PCX
`WORLD INTELLECTUAL PROPERTY ORGANIZATION
`International Bureau
`INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`WO 00/13671
`(51) International Patent Classification 7 ;
`A61K 9/20, 47/38, 38/55, A61P 7/02
`
`(11) International Publication Number:
`
`(43) International Publication Date:
`
`16 March 2000 (16.03.00)
`
`A1
`
`(21) International Application Number:
`
`PCT/SE99/01471
`
`(22) International Filing Date:
`
`27 August 1999 (27.08.99)
`
`(30) Priority Data:
`9802973-9
`
`3 September 1998 (03.09.98) SE
`
`(71) Applicant (for all designated States except US): ASTRA
`AKTIEBOLAG [SE/SE]; S-151 85 SOdertalje (SE).
`
`(81) Designated States: AE, AL, AM, AT, AU, AZ, BA, BB, BG,
`BR, BY, CA, CH, CN, CR, CU, CZ, DE, DK, DM, EE,
`
`ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP,
`KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, 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, YU, ZA, ZW, ARIPO patent (GH, GM, KE, LS, MW,
`SD, SL, SZ, UG, ZW), Eurasian patent (AM, AZ, BY, KG,
`KZ, MD, RU, TJ, TM), European patent (AT, BE, CH, CY,
`DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT,
`SE), OAPI patent (BF, BJ, CF, CG, CI, CM, GA, GN, GW,
`ML, MR, NE, SN, TD, TG).
`
`(72) Inventors; and
`(75) Inventors/Applicants (for US only):
`FORSMAN, Sigbrit
`Astra Hassle AB, S-431 83 MOlndal (SE). Published
`[SE/SE];
`KARLSSON, Christer [SE/SE]; Astra Hassle AB, S-431
`With international search report.
`83 MOlndal (SE). KARLSSON, Magnus [SE/SE]; Astra
`Before the expiration of the time limit for amending the
`Hassle AB, S-431 83 Molndal (SE).
`claims and to be republished in the event of the receipt of
`amendments.
`
`(74) Agent: ASTRA AKTIEBOLAG; Intellectual Property, Patents,
`S-151 85 Sodertalje (SE).
`
`(54) Title: IMMEDIATE RELEASE TABLET
`
`Example 1
`
`* too
`80
`8 <3 sy 60 -
`
`& t;
`
`1*0 -
`5 20
`o
`^ 0
`e
`o
`•so
`
`0
`
`4,
`
`•Jkr
`
`pH W
`—A— pH 6,8
`
`T
`5
`
`T
`10
`
`T
`15
`
`20
`
`T
`25
`Time (mm.)
`
`30
`
`(57) Abstract
`
`characterized
`A new oral IR formulation in solid form for a low molecular weight thrombin inhibitor having pH dependent dissolution,
`
`in that the formulation comprises a filler or a combination of fillers having disintegrant properties in an amount higher than 35 % w/w of
`the formulation.
`
`MYLAN - EXHIBIT 1007
`
`

`

`FOR THE PURPOSES OF INFORMATION ONLY
`
`Codes used to identify States party to the PCT on the front pages of pamphlets publishing international applications under the PCT.
`
`AL
`AM
`AT
`AU
`AZ
`BA
`BB
`BE
`BF
`BG
`BJ
`BR
`BY
`CA
`CF
`CG
`CH
`CI
`CM
`CN
`CU
`CZ
`DE
`DK
`EE
`
`Albania
`Armenia
`Austria
`Australia
`Azerbaijan
`Bosnia and Herzegovina
`Barbados
`Belgium
`Burkina Faso
`Bulgaria
`Benin
`Brazil
`Belarus
`Canada
`Central African Republic
`Congo
`Switzerland
`C&te d'lvoire
`Cameroon
`China
`Cuba
`Czech Republic
`Germany
`Denmark
`Estonia
`
`ES
`FI
`FR
`GA
`GB
`GE
`GH
`GN
`GR
`HU
`IE
`IL
`IS
`IT
`JP
`KE
`KG
`KP
`
`KR
`KZ
`LC
`LI
`LK
`LR
`
`Spain
`Finland
`France
`Gabon
`United Kingdom
`Georgia
`Ghana
`Guinea
`Greece
`Hungary
`Ireland
`Israel
`Iceland
`Italy
`Japan
`Kenya
`Kyrgyzstan
`Democratic People's
`Republic of Korea
`Republic of Korea
`Kazakstan
`Saint Lucia
`Liechtenstein
`Sri Lanka
`Liberia
`
`LS
`LT
`LU
`LV
`MC
`MD
`MG
`MK
`
`ML
`MN
`MR
`MW
`MX
`NE
`NL
`NO
`NZ
`PL
`PT
`RO
`RU
`SD
`SE
`SG
`
`Lesotho
`Lithuania
`Luxembourg
`Latvia
`Monaco
`Republic of Moldova
`Madagascar
`The former Yugoslav
`Republic of Macedonia
`Mali
`Mongolia
`Mauritania •
`Malawi
`Mexico
`Niger
`Netherlands
`Norway
`New Zealand
`Poland
`Portugal
`Romania
`Russian Federation
`Sudan
`Sweden
`Singapore
`
`SI
`SK
`SN
`SZ
`TD
`TG
`TJ
`TM
`TR
`TT
`UA
`UG
`US
`UZ
`VN
`YU
`ZW
`
`Slovenia
`Slovakia
`Senegal
`Swaziland
`Chad
`Togo
`Tajikistan
`Turkmenistan
`Turkey
`Trinidad and Tobago
`Ukraine
`Uganda
`United States of America
`Uzbekistan
`Viet Nam
`Yugoslavia
`Zimbabwe
`
`

`

`WO 00/13671
`
`PCT/SE99/01471
`
`1
`
`IMMEDIATE RELEASE TABLET
`
`Field of the invention
`
`5
`
`10
`
`The invention relates to a solid dosage form of a low molecular weight thrombin inhibitor
`formulated as immediate release (IR) tablets as well as a process for manufacture thereof.
`The invention also relates to the medical use of the formulation in the prophylaxis and / or
`treatment of thromboembolism.
`
`Background of the invention
`
`is
`
`The thrombin inhibitor, used in the formulation of the present invention is a low molecular
`weight drug with pH dependent solubility. It is characterised by a low solubility at basic
`pH which is dramatically increased in the protonated form at acidic pH. Thus, upon
`administration in conventional IR formulations, fast dissolution of the drug is obtained in
`acidic pH while markedly slower dissolution is obtained at more neutral pH. This
`variability in dissolution is not acceptable for safe, efficient and convenient therapy. The
`present invention provides an immediate release formulation based on conventional
`20 manufacturing processes with careful chosen excipients that provides a dissolution which
`is not, or very little dependent on pH.
`
`Several different ways have been suggested in order to prepare immediate-release solid
`dosage forms.
`
`25
`
`Lachman (The theory and practice of industrial pharmacy 1986, 343, appA) describes the
`composition and manufacturing of two different standard granulates for IR tablets. These
`two compositions gave very poor quality of the granulates, which gave unacceptable
`tablets with very low hardness. These compositions do not work with the low molecular
`30 weight thrombin inhibitors used in connection with the present invention. The tablets do
`
`

`

`WO 00/13671
`
`PCT/SE99/01471
`
`2
`
`not answer to the definition of a rapidly dissolving drug product presented in Guidance for
`Industry. Waiver of in Vivo Bioavailability and Bioequivalens Studies for Immediate
`Release Solids Dosage Forms Containing Certain Active Moieties/Active Ingredients
`Based on Biopharmaceutics Classification System. Tablets must release 85% or more of
`stated amount within 30 min.
`
`Description of the invention
`
`It lias now been found that low molecular weight peptide-based thrombin inhibitors with
`pH-dependent solubility - including their salts - can be formulated as IR tablets with no or
`very little pH depending dissolution.
`
`Therefore, the object of the present invention is to provide a novel pharmaceutical
`formulation comprising a low molecular weight peptide-based thrombin inhibitor
`formulated as an IR-tablet with no or very little pH depending dissolution and a process for
`the preparation of such formulation.
`
`Thrombin inhibitors referred to in this application are low molecular weight peptide-based
`thrombin inhibitors with pH dependent solubility. The term "low molecular weight
`peptide-based thrombin inhibitors" will be well understood by one skilled in the art to
`include thrombin inhibitors with one to four peptide linkages, and/or with a molecular
`weight below 1000, and includes those described generically and, more preferably,
`specifically in the review paper by Claesson 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, W093/11152, WO
`95/23609, WO95/35309, WO 96/25426, WO 94/29336, WO WO 93/18060 and WO
`95/01168; and European Patent Applications 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 601 459.
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`

`

`WO 00/13671
`
`PCT/SE99/01471
`
`3
`
`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
`93/11152 and the list of abbreviations therein) and HOOC-CH2-(R)Cgl-Aze-Pab-H (known
`as melagatran; see International Patent Application WO 94/29336 and the list of
`abbreviations therein).
`
`5
`
`The preferred low molecular weight peptide-based thrombin inhibitor is selected from the
`group consisting of inogatran, (Glycine, N-[2-[2-[[[3-[(aminoimino-
`10 methyl)amino]propyl] amino] carbonyl]-l-piperidinyl]-l-(cyclohexylmethyl)-2-oxoethyl]
`[2R-[2S]]-), melagatran, (Glycine, N-[2-[2-[[[[4 (aminoiminomethyl)phenyl]-
`methyl]amino]carbonylJ-l-azetidinyl]-l-cyclohexyl-2-oxoethyl]-, [2R-[2S]]-) and
`compound A, (Glycine, N-[l-cyclohexyl-2-[2-[[[[4-[(hydroxyimino)aminomethyl]-
`phenyl]methyl]amino]carbonyl]-l-azetidinyl]-2-oxoethyl]-, ethyl ester, [S-(R*, S*)]-).
`
`15
`
`20
`
`The particularly preferred low molecular weight thrombin inhibitor Compound A is
`effective for the treatment of thrombo-embolism. Compound A is described in the
`International Patent Application WO 97/23499. Compound A is a low molecular weight
`thrombin inhibitor with good oral bioavaibility, low variability and limited food
`interaction. No solid dosage forms containing this thrombin inhibitor have been reported.
`
`In order to produce tablets which provides a dissolution which is not or very little
`dependent on pH compound A should have a particle size less than 300 ^m, preferably
`less than 150 pm and with a preferred mean particle size less than 80 fim. With other low
`25 molecular weight thrombin inhibitor with low solubility at basic pH and pH dependent
`solubility the requirements on the particle size will depend on the level of low solubility.
`
`It has been found that by carefully selecting excipients the pH dependent dissolution could
`be reduced and giving a tablet release of more than 85% within 30 minutes in acidic as
`
`30
`
`

`

`WO 00/13671
`
`PCT/SE99/01471
`
`4
`
`well as neutral environment. This in spite of Compound A having an extremely pH
`dependent solubility.
`
`The formulation according to the invention comprises the thrombin inhibitor, a filler or a
`combination of fillers, said filler/fillers having disintegrant properties (due to swelling)
`and, optionally, non swelling filler(s) disintegrant(s), binder(s) and/or lubricant(s).
`
`The amount of filler/fillers having disintegrant properties constitutes more than 35% (w/w),
`preferably more than 50% (w/w) of the formulation.
`
`Some excipients can serve multiple purposes, e.g. be a filler and a disintegrant at the same
`time. An excipient used in higher amounts than 35 % is in the invention defined as a filler
`but may contribute with other important properties for the formulation e.g. disintegration,
`binding or lubrication.
`
`The filler with disintegrant properties is selected from the group consisting of cellulose per
`se (such as microcrystalline cellulose), microfine cellulose) starch per se (such as maize
`starch, sodium starch glycollate, potato starch, rice starch, wheat starch).
`
`5
`
`10
`
`15
`
`20
`
`The nonswelling filler is selected from the group sugars (such as mannitol, sorbitol,
`dextrose, xylitol, sucrose, laktos).
`
`25
`
`The disintegrant is selected from the group consisting of cellulose per se (such as
`microcrystalline cellulose, microfine cellulose, cross-linked sodium carboxymethyl
`cellulose, cross-linked hydroxypropyl cellulose), starch per se (such as sodium starch
`glycollate, pregelatinised starch, maize starch, potato starch, rice starch, wheat starch) and
`others (such as cross linked polyvinylpyrrolidone, cationic exchange resin).
`
`The binder is selected from the group consisting of cellulose per se (such as sodium
`carboxymethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methyl
`
`30
`
`

`

`WO 00/13671
`
`PCT/SE99/01471
`
`5
`
`cellulose), polymers (such as polyvinylpyrrolidone, polyethylene glycol), gelatins (such as
`hydrolysed gelatin), and traditional binders (such as starch, natural gums).
`
`The lubricant is selected from the group consisting of insoluble lubricants (such as
`5 magnesium stearate, calcium stearate, zink stearate, stearic acid, oils, talc, sodium stearyl
`fumarate), and soluble lubricants (such as polyethylene glycol, sodium benzoate, sodium
`lauryl sulphate).
`
`In the formulation according to the invention the different constituents are preferably
`included in the following proportions, calculated by per cent w/w of the finished tablet:
`
`10
`
`Thrombin inhibitor: 1-35 %, preferably 1 -15 %.
`
`is
`
`20
`
`Filler: 35 - 90 %, preferably 45 - 80 %, when microcrystalline cellulose 50 - 90 %,
`preferably 60 - 80 % and most preferably 72 - 76 %, when nonswelling filler 0-50% when
`mannitol 0-15 %, preferably 5 -10 %.
`
`Disintegrant: 0-35 %, preferably 7-35 %, when sodium starch glycollate 3 - 20 %,
`preferably 5-10 %.
`
`Binder: 0-15 %, preferably 4 -12 %, when polyvinylpyrrolidone 3-15 %, preferably
`5 -10%.
`
`Lubricant: 0-5 %, preferably 0.5 -1.5 %, when sodium stearyl fumarate 0.5 -1.5 %,
`preferably above 1 %.
`
`25
`
`In the invention it was found that a formulation comprising the active component with a
`particle size less than 300 (j.m, preferably less than 150 (am and with a preferred mean
`particle size less than 80 (am, fillers (e.g. microcrystalline cellulose (50-90%, preferably
`74%), mannitol ( 0 - 15%, preferably 8.5 %) disintegrant
`
`30
`
`

`

`WO 00/13671
`
`PCT/SE99/01471
`
`6
`
`(e.g. sodium starch glycollate 3 - 2 0 % , preferably 8.5 %), moistened with with a suitable
`binder (e.g. polyvinylpyrrolidone K 90 ( 3- 15 %, preferably 8 %) and final mixed with
`suitable lubricant (e.g. sodium stearyl fumarate (0.5 -1.5 %, preferably 1 %) provided a
`tablet having good technical properties and a very small pH dependent dissolution.
`
`The formulations according to the invention can preferably be prepared either by direct
`compression or by wet granulation technique.
`
`Direct compression
`
`10
`
`A low molecular weight thromin inhibitor is mixed with the filler of fillers and if necessary
`the disintegrant. This mixture is then mixed with the lubricant and compressed to the
`tablets.
`
`is Wet granulation
`
`A low molecular weight thrombin inhibitor is mixed with the filler of fillers, and if
`necessary the disintegrant. The mixture is then moistured with a suitable solvent in which
`the binder may be dissolved. After drying the granulate is milled and then mixed with the
`lubricant and compressed to tablets
`
`20
`
`

`

`WO 00/13671
`
`PCT/SE99/01471
`
`7
`
`Working Examples
`
`Example 1 Drug dissolution from tablets according to the invention
`
`IR tablets of the thrombin inhibitor. Compound A, were prepared by mixing Compound A
`microcrystalline cellulose, sodium starch glycollate and mannitol The mixture was
`moistured with a suitable amount of polyvinylpyrrolidone K 90 dissolved in water.
`After drying, the granulate was milled and then mixed with sodium stearyl fumarate and
`compressed to tablets.
`
`mg/tabl
`
`Compound A
`24
`Microcrystalline cellulose (MCC pH 101) 140
`16
`Sodium starch glycollate
`Mannitol
`16
`Polyvinylpyrrolidone K 90
`15
`Water
`q.s.
`2
`Sodium stearyl fumarate
`
`Punches:
`Tablet weight:
`Hardness:
`
`9mm
`213 mg
`HON
`
`The obtained tablets were analysed with regard to dissolution of Compound A using a USP
`dissolution apparatus No. 2 (paddle), 100 rpm, 500 ml. The dissolution medium used had a
`temperature of 370C. Two different dissolution medium were used, 0.1 M HC1 pH 1 and
`phosphate buffer pH 6.8 (ionic strength 0.1). The amount of Compound A released was
`determined by UV-spectrometry.
`
`5
`
`10
`
`is
`
`20
`
`25
`
`30
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`

`

`WO 00/13671
`
`PCT/SE99/01471
`
`8
`
`Results are shown in Figure 1. After 30 minutes the amount of Compound A dissolved was
`94 % (average n=3) in 0.1 M HC1 and 94 % (average n=3) in phosphate buffer pH 6.8.
`
`Example lb Drug dissolution from tablets according to the invention
`
`5
`
`10
`
`IR tablets of thrombin inhibitor, Compound A were prepared by mixing Compound A,
`microcrystalline cellulose and maize starch and the mixture was moistured with a suitable
`amount of maize starch (paste). After drying the granulate was milled and then mixed with
`polyvinylpyrrolidone crosslinked. Finally the sodium stearyl fumarate was admixed and
`the granulate was compressed into tablets.
`
`Compound A
`is Microcrystalline cellulose
`Maize starch
`Maize starch (paste)
`Water
`Polyvinylpyrrolidone crosslinked
`Sodium stearyl fumarate
`
`20
`
`Punches:
`Tablet weight:
`Hardness:
`
`mg/tabl
`
`30
`115
`55
`6
`q.s.
`10
`2.2
`
`8.5 mm
`219 mg
`H O N
`
`25
`
`30
`
`The obtained tablets were analysed for dissolution of Compound A according to the
`method described in Example 1. Results are shown in Figure 2. After 30 minutes the
`amount of Compound A dissolved was 100 % (average n=3) in 0.1 M HC1 and 97 %
`(average n=3) in phosphate buffer pH 6.8.
`
`

`

`WO 00/13671
`
`PCT/SE99/01471
`
`9
`
`Example 2 Drug dissolution from tablets according to the reference
`
`5
`
`Lachman ((The theory and practice of industrial pharmacy 1986,343,appA) describes
`another composition and manufacturing of a"standard" granulate for an IR tablet. IR tablets
`of the thrombin inhibitor. Compound A were prepared according to this method by mixing
`Compound A, tricalcium phosphate and the mixture was moistured with pre-gelatinated
`maize starch dissolved in water. After drying the granulate was milled and then mixed with
`talc Finally, the mineral oil was admixed and the granulate was compressed to tablets.
`
`10 Compound A
`Tricalcium phosphate
`Pregelatinized starch
`Water
`Talc
`is Mineral oil, light
`
`Punches:
`Tablet weight:
`Hardness:
`
`24
`100
`15
`q.s.
`60
`4
`
`9 mm
`198 mg
`12 N
`
`20
`
`25
`
`The obtained tablets were analysed for dissolution of Compound A according to the
`method described in Example 1. Results are shown in Figure 2. After 30 minutes the
`amount of Compound A dissolved was 40 % (average n=3) in 0.1 M HC1 and 5 % (average
`n=3) in phosphate buffer pH 6.8.
`
`

`

`WO 00/13671
`
`PCT/SE99/01471
`
`10
`
`Example 3 Drug dissolution from tablets according to the reference
`
`Lachman (The theory and practice of industrial pharmacy 1986,343,appA) describes
`composition and manufacturing of a another "standard" granulate for an IR tablet. IR
`tablets of thrombin inhibitor. Compound A were prepared according to this method by
`mixing Compound A, lactose and the mixture was moistured with starch dissolved in
`water.
`After drying the granulate was milled and then mixed with dry starch and talc. Finally the
`mineral oil was admixed and the granulate was compressed to tablets.
`
`Compound A
`Lactose
`Starch(paste)
`Starch
`Talc
`Mineral oil 50 cps
`
`Punches:
`Tablet weight
`Hardness:
`
`24
`110
`5
`28
`28
`11
`
`9mm
`206 mg
`13 N
`
`The obtained tablets were analysed for dissolution of Compound A according to the
`method described in Example 1. Results are shown in Figure 3. After 30 minutes the
`amount of Compound A dissolved was 100 % (average n=3) in 0.1 M HC1 and 74 %
`(average n=3) in phosphate buffer pH 6.8.
`
`5
`
`10
`
`is
`
`20
`
`25
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`

`

`WO 00/13671
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`PCT/SE99/01471
`
`11
`
`Short description of the Figures
`
`Figure 1: Dissolution of the thrombin inhibitor Compound A from tablets according to the
`invention as described in Example 1. (No figure is given for example lb).
`
`5
`
`Figure 2: Dissolution of the thrombin inhibitor Compound A from tablets according to the
`reference as described in Example 2
`
`Figure 3: Dissolution of the thrombin inhibitor Compound A from tablets according to the
`reference as described in Example 3
`
`10
`
`Conclusion (Examples)
`
`From the Examples it is obvious that a sufficient quality of the product is not achieved
`is when using a "standard" granulate. Either the technical properties are bad [Example 2 and
`3,] and/or the dissolution in phosphate buffer pH 6.8 does not meet the definition of a
`rapidly dissolving drug product in Guidance for Industry. Waiver of in Vivo
`Bioavailability and Bioequivalens Studies for Immediate Release Solids Dosage Forms
`Containing Certain Active Moieties/Active Ingredients Based on Biopharmaceutics
`20 Classification System. With the formulation according to the invention the dissolution is
`fast in both medias and the technical properties are excellent.
`
`

`

`WO 00/13671
`
`CLAIMS
`
`PCT/SE99/01471
`
`12
`
`5
`
`1. An oral immediate release formulation in solid form of a low molecular weight peptide-
`based thrombin inhibitor having pH dependent solubility characterized in that the
`formulation comprises a filler or a combination of fillers having disintegrant properties in
`an amount higher than 35% w/w of the formulation, selected from the group consisting of a
`cellulose per se and a starch per se.
`
`2. An oral formulation according to claim 1, characterized in that the formulation
`optionally contains a sugar, a disintegrant, a binder and/or a lubricant.
`
`10
`
`3. An oral formulation according to any of the preceding claims, characterized in that the
`thrombin inhibitor is having a particle size of less than 300 |jm, preferably less than 150
`jam and a preferred mean particle size less than 80 jam.
`
`15
`
`4. An oral formulation according to claims any of the preceding claims
`in that it comprises a combination of microcrystalline cellulose and
`
`mannitol.
`
`20
`
`5. An oral formulation according to claim 4, characterized in that microcrystalline
`cellulose constitutes 50 - 90 % (w/w) of the formulation.
`
`6. An oral formulation according to claim 4, characterized in that mannitol
`constitutes 0 - 15 % (w/w) of the formulation.
`
`25
`
`7. An oral formulation according to any of the preceding claims wherein the thrombin
`inhibitor is glycine, N-[l-cyclohexyl-2-[2-[[[[4-[(hydroxyimino)aminomethyl]-
`phenyl]methyl]amino]carbonyl]-l-azetidinyl]-2-oxoethyl]-, ethyl ester, [S-(R*, S*)]-).
`
`30
`
`8. An oral formulation according to any of the preceding claims for use in therapy.
`
`

`

`WO 00/13671
`
`PCT/SE99/01471
`
`13
`
`9. The use of a low molecular weight peptide-based thrombin inhibitor, a filler or a
`combination of fillers having disintegrant properties in an amount higher than 35% w/w
`according to claim 1 in the manufacture of a formulation for prophylaxis and / or treatment
`of thrombo-embolism.
`
`10. A method for prophylaxis and / or treatment of thrombo-embolism wherein a
`therapeutically effective amount of a formulation according to claim 1 is administered to a
`mammal in the need of such treatment.
`
`11. A process for the preparation of an oral immediate release formulation according to
`claim 1 characterized in that the preparation is by direct compression or by wet
`granulation technique.
`
`12. Use of a filler selected from the group consisting of a cellulose derivative, and a starch
`derivative, optionally a sugar, a disintegrant, a binder and/or a lubricant in the preparation
`of an oral immediate release formulation containing a low molecular weight peptide-based
`thrombin inhibitor having pH dependent solubility.
`
`10
`
`15
`
`20
`
`

`

`WO 00/13671
`
`PCT/SE99/01471
`
`1 / 2
`
`e wo -
`
`"8 80 :
`_
`to
`-S 60 -
`| itO'-
`
`1 20 ~-
`o
`^ 0
`e
`5
`
`0
`
`Example 1
`
`-hr
`
`•ii
`
`-+r- p H 1 . 0
`-£r-pH 6.8
`
`5
`
`10
`
`15
`
`20
`
`25
`Time (min.)
`
`30
`
`

`

`WO 00/13671
`
`PCT/SE99/01471
`
`ttn.Z
`
`L
`
`100
`
`g 80 -
`
`QJ 60 -
`d CJ
`-
`| <0 -
`5 20 -
`§
`I o
`CL
`e
`o
`
`n
`0 **
`0
`
`<>0
`
`2 / 2
`
`Example 2
`
`pH 10
`pH 6.8
`
`tjr
`5
`
`&
`10
`
`15
`
`-A-
`20
`
`t\
`30
`
`•A-
`25
`Time (min.)
`
`Exampel 3
`
`^ 100 -
`
`-*r
`
`+
`
`"S 80 -
`UJ C3
`"
`^ 60 -
`a:
`
`3 40 -120 -
`CL
`a
`g" 0
`
`0
`
`5
`
`T
`10
`
`15
`
`20
`
`-^kr-pH 1.0
`-*r-pH 6.8
`
`30
`25
`Time (min.)
`
`

`

`1
`
`INTERNATIONAL SEARCH REPORT
`
`A. CLASSIFICATION OF SUBJECT MATTER
`
`International application No.
`PCT/SE 99/01471
`
`IPC7: A61K 9/20, A61K 47/38, A61K 38/55, A61P 7/02
`According to International Patent Ciassification (IPC) or to both national classification and IPC
`B. FIELDS SEARCHED
`Minimum documentation searched (classification system followed by classification symbols)
`IPC7: A61K
`Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched
`SE,DK,FI,N0 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
`
`X
`
`Category* Citation of document, with indication, where appropriate, of the relevant passages
`EP 0803251 A1 (JANSSEN PHARMACEUTICA N.V.),
`29 October 1997 (29.10.97), see page 5, line 18 -
`page 7, line 37
`
`A
`
`A
`
`WO 9813029 A1 (DUPHAR INTERNATIONAL RESEARCH B.V.),
`2 April 1998 (02.04.98), see abstract and example
`20
`
`WO 9723499 A1 (ASTRA AKTIEBOLAG), 3 July 1997
`(03.07.97), see claim 39
`
`Relevant to claim No.
`
`1-12
`
`1-12
`
`1-12
`
`| | Further documents are listed in the continuation of Box C.
`
`| y| See patent family annex.
`
`Special categories of cited documents:
`*
`"A" document defining the general state of the art which is not considered
`to be of particular relevance
`"E" erlier document but published on or after the international filing date
`"L" document which may throw doubts on priority claim{s) or which is
`cited to establish the publication date of another citation or other
`special reason (as specified)
`"O" document referring to an oral disclosure, use, exhibition or other
`means
`"P" document published prior to the international filing date but later than
`the priority date claimed
`Date of the actual completion of the international search
`
`9 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 PCT/ISA/210 (second sheet) (July 1992)
`
`T" later document published after the international filing date or priority
`date and not in conflict with the application but cited to understand
`the principle or theory underlying the invention
`"X" document of particular relevance: the claimed invention cannot be
`considered novel or cannot be considered to involve an inventive
`step when the document is taken alone
`"Y" document of particular relevance: the claimed invention cannot be
`considered to involve an inventive step when the document is
`combined with one or more other such documents, such combination
`being obvious to a person stalled in the art
`"&* document member of the same patent family
`Date of mailing of the international search report
`I 0 -01- 2000
`
`Authorized officer
`Hampus Rystedt/EB
`Telephone No. + 46 8 782 25 00
`
`

`

`INTERNATIONAL SEARCH REPORT
`
`International application No.
`PCT/SE 99/01471
`
`Box I
`
`Observations where certain claims were found unsearchable (Continuation of item 1 of first sheet)
`
`1-
`
`This international search report has not been established in respect of certain claims under Article 17(2Xa) for the following reasons:
`Claims Nos.: 10
`because they relate to subject matter not required to be searched by this Authority, namely:
`Although claim 10 relates to a method for treatment of the human
`or animal body (see PCT Rule 39.1(iv)), a search has been
`carried out. The search has been based on the effects of the
`claimed composition.
`2. Q Claims Nos.:
`because they relate to parts of the international application that do not comply with the prescribed requirements to such
`an extent that no meaningful international search am be carried out, specifically:
`
`Box II
`
`Observations where unity of invention is lacking (Continuation of item 2 of first sheet)
`
`This International Searching Authority found multiple inventions in this international application, as follows:
`
`1.
`
`2.
`
`As all required additional search fees were timely paid by the applicant, this international search report covers all
`searchable claims.
`
`As all searchable claims could be searched without effort justifying an additional fee, this Authority did not invite payment
`of any additional fee.
`
`3. Q As only some of the required additional search fees were timely paid by the applicant, this international search report
`covers only those claims for which fees were paid, specifically claims Nos.:
`
`4. Q No required additional search fees were timely paid by the applicant. Consequently, this international search report is
`restricted to the invention first mentioned in the claims; it is covered by claims Nos.:
`
`Remark on Protest
`
`| | The additional search fees were accompanied by the applicant's protest.
`| | No protest accompanied the payment of additional search fees.
`
`Form PCT/ISA/210 (continuation of first sheet (1)) (Ju!yl992)
`
`

`

`INTERNATIONAL SEARCH REPORT
`Information on patent family members
`
`02/11/99
`Patent family
`member(s)
`2290497 A
`102812 A
`2201264 A
`1216467 A
`9803325 A
`125979 D
`10510559 T
`984016 A
`328917 A
`9739744 A
`9703449 A
`4557097 A
`9900995 A
`0939623 A
`970493 A
`991385 A
`332245 A
`706350 B
`1217897 A
`2238737 A
`1209139 A
`9801770 A
`869966 T
`0869966 A
`2128283 T
`9526273 D
`9900115 A
`124857 D
`982809 A
`327569 A
`82198 A
`5708296 A
`0870167 A
`9600556 D
`5945628 A
`
`International application No.
`PCT/SE 99/01471
`Publication
`date
`12/11/97
`31/05/99
`23/10/97
`12/05/99
`13/01/99
`00/00/00
`13/10/98
`23/12/98
`01/03/99
`30/10/97
`22/10/98
`17/04/98
`16/06/99
`08/09/99
`31/08/98
`25/05/99
`30/08/99
`17/06/99
`17/07/97
`03/07/97
`24/02/99
`13/01/99
`10/06/99
`14/10/98
`16/05/99
`00/00/00
`28/05/99
`00/00/00
`20/08/98
`21/12/98
`02/12/98
`21/11/96
`14/10/98
`00/00/00
`31/08/99
`
`AU
`BG
`CA
`CN
`CZ
`IL
`JP
`NO
`PL
`WO
`ZA
`AU
`CZ
`EP
`HR
`NO
`PL
`AU
`AU
`CA
`CN
`CZ
`DE
`EP
`ES
`GB
`HU
`IL
`NO
`PL
`SK
`AU
`EP
`SE
`US
`
`Patent document
`cited in search report
`0803251 A1
`EP
`
`Publication
`date
`29/10/97
`
`WO
`
`9813029 A1
`
`02/04/98
`
`WO
`
`9723499 A1
`
`03/07/97
`
`Form PCT/ISA/210 (patent family annex) (July 1992)
`
`