->
`o
`
`Approved
`
`for
`
`PTO/SB/05
`use
`
`(09-04)
`
`the
`
`0001
`
`AGILA ET AL - EXHIBIT 1017 (PART 1 OF 4)
`
`

`
`Approved
`
`for
`
`PTO/SB/17
`use
`
`(12-04V2)
`
`. _
`
`0002
`
`

`
`->
`o
`
`Approved
`
`for
`
`PTO/SB/05
`use
`
`(09-04)
`
`0003
`
`

`
`Approved
`
`for
`
`PTO/SB/17
`use
`
`(12-04V2)
`
`. _
`
`0004
`
`

`
`t
`
`CP391
`
`PATENT
`
`BENDAMUSTINE PHARMACEUTICAL COMPOSITIONS
`
`FIELD OF
`
`THE
`The present
`
`INVENTION
`invention
`
`pertains
`
`0005
`
`

`
`CPS 91
`
`PATENT
`
`Cl""^
`
`CI
`
`\
`Formula I
`
`Q
`
`OH -HCI
`
`Bendamustine was
`
`initially
`
`synthesized in
`
`0006
`
`

`
`CPS 91
`
`PATENT
`
`The reconstitution
`
`of
`
`the
`
`present
`
`0007
`
`

`
`CP391
`
`PATENT
`
`Teagarden et
`
`al.
`
`disclose
`
`lyophilized
`
`0008
`
`

`
`CP391
`
`Yet another
`
`embodiment
`
`of
`
`PATENT
`
`the
`
`0009
`
`

`
`CP391
`
`PATENT
`
`Another embodiment
`
`of
`
`the
`
`invention
`
`0010
`
`

`
`CP391
`
`The present
`
`invention
`
`involves
`
`PATENT
`
`a
`
`0011
`
`

`
`CP391
`
`PATENT
`
`Another embodiment
`
`of
`
`the
`
`invention is
`
`0012
`
`

`
`CP391
`
`after reconstitution
`
`of
`
`the
`
`PATENT
`
`lyophilized
`
`0013
`
`

`
`CP391
`
`PATENT
`
`Another embodiment
`
`of
`
`the
`
`invention is
`
`0014
`
`

`
`CP391
`
`PATENT
`
`ramping to
`
`-25°C
`
`over
`
`about
`
`3
`
`0015
`
`

`
`CPS 91
`
`PATENT
`
`about 15
`
`mg/mL,
`
`mannitol
`
`about
`
`25.5
`
`0016
`
`

`
`CP391
`
`PATENT
`
`By "stable
`
`pharmaceutical composition"
`
`is
`having sufficient
`
`meant any
`stability
`
`0017
`
`

`
`CP391
`
`PATENT
`
`life expectancy
`
`of
`
`a patient
`
`afflicted
`
`with
`
`a
`
`0018
`
`

`
`CP391
`
`PATENT
`
`use of
`
`alcohols
`
`and/or other
`
`organic
`
`solvents
`
`in the
`
`0019
`
`

`
`CP391
`
`PATENT
`
`pharmaceutical dosage
`
`form
`
`suitable
`
`0020
`
`

`
`CP391
`
`PATENT
`
`organic solvent
`
`is
`
`that
`
`amount
`
`that
`
`0021
`
`

`
`CP391
`
`Anti-neoplastic agents
`
`which
`
`PATENT
`
`may
`
`0022
`
`

`
`CP391
`
`PATENT
`
`alkylating-type antineoplastic
`
`agents
`
`may be
`
`selected
`
`0023
`
`

`
`CP391
`
`PATENT
`
`oxaunomycin, peplomycin,
`
`pilatin,
`
`pirarubicin,
`
`0024
`
`

`
`CP391
`
`PATENT
`
`merbarone, merocyanine
`
`derivatives,
`
`methylanilinoacridine,
`
`0025
`
`

`
`CP391
`
`Preferred anti-neoplastic
`
`agents
`
`PATENT
`
`include,
`
`0026
`
`

`
`CPS 91
`
`PATENT
`
`Cytarabine WITH
`Daunorubicin OR
`7 + 3
`
`Idarobicin
`
`AML (induction)
`OR Mitoxantrone
`
`Cytarabine WITH
`Daunorubicin OR
`5 + 2
`
`HiDAC
`
`0027
`
`

`
`CP391
`
`PATENT
`
`Dexamethasone, Cisplatin,
`Cytarabine
`
`DHAP
`
`Non-Hodgkin's
`
`ESHAP
`
`Etoposide,
`Methylprednisilone,
`Cisplatin, Cytarabine
`
`Non-Hodgkin's
`
`Methotrexate, Leucovorin,
`Doxorubicin,
`Cyclophosphamide,
`Vincristine, Prednisone,
`MACOP-B
`Bleomycin, Septra,
`Ketoconazole
`
`Methotrexate, Leucovorin,
`
`m-BACOD
`
`0028
`
`

`
`CP391
`
`PATENT
`
`Melphalan, Prednisone
`
`Melphalan, Prednisone
`
`MP
`
`Multiple Myeloma
`
`Vincristine, Doxorubicin,
`Dexamethasone
`
`VAD
`
`Multiple Myeloma
`
`VBMCP
`
`Vincristine, Carmustine,
`Melphalan,
`Cyclophosphamide,
`Prednisone
`
`As described herein,
`
`0029
`
`

`
`CP391
`
`PATENT
`
`carbohydrates such
`
`as
`
`lactose,
`
`sucrose, maltose,
`
`0030
`
`

`
`CPS 91
`
`PATENT
`
`The pre-lyophilization
`
`solution
`
`or dispersion
`
`can
`
`be
`lyophilization, sterilization
`
`0031
`
`

`
`CP391
`
`PATENT
`
`temperature to
`
`about
`
`25
`
`o
`
`C-40
`
`0032
`
`

`
`CP391
`
`PATENT
`
`injection following
`
`further
`
`dilution
`
`into an
`
`0033
`
`

`
`CP391
`
`PATENT
`
`CCS
`CCS
`CCS
`
`10%
`20%
`30%
`Iso-propanol (v/v)
`5%
`10%
`20%
`30%
`n-Butanol (v/v)
`5%
`10%
`
`CCS
`CCS
`CCS
`
`CCS
`CCS
`CCS
`CCS
`
`CCS
`CCS
`CCS
`
`CCS
`CCS
`CCS
`
`Precipitate
`CCS
`CCS
`CCS
`
`Precipitate
`CCS
`CCS
`CCS
`
`Precipitate
`CCS
`CCS
`CCS
`
`20%
`
`CCS
`CCS
`2 layers
`2 layers
`30%
`Tert-Butanol (v/v)
`5%
`10%
`20%
`30%
`CCS stands
`
`CCS
`CCS
`2 layers
`2 layers
`
`CCS
`CCS
`
`CCS
`CCS
`2 layers
`2 layers
`
`2 layers
`2 layers
`
`CCS
`CCS
`CCS
`CCS
`for
`
`CCS
`CCS
`CCS
`CCS
`clear
`
`CCS
`CCS
`CCS
`CCS
`
`0034
`
`

`
`CP391
`
`PATENT
`
`pharmaceutical use.
`
`However, during
`
`the
`
`manufacturing
`aqueous solutions
`
`0035
`
`

`
`BLANK (usnoi
`
`0036
`
`0036
`
`

`
`CP391
`
`PATENT
`
`The other
`
`major
`
`degradant observed
`
`during
`
`this
`
`0037
`
`

`
`CP391
`
`PATENT
`
`9. The purity
`
`was
`
`highest
`
`in
`
`solutions containing
`
`0038
`
`

`
`CP391
`
`PATENT
`
`99.10
`98.85
`97.58
`
`99.46
`99.26
`99.05
`98.04
`
`3 hours
`6 hours
`24 hours
`0 hours
`10% Tert-
`3 hours
`butanol
`6 hours
`24 hours
`0 hours
`20% Tert-
`3 hours
`butanol
`6 hours
`24 hours
`30% Tert-
`0 hours
`3 hours
`butanol
`6 hours
`24 hours
`
`0.64
`0.88
`2.09
`
`99.59
`99.48
`99.35
`98.35
`
`0.14
`0.13
`0.20
`
`0.30
`0.48
`0.69
`1.64
`
`0.17
`
`99.63
`99.60
`99.58
`99.42
`
`0.11
`0.12
`0.13
`0.19
`
`0.29
`0.40
`1.27
`
`0.11
`0.11
`0.12
`0.20
`0.13
`0.16
`0.18
`0.34
`
`Table 6.
`
`HPLC
`
`stability results
`
`for
`
`0039
`
`

`
`CP391
`
`PATENT
`
`0 hours
`30% Iso-
`3 hours
`propanol
`6 hours
`24 hours
`
`0.15
`
`99.56
`99.47
`99.40
`99.15
`
`0.20
`0.24
`0.52
`
`0.10
`
`0.12
`0.11
`0.14
`
`Table 8.
`
`HPLC
`
`stability
`
`results for
`
`bendamustine
`
`0040
`
`

`
`CP391
`
`PATENT
`
`Table 10.
`
`HPLC stability
`
`results
`
`for
`
`bendamustine
`
`0041
`
`

`
`CP391
`
`PATENT
`
`Mannitol
`Alcohol
`Water, q.s.
`
`10-30 mg/mL
`5-40% (v/v)
`to
`
`desired volume
`
`Ingredients
`5
`Bendamustine HC1
`Mannitol
`
`Concentration
`
`about 12-17
`
`0042
`
`

`
`CP391
`
`PATENT
`
`about 15
`
`mg/mL
`about 25.5
`
`Bendamustine HC1
`mg/mL
`Mannitol
`about 10%
`(v/v)
`Butanol
`desired volume
`Water, q.s.
`to
`5
`
`Ingredients
`Bendamustine HC1
`
`0043
`
`

`
`CP391
`
`PATENT
`
`Concentration
`about 12-17 mg/mL
`about 20-30
`
`mg/mL
`about 10-50
`
`Ingredients
`Bendamustine HC1
`Mannitol
`(v/v)
`Tertiary butanol
`desired volume
`Water, q.s.
`5
`
`%
`
`0044
`
`

`
`CPS 91
`
`PATENT
`
`Methanol, HPLC
`
`grade
`
`or
`
`equivalent
`
`0045
`
`

`
`CP391
`
`30 0 C
`Column temp.:
`5 0 C
`Sample temp.:
`10 /xL
`Injection Volume:
`Sample Concentration:0.25
`
`PATENT
`
`mg/mL
`
`0046
`
`

`
`CP391
`
`Sample preparation-
`
`dissolve
`
`the drug
`
`PATENT
`
`with
`product
`minutes. The solution
`
`0047
`
`

`
`CP391
`
`PATENT
`
`Table 11:
`
`Retention
`
`Time
`
`for Bendamustine
`
`and
`
`0048
`
`

`
`CPS 91
`
`PATENT
`
`The solubility
`
`of bendamustine
`
`HC1
`
`(bendamustine) in
`
`water
`
`0049
`
`

`
`CP391
`
`Example 3-Stability
`A. Stability in
`
`PATENT
`
`Water
`Solutions of
`
`bendamustine
`
`(15 mg/mL),
`
`0050
`
`

`
`CP391
`
`PATENT
`
`anticipated that
`
`the
`
`vial
`
`size
`
`0051
`
`

`
`CP391
`
`PATENT
`
`acceptable cake
`
`was
`
`30%
`
`TBA. Additionally, reconstitution
`
`0052
`
`

`
`CP391
`
`PATENT
`
`Example 5-
`
`Impurity
`
`ass
`
`essment
`Major impurities
`introduced
`
`0053
`
`

`
`CP391
`
`A. Freezing Rate
`The literature
`
`PATENT
`
`reports
`
`that
`
`TBA
`
`0054
`
`

`
`CP391
`
`PATENT
`
`these gentle
`
`conditions
`
`(Fig. 5).
`
`There were
`
`no
`
`immediate
`
`0055
`
`

`
`CP391
`
`PATENT
`
`the same
`
`extent
`
`as
`
`if each
`
`individual
`
`publication
`
`0056
`
`

`
`CP391
`
`PATENT
`
`What is
`
`claimed
`
`is:
`
`1. A pharmaceutical
`
`composition
`
`of
`
`0057
`
`

`
`CP391
`
`PATENT
`
`7. The lyophilized
`
`preparation
`
`according
`
`to
`
`0058
`
`

`
`CPS 91
`
`PATENT
`
`17. A pharmaceutical
`
`dosage
`
`form
`
`of
`
`0059
`
`

`
`CP391
`
`PATENT
`
`25. In a method
`
`for
`
`obtaining
`
`agency approval for
`improvement which
`
`a bendamustine
`comprises
`
`0060
`
`

`
`CP391
`
`PATENT
`
`bendamustine) at
`
`release
`
`and
`
`the
`
`0061
`
`

`
`CP391
`
`PATENT
`
`34. A bendamustine
`
`pre-lyophilization
`
`dispersion
`solution or
`organic solvents,
`
`comprising one
`wherein
`
`0062
`
`

`
`CP391
`
`PATENT
`
`39. A method
`
`according
`
`to
`
`claim
`
`36,
`
`0063
`
`

`
`CP391
`
`PATENT
`
`48. A method according
`
`to
`
`claim
`
`47, wherein said
`
`alcohol
`
`0064
`
`

`
`CP391
`
`PATENT
`
`57. A method
`
`according
`
`to
`
`claim
`
`36
`
`0065
`
`

`
`CP391
`
`PATENT
`
`63. A method
`
`of
`
`treating according
`
`to
`
`claim
`
`0066
`
`

`
`CPS 91
`
`PATENT
`
`pharmaceutically acceptable
`
`container,
`
`wherein said
`
`0067
`
`

`
`CP391
`
`PATENT
`
`Abstract
`
`The present
`
`invention
`
`provides
`
`pharmaceutical
`
`0068
`
`

`
`"Bendamustine Pharmaceutical
`
`Compositions"
`
`Brittain et
`
`al.
`Attorney Docket
`
`-7&
`€0
`
`E
`O)
`E
`
`0069
`
`

`
`"Bendamustine Pharmaceutical
`
`Compositions"
`
`Brittain et
`
`al.
`Attorney Docket
`
`0070
`
`

`
`Bendamustine Pharmaceutical
`
`Co
`
`Brittain et
`
`Attorney Docket
`
`HP1 formation
`
`0071
`
`

`
`"Bendamustine Pharmaceutical
`
`Compositions"
`
`Brittain et
`
`Figure 4.
`
`0072
`
`

`
`/ /
`
`"Bendamustine Pharmaceutical
`
`Compositions"
`
`Brittain et
`
`Attorney Docket
`
`+
`8
`§
`
`0073
`
`

`
`"Bendamustine Pharmaceutical
`
`Compositions
`
`Brittain et
`
`OM
`o.eo-
`3
`0.4^
`
`0.20-
`om
`
`-JL
`
`T—f-r-r
`
`T
`
`0074
`
`

`
`IN THE
`
`UNITED
`
`STATES
`
`PATENT
`
`CP391
`
`In Re Application
`
`0075
`
`

`
`Priority
`Claimed
`
`Country
`
`(IfX'd)
`
`Serial Number
`
`Date Filed
`
`CP391
`
`I hereby claim
`
`the
`
`benefit
`
`under
`
`0076
`
`

`
`true and
`knowledge are
`of my own
`I hereby declare that all statements made herein
`statements made on information and belief are believed to be true; and further that these
`statements were
`made with
`the knowledge
`that willful
`punishable by
`
`CP391
`
`0077
`
`

`
`"* 4-
`
`CP391
`
`I hereby declare
`
`that all statements made
`
`knowledge are
`my own
`herein of
`statements made on information and belief are believed to be true; and further that these
`statements were
`made
`with the
`
`0078
`
`

`
`PATENT APPLICATION SERIAL NO
`
`U.S. DEPARTMENT OF COMMERCE
`PATENT AND TRADEMARK
`OFFICE
`FEE RECORD SHEET
`
`i
`
`11330868
`
`01/17/2006 YP0LITE1 00000054 031195
`01 FC:1011
`02 FC:1111
`03 FC:1311
`04 FC:1202
`05 FC:1201
`
`300.00 DA
`500.00 DA
`200.00 DA
`2900.00 DA
`3600.00 DA
`
`PTO-1556
`(5/87)
`
`$
`
`*V.a Ovrnm*
`
`Oto: WB
`
`—
`
`0079
`
`

`
`Approved (or
`
`PTCVSB/M (12-04)
`through 7/31/3006.
`UM
`
`0080
`
`

`
`Application Data
`
`Sheet
`
`Application Information
`Application Type::
`Subject Matter::
`Suggested Classification
`Suggested Group
`
`0081
`
`

`
`Name Suffix::
`City of
`
`Residence::
`State or
`
`Province
`Country of
`
`of Residence::
`Residence::
`Street of
`
`Mailing Address::
`
`City of
`
`Mailing Address-
`State or
`
`0082
`
`

`
`Fax Number-
`E-Mail address::
`
`610-738-6590
`intprop@cephalon.com
`
`Representative Information
`Representative Customer
`
`Number::
`
`Domestic Priority
`
`Information
`
`0083
`
`

`
`Page 1
`
`of
`
`UNITED STATES R\TENT AND
`
`TRADEMARK OFFICE
`
`UNITED STATES
`
`0084
`
`

`
`SUMMARY OF
`
`FEES DUE:
`
`Total additional
`
`fee(s)
`
`required
`
`Page 2
`
`of
`
`0085
`
`

`
`03/14/06 15:13'FAX 61'07386590
`
`CEPHALON, INC.
`
`- USPTO MAIN
`
`@001
`
`Approved for
`
`PTO/SB/21 (04-04)
`use
`through 07/31/2006.
`U.S. Patent
`and
`
`OMB
`
`0086
`
`

`
`03/14/06 15:14 FAI 6107386590
`
`CEPHALON, INC.
`
`-
`
`USPTO MAIN
`
`@002
`
`Attorney Docket:
`
`CP391
`
`PATENT
`
`RECEIVED
`CENTRAL FAX
`
`IN THE UNITED
`
`STATES
`
`0087
`
`

`
`03/14/06 15:14 FAI 6107386590
`
`CEPHALON, INC.
`
`-> USPTO MAIN
`
`BEST AVAILABLE COPY
`
`@003
`Page
`1 of2
`
`UNITED STATES
`
`RCTENT AND
`
`TUMJEMARK OFFICE
`
`UNITED STATES
`
`DEPARTMENT OP
`United States Patost
`AMwr COMMISSIONER TOR
`
`| AFPLICATION NUMBER
`
`0088
`
`

`
`03/14/06 15:14 FAX 6107386590
`
`CEPHALON, INC.
`
`BEST AVAILABLE COPY
`
`- USPTO MAIN
`@004
`Page 2
`
`of2
`
`SUMMARY OF
`
`FEES
`
`DUE;
`
`Total additional
`
`fee(s)
`
`required for
`
`• $130 Surcharge.
`
`0089
`
`

`
`03/14/06 15:15.
`
`FAX
`
`6107386590
`
`- U S F R O MAIN
`
`RECEIVM)
`
`IN THE
`
`UNITED
`
`0090
`
`

`
`03/14/06 15:15 FAX 6107386590
`
`CEPHALON, INC.
`
`- USPTO MAIN
`
`@1006
`
`Serial Number
`
`Date Filed
`
`CP391
`
`Priority
`Claimed
`(IfX'd)
`
`Country
`
`• • • •
`
`I hereby claim
`
`the
`
`benefit
`
`U.S.C. §
`under 35
`below and,
`insofar
`
`120 of
`
`0091
`
`

`
`03/14/06 15:15 FAX 6107386590
`
`CEPHALON, INC.
`
`-» USPTO MAIN
`
`111007
`
`I hereby declare
`
`that
`
`all statements made
`
`herein
`
`of my
`statements made
`
`CP391
`
`0092
`
`

`
`03/14/06 15:15 FAX 6107386590
`
`CEPHALON, INC.
`
`-> USPTO MAIN
`
`1)008
`
`I hereby declare
`
`that all
`
`statements
`
`made herein
`
`CP391
`
`knowledge are
`my own
`of
`and belief arc believed to be true; and further that these
`statements made on information
`statements were
`made with
`punishable by fine
`
`0093
`
`

`
`03/14/06 15:16 FAX 6107386590
`
`CEPHALON. INC.
`
`-> USPTO MAIN
`
`@009
`
`IN THE UNITED STATES
`
`PATENT AND TRADEMARK
`
`OFFICE
`
`In Re
`
`Application
`
`of:
`
`CP391
`
`Brittain et
`
`al.
`
`Group Art
`
`Unit: Not
`
`For: BENDAMUSTLNE PHARMACEUTICAL
`COMPOSITION
`
`DECLARATION AND
`
`0094
`
`

`
`03/14/06 15:16 FAX 6107386590
`
`CEPHALON. INC.
`
`-> USPTO MAIN
`
`@010
`
`- 2-
`
`CP391
`
`Country
`
`Serial Number
`
`Date Filed
`
`Priority
`Claimed
`
`QfX'd) • • • •
`
`I hereby claim
`
`the benefit
`
`application(s) listed
`any United States
`U.S.C. § 120 of
`under 35
`below and,
`insofar as
`die subject matter
`disclosed in
`
`0095
`
`

`
`03/14/06 15:16 FAX 6107386590
`
`CEPHALON. INC.
`
`-> USPTO MAIN
`
`@011
`
`I hereby declare
`
`that
`
`all
`
`CP391
`
`statements
`
`0096
`
`

`
`03/14/06 15:16 FAX 6107386590
`
`CEPHALON. INC.
`
`-» USPTO MAIN
`
`@012
`
`I hereby declare
`
`that
`
`all
`
`statements made
`
`herein
`
`CP391
`
`0097
`
`

`
`03/14/06 15:17 'FAX 6107386590
`
`CEPHALON. INC.
`
`-» USPTO MAIN
`
`@013
`
`Supplemental Application
`
`Data
`
`Sheet
`
`Application Information
`Application Type::
`
`0098
`
`

`
`03/14/06 15:17 FAX 6187386590
`
`CEPHALON. INC.
`
`-» USPTO MAIN
`
`@014
`
`Name Suffix::
`City of
`
`Residence::
`State or
`
`Province of
`
`Residence::
`Country of
`Residence::
`Street of
`Mailing
`
`Address::
`
`City of
`
`0099
`
`

`
`03/14/06 15:17 FAI 6107386590
`
`CEPEALON.
`
`INC.
`
`-> USPTO MAIN
`
`@015
`
`Fax Number::
`E-Mail address::
`
`610-738-6590
`intprop@cephalon.com
`
`Representative Information
`Representative Customer
`
`Number::
`
`Domestic Priority Information
`Application:: Continuity Type::
`
`This
`
`0100
`
`

`
`Page 1
`
`of2
`
`UNITED STATES PATENT AND TRADEMARK QFFIGE
`
`UNITED STATES
`
`DEPARTMENT
`
`0101
`
`

`
`Page 2
`
`of
`
`A copy
`
`of
`
`this
`
`notice
`
`MUST
`
`0102
`
`

`
`04/04/06 12:09 FAX 6107386590
`
`CEPHALON, INC.
`
`-• USPTO MAIN
`
`@001
`
`Approved tor
`
`PTO/SB/21 (04-04)
`use through
`
`07/31/2006.
`U.S. Patenl
`
`and
`
`0103
`
`

`
`04/04/06 12:09 FAX 6107386590
`
`CBPHALON, INC.
`
`-• USPTO MAIN
`
`@002
`
`Attorney Docket:
`
`CP391
`
`PATENT
`
`IN THE UNITED STATES
`
`PATENT
`
`RECEIVED
`AND
`
`0104
`
`

`
`v
`
`04/04/06 12:10 FAX 6107386590
`
`CEPHALON. INC.
`
`@004
`- USPTO MAIN
`Page 1 of2
`
`UNITED STATES B^TENT AND
`
`IhAPEMARK OFFICE
`
`UNITED STATES
`
`DEPABTMENT OF
`United State*
`
`Si
`
`| APPLICATION NUMBER
`
`0105
`
`

`
`04/04/06 12:10 FAX 6107386590
`
`CEPHALON, INC.
`
`-» USPTO MAIN
`
`Q|005
`Page 2 of2
`
`A copy of
`
`this notice MUST be
`
`returned
`
`with the
`
`reply.
`
`Lr
`
`Initial
`
`Office of
`
`Patent
`
`Examination
`
`(571) 272-4000,
`
`0106
`
`

`
`J
`
`f/ff
`
`Shelf Condenser Vacuum 1 Windmill
`4440
`Cft 3 O
`c
`
`I
`
`I 1
`
`I I I
`
`3885
` I I
`
`i
`
`3330
` 1 I I I
`
`l
`
`l l I
`
`2775
`I I
`I l
`
`
`
`I I
`
`l
`
`Product 4
`2220
`l
`I l
`I
`
`I
`
`I 1
`
`
`
`Product 3
`
`Product 2
`
`1110
`1665
`l
` l
`I 11 l
`I l
`^Vacuum
`
`11 I l
`
`
`
`555
` I l I l
`
`l
`
`l
`
`Product 1
`0
`0 -100
`I l
`
`I 1
`
` l
`
` I I
`I
`
`l
`
`o
`
`o
`r
`"0 §2
`o m
`
`2
`
`o
`
`CJ>
`
`oi
`
`Cond. Temp
`
`Shelf Temp
`
`Prod. Temp
`
`-i c>>
`M
`<Ji
`
`o
`
`ai
`00
`
`o
`
`•
`
`o
`
`<o
`
`ro
`
`Oi
`O
`N
`•u
`
`o
`
`t
`o
`"8
`I 0)
`
`I I I
`I
`
`-75—
`
`250
`
`-50
`
`500
`
`25
`
`750
`
`0
`
`1000
`
`25--
`
`1250
`
`1
`
`0
`§
`3 00 cn m
`
`u s
`»
`
`a
`
`u
`&
`?
`3
`
`o
`
`TJ
`
`g
`S
`3 ,2,
`2
`(a
`
`CO
`
`50--
`
`1500
`
`3
`ft
`•H S
`s
`ci
`s
`§ r
`§
`r-
`
`>
`g
`s
`g
`fi
`V
`
`0107
`
`

`
`V . E ^
`\
`
`Approved for
`
`PT0/SB/21 (09-04)
`use
`
`^0
`
`through
`
`0108
`
`

`
`\? E
`
`^^ttorney Docket
`
`O
`
`No.:
`
`1#
`
`CP391
`
`IN THE
`
`UNITED
`
`STATES
`
`0109
`
`

`
`Y E
`
`\ O
`
`F
`0
`
`Attorney Docket
`
`CP391
`
`PTO-1449
`Application Number
`jfcH ^ ^ INTORMATION DISCLOSURE
`S^TEMENT
`
`11/330,868
`
`APPLICANT
`
`BY
`
`0110
`
`

`
`FORM PTO-1449
`
`Attorney Docket
`
`CP391
`
`Application Number
`INFORMATION DISCLOSURE
`STATEMENT BY
`
`11/330,868
`
`APPLICANT
`
`0111
`
`

`
`FORM PTO-1449
`
`Attorney Docket
`
`CPS 91
`
`Application Number
`INFORMATION DISCLOSURE
`STATEMENT BY
`
`11/330,868
`
`APPLICANT
`
`0112
`
`

`
`FORM PTO-1449
`
`Attorney Docket
`
`CP391
`
`Application Number
`INFORMATION DISCLOSURE
`STATEMENT BY
`
`11/330,868
`
`APPLICANT
`
`0113
`
`

`
`FORM PTO-1449
`
`Attorney Docket
`
`CPS 91
`
`Application Number
`INFORMATION DISCLOSURE
`STATEMENT BY APPLICANT
`
`11/330,868
`
`0114
`
`

`
`Europaisches
`
`Patentamt
`
`European Patent
`
`Office
`
`(19)
`
`Office europeen
`
`des
`
`brevets J
`
`0115
`
`

`
`EP 1
`1
`
`444 989
`
`A1
`
`2
`
`of cancer cells,
`
`cause severe
`which, in turn, can
`effects on
`[0006] Thus, the problem underlying the present
`vention refers to the identification of compounds that
`specifically modulate distinct steps in the apoptosis
`pathway without
`
`s
`
`0116
`
`

`
`3
`
`EP 1
`
`444 989
`
`A1
`
`4
`
`resistant to apoptosis, thereby favoring malignant
`growth. Moreover, since many chemotherapeutic
`agents kill tumor cells
`by inducing apoptosis, overex-
`can lead
`pression of
`Bcl-2 or
`Bcl-xL
`sistant phenotype.
`[0011] The expression
`
`to
`
`a multi-drug
`
`re­
`
`of
`
`in the
`
`0117
`
`

`
`5
`
`EP 1
`
`444 989
`
`A1
`
`receptor. It
`
`is
`
`obvious
`
`to
`
`6
`
`the
`
`person skilled
`
`0118
`
`

`
`7
`EP 1
`
`444 989
`
`A1
`
`8
`
`one epitope being particularly useful and a second
`epitope being
`immunodominant.
`of the present
`[0031]
`In a preferred embodiment
`cytokine antagonist refers to
`vention, the
`s against
`IL-4,
`
`0119
`
`

`
`9
`
`EP 1
`
`444 989
`
`A1
`
`10
`
`[0035]
`
`In a
`
`further
`
`embodiment
`
`of
`tion the
`
`cytokine
`
`the present
`antagonist
`
`inven­
`
`0120
`
`

`
`EP 1
`
`444
`
`989
`11
`
`A1
`
`12
`
`both tumor
`
`and normal
`
`regimen is
`
`0121
`
`

`
`13
`
`EP 1
`
`444
`
`989
`
`A1
`
`14
`
`stricted to (i) antimetabolites, such as cytarabine,
`fludarabine, S-fluoro^'-deoxyuiridine,
`
`gemcitabine,
`droxyurea or methotrexate; (ii) DNA-fragmenting
`agents, such as bleomycin, (ill) DNA-crosslinking
`agents, such
`as
`
`0122
`
`

`
`15
`
`EP 1
`
`444
`
`989 A1
`
`16
`
`sions, or
`
`rectally,
`
`for
`
`example
`
`in
`
`0123
`
`

`
`17
`
`EP 1 444
`
`989
`
`A1
`
`18
`
`gressing glomerulonephritis and membrane-prolifera-
`such
`tive glomerulonephritis
`type II,
`endocrine diseases
`as type-l diabetes, autoimmune polyendocrinopathy-
`candidiasis-ectodermal dystrophy
`
`(APECED), autoim­
`mune parathyreoidism, pernicious anemia, gonad
`ficiency, idiopathic Morbus Addison, hyperthyreosis,
`Hashimoto thyroiditis
`and primary
`eases such
`as Pemphigus
`
`0124
`
`

`
`EP 1 444
`19
`
`989
`
`A1
`
`20
`
`EXAMPLES
`
`Example 3:
`
`Exogenous
`
`0125
`
`

`
`21
`
`EP 1
`
`444 989
`
`A1
`
`22
`
`Example 5:
`
`IL-4
`
`and
`
`IL-10
`
`protect thyrocytes
`cell death
`
`Induced
`
`0126
`
`

`
`23
`
`EP 1
`
`444
`
`989
`
`nM) and
`
`taxol (5
`
`nM) (Sigma)
`
`A1
`
`or
`
`24
`
`TRAIL
`
`(Alexis, San
`ego, USA). For
`
`0127
`
`

`
`25
`
`shown).
`
`EP 1
`
`444 989
`
`A1
`
`26
`
`Claims
`
`Figure 3. Protection from chemotherapy-in­
`duced cell
`death
`in
`
`thyrocytes transduced
`Bcl-xL
`
`and
`
`with
`Bcl-2. Immunoblot
`
`0128
`
`

`
`27
`
`EP 1
`
`444
`
`989
`
`A1
`
`28
`
`of or
`
`into
`
`the
`
`target
`
`cell.
`
`0129
`
`

`
`29
`
`EP 1
`
`444
`
`989
`
`A1
`
`30
`
`proteins, preferably
`
`lAPs.
`
`0130
`
`

`
`Time (hours)
`
`24
`
`12
`
`6
`
`0
`
`yy.
`
`0
`
`<
`a. 25 -
`
`Time (hours)
`24
`12
`
`6
`
`0
`
`0
`
`*0
`
`o 50 -
`
`o
`O
`
`-'i
`
`^ rif
`
`a 25 -
`
`<
`
`---A--- UTC
`
`-o— FTC
`
`PTC
`Control
`
`S- 75 -
`
`P"
`
`100 n
`
`Taxol
`
`24
`
`•rf
`
`Time (hours)
`6
`T
`
`12
`
`0
`
`0
`
`—4
`
`S. 25 -
`
`<
`
`o 50 -
`U
`Q)
`J2
`^ 75 -
`s-
`
`100
`
`Doxorubicin
`
`o 50 -
`O
`0)
`
`o
`
`si 75 -
`
`100
`
`Cisplatinum
`
`0131
`
`

`
`EP 1
`
`444 989
`
`A1
`
`Nonnal
`
`-FTC-'
`
`i)
`
`_r 'N«nua
`
`FTC
`
`SSc®
`
`.v» i
`
`ISIl^ifflt
`WW&k
`NWyWfMI^888898
`
`!*3^,
`
`3fiS^^S''**-'*'^3
`
`^SE3sSS2T
`
`••
`
`s^l
`
`- e
`
`wmmm
`jt^fH
`
`nKS
`
`wMr'
`
`PTC;
`
`UT,C
`
`: M
`M—I
`•v ''•%
`
`iWttS
`'"Bctx,.
`"i3-^^EEBI
`
`^Cig-'-Vl
`
`'^-aftm:
`
`0132
`
`

`
`EP 1
`
`444
`
`989
`
`A1
`
`.<fr ^
`
`tie
`
`MBa-4.
`
`i-J2a
`
`kD
`
`33
`
`=//
`
`Bcl-2
`
`c
`
`Cwplatmam
`
`Doxorubicin
`
`Vecloi
`
`b
`
`too r
`
`5? 75 - -
`';S
`I' 50-
`•S- a-
`0 . ^ JL^L^
`
`%3r •il
`
`Bcl-iq.
`'i
`
`i
`
`••#'
`
`OBcHct
`• Itoia'
`
`E
`»
`%
`%
`*®, *
`*? --
`
`Bcl-2
`
`_|_
`
`r
`
`JE
`
`'%
`
`*z
`
`%r #
`
`0133
`
`

`
`EP 1
`
`444
`
`989
`
`A1
`
`-Nonoal
`
`•PTC
`
`FTC'
`
`UTC
`
`IFN-r i
`
`t?.
`nmmm. m
`is
`Ui
`
`im.
`
`^ZaSr1
`is
`
`\£Z.
`
`imm.
`•^ssma
`•m 'mSk6AwM
`
`Wfcj
`
`P:
`
`•?*>' m
`Hnl Ah**** ^ *"
`immrn
`fMlf#
`^mm.*
`IHISM
`
`fe
`
`m
`wm
`WM s&mu m
`illlllili
`
`3»
`
`20
`
`0134
`
`

`
`EP 1
`
`444
`
`989
`
`A1
`
`b
`
`IFH-T
`
`Noimal.
`
`iPTC
`
`FTC
`
`•UTC
`
`SS^M
`
`iLio
`
`'
`
`kD
`
`M-
`
`m -
`
`• 21—;•/, ^ rr-:
`
`0135
`
`

`
`Fig.^ Stassi et al.
`
`ji-actin
`
`. <y
`
`<y
`
`kD
`
`Bcl-2
`
`Bcl-XL
`
`IS s
`> ^ ^
`
`kD
`
`> ^
`
`HHMW
`
`IcD
`
`b
`
`ro ro
`
`_ • B B 1 *U i, S, a
`
`DOX
`
`Control CIS
`
`TAX
`
`DOX
`
`Control CIS
`
`0 - —
`
`y 50-
`Q>
`
`— 75 -
`
`ST
`
`100
`
`TAX
`
`. Control CIS DOX
`
`o 25 -
`&
`so - o
`
`<
`Q.
`
`g
`
`— 75 -
`
`. ^
`
`100 i
`
`o •
`<
`a 25-
`
`.y so-
`o
`75 ;
`
`g
`100 n
`
`Normal Thyiocytes+TL-10
`
`Normal Thyrocytes+IL-4
`
`n
`
`Normal Thyrocytes
`
`0136
`
`

`
`al.
`
`Sl'assi el
`
`Fig. 6
`
`"D
`m
`
`anti-IL4+anti-lLlO
`anti-IL-10
`
`-o- - anti-IL-4
`• • Untreated
`
`•••-•ft
`
`^7
`
`ik
`
`%
`
`72
`
`60
`
`Hours
`
`54
`
`48
`
`0
`
`drugs
`
`Chemotherapeutic
`
`0
`
`25 -
`
`CO
`ro
`
`Anti-cylokines
`
`100 n t sa-
`
`75 -
`
`>
`.2
`X3
`o
`• O
`50 -
`
`Q)
`=
`g
`
`a
`
`0137
`
`

`
`Fig-tf Stassi etal.
`
`UTC
`
`in
`
`%
`
`FTC
`
`PTC
`
`i
`rXf
`
`iRI
`
`0
`
`25 -
`
`50 -
`
`£ 75 -I
`
`<
`a
`o
`
`o
`U
`0)
`W
`
`ETaxol
`• Doxorubicin
`
`13 Cisplatinum
`
`• Untreated
`
`UTC
`
`;•§
`&
`iT'
`i
`
`FTC
`ill
`%
`in
`
`I
`
`PTC
`
`0
`
`M
`
`> 25 -
`•s
`o
`g 50 -
`
`ri
`
`sr
`75 -
`
`100
`
`24 hours
`
`100 n
`
`12 hours
`
`0
`
`Anti-IL-4+Anti-ILl
`
`b
`
`0138
`
`

`
`EP 1
`
`444
`
`989
`
`A1
`
`J
`
`PARTIAL EUROPEAN
`
`SEARCH
`
`European Patent
`
`0139
`
`

`
`EP 1
`
`444
`
`989
`
`A1
`
`$ European Patent
`
`Office
`
`INCOMPLETE SEARCH
`SHEET C
`
`1-12, 25 are directed to a Although claims
`
`diagnostic of the human/animal body (Article 52(4)
`been carried out and based on the alleged
`compound/composi ti on.
`
`Claim(s) not searched:
`1-12, 25
`
`Reason for the limitation of the search (non-patentable invention(s)):
`
`Article 52 (4) EPC - Method
`therapy
`
`Further limitation of the search
`
`Claim(s) searched incompletely:
`
`Reason for the limitation of the search:
`
`The present application refers to a
`acting on numerous cytokines, which in their turn influence numerous cell
`death preventing proteins in an extremely high amount of cells. The broad
`nature of the claims is further
`
`0140
`
`

`
`EP 1
`
`444
`
`989
`
`A1
`
`J) European Patent
`
`Oflloe
`
`INCOMPLETE SEARCH
`
`keywords "cytokine antagonist", "cell death/apoptosis" and "cancer".
`
`It
`
`is
`
`emphasized
`known for the treatment of cancer or for promoting cell death, and which
`fall
`
`0141
`
`

`
`EP 1
`
`444 989
`
`A1
`
`PARTIAL EUROPEAN
`
`SEARCH
`
`European Patent
`Office
`
`J
`
`0142
`
`

`
`EP 1
`
`444 989
`
`A1
`
`J European Patent
`
`PARTIAL EUROPEAN
`Office
`
`SEARCH
`
`DOCUMENTS CONSIDERED
`
`0143
`
`

`
`EP 1
`
`444 989
`
`A1
`
`ANNEX TO
`
`THE
`
`EUROPEAN
`
`0144
`
`

`
`Europaisches Patentamt
`
`European Patent
`
`Ill
`
`Office
`
`Office europeen
`
`des
`
`brevets J)
`
`(19)
`
`0145
`
`

`
`EP 1
`
`354
`
`1
`952
`
`A1
`
`the release
`
`of
`
`0146
`
`

`
`3
`
`EP 1
`
`354
`
`952
`
`A1
`
`4
`
`low transfer
`
`efficiency or
`
`complex
`would preclude
`
`manipulation, which
`their routine
`
`use
`
`0147
`
`

`
`EP 1
`5
`
`354 952
`
`A1
`
`6
`
`bicin) or
`
`mitoxantrone;
`
`(v)
`
`protein
`such as
`
`synthesis inhibitors,
`L-asparaginase,
`
`cycloheximide,
`diphteria toxin;
`
`0148
`
`

`
`EP 1
`7
`
`354 952
`
`A1
`
`8
`
`ample, microcapsules,
`
`implants
`
`or
`
`0149
`
`

`
`9
`
`EP 1
`
`354 952
`
`A1
`
`10
`
`type-2, primary
`
`diseas­
`sclerosing cholangitis, neuronal
`es such as multiple sclerosis, Myastenia gravis,
`myasthenic Lambert-Eaton syndrome,
`
`acquired
`myotony, Guillain-Barr6 syndrome
`
`0150
`
`

`
`11
`
`EP 1
`
`354 952
`
`A1
`
`[0044] A preferred
`
`fragment
`
`of
`
`12
`
`the
`
`Smac
`
`0151
`
`

`
`EP 1
`13
`
`354 952
`
`A1
`
`14
`
`lines maintained in long-term culture, primary tumor
`cells derived
`from
`a
`
`malignant pleural
`
`effusion
`
`0152
`
`

`
`15
`
`EP 1
`
`354 952
`
`A1
`
`16
`
`b. Effect
`
`of
`
`Smac overexpression
`
`on
`
`TRAIL-in­
`duced DNA
`fragmentation.
`
`0153
`
`

`
`17
`
`EP 1
`
`354 952
`
`A1
`
`18
`
`d. Effect
`
`of
`
`Smac
`
`peptides
`
`on
`
`0154
`
`

`
`19
`
`EP 1
`
`354 952
`
`A1
`
`20
`
`polyphenols preferably quercetin,
`piceatannol, epigallocatechine
`
`resveratrol,
`
`gallate,
`
`theaflavins,
`flavanols, procyanidins, betulinic acid; hormones
`preferably glucocorticoids
`antagonists, preferably tamoxifen, finasteride or
`LHRH antagonists;
`
`0155
`
`

`
`21
`
`EP 1
`
`354 952
`
`A1
`
`22
`
`carcinoma, non-small
`
`carcinoma, multiple
`ceil lung
`myeloma, basalioma, teratoma, retinoblastoma,
`choroidea melanoma,
`seminoma, rhabdomyosar­
`coma, craniopharyngeoma,
`osteosarcoma,
`rosarcoma, myosarcoma,
`
`0156
`
`

`
`EP 1
`
`354 952
`
`A1
`
`European Patent
`PARTIAL EUROPEAN
`Office
`
`SEARCH REPORT
`which under
`
`Rule
`
`45
`
`J
`
`0157
`
`

`
`EP 1
`
`354 952
`
`A1
`
`J European Patent
`
`Office
`
`INCOMPLETE SEARCH
`SHEET C
`
`Application Number
`
`Claim(s) searched incompletely:
`1-35
`
`Reason for the limitation of the search:
`
`Present claims 1-35 relate to an extremely large number of possible
`compounds, as well as their use. Support within the meaning of Article 84
`EPC and/or disclosure within the meaning of Article 83 EPC is to be
`found, however, for only the expression of the Smac protein. For the
`protein-carrier combination, no actual example is given. In the present
`case, the claims so lack support, and the application so lacks
`disclosure, that a meaningful search over the whole of the claimed scope
`is impossible.
`Consequently, the search has been carried out for those parts of the
`claims which appear to be supported and disclosed, namely those parts
`relating to the compounds specifically prepared in the examples.
`
`14
`
`0158
`
`

`
`EP 1
`
`354 952
`
`A1
`
`J
`
`PARTIAL EUROPEAN European Patent
`
`Office
`
`SEARCH REPORT
`
`Application Number
`EP 02 00 8199
`
`DOCUMENTS CONSIDERED
`
`CLASSIFICATION OF
`
`0159
`
`

`
`EP 1
`
`354 952
`
`A1
`
`PARTIAL EUROPEAN
`
`SEARCH
`
`European Patent
`Office
`
`0
`
`0160
`
`

`
`EP 1
`
`354 952
`
`A1
`
`0 European Patent
`
`Office
`
`Application Number
`
`EP 02 00 8199
`
`CLAIMS INCURRING
`
`FEES
`
`The present
`
`European
`
`patent application
`
`comprised
`
`at
`
`0161
`
`

`
`EP 1
`
`354 952
`
`A1
`
`J European Patent
`
`Office
`
`LACK OF
`
`Appllcatlsn Number
`INVENTION
`UNITY OF
`SHEET B
`
`The Search
`
`Division
`
`considers that
`
`the
`
`0162
`
`

`
`EP 1
`
`354 952
`
`A1
`
`ANNEX TO
`
`THE
`
`EUROPEAN
`ON EUROPEAN PATENT
`
`SEARCH REPORT
`APPLICATION
`
`This annex
`
`lists
`
`0163
`
`

`
`© BUNDESREPUBLIK
`DEUTSCHLAND
`
`© Offenlegungsschrift
`®DE 10306 724 At
`
`(g) Int. CI.
`
`7
`
`:
`A 61 K 31/4184
`A 61
`K
`A 61
`
`® Aktenzeichen:
`@ Anmeldetag:
`DEUTSCHES
`@ Offenlegungstag:
`PATENT- UNO
`MARKENAMT
`
`103 06
`
`724.8
`17. 2.2003
`18. 9.2003
`
`(§) Innere Prioritat:
`
`0164
`
`

`
`4
`
`DE 103 06
`
`724
`Beschreibung
`
`A 1
`
`[0001] Die Erfindung
`
`betrifft
`
`vesikular
`
`verkapseltes
`
`0165
`
`

`
`DE 103 06
`sich
`bekannten
`
`724
`
`A 1
`Verfahren
`
`nach an
`
`zur
`
`0166
`
`

`
`DE 103 06
`cethylphosphats, der
`
`724
`Palmitinsaure,
`
`A 1
`
`der
`
`0167
`
`

`
`»'
`
`||||llll\|l|||Il|fl|flllll||llJl||ll|
`
`llllllflllllllllllllllllllllfllllfllllfllllllllmllfilllfllllll
`
`
`(19)
`“9’
`Bundesrepublik Deutschland
`Deutsches Patent- und Markenamt
`
`(10) DE
`103
`04
`0°) DE 103 O4 403 A1 2004.08.05
`
`403
`
`<12)
`
`Offenlegungssch rift
`
`(21) Aktenzeichen: 103 04 403.5
`(22) Anmeldetagz 28.01.2003
`(43) Offenlegungstagz 05.08.2004
`
`(51) Int CL’: A61 K 9/14
`A61K 9/20, A61K 47/12
`
`
`
` (71)Anme|der:
`(72) Erfinder:
`R6hm GmbH & Co. KG. 64293 Darmstadt, DE
`Petereit, Hans-Ulrich, 64291 Dannstadt, DE; Meier,
`Christian, Dr., 64295 Darmstadt, DE; Gryczke,
`Andreas, 64347 Griesheim, DE
`Die folgenden Angaben sind den vom Anmelder eingereichten Unterlagen entnommen
`(54) Bezeichnung: Verfahren zur Herstellung einer oralen Arzneiform mit unmittelbarem Zerfall und VWrkstofffreiset-
`zung
`
`(57) Zusammenfassung: Die Erfindung betrifft ein Verfah-
`ren zur Herstellung einer oralen Arzneiform mit unmittelba-
`rem Zerfall und Wirkstofffreisetzung bereits im Mund, durch
`intensives Mischen
`(a) eines anionischen pharmazeutischen Wirkstoffs mit
`(b) einem Copolymer, bestehend aus radikalisch polymeri-
`sierten C,- bis C,-Estern der Acry|— oder Methacrylsaure
`und weiteren (Meth)acryIat-Monomeren, die funktionelle
`tertifire Aminogruppen aufweisen, sowie
`(c) 5 bis 50 Gew.-%, bezogen auf (b), einer C,Z- bis C22-Can
`bonséure
`in der Schmelze, Erstarren der Mischung und Mahlen zu ei-
`nem wirkstoffhaltigen Pulver mit einer mittleren Korngr6l3e
`von 200 pm oder weniger, Einbetten des Pulvers in eine
`wasserltisliche Matrix aus pharmazeutisch Ublichen Hi|fs-
`stoffen, mit der Mal3gabe, dal3 nicht mehr als 3 Gew.-%. be-
`zogen auf das Copolymer, an Emulgatoren mit einem
`HLB-Wert von mindestens 14 enthalten sein dflrfen. Die Er-
`findung betriffl weiterhin das wirkstoffhaltige Pulver und
`dessen Verwendungen.
`
`0168
`
`0168
`
`

`
`r
`
`DE 103
`
`04
`
`403
`
`A1
`
`2004.08.05
`Beschreibung
`
`0169
`
`

`
`DE 103
`04
`403
`DE 103 04 403 A1 2004.08.05
`
`A1
`
`2004.08.05
`
`bivolol
`
`Antidiabetika: Metformin, Miglitol, Repaglinid
`H1 Antihistaminika: Diphenhydramin, Fexofenadin.
`Mizolastin
`
`H2 Antihistaminika: Cimetidin, Nizatidin, 1'iclopidin,
`Cetridin, Ranitidin, Vitamine: Thiaminenitrate;
`sowie weitere Vwrkstoffez Chinidin-Sulfat, Amiloprilo-
`se-HCI, Pseudoephedrin-HCI. Sildenafil, Topiramat,
`Granisetron_ Rebamipide, Chinin-HCI
`
`Aufgabenstellung
`
`[0007] Ein Problem bei vielen oralen Arzneiformen,
`ist dai3 das Herunterschlucken oflmals die Zuhi|fe-
`nahme von Fliissigkeit, z. B. einem Schluck Wasser,
`erfordert. Dies ist ungunstig, wenn im Bedarfsfall kein
`Getrank zur Verfugung steht oder etwa die momenta-
`ne berufliche Tatigkeit unterbrochen werden mul3,
`um das Medikament einnehmen zu konnen. Fur viele
`
`Patienten ist es zudem unangenehm in Gegenwart
`anderer Personen quasi beobachtet und Aufmerk-
`samkeit erregend ihr Medikament einzunehmen, was
`umso auffalliger ist, wenn nach einem Getrank be-
`nutzt werden mui3 oder fiir diesen Zweck gar erbeten
`werden mull».
`
`[0008] Viele Patienten, insbesondere zu nennen al-
`tere Menschen und Kinder. wiinschen daher orale
`Arzneiformen, die einfach und unauffallig praktisch
`an beliebigen Orten eingenommen werden konnen.
`Dies ist insbesondere bei Krankheiten der Fall, die
`sehr punktlich oder bei Bedarf unverziiglich einge-
`nommen werden sollen oder miissen, wie z. B. bei
`Schmerzmitteln.
`
`[0009] Es besteht zusa'tz|ich ein Bedarf an Arznei-
`formen, die den enthalten Wirkstoff z. B. Schmerzmit-
`tel bei oraler Einnahme bereits im Mund freisetzen
`und auf diese Weise rasch wirken konnen. Bekannte
`Appiikationsformen sind 2. B. verpreisten Tabletten
`oder Lutschtabletten, gefriergetrockneten Tabletten,
`gegossenen Tabletten oder Pastillen, Sachets. Kau-
`tabletten, Trockensaften und/oder flt'issigkeitsgeffl|l-
`ten Bonbons.
`
`[0010] Viele dieser schnell zerfallenden Arzneifor-
`men habenjedoch den Nachteil, dais sie einen sandi-
`gen Mundgeschmack bewirken, der einige Minuten
`andauern kann, bis sich die Tablettenbestanteile vol-
`Iig aufgelost haben. Das sandige Mundgeschmack
`wird als unangenehm empfunden wird und kann ei-
`nen Hustenreiz bewirken. Ein weiteres Problem ist
`dabei die Geschmacksisolierung von bitter schme-
`ckenden Vifirkstoffen. Wegen der Anforderung der
`Wirkstoffreisetzung im Mund konnen die bekannten
`geschmacksisolierenden Uberziige nicht verwendet
`werden.
`
`[0011] Zur Losung dieser Probleme sollte eine Arz-
`neiform bereitgestellt werden, die ohne Flussigkeit
`einnehmbar ist und den V\firkstoff ummittelbar frei-
`
`setzt. Dabei sol! ein sandiger Mundgeschmack aus-
`bleiben. Die Arzneiform soll ftir eine Vielzahl von
`
`Wirkstoffen, insbesondere jedoch fur Schmerzmittel
`
`der Klasse derAntirheumatika oder fiJrAntibiotika ge-
`eignet sein.
`[0012] Die Aufgabe wird gelbst durch ein Verfahren
`zur Herstellung einer oralen Arzneiform mit unmittel-
`barem Zerfall und Vwrkstofffreisetzung bereits im
`Mund, durch intensives Mischen
`(a) eines anionischen pharmazeutischen V\firk-
`stoffs mit
`
`(b) einem Copolymer, bestehend aus radikalisch
`polymerisierten C1- bis C4-Estern der AcryI- oder
`Methacrylsaure und weiteren (Meth)acrylat-Mo-
`nomeren die funktionelle tertiare Aminogruppen
`aufweisen. sowie
`
`(c) 5 bis 50 Gew.-%, bezogen auf (b), einer C12-
`bis C22-Carbonsaure
`
`in der Schmelze, Erstarren der Mischung und Mah-
`len zum einem wirkstoffhaltigen Pulver mit einer mitt-
`leren Korngrolze von 200 um oder weniger, Einbetten
`des Pulvers in eine wasserlosliche Matrix aus phar-
`mazeutisch iiblichen Hilfsstoffen, mit der Ma13gabe,
`dar5 nicht mehr als 3 Gew.-%, bezogen auf das Copo-
`lymer, an Emulgatoren mit einem HLB-Wert von min-
`destens 14 enthalten sein durfen.
`
`In bisher nicht verstandener Weise ergeben
`[0013]
`sich die-Vorteile der Erfindung anders als bei der WO
`02/67906 nur bei anionischen Wirkstoffen. Mog|icher-
`weise ergibt sich eine thermisch induzierte Wechse|-
`wirkung der anspruchsgemarsen Bestandteile (a), (b)
`und (c), die in dieser Weise nicht aus der WO
`02/67906 abieitbar ist. Die erfindungsgemail erh'a|t|i—
`chen Arzneiformen sind gut ohne zusatzliche Flus-
`sigkeit einnehmbar und verursachen nach V\firkstoff-
`freisetzung im Mund keinen sandigen Geschmack.
`
`Ausfiiihrung der Erfindung
`
`[0014] Die Erfindung betrifft ein Verfahren zur Her-
`stellung einer oralen Arzneiform mit unmittelbarem
`Zerfall und Wirkstofffreisetzung bereits im Mund,
`durch intensives Mischen
`(a) eines anionischen pharmazeutischen Wirk-
`stoffs mit (b) ei