ZA200309316B - Pharmaceutical formulation. - Google Patents

Pharmaceutical formulation. Download PDF

Info

Publication number: ZA200309316B
Authority: ZA; South Africa
Prior art keywords: formulation; carrageenan; active ingredient; iota; mmol
Prior art date: 2001-06-21

Application number

ZA200309316A

Other languages

English (en)

Inventor

Cynthia Gaik-Lim Khoo

Helena Gustafsson

Original Assignee

Astrazeneca Ab

Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)

2001-06-21

Filing date

2003-11-28

Publication date

2005-02-28

2001-06-21 Priority claimed from SE0102069A external-priority patent/SE0102069D0/xx

2002-05-31 Priority claimed from SE0201660A external-priority patent/SE0201660D0/xx

2003-11-28 Application filed by Astrazeneca Ab filed Critical Astrazeneca Ab

2005-02-28 Publication of ZA200309316B publication Critical patent/ZA200309316B/en

Links

239000008194 pharmaceutical composition Substances 0.000 title claims description 10
239000000203 mixture Substances 0.000 claims description 156
229920001525 carrageenan Polymers 0.000 claims description 64
239000000679 carrageenan Substances 0.000 claims description 63
229940113118 carrageenan Drugs 0.000 claims description 63
229920000642 polymer Polymers 0.000 claims description 63
229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 54
238000009472 formulation Methods 0.000 claims description 49
230000007935 neutral effect Effects 0.000 claims description 40
239000004480 active ingredient Substances 0.000 claims description 37
229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 36
235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 34
239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 33
239000003814 drug Substances 0.000 claims description 27
238000000034 method Methods 0.000 claims description 22
229920001223 polyethylene glycol Polymers 0.000 claims description 14
239000002202 Polyethylene glycol Substances 0.000 claims description 13
-1 tert-butyl 2-{ 7-[3-(4-cyanoanilino)propyl]-9-oxa-3 ,1-diazabicyclo-[3.3.1]non-3- yl }ethylcarbamate Chemical compound 0.000 claims description 12
239000000126 substance Substances 0.000 claims description 10
238000004519 manufacturing process Methods 0.000 claims description 8
238000002156 mixing Methods 0.000 claims description 7
238000011282 treatment Methods 0.000 claims description 7
230000002378 acidificating effect Effects 0.000 claims description 6
208000024172 Cardiovascular disease Diseases 0.000 claims description 4
239000008203 oral pharmaceutical composition Substances 0.000 claims description 4
229920002678 cellulose Polymers 0.000 claims description 3
239000001913 cellulose Substances 0.000 claims description 3
235000010980 cellulose Nutrition 0.000 claims description 3
230000008569 process Effects 0.000 claims description 3
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 2
IUBSYMUCCVWXPE-UHFFFAOYSA-N metoprolol Chemical group COCCC1=CC=C(OCC(O)CNC(C)C)C=C1 IUBSYMUCCVWXPE-UHFFFAOYSA-N 0.000 claims description 2
229960002237 metoprolol Drugs 0.000 claims description 2
ZEEVEFOISWRYMK-UHFFFAOYSA-N tert-butyl n-[2-[7-[4-(4-cyanophenyl)butyl]-9-oxa-3,7-diazabicyclo[3.3.1]nonan-3-yl]ethyl]carbamate Chemical compound C1C(O2)CN(CCNC(=O)OC(C)(C)C)CC2CN1CCCCC1=CC=C(C#N)C=C1 ZEEVEFOISWRYMK-UHFFFAOYSA-N 0.000 claims description 2
ZXIBCJHYVWYIKI-PZJWPPBQSA-N ximelagatran Chemical compound C1([C@@H](NCC(=O)OCC)C(=O)N2[C@@H](CC2)C(=O)NCC=2C=CC(=CC=2)C(\N)=N\O)CCCCC1 ZXIBCJHYVWYIKI-PZJWPPBQSA-N 0.000 claims description 2
229960001522 ximelagatran Drugs 0.000 claims description 2
KZOCHEDMAHPYCK-UHFFFAOYSA-N 4-[3-[3-(3,3-dimethyl-2-oxobutyl)-9-oxa-3,7-diazabicyclo[3.3.1]nonan-7-yl]propylamino]benzonitrile Chemical compound C1C(O2)CN(CC(=O)C(C)(C)C)CC2CN1CCCNC1=CC=C(C#N)C=C1 KZOCHEDMAHPYCK-UHFFFAOYSA-N 0.000 claims 1
UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical group OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims 1
JRHUUZPSMQIWBQ-PELRDEGISA-N tert-butyl n-[2-[3-[(2s)-3-(4-cyanophenoxy)-2-hydroxypropyl]-9-oxa-3,7-diazabicyclo[3.3.1]nonan-7-yl]ethyl]carbamate Chemical compound C([C@@H](O)CN1CC2CN(CC(C1)O2)CCNC(=O)OC(C)(C)C)OC1=CC=C(C#N)C=C1 JRHUUZPSMQIWBQ-PELRDEGISA-N 0.000 claims 1
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 77
239000003826 tablet Substances 0.000 description 60
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 49
150000001875 compounds Chemical class 0.000 description 49
238000005481 NMR spectroscopy Methods 0.000 description 40
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 36
235000019439 ethyl acetate Nutrition 0.000 description 36
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 33
HSHXDCVZWHOWCS-UHFFFAOYSA-N N'-hexadecylthiophene-2-carbohydrazide Chemical compound CCCCCCCCCCCCCCCCNNC(=O)c1cccs1 HSHXDCVZWHOWCS-UHFFFAOYSA-N 0.000 description 32
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 24
239000000243 solution Substances 0.000 description 24
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 22
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 22
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 20
229940079593 drug Drugs 0.000 description 20
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 15
MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 description 15
229940045902 sodium stearyl fumarate Drugs 0.000 description 15
238000006243 chemical reaction Methods 0.000 description 14
238000000746 purification Methods 0.000 description 14
239000000741 silica gel Substances 0.000 description 14
229910002027 silica gel Inorganic materials 0.000 description 14
239000011734 sodium Substances 0.000 description 14
JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 12
HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 12
239000012267 brine Substances 0.000 description 12
230000001419 dependent effect Effects 0.000 description 12
238000004090 dissolution Methods 0.000 description 12
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 12
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
229940126062 Compound A Drugs 0.000 description 10
NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 10
DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 10
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 10
238000002360 preparation method Methods 0.000 description 10
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 9
238000004458 analytical method Methods 0.000 description 9
229920006318 anionic polymer Polymers 0.000 description 9
239000000314 lubricant Substances 0.000 description 9
239000011541 reaction mixture Substances 0.000 description 9
238000007907 direct compression Methods 0.000 description 8
239000012738 dissolution medium Substances 0.000 description 8
239000012074 organic phase Substances 0.000 description 8
108090000765 processed proteins & peptides Proteins 0.000 description 8
239000000047 product Substances 0.000 description 8
239000002904 solvent Substances 0.000 description 8
229920000663 Hydroxyethyl cellulose Polymers 0.000 description 7
239000007864 aqueous solution Substances 0.000 description 7
125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 7
238000003818 flash chromatography Methods 0.000 description 7
IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 7
229910000041 hydrogen chloride Inorganic materials 0.000 description 7
235000019447 hydroxyethyl cellulose Nutrition 0.000 description 7
239000010410 layer Substances 0.000 description 7
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 7
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 6
KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
229940122388 Thrombin inhibitor Drugs 0.000 description 6
239000012044 organic layer Substances 0.000 description 6
239000012071 phase Substances 0.000 description 6
239000007787 solid Substances 0.000 description 6
239000003868 thrombin inhibitor Substances 0.000 description 6
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 5
239000004354 Hydroxyethyl cellulose Substances 0.000 description 5
BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 5
208000001435 Thromboembolism Diseases 0.000 description 5
150000001409 amidines Chemical class 0.000 description 5
238000013270 controlled release Methods 0.000 description 5
239000011159 matrix material Substances 0.000 description 5
229910052757 nitrogen Inorganic materials 0.000 description 5
239000000546 pharmaceutical excipient Substances 0.000 description 5
239000008363 phosphate buffer Substances 0.000 description 5
239000000651 prodrug Substances 0.000 description 5
229940002612 prodrug Drugs 0.000 description 5
238000003756 stirring Methods 0.000 description 5
XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 4
IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 4
239000002775 capsule Substances 0.000 description 4
235000010418 carrageenan Nutrition 0.000 description 4
238000012512 characterization method Methods 0.000 description 4
239000012043 crude product Substances 0.000 description 4
230000003628 erosive effect Effects 0.000 description 4
239000000284 extract Substances 0.000 description 4
210000001035 gastrointestinal tract Anatomy 0.000 description 4
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
201000005665 thrombophilia Diseases 0.000 description 4
238000005160 1H NMR spectroscopy Methods 0.000 description 3
VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 3
WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
229910004373 HOAc Inorganic materials 0.000 description 3
241001465754 Metazoa Species 0.000 description 3
229910000831 Steel Inorganic materials 0.000 description 3
239000004809 Teflon Substances 0.000 description 3
229920006362 Teflon® Polymers 0.000 description 3
150000003863 ammonium salts Chemical class 0.000 description 3
239000008346 aqueous phase Substances 0.000 description 3
238000000668 atmospheric pressure chemical ionisation mass spectrometry Methods 0.000 description 3
JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 3
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238000010168 coupling process Methods 0.000 description 3
238000005859 coupling reaction Methods 0.000 description 3
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230000000694 effects Effects 0.000 description 3
238000005516 engineering process Methods 0.000 description 3
239000008187 granular material Substances 0.000 description 3
238000004128 high performance liquid chromatography Methods 0.000 description 3
229960004592 isopropanol Drugs 0.000 description 3
239000000825 pharmaceutical preparation Substances 0.000 description 3
LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 3
238000010992 reflux Methods 0.000 description 3
150000003839 salts Chemical class 0.000 description 3
229920006395 saturated elastomer Polymers 0.000 description 3
229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
235000017557 sodium bicarbonate Nutrition 0.000 description 3
239000010959 steel Substances 0.000 description 3
238000012360 testing method Methods 0.000 description 3
238000004809 thin layer chromatography Methods 0.000 description 3
UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 3
YKPJCGLEIYYUEP-UHFFFAOYSA-N (4-cyano-2,6-difluorophenyl)methyl methanesulfonate Chemical compound CS(=O)(=O)OCC1=C(F)C=C(C#N)C=C1F YKPJCGLEIYYUEP-UHFFFAOYSA-N 0.000 description 2
IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 2
YGFKNUJLXOQZEK-UHFFFAOYSA-N 2,6-difluoro-4-(hydroxymethyl)benzonitrile Chemical compound OCC1=CC(F)=C(C#N)C(F)=C1 YGFKNUJLXOQZEK-UHFFFAOYSA-N 0.000 description 2
CDPROXZBMHOBTQ-SJORKVTESA-N 2-[[(2r)-3-cyclohexyl-1-[(2s)-2-[3-(diaminomethylideneamino)propylcarbamoyl]piperidin-1-yl]-1-oxopropan-2-yl]amino]acetic acid Chemical compound NC(N)=NCCCNC(=O)[C@@H]1CCCCN1C(=O)[C@H](NCC(O)=O)CC1CCCCC1 CDPROXZBMHOBTQ-SJORKVTESA-N 0.000 description 2
KFSUGKJDSATWCW-UHFFFAOYSA-N 3-chloro-5-(2-fluoroethoxy)benzaldehyde Chemical compound FCCOC1=CC(Cl)=CC(C=O)=C1 KFSUGKJDSATWCW-UHFFFAOYSA-N 0.000 description 2
YNVVWUCXMBDGHQ-UHFFFAOYSA-N 3-chloro-5-(difluoromethoxy)benzaldehyde Chemical compound FC(F)OC1=CC(Cl)=CC(C=O)=C1 YNVVWUCXMBDGHQ-UHFFFAOYSA-N 0.000 description 2
BJENCCAVAIAGOF-UHFFFAOYSA-N 3-chloro-5-hydroxybenzaldehyde Chemical compound OC1=CC(Cl)=CC(C=O)=C1 BJENCCAVAIAGOF-UHFFFAOYSA-N 0.000 description 2
BJXFKAAHNWGWCF-UHFFFAOYSA-N 4-(aminomethyl)-2,6-difluorobenzonitrile Chemical compound NCC1=CC(F)=C(C#N)C(F)=C1 BJXFKAAHNWGWCF-UHFFFAOYSA-N 0.000 description 2
SUHIECZUTZAADK-UHFFFAOYSA-N 4-(azidomethyl)-2,6-difluorobenzonitrile Chemical compound FC1=CC(CN=[N+]=[N-])=CC(F)=C1C#N SUHIECZUTZAADK-UHFFFAOYSA-N 0.000 description 2
206010051055 Deep vein thrombosis Diseases 0.000 description 2
OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 2
QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
208000005189 Embolism Diseases 0.000 description 2
239000004471 Glycine Substances 0.000 description 2
239000004367 Lipase Substances 0.000 description 2
102000004882 Lipase Human genes 0.000 description 2
108090001060 Lipase Proteins 0.000 description 2
CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 description 2
239000012359 Methanesulfonyl chloride Substances 0.000 description 2
MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
239000012317 TBTU Substances 0.000 description 2
XTXRWKRVRITETP-UHFFFAOYSA-N Vinyl acetate Chemical compound CC(=O)OC=C XTXRWKRVRITETP-UHFFFAOYSA-N 0.000 description 2
239000013543 active substance Substances 0.000 description 2
239000000654 additive Substances 0.000 description 2
230000000996 additive effect Effects 0.000 description 2
229910052786 argon Inorganic materials 0.000 description 2
239000008280 blood Substances 0.000 description 2
210000004369 blood Anatomy 0.000 description 2
ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 2
229910052799 carbon Inorganic materials 0.000 description 2
238000004587 chromatography analysis Methods 0.000 description 2
JNGZXGGOCLZBFB-IVCQMTBJSA-N compound E Chemical compound N([C@@H](C)C(=O)N[C@@H]1C(N(C)C2=CC=CC=C2C(C=2C=CC=CC=2)=N1)=O)C(=O)CC1=CC(F)=CC(F)=C1 JNGZXGGOCLZBFB-IVCQMTBJSA-N 0.000 description 2
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238000005469 granulation Methods 0.000 description 2
XNXVOSBNFZWHBV-UHFFFAOYSA-N hydron;o-methylhydroxylamine;chloride Chemical compound Cl.CON XNXVOSBNFZWHBV-UHFFFAOYSA-N 0.000 description 2
238000010348 incorporation Methods 0.000 description 2
229950003291 inogatran Drugs 0.000 description 2
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235000019421 lipase Nutrition 0.000 description 2
239000007788 liquid Substances 0.000 description 2
HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
238000001819 mass spectrum Methods 0.000 description 2
239000000463 material Substances 0.000 description 2
230000007246 mechanism Effects 0.000 description 2
DKWNMCUOEDMMIN-PKOBYXMFSA-N melagatran Chemical compound C1=CC(C(=N)N)=CC=C1CNC(=O)[C@H]1N(C(=O)[C@H](NCC(O)=O)C2CCCCC2)CC1 DKWNMCUOEDMMIN-PKOBYXMFSA-N 0.000 description 2
229960002137 melagatran Drugs 0.000 description 2
QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 2
BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
239000008188 pellet Substances 0.000 description 2
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
238000007745 plasma electrolytic oxidation reaction Methods 0.000 description 2
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229910000027 potassium carbonate Inorganic materials 0.000 description 2
238000012545 processing Methods 0.000 description 2
125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
235000010413 sodium alginate Nutrition 0.000 description 2
239000000661 sodium alginate Substances 0.000 description 2
229940005550 sodium alginate Drugs 0.000 description 2
239000012279 sodium borohydride Substances 0.000 description 2
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239000012064 sodium phosphate buffer Substances 0.000 description 2
239000003381 stabilizer Substances 0.000 description 2
230000008961 swelling Effects 0.000 description 2
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Classifications

- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives

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Health & Medical Sciences (AREA)
Chemical & Material Sciences (AREA)
Medicinal Chemistry (AREA)
Pharmacology & Pharmacy (AREA)
Life Sciences & Earth Sciences (AREA)
Animal Behavior & Ethology (AREA)
General Health & Medical Sciences (AREA)
Public Health (AREA)
Veterinary Medicine (AREA)
Epidemiology (AREA)
Cardiology (AREA)
Bioinformatics & Cheminformatics (AREA)
Engineering & Computer Science (AREA)
Heart & Thoracic Surgery (AREA)
Organic Chemistry (AREA)
General Chemical & Material Sciences (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
Chemical Kinetics & Catalysis (AREA)
Inorganic Chemistry (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Medicinal Preparation (AREA)
Saccharide Compounds (AREA)
Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

ZA200309316A 2001-06-21 2003-11-28 Pharmaceutical formulation. ZA200309316B (en)

Applications Claiming Priority (3)

Application Number	Priority Date	Filing Date	Title
SE0102069A SE0102069D0 (sv)	2001-06-21	2001-06-21	Pharmaceutical formulation
SE0104049		2001-11-30
SE0201660A SE0201660D0 (sv)	2002-05-31	2002-05-31	Pharmaceutical formulation

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Publication Number	Publication Date
ZA200309316B true ZA200309316B (en)	2005-02-28

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US (1)	US7700582B2 (et)
EP (1)	EP1401502B1 (et)
JP (1)	JP2005501024A (et)
KR (1)	KR20040011542A (et)
CN (1)	CN1518462A (et)
AR (1)	AR034517A1 (et)
AT (1)	ATE314093T1 (et)
AU (1)	AU2002345463B2 (et)
BG (1)	BG108516A (et)
BR (1)	BR0210489A (et)
CA (1)	CA2450449A1 (et)
CO (1)	CO5550466A2 (et)
CZ (1)	CZ299859B6 (et)
DE (1)	DE60208369T2 (et)
DK (1)	DK1401502T3 (et)
EE (1)	EE200400028A (et)
ES (1)	ES2254699T3 (et)
HU (1)	HUP0400850A3 (et)
IL (2)	IL159217A0 (et)
IS (1)	IS2347B (et)
MX (1)	MXPA03011546A (et)
MY (1)	MY130332A (et)
NO (1)	NO20035627D0 (et)
NZ (1)	NZ530086A (et)
PL (1)	PL366432A1 (et)
RU (1)	RU2323006C2 (et)
SI (1)	SI1401502T1 (et)
SK (1)	SK286238B6 (et)
UA (1)	UA77959C2 (et)
WO (1)	WO2003000293A1 (et)
ZA (1)	ZA200309316B (et)

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Publication number	Priority date	Publication date	Assignee	Title
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2002
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- 2002-06-19 SK SK1591-2003A patent/SK286238B6/sk not_active IP Right Cessation
- 2002-06-19 UA UA20031211097A patent/UA77959C2/uk unknown
- 2002-06-19 KR KR10-2003-7016620A patent/KR20040011542A/ko not_active Application Discontinuation
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Also Published As

Publication number	Publication date
RU2323006C2 (ru)	2008-04-27
BR0210489A (pt)	2004-06-22
JP2005501024A (ja)	2005-01-13
SK286238B6 (sk)	2008-06-06
CZ20033491A3 (en)	2004-03-17
AU2002345463B2 (en)	2007-08-30
CO5550466A2 (es)	2005-08-31
ATE314093T1 (de)	2006-01-15
IS7081A (is)	2003-12-16
SK15912003A3 (sk)	2004-05-04
ES2254699T3 (es)	2006-06-16
AR034517A1 (es)	2004-02-25
EP1401502B1 (en)	2005-12-28
US7700582B2 (en)	2010-04-20
KR20040011542A (ko)	2004-02-05
PL366432A1 (en)	2005-01-24
MY130332A (en)	2007-06-29
EE200400028A (et)	2004-04-15
IL159217A (en)	2009-02-11
DK1401502T3 (da)	2006-04-10
HUP0400850A3 (en)	2010-10-28
IS2347B (is)	2008-03-15
MXPA03011546A (es)	2004-03-19
CN1518462A (zh)	2004-08-04
NO20035627D0 (no)	2003-12-15
NZ530086A (en)	2005-09-30
RU2003136155A (ru)	2005-05-20
US20040242536A1 (en)	2004-12-02
UA77959C2 (en)	2007-02-15
WO2003000293A1 (en)	2003-01-03
HUP0400850A2 (hu)	2004-08-30
SI1401502T1 (sl)	2006-06-30
BG108516A (en)	2004-12-30
DE60208369D1 (de)	2006-02-02
DE60208369T2 (de)	2006-08-24
IL159217A0 (en)	2004-06-01
CZ299859B6 (cs)	2008-12-17
CA2450449A1 (en)	2003-01-03
EP1401502A1 (en)	2004-03-31

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