PTO/SB/OBA (OB-00)
`Approved for use through 10/31/2002. OMB 0651-0031
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`
`INFORMATION DISCLOSURE
`
`
`
`STATEMENT BY APPLICANT
`(use as many sheets as necessary)
`Sheet 1 of 3
`
`Examiner Name
`Attorney Docket Number
`U.S. PATENT DOCUMENTS
`
`Clayto r, Deirdre
`PRD2901USNP
`
`U.S. Patent Document
`
`Examiner
`Initials
`
`'
`
`— Name of Patentee or Applicant
`Kind Code
`fC't d D
`t
`(if known)
`' e
`
`ocumen
`
`0
`
`Date of Publication
`of Cited Document
`mm-dd-yyyy
`
`Pages, Columns, Lines,
`where relevant passages or
`relevant figures appear
`
`10/18/2012
`
`
`elle, William E.
`
`rancois et al.
`
`06/27/2002
`
`08/21/2003
`
`ewyn-Briscoe et al.
`
`05/05/2011
`
`rancois et al.
`
`Foreign Patent Document
`
`FOREIGN PATENT DOCUMENTS
`
`No
`
`xaminer
`.
`.
`E
`Name of Patentee or
`.
`.
`A licant of Cited Document
`'“It'a'S
`_1
`Office3
`Number4
`KindCode5
`pp
`--- 2004/010981 - ALZA Corporation
`WO
`2008/021342
`Teva Pharmaceutical
`
`Industries, LTD.
`
`t
`
`Pages, Columns,
`Publication of
`Lines, where relevant
`I e
`ocumen
`passages or re evan
`C't d D
`l
`t
`-
`mm-dd-yyyy
`figures appear
`02/05/2004 _-
`02/21/2008
`
`WO
`
`2009/025859
`
`Teva Pharmaceutical
`
`02/26/2009
`
`Industries, LTD.
`--____l
`WO
`2011/053829
`Janssen
`05/05/2011
`Pharmaceutica NV
`
`Date
`Examiner
`Considered
`Sionature
`*EXAMINER: Initial if reference considered, whether or not citation is in conformance with MPEP 609. Draw line through citation if not in conformance and not
`considered. Include copy of this form with next communication to applicant.
`
`1 Unique citation designation number. 2 See attached Kinds of U.S. Patent Documents. 3 Enter Office that issued the document, by the two-letter
`code (WIPO Standard ST.3). 4 For Japanese patent documents, the indication of the year of the reign of the Emperor must precede the serial
`number of the patent document. 5 Kind of document by the appropriate symbols as indicated on the document under WIPO Standard ST. 16 if
`possible. eApplicant is to place a check mark here if English language Translation is attached.
`
`Mylan V. Janssen (IPR2020-00440) EX. 1019 Part 2, p. 315
`
`Mylan v. Janssen (IPR2020-00440) Ex. 1019 Part 2, p. 315
`
`

`

`PTO/SB/OBA (08-00)
`Approved for use through 10/31/2002. OMB 0651-0031
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`Under the Paerwork Reduction Act of 1995, no ersons are reuired to resond to a collection of information unless it disla s a valid OMB control number.
`Subs‘im‘e f°' f°'"‘ 1449””
`
`INFORMATION DISCLOSURE
`STATEMENT BYAPPLICANT
`("59 as many sheets as necessary)
`Sheet 2 of 3
`
`-——
`G Am“
`1627
`
`Examiner Name
`Claytor, Deirdre
`Attorney Docket Number
`PRD2901USNP
`
`Examiner‘s
`Initials*
`
`'
`
`.
`
`OTHER PRIOR ART - NON PATENT LITERATURE DOCUMENTS
`
`Include name of the author (in CAPITAL LETTERS), title of the article (when appropriate), title of the item
`(book, magazine, journal, serial, symposium, catalog, etc.), date, page(s), volume-issue number(s),
`oublisher, cit and/or countr where oublished
`
`m
`
`
`
`New Drug Application (NDA) dated October 25, 2007 submitted under section
`505(b) of the Federal Food, Drug, and Cosmetic Act for Invega Sustenna
`(paliperidone palmitate) 39mg, 78mg, 117mg, 156mg, and 234 mg extended-
`release in'ectable suspension
`Supplemental New Drug Application (sNDA) dated March 14, 2011, submitted
`under section 505(b) of the Federal Food, Drug, and Cosmetic Act (FDCA) for
`Invega Sustenna (paliperidone palmitate) extended-release injectable suspension,
`
`39 mg, 78 mg, 117 mg, 156 mg, and 234 mg
`
`Alphs et al. Annals of General Psychiatry 2011, 10:12
`Altamura et al., Intramuscular preparations of antipsychotics: uses and relevance in
`clinical oractice. Dru-s. 2003; 63 5 : 493-512
`Berwaerts et al., Journal of Affective Disorders 138 2012 247—258
`Canuso et al. 2010, Expert Opinion Pharmacother., Volume 11 (15), pages 2557-
`2567.
`
`Cleton et al., ASSESSMENT OF THE DOSE PROPORTIONALITY OF
`PALIPERIDONE PALMITATE 25, 50, 100 AND 150 MG EQ., A NEW LONG-
`ACTING INJECTABLE ANTIPSYCHOTIC FOLLOWING ADMINISTRATION IN THE
`
`DELTOID OR GLUTEAL MUSCLES, PI-74, Clinical Pharmacology & Therapeutics,
`Volume 83, Supplement 1, MARCH 2008, S31
`Ereshefsky L., Pharmacokinetics and drug interactions: update for new
`antips chotics. J Clin Ps chiatr . 1996;57 Suppl 11:12-25
`Gefvert et al. Pharmacokinetics and D2 receptor occupancy of long-acting
`injectable risperidone (Risperdal Consta) in patients with schizophrenia. Int J
`
`Neuropsychopharmacol. 2005; 8(1): 27-36
`Kane et al., Guidelines for depot antipsychotic treatment in schizophrenia.
`European Neuropsychopharmacology Consensus Conference in Siena, Italy. Eur
`Neuropsychopharmacol. 1998; 8(1): 55-66
`Levron et al., Clinical pharmacokinetics of haloperidol decanoate. Comparison with
`other prolonged-action neuroleptics. Encephale. 1987; 13(2): 83-7 [see English
`Summar as provided]
`Markowitz et al., “Benefit-Risk Assessment of Maintenance Therapy in
`Schizophrenia Comparing Long-Acting Injectable (LAI) Paliperidone Palmitate with
`Paliperidone ER”, Presented at the 164th Annual Meeting of the American
`Psychiatric Association, May 14-18, 2011, Honolulu, HI, USA
`
`Examiner
`Sionature
`*EXAMINER: Initial if reference considered, whether or not citation is in conformance with MPEP 609. Draw line through citation if not in conformance
`and not considered. Include copy of this form with next communication to applicant.
`
`Date
`Considered
`
`Mylan V. Janssen (IPR2020-00440) EX. 1019 Part 2, p. 316
`
`Mylan v. Janssen (IPR2020-00440) Ex. 1019 Part 2, p. 316
`
`

`

`PTO/SB/OBA (08-00)
`Approved for use through 10/31/2002. OMB 0651-0031
`US. Patent and Trademark Office: US. DEPARTMENT OF COMMERCE
`Under the Paerwork Reduction Act of 1995, no ersons are reuired to resond to a collection of information unless it disla s a valid OMB control number.
`Subs‘im‘e f°' f°'"‘ 1449””
`
`INFORMATION DISCLOSURE
`STATEMENT BYAPPLICANT
`("59 as many sheets as necessary)
`Sheet 3 of 3
`
`-——
`G Am“
`1627
`
`Examiner Name
`Claytor, Deirdre
`Attorney Docket Number
`PRD2901USNP
`
`Examiner‘s
`Initials*
`
`'
`
`.
`
`OTHER PRIOR ART - NON PATENT LITERATURE DOCUMENTS
`
`Include name of the author (in CAPITAL LETTERS), title of the article (when appropriate), title of the item
`(book, magazine, journal, serial, symposium, catalog, etc.), date, page(s), volume-issue number(s),
`oublisher, cit and/or countr where oublished
`
`Mauri et al., Clinical pharmacokinetics of atypical antipsychotics: a critical review of
`the relationship between plasma concentrations and clinical response. Clin
`Pharmacokinet. 2007;46 5 :359-88
`Pandina et al., Progress in Neuro-Psychopharmacology & Biological Psychiatry 35
`2011 218—226
`
`Sheehan et al., Comparison of the Peak-to-trough Fluctuation in Plasma
`Concentration of Long-acting Injectable Antipsychotics and Their Oral Equivalents,
`
`lnnov Clin Neurosci. 2012;9(7—8):17—23
`Vermeir et al., Absorption, metabolism, and excretion of paliperidone, a new
`
`monoaminergic antagonist, in humans. Drug Metab Dispos. 2008 Apr;36(4):769-79
`
`
`
`
`
`
`
`
`
`
`
`
` _
`
`
`_________
`
`
`
`Examiner
`Sionature
`
`Date
`Considered
`
`*EXAMINER: Initial if reference considered, whether or not citation is in conformance with MPEP 609. Draw line through citation if not in conformance
`and not considered. Include copy of this form with next communication to applicant.
`
`Mylan V. Janssen (IPR2020-00440) EX. 1019 Part 2, p. 317
`
`Mylan v. Janssen (IPR2020-00440) Ex. 1019 Part 2, p. 317
`
`

`

`12/337,144
`A o olication Number
`
`Filing Date
`12/17/2008
`First Named Inventor
`An Vermeulen
`
`SUBMISSION UNDER MPEP 609.06
`
`pa . e 1 Of 1
`
`Grow A” Unit
`Examiner Name
`Attorney Docket Number
`U.S. PATENT DOCUMENTS
`U.S. Patent Document
`
`Claytor, Deirdre
`PRD2901USNP
`
`Examiner
`
`Name of Patentee or Applicant
`
`Lewyn-Briscoe et al.
`
`Number
`
`13/903,638
`(PRD3131USDIV1)
`
`0 e
`”1
`(if known)
`
`Pages, Columns, Lines,
`where relevant passages or
`relevant figures appear
`
`
`of Cited Document
`
`FOREIGN PATENT DOCUMENTS
`Foreign Patent Document
`
`Name of Patentee or
`Applicant of Cited Document
`
`Number4
`
`KindCode5
`
`Pages, Columns, Lines,
`where relevant passages
`or relevant figures
`appear
`
`
`
`Examiner‘s
`Initials*
`
`Cite
`No.1
`
`OTHER PRIOR ART - NON PATENT LITERATURE DOCUMENTS
`Include name of the author (in CAPITOL LETTERS), title ofthe article (when appropriate),
`title of the item (book, magazine, journal, serial, symposium, catalog, etc.), date, page(s),
`volume-issue number s , uublisher, cit and/or countr where uublished
`International Search Report Re: International Application No.:
`PCT/U82010/054807 dated Januar 11, 2011 PRD3131WOPCT .
`Office Action mailed February 28, 2013 in US Serial No. 12/916910;
`Attorne Docket No. PRD3131USNP
`
`
`
`
`Examiner
`Sinature
`
`Date
`Considered
`
`Mylan V. Janssen (IPR2020-00440) EX. 1019 Part 2, p. 318
`
`Mylan v. Janssen (IPR2020-00440) Ex. 1019 Part 2, p. 318
`
`

`

`(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property
`Organization
`International Bureau
`
`
`
`(43) International Publication Date
`5 February 2004 (05.02.2004)
`
`(10) International Publication Nmnber
`
`WO 2004/010981 A1
`
`(51)
`
`International Patent Classificati0n7:
`3 1/506, A61P 25/18
`
`A61K 9/24,
`
`(21)
`
`International Application Number:
`PCT/US2003/023433
`
`International Filing Date:
`
`28 July 2003 (28.07.2003)
`
`Filing Language:
`
`Publication Language:
`
`English
`
`English
`
`Priority Data:
`60/399,590
`60/406,005
`
`29 July 2002 (29.07.2002)
`26 August 2002 (26.08.2002)
`
`US
`US
`
`Applicant: ALZA CORPORATION [US/US]; 1900
`Charleston Road, P.O. Box 7210, Mountain View, CA
`94039—7210 (US).
`
`Inventors: YAM, Noynli, V.; 386 Dennis Avenue, Sunny—
`vale, CA 94086 (US). REYES, Iran; 3276 Meridian Av—
`enue, San Jose, CA 95124 (US). DAVAR, Nipun; 34575
`Melissa Terrace, Fremont, CA 94555 (US). AYER, Atul,
`D.; 931 Bautista Court, Palo Alto, CA 94303 (US). LEE,
`Julie; 994—B La Mesa Terrace, Sunnyvale, CA 94086 (US).
`
`(22)
`
`(25)
`
`(26)
`
`(30)
`
`(71)
`
`(72)
`
`(74)
`
`(81) Designated States (national): AE, AG, AL, AM, AT, AU,
`AZ, BA, BB, BG, BR, BY, BZ, CA, CH, CN, CO, CR, CU,
`CZ, DE, DK, DM, DZ, EC, EE, ES, El, GB, GD, GE, GH,
`GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC,
`LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW,
`MX, MZ, NI, NO, NZ, OM, PG, PH, PL, PT, RO, RU, SC,
`SD, SE, SG, SK, SL, SY, TJ, TM, TN, TR, TT, TZ, UA,
`UG, UZ, VC, VN, YU, ZA, ZM, ZW.
`
`(84) Designated States (regional): ARIPO patent (GH, GM,
`KE, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZM, ZW),
`Eurasian patent (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM),
`European patent (AT, BE, BG, CH, CY, CZ, DE, DK, EE,
`ES, FI, FR, GB, GR, HU, IE, IT, LU, MC, NL, PT, RO,
`SE, SI, SK, TR), OAPI patent (BF, BJ, CF, CG, CI, CM,
`GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG).
`
`Published:
`
`with international search report
`before the expiration of the time limit for amending the
`claims and to be republished in the event of receipt of
`amendments
`
`Agent: NELLER, Robert, R.; Alza Corporation, c/o
`Johnson & Johnson, One Johnson & Johnson Plaza,
`WII3221, New Brunswick, NJ 08933 (US).
`
`For tworletter codes and other abbreviations, refer to the ”Guide
`ance Notes on Codes andAbbreviations” appearing at the begin—
`ning of each regular issue of the PCT Gazette.
`
`(54) Title: METHODS AND DOSAGE FORMS FOR CONTROLLED DELIVERY OF PALIPERIDONE
`
`0. 15
`
`RES/DUALS = 1%
`
`MEMBRANE WEIGHT
`
`
`
`STUDY-54 mg
`
`
`
`
`
`
`
`L.
`
`Q E
`
`1
`5,010
`52
`
`N 0
`
`: $
`
`0.05
`0.)
`
`EO
`
`:
`
`2468
`
`10
`
`12
`
`14
`
`16
`
`18 20 22 24
`
`Time, Hours
`
`(57) Abstract: Dosage forms and methods for providing a substantially ascending rate of release of paliperidone are provided.
`The sustained release dosage forms provide therapeutically effective average steady—state plasma paliperidone concentrations when
`administered once per day. This oncerarday dosing regimen results in only one peak plasma paliperidone concentration occurrence
`in each 24 hour period. In addition, the peak plasma paliperidone concentration occurs at a later time following dose administration
`and exhibits a lesser magnitude than the peak plasma paliperidone concentration that occurs following administration of paliperidone
`in an immediate—release dosage form.
`
`Mylan V. Janssen (IPR2020-00440) EX. 1019 Part 2, p. 319
`
`
`
`W02004/010981A1||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||1
`
`Mylan v. Janssen (IPR2020-00440) Ex. 1019 Part 2, p. 319
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`

`

`WO 2004/010981
`
`PCT/US2003/023433
`
`METHODS AND DOSAGE FORMS FOR CONTROLLED DELIVERY OF
`
`PALIPERIDONE
`
`FIELD OF THE INVENTION
`
`[0001]
`
`This invention pertains to the controlled delivery of pharmaceutical
`
`agents and methods, dosage forms and devices. ,In particular, the invention is
`
`directed to methods, dosage forms and devices for the controlled delivery of
`
`paliperidone, with reduced degradation of the active agent.
`
`1O
`
`BACKGROUND OF THE INVENTION
`
`[0002]
`
`The art is replete with descriptions of oral dosage forms for the
`
`controlled release of pharmaceutical agents. While a variety of sustained '
`
`15
`
`release dosage forms for delivering certain drugs exhibiting short half—life may
`
`be known, not every drug may be suitably delivered from those dosage forms
`
`because of solubility, metabolic processes, absorption and other physical,
`
`chemical and physiological parameters that may be unique to the drug and the
`
`mode of delivery. Examples of such drugs that are not likely candidates for
`
`20
`
`controlled release dosage forms are those exhibiting a long half—life such as
`
`paliperidone.
`
`It has also been found that paliperidone degrades into notable
`
`amounts of impurities. The major degradation products include C-9 ketone, N—
`
`oxides, and various dimmers of its degradants.
`
`[0003]
`
`Paliperidone is more fully described in US Pat. No. 4,804,663. The
`
`25
`
`paliperidone compound differs from risperidone and related prior art
`
`compounds described in US Pat. Nos. 4,352,811 and 4,458,076 by its
`
`substitution on the 1-position of the piperidine moiety.
`
`[0004]
`
`Paliperidone is practically insoluble in water, freely soluble in
`
`methylene chloride and soluble in methanol and 0.1 N hydrochloric acid.
`
`30
`
`Additionally, since paliperidone has a long half-life of about one day, it is not a
`
`typical candidate for extended delivery. However, side effects such as anxiety,
`
`somnolence, dizziness, constipation, extrapyramidal symptoms, may be related
`
`Mylan V. Janssen (IPR2020-00440) EX. 1019 Part 2, p. 320
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`Mylan v. Janssen (IPR2020-00440) Ex. 1019 Part 2, p. 320
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`

`

`WO 2004/010981
`
`PCT/US2003/023433
`
`to high blood plasma concentration levels restricting the ability to administer a
`
`single daily immediate release dose.
`
`[0005]
`
`Traditional stability improvements for pharmaceutical agents were
`
`explored including use of antioxidants (increased levels of BHT), and
`
`incorporation of chelating agents. These traditional methods for reducing
`
`degradation proved insufficient.
`
`[0006]
`
`It is expected that the side effects are likely a result of either rate of
`
`rise and/or actual drug blood plasma concentrations exceeding a threshold
`
`maximum tolerable concentration (MTC). However, in order to obtain a
`
`1O
`
`therapeutic effect, concentrations need to be sustained above a minimum
`
`pharmacodynamic concentration (MPG).
`
`[0007]
`
`Another aspect of delivery of paliperidone is that administration may
`
`require low drug loading in the dosage form. Dosage forms may need to
`
`contain drug in the range of 5% to 20% of the overall weight of the dosage
`
`15
`
`form. The low drug loading requirement presents problems in formulating
`
`compositions and fabricating dosage forms that are suitable for oral
`
`administration that deliver at the desired rate of release for an extended period
`
`of time.
`
`[0008]
`
`Prior art osmotic dosage forms mention delivery of risperidone from
`
`20
`
`a liquid gelatin capsule without mention of delivery of paliperidone or of a
`
`preferred rate of delivery or identification of a solid capsule dosage form.
`
`Published patent application by ALZA Corporation, WO 00/35419.
`
`[0009]
`
`Other art discloses delivery of risperidone through transdermal
`
`methods with patches without claiming any rate of release or desired plasma
`
`25
`
`concentration profile. Published patent application by Janssen, WO 96/31201.
`
`Furthermore, this art does not identify delivery of paliperidone much less
`
`delivery of paliperidone through oral controlled release delivery.
`
`[00010] There is also art disclosing delivery of risperidone and/or
`
`paliperidone through injectable implants for long term, multi-day, delivery. This
`
`30
`
`art includes the published patent application by Alkermes WO 01/34120, and
`
`US Pat. Nos. 5,654,008; 5650,173; 5,770,231; 6,077,843; 6,368,632;
`
`6,110,923; 5,965,168; and 5,692,477 by Alkermes. US patents claiming
`
`injectable dosage forms to provide almost zero order delivery include US Pat.
`
`2
`
`Mylan V. Janssen (IPR2020-00440) EX. 1019 Part 2, p. 321
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`Mylan v. Janssen (IPR2020-00440) Ex. 1019 Part 2, p. 321
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`

`

`WO 2004/010981
`
`PCT/US2003/023433
`
`Nos. 5,871,778 and 5,656,299 by Yoishitomi Pharmaceutical Industries. This
`
`art does not disclose preferred release rates and does not teach or motivate
`
`toward an ascending rate of release, much less such release through an oral
`
`delivery system.
`
`[00011] Prior art for oral delivery does not address delivery of extended,
`
`controlled release paliperidone.
`
`[00012] Oral controlled release dosage forms include, US Pat. No. 5,536,507
`
`which describes a three component pharmaceutical formulation that utilizes,
`
`inter alia, a pH sensitive polymer and optionally an osmotic agent that will swell
`
`10
`
`in the higher pH regions of the lower portion of the small intestine and the large
`
`intestine to release drug in those environments. Additional components of the
`
`dosage form include a delayed release coating and an enteric coating to
`
`provide a dosage form that releases very little, if any, of the drug in the
`
`stomach, a relatively minimal amount in the small intestine and reportedly
`
`15
`
`about 85% or more in the large intestine. Such a dosage form provides for a
`
`widely varying time-release of drug after administration that may not begin for
`
`1-3 hours until the dosage form has passed from the stomach and an
`
`additional 3 hours or more for the dosage form to pass into the large intestine.
`
`[00013] Exemplary sustained release paliperidone dosage forms, methods of
`
`20
`
`preparing such dosage forms and methods of using such dosage forms
`
`described herein are directed to osmotic dosage forms for oral administration.
`
`[00014]
`
`In addition to osmotic systems as described herein, however, there
`
`are many other approaches to achieving sustained release of drugs from oral
`
`dosage forms known in the art. These different approaches include, for
`
`25
`
`example, diffusion systems such as reservoir devices and matrix devices,
`
`dissolution systems such as encapsulated dissolution systems (including, for
`
`example, “tiny time pills") and matrix dissolution systems, combination
`
`diffusion/dissolution systems and ion-exchange resin systems as described in
`
`Remington’s Pharmaceutical Sciences, 1990 ed., pp. 1682-1685.
`
`30
`
`Paliperidone dosage forms that operate in accord with these other approaches
`
`are encompassed by the scope of the disclosure herein to the extent that the
`
`drug release characteristics and/or the blood plasma paliperidone
`
`3
`
`Mylan V. Janssen (IPR2020-00440) EX. 1019 Part 2, p. 322
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`Mylan v. Janssen (IPR2020-00440) Ex. 1019 Part 2, p. 322
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`

`

`WO 2004/010981
`
`PCT/US2003/023433
`
`concentration characteristics as recited herein and in the claims describe those
`
`dosage forms either literally or equivalently.
`
`[00015] Osmotic dosage forms in general utilize osmotic pressure to
`
`generate a driving force for imbibing fluid into a compartment formed, at least
`
`in part, by a semipermeable membrane that permits free diffusion of fluid but
`
`not drug or osmotic agent(s), if present. A significant advantage to osmotic
`
`systems is that operation is pH-independent and thus continues at the
`
`osmotically determined rate throughout an extended time period even as the
`
`dosage form transits the gastrointestinal tract and encounters differing
`
`1O
`
`microenvlronments having significantly different pH values. A review of such
`
`dosage forms is found in Santus and Baker, “Osmotic drug delivery: a review of
`
`the patent literature,” Journal of Controlled Release 35 (1995) 1-21,
`
`incorporated in its entirety by reference herein.
`
`In particular, the following US.
`
`Patents, owned by the assignee of the present application, ALZA Corporation,
`
`15
`
`directed to osmotic dosage forms, are each incorporated in their entirety
`
`herein: Nos. 3,845,770; 3,916,899; 3,995,631; 4,008,719; 4,111,202;
`
`4,160,020; 4,327,725; 4,519,801; 4,578,075; 4,681,583; 5,019,397; and
`
`5,156,850.
`
`[00016] Devices in which a drug composition is delivered as a slurry,
`
`20
`
`suspension or solution from a small exit orifice by the action of an expandable
`
`layer are described in U. 8. Patents Nos. 5,633,011; 5,190,765; 5,252,338;
`
`5,620,705; 4,931,285; 5,006,346; 5,024,842; and 5,160,743, which are
`
`incorporated herein by reference. Typical devices include an expandable push
`
`layer and a drug layer surrounded by a semipermeable membrane.
`
`In certain
`
`25
`
`instances, the drug layer is provided with a subcoat to delay release of the drug
`
`composition to the environment of use or to form an annealed coating in
`
`conjunction with the semipermeable membrane.
`
`[00017] Devices in which a drug composition is delivered in a dry state from a
`
`large exit orifice by the action of an expandable layer are described in
`
`30
`
`US Patent Nos. 4,892,778, 4,915,949 and 4,940,465. Those references
`
`describe a dispenser for delivering a beneficial agent to an environment of use
`
`that includes a semipermeable wall containing a layer of expandable material
`
`that pushes a dry drug layer out of the compartment formed by the wall. The
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`4
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`exit orifice in the device is substantially the same diameter as the inner
`
`diameter of the compartment formed by the wall.
`
`[00018] While dosage forms delivering the drug composition to the
`environment of use in the dry state may provide suitable release of drug at
`
`various drug loadings over a prolonged period of time, the exposure of the drug
`layer to the environment of use may result in agitation-dependent release of
`drug that in some circumstances is difficult to control. Accordingly, it may be
`advantageous to release the drug as a slurry or suspension that may be
`metered by control of rate of expansion of the push layer and the size of the
`
`1O
`
`exit orifice in the dosage form as in accordance with this invention.
`
`[00019] US Patent 5,169,638 describes a buoyant controlled release
`pharmaceutical powder formulation to be filled into capsules that uses a pH
`dependent polymer formed from alginic acid and hydroxypropylmethyl cellulose
`to release pharmaceuticals at a controlled rate.
`It appears that this capsule
`formulation was intended to mimic the characteristics of a tableted formulation.
`
`[00020] No description is provided of a formulation that provides the uniform
`release characteristics of. the dosage forms containing paliperidone and related
`
`compounds of the present invention.
`[00021] US Patent Nos. 4,892,778 and 4,940,465, describe a dispenser for
`delivering a beneficial agent to an environment of use that includes a
`
`semipermeable wall containing a layer of expandable material that pushes a
`drug layer out of the compartment formed by the wall. The exit orifice in the
`device is substantially the same diameter as the inner diameter of the
`
`15
`
`20
`
`compartment formed by the wall.
`
`25
`
`[00022] US Patent No. 4,915,949, describes a dispenser for delivering a
`beneficial agent to an environment of use that includes a semipermeable wall
`
`containing a layer of expandable material that pushes a drug layer out of the
`compartment formed by the wall. The drug layer contains discrete tiny pills
`
`dispersed in a carrier. The exit orifice in the device is substantially the same
`diameter as the inner diameter of the compartment formed by the wall.
`
`30
`
`[00023] US Patent No. 5,126,142, describes a device for delivering an
`ionophore to livestock that includes a semipermeable housing in which a
`composition containing the ionophore and a carrier and an expandable
`
`5
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`hydrophilic layer is located, along with an additional element that imparts
`
`sufficient density to the device to retain it in the rumen—reticular sac of a
`
`ruminant animal. The ionophore and carrier are present in a dry state during
`
`storage and the composition changes to a dispensable, fluid-like state when it
`
`is in contact with the fluid environment of use. A number of different exit
`
`arrangements are described, including a plurality of holes in the end of the
`
`device and a single exit of varying diameter to control the amount of drug
`
`released per unit time due to diffusion and osmotic pumping.
`
`[00024]
`
`Prior to this invention, paliperidone’s related compound, risperidone,
`
`10
`
`was administered in conventional forms, such as a nonrate-controlling, dose-
`
`dumping immediate release tablet, or by a dose—dumping capsule, and usually
`
`at multiple, repetitive dosing intervals throughout the day. The product is
`
`marketed as Risperdal® by Janssen Pharmaceutica Products, L.P. Physicians’
`Desk Reference, Thompson Healthcare, 56th Ed., pp. 1796-1800 (2002).
`
`15
`
`[00025] The Risperdal® mode of therapy, however, continues to lead to an
`
`initial high dose of risperidone in the blood plasma after administration,
`
`followed by a decreased level of risperidone in the blood plasma. Moreover,
`
`this peak and trough occurs twice to three times during a 24—hour period due to
`
`the multiple dosing regimen. The concentration differences in dosing patterns
`
`20
`
`are related to the presence and absence of administered drug, which is a
`
`major disadvantage, associated with this prior dosage form and mode of
`
`administration.
`
`[00026] Conventional dosage forms and their mode of operation, including
`
`dose peaks and valleys, are discussed in Pharmaceutical Sciences,
`
`25
`
`Remington, 18th Ed., pp. 1676-1686 (1990), Mack Publishing 00.; m
`
`Pharmaceutical and Clinical Pharmacokinetics, 3rd Ed., pp. 1-28 (1984), Lea
`
`and Febreger, Philadelphia; and in U.S. Patents Nos. 3,598,122 and
`
`3,598,123, both issued to Zaffaroni.
`
`[00027] A dosage form exhibiting substantially ascending release rate profile
`
`30
`
`is Concerta® marketed by McNeil Consumer Healthcare and ALZA
`Pharmaceuticals. Physicians’ Desk Reference, Thompson Healthcare, 56th
`Ed., pp. 1998—2001 (2002). The Concerta® product, however indicated for
`
`6
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`once—a-day administration, only delivers at a substantially ascending rate of
`
`release for up to about 8 hours.
`[00028] Patent applications relating to Concerta® include published PCT Pat.
`
`Application No. W099/62496A1. This patent application discloses the
`substantially ascending release rate profile related to Concerta® for delivery
`
`over about 8 hours for once—a-day dosing.
`
`[00029] Related patent applications include published PCT Pat. Application
`
`No. W098/14168; W098/23263; W0 98/06380A2 and US 2001/0012847A1.
`
`[00030]
`
`Still other applications relating to providing increasing rate of release
`
`1O
`
`delivery profile include US 2002/OO35357A1; WO O1/52819A1 and W0
`
`01/37813A2 & A3.
`
`[00031] There remains a need for effective dosing methods, dosage forms
`
`and devices that will permit the controlled release of paliperidone and related
`
`compounds over a prolonged period of time at a substantially ascending rate of
`
`15
`
`release to reduce the amount of the active agent that the patient is exposed to
`
`at any particular time and to increase the time between dosing, preferably to
`
`obtain a once-a-day dosing regimen while reducing associated side effects.
`
`20
`
`SUMMARY OF THE INVENTION
`
`[00032] The present invention is designed for once—a-day administration of
`
`an oral dosage form to deliver paliperidone for more than about 22 hours
`
`utilizing a capsule-shaped tablet. This approximately 22 hours of release is at
`
`a substantially ascending rate of release from the core with 90% delivery
`
`25
`
`occurring at about 20 hours. This novel profile provides therapeutic delivery
`
`above the MPC while keeping the plasma levels below the MTC and low
`
`enough such that side effects will be reduced and the development of
`
`tolerance is increased. This delivery profile provides 24 hours of efficacy
`
`without high plasma levels.
`
`30
`
`[00033] The present invention provides for a substantially ascending release
`
`rate.
`
`It has been surprisingly discovered that the instant profile best provides
`
`efficacious therapy over 24 hours while potentially reducing negative side
`
`effects associated with administration of the drug.
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`7
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`[00034] The present invention utilizes a slow, but substantially ascending,
`rate of release when the dosage form is likely to be in the colonic region of the
`
`gastrointestinal (GI) tract. The profile is not previously used to deliver any
`drug, but is designed to increase the therapeutic index of paliperidone.
`
`It has been surprisingly found that the described ascending release
`[00035]
`rate can provide for a substantially ascending blood plasma concentration of
`
`drug with peak concentration occurring later than about 16 hours after
`administration. This ascending blood plasma concentration reduces the
`
`intraday tolerance effect developed.
`
`1O
`
`[00036]
`
`It has been further surprisingly discovered that the addition of an
`
`osmagent, salt, into the first drug layer, but not in the second drug layer,
`
`impacts the delivery profile such that a substantially ascending release rate
`
`results.
`
`It has been further surprisingly discovered that maintaining the ratio
`[00037]
`of the concentration of drug in the first drug layer and the concentration of drug
`
`15
`
`in the second drug layer impacts the delivery profile such that the desired
`
`substantially ascending rate of release results.
`
`[00038] The dosage form utilizes a semipermeable membrane surrounding a
`three-layer core:
`the first layer is referred to as a first drug layer and contains
`
`20
`
`low amounts of drug and an osmotic agent such as salt; the middle layer
`
`referred to as the second drug layer contains higher amounts of drug,
`
`excipients and no salt; and the third layer referred to as the push layer contains
`
`osmotic agents and no drug. At least one orifice is drilled through the
`
`membrane on the first drug layer end of the capsule-shaped tablet.
`
`25
`
`[00039]
`
`In the aqueous environment of the GI tract, water is imbibed through
`
`the semipermeable membrane at a controlled rate determined by the
`
`properties of the membrane and the osmolality of the core consitituents. This
`
`causes the push layer to swell and the drug layers to hydrate and form viscous,
`
`but deformable, masses. The push layer expands against the second drug
`
`30
`
`layer, which in turn pushes against the hydrated first drug layer. The first drug
`layer, followed by the second drug layer, exits the system through the orifice(s)
`in the membrane at the same rate that water is imbibed into the core. The
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`biologically inert components of the tablet remain intact during the GI transit
`
`and are eliminated as a shell along with insoluble core components.
`
`[00040] The dosage form incorporating the present invention is designed to
`
`be a once-a-day dosage form that is therapeutically effective while providing
`
`increased stability.
`
`[00041]
`
`In still another aspect, the invention comprises a dosage form
`
`comprising a membrane defining a compartment, the membrane surrounding
`
`an inner protective subcoat, at least one exit orifice formed or formable therein
`
`and at least a portion of the membrane being semipermeable; an expandable
`
`1O
`
`layer located within the compartment remote from the exit orifice and in fluid
`
`communication with the semipermeable portion of the membrane; a first drug
`
`layer located adjacent the exit orifice; and a second drug layer located within
`
`