EP2150238A1 - Herstellungsverfahren für adsorbate eines rasagilinsalzes mit einem wasserlöslichen hilfsstoff - Google Patents
Herstellungsverfahren für adsorbate eines rasagilinsalzes mit einem wasserlöslichen hilfsstoffInfo
- Publication number
- EP2150238A1 EP2150238A1 EP08749245A EP08749245A EP2150238A1 EP 2150238 A1 EP2150238 A1 EP 2150238A1 EP 08749245 A EP08749245 A EP 08749245A EP 08749245 A EP08749245 A EP 08749245A EP 2150238 A1 EP2150238 A1 EP 2150238A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- pharmaceutically acceptable
- water
- soluble
- rasagiline
- organic
- Prior art date
- Legal status (The legal status 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 status listed.)
- Withdrawn
Links
- RUOKEQAAGRXIBM-GFCCVEGCSA-N rasagiline Chemical class C1=CC=C2[C@H](NCC#C)CCC2=C1 RUOKEQAAGRXIBM-GFCCVEGCSA-N 0.000 title claims abstract description 59
- 239000002156 adsorbate Substances 0.000 title claims abstract description 55
- 239000002671 adjuvant Substances 0.000 title claims abstract description 17
- 238000000034 method Methods 0.000 title claims description 20
- 238000004519 manufacturing process Methods 0.000 title claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 title description 19
- 229960000245 rasagiline Drugs 0.000 claims abstract description 55
- 150000003839 salts Chemical class 0.000 claims abstract description 49
- 239000000126 substance Substances 0.000 claims abstract description 7
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 35
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 13
- 239000008012 organic excipient Substances 0.000 claims description 13
- 239000003826 tablet Substances 0.000 claims description 9
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical class CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 8
- 238000001694 spray drying Methods 0.000 claims description 8
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 7
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 7
- 239000008187 granular material Substances 0.000 claims description 6
- 239000008188 pellet Substances 0.000 claims description 6
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 5
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 5
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 5
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 5
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 5
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 5
- 239000012736 aqueous medium Substances 0.000 claims description 4
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 4
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 3
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 3
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 3
- 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 description 3
- 150000007524 organic acids Chemical class 0.000 claims description 3
- 239000000654 additive Substances 0.000 claims description 2
- 239000002775 capsule Substances 0.000 claims description 2
- 229920003086 cellulose ether Polymers 0.000 claims description 2
- 235000015165 citric acid Nutrition 0.000 claims 1
- 239000006191 orally-disintegrating tablet Substances 0.000 claims 1
- 235000005985 organic acids Nutrition 0.000 claims 1
- 239000007939 sustained release tablet Substances 0.000 claims 1
- 235000002639 sodium chloride Nutrition 0.000 description 40
- 239000003814 drug Substances 0.000 description 20
- 229940079593 drug Drugs 0.000 description 15
- 239000000203 mixture Substances 0.000 description 12
- 239000007921 spray Substances 0.000 description 12
- 239000004480 active ingredient Substances 0.000 description 10
- 238000002441 X-ray diffraction Methods 0.000 description 7
- 238000003860 storage Methods 0.000 description 7
- 239000002245 particle Substances 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 229920002472 Starch Polymers 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
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- 239000013543 active substance Substances 0.000 description 4
- 239000000470 constituent Substances 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 238000005259 measurement Methods 0.000 description 4
- AZUYLZMQTIKGSC-UHFFFAOYSA-N 1-[6-[4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(1-methylindazol-5-yl)pyrazol-1-yl]-2-azaspiro[3.3]heptan-2-yl]prop-2-en-1-one Chemical compound ClC=1C(=C2C=NNC2=CC=1C)C=1C(=NN(C=1C)C1CC2(CN(C2)C(C=C)=O)C1)C=1C=C2C=NN(C2=CC=1)C AZUYLZMQTIKGSC-UHFFFAOYSA-N 0.000 description 3
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- 238000012545 processing Methods 0.000 description 3
- 229920003169 water-soluble polymer Polymers 0.000 description 3
- 229920001817 Agar Polymers 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N Iron oxide Chemical compound [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 2
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical group [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000008272 agar Substances 0.000 description 2
- 235000010419 agar Nutrition 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- 239000001506 calcium phosphate Substances 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 239000001913 cellulose Chemical class 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000009513 drug distribution Methods 0.000 description 2
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- 239000000975 dye Substances 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 235000010981 methylcellulose Nutrition 0.000 description 2
- 229940069328 povidone Drugs 0.000 description 2
- 230000005855 radiation Effects 0.000 description 2
- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical class [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000005507 spraying Methods 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 239000001993 wax Substances 0.000 description 2
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- 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 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 229910002012 Aerosil® Inorganic materials 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- GUBGYTABKSRVRQ-DCSYEGIMSA-N Beta-Lactose Chemical compound OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-DCSYEGIMSA-N 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Chemical class OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical class OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 206010012289 Dementia Diseases 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- JIGUQPWFLRLWPJ-UHFFFAOYSA-N Ethyl acrylate Chemical compound CCOC(=O)C=C JIGUQPWFLRLWPJ-UHFFFAOYSA-N 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 208000026139 Memory disease Diseases 0.000 description 1
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 description 1
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 229920003080 Povidone K 25 Polymers 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- BCKXLBQYZLBQEK-KVVVOXFISA-M Sodium oleate Chemical compound [Na+].CCCCCCCC\C=C/CCCCCCCC([O-])=O BCKXLBQYZLBQEK-KVVVOXFISA-M 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 229940023476 agar Drugs 0.000 description 1
- 238000005280 amorphization Methods 0.000 description 1
- 229960004543 anhydrous citric acid Drugs 0.000 description 1
- 239000000440 bentonite Substances 0.000 description 1
- 229910000278 bentonite Inorganic materials 0.000 description 1
- 229940092782 bentonite Drugs 0.000 description 1
- 235000012216 bentonite Nutrition 0.000 description 1
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 235000012241 calcium silicate Nutrition 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
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- 229920001577 copolymer Polymers 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
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- 229910052593 corundum Inorganic materials 0.000 description 1
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- 238000002425 crystallisation Methods 0.000 description 1
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- 239000007950 delayed release tablet Substances 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 238000007907 direct compression Methods 0.000 description 1
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- 239000012153 distilled water Substances 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
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- 239000008298 dragée Substances 0.000 description 1
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
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- 150000002484 inorganic compounds Chemical class 0.000 description 1
- 229910010272 inorganic material Inorganic materials 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229960001375 lactose Drugs 0.000 description 1
- JDBJJCWRXSVHOQ-UTONKHPSSA-N methanesulfonic acid;(1r)-n-prop-2-ynyl-2,3-dihydro-1h-inden-1-amine Chemical compound CS(O)(=O)=O.C1=CC=C2[C@H](NCC#C)CCC2=C1 JDBJJCWRXSVHOQ-UTONKHPSSA-N 0.000 description 1
- 229960002900 methylcellulose Drugs 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000002899 monoamine oxidase inhibitor Substances 0.000 description 1
- RUOKEQAAGRXIBM-UHFFFAOYSA-N n-prop-2-ynyl-2,3-dihydro-1h-inden-1-amine Chemical compound C1=CC=C2C(NCC#C)CCC2=C1 RUOKEQAAGRXIBM-UHFFFAOYSA-N 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 239000004745 nonwoven fabric Substances 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- PNJWIWWMYCMZRO-UHFFFAOYSA-N pent‐4‐en‐2‐one Natural products CC(=O)CC=C PNJWIWWMYCMZRO-UHFFFAOYSA-N 0.000 description 1
- 229920000058 polyacrylate Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
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- 239000010695 polyglycol Substances 0.000 description 1
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- 239000011118 polyvinyl acetate Substances 0.000 description 1
- 238000000634 powder X-ray diffraction Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 150000004040 pyrrolidinones Chemical class 0.000 description 1
- 229960001956 rasagiline mesylate Drugs 0.000 description 1
- 230000011514 reflex Effects 0.000 description 1
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- 201000000980 schizophrenia Diseases 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
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- 229940005550 sodium alginate Drugs 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000000600 sorbitol Chemical class 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 230000003068 static effect Effects 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 150000003628 tricarboxylic acids Chemical class 0.000 description 1
- 238000009827 uniform distribution Methods 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
- 229930195724 β-lactose Natural products 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
-
- 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
- A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
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Definitions
- the present invention relates to novel adsorbates of pharmaceutically acceptable salts of the known active ingredient rasagiline with water-soluble, pharmaceutically acceptable, organic excipients and processes for their preparation.
- the pharmaceutically acceptable salt of rasagiline is in an amorphous form which is stable and does not convert into a drug, even after prolonged storage after incorporation of the adsorbate in one drug, e.g. crystalline form of the pharmaceutically acceptable salt of rasagiline converts.
- Rasagiline is the name given to the chemical compound R (+) - N-propargyl-1-aminoindan, also referred to as R (+) PAI.
- Rasagiline is a long-standing MAO inhibitor used as an active ingredient in the treatment of a variety of disorders.
- US 5,532,415 discloses the manufacture of rasagiline and its salts and the use of the active ingredient for the treatment of a number of diseases, e.g. Parkinson's disease, memory disorders, dementia, depression, schizophrenia, hyperactivity, etc.
- a process for the preparation of salts of rasagiline is also disclosed in WO 02/068376.
- WO 2006/091657 proposes to use active substance particles of a certain size. It is also of increasing importance in the field of drug formulations that the physical form of an active substance (ie the polymorphic or amorphous form) does not change during the storage period of the drug formulation and the drugs contain the active ingredient in a defined and reproducible polymorphic or amorphous form.
- the pharmaceutically acceptable salts of rasagiline are usually present in crystalline form, the appearance of polymorphs is therefore very likely.
- the object of the invention is therefore to provide pharmaceutically acceptable salts of rasagiline in a form available, so that after incorporation into a drug, the active ingredient over the storage life of the drug is stable, there are no transformations in other physical forms of the drug and on a simple way, a homogeneity of drug distribution in the drug can be ensured.
- the form of the pharmaceutically acceptable salts of rasagiline should also be easy to prepare and process well.
- aqueous solutions containing a pharmaceutically acceptable salt of rasagiline and a water-soluble, organic, pharmaceutically acceptable excipient after removing the solvent adsorbates between the pharmaceutically acceptable salt of rasagiline and the pharmaceutically acceptable, form organic excipient in which the pharmaceutically acceptable salt of rasagiline is in amorphous form.
- These adsorbates are very easy to process, are very stable in pharmaceutical formulations, especially in tablets, capsules, pellets and granules, they provide drugs with a high uniformity of drug distribution, and in particular changes the amorphous form of rasagiline after incorporation into drugs and during storage of the drug does not change to other physical forms.
- the invention therefore provides an adsorbate of a pharmaceutically acceptable salt of rasagiline with at least one pharmaceutically acceptable excipient, wherein the at least one pharmaceutically acceptable excipient is a water soluble, organic excipient and the salt of rasagiline is present in the adsorbate as an amorphous substance.
- the adsorbates are obtainable by a process in which a pharmaceutically acceptable salt of rasagiline and at least one pharmaceutically acceptable, water-soluble, organic excipient are dissolved in an aqueous medium and then the aqueous medium is removed.
- the invention also provides the process for preparing the adsorbates and pharmaceutical compositions containing these adsorbates. The following statements apply both to the adsorbates according to the invention and to the processes for their preparation.
- the adsorbates of the invention preferably contain no inorganic adjuvant.
- Pharmaceutically acceptable salts of rasagiline are generally produced as a crystalline substance in their preparation. Dissolving these salts in water (or an aqueous solvent) and removing the water, for example by spray drying, again crystalline or semi-crystalline substances. Surprisingly, it has now been found that in the case where a pharmaceutically acceptable salt of rasagiline is dissolved with an organic, water-soluble, pharmaceutically acceptable excipient and then the water is removed, e.g. by spray-drying, an adsorbate is formed between the pharmaceutically acceptable salt of rasagiline and the organic, water-soluble, pharmaceutically acceptable excipient in which the pharmaceutically acceptable salt of rasagiline is in amorphous form.
- Amorphous form is understood according to the invention to mean a form of the active substance in which the diffraction reflexes of the active substance no longer occur in an X-ray diffractogram.
- the pharmaceutically acceptable salts of rasagiline are not particularly limited, for this purpose, all commonly used, pharmaceutically acceptable salts can be used.
- Preferred salts are the tatrates, the esylates, the mesylates, the edisilates, and the sulfates, most preferably the mesylate salt of rasagiline.
- the adsorbate consists of the pharmaceutically acceptable salt of rasagiline and one or more, preferably one, pharmaceutically acceptable, water-soluble, organic excipient. In this embodiment, the adsorbate contains no water-insoluble constituents and no inorganic constituents.
- the adsorbate consists of the pharmaceutically acceptable salt of rasagiline and one or more, preferably one, pharmaceutically acceptable, organic, water-soluble excipient and one or more, preferably a water-insoluble excipient.
- the water-insoluble excipient is preferably also an organic compound, the presence of inorganic compounds in the adsorbates is not preferred according to the invention.
- water-insoluble, pharmaceutically acceptable excipients are part of the adsorbate, these are preferably water-insoluble, pharmaceutically acceptable auxiliaries having a particle size of 150 ⁇ m or below, more preferably of 100 ⁇ m or below, in particular in the range of about 50 ⁇ m.
- the lower limit of the particle size of the pharmaceutically acceptable, water-insoluble excipients is about 10 microns, more preferably about 20 microns.
- it is microcrystalline cellulose, more preferably microcrystalline cellulose having an average particle size of 150 microns or less, more preferably 100 microns or less, more preferably about 50 microns.
- Very particular preference is given to the microcrystalline cellulose Avicel PH101.
- An essential constituent of the adsorbates according to the invention is at least one pharmaceutically acceptable adjuvant, which is a water-soluble organic adjuvant.
- the adsorbate of the invention contains a water-soluble, organic, pharmaceutically acceptable excipient, but it is also possible that several water-soluble, pharmaceutically acceptable, organic excipients are used, e.g. two, three or four such excipients.
- the pharmaceutically acceptable, water-soluble, organic auxiliaries are preferably water-soluble polymers, for example those which are used in the prior art as binders for medicaments, for example cellulose ethers or polyvinylpyrrolidone. Particularly preferred are Hydroxypropylmethylcellulose, hydroxypropylcellulose or polyvinylpyrrolidone. If such a water-soluble polymer is used as the water-soluble, organic, pharmaceutically acceptable excipient, the adsorbate preferably has no water-insoluble adjuvant.
- Another preferred water-soluble excipient is an organic acid, such as in particular an organic mono-, di- or tricarboxylic acid having up to ten carbon atoms, which optionally and preferably contains one to three hydroxyl groups.
- the most preferred organic, water-soluble acid is citric acid. If the organic, pharmaceutical, water-soluble excipient is not a water-soluble polymer, but, for example, an organic, water-soluble acid, such as citric acid, it is preferred that this organic, water-soluble, pharmaceutically acceptable excipient be used together with a water-insoluble, pharmaceutically acceptable excipient as defined above , Of course, instead of the organic acid, a salt of this acid may also be used.
- the ratio between the pharmaceutically acceptable salt of rasagiline and the at least one pharmaceutically acceptable, water-soluble, organic excipient in the adsorbate is preferably in the range of 5: 1 to 1:20, more preferably in the range of 2: 1 to 1:15.
- the amount of pharmaceutically acceptable, water soluble, organic adjuvant is at least as large or greater than the amount of the pharmaceutically acceptable salt of rasagiline such that the ratio between the salt and the adjuvant is most preferably in the range of 1: 1 to 1:10.
- the above information on the relationship between the pharmaceutically acceptable salt of rasagiline and the at least one pharmaceutically acceptable, water-soluble, organic adjuvant also apply to the preferred ratios between the pharmaceutical tolerable salt of rasagiline and the sum of all pharmaceutically acceptable, water-soluble, organic excipients in the adsorbate.
- the ratio between the pharmaceutically acceptable salt of rasagiline and the one or more (preferably one) pharmaceutically acceptable, water-insoluble excipients preferably in the range of 5: 1 to 1:20, more preferably in the range of 2: 1 to 1:15, and most preferably in the range of 1: 1 to 1:10.
- An adjuvant is water-soluble in the sense of this application if more than 0.1 mg of the excipient can be dissolved in 1 ml of water.
- a water-soluble excipient is so soluble that more than 1 mg, more preferably more than 10 mg, especially more than 100 mg, e.g. 1000 mg or more can be dissolved in 1 ml of water.
- An adjuvant is water-insoluble in the sense of this application if at most 0.1 mg of the active ingredient can be dissolved in 1 ml of water.
- the adsorbates of the invention can be prepared in a simple manner by dissolving a pharmaceutically acceptable salt of rasagiline and the at least one organic, water-soluble, pharmaceutically acceptable excipient and optionally further water-soluble constituents of the adsorbate in water or an aqueous solvent. If water-insoluble ingredients are to be present in the adsorbate, these water-insoluble ingredients are subsequently (or previously) dispersed in the solvent. Subsequently, the solvent is removed, preferably by spray drying.
- the spray drying can be carried out in a conventional manner, for example using a spray drier Buchi B-191 type, for example, at a temperature of 130 0 C and a spray rate of 5, 10 or 20%.
- the spraying conditions are not critical unless a temperature is used at which the rasagiline decomposes during the spraying time.
- an aqueous solvent is understood as meaning a solvent which consists of at least 50%, more preferably at least 70% water, the remainder consisting of one or more water-miscible solvents, in particular of an alcohol such as ethanol or isopropanol.
- an alcohol such as ethanol or isopropanol.
- the adsorbates according to the invention can be further processed into medicaments in the usual way. If desired, the adsorbates may be ground to an advantageous particle size and sieved to an advantageous particle distribution.
- the adsorbates according to the invention may generally be prepared for oral, parenteral, rectal or transdermal administration, preferably for oral administration.
- Suitable dosage forms are, for example, tablets (produced by granulation or direct compression), tablets disintegrating in the mouth, delayed-release tablets, pellets or granules, which are incorporated, for example, in dragees, sachets, hard or soft gelatin capsules, etc.
- the processing into tablets, pellets or granules then takes place as described in the prior art and is known in the art, for example, the standard textbook "The Tablet", Wolfgang A. Ritschel and Anette Bauer-Brandl, 2nd edition, Editio Cantor Publisher, 2002, can be referenced.
- the tablets, pellets or granules according to the invention may contain, for example, suitable carriers (or fillers) binders, lubricants, disintegrants, dyes, flavoring agents, nonwovens, film coatings and optionally fluxing agents and other customary auxiliaries and additives.
- Suitable carriers include, for example, sugar-based and microcrystalline-based pellets, lactose, alpha-lactose monohydrate, gelatin, agar, starch, corn starch, sucrose, glucose, methyl cellulose, dicalcium phosphate, calcium phosphate, calcium silicates, mannitol, sorbitol, microcrystalline cellulose, cellulose derivatives, fatty acid, Fats, stearates, oils, waxes, paraffins, etc.
- Suitable binders include starch, gelatin, natural sugars such as glucose or ⁇ -lactose, starch, gum arabic, tragacanth, sodium alginate, povidone, carboxymethyl cellulose, polyethylene glycol, wax, hydroxypropylmethyl cellulose, hydroxypropyl cellulose etc. one.
- Lubricants are, for example, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, stearic acid, sodium stearyl fumarate, talc, etc.
- Disintegrants include the known "super disintegrants", but also starch, methyl cellulose, agar, bentonite, xanthan gum, pyrrolidones, etc.
- films as well as functional enteric and retarding film coatings are suitable celluloses and their derivatives, polyglycols, povidone, acrylic polymers, copolymers based on the ethyl acrylate, methyl methacrylate, polyvinyl acetate and methacrylic acid.
- the drugs may contain, for example, suitable iron oxide-based dyes.
- the amorphization was checked by X-ray diffractometry.
- the measurements are carried out on a Bruker Advance D8, with Theta-2 Theta Goniometer (435 mm diameter) in reflection geometry (Bragg-Brentano).
- a position sensitive detector PSD
- a Vantec-1 detector (12 ° 2 ⁇ detector aperture angle
- X-ray diffraction is recorded in the range 3 ° 2 ⁇ to 55 ° 2 ⁇ , with a step size of 0.016 ° 2 ⁇ (steps 2465) steptime: 75 ns.
- a secondary nickel filter 0.1 mm
- Primary and secondary Soller gap 2.5 °
- the samples are delivered with a horizontal sample changer (9 samples). To check the correct operation of the measuring arrangement, a standard corundum sample is measured before each measurement series.
- Adsorbates of rasagiline with various excipients were prepared according to the following table:
- Kollidon 25 is a water-soluble polyvinylpyrrolidone.
- Hypromellose (HPMC) was used as the cellulose derivative.
- the citric acid used carries as commercial product name citric acid, anhydrous, granules.
- Example 1a ( Figure 2) was adhered to a support due to a small amount of amorphous substance and examined. The resulting peaks are due to the carrier. An examination of crystalline Rasagilinmesylat applied to the same carrier confirms this ( Figure 8).
- Example 2
- Example 2 describes a selected production method of a solid dosage form with a rasagiline mesylate adsorbate of Example 1d.
- Example 2 was repeated, except that instead of the adsorbate of Example 1d, the adsorbate of Example 1a was used.
- the 3.27 mg rasagiline adsorbate is equivalent to 1 mg rasagiline base.
- Rasagiline tablets according to Example 3 were stored for up to 12 weeks at 40 ° C. and 75% relative humidity (RH) in open or closed glass bottles. At certain times, samples were taken and the appearance, hardness, disintegration time, and water content (Kart Fischer titration) of the tablets were determined. In addition, by means of HPLC determines the content of active ingredient and its optical purity and the content of related substances. Furthermore, X-ray diffractometry (XRPD) was used to investigate whether the amorphous drug has rearranged into other physical forms. The active ingredient proved to be sufficiently stable, especially with regard to its physical form. FIG.
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Abstract
Description
Claims
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
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EP08749245A EP2150238A1 (de) | 2007-04-30 | 2008-04-30 | Herstellungsverfahren für adsorbate eines rasagilinsalzes mit einem wasserlöslichen hilfsstoff |
Applications Claiming Priority (3)
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EP07008755A EP1987816A1 (de) | 2007-04-30 | 2007-04-30 | Adsorbate eines Rasagilinsalzes mit einem wasserlöslichen Hilfsstoff |
EP08749245A EP2150238A1 (de) | 2007-04-30 | 2008-04-30 | Herstellungsverfahren für adsorbate eines rasagilinsalzes mit einem wasserlöslichen hilfsstoff |
PCT/EP2008/003498 WO2008131961A1 (de) | 2007-04-30 | 2008-04-30 | Herstellungsverfahren für adsorbate eines rasagilinsalzes mit einem wasserlöslichen hilfsstoff |
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EP07008755A Withdrawn EP1987816A1 (de) | 2007-04-30 | 2007-04-30 | Adsorbate eines Rasagilinsalzes mit einem wasserlöslichen Hilfsstoff |
EP08749245A Withdrawn EP2150238A1 (de) | 2007-04-30 | 2008-04-30 | Herstellungsverfahren für adsorbate eines rasagilinsalzes mit einem wasserlöslichen hilfsstoff |
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US (2) | US20100137447A1 (de) |
EP (2) | EP1987816A1 (de) |
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WO (1) | WO2008131961A1 (de) |
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US20060018957A1 (en) * | 2004-07-26 | 2006-01-26 | Lerner E I | Pharmaceutical dosage forms including rasagiline |
ZA200704917B (en) * | 2004-11-24 | 2008-11-26 | Teva Pharma | Rasagiline orally disintegrating compositions |
CA2901244A1 (en) | 2005-02-23 | 2006-08-31 | Teva Pharmaceutical Industries, Ltd. | Rasagiline formulations of improved content uniformity |
US7572834B1 (en) | 2005-12-06 | 2009-08-11 | Teva Pharmaceutical Industries, Ltd. | Rasagiline formulations and processes for their preparation |
ES2551481T3 (es) * | 2006-02-21 | 2015-11-19 | Teva Pharmaceutical Industries, Ltd. | Uso de rasagilina para el tratamiento de atrofia multisistémica |
NZ571591A (en) * | 2006-04-03 | 2011-09-30 | Teva Pharma | Use of rasagiline for the treatment of restless legs syndrome |
EP1892233A1 (de) | 2006-08-18 | 2008-02-27 | Ratiopharm GmbH | Neue Salze des Wirkstoffs Rasagilin |
BRPI0718339A2 (pt) | 2006-12-14 | 2014-02-18 | Teva Pharma | Composto, composição, composição farmacêutica e processo de fabricação de tanato de rasagilina |
AU2007334428B2 (en) * | 2006-12-14 | 2014-05-29 | Teva Pharmaceutical Industries, Ltd. | Crystalline solid rasagiline base |
US20090062400A1 (en) * | 2007-09-05 | 2009-03-05 | Laurence Oron | Method of treating glaucoma using rasagiline |
US8188149B2 (en) * | 2007-09-17 | 2012-05-29 | Teva Pharmaceutical Industries, Ltd. | Use of R(+)-N-propargy1-1-aminoindan to treat or prevent hearing loss |
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2007
- 2007-04-30 EP EP07008755A patent/EP1987816A1/de not_active Withdrawn
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2008
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- 2008-04-30 EP EP08749245A patent/EP2150238A1/de not_active Withdrawn
- 2008-04-30 CA CA2684977A patent/CA2684977C/en not_active Expired - Fee Related
- 2008-04-30 US US12/598,301 patent/US20100137447A1/en not_active Abandoned
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2013
- 2013-09-03 US US14/016,960 patent/US20140072526A1/en not_active Abandoned
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CA2684977C (en) | 2015-02-24 |
EP1987816A1 (de) | 2008-11-05 |
WO2008131961A1 (de) | 2008-11-06 |
US20100137447A1 (en) | 2010-06-03 |
CA2684977A1 (en) | 2008-11-06 |
US20140072526A1 (en) | 2014-03-13 |
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