EP2367533A1 - Solid composition containing the ingredient rasagiline - Google Patents
Solid composition containing the ingredient rasagilineInfo
- Publication number
- EP2367533A1 EP2367533A1 EP09795429A EP09795429A EP2367533A1 EP 2367533 A1 EP2367533 A1 EP 2367533A1 EP 09795429 A EP09795429 A EP 09795429A EP 09795429 A EP09795429 A EP 09795429A EP 2367533 A1 EP2367533 A1 EP 2367533A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- active ingredient
- solid composition
- composition according
- rasagiline
- pharmaceutically acceptable
- 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- Withdrawn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
- 239000008247 solid mixture Substances 0.000 title claims abstract description 31
- RUOKEQAAGRXIBM-GFCCVEGCSA-N rasagiline Chemical compound C1=CC=C2[C@H](NCC#C)CCC2=C1 RUOKEQAAGRXIBM-GFCCVEGCSA-N 0.000 title claims abstract description 27
- 229960000245 rasagiline Drugs 0.000 title claims abstract description 26
- 239000004615 ingredient Substances 0.000 title abstract 2
- 239000004480 active ingredient Substances 0.000 claims abstract description 59
- 239000003814 drug Substances 0.000 claims abstract description 14
- 150000003839 salts Chemical class 0.000 claims abstract description 13
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 37
- 239000000203 mixture Substances 0.000 claims description 36
- 239000003826 tablet Substances 0.000 claims description 18
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 15
- 239000002245 particle Substances 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 11
- 239000008188 pellet Substances 0.000 claims description 10
- 239000012458 free base Substances 0.000 claims description 9
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 9
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 claims description 8
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 8
- 238000002156 mixing Methods 0.000 claims description 8
- 229920001223 polyethylene glycol Polymers 0.000 claims description 8
- 239000000600 sorbitol Substances 0.000 claims description 8
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 5
- 239000002202 Polyethylene glycol Substances 0.000 claims description 5
- 238000001704 evaporation Methods 0.000 claims description 5
- 229960003511 macrogol Drugs 0.000 claims description 5
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 5
- ARIWANIATODDMH-UHFFFAOYSA-N Lauric acid monoglyceride Natural products CCCCCCCCCCCC(=O)OCC(O)CO ARIWANIATODDMH-UHFFFAOYSA-N 0.000 claims description 4
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 3
- 229920001577 copolymer Polymers 0.000 claims description 3
- 229920000642 polymer Polymers 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- 150000005846 sugar alcohols Chemical class 0.000 claims description 3
- OUUCZGCOAXRCHN-UHFFFAOYSA-N 1-hexadecoxyoctadecane Chemical compound CCCCCCCCCCCCCCCCCCOCCCCCCCCCCCCCCCC OUUCZGCOAXRCHN-UHFFFAOYSA-N 0.000 claims description 2
- RFVNOJDQRGSOEL-UHFFFAOYSA-N 2-hydroxyethyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCO RFVNOJDQRGSOEL-UHFFFAOYSA-N 0.000 claims description 2
- 229920003134 Eudragit® polymer Polymers 0.000 claims description 2
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 claims description 2
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 2
- 229930006000 Sucrose Natural products 0.000 claims description 2
- 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 claims description 2
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 claims description 2
- 239000002775 capsule Substances 0.000 claims description 2
- 150000001720 carbohydrates Chemical class 0.000 claims description 2
- 229920002678 cellulose Polymers 0.000 claims description 2
- 239000001913 cellulose Substances 0.000 claims description 2
- 229920001531 copovidone Polymers 0.000 claims description 2
- 238000001125 extrusion Methods 0.000 claims description 2
- 150000004676 glycans Chemical class 0.000 claims description 2
- 239000008187 granular material Substances 0.000 claims description 2
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 claims description 2
- 150000002734 metacrylic acid derivatives Chemical class 0.000 claims description 2
- 229920001542 oligosaccharide Polymers 0.000 claims description 2
- 150000002482 oligosaccharides Chemical class 0.000 claims description 2
- 239000006191 orally-disintegrating tablet Substances 0.000 claims description 2
- -1 polyoxyethylene Polymers 0.000 claims description 2
- 229920001282 polysaccharide Polymers 0.000 claims description 2
- 239000005017 polysaccharide Substances 0.000 claims description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 2
- 239000005720 sucrose Substances 0.000 claims description 2
- 239000007939 sustained release tablet Substances 0.000 claims description 2
- 239000000811 xylitol Substances 0.000 claims description 2
- 235000010447 xylitol Nutrition 0.000 claims description 2
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 claims description 2
- 229960002675 xylitol Drugs 0.000 claims description 2
- YQEMORVAKMFKLG-UHFFFAOYSA-N glycerine monostearate Natural products CCCCCCCCCCCCCCCCCC(=O)OC(CO)CO YQEMORVAKMFKLG-UHFFFAOYSA-N 0.000 claims 1
- SVUQHVRAGMNPLW-UHFFFAOYSA-N glycerol monostearate Natural products CCCCCCCCCCCCCCCCC(=O)OCC(O)CO SVUQHVRAGMNPLW-UHFFFAOYSA-N 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 239000000243 solution Substances 0.000 description 25
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 21
- 238000003860 storage Methods 0.000 description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- 239000013543 active substance Substances 0.000 description 14
- 238000004128 high performance liquid chromatography Methods 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- 239000007921 spray Substances 0.000 description 13
- 229940079593 drug Drugs 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- 239000012535 impurity Substances 0.000 description 10
- 239000002671 adjuvant Substances 0.000 description 9
- YGKHOZXCTLKSLJ-KHAGDFGNSA-N (2r,3r)-2,3-dihydroxybutanedioic acid;(1r)-n-prop-2-ynyl-2,3-dihydro-1h-inden-1-amine Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O.C1=CC=C2[C@H](NCC#C)CCC2=C1.C1=CC=C2[C@H](NCC#C)CCC2=C1 YGKHOZXCTLKSLJ-KHAGDFGNSA-N 0.000 description 7
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 7
- 229950010683 rasagiline tartrate Drugs 0.000 description 7
- 238000011179 visual inspection Methods 0.000 description 7
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 6
- 229920001030 Polyethylene Glycol 4000 Polymers 0.000 description 6
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 6
- 229910052782 aluminium Inorganic materials 0.000 description 6
- 229920001903 high density polyethylene Polymers 0.000 description 6
- 239000004700 high-density polyethylene Substances 0.000 description 6
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 6
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 6
- 229940095064 tartrate Drugs 0.000 description 6
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 5
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 239000006104 solid solution Substances 0.000 description 5
- 238000004090 dissolution Methods 0.000 description 4
- HQPMKSGTIOYHJT-UHFFFAOYSA-N ethane-1,2-diol;propane-1,2-diol Chemical compound OCCO.CC(O)CO HQPMKSGTIOYHJT-UHFFFAOYSA-N 0.000 description 4
- 239000011521 glass Substances 0.000 description 4
- 238000000386 microscopy Methods 0.000 description 4
- 229920001993 poloxamer 188 Polymers 0.000 description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 4
- 238000009827 uniform distribution Methods 0.000 description 4
- 230000000007 visual effect Effects 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 229920002261 Corn starch Polymers 0.000 description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 229920002538 Polyethylene Glycol 20000 Polymers 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 3
- 239000008120 corn starch Substances 0.000 description 3
- 229940099112 cornstarch Drugs 0.000 description 3
- 238000009826 distribution Methods 0.000 description 3
- 239000008240 homogeneous mixture Substances 0.000 description 3
- 229910002012 Aerosil® Inorganic materials 0.000 description 2
- 206010012289 Dementia Diseases 0.000 description 2
- 101000658138 Homo sapiens Thymosin beta-10 Proteins 0.000 description 2
- 229920003083 Kollidon® VA64 Polymers 0.000 description 2
- 229920003094 Methocel™ K4M Polymers 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 102100034998 Thymosin beta-10 Human genes 0.000 description 2
- 239000002156 adsorbate Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000007907 direct compression Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- FETSQPAGYOVAQU-UHFFFAOYSA-N glyceryl palmitostearate Chemical compound OCC(O)CO.CCCCCCCCCCCCCCCC(O)=O.CCCCCCCCCCCCCCCCCC(O)=O FETSQPAGYOVAQU-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- 238000013507 mapping Methods 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 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
- 239000008389 polyethoxylated castor oil Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000003825 pressing Methods 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- STFSJTPVIIDAQX-LTRPLHCISA-M sodium;(e)-4-octadecoxy-4-oxobut-2-enoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCCOC(=O)\C=C\C([O-])=O STFSJTPVIIDAQX-LTRPLHCISA-M 0.000 description 2
- 238000001694 spray drying Methods 0.000 description 2
- 238000005507 spraying Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- LQIAZOCLNBBZQK-UHFFFAOYSA-N 1-(1,2-Diphosphanylethyl)pyrrolidin-2-one Chemical compound PCC(P)N1CCCC1=O LQIAZOCLNBBZQK-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 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 1
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 229920003085 Kollidon® CL Polymers 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 208000026139 Memory disease Diseases 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- GOOHAUXETOMSMM-UHFFFAOYSA-N Propylene oxide Chemical compound CC1CO1 GOOHAUXETOMSMM-UHFFFAOYSA-N 0.000 description 1
- 238000001069 Raman spectroscopy Methods 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- XTXRWKRVRITETP-UHFFFAOYSA-N Vinyl acetate Chemical compound CC(=O)OC=C XTXRWKRVRITETP-UHFFFAOYSA-N 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 238000005054 agglomeration Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 229920001400 block copolymer Polymers 0.000 description 1
- 239000004067 bulking agent Substances 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 229920003086 cellulose ether Polymers 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 238000000794 confocal Raman spectroscopy Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000007786 electrostatic charging Methods 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 235000011167 hydrochloric acid Nutrition 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound 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 description 1
- 208000013403 hyperactivity Diseases 0.000 description 1
- 229940127021 low-dose drug Drugs 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 238000003801 milling Methods 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000001788 mono and diglycerides of fatty acids 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
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 238000000053 physical method Methods 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 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
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
- A61K9/1676—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface having a drug-free core with discrete complete coating layer containing drug
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1682—Processes
- A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
Definitions
- the present invention relates to a solid composition containing at least one pharmaceutically acceptable excipient and, as an active ingredient, rasagiline or a pharmaceutically acceptable salt thereof.
- the invention further relates to a process for the preparation of this solid composition and to a pharmaceutical composition containing this solid composition.
- Rasagiline the R (+) - enantiomer of N-propargyl-1-aminoindan
- US Pat. No. 5,532,415 discloses the manufacture of rasagiline and various salts of this compound as well as the use of the drug for the treatment of a variety of diseases such as Parkinson's, memory disorders, dementia, depression, schizophrenia, hyperactivity, etc.
- Another method for the production of Salts of rasagiline is disclosed in WO 2002/068376.
- rasagiline is disclosed in EP-A-0 436 492 which discloses rasagiline and generally pharmaceutically acceptable acid addition salts thereof, specifically the hydrochloride and tartrate of rasagiline.
- Further salts of rasagiline are described in WO 95/11016, namely the sulfate, phosphate, mesylate, maleate, esylate, acetate, fumarate, hydrobromide, tosylate and benzoate.
- Further acid addition salts of rasagiline are described in WO 2008/019871.
- Active ingredients are often mixed in pharmaceutical formulations in finely ground form as a powder with various adjuvants and optionally compressed after granulation to tablets.
- the physical form of the active substance ie the polymorphic or amorphous form
- the active ingredient mix well with the auxiliaries used and can be further processed.
- a uniform distribution within the amounts of excipients used is necessary to ensure that, for example, tablets produced from the mixture each contain the same amount of active substance.
- WO 2008/131961 which provides adsorbates which contain, in addition to a pharmaceutically acceptable, water-soluble, organic active ingredient, a pharmaceutically acceptable salt of rasagiline in amorphous form, deals with the problem of the stability of the physical form of the active substance rasagiline.
- the adsorbates are prepared by spray-drying a solution of active ingredient and excipient. As a result, the active ingredient is adsorbed on the excipient particles, so that separate active and auxiliary phases are present.
- WO 2006/091657 deals with the second problem of the homogeneous distribution of active ingredient particles in excipient mixtures.
- a particularly uniform distribution of the active ingredient particles in an adjuvant mixture is achieved by milling the pharmaceutically acceptable salt of rasagiline such that more than 90% of the volume of the active ingredient particles has a size of less than 250 ⁇ m.
- micronized drug particles have the disadvantage that it may come during grinding and further processing to electrostatic charging and agglomeration.
- micronized active ingredients have a reduced flowability, so that this can lead to problems during further processing.
- the form should optionally be able to process with other excipients easily to drugs and thereby ensure a uniform distribution of the drug and thus the uniformity of the active substance content in the drug.
- the active ingredient form in the finished drug during the storage time in particular be physically stable.
- the present invention thus relates to a solid composition containing at least one pharmaceutically acceptable excipient and, as an active ingredient, rasagiline or a pharmaceutically acceptable salt thereof, characterized in that the excipient and the active ingredient are present in a homogeneous, molecularly disperse mixture.
- a homogeneous mixture is understood as meaning a solid solution of the active ingredient in the excipient.
- the solid composition thus has only one phase, wherein the dissolved active ingredient is uniformly distributed in the excipient.
- the homogeneous mixture thus contains at least substantially no phases of pure excipient or pure active ingredient.
- the excipient and active ingredient are rather mixed together at the molecular level, so that neither visually nor with other physical methods phase boundaries between auxiliary and active substance can be observed. Accordingly, the active ingredient in the solid composition according to the invention is also present in neither crystalline nor amorphous form. The active ingredient is rather distributed at the molecular level between the molecules of the excipient.
- the active substance can therefore no longer be detected by, for example, X-ray powder diffractograms but by spectroscopic methods such as, for example, confocal Raman spectroscopy.
- pellets are produced from the samples, on the smooth surface of which a confocal mapping can be carried out.
- the mappings are carried out in an area of 10 ⁇ m x 10 ⁇ m.
- a NT-MDT NTEG RA-Spektra Nanofinder
- Raman spectrometer with a maximum lateral resolution of ⁇ x, ⁇ y ⁇ 400 nm, height resolution ⁇ z ⁇ 700 nm, laser excitation 488 nm (Ar laser), 632.8 nm (HeNe laser).
- the detector used is a PMT (photomultiplier tube).
- the present invention also encompasses those solid compositions which still contain small amounts of undissolved drug particles. Such small amounts of undissolved particles do not disturb the advantageous properties of the composition according to the invention. In the solid composition, however, should less than 15 wt .-%, preferably less than 10 wt .-%, more preferably less than 5 wt .-% and particularly preferably less than 1 wt .-% of the total amount of the active ingredient in the form of particles.
- composition according to the invention particularly preferably contains no active substance particles, in particular no active substance particles, which can be observed visually, for example under a light microscope, due to the phase boundaries between the active substance and the adjuvant occurring.
- the solid composition according to the invention should therefore show a completely homogeneous image on visual inspection, in which no phase boundaries can be recognized.
- the active ingredient is evenly distributed in the adjuvant and thus "prediluted".
- the composition thus obtained can be processed either directly or, for example, with other excipients easily to drugs.
- the composition of the invention allows a uniform mixing with other excipients, without a complex micronization would be necessary.
- prediluting the active ingredient a homogeneous distribution in pharmaceutical formulations prepared therefrom and hence uniformity of the active ingredient content of these formulations are ensured. This facilitates, for example, the production of 200 mg tablets containing only 1 mg of rasagiline.
- Another advantage of the composition of the invention is that the molecular disperse distribution of the active ingredient in the excipient accelerates the dissolution of the active ingredient. This may be important, for example, if a rasagiline salt which is sparingly soluble in water or at least less soluble, for example rasagiline tartrate, is used.
- the amount of the active ingredient in the solid composition of the present invention is not particularly limited. Rather, it depends on the one hand on the desired dilution effect and on the other hand on the solubility of the active ingredient in the selected excipient.
- the composition according to the invention may contain from 0.5% to 25% by weight of active ingredient, calculated as the free base, based on the total weight of auxiliary and active substance.
- the composition of the invention contains 5 wt .-% to 15 wt .-% active ingredient, calculated as the free base based on the total weight of auxiliary and active ingredient.
- any pharmaceutically acceptable excipient capable of producing a homogeneous, molecularly disperse mixture with rasagiline or the like can be selected selected pharmaceutically acceptable salt thereof.
- the excipient must thus be able to dissolve the active ingredient in the desired concentration.
- auxiliaries are, for example, polymers, copolymers, saccharides, oligosaccharides, polysaccharides and sugar alcohols.
- auxiliaries have proven to be particularly suitable: sucrose, sorbitol, xylitol, Eudragit, polyethylene glycol (PEG, for example PEG 4000 or PEG 20000), polyoxyethylene glycol monostearate, glycerol polyethylene glycol ricinolate, macrogol glycerol stearate (eg Gelucire),
- Glycerol palmitole stearate eg Precirol
- Macrogolglycerollaurat eg Gelucire 50
- Polyethylenglykolcetylstearylether eg Cremophor A25
- Glycerolmonostearat eg Imwitor
- polyvinylpyrrolidone PVP, for example PVP 30 or Kollidon VA64
- methacrylates cellulose derivatives, such as cellulose ethers (for example Methocel K4M CR Premium ), Methyl cellulose (MC), hydroxypropyl cellulose (HPC, for example HPC HF) and hydroxypropylmethyl cellulose (HPMC, for example HPMC 615), and copolymers such as copovidone (from vinyl acetate and vinyl pyrrolidone) or Pluronic, eg Pluronic F68, a block copolymer of ethylene oxide and propylene oxide.
- Pluronic eg Pluronic F68
- composition of the invention may contain an adjuvant or a mixture of two or more adjuvants.
- the solid compositions of the invention can be prepared by mixing the excipient and the active ingredient to give a homogeneous, molecularly dispersed mixture.
- a corresponding mixing in a common melt of auxiliary and active ingredient preferably by melt extrusion, take place.
- the mixing takes place by dissolving auxiliaries and active substance in a solvent and then evaporating off the solvent.
- care must be taken that the auxiliary and the active ingredient do not precipitate side by side but form the desired homogeneous, molecularly disperse mixture.
- the evaporation step may be slow over a longer period of time, for example at least 24 hours, preferably in a period of for example 24 hours to 150 hours, in particular in a period of 72 hours to 120 Hours.
- a solvent any solvent can be used which is able to solve both the active ingredient and the excipient.
- water or a mixture of water and ethanol for example, about 20 vol.% To 30 vol.% Aqueous ethanol solution is suitable.
- the solution may be acidified with, for example, an inorganic or organic acid such as hydrochloric acid, acetic acid, formic acid, benzoic acid, citric acid, malic acid, tartaric acid, oxalic acid, fumaric acid, succinic acid, maleic acid and salicylic acid.
- hydrochloric acid and citric acid, especially citric acid are preferred acids.
- the solution onto, for example, inert excipient particles, so-called nonpareils.
- the spraying can take place, for example, in a fluidized-bed granulator.
- the auxiliary and active substance are separated from the solution together as a homogeneous, molecularly disperse mixture.
- the solid composition according to the invention can be further processed into a pharmaceutical, in particular a solid dosage form, by conventional methods known to those skilled in the art.
- a pharmaceutical in particular a solid dosage form
- This is preferably a capsule, tablet, orally disintegrating tablet, sustained-release tablet, pellets or granules. Preference is given to tablets which are prepared by direct compression with the auxiliaries customarily used for this purpose.
- the pharmaceutical composition containing the solid composition according to the invention is in particular in the form of a tablet containing from 0.2% to 20% by weight of active ingredient, from 40% to 95% by weight of one or more bulking agents Wt .-% to 30 wt .-% of one or more disintegrants and 0 wt .-% to 5 wt .-% of one or more lubricants, each based on the total weight of the drug without any existing coatings.
- Corresponding drugs have an excellent uniformity of the content, as can not be achieved in particular in tablets with direct compression, in particular at low active ingredient content of ⁇ 5 wt .-%, usually.
- Rasagiline tartrate based on 10 g of the free base, was mixed with 100 g of a polymer or sugar alcohol in a Petri dish and heated in a heating oven at 150 0 C until melted (about 1 h).
- the products were analyzed visually, ie by light microscopy and with the naked eye (for homogeneity) and by means of HPLC (active ingredient content and impurities).
- Sorbitol, PEG 4000, glycerol palmitole stearate (Precirol), macrogol glycerol laurate (Gelucire 50), PEG cetyl stearyl ether (Cremophor A25) and glyceryl monostearate (Imwitor) proved to be particularly suitable solvents.
- the melts prepared with these excipients also proved to be stable (visual and HPLC) after four weeks storage at 40 ° C. and 75% relative humidity.
- Rasagihntartrat based on 50 g of the free base, was mixed with 500 g of PEG in a free-radical mixer (Turbula TB10) for 15 min and extruded in a twin-screw extruder (Leistritz Micro 18), with several heatable cylinders along the screw individually at increasing temperatures of 20 0 C to 65 0 C were set. The resulting extrudate was cooled to room temperature and ground to particles having an average size of 800 to 1000 ⁇ m.
- Rasagiline tartrate based on 100 g of the free base, was mixed with 500 g Gelucire in a tumbler (Turbula TB10) for 15 min and extruded in a twin screw extruder (Leistritz Micro 18), with several heatable cylinders along the screw individually at increasing temperatures of 25 ° C to 100 0 C were set.
- Excipient and rasagiline were mixed in a weight ratio of 10: 1 in a petri dish or beaker. Purified water was added to the solid mixture and the whole was added to a solution (about 2 h) until complete dissolution Stirred magnetic stirrer. Subsequently, the solution was dried in a vacuum oven at 30 0 C and 0.1 bar for 72 h. The products were analyzed visually, ie by light microscopy and with the naked eye (for homogeneity) and by means of HPLC (active ingredient content and impurities). Sorbitol proved to be a particularly suitable excipient. The solid solutions prepared with sorbitol were found to be stable (visual and HPLC) after four weeks storage at 40 ° C and 75% humidity.
- Excipient and rasagiline were mixed in a weight ratio of 10: 1 and 2: 1, respectively, in a petri dish or beaker.
- a 30% (by volume) aqueous ethanol solution was added to the solid mixture and the whole was stirred on a magnetic stirrer until complete (about 2 hours).
- the solution was dried in a vacuum oven at 40 0 C and 0.1 bar for 120 h.
- the products were analyzed visually, ie by light microscopy and with the naked eye (for homogeneity) and by means of HPLC (active ingredient content and impurities).
- auxiliaries proved to be PVP 30, HPMC 615 and Kollidon VA 64 in the weight ratio 2: 1, PEG 20000, HPC HF and Pluronic F68 in a weight ratio of 10: 1 and Methocel K4M CR Premium and PEG 4000 in both weight ratios.
- the solid solutions prepared with these adjuvants in the respective weight ratios also proved to be stable (visual and HPLC) after storage at 40 ° C. and 75% relative humidity for four weeks.
- Excipient and rasagiline were mixed in a weight ratio of 10: 1 and 2: 1, respectively, in a petri dish or beaker.
- a 30% (by volume) aqueous ethanolic solution was added to the solid mixture, acidified with 0.1 mol / l HCl (0.5 ml to 100 ml of solvent) and taken to complete solution ( ⁇ 2 h) on a magnetic stirrer touched. Subsequently, the solution was dried in a vacuum oven at 40 0 C and 0.1 bar for 120 h.
- the products were analyzed visually, ie by light microscopy and with the naked eye (for homogeneity) and by means of HPLC (active ingredient content and impurities).
- auxiliaries were found to be independent of the weight ratio of sorbitol, PVP 30, HPMC 615, PEG 4000, PEG 20000, HPC HF and Pluronic F68.
- the with these excipients solid solutions also proved to be stable (visual and HPLC) after four weeks of storage at 40 ° C. and 75% relative humidity.
- Rasagiiine tartrate based on 10 g of the free base, together with 20 g of sorbitol, 200 ml of a 30% (volume percent) aqueous ethanol solution was added. After addition of 1 ml of 0.1 molar hydrochloric acid was stirred for 3 h on the magnetic stirrer.
- the clear solution thus obtained was in a fluidized bed granulator (Glatt GPCG 3.1, inlet temperature 70 ° C, outlet temperature 45 0 C, spray pressure 1, 6 bar, spray rate about 1, 5 g / min) to 300 g Nonpareilles with a diameter of 500 microns sprayed.
- Rasagiiine tartrate based on 5 g of the free base, together with 50 g HPMC was added 500 ml of a 20% (volume percent) aqueous ethanol solution. After addition of 1 ml of 0.1 molar hydrochloric acid was stirred for 3 h on the magnetic stirrer.
- the clear solution thus obtained was in a fluidized bed granulator (Glatt GPCG 3.1, inlet temperature 70 0 C, outlet temperature 45 0 C, spray pressure 1, 6 bar, spray rate about 1, 5 g / min) onto nonpareils having a diameter of 400 to 500 microns sprayed.
- Rasagiiintartrat based on 1 g of the free base, together with 2 g Pluronic F68 was added with 100 ml of water and stirred for 3 h on the magnetic stirrer.
- the resulting clear solution was in a fluidized bed granulator (Glatt GPCG 3.1, inlet temperature 70 0 C, outlet temperature 45 0 C, spray pressure 1, 6 bar, spray speed about 1, 5 g / min) on Nonpareilles with a diameter of 500 to 600 microns sprayed.
- An extrudate of 72.05 g of rasagiline tartrate and 500 g of PEG 4000 was prepared according to Example 2 with the following temperature settings on the extruder: cylinder 1/55 0 C, cylinder 2/60 0 C, cylinder 3/63 0 C, cylinder 4/60 0 C, Cylinder 5/55 0 C, outlet nozzle / 55 0 C, product temperature / 55 ° C.
- Mannitol, corn starch and pregelatinised cornstarch were weighed into a glass jar, mixed for 20 minutes with a Turbula T10B shaker at 23 rpm and then sieved through a sieve of 500 ⁇ m mesh size.
- Stearic acid, talc and Aerosil were sieved through a 250 ⁇ m sieve and mixed together with the other excipients for 5 minutes. After addition of the extrudate, the entire batch was mixed for a further 7 minutes. From this mixture were pressed with a hand press and a pressing force of about 4 kN to 8 kN tablets.
- Avicel and pregelatinized cornstarch were weighed into a glass jar, mixed for 20 minutes with a Turbula T10B shaker at 23 rpm and then sieved through a 500 ⁇ m mesh sieve. Mg stearate, citric acid and Aerosil were sieved through a 250 ⁇ m sieve and mixed together with the other excipients for 5 minutes. After addition of the extrudate, the entire Mix mixed for another 7 minutes. From this mixture were pressed with a hand press and a pressing force of about 4 kN to 8 kN tablets.
Abstract
Description
Claims
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE102008064061A DE102008064061A1 (en) | 2008-12-19 | 2008-12-19 | Solid composition with the active ingredient rasagiline |
PCT/EP2009/067508 WO2010070090A1 (en) | 2008-12-19 | 2009-12-18 | Solid composition containing the ingredient rasagiline |
Publications (1)
Publication Number | Publication Date |
---|---|
EP2367533A1 true EP2367533A1 (en) | 2011-09-28 |
Family
ID=42154634
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP09795429A Withdrawn EP2367533A1 (en) | 2008-12-19 | 2009-12-18 | Solid composition containing the ingredient rasagiline |
Country Status (8)
Country | Link |
---|---|
US (2) | US20110313050A1 (en) |
EP (1) | EP2367533A1 (en) |
JP (1) | JP2012512840A (en) |
AU (1) | AU2009329529A1 (en) |
CA (1) | CA2747311A1 (en) |
DE (1) | DE102008064061A1 (en) |
IL (1) | IL213583A0 (en) |
WO (1) | WO2010070090A1 (en) |
Families Citing this family (23)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP5701485B2 (en) * | 2006-02-21 | 2015-04-15 | テバ ファーマシューティカル インダストリーズ リミティド | Use of rasagiline for the treatment of multiple system atrophy |
JP5769923B2 (en) | 2006-04-03 | 2015-08-26 | テバ ファーマシューティカル インダストリーズ リミティド | Use of rasagiline for the treatment of restless legs syndrome |
DK2101569T3 (en) * | 2006-12-14 | 2012-01-30 | Teva Pharma | Crystalline solid rasagiline base |
EP1987816A1 (en) * | 2007-04-30 | 2008-11-05 | Ratiopharm GmbH | Adsorbate of a rasagiline salt with a water-soluble inactive ingredient |
AU2008296908B2 (en) * | 2007-09-05 | 2014-01-09 | Teva Pharmaceutical Industries, Ltd. | 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 |
MX2010007601A (en) * | 2008-01-11 | 2010-08-03 | Teva Pharma | Rasagiline formulations, their preparation and use. |
JP2011524353A (en) * | 2008-06-10 | 2011-09-01 | テバ ファーマシューティカル インダストリーズ リミティド | Rasagiline soft gelatin capsule |
CN103893160A (en) * | 2008-06-13 | 2014-07-02 | 泰华制药工业有限公司 | Rasagiline for parkinson's disease modification |
AU2009260728B2 (en) | 2008-06-19 | 2015-01-29 | Teva Pharmaceutical Industries, Ltd. | Process for preparing and drying solid rasagiline base |
US20100189791A1 (en) | 2009-01-23 | 2010-07-29 | Teva Pharmaceutical Industries, Ltd. | Delayed release rasagiline malate formulation |
JP2012532843A (en) | 2009-07-09 | 2012-12-20 | ラティオファーム ゲーエムベーハー | Rasagiline salt and preparation thereof |
AU2010304755A1 (en) * | 2009-10-09 | 2012-05-24 | Teva Pharmaceutical Industries, Ltd. | Use of rasagiline for the treatment of Progressive Supranuclear Palsy |
EP2939669A1 (en) * | 2009-12-22 | 2015-11-04 | Teva Pharmaceutical Industries, Ltd. | 3-keto-n-propargyl-1-aminoindan |
EP2389927A1 (en) * | 2010-05-30 | 2011-11-30 | Abdi Ibrahim Ilac Sanayi ve Ticaret Anonim Sirketi | Pharmaceutical formulations of rasagiline |
AU2011282716A1 (en) | 2010-07-27 | 2013-03-14 | Teva Pharmaceutical Industries Ltd. | Dispersions of rasagiline citrate |
AU2011282720B2 (en) | 2010-07-27 | 2016-12-22 | Teva Pharmaceutical Industries Ltd. | Use of rasagiline for the treatment of olfactory dysfunction |
CA2851276A1 (en) | 2011-10-10 | 2013-04-18 | Teva Pharmaceutical Industries Ltd. | R(+)-n-formyl-propargyl-aminoindan |
BR112014008552A2 (en) | 2011-10-10 | 2017-04-18 | Teva Pharma | r (+) - n-methylpropargylaminoindane |
DE102012000786A1 (en) * | 2012-01-18 | 2013-07-18 | Stada Arzneimittel Ag | Process for the preparation of a solid pharmaceutical composition containing the active substance rasagiline |
WO2013139387A1 (en) * | 2012-03-21 | 2013-09-26 | Synthon Bv | Stabilized pharmaceutical compositions comprising rasagiline salts |
CA2882072A1 (en) | 2012-08-17 | 2014-02-20 | Teva Pharmaceutical Industries Ltd. | Parenteral formulations of rasagiline |
EP3079672B1 (en) * | 2013-12-11 | 2020-05-13 | KRKA, d.d., Novo mesto | Pharmaceutical composition comprising a pharmaceutically acceptable salt of rasagiline |
Family Cites Families (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IL92952A (en) | 1990-01-03 | 1994-06-24 | Teva Pharma | R-enantiomers of n-propargyl-1-aminoindan compounds, their preparation and pharmaceutical compositions containing them |
IL111240A (en) | 1993-10-18 | 2001-10-31 | Teva Pharma | Salts of r(+) - enantiomers of n- propargyl-1-aminoindan and pharmaceutical compositions comprising them |
IL141690A (en) | 2001-02-27 | 2004-06-20 | Isp Finetech Ltd | Process for preparation of rasagiline and its salts |
WO2006014973A2 (en) * | 2004-07-26 | 2006-02-09 | Teva Pharmaceutical Industries, Ltd. | Pharmaceutical dosage forms including rasagiline |
CA2588293C (en) * | 2004-11-24 | 2013-07-02 | Teva Pharmaceutical Industries Ltd. | Rasagiline orally disintegrating compositions |
MX2007010233A (en) | 2005-02-23 | 2007-11-07 | Teva Pharma | Rasagiline formulations of improved content uniformity. |
CN101032474B (en) * | 2006-03-06 | 2011-02-16 | 重庆医药工业研究院有限责任公司 | Rasagiline transparent patch for curing and preventing neurological diseases and the preparing method thereof |
EP1892233A1 (en) | 2006-08-18 | 2008-02-27 | Ratiopharm GmbH | New salts of the active component rasagiline |
EP1987816A1 (en) | 2007-04-30 | 2008-11-05 | Ratiopharm GmbH | Adsorbate of a rasagiline salt with a water-soluble inactive ingredient |
-
2008
- 2008-12-19 DE DE102008064061A patent/DE102008064061A1/en not_active Withdrawn
-
2009
- 2009-12-18 JP JP2011541468A patent/JP2012512840A/en active Pending
- 2009-12-18 AU AU2009329529A patent/AU2009329529A1/en not_active Abandoned
- 2009-12-18 CA CA2747311A patent/CA2747311A1/en not_active Abandoned
- 2009-12-18 EP EP09795429A patent/EP2367533A1/en not_active Withdrawn
- 2009-12-18 US US13/140,402 patent/US20110313050A1/en not_active Abandoned
- 2009-12-18 WO PCT/EP2009/067508 patent/WO2010070090A1/en active Application Filing
-
2011
- 2011-06-15 IL IL213583A patent/IL213583A0/en unknown
-
2013
- 2013-08-14 US US13/967,240 patent/US20130345310A1/en not_active Abandoned
Non-Patent Citations (2)
Title |
---|
None * |
See also references of WO2010070090A1 * |
Also Published As
Publication number | Publication date |
---|---|
CA2747311A1 (en) | 2010-06-24 |
US20110313050A1 (en) | 2011-12-22 |
IL213583A0 (en) | 2011-07-31 |
WO2010070090A1 (en) | 2010-06-24 |
JP2012512840A (en) | 2012-06-07 |
DE102008064061A1 (en) | 2010-06-24 |
US20130345310A1 (en) | 2013-12-26 |
AU2009329529A1 (en) | 2011-07-14 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP2367533A1 (en) | Solid composition containing the ingredient rasagiline | |
EP2054048B1 (en) | Novel salts of the active substance rasagiline | |
DE69832108T2 (en) | Fenofibrate-containing drug composition with increased bioavailability and process for its preparation | |
DE69726729T2 (en) | FUNGICIDES WITH IMPROVED BIOVAVAILABILITY | |
DE69829286T2 (en) | NEW METHOD FOR PRODUCING PAROXETINE-CONTAINING SOLID DISPERSIONS | |
EP0387782B2 (en) | Solid pharmaceutical preparations and process for their manufacture | |
DE60204897T2 (en) | CRYSTALLINE FREE BASE FROM CLINDAMYCIN | |
WO2008131961A1 (en) | Method for the production of adsorbates of a rasagiline salt having a water soluble adjuvant | |
EP2595607A2 (en) | Medicinal drug for oral administration comprising a mixture of silodosin and a basic copolymer | |
EP2334284A2 (en) | Compacted cinacalcet | |
WO2011047837A2 (en) | Melt-granulated cinacalcet | |
WO2007073888A2 (en) | Pharmaceutical composition containing donepezil hydrochloride, tablets produced therefrom and method for producing the same | |
WO2003039513A1 (en) | Method for the formation of ibuprofen crystals | |
EP0490193A1 (en) | Complex of an actif enantiomer of ibuprofen with cyclodextrin | |
DE602004010837T2 (en) | PHARMACEUTICAL COMPOSITION BASED ON IDAZOXANE SALT OR ITS POLYMORPHEN | |
DE102008000351B4 (en) | Process for the preparation of an ebastine-containing granule and a solid pharmaceutical composition, ebastine-containing granules and its use | |
DE60312635T3 (en) | A composition in the form of a solid dispersion containing itraconazole and a hydrophilic polymer having improved bioavailability | |
WO2005041855A2 (en) | Pharmaceutical formulation containing an ltb4 antagonist, method for the production thereof, and use thereof | |
EP1686965A2 (en) | Solid pharmaceutical preparation form | |
WO2016087322A1 (en) | Solid oral administration pharmaceutical dosage forms with rapid active principle release | |
DE102006036579A1 (en) | Composition, useful to treat hypertension, comprises nebivolol as active agent and a polymer carrier material, where the active agent is present in micronized form in a polymer carrier matrix and is essentially free of wetting agent | |
WO2002083101A1 (en) | Controlled-release nimodipine tablet and method for producing the same | |
EP2382967A1 (en) | Aliskiren in the form of a solid dispersion | |
DE29924843U1 (en) | Pellet for treating fungal infection comprises core coated with film of water soluble polymer and antifungal agent | |
WO2009129913A1 (en) | Solid pharmaceutical preparation comprising 1-[(4-chloro-phenyl)-amide]-2-{[4-(3-oxo-morpholine-4-yl)-phenyl]-amide}-4-hydroxy-pyrrolidine-1,2-dicarboxylic acid |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
17P | Request for examination filed |
Effective date: 20110617 |
|
AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO SE SI SK SM TR |
|
AX | Request for extension of the european patent |
Extension state: AL BA RS |
|
RIN1 | Information on inventor provided before grant (corrected) |
Inventor name: PAETZ, JANA Inventor name: MUSKULUS, FRANK Inventor name: RIMKUS, KATRIN Inventor name: BRUECK, SANDRA |
|
RAP1 | Party data changed (applicant data changed or rights of an application transferred) |
Owner name: RATIOPHARM GMBH |
|
RIC1 | Information provided on ipc code assigned before grant |
Ipc: A61K 31/135 20060101ALI20170113BHEP Ipc: A61K 9/14 20060101ALI20170113BHEP Ipc: A61K 9/16 20060101AFI20170113BHEP |
|
GRAP | Despatch of communication of intention to grant a patent |
Free format text: ORIGINAL CODE: EPIDOSNIGR1 |
|
INTG | Intention to grant announced |
Effective date: 20170407 |
|
TPAC | Observations filed by third parties |
Free format text: ORIGINAL CODE: EPIDOSNTIPA |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN |
|
18D | Application deemed to be withdrawn |
Effective date: 20170701 |