EP3975998A1 - Method for preparing pharmaceutical compositions containing amphiphilic active ingredients - Google Patents
Method for preparing pharmaceutical compositions containing amphiphilic active ingredientsInfo
- Publication number
- EP3975998A1 EP3975998A1 EP20728902.6A EP20728902A EP3975998A1 EP 3975998 A1 EP3975998 A1 EP 3975998A1 EP 20728902 A EP20728902 A EP 20728902A EP 3975998 A1 EP3975998 A1 EP 3975998A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- salt
- active principle
- granule
- amphiphilic
- nsaid
- 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.)
- Pending
Links
- 238000000034 method Methods 0.000 title claims abstract description 30
- 239000004480 active ingredient Substances 0.000 title claims abstract description 18
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 20
- 239000008187 granular material Substances 0.000 claims abstract description 53
- 150000003839 salts Chemical class 0.000 claims abstract description 30
- 239000011230 binding agent Substances 0.000 claims abstract description 26
- 238000000576 coating method Methods 0.000 claims abstract description 15
- 239000003880 polar aprotic solvent Substances 0.000 claims abstract description 14
- 239000011248 coating agent Substances 0.000 claims abstract description 13
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 claims description 29
- 239000003814 drug Substances 0.000 claims description 20
- 229960001680 ibuprofen Drugs 0.000 claims description 19
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 18
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 claims description 18
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 17
- 239000000203 mixture Substances 0.000 claims description 17
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 claims description 15
- 239000002775 capsule Substances 0.000 claims description 12
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 12
- 238000005469 granulation Methods 0.000 claims description 11
- 230000003179 granulation Effects 0.000 claims description 11
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 9
- 229920001577 copolymer Polymers 0.000 claims description 9
- 239000000314 lubricant Substances 0.000 claims description 9
- 159000000000 sodium salts Chemical class 0.000 claims description 9
- 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 claims description 8
- 229930195725 Mannitol Natural products 0.000 claims description 8
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 8
- 239000000594 mannitol Substances 0.000 claims description 8
- 235000010355 mannitol Nutrition 0.000 claims description 8
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 7
- 239000002202 Polyethylene glycol Substances 0.000 claims description 6
- 125000003118 aryl group Chemical group 0.000 claims description 6
- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 claims description 6
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
- 229920001223 polyethylene glycol Polymers 0.000 claims description 6
- 229920001531 copovidone Polymers 0.000 claims description 5
- 229940079593 drug Drugs 0.000 claims description 5
- -1 polyoxypropylene copolymer Polymers 0.000 claims description 5
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 4
- 208000002193 Pain Diseases 0.000 claims description 4
- 229960001948 caffeine Drugs 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- OROGSEYTTFOCAN-DNJOTXNNSA-N codeine Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC OROGSEYTTFOCAN-DNJOTXNNSA-N 0.000 claims description 4
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 4
- KWGRBVOPPLSCSI-UHFFFAOYSA-N d-ephedrine Natural products CNC(C)C(O)C1=CC=CC=C1 KWGRBVOPPLSCSI-UHFFFAOYSA-N 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 4
- 235000019359 magnesium stearate Nutrition 0.000 claims description 4
- 229940069328 povidone Drugs 0.000 claims description 4
- 239000000377 silicon dioxide Substances 0.000 claims description 4
- MNIPYSSQXLZQLJ-UHFFFAOYSA-N Biofenac Chemical compound OC(=O)COC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl MNIPYSSQXLZQLJ-UHFFFAOYSA-N 0.000 claims description 3
- 239000004381 Choline salt Substances 0.000 claims description 3
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical class CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 claims description 3
- CMWTZPSULFXXJA-UHFFFAOYSA-N Naproxen Natural products C1=C(C(C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-UHFFFAOYSA-N 0.000 claims description 3
- JZFPYUNJRRFVQU-UHFFFAOYSA-N Niflumic acid Chemical compound OC(=O)C1=CC=CN=C1NC1=CC=CC(C(F)(F)F)=C1 JZFPYUNJRRFVQU-UHFFFAOYSA-N 0.000 claims description 3
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical class OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 claims description 3
- XTXRWKRVRITETP-UHFFFAOYSA-N Vinyl acetate Chemical compound CC(=O)OC=C XTXRWKRVRITETP-UHFFFAOYSA-N 0.000 claims description 3
- 229960004420 aceclofenac Drugs 0.000 claims description 3
- 125000000637 arginyl group Chemical class N[C@@H](CCCNC(N)=N)C(=O)* 0.000 claims description 3
- 159000000007 calcium salts Chemical class 0.000 claims description 3
- 125000002843 carboxylic acid group Chemical group 0.000 claims description 3
- 235000019417 choline salt Nutrition 0.000 claims description 3
- 229960001259 diclofenac Drugs 0.000 claims description 3
- DCOPUUMXTXDBNB-UHFFFAOYSA-N diclofenac Chemical compound OC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl DCOPUUMXTXDBNB-UHFFFAOYSA-N 0.000 claims description 3
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical class OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 claims description 3
- 150000002169 ethanolamines Chemical class 0.000 claims description 3
- 125000003916 ethylene diamine group Chemical class 0.000 claims description 3
- 229960005293 etodolac Drugs 0.000 claims description 3
- XFBVBWWRPKNWHW-UHFFFAOYSA-N etodolac Chemical compound C1COC(CC)(CC(O)=O)C2=N[C]3C(CC)=CC=CC3=C21 XFBVBWWRPKNWHW-UHFFFAOYSA-N 0.000 claims description 3
- 229960002390 flurbiprofen Drugs 0.000 claims description 3
- SYTBZMRGLBWNTM-UHFFFAOYSA-N flurbiprofen Chemical compound FC1=CC(C(C(O)=O)C)=CC=C1C1=CC=CC=C1 SYTBZMRGLBWNTM-UHFFFAOYSA-N 0.000 claims description 3
- CYWFCPPBTWOZSF-UHFFFAOYSA-N ibufenac Chemical compound CC(C)CC1=CC=C(CC(O)=O)C=C1 CYWFCPPBTWOZSF-UHFFFAOYSA-N 0.000 claims description 3
- 229950009183 ibufenac Drugs 0.000 claims description 3
- 229960000905 indomethacin Drugs 0.000 claims description 3
- 229960004752 ketorolac Drugs 0.000 claims description 3
- OZWKMVRBQXNZKK-UHFFFAOYSA-N ketorolac Chemical compound OC(=O)C1CCN2C1=CC=C2C(=O)C1=CC=CC=C1 OZWKMVRBQXNZKK-UHFFFAOYSA-N 0.000 claims description 3
- 229910003002 lithium salt Inorganic materials 0.000 claims description 3
- 159000000002 lithium salts Chemical class 0.000 claims description 3
- 159000000003 magnesium salts Chemical class 0.000 claims description 3
- 229960003464 mefenamic acid Drugs 0.000 claims description 3
- HYYBABOKPJLUIN-UHFFFAOYSA-N mefenamic acid Chemical compound CC1=CC=CC(NC=2C(=CC=CC=2)C(O)=O)=C1C HYYBABOKPJLUIN-UHFFFAOYSA-N 0.000 claims description 3
- 229960002009 naproxen Drugs 0.000 claims description 3
- CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical compound C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 claims description 3
- 229960000916 niflumic acid Drugs 0.000 claims description 3
- 229920001451 polypropylene glycol Polymers 0.000 claims description 3
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 3
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 claims description 3
- 150000003248 quinolines Chemical class 0.000 claims description 3
- 229960000894 sulindac Drugs 0.000 claims description 3
- MLKXDPUZXIRXEP-MFOYZWKCSA-N sulindac Chemical compound CC1=C(CC(O)=O)C2=CC(F)=CC=C2\C1=C/C1=CC=C(S(C)=O)C=C1 MLKXDPUZXIRXEP-MFOYZWKCSA-N 0.000 claims description 3
- 150000003751 zinc Chemical class 0.000 claims description 3
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 claims description 2
- 206010061218 Inflammation Diseases 0.000 claims description 2
- LPHGQDQBBGAPDZ-UHFFFAOYSA-N Isocaffeine Natural products CN1C(=O)N(C)C(=O)C2=C1N(C)C=N2 LPHGQDQBBGAPDZ-UHFFFAOYSA-N 0.000 claims description 2
- BRUQQQPBMZOVGD-XFKAJCMBSA-N Oxycodone Chemical compound O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(OC)C2=C5[C@@]13CCN4C BRUQQQPBMZOVGD-XFKAJCMBSA-N 0.000 claims description 2
- 206010037660 Pyrexia Diseases 0.000 claims description 2
- GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 claims description 2
- 230000000202 analgesic effect Effects 0.000 claims description 2
- 230000001387 anti-histamine Effects 0.000 claims description 2
- 239000000739 antihistaminic agent Substances 0.000 claims description 2
- VJEONQKOZGKCAK-UHFFFAOYSA-N caffeine Natural products CN1C(=O)N(C)C(=O)C2=C1C=CN2C VJEONQKOZGKCAK-UHFFFAOYSA-N 0.000 claims description 2
- 229960004126 codeine Drugs 0.000 claims description 2
- OROGSEYTTFOCAN-UHFFFAOYSA-N hydrocodone Natural products C1C(N(CCC234)C)C2C=CC(O)C3OC2=C4C1=CC=C2OC OROGSEYTTFOCAN-UHFFFAOYSA-N 0.000 claims description 2
- 230000004054 inflammatory process Effects 0.000 claims description 2
- 229940100692 oral suspension Drugs 0.000 claims description 2
- OFPXSFXSNFPTHF-UHFFFAOYSA-N oxaprozin Chemical compound O1C(CCC(=O)O)=NC(C=2C=CC=CC=2)=C1C1=CC=CC=C1 OFPXSFXSNFPTHF-UHFFFAOYSA-N 0.000 claims description 2
- 229960002739 oxaprozin Drugs 0.000 claims description 2
- 229960002085 oxycodone Drugs 0.000 claims description 2
- 229960005489 paracetamol Drugs 0.000 claims description 2
- SONNWYBIRXJNDC-VIFPVBQESA-N phenylephrine Chemical compound CNC[C@H](O)C1=CC=CC(O)=C1 SONNWYBIRXJNDC-VIFPVBQESA-N 0.000 claims description 2
- 229960001802 phenylephrine Drugs 0.000 claims description 2
- 230000002265 prevention Effects 0.000 claims description 2
- 229960003908 pseudoephedrine Drugs 0.000 claims description 2
- KWGRBVOPPLSCSI-WCBMZHEXSA-N pseudoephedrine Chemical compound CN[C@@H](C)[C@@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WCBMZHEXSA-N 0.000 claims description 2
- 238000007873 sieving Methods 0.000 claims description 2
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical class [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 claims 2
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 claims 2
- DKYWVDODHFEZIM-UHFFFAOYSA-N ketoprofen Chemical compound OC(=O)C(C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 DKYWVDODHFEZIM-UHFFFAOYSA-N 0.000 claims 2
- 229960000991 ketoprofen Drugs 0.000 claims 2
- 230000003637 steroidlike Effects 0.000 claims 1
- 239000003826 tablet Substances 0.000 description 27
- 238000004090 dissolution Methods 0.000 description 16
- 239000013078 crystal Substances 0.000 description 13
- 239000002904 solvent Substances 0.000 description 10
- 238000009472 formulation Methods 0.000 description 9
- PTTPUWGBPLLBKW-UHFFFAOYSA-M sodium;2-[4-(2-methylpropyl)phenyl]propanoate Chemical compound [Na+].CC(C)CC1=CC=C(C(C)C([O-])=O)C=C1 PTTPUWGBPLLBKW-UHFFFAOYSA-M 0.000 description 8
- 239000002253 acid Substances 0.000 description 6
- 238000007906 compression Methods 0.000 description 5
- 230000006835 compression Effects 0.000 description 5
- 238000000338 in vitro Methods 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- WZWGGYFEOBVNLA-UHFFFAOYSA-N sodium;dihydrate Chemical compound O.O.[Na] WZWGGYFEOBVNLA-UHFFFAOYSA-N 0.000 description 4
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 239000007941 film coated tablet Substances 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- VYZAMTAEIAYCRO-UHFFFAOYSA-N Chromium Chemical compound [Cr] VYZAMTAEIAYCRO-UHFFFAOYSA-N 0.000 description 2
- 229920002785 Croscarmellose sodium Polymers 0.000 description 2
- 206010019233 Headaches Diseases 0.000 description 2
- 208000019695 Migraine disease Diseases 0.000 description 2
- 239000004372 Polyvinyl alcohol Substances 0.000 description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical group 0.000 description 2
- 229910052804 chromium Inorganic materials 0.000 description 2
- 239000011651 chromium Substances 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- 239000008119 colloidal silica Substances 0.000 description 2
- 229960001681 croscarmellose sodium Drugs 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 231100000869 headache Toxicity 0.000 description 2
- 230000002209 hydrophobic effect Effects 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 206010027599 migraine Diseases 0.000 description 2
- 229920002451 polyvinyl alcohol Polymers 0.000 description 2
- 238000000634 powder X-ray diffraction Methods 0.000 description 2
- 229960003447 pseudoephedrine hydrochloride Drugs 0.000 description 2
- BALXUFOVQVENIU-KXNXZCPBSA-N pseudoephedrine hydrochloride Chemical compound [H+].[Cl-].CN[C@@H](C)[C@@H](O)C1=CC=CC=C1 BALXUFOVQVENIU-KXNXZCPBSA-N 0.000 description 2
- 238000004626 scanning electron microscopy Methods 0.000 description 2
- 230000007017 scission Effects 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical class OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 208000005171 Dysmenorrhea Diseases 0.000 description 1
- 206010013935 Dysmenorrhoea Diseases 0.000 description 1
- 229920003134 Eudragit® polymer Polymers 0.000 description 1
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 1
- 208000016247 Soft tissue disease Diseases 0.000 description 1
- 201000002661 Spondylitis Diseases 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- NRTOMJZYCJJWKI-UHFFFAOYSA-N Titanium nitride Chemical compound [Ti]#N NRTOMJZYCJJWKI-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 150000007513 acids Chemical group 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- RWZYAGGXGHYGMB-UHFFFAOYSA-N anthranilic acid Chemical class NC1=CC=CC=C1C(O)=O RWZYAGGXGHYGMB-UHFFFAOYSA-N 0.000 description 1
- 229940124599 anti-inflammatory drug Drugs 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 238000000889 atomisation Methods 0.000 description 1
- SJKRCWUQJZIWQB-UHFFFAOYSA-N azane;chromium Chemical compound N.[Cr] SJKRCWUQJZIWQB-UHFFFAOYSA-N 0.000 description 1
- CXOWYMLTGOFURZ-UHFFFAOYSA-N azanylidynechromium Chemical compound [Cr]#N CXOWYMLTGOFURZ-UHFFFAOYSA-N 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 229920001688 coating polymer Polymers 0.000 description 1
- LRCFXGAMWKDGLA-UHFFFAOYSA-N dioxosilane;hydrate Chemical compound O.O=[Si]=O LRCFXGAMWKDGLA-UHFFFAOYSA-N 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 239000007888 film coating Substances 0.000 description 1
- 238000009501 film coating Methods 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 125000001072 heteroaryl group Chemical group 0.000 description 1
- 125000000487 histidyl group Chemical class [H]N([H])C(C(=O)O*)C([H])([H])C1=C([H])N([H])C([H])=N1 0.000 description 1
- 125000001183 hydrocarbyl group Chemical group 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 229960003943 hypromellose Drugs 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- TWXDDNPPQUTEOV-FVGYRXGTSA-N methamphetamine hydrochloride Chemical compound Cl.CN[C@@H](C)CC1=CC=CC=C1 TWXDDNPPQUTEOV-FVGYRXGTSA-N 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 238000002156 mixing Methods 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
- HGASFNYMVGEKTF-UHFFFAOYSA-N octan-1-ol;hydrate Chemical compound O.CCCCCCCCO HGASFNYMVGEKTF-UHFFFAOYSA-N 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 238000005192 partition Methods 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 229960000502 poloxamer Drugs 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 150000003873 salicylate salts Chemical class 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 229960004029 silicic acid Drugs 0.000 description 1
- 238000004513 sizing Methods 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 235000011182 sodium carbonates Nutrition 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- 235000011083 sodium citrates Nutrition 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 235000011008 sodium phosphates Nutrition 0.000 description 1
- 229960003594 sodium salt ibuprofen Drugs 0.000 description 1
- VTGPMVCGAVZLQI-UHFFFAOYSA-M sodium;2-[4-(2-methylpropyl)phenyl]propanoate;dihydrate Chemical compound O.O.[Na+].CC(C)CC1=CC=C(C(C)C([O-])=O)C=C1 VTGPMVCGAVZLQI-UHFFFAOYSA-M 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000007916 tablet composition Substances 0.000 description 1
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical class [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
Classifications
-
- 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
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- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
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- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
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- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
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- A61K9/1617—Organic compounds, e.g. phospholipids, fats
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- 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
- A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
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- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
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- A61K9/2013—Organic compounds, e.g. phospholipids, fats
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- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
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- A—HUMAN NECESSITIES
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- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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- A—HUMAN NECESSITIES
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
Definitions
- the present invention relates to a process for the preparation of granules of active principles used in the preparation of pharmaceutical compositions, as well as to the granules and the pharmaceutical compositions themselves.
- amphiphilic pharmaceutical active principles are characterized by a lipophilic hydrocarbon skeleton and one or more ionizable functions, generally weak acid or base, providing the hydrophilic character which can be amplified by their salification by a pharmaceutically acceptable anion or cation.
- amphiphilic active ingredients include non-steroidal anti-inflammatory drugs (NSAIDs), including anfhranilic, aryl-acetic and aryl-propionic (or propanoic) acids substituted in position 2 or 3.
- NSAIDs non-steroidal anti-inflammatory drugs
- active ingredients are mainly used as analgesics in the treatment of mild to moderate pain associated with dysmenorrhea, headaches, migraine, postoperative and dental pain and as anti-inflammatory drugs in the treatment of spondylitis, headache, migraine. osteoarthritis, rheumatoid arthritis and soft tissue disorders.
- active ingredients when they are intended for compositions which can be administered orally, are generally subjected to granulation by wet method particularly suited to the amphiphilic nature of NSAIDs.
- the granules thus obtained pose a certain number of technological problems during the formulation phase, in particular in the form of tablets, such as problems of poor flow, sticking, seizing or cleavage.
- the present invention results from the unexpected demonstration, by the inventors, that a granulation of an amphiphilic active principle in a polar aprotic solvent medium with a coating polymer made it possible to avoid the interactions resulting from the amphiphilic structure of these principles. assets, in particular the phenomenon of sticking.
- this granulation process also makes it possible to optimize the rate of dissolution of the active principle.
- the present invention thus relates to a process for granulating an amphiphilic active principle, or a pharmaceutically acceptable salt thereof, comprising a step of coating the active principle in a polar aprotic solvent in the presence of a polymeric binder, to obtain a granule.
- the method defined above further comprises a step of drying and / or sieving the granule.
- the present invention also relates to a granule obtainable by the process defined above.
- the present invention also relates to a granule comprising a polar active principle, or a pharmaceutically acceptable salt thereof, coated with a polymeric binder, and having a density of 0.5 to 0.7 g / mL and / or a speed flow rate of 3 to 15 g / sec.
- the present invention also relates to a pharmaceutical or medicament composition comprising a granule as defined above.
- the pharmaceutical or drug composition as defined above further comprises at least one other active principle, preferably an analgesic and / or an antihistamine.
- the pharmaceutical or medicament composition as defined above is for use in the prevention or treatment of pain, fever and / or inflammation.
- the amphiphilic active principle according to the invention comprises at least one carboxylic acid group and at least one aryl group comprising from 6 to 50 carbon atoms.
- amphiphilic active principle is a non-steroidal anti-inflammatory drug (NSAID).
- NSAID non-steroidal anti-inflammatory drug
- amphiphilic active ingredients also called bipolar
- the amphiphilic active ingredients are molecules whose hydrophobic character is characterized by their octanol-water partition coefficient (Log Po / w), preferably between 2 and 5 ), and whose hydrophilic character is characterized by their weak carboxylic acid function (preferably with a pKa of the order of 4).
- These amphiphilic structures develop a measurable surface tension in solution.
- the amphiphilic active principle is an arylacefic NSAID, an aryl propionic NSAID or an anthranilic NSAID.
- the amphiphilic active principle is selected from the group consisting of ibuprofen, kefoprofen, naproxen, flurbiprofen, oxaprozin, ibufenac, diclofenac, aceclofenac, sulindac, l 'etodolac, ketorolac, indomethacin, mefenamic acid and niflumic acid.
- the pharmaceuquemenf acceptable salt of the amphiphilic active ingredient is selected from the group consisting of a lithium salt, a sodium salt, a potassium salt, a calcium salt, a salt. aluminum, a magnesium salt, a zinc salt, an arginine salt, a lysine salt, a histidine salt, a choline salt, an ethanolamine salt, a diethanolamine salt, a triethanolamine salt, an ethylene diamine salt, and a meglumine salt.
- the amphiphilic active principle or the pharmaceutically acceptable salt thereof is the lysine salt or the sodium salt of ibuprofen.
- the amphiphilic active principle, or the pharmaceutically acceptable salt thereof is in crystalline form.
- the process according to the invention is thus a crystal coating process, in particular a crystal coating process with an amphiphilic active principle or a pharmaceutically acceptable salt thereof.
- the polymeric binder is a polyvinylpyrolidone (povidone) or a polyvinylpyrolidone copolymer, in particular copovidone (copolymer of polyvinylpyrrolidone and vinyl acetate), a polyethylene glycol (PEG), a polyoxypropylene copolymer (in particular of POLOXAMER ® type), a methacrylate copolymer (in particular of EUDRAGIT ® type).
- a polyvinylpyrolidone povidone
- a polyvinylpyrolidone copolymer in particular copovidone (copolymer of polyvinylpyrrolidone and vinyl acetate)
- PEG polyethylene glycol
- POLOXAMER ® type polyoxypropylene copolymer
- EUDRAGIT ® type methacrylate copolymer
- the amount of polymeric binder is at least 5% by weight relative to the weight of active principle.
- a polar aprotic solvent has a significantly lower dielectric constant than that of water at a higher or comparable dipole moment.
- the polar aprotic solvent according to the invention is a pharmaceutically acceptable solvent, in particular a class 2 or 3 solvent according to the classification of the European Pharmacopoeia.
- the polar aprofic solvent according to the invention is selected from the group consisting of acetone, ethyl acetate, acetonitrile and N, N-dimethyl-formamide.
- N.A. not applicable / N.D.: not determined
- Solubility Log10 of the mole fraction of the sodium salt of ibuprofen dissolved in the solvent (after Bustamante et al. (2000) International Journal of Pharmaceutics 194: 1 17-124 which is incorporated herein by reference).
- acetonitrile, N, N-dimethyl-formamide, acetone and ethyl acetate essentially do not solubilize the dihydrate sodium salt of ibuprofen, that is to say that 1 g of the active principle considered is not dissolved by 10'000 ml of solvent, which makes it possible to facilitate the granulation thereof.
- the amphiphilic active principle, or the pharmaceutically acceptable salt thereof is essentially not solubilized, or essentially not dissolved, in the polar aprotic solvent according to the invention, that is, that is, the Log10 of the mole fraction of the amphiphilic active ingredient, or of a pharmaceutically acceptable salt thereof, dissolved in the solvent is preferably less than -5, more preferably less than -6, under conditions temperature and pressure standard.
- the polymeric binder is soluble, or dissolved, in the polar aprotic solvent according to the invention.
- the granule according to the invention is preferably a granule coated with the polymeric binder, in which the amphiphilic active principle, or the pharmaceutically acceptable salt thereof, is in the form crystalline.
- the granule according to the invention comprises, or consists of, at least one crystal of amphiphilic active principle according to the invention or of a pharmaceuly acceptable salt thereof, which is coated with the polymeric binder. according to the invention.
- the granule according to the invention consists essentially of the amphiphilic active principle, or of a pharmaceutically acceptable salt thereof, and of the polymeric binder, that is to say that the granule according to the invention comprises the amphiphilic active ingredient, or a pharmaceueutically acceptable salt thereof, the polymeric binder, and optionally water and / or impurities.
- the coating according to the invention is carried out by mixing the amphiphilic active principle, or a pharmaceuly acceptable salt thereof, and the polymeric binder in a ratio by weight of between 10 and 20% of binder relative to the weight. of active principle or of the pharmaceutically acceptable salt thereof, in particular for a volume of solvent of between 15 and 35% relative to the weight of active principle or of pharmaceueutically acceptable salt thereof.
- the coating can be carried out in a granulating mixer which can operate under reduced pressure and an inert atmosphere.
- the pressure difference between the mixer and the outside can be used to introduce the solvent and to dry the granule obtained.
- the granule obtained can be sieved, in particular through two sieves whose nominal mesh dimensions are respectively 1, 5 mm and 1 mm.
- the process according to the invention makes it possible to remove the crystals of amphiphilic active principle according to the invention, or of pharmaceutically acceptable salt thereof, given the size is less than 75 miti, in particular less than 50 miti, or decrease their quantity.
- the size of a granule according to the invention which comprises at least one crystal of amphiphilic active principle according to the invention, or of a pharmaceutically acceptable salt thereof, is about 1, 3 to 1, 7 times, preferably about 1.4 to 1.6 times, even more preferably about 1.5 times, the size of the crystal of the amphiphilic active ingredient according to the invention, or of the pharmaceutically acceptable salt thereof. this.
- the size is measured as the largest dimension of the granule or crystal.
- the method according to the invention avoids conventional crumbling and / or sizing operations.
- the process according to the invention does not include a stage of drying in a fluidized bed, by spraying or by atomization. Also preferably, the process according to the invention does not include a step of precipitation of the amphiphilic active principle, or of a pharmaceutically acceptable salt thereof, and / or of the polymeric binder.
- the granules obtained have a density of the order of 0.50 to 0.70 g / ml and a flow rate of the order of 3 to 15 g / sec.
- the pharmaceutical composition or the medicament according to the invention is intended or is in a form suitable for oral administration.
- the pharmaceutical composition or the medicament according to the invention is in the form of a tablet, a capsule or granules for oral suspension.
- the pharmaceutical composition or the drug according to the invention is rapidly dissolving.
- the pharmaceutical composition or the medicament according to the invention also comprises at least one pharmaceutically acceptable vehicle or excipient.
- the pharmaceutical composition or the drug according to the invention is in the form of a tablet, or of a capsule, comprising at least one hydrophilic excipient, preferably silica and mannitol, at least one disintegrating agent, preferably sodium croscarmellose, and at least one lubricating agent, preferably magnesium stearate.
- at least one hydrophilic excipient preferably silica and mannitol
- at least one disintegrating agent preferably sodium croscarmellose
- at least one lubricating agent preferably magnesium stearate.
- an external phase is added to the granules according to the invention to form a tablet or a capsule.
- the above excipients and agents constitute the external phase of the tablet or the capsule.
- the external phase more particularly comprises agents chosen from:
- fillers such as mannitol or PROSOLV HD90® (composition comprising 98% microcrystalline cellulose and 2% colloidal silica);
- disintegrating agents such as croscarmellose sodium
- flow agents such as hydrated colloidal silica, in particular according to the European Pharmacopoeia (in particular precipitated silica type LEVILITE ® or mesoporous silica type SYLOID ® )
- lubricating agents such as magnesium stearate.
- the granules according to the invention are such that it is not always necessary to add a lubricant to the external phase in order to prepare a tablet or a capsule.
- the pharmaceutical compositions and medicaments according to the invention in particular in the form of tablets or capsules, not comprising a lubricating agent.
- the pharmaceutical compositions and medicaments according to the invention in particular the tablets according to the invention, do not include excipients capable of modifying the gastric pH and of generating carbon dioxide gas in the stomach.
- the pharmaceutical compositions and medicaments according to the invention in particular the tablets according to the invention, do not comprise sodium carbonates and bicarbonates, sodium citrates and phosphates or strong bases, such as potassium hydroxide.
- the external phase represents less than 50% of the weight of the mixture of the granule and of the external phase.
- Compression of the tablet can be carried out on a rotary machine with conventional punches.
- the coating of the tablet can be carried out conventionally in a coating machine.
- the coating of the tablet will be carried out at a temperature below 35 ° C.
- the coating agents for the tablet are chosen such that they adhere to the surface of the tablets taking into account the surface tension of the sodium salt of ibuprofen.
- coatings based on polyvinyl alcohol are preferred to those based on hypromellose.
- the other active principle is selected from the group consisting of paracetamol, codeine, oxycodone, caffeine, phenylephrine and pseudoephedrine.
- FIG. 1 is a diagram for the preparation of a tablet according to the invention.
- FIG. 3 represents the percentage of dissolution of a tablet according to the invention (IBUNA 512 mg) and of the specialty NUROFEN ® 400 mg batch DL 365 (ordinate axis, in ug / mL) as a function of time (abscissa axis , in minutes) in 900 mL of a solution at pH 6.8, with stirring at 50 revolutions per minute.
- FIG. 5 represents images obtained by scanning electron microscopy (magnification 10 kV ⁇ 100) of crystals of ibuprofen sodium salt dihydrate (on the left) and of granules according to the invention obtained from these crystals by coating in a binder polymeric (right).
- Fig. 6 represents images obtained by scanning electron microscopy (magnification 10 kV ⁇ 100) of crystals of ibuprofen sodium salt dihydrate (on the left) and of granules according to the invention obtained from these crystals by coating in a binder polymeric (right).
- Fig. 6 represents images obtained by scanning electron microscopy (magnification 10 kV ⁇ 100) of crystals of ibuprofen sodium salt dihydrate (on the left) and of granules according to the invention obtained from these crystals by coating in a binder polymeric (right).
- Fig. 6 represents images obtained by scanning electron microscopy (magnification 10 kV ⁇ 100) of crystals of ibupro
- Figure 6 shows, from top to bottom, the powder X-ray diffraction (XRPD) spectra of ibuprofen sodium salt dihydrate:
- a granule according to the invention obtained from copovidone (polymeric binder) and acetonitrile (polar aprotic solvent).
- the x-axis represents the value of the 2-Theta angle in degrees and the y-axis represents the intensity of the diffracted rays.
- the compression is carried out on a rotary machine type KYLLIAN LX20 with conventional punches.
- the tablet is coated in a DRIACOATER type film-coating machine (DRIAM GmbH).
- Examples 1, 2 and 3 Ibuprofen sodium salt tablets obtained by granulation in a polar aprotic solvent
- FIG. 5 shows crystals of ibuprofen sodium salt dihydrate and granules according to the invention obtained from these crystals by coating in a polymeric binder by scanning electron microscopy.
- the external phases of the tablets include:
- a lubricant magnesium stearate.
- Example 3 ethyl acetate granulation
- Example 2 The formulation below is taken from Example 2 above. After adding the external phase and compressing to form the tablet, it is finalized with a film-forming composition based on polyvinyl alcohol:
- FIG. 6 shows that both in the film-coated tablets according to the invention and in the granules according to the invention, the crystalline structure of ibuprofen sodium salt dihydrate is maintained. It is in fact observed that the characteristic peaks of sodium ibuprofen dihydrate (from 16 ° to 21 ° and at 22 ° (2-Theta angle)) are preserved in each of these products.
- Example 5 Ibuprofen tablets sodium salt dihydrate 512 ma + anhydrous caffeine 100 ma
- anhydrous caffeine according to the European Pharmacopoeia is preferred, it is added directly to the external phase of the formulation of the 512 mg ibuprofen sodium salt dihydrate tablet formulation.
- Example 6 Ibuprofen capsules sodium salt dihydrate 256 and 512 ma
- Example 7 Ibuprofen capsules sodium salt dihydrate 256 ma and pseudoephedrine hydrochloride 30 ma
- a combination with pseudoephedrine hydrochloride which is added in the external phase as well as mannitol and a lubricant.
- the mannitol is added in variable quantity in order to correct the variations in density of the granule and to allow the filling and the production of capsules, in particular of size 1, by stuffing / leveling.
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- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
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- Biophysics (AREA)
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Abstract
Description
Claims
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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FR1905539A FR3096264B1 (en) | 2019-05-24 | 2019-05-24 | Process for the preparation of pharmaceutical compositions containing amphiphilic active principles |
PCT/EP2020/064345 WO2020239645A1 (en) | 2019-05-24 | 2020-05-23 | Method for preparing pharmaceutical compositions containing amphiphilic active ingredients |
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EP3975998A1 true EP3975998A1 (en) | 2022-04-06 |
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US (1) | US20220378705A1 (en) |
EP (1) | EP3975998A1 (en) |
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US10668156B2 (en) * | 2012-06-22 | 2020-06-02 | Basf Se | Active-ingredient-containing solid dispersions based on diethylaminoethyl methacrylate copolymers |
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2019
- 2019-05-24 FR FR1905539A patent/FR3096264B1/en active Active
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2020
- 2020-05-23 WO PCT/EP2020/064345 patent/WO2020239645A1/en unknown
- 2020-05-23 US US17/614,076 patent/US20220378705A1/en active Pending
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MA56024A (en) | 2022-04-06 |
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US20220378705A1 (en) | 2022-12-01 |
WO2020239645A1 (en) | 2020-12-03 |
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