PATENT
`Attorney Docket No. 05273.0147-02
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`Commissioner for Patents
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`Prior Application Art Unit: 1627
`
`Prior Application Examiner: Sarah PIHONAK
`
`Commissioner: This is a request for filing a
`~ Continuation D Continuation-in-Part D Divisional Application under 37 C.F.R. § 1.53(b) of
`pending prior Application No. 14/183,283, filed February 18, 2014, of Kazuyuki FUJIHARA for
`PHARMACEUTICAL COMPOSITION.
`
`1.
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`D
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`D
`D
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`~
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`2.
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`3.
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`4.
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`5.
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`Enclosed is a complete copy of the prior application and drawings, as originally
`filed. The attached papers are a true copy of prior Application No. 14/183,283,
`filed February 18, 2014, which is a continuation of Application No. 11/919,678,
`filed October 31, 2007, which issued on May 20, 2014 as U.S. Patent
`No. 8,729,085, which is a National Stage Entry of International Application
`No. PCT/JP2006/31 0571, filed May 26, 2006, which claims priority to Japanese
`Patent Application No. 2005-153508, filed May 26, 2005, the content of each of
`which is incorporated herein by reference.
`
`Certification and Request for Prioritized Examination under 37 C.F.R. § 1.102(e)
`
`A Preliminary Amendment is submitted herewith.
`
`A copy of a declaration submitted in prior Application No. 14/183,283 is
`submitted herewith.
`
`An Application Data Sheet is enclosed.
`
`Par Pharm., Inc.
`Exhibit 1013
`Page 001
`
`

`

`Basic Utility Application Filing Fee
`
`Search Fee
`
`Examination Fee
`
`Prioritized Examination Fee
`
`Application No.: To be assigned
`Attorney Docket No.: 05273.0147-02
`Page 2 of 3
`
`$
`
`$280
`
`$600
`
`$720
`
`280.00
`
`600.00
`
`720.00
`
`Total Claims
`
`Number of Claims
`35 -
`4 -
`
`Basic
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`Extra
`
`20
`
`15 X $80
`
`3
`
`1 X $420
`
`+ $780
`
`1200.00
`
`420.00
`
`Independent Claims
`D Presentation of Multiple Dep. Claim(s)
`Size Fee: Paper Filing
`Total Application Pages
`(specification, drawings,
`printed sequence or computer
`listing, preliminary
`amendment)
`Additional Fee for Paper Filing New Application $400
`(DELETE if filing new application via EFS Web -fee not required for EFS new
`application submissions)
`Size Fee: EFS-Web Filing
`Total Application Pages
`(specification, drawings,
`printed sequence or computer
`listing, preliminary
`amendment)
`
`[Total] - 100 + 50 = [number]* x $400
`
`*Rounded up to next whole number
`
`[Total] X .75- 100 +50= [number]* x $400
`
`*Rounded up to next whole number
`
`Processing Fee, except in provisional applications- $140
`For the Track I (Prioritized Examination) Program, the processing fee is required.
`
`Subtotal
`
`Reduction by 1/2 if small entity [fore-filing ONLY: small entity fee for Basic
`filing fee - $70)
`TOTAL FEES DUE
`
`140.00
`
`3,360.00
`
`3,360.00
`
`$
`-
`
`$
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`6.
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`7.
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`The fee of $3,360.00 is submitted herewith.
`
`The Commissioner is hereby authorized to charge any fees which may be
`required including fees due under 37 C. F. R. § 1.16 and any other fees due under
`37 C.F.R. § 1.17, or credit any overpayment during the pendency of this
`application to Deposit Account No. 06-0916.
`
`Par Pharm., Inc.
`Exhibit 1013
`Page 002
`
`

`

`Application No.: To be assigned
`Attorney Docket No.: 05273.0147-02
`Page 3 of 3
`
`8.
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`9.
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`10.
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`11.
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`12.
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`The prior application is assigned of record to: SUMITOMO DAINIPPON
`PHARMA CO., LTD., by virtue of a change of name submission recorded in the
`U.S. Patent and Trademark Office (USPTO) at Reel 033905, Frame 0778. The
`prior application was assigned to DAINIPPON SUMITOMO PHARMA CO., LTD.
`by virtue of an assignment from the inventor recorded in the U.S. Patent and
`Trademark Office (USPTO) at Reel 020124, Frame 0821. A corrective
`assignment was recorded in the USPTO at Reel 021008, Frame 0209, to correct
`the address of the assignee.
`
`The power of attorney in the prior application is to FINNEGAN, HENDERSON,
`FARABOW, GARRETT & DUNNER, L.L.P., Customer No. 22,852.
`
`Please address all correspondence to FINNEGAN, HENDERSON, FARABOW,
`GARRETT and DUNNER, L.L.P., Customer Number 22,852.
`
`D
`D
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`A new power of attorney is enclosed.
`
`Information Disclosure Statement is enclosed.
`
`PETITION FOR EXTENSION. If any extension of time is necessary for the filing of this
`application, including any extension in parent Application No. 14/183,283, filed
`February 18, 2014, for the purpose of maintaining copendency between the parent application
`and this application, and such extension has not otherwise been requested, such an extension
`is hereby requested, and the Commissioner is authorized to charge necessary fees for such an
`extension to Deposit Account No. 06-0916.
`
`Dated: October 10, 2014
`
`Respectfully submitted,
`
`FINNEGAN, HENDERSON, FARABOW,
`GARRETT & DUNNER, L.L.P.
`
`By: ___ ~--=---tz_l/._ll..-_~--
`
`Charles E. Van Horn
`Reg. No. 40,266
`(202) 408-4000
`
`Par Pharm., Inc.
`Exhibit 1013
`Page 003
`
`

`

`\
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`· rt/9.19 6 78 :
`fAP05Rec'ci PST 81 ·ocr zaOTJ·
`
`1
`
`DESCRIPTION
`
`PHARMACEUTICAL COMPOSITION
`
`5
`
`TECHNICAL FIELD
`
`[0001]
`
`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]-
`
`10
`
`(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
`
`preparation for oral administration, particularly a tablet, comprising
`
`lurasidone as an active ingredient, which has an equivalent dissolution
`
`profile of the active ingredient even though contents of the active
`
`15
`
`ingredient therein are varied.
`
`BACKGROUND ART
`
`[0002]
`
`Patent Document 1 discloses
`
`that a compound such as
`
`20
`
`lurasidone can be orally administered and an oral preparation 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
`
`25
`
`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.
`
`[0003]
`
`30
`
`For the purpose of securing the bioequivalence when
`
`Par Pharm., Inc.
`Exhibit 1013
`Page 004
`
`

`

`.-
`
`2
`
`pharmaceutical 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 Bioequivalence Studies of
`
`Oral Solid Dosage Forms with Different Content" (Notification No. 64 of
`
`5
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`the Evaluation and Licensing Division, Pharmaceutical and Food Safety
`
`Bureau, promulgated on February 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
`
`10
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`values of stomach, intestine and oral cavity, respectively), water, and
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`saline.
`
`[0004]
`
`Patent Document 2 discloses an oral preparation comprising
`
`lurasidone as an active ingredient, which shows a rapid dissolution and
`
`15
`
`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
`
`20
`
`active ingredient therefrom at a desired concentration.
`
`[0005]
`
`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 ingredient therein are
`
`25
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`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 40 mg), 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
`
`30
`
`effects, or a preparation which has an equivalent dissolution profile to
`
`Par Pharm., Inc.
`Exhibit 1013
`Page 005
`
`

`

`3
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`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 has an
`
`5
`
`equivalent dissolution profile in the range of 5 mg to 40 mg of
`
`lurasidone per tablet, as shown in Figure 1. However, as shown in
`
`Figure 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. Henee,' it·· ;remains in· a· state of administering
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`10
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`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 equivalent dissolution profile even in high
`
`content or in wider ranges of contents of the active ingredient.
`
`15
`
`[0006]
`
`In Patent Document 2, a water-soluble polymer binder includes
`
`starch, but there is no description about a pregelatinized starch therein.
`
`The pregelatinized starch
`
`is known
`
`to
`
`remarkably
`
`improve a
`
`disintegration and a dissolution of a pharmaceutical composition as
`
`20
`
`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.
`
`[0007]
`
`Patent Document 1:
`
`25
`
`Patent Document 2:
`
`Patent Document 3:
`
`JP2800953
`W02002 I 024166
`JP2000-26292
`
`Non-patent Document 1:
`
`Handbook of Pharmaceutical Excipients,
`
`2nd edition, 491, 1994, The Pharmaceutical Press
`
`30
`
`DISCLOSURE OF INVENTION
`
`Par Pharm., Inc.
`Exhibit 1013
`Page 006
`
`

`

`4
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`PROBLEMS TO BE RESOLVED BY THE INVENTION
`
`. [0008]
`
`The present invention is directed to provide an oral preparation
`
`comprising lurasidone as an active ingredient which shows a rapid
`
`5
`
`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
`
`10
`
`release the active ingredient therefrom at a desired concentration.
`
`[0009]
`
`The present invention is directed to provide a preparation for oral
`
`administration which comprises as an active ingredient N-[4-[4-(1,2-
`
`benzisothiazol-3-yl)-1-piperazinyl]-(2R,3R)-2,3-tetramethylene-butyl]-
`
`15
`
`(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
`
`dissolution profile of the active ingredient even though contents of the
`
`active ingredient therein are varied.
`
`MEANS OF SOLVING THE PROBLEMS
`
`20
`
`[0010]
`
`The present inventors have intensively studied in order to solve
`
`the above problems and found to solve said problems by means of the
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`following methods.
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`[00 11]
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`25
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`The present invention includes the following embodiments:
`
`[0012]
`
`(1)
`
`An oral preparation which comprises 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) of
`
`30
`
`the formula (1):
`
`Par Pharm., Inc.
`Exhibit 1013
`Page 007
`
`

`

`5
`
`HCI
`
`(1)
`
`a pregelatinized starch, a water-soluble excipient and a water-soluble
`
`polymer binder.
`
`(2)
`
`An oral preparation which is prepared by granulating a powder
`
`5
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`mixture comprising lurasidone, a pregelatinized starch and a water(cid:173)
`
`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 lurasidone and a water-soluble
`
`1 0
`
`polymer binder.
`
`(4)
`
`The oral pre:paration 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 lurasidone, a pregelatinized
`
`15
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`starch and a water-soluble excipient by using a solution of a water(cid:173)
`
`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
`
`20
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`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)
`
`25
`
`based on the weight of the preparation.
`
`(9)
`
`The oral preparation of any one of (1)
`
`to (4) wherein the
`
`Par Pharm., Inc.
`Exhibit 1013
`Page 008
`
`

`

`6
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`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).
`
`5
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`(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
`
`-'• ~
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`: lurasidqne per tablet is 10 to 160 mg.
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`(13) · The oral preparation of any one of (1) to (4) wherein a content of
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`10
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`lurasidone per tablet is 20 to 120 mg.
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`(14) The oral preparation of any one of (1) to (4) wherein a content of
`
`lurasidone per tablet is 40 to 120 mg.
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`(15) The oral preparation of any one of (1) to (4) wherein the water(cid:173)
`
`soluble excipient is mannitol or lactose and the pregelatinized starch is
`
`15
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`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(cid:173)
`
`soluble excipient is mannitol or lactose and a content of lurasidone in
`
`the preparation is 25 to 40% (wt/wt).
`
`20
`
`(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-
`
`25
`
`soluble excipient is mannitol or lactose, 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).
`
`(19) The oral preparation of any one of (1) to (4) wherein the water-
`
`30
`
`soluble excipient is mannitol or lactose, the pregelatinized starch is
`
`Par Pharm., Inc.
`Exhibit 1013
`Page 009
`
`

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`7
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`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-
`
`S
`
`soluble excipient is mannitol or lactose, the pregelatinized 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%.
`
`10
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`(22) The oral preparation of any one of (1) to (4) wherein an average
`
`particle size of lurasidone is 0.1 to 8 p.m.
`
`(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-
`
`15
`
`soluble excipient is mannitol or lactose, the pregelatinized 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
`
`20
`
`[0013]
`
`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
`
`25
`
`contents of lurasidone could not have an equivalent dis·solution profile.
`
`Therefore, 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
`
`30
`
`present invention which comprises a pregelatinized starch can provide
`
`Par Pharm., Inc.
`Exhibit 1013
`Page 010
`
`

`

`8
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`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 administration which has an equivalent dissolution
`
`5
`
`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
`
`[0014]
`
`10
`
`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]heptane(cid:173)
`
`dicarboxyimide hydrochloride (lurasidone) refers to a compound of the
`
`following formula:
`
`[0015]
`
`15
`
`HCI
`
`(1)
`
`(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
`
`20
`
`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 pm or less of particle size, and average
`
`particle size in a volume ratio (i.e. 50% by volume particle size) includes,
`
`25
`
`for example, in the range of 0.1 to 8 pm, preferably in the range of 1 to
`
`4 p.m. The contents of lurasidone are 10 to 160 mg, preferably 20 to
`
`Par Pharm., Inc.
`Exhibit 1013
`Page 011
`
`

`

`9
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`120 mg, more preferably 40 to 120 mg per tablet.
`
`[00 16]
`
`The
`
`"pregelatinized
`
`starch"
`
`refers
`
`to
`
`those. prepared by
`
`pregelatinizing various kinds of starch (e.g. corn starch, potato starch,
`
`5
`
`wheat starch, rice starch, tapioca starch, etc.), and may include
`
`. pregelatinized starch or partly pregelatinized starch described in
`
`Japanese Pharmaceutical Excipients. 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%.
`
`10
`
`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 pm, preferably in the range of 1
`
`to 500 pm, more · preferably in the range of 1 0
`
`to 1 00 pm: A
`
`15
`
`commercially available pregelatinized 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. Among the
`
`above pregelatinized starch, partly pregelatinized starch such as PCS
`
`20
`
`(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%, preferably in the range of 10% to 40%, particularly in
`
`25
`
`the range of 20% to 30% by weight of the preparation.
`
`[0017]
`
`The "water-soluble excipient" includes, for example, mannitol,
`
`lactose, saccharose, sorbitol, D-sorbitol, erythritol, xylitol, etc. More
`
`preferable one includes mannitol and lactose. Further preferable one
`
`30
`
`may include mannitol. Also, said water-soluble excipient may be used
`
`Par Pharm., Inc.
`Exhibit 1013
`Page 012
`
`

`

`10
`
`alone, or two or more thereof may be used together. The water-soluble
`
`excipient is incorporated in an amount of, for example, the 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
`
`5
`
`mannitol is, for example, in the range of 10 to 200 p.m.
`
`[0018]
`
`The "water-soluble polymer binder" includes, for example,
`
`hydroxypropylcellulose, hydroxypropyl methylcellulose,
`
`polyvinylpyrrolidone, polyvinyl alcohol, etc. More preferable one
`
`10
`
`includes hydroxypropylcellulose, hydroxypropyl 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 of 0.5 to 10% by weight, preferably the range of 1 to
`
`15
`
`5% by weight on the basis of the total weight of a tablet.
`
`The oral preparation in the form of a pharmaceutical composition
`
`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,
`
`20
`
`capsule, granule or fine granule by using water-soluble excipient as well
`
`as water-insoluble excipient, binder, disintegrant, lubricant, etc. The
`
`following agents may be added thereto.
`
`[0019]
`
`The "water-insoluble excipient" includes, for example, com starch,
`
`25
`
`crystalline cellulose, etc. Said water-insoluble excipient may be used
`
`alone, or two or more thereof may be used together.
`
`[0020]
`
`The "disintegrant" includes, for example, corn starch, crystalline
`
`cellulose,
`
`low
`
`substituted
`
`hydroxypropylcellulose,
`
`carmellose,
`
`30
`
`carmellose calcium, carmellose
`
`sodium, croscarmellose
`
`sodium,
`
`Par Pharm., Inc.
`Exhibit 1013
`Page 013
`
`

`

`11
`
`carboxymethyl starch sodium, 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
`
`5
`
`the total weight of a tablet.
`
`[0021]
`
`The "lubricant" includes, for example, magnesium stearate, talc,
`
`polyethylene glycol, silica, hydrogenated vegetable oil, etc.
`
`[0022]
`
`10
`
`The oral preparation of the present invention may be prepared
`
`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.
`
`15
`
`The amount of the water-soluble polymer binder is, 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
`
`20
`
`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.
`
`[0023]
`
`The apparatus
`
`for granulation
`
`includes,
`
`for example, one
`
`25
`
`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 atmospheric pressure. The drying is carried out so that the
`
`30
`
`loss on dry measured by infrared moisture meter is, for example, within
`
`Par Pharm., Inc.
`Exhibit 1013
`Page 014
`
`

`

`12
`
`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
`
`5
`
`diffusion mixers [Tumble] is used.
`
`Specifically, 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.
`
`10
`
`[0024]
`
`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.
`
`(6)
`
`Film-coating is optionally carried out:
`
`15
`
`The above-obtained tablet may be optionally subjected to film(cid:173)
`
`coating, if necessary. The apparatus for coating includes, for example,
`
`one classified into a coating pan. Preferable one includes one classified
`
`by perforated coating system.
`
`[0025]
`
`20
`
`The coating agent includes, for example, a mixture of base
`
`material
`
`(e.g. hydroxypropyl methylcellulose, hydropropylcellulose,
`
`polyvinylpyrrolidone, polyvinyl alcohol, etc.) and plasticizer
`
`(e.g.
`
`polyethylene glycol, propylene glycol, triacetin, triethyl citrate, glycerin,
`
`glycerin fatty acid ester, polyethylene glycol, etc.).
`
`If necessary, an
`
`25
`
`additive such as titanium oxide may be also added therein. After film(cid:173)
`
`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
`
`30
`
`either under reduced pressure or atmospheric pressure so that the loss
`
`Par Pharm., Inc.
`Exhibit 1013
`Page 015
`
`

`

`13
`
`on dry measured by infrared moisture meter is, for example, within 3%
`
`by weight, preferably 1 to 2% by weight.
`
`[0026]
`
`Examples ·of the present invention are illustrated below. Said
`
`5
`
`examples are intended to exemplify the present invention but not to
`
`limit the present invention thereto.
`
`EXAMPLES
`
`Example 1
`
`10
`
`[0027]
`
`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 charging amounts
`
`shown in parentheses in the following description are an example for
`
`15
`
`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 formulations.
`
`[0028]
`
`20
`
`B.
`
`(1)
`
`Preparation method
`
`Preparation of binding solution (5% aqueous hydroxypropyl
`
`methylcellulose solution):
`
`Hydroxypropyl methylcellulose (32 g) as water-soluble polymer
`
`binder was dissolved in purified water (608 g) to give binding solution.
`
`25
`
`(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/manufactured by Powrex Corporation),
`
`and the mixture was granulated ·by spray granulation under the
`
`30
`
`following conditions using the binding solution prepared in the above ( 1)
`
`Par Pharm., Inc.
`Exhibit 1013
`Page 016
`
`

`

`14
`
`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). Magnesium stearate
`
`was mixed in amounts calculated from a formulation on· the basis of
`
`5
`
`yields of granule powder.
`
`Conditions for granulation
`
`Temperature for supplying air: 60°C
`
`Airflow: 50 to 65m3 fhr
`
`Spray speed: 13 g/ min
`
`10
`
`Diameter of spray nozzle: 1.2 mm
`
`Spray pressure: 0.12MPa
`
`Gun position: the middle stand
`
`(3) Compression:
`
`The granule for compression prepared in the above (2) was
`
`15
`
`compressed by HT-AP12SS-II (manufactured by Hata Iron Works Co.,
`
`Ltd.) to give a tablet.
`
`Pestle size: cp10 mm 14R
`
`Thickness: 4.20 to 4.30 mm
`
`Compression pressure: 10 KN
`
`20
`
`(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
`
`25
`
`film-coated tablet.
`
`FC conditions
`
`Temperature for supplying air: 80°C
`Airflow: 0. 6 m 3 I min
`Rotation rate of pan: 25 rpm
`
`30
`
`Spray pressure: 0 .15MPa
`
`Par Pharm., Inc.
`Exhibit 1013
`Page 017
`
`

`

`15
`
`Liquid flow rate: 5 g/ min
`
`The preparation obtained in the above method was evaluated a
`
`quality thereof according to the following methods, and the present
`
`invention has been achieved on the basis of the. knowledge obtained
`
`5
`
`therein.
`
`[0029]
`
`C.
`
`Quality evaluation
`
`( 1) Dissolution test
`
`A manufactured preparation was subjected to the dissolution test
`
`10
`
`according to the Japanese Pharmacopoeia, Dissolution 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
`
`15
`
`(2) Similarity of dissolution profiles
`
`A similarity factor f2 shown in Scale-Up and Past-Approval
`
`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 following equation.
`
`It was determined that each
`
`20
`
`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 50sf2s100. 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.
`
`25
`
`[0030]
`
`f2= 50• LOG
`
`100
`
`~ ~(Ti-Ri) 2
`
`1 + ...:..•==..:...] - - - - (cid:173)
`rz
`
`Par Pharm., Inc.
`Exhibit 1013
`Page 018
`
`

`

`16
`
`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
`
`5
`
`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: 0.4MPa or more
`Tumtable rotation speed: 2
`Parameter setting
`Environmental setting
`Monitoring average:
`
`Dark measuring average:
`Light intensity
`display Max:
`Previous blank:
`Printer: monochrome
`
`Refractive parameter
`Standard refraction:
`Measuring conditions setting
`Measuring average:
`Measuring interval (sec):
`Average:
`
`Measured absorbance
`range (Max):
`(Min):
`Trigger mode:
`Dry threshold:
`
`[0031]
`
`16
`
`2
`
`2000
`
`(bps):
`reading Blank measurable Max:
`Blank measurable
`variation range:
`
`Measuring optimum range
`(Max):
`(Min):
`(CH-1)
`
`baud
`
`1500
`
`700
`rate
`9600
`
`300
`
`20
`
`1.70-0.20i
`
`Dry permissible Min:
`
`300
`Max: 2500
`
`Granule range
`for evaluation (Min):
`Granule range
`for evaluation (Max):
`Start position of sensor usage: 1
`
`0.1
`
`2000
`
`1
`1
`
`64
`
`0.1
`
`0.05
`OFF
`300
`
`Par Pharm., Inc.
`Exhibit 1013
`Page 019
`
`

`

`17
`
`<Test 1>
`
`In Examples
`
`1,
`
`2
`
`and 3,
`
`tablets comprising
`
`specific
`
`pharmaceutical compositions comprising water-soluble
`
`excipient
`
`comprising 20 mg, 40 mg and 80 mg, respectively, of lurasidone per
`
`5
`
`tablet, partly pregelatinized starch and water-soluble polymer binder
`
`were manufactured.
`
`In Comparative experiments 1 and 2, tablets
`
`comprising 40 mg and 80 mg, respectively, of lurasidone per tablet were
`
`manufactured on the ·basis of the formulation disclosed in Patent
`
`Document 2.
`
`10
`
`The manufactured preparations were subjected to the dissolution
`
`tests under conditions shown in (d) and (e), and similarities of
`
`dis