Amounts of sample: 2 g
`Air pressure: 0.4 MPa or
`more
`60 Turntable rotation speed: 2
`Parameter settin