PCT
`INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCI')
`wo 00112043
`9 March 2000 (09.03.00)
`
`(51) International Patent Classification 7 :
`A61J 1/05, 1/14
`
`Al
`
`WORLD INTELLECTUAL PROPERTY ORGANIZATION
`International BUTCau
`
`(11) International Publication Number :
`
`(43) International Publication Date:
`
`(21) International Application Number:
`
`PCf/SE99/0 1440
`
`(22) International Filing Date:
`
`24 August 1999 (24.08.99)
`
`(30) Priority Data:
`9802938- 2
`
`I September 1998 (0 1.09.98)
`
`SE
`
`(71) Applicant (for all designated Stales e~cept US): ASTRA
`AKTIEBOLAG [SEISE]; S-15 1 85 SMertalje (SE).
`
`(72) InventQrs; and
`(75) Invent()rs/Applicants (for US only): LUNDGREN, Anna
`[SEfSE]; Astra H!!ssle AB, S-431 83 M01nda1 (SE).
`SUNDGREN, Mats [SEISE]; Astra Hassle AB, S-431 83
`Molndal (SE).
`
`(74) Agent: ASTRA AKTIEBOLAG; Intellectual Property, Patents,
`S-15 1 85 Stidertiilje (SE).
`
`(81) Designated States: AE, AL, AM, AT, AU, AZ, BA, BB, BG,
`BR, BY, C A, CH, CN, CR , CU, CZ, DE, DK, OM, EE,
`ES, Fl, GB, GD, GE, GH, GM, HR, HU, ID, JL, IN, IS, JP,
`KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, L U, LV, MD,
`MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD,
`SE, SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG, US, UZ,
`VN, Y U, ZA, ZW, ARIPO patent (GH, GM, KE, LS, MW,
`SD, SL, SZ, UG, ZW), Eurasian patent (AM, AZ, BY, KG,
`KZ, MD, R U, TJ, TM), European patent (AT, BE, CH, CY,
`DE, DK, ES, Fl, FR., GB, GR, IE, IT, LU, MC, NL, PT,
`SE), OAPI patent (BF, BJ, CF, CG, Cl , CM, GA, GN, 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 the receipt of
`amendments.
`
`(54} Title: IMPROVED STABU..ITY FOR INJECTION SOLUTIONS
`
`(57) Abstract
`
`A primary package containi ng a low molecular weight peptide-based thrombin inhibitors which package is sealed with a rubber
`stopper or plunger containing bromobutyl rubber.
`
`Dr. Reddy's Laboratories
`v.
`Fresenius Kabi USA, LLC
`U.S. Patent No. 8,476,010
`Exhibit 1031
`
`-
`
`Exh. 1031
`
`

`
`Codes used to identify States party to the Per on the front pages of pamphlets publishing international applications under the PCT.
`
`FOR THE PURPOSES OF INFORMATION ONLY
`
`AL
`AM
`AT
`AU
`AZ
`BA
`BB
`BE
`BF
`BG
`BJ
`BR
`BY
`CA
`CF
`CG
`CH
`Cl
`CM
`CN
`cu
`cz
`DE
`DK
`EE
`
`Albania
`Annenia
`Austria
`Australia
`Azerbaijan
`Bosnia and Herzegovina
`Barbados
`Belgium
`Bul1<ina Faso
`Bulgaria
`Benin
`Brazil
`Belarus
`Canada
`Centnl African Republic
`Congo
`Switzerland
`C&e d'Ivoite
`Cameroon
`China
`Cuba
`C~ec h Republic
`Gennany
`Denmark
`Estonia
`
`ES
`Fl
`F R
`GA
`GB
`GE
`GH
`GN
`GR
`HU
`IE
`I L
`IS
`IT
`JP
`KE
`KG
`KP
`
`KR
`KZ
`l .C
`LJ
`LK
`LR
`
`Spain
`Finland
`France
`Gabon
`United Ki"gdom
`Geo<gia
`Ghana
`Guinea
`Greece
`Hungary
`Ireland
`Israel
`Iceland
`Italy
`Japan
`Kenya
`Kyrgyzstan
`Democratic People's
`Republic of Korea
`Republic of Korea
`Kuakstan
`Saint tocia
`Liechtenstein
`Sri Lanka
`L iberia
`
`LS
`LT
`LU
`LV
`MC
`MD
`MG
`MK
`
`ML
`MN
`M R
`M W
`MX
`NE
`NL
`NO
`NZ
`PL
`PT
`RO
`IUJ
`so
`SE
`SG
`
`Lesotho
`Lithuania
`Luxembourg
`Latvia
`Monaco
`Republic of Moldova
`Madagascar
`The former Yugoslav
`Republic of Macedonia
`Mali
`Mongolia
`Mauritania
`Malawi
`MCJtioo
`Niger
`Netherlands
`Norway
`New Zealand
`Poland
`Ponugal
`Romania
`Russian Fedemtion
`Sudan
`Sweden
`Singapore
`
`Sl
`SK
`SN
`sz
`TD
`1'G
`TJ
`TM
`TR
`TT
`UA
`UG
`us
`uz
`VN
`YU
`'LW
`
`Slovenia
`Slovakia
`Senegal
`Swaziland
`Chad
`Togo
`Tajikistan
`1\nianenislan
`Turkey
`Trinidad and Tobago
`Ukraine
`Uganda
`United States of America
`Uzbekistan
`VietNam
`Yugoslavia
`Zimbabwe
`
`Exh. 1031
`
`

`
`W000/12043
`
`PCT/SE99/01440
`
`IMPROVED STABILITY FOR INJECTION SOLUTIONS
`
`Field of the invention
`
`s The present invention relates to solutions of low molecular weight thrombin inhibitors
`
`stored in primary packages containing rubber components, such as vials, bottles, cartridges
`
`and prefilled syringes. The invention also relates to the medical use of such stored
`
`thrombin inhibitor solutions.
`
`10
`
`Background of the invention
`
`Solutions for parentheral use of pharmaceutically active substances ar:e nonnally stored in
`
`primary packages such as, vials, bottles, cartridges or in prefilled syringes. The primary
`
`packages are sealed by a rubber stopper or plunger. A commonly used rubber material
`
`ts
`
`contains chlorobutyl. Solutions oflow molecular weight thrombin inhibitors stored in
`
`vials, bottles, cartridges and prefilled syringes sealed by a stopper or plunger containing
`
`chlorobutyl rubber exhibits increased degradation, leading to shortened time of storage.
`
`Disclosure of the invention
`
`20
`
`It has now surprisingly been found that by using rubber material containing bromobutyl
`
`instead of chlorobutyl, the stability of the low molecular weight thrombin inhibitors in
`
`solution can be considerably improved.
`
`25
`
`The present invention provides a primary package, such as a vial, a bottle, a cartridge or a
`
`prefilled syringe containing a solution of a low molecular weight thrombin inhibitor for
`
`parentheral injection, sealed by a rubber stopper or plunger containing bromobutyl rubber
`
`instead of chlorobutyl rubber.
`
`Exh. 1031
`
`

`
`W000/12043
`
`PCT/SE99/0 1440
`
`2
`
`The present invention further provides a medical use of such thrombin inhibitor, or salts o f
`
`such tlrrombin inhibitor, solutions kept in a primary package as mentioned above
`
`sealed by bromobutyl stoppers or plungers.
`
`s The present inventi~n further provides an aqueous solution for parenteral administration
`
`comprising a low molecular weight peptide-based tlrrombin inhibitor or a salt thereof,
`
`having a pH in the range 3 to 8, preferably a pH about 5 and stored in a primary package,
`
`such as a vial, a bottle, a cartridge or a prefilled syringe, sealed by a rubber stopper or
`
`plunger containing bromobutyl.
`
`10
`
`Tlrrombin inhibitors referred to in this application are low molecular weight peptide-based
`
`thrombin inhibitors. The term "low molecular weight peptide-based tlrrombin inhibitors"
`
`will be well understood by one skilled in the art to include tlrrombin inhibitors with one to
`
`four peptide linkages, and/or with a molecular weight below 1000, and includes those
`
`15
`
`described generically and, more preferably, specifically in the review paper by C1aesson in
`
`Blood Coagul. Fibrin. (1994) 5, 411, as well as those disclosed in US Patent No.
`
`4,346,078; International Patent Applications WO 97/23499, WO 97/02284, W097/46577,
`
`WO 98/01422, WO 93/05069, W093111152, WO 95/23609, W095/35309, WO 96/25426,
`
`WO 94/29336, WO WO 93118060 and WO 95/01168; and European Patent Applications
`
`20
`
`623 596,648 780,468 231,559 046,641 779, 185 390,526 877,542 525, 195 212,
`
`362 002,364 344,530 167,293 881,686 642,669 317 and 601459.
`
`Preferred low molecular weight peptide-based thrombin inhibitors include those known
`
`collectively as the "gatrans". Particular gatrans which may be mentioned include HOOC-
`CH2(R)Cha-Pic-Nag-H (known as inogatran; see International Patent Application WO
`93/1 1152 and the list of abbreviations therein) and HOOC-CHr(R)Cgl-Aze-Pab-H (known
`
`as melagatran; see International Patent Application WO 94/29336 and the list of
`
`abbreviations therein).
`
`25
`
`30
`
`Exh. 1031
`
`

`
`W000/12043
`
`PCT/SE99/01441J
`
`3
`
`The preferred low molecular weight peptide-based thrombin inhibitor to be kept in glass
`
`vials or syringes is selected from the group consisting of inogatran, (Glycine, N-[2-[2-[[[3-
`[ ( aminoimino-methyl)amino J propyl] amino J carbonyl} -1-piperidinylj -1-( cyclohexylmethyl)-
`
`5
`
`2-oxoethyl}-, [2R-[2S}]-). melagatran, (Glycine, N-[2-[2-[[[[4
`
`(aminoiminomethyl)phenyl} -methyl} amino] carbonyl]-1-azetidiny/j -1-cyclohexyl-2-
`
`oxoethyl}-. [2R-[2Sj}-) and
`
`compound A, (Glycine, N-[ 1 -cyclohexyl-2-{2-[[[[ 4-[(hydroxyimino)aminomethyl}(cid:173)
`
`phenyl}methyl]amino }carbonyl}-1 -azetidinylj -2 -oxoethy/} -. ethyl ester, [S-(R *, S*) ]-}.
`
`10
`
`In one embodiment of the invention the thrombin inhibitor (preferably melagatran)
`
`solutions for parenthcral injection is a water solution and are kept in primary packages such
`
`as vials, bottles, cartridges or prefilled syringes having a rubber stopper or plunger
`
`1.s
`
`containing brornobutyl.
`
`In another embodiment of the invention; the thrombin inhibitor for parentheral injection is
`
`in a water solution with an addition ofhydroxy-propyl-~-cyclodextrin (HPPCD). The
`
`concentration of the thrombin inhibitor is in the range 0.001 -100 mg/ml, preferably 2.5-20
`
`20 mg/ml.
`
`Working Exampl e
`
`Analytical technique
`
`25
`
`30
`
`Liquid Chromatography (LC), for all analysis
`
`The following equipment and parameters were used at the analysis ofmelagatran in
`
`solution.
`
`Exh. 1031
`
`

`
`wo 00/12043
`
`PCT/SE99/01440"
`
`4
`
`Flowrate
`
`1.0 ml/min
`
`Wavelength
`
`237nm
`
`Injection volume
`
`20 J.il
`
`Analytical column
`
`Waters Synunetry C8, 150 x 3.9 mm
`
`Guard column
`
`Waters Symmetry C8, 22 x 3.9 mm
`
`Mobile phase
`
`20% (v/v) acetonitrile in phosphate buffer, pH 2.0 with 4.6 mM
`
`octanesulphonic acid.
`
`EVALUATION
`
`10
`
`IS
`
`Results in tables are presented as total degradation of melagatran. This means that all by(cid:173)
`
`products are included and presented as area% of melagatran.
`
`Example 1.
`
`This example shows a comparison of melagatran in HPPCD-solution in prefilled syringes
`
`(1.0 ml) having rubber plungers containing bromobutyl and chlorobutyl, respectively. The
`
`syringes were stored at 4, 25 and 50 °C for up to 6 months.
`
`20
`
`The melagatran solution was in direct contact with the different rubber materials.
`
`MANUFATURING OF SAMPLES
`
`Melagatran, 2.5 mg/ml, in HPPCD water solution (40% w/w), pH about 5
`
`2s Batch HF 839-2601
`
`Melagatran
`
`HPPCD
`
`HCl, I M
`
`30 NaOH, 1 M
`
`442.1 mg
`
`80.0 g
`
`qs
`qs
`
`Exh. 1031
`
`

`
`wo 00/12043
`
`PCT/SE99/01440-
`
`5
`
`water for inj ection
`
`to 200 g final weight (density 1.145 g/ml)
`
`Melagatran was dissolved in water in a separate beaker and adjusted to pH 5.06. HP~CD
`
`powder was mixed with this solution together with water. The final solution was mixed
`
`s with a magnetic stirrer until the substance was completely dissolved and pH was finally
`
`adjusted to 5.02, and the solution was filtrated with a 0.22 11m sterile filter.
`
`Melagatran, 10 mg/ml, in HPI)CD water solution (40% w/w), pH about 5
`
`10 Batch HF 839-2602
`
`Melagatran
`
`HP~CD
`
`HCl, 1M
`
`15 NaOH, 1M
`
`1.77 mg
`
`80.0 g
`
`qs
`
`qs
`
`water for injection
`
`to 200 g final weight (density 1.145 g/ml)
`
`Melagatran was d issolved in water in a separate beaker and adjusted to pH 4.88. HP~CD
`
`powder was mixed with this solution together with water. The final solution was mixed
`
`20 with a magnetic stirrer until the substance was completely dissolved and pH was finally
`
`adjusted to 5.0, and the solution was filtrated w ith a 0.22 ~m sterile filter.
`
`FILLING OF SYRINGES (1.0 ml)
`
`25
`
`Sample Al (HF 839-2613) 10 rng/ml
`
`0.5 ml ofHF 839-2602 was filled in 1 ml HYP AK® syringes from Becton Dickinson with
`
`a black plunger material (PH 70 1150 from The West Company) containing chlorobutyl
`
`rubber.
`
`Exh. 1031
`
`

`
`WO 00/12043
`
`PCT/SE99/01440
`
`.
`
`6
`
`Sample Bl (HF 839-2614) 10 mg/ml
`
`0.5 ml ofHF 839-2602 was filled in 1 ml HYPAK.® syringes from Becton Dickinson with
`
`a grey plunger material (PH 4416/50 from The West Company) containing bromobutyl
`
`rubber.
`
`Sample Cl (HF 839-2615) 2.5 mg/ml
`
`0.5 ml ofHF 839-2601 was filled in I ml HYPAK.® syringes from Becton Dickinson with ,
`
`a grey plunger material (PH 4416/50 from The West Company) containing bromobutyl
`
`rubber.
`
`Sample Dl (HF 839-2616) 10 mg/ml
`
`0.5 ml ofHF 839-2602 was filled in l ml HYPAK.® syringes from Becton Dickinson with
`
`a black plunger material (PH 701/50 from The West Company) containing chlorobutyl
`
`rubber.
`
`RESULTS OF STABILITY STUDIES
`
`Sample Al (HF 839-2613) 10 mg/ml - ChJorobutyl rubber
`
`5
`
`10
`
`15
`
`Storage time
`
`(months)
`
`0
`
`1
`
`1
`
`3
`
`3
`
`3
`
`6
`
`6
`
`pH
`
`5.2
`
`5.2
`
`5.3
`
`5.1
`
`5.1
`
`5.2
`
`5. 1
`
`5.1
`
`Temperature
`
`Total degradation
`
`(°C) -
`-
`4
`so
`4
`
`25
`
`50
`
`4
`
`25
`
`(area % of melagatran)
`
`1.2
`
`1.0
`
`7.4
`
`1.2
`
`4.5
`
`14.9
`
`1.2
`
`3.7
`
`Exh. 1031
`
`

`
`wo 00/12043
`
`PCT/SE99/0l440
`
`7
`
`.
`Sample Bl (HF 839-2614) 10 mg/ml - Bromobutvl rubber
`
`Storage time
`
`(months)
`
`0
`
`I
`
`1
`
`3
`
`3
`
`3
`
`6
`
`6
`
`pH
`
`5.2
`
`5.2
`
`5.2
`
`5. 1
`
`5.1
`
`5.2
`
`5.1
`
`5.1
`
`Temperature
`
`Total degradation
`
`COC)
`
`(area% ofmelagatran)
`
`-
`
`4
`
`50
`
`4
`
`25
`
`50
`
`4
`
`25
`
`1.1
`
`1.0
`
`6.4'
`1.2
`
`2.4
`
`12.8
`
`1.1
`
`3.1
`
`Sample Cl (HF 839-2615) 2.5 mg/ml - Bromobutyl rubber
`
`Storage time
`
`(months)
`
`0
`
`1
`
`1
`
`3
`
`3
`
`3
`
`6
`
`6
`
`pH
`
`5.3
`
`5.4
`
`5.3
`
`5.3
`
`5.3
`
`5.2
`
`5.2
`
`5.2
`
`Temperature
`(°C)
`-
`4
`
`50
`
`4
`
`25
`
`50
`
`4
`
`25
`
`Total degradation
`
`(area% ofmelagatran)
`
`1.2
`
`1.1
`
`7.2
`
`1.3
`
`3.9
`
`14.2
`
`1.2
`
`5.7
`
`Exh. 1031
`
`

`
`W000/12043
`
`8
`
`-
`PCT/SE99/0l440
`
`Sample Dl (HF 839-2616) 10 mg/rnl- Chlorobutyl rubber
`
`Storage time
`
`(months)
`
`0
`
`I
`
`1
`
`3
`
`3
`
`3
`
`6
`
`6
`
`Conclusion
`
`pH
`
`5.3
`
`5.4
`
`5.3
`
`5.3
`
`S.3
`
`5.2
`
`5.2
`
`5.2
`
`Temperature
`
`Total degradation
`
`(oC)
`
`(area% ofmelagatran)
`
`-
`
`4
`so
`4
`
`? -_)
`so
`4
`
`25
`
`1.2
`
`1.2
`
`8.6
`
`1.2:
`
`3.1
`
`17.4
`
`1.4
`
`9.9
`
`s Rubber plungers containing chlorobutyl result in a more pronounced degradation compared
`
`to rubber plungers containing bromobutyl. This is true for high concentrations as well as
`
`low concentrations of melagatran in aqueous solutions.
`
`The most pronounced difference was seen between plungers of chlorobutyl rubber and
`bromo butyl rubber when the 4ose of melagatran in aqueous solution was as low as 2.5
`
`10
`
`mg/ml.
`
`Example 2.
`
`15
`
`This example is a comparison of melagatran in a water solution ofHPPCD and melagatran
`
`in a water solution ofNaCl. Both solutions are in direct contact with rubber plungers
`
`containing bromobutyl.
`
`Exh. 1031
`
`

`
`wo 00/12043
`
`PCT/SE99/01440
`
`9
`
`3 plungers of the quality FM 257 (from Helvoet Phanna N.V.) were placed in each 3 ml
`
`glass vial together with 1 ml solution of melagatran (NaCl water solution and HP~CD
`
`water solution, respectively). Reference samples, that is melagatran in NaCI water solution
`
`and in HP~CD water solution having no contact with plunger material. The reference
`
`5
`
`samples were treated in the same way as the other samples. The vials were stored at 50 °C
`
`for up to 3 months.
`
`Compared to the study of Example 1 the ratio between solution exposed plunger surface
`
`and the quantity of melagatran solution is 16 times higher.
`
`10
`
`MANUFATURING OF SAMPLES
`
`Melagatran, 7.5 mg/ml, in HPPCD water solution (40 % w/w), pH about 5.
`
`Batcb HF 839-2679
`
`15
`
`Melagatran
`
`HP~CD
`
`HCl, 1M
`
`NaOH, 1M
`
`928.8 mg
`
`55.0 g
`
`qs
`
`qs
`
`water for injection
`
`137.4 g (density 1.145 g/ml)
`
`20
`
`Melagatran and HP~CD were dissolved in water and adjusted to pH 4.96. The final
`
`solution was diluted with water to final weight and sterile filtrated with 0.45 J.Lm filter.
`
`25 Melagatran, 7.5 mg/ml, in NaCI water solution, pH about 5.
`
`Ba tcb HF 839-2680
`
`Melagatran
`
`NaCl
`
`Jo HCl, 1M
`
`1315.5g
`
`1.441 g
`
`qs
`
`Exh. 1031
`
`

`
`W000/ 12043
`
`PCT/SE99/01440'
`
`10
`
`NaOH, I M
`
`qs
`
`water for injection
`
`to 170 (density 1.0 g/ml)
`
`Melagatran and NaCl were dissolved in water and adjusted to pH 5.03. The final solution
`
`s was diluted with water to final weight and sterile filtrated with 0.22 J..Lm filter.
`
`FILLING OF VIALS
`
`Sam ple A2 {HF 839-2682) 7.5 mg/ml in NaCI
`
`10
`
`1.0 ml ofHF 839-2680 was filled in 3 ml vials together with 3 black unsiliconized plungers
`
`(FM 257 from Helvoet Pharma N.V.) containing bromobutyl rubber.
`
`Sample B2 (HF 839-2683) 7.5 mg/ml in NaCI
`
`1.0 ml ofHF 839-2680 was filled in 3 ml vials together with 3 black siliconized plungers
`
`15
`
`(FM 257 from Helvoet Pharma N.Y.) containing bromobutyl rubber.
`
`Sample C2 (HF 839-2684) 7.5 mg/ml in NaCl
`
`1.0 ml of HF 839-2680 was filled in 3 ml vials together with 3 grey siliconized plungers
`
`(FM 257 from Helvoet Pharma N.Y.) containing bromobuty l rubber.
`
`20
`
`Sample 02 (HF 839-2688) 7.5 mg/ml in NaCI
`
`1.0 ml ofHF 839-2680 was filled in 3 ml vials (Reference).
`
`Sample E2 (HF 839-2689) 7.5 mg/ml in HPPCD
`
`25
`
`1.0 ml ofHF 839-2679 was filled in 3 ml vials together with 3 black unsiliconized plungers
`
`(FM 257 from Helvoet Pharma N.V.) containing bromobutyl rubber.
`
`Sample F2 (HF 839-2690) 7.5 mg/ml in HPPCD
`
`1.0 ml ofHF 839-2679 was filled in 3 ml vials together with 3 black siliconized plungers
`
`JO
`
`(FM 257 from Helvoet Phanna N.V.) containing bromobulyl rubber.
`
`Exh. 1031
`
`

`
`W000/12043
`
`PCT/SE99/01440"
`
`11
`
`5
`
`10
`
`15
`
`Sample G2 (HF 839-2691) 7.5 mg/ml in HP~CD
`
`1.0 ml of HF 839-2679 was filled in 3 ml vials together with 3 grey siliconized plungers
`
`(FM 257 from Helvoet Pharma N.Y.) containing bromobutyl rubber.
`
`Sample H2 (HF 839-2695) 7.5 mg/ml in HPj3CD
`
`1.0 ml <>fHF 839-2679 was filled in 3 ml vials (Reference).
`
`RESULTS OF STABILITY STUDIES
`
`Sample A2 (HF 839-2682) 7.5 mglml in NaCI- Bromobutyl r ubber
`
`Storage time
`
`(months)
`
`1
`
`3
`
`pH
`
`5.9
`
`6.0
`
`Temperature
`
`Total degradation
`
`(OC)
`
`50
`
`50
`
`(area% of melagatran)
`
`4.2
`
`9.3
`
`Sample B2 (HF 839-2683) 7.5 mg/ml in NaCI - Bromobutyl rubber
`
`Storage time
`
`(months)
`
`1
`
`3
`
`pH
`
`5.8
`
`6.0
`
`Temperature
`
`Total degradation
`
`(oC)
`
`50
`
`50
`
`(area% ofmelagatran)
`
`4.0
`
`8.7
`
`Sample C2 (HF 839-2684) 7.5 mglml in NaCI - Bromobutyl rubber
`
`Storage time
`
`(months)
`
`1
`
`3
`
`pH
`
`5.8
`
`5.8
`
`Temperature
`
`Total degradation
`
`(OC)
`so
`50
`
`(area% ofmelagatran)
`
`3.7
`
`7.9
`
`Exh. 1031
`
`

`
`W000/12043
`
`PCT/SE99/0144()
`
`12
`
`Sample 02 (HF 839-2688) 7.5 rng/ml in NaCI - Reference
`
`Storage time
`
`(months)
`
`l
`
`3
`
`1
`
`3
`
`pH
`
`5.2
`
`5.3
`
`5.4
`
`5.6
`
`Temperature
`
`Total degradation
`
`(°C)
`
`(area % ofmelagatran)
`
`4
`
`4
`
`50
`
`50
`
`1.4
`
`1.4
`
`3.4
`
`6.8
`
`Sample E2 (HF 839-2689) 7.5 mg/ml in HPPCD - Bromobutyl rubber
`
`Storage time
`
`(months)
`
`1
`
`3
`
`pH
`
`5.5
`
`5.6
`
`Temperature
`
`Total degradation
`
`(°C)
`
`50
`
`50
`
`(area% melagatran)
`
`5.5
`
`11.3
`
`Sample F2 (HF 839-2690) 7.5 mg/ml in HPPCD - Bromobutyl rubber
`
`Storage time
`
`(months)
`
`l
`
`3
`
`pH
`
`5.4
`
`5.5
`
`Temperature
`
`Total degradation
`
`(°C)
`
`50
`
`50
`
`(area% ofmelagatran)
`
`5.4
`
`11.3
`
`Sample G2 {H F 839-2691) 7.5 mg/ml in HPPCD - Brornobutyl rubber
`
`Storage time
`
`(months)
`
`1
`
`3
`
`pH
`
`5.4
`
`5.5
`
`Temperature
`
`Total degradation
`
`(°C)
`
`50
`
`50
`
`(area% ofmelagatran)
`
`5.4
`
`10.3
`
`Exh. 1031
`
`

`
`wo 00/12043
`
`PCT/SE99/01440
`
`13
`
`Sample H2 (HF 839-2695) 7.5 mg/ml in HPPCD - Reference
`
`Storage time
`
`(months)
`
`I
`
`3
`
`l
`
`3
`
`Conclusion
`
`pH
`
`5.2
`
`5.3
`
`5.3
`
`5.4
`
`Temperature
`
`Total degradation
`
`(OC)
`
`4
`
`4
`
`50
`
`50
`
`(area% ofmelagatran)
`
`1.5
`
`1.7
`
`5.7 :
`
`10.7
`
`5
`
`10
`
`Melagatran in a water solution ofNaCl exhibits a somewhat lower degradation compared
`
`to melagatran in a water solution ofHPPCD. This is true both for solutions in contact with
`
`plunger material (FM 257 bromobutyl) 8%* compared to 11 %*,and solutions in absence
`
`of plunger material (reference) 7%* compared to 11 %*.
`
`*;is total degradation in area% ofrnelagatran
`
`Example 3.
`
`15
`
`This example shows a comparison of different kinds of stopper and plunger materials
`
`containing either bromobutyl rubber or chlorobutyl rubber in contact with a melagatran
`
`solution (NaCl, pH 5). Melagatran solution was filled in glass vials (3 ml) together with
`
`stoppers and plungers of different brands. 5 different rubber materials were used in the
`
`study. There were 3 different bromobutyl and 2 different chlorobutyl rubbers. As reference,
`
`zo NaCI water solution of melagatran was stored without any contact with stopper or plunger
`
`material.
`
`Exh. 1031
`
`

`
`wo 00/12043
`
`PCT/SE99/01440
`
`14
`
`The ratio between exposed plunger or stopper surface and melagatran in water solution is
`
`higher than in Example 1. A calculation has been made of exposed area of each tested
`
`plunger or stopper material. In the study the area ratio is 10-15 times higher compared to
`
`the area represented in Example 1. The vials were studied up to 19 days at a temperature of
`
`5
`
`50°C.
`
`MANUFACTURING OF SAMPLES
`
`Melagatran, 5 mg/ml, in isotonic NaCl solution, pH about 5.
`
`10
`
`Batch HF 839-2719
`
`Melagatran
`
`NaCl
`
`HCI, 1M
`
`•s NaOH, 1M
`
`10.0 mg
`
`17.6 g
`
`qs
`
`qs
`
`water for injection
`
`To 2000 g final weight (density 1.0 g/ml)
`
`Melagatran and NaCl were dissolved in water and pH adjusted to 4.95 The solution was
`
`diluted to final weight with water.
`
`20
`
`FILLING OF VIALS
`
`The total contact surface between the rubber material and the solution was enhanced in
`
`different ways and different extent. One way was by putting pieces of vial stopper material
`
`2s
`
`into each vial. For sample A3, the stopper material was divided into eight equal parts, and
`
`two parts in each vial (total of2/8). Another way to enhance the contact surface was to put
`
`2-3 plungers in each vial. For sample E3, three plungers were put in each vial. In samples
`
`A3 to F3, the contact surface was increased of 10-15 times compared to the normal contact
`
`surface between plunger and solution in a 1 ml syringe (used in Example I).
`
`Exh. 1031
`
`

`
`wo 00/12043
`
`PCT/SE99/01440~
`
`15
`
`Sample A3 (HF 839-2727) 5 mg/ml in NaCl
`
`1.5 ml of HF 839-2719 was filled in a 3 ml vial together with two 1/8 parts of a I 0 ml vial
`
`stopper (FM 50 from Helvoet Phanna N.Y.) containing chlorobutyl rubber.
`
`s
`
`Sample B3 (HF 839-2728) 5 mg/ml in NaCI
`
`1.5 ml ofHF 839-271 9 was filled in 3 ml vial together with 2 grey plungers (PH 4023/50
`
`from The West Company) containing bromobutyl rubber.
`
`10
`
`Sample C3 (HF 839-2729) 5 mg/ml in NaCl
`
`1.5 ml of HF 839-2719 was filled in 3 ml vial together with 2 black plungers (PH 701/50
`
`from The West Company) containing chlorobutyl rubber.
`
`Samp1e D3 (HF 839-2730) 5 mglml in NaCI
`
`1s
`
`1.5 ml ofHF 839-2719 was filled in 3 ml vial together with 2 grey plungers (W 4416/50
`
`from The West Company) containing bromobutyl rubber.
`
`Sample E3 (HF 839-2731) 5 mg/ml in NaCI
`
`1.5 ml ofHF 839-2719 was filled in 3 ml vial together with 3 black plungers (FM 257 from
`
`20 Helvoet Phanna N.V.) containing bromobutyl rubber.
`
`Sample F3 (HF 839-2732) 5 mg/ml in NaCI
`
`1.5 ml ofHF 839-2719 was filled in 3 ml vial (Reference).
`
`Exh. 1031
`
`

`
`wo 00/12043
`
`PCT/SE99/ .. 1440
`
`16
`
`RESULTS OF STABILITY STUDIES
`
`Sample A3 (HF 839-2727) 5 mg/ml in NaCI - Chlorobutyl rubber
`
`Storage time
`
`(days)
`
`11
`
`19
`
`pH
`
`-5.0
`
`-5.0
`
`Temperature
`
`Total degradation
`
`(°C)
`
`50
`
`50
`
`(area % ofmelagatran)
`
`8.0
`
`11$
`
`s Sample B3 (HF 839-2728) 5 mg/ml in NaCI - Bromobutyl rubber
`
`Storage time
`
`(days)
`
`11
`
`19
`
`pH
`
`-5.0
`
`-5.0
`
`Temperature
`
`Total degradation
`
`(°C)
`
`50
`
`50
`
`(area% ofmelagatran)
`
`0.9
`..
`1.4
`
`Sample C3 (HF 839-2729) 5 mgfml in NaCI- Cblorobutyl rubber
`
`Storage time
`
`(days)
`
`11
`
`19
`
`pH
`
`-5.0
`
`-5.0
`
`Temperature
`
`Total degradation
`
`CCC)
`
`50
`so
`
`(area% ofmelagatran)
`
`1.5
`
`2.4
`
`Sample D3 (HF 839-2730) 5 mg/ml in NaCI- Bromobutyl rubber
`
`Storage time
`
`(days)
`
`11
`
`19
`
`pH
`
`-5.0
`
`-5.0
`
`Temperature
`coq
`
`Total degradation
`
`(area % ofmelagatran)
`
`50
`
`50
`
`1.3
`
`1.6
`
`Exh. 1031
`
`

`
`wo 00/12043
`
`PCT/SE99/01440
`
`17
`
`Sample E3 (HF 839-2731) 5 mg/ml in NaCI- Bromobutyl rubber
`
`Storage time
`
`(days)
`
`11
`
`19
`
`pH
`
`-5.0
`
`-5.0
`
`Temperature
`
`Total degradation
`
`(°C)
`
`50
`
`50
`
`(area% ofmelagatran)
`
`1.2
`
`1.4
`
`Sample F3 (HF 839-2732) 5 mglml in NaCI - Reference
`
`Storage time
`
`(days)
`
`11
`
`19
`
`Conclusion
`
`pH
`
`-5.0
`
`-5.0
`
`Temperature
`
`Total degradation
`
`(OC)
`
`50
`
`50
`
`(area % of melagatran)
`
`0.6
`
`1.0
`
`All three bromobutyl rubber materials demonstrate lower melagatran degradation
`
`compared to the two chlorobutyl rubber materials.
`
`Sununary conclusion
`
`s
`
`10
`
`It is shown in Example 1 that, for water solutions containing melagatran stored in
`
`HYPAK® syringes (from Becton Dickinson), improved stability is demonstrated using
`
`15
`
`plungers containing bromobutyl rubber compared to the corresponding plungers containing
`
`chlorobutyl rubber.
`
`It is shown in Example 2 that, for water solutions of melagatran stored in glass vials,
`
`improved stability is demonstrated using a NaCl water solution compared to a HPPCD
`
`zo water solution. This is true for melagatran in solution with and without contact of plungers
`
`containing bromobutyl rubber.
`
`Exh. 1031
`
`

`
`wo 00/12043
`
`PCT/SE99/01440'
`
`18
`
`It is shown in Example 3 that for melagatran in a NaCl water solution, improved stability is
`
`demonstrated using rubber materials containing bromobutyl compared to rubber materials
`
`containing chlorobutyl.
`
`Exh. 1031
`
`

`
`W000/12043
`
`PCT/SE99/01440
`
`19
`
`CLAIMS
`
`1. A primary package containing an aqueous solution for parenteral administration
`
`s
`
`comprising a low molecular weight peptide-based thrombin inhibitor or a salt thereof,
`
`having a pH in the range 3 to 8, the primary package being sealed with a rubber stopper or
`
`plunger containing bromobutyl rubber.
`
`2. A primary package according to claim 1, wherein the primary package is a vial.
`
`10
`
`J. A primary package according to claim 1, wherein the primary package is a bottle.
`
`4. A primary package according to claim 1, wherein the primary package is a cartridge.
`
`IS
`
`5. A primary package according to claim 1, wherein the primary package is a prefilled
`
`synnge.
`
`6. A primary package according to any of the preceding claims, wherein the solution is a
`
`NaCl solution.
`
`20
`
`7. A primary package according to any of the preceding claims, wherein the solution also
`
`comprises hydroxy-propyl-~-cyclodextrin.
`
`8. A primary package according to any of the preceding claims, wherein the concentration
`
`2s
`
`of the thrombin inhibitor in the solution is in the range 0.001-100 mg/ml, preferably 2.5-20
`
`mglml.
`
`9. A primary package according to any of the preceding claims, wherein the pH of the
`
`solution is in the range 3-8.
`
`30
`
`Exh. 1031
`
`

`
`wo 00112043
`
`PCT/SE99/01440.
`
`20
`
`10. A primary package according to claim 9, wherein the pH of the solution is about 5.
`
`11 . A primary package according to any of the preceding claims, wherein the thrombin
`
`inhibitor is melagatran.
`
`5
`
`12.. A primary package according to any of the preceding claims, wherein the thrombin
`
`inhibitor in the solution is inogatran.
`
`13. A primary package according to any of the preceding claims, wherein the thrombin
`
`10
`
`inhibitor in the solution is compound A.
`
`14. A primary package according to any ofthe preceding claims, wherein the bromobutyl
`
`rubber material consists of, or correspond to, the quality PH 4023/53.
`
`15
`
`15. A primary package according to any of claims 1-13, wherein the bromobutyl rubber
`
`material consists of, or correspond to, the quality W 4416/50.
`
`16. A primary package according to any of claims 1-13, wherein the brornobutyl rubber
`
`material consists of, or correspond to, the quality FM 257.
`
`20
`
`17. Use of a rubber stopper or plunger containing bromobutyl rubber for sealing a primary
`
`package, such as a vial, a bottle, a cartridge or a prefilled syringe, containing a low
`
`molecular weight peptide-based thrombin inhibitor in an aqueous solution.
`
`25
`
`18. A process for the manufacture of a primary package according to claim 1
`
`comprising the steps of dissolving a low molecular weight peptide-based thrombin
`
`inhibitor in an aqueous solution, adjusting the pH of the solution to be in the range 3 to 8,
`
`optionally adding a cyclodextrin substance, sterile filtering the solution and filling it on a
`
`primary package which is then sealed with a rubber stopper or plunger containing
`
`30
`
`bromobutyl rubber.
`
`Exh. 1031
`
`

`
`1
`INTERNATIONAL SEARCH REPORT .
`
`International application No.
`PCT/SE 99/01440
`
`A. CLASSIFICATION OF SUBJECT MAlTER
`
`IPC7: A61J 1/05, A61J 1/14
`According to 1 ntcrnational Patent Classification (I PC) or to both national classification and 1 PC
`B. FIELDS SEARCHED
`Minimum documentation searched (classification system followed by classification symbols)
`
`I PC7: A61J
`Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched
`SE,DK,FI,NO classes as above
`
`Electronic data base consulted during the International search (name of data base and, where practicable, search terms used)
`
`c. DOCUMENTS CONSIDERED TO BE RELEVANT
`
`Category• Citation of document, with indication, where appropriate, of the r,e]evant passages
`
`Relevant to claim No.
`
`X
`
`X
`
`A
`
`WO 9633216 A1 (PHARMACIA AB), 24 October 1996
`(24.10.96), page 6, line 17 - line 19
`--
`EP 0390244 Al (DUPHAR INTERNATI0NAL RESEARCH B.V.),
`3 October 1990 (03.10.90), page 2,
`line 48 - line 51; page 3, l ine 14 - line 15,
`page 4, Table A
`
`--
`WO 9739770 Al (ASTRA AKTIEBOLAG), 30 October 1997
`(30.10.97)
`
`1-18
`
`1-18
`
`1-18
`
`--
`--------
`
`[ ] See patent family annex.
`
`0 Further documents are listed in the continuation of Box C.
`•
`-r· later document published allcr lhe international filing elate or priority
`Spc~:~al categOries of cited documents:
`date and not in tonO•ct With lhe applitation but ated to underNr~d
`• A." docwnent defining the general .state of the 1111 \vhieh is not eonsi dered
`the prinaple or theory IDlde:lyina the invention
`to be of particular relevance
`·x· docwnent of particular relevance: the claimed invention cannot be
`"E" erlier document but publimed on or after the mtemational filing date
`comidered novel or cannot be considered to involve an inventive
`"L" docurnent which may throw doubts on priority claim(s} or which is
`step when the do<:wnent is IBm alone
`cited to e.~ablish the publication date of another citation or other
`·v· doewnent of particular relevance: the claimed invention cannot be
`special reason (as specified}
`·o· docwnent referring to an oral disclosure, use, exhibition or other
`considered to involve an inventive step when the document is
`combined with one or more other such documents, such combination
`means
`being obvio\1$ to a person lllilled in the 1111
`•p• docwnent puhlimed prior to the international 1ilina date but later than
`·&: document member of the sa:ne patent family
`the priority date claimed
`Date of mailing of the international search report
`
`Date of the actual completion of the international search
`
`2.7 December 1999
`Name and mailing address of the ISA/
`Swedish Patent Office
`Box 5055, S-102 42 STOCKHOLM
`Facsimile No. + 46 8 666 02 86
`Form Per /ISA./210 (second sheeq (July 1992}
`
`Authorized officer
`
`Nebil Gecer/Els
`Telephone No. + 46 8 782 25 00
`
`Exh. 1031
`
`

`
`INTERNATIONAL SEARCH REPORT
`Information on patent family members
`
`02/12/99
`
`International application No.
`PCT/SE 99/01440
`
`I Publication
`
`date
`
`I
`
`Patent family
`member(s)
`
`I
`
`Patent document
`cited in search report
`
`wo
`
`9633216 AI
`
`24/10/96
`
`Publication
`date
`07/11/96
`5412996 A
`AU
`21/10/98
`0871959 A
`EP
`Il
`00/00/00
`117907 0
`20/10/98
`JP 10510925 T
`SE
`00/ 00/00
`9501472 0
`us
`19/01/99
`5862196 A
`----------------------------------------------------·---------------------
`SE
`EP
`0390244 A1
`03/10/90
`0390244 T3
`AT
`84205 T
`15/01/93
`CA
`2012919 A
`28/09/90
`OK
`390244 T
`08/02/93
`93881 A
`07/10/94
`Il
`JP
`2283377 A
`20/11/90
`Nl
`8900747 A
`16/10/90
`us
`5383864 A
`24/01/95
`-------------------------------------------------------------------------
`wo
`AU
`9739770 A1
`30/10/97
`2719597 A
`12/11/97
`AU
`7716496 A
`19/06/97
`EP
`0864173 A
`16/09/98
`SE
`9601556 D
`00/00/00
`-------------------------------------------------------------------------
`
`Form PCI'/ISA/210 (patent fam1ly annex) (July 1992)
`
`Exh. 1031