`Fujihara
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 8,883,794 B2
`*Nov. 11, 2014
`
`US008883794B2
`
`(54) PHARMACEUTICAL COMPOSITION
`(71) Applicant: Dainippon Sumitomo Pharma Co.,
`Ltd., Osaka (JP)
`(72) Inventor: Kazuyuki Fujihara, Suzuka (JP)
`(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.
`This patent is subject to a terminal dis
`claimer.
`
`(*) Notice:
`
`(21) Appl. No.: 14/183,283
`
`(22) Filed:
`
`Feb. 18, 2014
`
`(65)
`
`Prior Publication Data
`|US 2014/0235651 A1
`Aug. 21, 2014
`
`Related U.S. Application Data
`(63) Continuation of application No. 1 1/919,678, filed as
`application No. PCT/JP2006/310571 on May 26,
`2006, now Pat. No. 8,729,085.
`
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`
`(51) Int. Cl.
`A6 IK 31/497
`C07D 413/00
`C07D 417/00
`C07D 41.9/00
`A6 IK 31/496
`(52) U.S. CI.
`CPC .................................... A61K3I/496 (2013.01)
`USPC ...................................... 514/254.04; 544/368
`(58) Field of Classification Search
`USPC ...................................... 514/254.04; 544/368
`See application file for complete search history.
`
`
`
`(56)
`
`References Cited
`
`|U.S. PATENT DOCUMENTS
`
`4,600,579 A
`5,532,372 A
`2004/0028741 A1
`
`7/1986 Salpekar et al.
`7/1996 Saji et al.
`2/2004 Fujihara
`
`FOREIGN PATENT DOCUMENTS
`
`7/2003
`1327.440 A1
`EP
`12/1996
`08-325 146
`JP
`1/2000
`2000-26292
`JP
`WO 01/76557 A1 10/2001
`WO
`WO 02/24.166 A1
`3/2002
`WO
`WO WO 2004/078.173 A1
`9/2004
`
`OTHER PUBLICATIONS
`
`Request for Invalidation from invalidity proceedings in correspond
`ing Chinese Application No. 200680018223.4 (original Chinese ver
`sion 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.” Chinese
`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 Jour
`nal of Modern Applied Pharmacy, vol. 8, Issue 1, Feb. 1991, pub
`lished in Feb. 1991.
`“In Vitro Dissolution and Bioavailability of Acyclovir Capsules For
`mulated with Pregelatinized Starch.” Chinese Journal of Pharmaceu
`ticals, 1998, 29(5), published on May 20, 1998.
`Dissolution of Drug Solid Preparation, “Factors Influencing Disso
`lution Rates.” Wu Guangchen, Yue Zhiwei, People’s Medical Pub
`lishing House, published in Oct. 1994.
`Reply Brief from invalidity proceedings in corresponding Chinese
`Application No. 2006800182234 (original Chinese version and
`English-language translation), Oct. 25, 2012.
`Examination Decision on the Request for Invalidation in correspond
`ing Chinese Application No. 200680018223.4 (original Chinese ver
`sion and English-language translation), Apr. 26, 2013.
`EPO Communication dated Feb. 1, 2012, with enclosed Supplemen
`tal 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 al., “Manufacturing Technologies of Drugs.”
`Promyshlennaya Technologiya Lekarstv, vol. 2, pp. 10-11 (1999).
`Russian Official Action (2009).
`Makino, T., et al., “Importance of Gelatinization Degree of Starch
`Past Binder in Hardness and Disintegration Time of Tablets.” Chem.
`Pharm. Bull., vol.43, No. 3, pp. 514-116 (1995).
`Primary Examiner – Sarah Pihonak
`(74) Attorney, Agent, or Firm – Finnegan, Henderson,
`Farabow, Garrett & Dunner, L.L.P.
`
`ABSTRACT
`(57)
`A preparation for oral administration comprising: a pregela
`tinized 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]-heptanedicarboxylmide
`hydrochloride (lurasidone) represented by the formula (1) as
`an active ingredient; a water-soluble excipient; and a water
`soluble polymeric binder, the preparation exhibiting an
`invariant levelofelution behavior even when the content of its
`active ingredient is varied.
`
`14 Claims, 3 Drawing Sheets
`
`Par Pharm., Inc.
`Exhibit 1040
`Page 001
`
`
`
`U.S. Patent
`
`Nov. 11, 2014
`
`Sheet 1 of 3
`
`US 8,883,794 B2
`
`Figure i
`
`
`
`Tirne (min}
`–8– 10 mg tablet (4 tablets)
`-º- 40 rpg tablet
`
`Par Pharm., Inc.
`Exhibit 1040
`Page 002
`
`
`
`U.S. Patent
`
`Nov. 11, 2014
`
`Sheet 2 of 3
`
`US 8,883,794 B2
`
`{}
`
`35
`
`30
`
`45
`
`Tirne train;
`~$– 4:3 mg tablet (2 tablets;
`~5-80 mg tablet
`
`Par Pharm., Inc.
`Exhibit 1040
`Page 003
`
`
`
`U.S. Patent
`
`Nov.11, 2014
`
`Sheet 3 of 3
`
`US 8,883,794 B2
`
`Figure 3
`
`
`
`0
`
`LS
`
`rate(%)
`Dissohitian
`
`30
`
`45
`
`Time fmin}
`
`—e— 8D mg tablet
`
`~o— 40 me tablet
`{2 tablets}
`—4-- 20 mg tablet
`{4 tablets}
`
`a
`f2 = a8
`(Q tablets of 40 mg tablet for 80 mg tabiet}
`
`;
`{2 = 97
`{4 tablets of 20 mg tablet for 80 mg tablet)
`
`Par Pharm., Inc.
`Exhibit 1040
`Page 004
`
`Par Pharm., Inc.
`Exhibit 1040
`Page 004
`
`
`
`1
`PHARMACEUTICAL COMPOSITION
`
`US 8,883,794 B2
`
`2
`that of multiple tablets and can release the active ingredient
`therefrom at a desired concentration in wider ranges of con
`tents in order to adjust clinical effects depending on condi
`tions of patients. The art disclosed in Patent Document 2 may
`provide an oral preparation which has an equivalent dissolu
`tion profile in the range of 5 mg to 40 mg of lurasidone 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 in a state of administer
`ing multiple tablets at one time or using a tablet having a big
`size which is difficult to administer. Therefore, for such a
`slightly water-soluble active ingredient as lurasidone, it has
`been difficult to provide an oral preparation having an equiva
`lent dissolution profile even in high contentorin widerranges
`of contents of the active ingredient.
`In Patent Document 2, a water-soluble polymer binder
`includes starch, but there is no description about a pregelati
`nized starch therein. The pregelatinized starch is known to
`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.
`Patent Document 1: JP2800.953
`Patent Document 2: WO2002/024166
`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 prepa
`ration comprising 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 in the wide range, particularly an oral preparation
`with increased contents of the active ingredient 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 concen
`tration.
`The present invention is directed to provide a preparation
`for oral administration which comprises as an active ingredi
`ent
`N-[4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]-(2R,
`3R)-2,3-tetramethylene-butyl]-(1R,2S,3R,4'S)-2,3-bicyclo
`[2.2.1]heptanedicarboxylmide hydrochloride (hereinafter
`referred to as lurasidone), which has an equivalent dissolution
`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.
`The present invention includes the following embodi
`ments:
`(1) An oral preparation which comprises N-[4-(4-(1,2-ben
`zisothiazol-3-yl)-1-piperazinyl]-(2R,3R)-2,3-tetramethyl
`ene-butyl]-(1'R,2S,3R,4'S)-2,3-bicyclo[2.2.1]heptanedicar
`boxylmide hydrochloride (lurasidone) of the formula (1):
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`This is a continuation of prior application Ser. No. 1 1/919,
`678, which is a National Stage Entry of International Appli
`cation No. PCT/JP2006/310571, filed May 26, 2006, in the
`name of Kazuyuki FUJIHARA for PHARMACEUTICAL
`COMPOSITION, the content of each of which is incorpo
`rated herein by reference.
`
`TECHNICAL FIELD
`
`The present invention relates to an oral preparation with a
`good disintegration which comprises as an active ingredient
`N-[4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]-(2R,3R)-2,
`3-tetramethylene-butyl]-(1'R,2S,3R,4'S)-2,3-bicyclo[2.2.1]
`heptanedicarboxylmide hydrochloride (lurasidone). More
`particularly, the present invention relates to a preparation for
`oral administration, particularly a tablet, comprising lurasi
`done as an active ingredient, which has an equivalent disso
`lution 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 preparation
`can be prepared by blending an active ingredient with a con
`ventional 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 ingre
`dient therein are varied in the wide range, particularly an oral
`preparation with increased contents of 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 bioeduivalence when phar
`maceutical preparations with different contents of the active
`ingredient were administered so as to be the same dose to each
`other, a guideline has been issued, i.e., “Guideline for
`Bioeduivalence Studies of Oral Solid Dosage Forms with
`Different Content” (Notification No. 64 of the Evaluation and
`Licensing Division, Pharmaceutical and Food 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, intestine and oral
`cavity, respectively), water, and saline.
`Patent Document 2 discloses an oral preparation compris
`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,
`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-soluble
`active ingredient therefrom at a desired concentration.
`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 ingredi
`ent therein are varied in the range of several mg to several tens
`of mg (e.g. in the range of 5 mg to 20 mg or in the range of 5
`mg to 40mg), and further has an equivalent dissolution 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
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`Par Pharm., Inc.
`Exhibit 1040
`Page 005
`
`
`
`US 8,883,794 B2
`
`(1)
`
`4
`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
`water-soluble excipient is mannitol or lactose, the pregelati
`nized 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 pregelati
`nized 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 plm.
`(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 pregelati
`nized 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
`content of lurasidone per tablet is 20 to 120 mg.
`
`Effects of Invention
`
`It has been confirmed in the art disclosed in Patent Docu
`ment 2 that a pharmaceutical preparation with low contents of
`lurasidone up to 40 mg per tablet could provide an oral prepa
`ration having an equivalent dissolution profile. However, a
`pharmaceutical preparation with higher contents of lurasi
`done could not have an equivalent dissolution profile. There
`fore, double amounts or more of the preparation 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 provide an oral prepa
`ration 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 lurasi
`done, and a preparation for oral administration which has an
`equivalent dissolution profile even though contents of lurasi
`done therein are varied. Moreover, the preparations are excel
`lent for a long-term conservation.
`
`BEST MODE FOR CARRYING OUT THE
`INVENTION
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`a pregelatinized starch, a water-soluble excipient and a 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 lurasi
`done and a water-soluble polymer binder.
`(4) The oral preparation of any one of (1) to (3) wherein the
`water-soluble excipient is mannitol or lactose.
`(5) A method of granulation of a powder mixture which
`comprises granulating a powder mixture comprising lurasi
`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 prege
`latinized starch and a water-soluble excipient by using a solu
`tion or dispersion of lurasidone and a water-soluble polymer
`binder.
`(7) The method of granulation of (5) wherein the water
`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 of lurasidone in the preparation is 20 to 45% (wt/wt).
`(11) The oral preparation of any one of (1) to (4) wherein a
`content of lurasidone 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
`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
`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 excipientis 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
`50% (wt/wt) based on the weight of the preparation and a
`content of lurasidone 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 pregelati
`nized starch is incorporated in an amount of 10 to 50% (wt/
`
`50
`
`[2.2.1]heptanedicarboxylmide hydrochloride (lurasidone)
`refers to a compound of the following formula:
`
`55
`
`
`
`60
`
`65
`
`(1)
`
`HCI
`
`Par Pharm., Inc.
`Exhibit 1040
`Page 006
`
`
`
`US 8,883,794 B2
`
`0
`
`a 5
`
`IcS
`
`5
`(see, for example, JP2800953). Lurasidone is known to
`exhibit a psychotropic effect, and it is useful as a therapeutic
`agent for schizophrenia, etc. Said compoundis 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 onthe basis
`of the total weight of a tablet. Additionally, the compoundis
`preferably finely milled, for example, 90% by volume or
`more of particles have 27 um orless of particle size, and
`average particle size in a volumeratio (i.e. 50% by volume
`particle size) includes, for example, in the range of 0.1 to 8
`um, preferably in the range of 1 to 4 um. The contents of
`lurasidone are 10 to 160 mg, preferably 20 to 120 mg, more
`preferably 40 to 120 mgpertablet.
`The “pregelatinized starch” refers to those prepared by
`pregelalinizing various kinds of starch (e.g. corn starch,
`potato starch, wheat starch, rice starch, tapioca starch,etc.),
`and may include pregelatinized starch or partly pregelati-
`
`nized starch described in Japanese Pharmaceutical Excipi-
`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
`i]a
`less. Sucha pregelatinized starch is typically used inapowder :
`whichaverage particle size is in the range of1 to 1000 um,
`preferably in the range of 1 to 500 um, morepreferably in the
`range of 10 to 100 um. A commercially available pregelati-
`nized starch suitable for the present invention includes, for
`example, partly pregelatinized starch such as PCS (brand
`name, manufactured by Asahi Kasei Corporation) or Starch
`1500 (brand name, manufactured by Colorcon, Inc.}, etc.
`Amongthe above pregelatinizedstarch, 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 present invention is in the
`range of 10% to 50%,preferablyin the range of 10% to 40%,
`particularly in the range of 20% to 30% byweight of the
`preparation.
`The “water-soluble excipient”includes, for example, man-
`nitol,
`lactose, saccharose, sorbitol, D-sorbitol, erythritol,
`xylitol, etc. More preferable one includes mannitol and lac-
`tose. 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 excipientis
`incorporated in an amountof, for example, the range of 30 to
`80%by weight, preferably the range of 40 to 60% by weight
`i2
`on thebasis ofthe total weight ofa tablet. The average particle 5
`size ofmannitolis, for example, in the range of 10 to 200 um.
`The
`‘water-soluble polymer binder’
`includes,
`for
`example, hydroxypropylcellulose, hydroxypropyl methyl-
`cellulose, polyvinylpyrrolidone, polyvinyl alcohol, etc. More
`preferable one includes hydroxypropylcecllulose, hydrox-
`ypropyl methylcellulose, polyvinylpyrrolidone or polyvinyl
`alcohol. Said water-soluble polymer binder may be used
`alone, or two or more thereof may be used together. 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% byweight onthebasisofthe total weight
`of a tablet.
`Theoral preparation in the form of a pharmaceutical com-
`position of the present invention refers to a pharmaceutical
`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
`
`5
`
`65
`
`6
`granule by using water-soluble excipient as well as water-
`insoluble excipient, binder, disintegrant, lubricant, etc. The
`following agents may be addedthereto.
`‘The “water-insoluble excipient” includes, for example,
`corn starch, crystalline cellulose, ctc. Said water-insoluble
`excipient maybe used alone, or two or more thereof may be
`used together.
`The“disintegrant” includes, for example, cornstarch, crys-
`talline cellulose,
`low substituted hydroxypropylcellulose,
`carmellose, carmellose calcium, carmellose sodium, croscar-
`mellose sodium, carboxymethy! starch sodium, crospovi-
`done,etc. Said disintegrant may be used alone, or two or more
`thereof may be used together. ‘The disintegrantis used in an
`amount of, for cxample, the range of 0 to 10%by weight,
`preferably the range of0.5 to 5% by weight on the basis ofthe
`total weight of a tablet.
`The “lubricant” includes, for example, magnesiumstear-
`ate, talc, polyethylene glycol, silica, hydrogenated vegetable
`oil, etc.
`The oral preparation of the present invention maybe pre-
`pared according, to a conventional method depending on 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 amountofthe water-soluble polymerbinderis, for
`example, in the range of 1 to 20% byweight, 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
`disintegrant, and thereto is sprayed the water-soluble polymer
`binder prepared in the above process (1) to be granulated.
`The apparatus for granulation includes, for example, one
`classified into fluid bed granulation, high share granulation,
`roto 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 almospheric pressure. The drying is carried oul so
`that the loss on dry measured by infrared moisture meteris,
`for example, within 3% by weight, preferably 1
`to 2% by
`weight.
`(4) Blending of Lubricant:
`To the granuledriedin the above (3) is added lubricant to be
`mixed. For mixing, for example, a blending machine classi-
`fied into diffusion mixers [Tumble] is used. Specifically,
`tumble blender, V blenders, double cone, bin tumble,etc. are
`used, bul il is not limited thereto.
`(5) Compression:
`The above mixture is compressedto give a tablet.
`The apparatus for compression includes, for example, one
`classified into tablet press, etc. The compression hardness is
`selected, for example, fromthe range of 30 to 200N.
`(6) Film-Coating is Optionally Carried Out:
`The above-obtained tablet may be optionally subjected to
`film-coating, ifnecessary. The apparatus for coating includes,
`for example, one classified into a coating pan. Preferable one
`includes oneclassified by perforated coating system.
`The coating agent includes, for example. a mixture of base
`material (e.g. hydroxypropyl methylcellulose, hydropropyl-
`cellulose. polyvinylpyrrolidone, polyvinyl alcohol, etc.) and
`plasticizer (e.g. polyethylene glycol, propylene glycol, triace-
`tin, triethyl citrate, glycerin, glycerin fatty acid ester, poly-
`ethylene glycol, ctc.). If necessary, an additive suchastita-
`nium oxide may be also added therein. After film-coating,
`camauba wax, elc. may be also added as polishing agent
`therein.
`
`Par Pharm., Inc.
`Exhibit 1040
`Page 007
`
`Par Pharm., Inc.
`Exhibit 1040
`Page 007
`
`
`
`US 8,883,794 B2
`
`7
`
`(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
`tion but not to limit the present invention thereto.
`
`8
`
`FC Conditions
`Temperature for supplying air: 80°C.
`Airflow: 0.6 mº/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
`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
`
`(1) Dissolution Test
`A manufactured preparation was subjected to the dissolu
`tion test according to the Japanese Pharmacopoeia, Dissolu
`tion test, Method 2. Measuring conditions are shown below.
`Test solution: Diluted Mcllvaine 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-Ap
`proval Changes for Intermediate Release Products (SUPAC
`IR) was used as an indicative for evaluating a similarity of
`dissolution profiles. The f2 value is calculated by the follow
`ing equation. It was determined that each manufactured
`preparation had a similar dissolution profile in case that the f2
`value calculated from dissolution ratio of each preparation by
`SUPAC-IR was in the range of 50sf2=100. 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.
`
`f2 = 50. LOG
`
`1()()
`
`:
`(Ti — Riy”
`
`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:
`Air pressure:
`Turntable rotation speed:
`Parameter setting
`Environmental setting
`
`Monitoring average:
`Dark measuring average:
`Light intensity display Max:
`Previous blank:
`Printer:
`Refractive parameter
`
`Standard refraction:
`Measuring conditions setting
`
`Measuring average:
`Measuring interval (sec):
`Average:
`Measured absorbance range
`
`(Max):
`(Min):
`
`2 g
`0.4 MPa or more
`2
`
`16
`2
`2000
`reading
`monochrome
`
`1.70-0.20i
`
`1
`1
`64
`
`0.1
`0.05
`
`EXAMPLES
`
`Example 1
`
`A. A Film-Coated Tablet Comprising 80 Mg of
`Lurasidone (Example 1)
`
`10
`
`15
`
`Granules, uncoated tablets and FC tablets comprising the
`following components are sequentially prepared. The charg
`ing amounts shown in parentheses in the following descrip
`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
`tions.
`
`20
`
`25
`
`B. Preparation Method
`
`30
`
`35
`
`40
`
`(1) Preparation of Binding Solution (5% Aqueous Hydrox
`ypropyl 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 pregelatinized
`starch (320 g) and croscarmellose sodium (16 g) were
`charged to a fluid bed granulator (Multiplex MP-01/manufac
`tured by Powrex Corporation), and the mixture was granu
`lated by spray granulation under the following conditions
`using the binding solution prepared in the above (1) to 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). Magne
`45
`sium stearate was mixed in amounts calculated from a for
`mulation on the basis of yields of granule powder.
`Conditions for Granulation
`Temperature for supplying air. 60° C.
`Airflow: 50 to 65 mº/hr
`Spray speed: 13 g/min
`Diameter of spray nozzle: 1.2 mm
`Spray pressure: 0.12 MPa
`Gun position: the middle stand
`(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: p.10 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.
`
`50
`
`55
`
`60
`
`65
`
`Par Pharm., Inc.
`Exhibit 1040
`Page 008
`
`
`
`9
`-continued
`
`US 8,883,794 B2
`
`10
`(c) Formulations of FC Tablets
`
`Trigger mode:
`Dry threshold:
`Measuring optimum range
`
`(Max):
`(Min):
`(CH-1) baud rate (bps):
`Blank measurable Max:
`Blank measurable variation range:
`Dry permissible
`
`Min:
`Max:
`Granule range for evaluation (Min):
`Granule range for evaluation (Max):
`Start position of sensor usage:
`
`OFF
`300
`
`1500
`700
`96.00
`300
`20
`
`300
`2500
`0.1
`2000
`1
`
`<Test 1
`In Examples 1, 2 and 3, tablets comprising specific phar
`maceutical compositions comprising water-soluble excipient
`comprising 20 mg, 40 mg and 80 mg, respectively, of lurasi
`done pertablet, partly pregelatinized starch and water-soluble
`polymer binder were manufactured. In Comparative experi
`ments 1 and 2, tablets comprising 40 mg and 80 mg, respec
`tively, of lurasidone pertablet were manufactured on the basis
`of the formulation disclosed in Patent Document 2.
`The manufactured preparations were subjected to the dis
`solution tests under conditions shown in (d) and (e), and
`similarities of dissolution profiles were evaluated. Addition
`ally, preproductions in Comparative experiments 1 and 2
`were shown in Test 8.
`Results were shown in Tables 4 and 5. Temporal dissolu
`tion ratios in (d) were shown in FIGS. 2 and 3.
`(a) Formulations of Granule Powders
`
`TABLE 1
`
`TABLE 3
`
`Example No.
`
`Unit: mg
`Compar. Ex: No.
`
`Component
`
`1
`
`2
`
`3
`
`1
`
`2
`
`Uncoated tablets in
`the above (b)
`Hydroxypropyl
`methylcellulose
`Titanium oxide
`Polyethylene glycol 6000
`Carnauba wax
`
`320
`
`160
`
`80
`
`320
`
`320
`
`3.25
`
`1.95
`
`1.3
`
`2.6
`
`2.6
`
`1
`0.75
`0.01
`
`0.6
`0.45
`0.006
`
`0.4
`0.3
`0.004
`
`0.8
`0.6
`0.01
`
`0.8
`0.6
`0.01
`
`(d) Dissolution Test in the System Comprising 80 Mg of
`Lurasidone in Each Vessel
`Each film-coated tablet comprising 80 mg, 40 mg or 20 mg
`oflurasidone in the system comprising 80 mg of lurasidone in
`each vessel was subjected to the dissolution test, and a simi
`larity of each dissolution profile was evaluated by f2 value.
`As evidenced by Table 4, f2 values in Examples 2 and 3
`showed similarities to Example 1, but f2 value in Compara
`tive experiment 2 did not show a similarity to Comparative
`experiment 1. In other words, as evidenced by Table 4 and
`FIG. 3, in Examples 1 to 3, f2 values which represen