WO2011154009A1 - Composition comprising an active principle in an amorphous form and a porous adsorbent material - Google Patents
Composition comprising an active principle in an amorphous form and a porous adsorbent material Download PDFInfo
- Publication number
- WO2011154009A1 WO2011154009A1 PCT/DK2011/050204 DK2011050204W WO2011154009A1 WO 2011154009 A1 WO2011154009 A1 WO 2011154009A1 DK 2011050204 W DK2011050204 W DK 2011050204W WO 2011154009 A1 WO2011154009 A1 WO 2011154009A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- active ingredient
- composition
- pharmaceutically active
- class
- amorphous form
- Prior art date
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 259
- 239000000463 material Substances 0.000 title claims abstract description 63
- 239000003463 adsorbent Substances 0.000 title claims abstract description 60
- 239000004480 active ingredient Substances 0.000 claims abstract description 227
- 238000000034 method Methods 0.000 claims abstract description 91
- 239000008187 granular material Substances 0.000 claims description 112
- 238000002844 melting Methods 0.000 claims description 77
- 230000008018 melting Effects 0.000 claims description 77
- 238000010438 heat treatment Methods 0.000 claims description 70
- 239000002904 solvent Substances 0.000 claims description 57
- 238000011068 loading method Methods 0.000 claims description 53
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 51
- 239000003960 organic solvent Substances 0.000 claims description 42
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 35
- 238000002360 preparation method Methods 0.000 claims description 27
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 18
- 238000000465 moulding Methods 0.000 claims description 17
- YKTSYUJCYHOUJP-UHFFFAOYSA-N [O--].[Al+3].[Al+3].[O-][Si]([O-])([O-])[O-] Chemical compound [O--].[Al+3].[Al+3].[O-][Si]([O-])([O-])[O-] YKTSYUJCYHOUJP-UHFFFAOYSA-N 0.000 claims description 15
- OYACROKNLOSFPA-UHFFFAOYSA-N calcium;dioxido(oxo)silane Chemical compound [Ca+2].[O-][Si]([O-])=O OYACROKNLOSFPA-UHFFFAOYSA-N 0.000 claims description 14
- 239000000378 calcium silicate Substances 0.000 claims description 13
- 229910052918 calcium silicate Inorganic materials 0.000 claims description 13
- 235000012241 calcium silicate Nutrition 0.000 claims description 13
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 12
- 239000002253 acid Substances 0.000 claims description 12
- SNAAJJQQZSMGQD-UHFFFAOYSA-N aluminum magnesium Chemical compound [Mg].[Al] SNAAJJQQZSMGQD-UHFFFAOYSA-N 0.000 claims description 12
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 claims description 12
- 229910052751 metal Inorganic materials 0.000 claims description 12
- 239000002184 metal Substances 0.000 claims description 12
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 11
- 238000001704 evaporation Methods 0.000 claims description 10
- 230000008020 evaporation Effects 0.000 claims description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 8
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 8
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 claims description 8
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 claims description 8
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 229910052782 aluminium Inorganic materials 0.000 claims description 8
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 claims description 8
- RWGFKTVRMDUZSP-UHFFFAOYSA-N cumene Chemical compound CC(C)C1=CC=CC=C1 RWGFKTVRMDUZSP-UHFFFAOYSA-N 0.000 claims description 8
- PHTQWCKDNZKARW-UHFFFAOYSA-N isoamylol Chemical compound CC(C)CCO PHTQWCKDNZKARW-UHFFFAOYSA-N 0.000 claims description 8
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 claims description 8
- 229960004592 isopropanol Drugs 0.000 claims description 8
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 8
- 238000002156 mixing Methods 0.000 claims description 8
- 239000004411 aluminium Substances 0.000 claims description 7
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims description 7
- BPQQTUXANYXVAA-UHFFFAOYSA-N Orthosilicate Chemical compound [O-][Si]([O-])([O-])[O-] BPQQTUXANYXVAA-UHFFFAOYSA-N 0.000 claims description 6
- 235000012239 silicon dioxide Nutrition 0.000 claims description 6
- 235000012211 aluminium silicate Nutrition 0.000 claims description 5
- 229910001463 metal phosphate Inorganic materials 0.000 claims description 5
- 229940044613 1-propanol Drugs 0.000 claims description 4
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical group COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 4
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 4
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims description 4
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 claims description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 4
- 229910000503 Na-aluminosilicate Inorganic materials 0.000 claims description 4
- 239000004111 Potassium silicate Substances 0.000 claims description 4
- 239000004115 Sodium Silicate Substances 0.000 claims description 4
- 239000004110 Zinc silicate Substances 0.000 claims description 4
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 4
- 229910000323 aluminium silicate Inorganic materials 0.000 claims description 4
- 150000004649 carbonic acid derivatives Chemical class 0.000 claims description 4
- ZOIVSVWBENBHNT-UHFFFAOYSA-N dizinc;silicate Chemical compound [Zn+2].[Zn+2].[O-][Si]([O-])([O-])[O-] ZOIVSVWBENBHNT-UHFFFAOYSA-N 0.000 claims description 4
- 235000019253 formic acid Nutrition 0.000 claims description 4
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 claims description 4
- 239000000499 gel Substances 0.000 claims description 4
- GJRQTCIYDGXPES-UHFFFAOYSA-N iso-butyl acetate Natural products CC(C)COC(C)=O GJRQTCIYDGXPES-UHFFFAOYSA-N 0.000 claims description 4
- FGKJLKRYENPLQH-UHFFFAOYSA-M isocaproate Chemical compound CC(C)CCC([O-])=O FGKJLKRYENPLQH-UHFFFAOYSA-M 0.000 claims description 4
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 4
- 229940011051 isopropyl acetate Drugs 0.000 claims description 4
- OQAGVSWESNCJJT-UHFFFAOYSA-N isovaleric acid methyl ester Natural products COC(=O)CC(C)C OQAGVSWESNCJJT-UHFFFAOYSA-N 0.000 claims description 4
- HCWCAKKEBCNQJP-UHFFFAOYSA-N magnesium orthosilicate Chemical compound [Mg+2].[Mg+2].[O-][Si]([O-])([O-])[O-] HCWCAKKEBCNQJP-UHFFFAOYSA-N 0.000 claims description 4
- 239000000391 magnesium silicate Substances 0.000 claims description 4
- 235000019792 magnesium silicate Nutrition 0.000 claims description 4
- 229910052919 magnesium silicate Inorganic materials 0.000 claims description 4
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 claims description 4
- 229940043265 methyl isobutyl ketone Drugs 0.000 claims description 4
- YKYONYBAUNKHLG-UHFFFAOYSA-N n-Propyl acetate Natural products CCCOC(C)=O YKYONYBAUNKHLG-UHFFFAOYSA-N 0.000 claims description 4
- 235000019353 potassium silicate Nutrition 0.000 claims description 4
- NNHHDJVEYQHLHG-UHFFFAOYSA-N potassium silicate Chemical compound [K+].[K+].[O-][Si]([O-])=O NNHHDJVEYQHLHG-UHFFFAOYSA-N 0.000 claims description 4
- 229910052913 potassium silicate Inorganic materials 0.000 claims description 4
- 229940090181 propyl acetate Drugs 0.000 claims description 4
- 239000000377 silicon dioxide Substances 0.000 claims description 4
- 239000000429 sodium aluminium silicate Substances 0.000 claims description 4
- 235000012217 sodium aluminium silicate Nutrition 0.000 claims description 4
- NTHWMYGWWRZVTN-UHFFFAOYSA-N sodium silicate Chemical compound [Na+].[Na+].[O-][Si]([O-])=O NTHWMYGWWRZVTN-UHFFFAOYSA-N 0.000 claims description 4
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- 235000019794 sodium silicate Nutrition 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
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- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 claims 1
- RZEKVGVHFLEQIL-UHFFFAOYSA-N celecoxib Chemical compound C1=CC(C)=CC=C1C1=CC(C(F)(F)F)=NN1C1=CC=C(S(N)(=O)=O)C=C1 RZEKVGVHFLEQIL-UHFFFAOYSA-N 0.000 abstract description 31
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- RAGOYPUPXAKGKH-XAKZXMRKSA-N posaconazole Chemical compound O=C1N([C@H]([C@H](C)O)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@H]3C[C@@](CN4N=CN=C4)(OC3)C=3C(=CC(F)=CC=3)F)=CC=2)C=C1 RAGOYPUPXAKGKH-XAKZXMRKSA-N 0.000 abstract description 18
- 229960001589 posaconazole Drugs 0.000 abstract description 17
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 abstract description 11
- 229960001680 ibuprofen Drugs 0.000 abstract description 11
- 239000003826 tablet Substances 0.000 description 94
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- WMGSQTMJHBYJMQ-UHFFFAOYSA-N aluminum;magnesium;silicate Chemical compound [Mg+2].[Al+3].[O-][Si]([O-])([O-])[O-] WMGSQTMJHBYJMQ-UHFFFAOYSA-N 0.000 description 12
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- CKRORYDHXIRZCH-UHFFFAOYSA-N phosphoric acid;dihydrate Chemical compound O.O.OP(O)(O)=O CKRORYDHXIRZCH-UHFFFAOYSA-N 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 229920001993 poloxamer 188 Polymers 0.000 description 1
- 229940044519 poloxamer 188 Drugs 0.000 description 1
- 229920001992 poloxamer 407 Polymers 0.000 description 1
- 229940044476 poloxamer 407 Drugs 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 229940068977 polysorbate 20 Drugs 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 229920002689 polyvinyl acetate Polymers 0.000 description 1
- 239000011118 polyvinyl acetate Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 1
- 229910000343 potassium bisulfate Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 1
- RWPGFSMJFRPDDP-UHFFFAOYSA-L potassium metabisulfite Chemical compound [K+].[K+].[O-]S(=O)S([O-])(=O)=O RWPGFSMJFRPDDP-UHFFFAOYSA-L 0.000 description 1
- 229940043349 potassium metabisulfite Drugs 0.000 description 1
- 235000010263 potassium metabisulphite Nutrition 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- OTYBMLCTZGSZBG-UHFFFAOYSA-L potassium sulfate Chemical compound [K+].[K+].[O-]S([O-])(=O)=O OTYBMLCTZGSZBG-UHFFFAOYSA-L 0.000 description 1
- 229910052939 potassium sulfate Inorganic materials 0.000 description 1
- 235000011151 potassium sulphates Nutrition 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 235000019814 powdered cellulose Nutrition 0.000 description 1
- 229920003124 powdered cellulose Polymers 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 235000010388 propyl gallate Nutrition 0.000 description 1
- 239000000473 propyl gallate Substances 0.000 description 1
- 229940075579 propyl gallate Drugs 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 229940100486 rice starch Drugs 0.000 description 1
- 229940082569 selenite Drugs 0.000 description 1
- MCAHWIHFGHIESP-UHFFFAOYSA-L selenite(2-) Chemical compound [O-][Se]([O-])=O MCAHWIHFGHIESP-UHFFFAOYSA-L 0.000 description 1
- 150000004760 silicates Chemical class 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 1
- 229910000342 sodium bisulfate Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 229940001584 sodium metabisulfite Drugs 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 235000011008 sodium phosphates Nutrition 0.000 description 1
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 229940001474 sodium thiosulfate Drugs 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 230000007928 solubilization Effects 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- 229940035044 sorbitan monolaurate Drugs 0.000 description 1
- 235000011067 sorbitan monolaureate Nutrition 0.000 description 1
- 235000011069 sorbitan monooleate Nutrition 0.000 description 1
- 239000001593 sorbitan monooleate Substances 0.000 description 1
- 229940035049 sorbitan monooleate Drugs 0.000 description 1
- 235000011076 sorbitan monostearate Nutrition 0.000 description 1
- 239000001587 sorbitan monostearate Substances 0.000 description 1
- 229940035048 sorbitan monostearate Drugs 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 229940044609 sulfur dioxide Drugs 0.000 description 1
- 235000010269 sulphur dioxide Nutrition 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000007916 tablet composition Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 239000006068 taste-masking agent Substances 0.000 description 1
- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical class C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
- 229910052719 titanium Inorganic materials 0.000 description 1
- 239000010936 titanium Substances 0.000 description 1
- 229940042585 tocopherol acetate Drugs 0.000 description 1
- 150000003611 tocopherol derivatives Chemical class 0.000 description 1
- 231100000721 toxic potential Toxicity 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 229940078499 tricalcium phosphate Drugs 0.000 description 1
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 239000011667 zinc carbonate Substances 0.000 description 1
- 235000004416 zinc carbonate Nutrition 0.000 description 1
- 229910000010 zinc carbonate Inorganic materials 0.000 description 1
- 239000011787 zinc oxide Substances 0.000 description 1
- LRXTYHSAJDENHV-UHFFFAOYSA-H zinc phosphate Chemical compound [Zn+2].[Zn+2].[Zn+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O LRXTYHSAJDENHV-UHFFFAOYSA-H 0.000 description 1
- 229910000165 zinc phosphate Inorganic materials 0.000 description 1
- 229940077935 zinc phosphate Drugs 0.000 description 1
- NWONKYPBYAMBJT-UHFFFAOYSA-L zinc sulfate Chemical compound [Zn+2].[O-]S([O-])(=O)=O NWONKYPBYAMBJT-UHFFFAOYSA-L 0.000 description 1
- 229960001763 zinc sulfate Drugs 0.000 description 1
- 229910000368 zinc sulfate Inorganic materials 0.000 description 1
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 1
- 229930195724 β-lactose Natural products 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K9/1611—Inorganic compounds
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- 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
-
- 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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
-
- 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
- A61K31/33—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
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2009—Inorganic compounds
Definitions
- the present invention relates to a composition
- a composition comprising a porous adsorbent material and a pharmaceutically active ingredient, where essentially all active ingredient is present in amorphous form.
- the composition may typically be a tablet.
- the invention also provides methods for the preparation of the composition of the invention. One method of preparation is a dry method, whereas another method of preparation involves use of organic solvents for loading the pharmaceutically active ingredient into the composition and, typically, subsequent removal of the solvent.
- the composition is intended for oral administration to mammals such as human subjects.
- Drugs or pharmaceutical compositions usually comprise one or more active substances and various excipients.
- One reason for preparing such pharmaceutical compositions is to manipulate the availability of the active compound in the body of the patient after ingestion of the pharmaceutical composition.
- compositions for oral administration are conventionally provided as granules incorporating the active pharmaceutical ingredient or substance. Such granulate or granules may be compressed into tablets or filled into capsules.
- One commonly used technique for granulation is a wet granulation, where a mixture of powders including the active compound is mixed with a liquid, usually an aqueous liquid, under mechanical influence for the preparation of granules.
- a liquid usually an aqueous liquid
- the granules prepared by wet granulation are dried before use.
- WO2006/000229A2 discloses the preparation of a tablet solely containing inert pharmaceutically acceptable excipients (although in some cases it may be suitable also to incorporate an active substance therein).
- a pharmaceutically acceptable liquid formulation e.g. containing the active pharmaceutically ingredient (substance)
- the tablet will due to its porosity - absorb the liquid formulation (adsorbed to the walls of the inert tablet pores).
- This loading of an inert tablet takes place within a relatively short period of time and is reproducible, i.e. the same amount of liquid formulation is sorbed when the same type and size of tablet and liquid formulation is used.
- the pharmaceutically acceptable liquid formulation containing the active substance is described as an oil or an oily-like material, and it is intended that the oil or oily-like material containing the active substance remains in the tablet until administration to a mammal or human subject, and hereafter release occurs.
- the inventors of the present invention have found a method for providing a pharmaceutically active ingredient in amorphous form in a pharmaceutical composition, especially providing essentially all the active ingredient in amorphous form.
- a composition may be advantageous by providing the active ingredient in an improved, more soluble form.
- the present invention relates to a composition
- a composition comprising a porous adsorbent material and a pharmaceutically active ingredient classified according to the Biopharmaceutics Classification System (BCS) as belonging to Class II and IV, wherein the pharmaceutically active ingredient is in amorphous form or essentially all the active pharmaceutical ingredient is in amorphous form.
- BCS Biopharmaceutics Classification System
- the loadable composition may be prepared as described in WO2006/000229A2 using the porous adsorbent material as described herein.
- Such loadable composition or tablet may, after preparation, be loaded with a pharmaceutically active ingredient dissolved in an organic solvent, followed by removal of the solvent as described herein, thus providing the composition of the present invention.
- the composition of the present invention may also be provided by other methods, such methods being disclosed herein. Two main aspects of removing solvent in order to providing the amorphous ingredient preparation are contemplated, that is, 1 ) heating of composition, granulate or granules above melting point of a pharmaceutically active ingredient to evaporate solvent and to form amorphous active ingredient and 2) evaporation of solvent, e.g. under reduced pressure or by freeze drying, followed by heating the composition or granules at a temperature above the melting point of the pharmaceutically active ingredient to form the amorphous active ingredient.
- Another aspect of the present invention is a method of dry formulation of the pharmaceutically active ingredient with the porous adsorbent material and heating to provide the amorphous form of the active ingredient.
- Figure 1 DSC chromatogram of physical mixture of fenofibrate, Neusilin US2 and magnesium stearate showing melting peak for fenofibrate.
- Figure 2 DSC chromatogram of tablets loaded with fenofibrate solution showing no melting peak for fenofibrate.
- Figure 3 DSC chromatogram of tablets loaded with celecoxib solution showing no melting peak for celecoxib.
- Figure 4 DSC chromatogram of granule mixture of posaconazole before heat treatment, showing a melting peak for posaconazole.
- Figure 5 DSC chromatogram of granule mixture of posaconazole after heat treatment, showing no melting peak for posaconazole
- Figure 6 DSC chromatogram of granule mixture of celecoxib after solvent treatment and evapoation, showing no melting peak for celecoxib.
- Figure 7 DSC chromatogram of granule mixture of celecoxib after solvent treatment and evapoation, showing no melting peak for celecoxib.
- the present invention relates to a composition
- a composition comprising a porous adsorbent material and a pharmaceutically active ingredient classified according to the
- Biopharmaceutics Classification System as belonging to Class II and IV, wherein essentially all active ingredient is present in amorphous form.
- compositions of the present invention when in form of a tablet are sufficiently robust to withstand the normal handling of tablets, i.e. they have a hardness of 20 N or more, typically, the tablet has a hardness of 25 N or more, about 30 N or more, about 35 N or more, about 40 N or more, about 45 N or more, about 50 N or more, about 60 N or more, about 70 N or more, about 90 N or more, about 100 N or more, about 150 N or more or about 200 N, typically from about 30 N to about 150 N, such as 30 N to 100 N.
- the loaded tablets are sufficiently robust to withstand the normal handling of tablets during further processing (e.g. coating), packaging, storage etc., i.e.
- the tablets according to the invention have a friability of about 5% or less such as, e.g., about 4% or less, about 3% or less, about 2% or less such as about 1 % or less.
- the composition of the present invention preferably has a porosity, which is sufficient to provide the amorphous active ingredient, and typically such composition has a porosity of 30 % v/v or more, such as 40 % v/v or more, 50 % v/v or more, 60 % v/v or more, 70 % v/v or more, 80 % v/v or more, or 90 % v/v or more.
- the porous adsorbent material is present in a concentration of about 20% w/w or more, about 25% w/w or more, about 30% w/w or more, about 35% w/w or more, about 40% w/w or more, about 45% w/w or more, about 50 w/w or more, about 60% w/w or more, about 70% or more, about 80% or more, about 90% or more, about 95% or more, or about 98% or more in the unloaded composition.
- composition of the present invention releases the pharmaceutically active ingredient from the composition upon contact with an aqueous environment, such as administration to a mammal.
- the composition of the present invention is weighing from 1 mg to 2000 mg, such as from 1 mg to 10 mg, or from 200 mg to 1000 mg, or 60 mg to 1500 mg in dried form (unit dosage form).
- the concentration of the pharmaceutically active ingredient in the composition will depend on the use as a medicine, whether in immediate release form or modified release form, and is typically about 1 % w/w or more, for instance, about 5% w/w or more such as, e.g., about 10% w/w or more, about 15% w/w or more, about 20% w/w or more, about 25% w/w or more, about 30% w/w or more, about 35% w/w or more, about 40% w/w or more, about 45% w/w or more, about 50 w/w or more, about 60% w/w or more or about 70% or more.
- composition of the present invention comprising a porous adsorbent material and a pharmaceutically active ingredient classified according to the
- Biopharmaceutics Classification System as belonging to Class II and IV, wherein essentially all active ingredient is present in amorphous form, can be obtained by the methods as described herein after. Accordingly, a certain aspect of the present invention is such a composition obtainable by any one of the described methods.
- the present invention relates to a method for the preparation of a composition comprising a porous adsorbent material and a pharmaceutically active ingredient classified according to the Biopharmaceutics Classification System as belonging to Class II and IV, where essentially all active ingredients are present in amorphous form, the method comprising the steps of:
- the temperature in step iv) is exceeding the melting point of the pharmaceutically active ingredient. If the pharmaceutically active ingredient becomes amorphous at a temperature lower than its melting point, then it will not be necessary to heat above melting point in such circumstances.
- heating of the granules or composition is done from about 5°C above to about 80°C above the melting point of the pharmaceutically active ingredient, such as from about 10°C above to about 70°C above the melting point of the pharmaceutically active ingredient, such as from about 20°C above to about 50°C above the melting point of the pharmaceutically active ingredient. This also applies to any one of the further aspects and embodiments described hereunder.
- the heating of the granules in step iv) is done at a temperature from 50 to 200°C, such as 80°C to 1 10°C, until constant weight is obtained. Such heating is carried out for as long as necessary, and typically for a time period of from 30 min to 24 hours, such as 3 to 20 hours.
- the present invention relates to a method for the preparation of a composition
- a composition comprising a porous adsorbent material and a pharmaceutically active ingredient classified according to the Biopharmaceutics Classification System as belonging to Class II and IV, where essentially all active ingredients are present in amorphous form, the method comprising the steps of:
- step v) exceeds the melting point of the pharmaceutically active ingredient.
- step iv) is removed under reduced pressure or by freeze drying for a time period of from 30 min to 24 hours, such as 3 to 20 hours.
- the heating of the granules in step v) is done at a temperature from 50 to 200°C, such as 80°C to 1 10°C, to a constant weight.
- heating of the granules is done from about 5°C above to about 80°C above the melting point of the pharmaceutically active ingredient, such as from about 10°C above to about 70°C above the melting point of the pharmaceutically active ingredient, such as from about 20°C above to about 50°C above the melting point of the pharmaceutically active ingredient.
- Such heating is carried out for as long as necessary, and typically for a time period of from 30 min to 24 hours, such as 3 to 20 hours.
- the present invention relates to a method for the preparation of a composition
- a composition comprising a porous adsorbent material and a
- step v) exceeds the melting point of the pharmaceutically active ingredient.
- heating of the composition in step v) is done at a temperature from 50 to 200°C, such as 80°C to 1 10°C, to a constant weight.
- heating of the composition is done from about 5°C above to about 80°C above the melting point of the pharmaceutically active ingredient, such as from about 10°C above to about 70°C above the melting point of the pharmaceutically active ingredient, such as from about 20°C above to about 50°C above the melting point of the
- Such heating is carried out for as long as necessary, and typically for a time period of from 30 min to 24 hours, such as 3 to 20 hours.
- the present invention relates to a method for the preparation of a composition
- a composition comprising a porous adsorbent material and a
- composition vi) heating the composition at a temperature and for a sufficient time to a constant weight, to bring essentially all pharmaceutically active ingredient in amorphous form, to provide the composition.
- This method may involve optionally treating a composition of the porous adsorbent material, by heating the empty composition before loading with a solvent.
- step v) the solvent in step v) is removed under reduced pressure or by freeze drying for a time period of from 30 min to 24 hours, such as 3 to 20 hours.
- the heating of the composition in step vi) is done at a temperature from 50 to 200°C, such as 80°C to 1 10°C, until constant weight is obtained.
- heating of the composition is done from about 5°C above to about 80°C above the melting point of the pharmaceutically active ingredient, such as from about 10°C above to about 70°C above the melting point of the pharmaceutically active ingredient, such as from about 20°C above to about 50°C above the melting point of the pharmaceutically active ingredient.
- Such heating is carried out for as long as necessary, and typically for a time period of from 30 min to 24 hours, such as 3 to 20 hours.
- the present invention relates to a method for the preparation of a composition
- a composition comprising a porous adsorbent material and a
- composition iii) compacting, such as compressing or molding, the granulate into a composition, iv) heating the composition at a temperature and for a sufficient time to a constant weight, to bring essentially all pharmaceutically active ingredient in amorphous form, to provide the composition.
- step iv) exceeds the melting point of the pharmaceutically active ingredient.
- the heating of the composition in step iv) is carried out at a temperature from 50 to 200°C, such as 80°C to 1 10°C, until constant weight is obtained.
- heating of the composition is done from about 5°C above to about 80°C above the melting point of the pharmaceutically active ingredient, such as from about 10°C above to about 70°C above the melting point of the pharmaceutically active ingredient, such as from about 20°C above to about 50°C above the melting point of the pharmaceutically active ingredient.
- Such heating is carried out for as long as necessary, and typically for a time period of from 30 min to 24 hours, such as 3 to 20 hours.
- the present invention relates to a method for the preparation of a composition comprising a porous adsorbent material and a
- composition vi) heating the composition at a temperature and for a sufficient time to a constant weight, to bring essentially all pharmaceutically active ingredient in amorphous form, to provide the composition.
- step vi) exceeds the melting point of the pharmaceutically active ingredient.
- the heating of the composition in step vi) is carried out at a temperature from 50 to 200°C, such as 80°C to 1 10°C, to a constant weight.
- heating of the composition is done from about 5°C above to about 80°C above the melting point of the pharmaceutically active ingredient, such as from about 10°C above to about 70°C above the melting point of the pharmaceutically active ingredient, such as from about 20°C above to about 50°C above the melting point of the pharmaceutically active ingredient.
- Such heating is done for as long as necessary, and typically for a time period of from 30 min to 24 hours, such as 3 to 20 hours.
- a surfactant to the composition and such surfactant is then mixed with the granulate before compacting the solid porous granulate into the composition.
- a disintegrant may be added to the granulate before compacting the solid porous granulate into the composition.
- the present invention relates to a composition comprising a porous adsorbent material and a pharmaceutically active ingredient classified according to the Biopharmaceutics Classification System as belonging to Class II and IV, wherein essentially all the pharmaceutically active ingredient is present amorphous form, this physical state being obtainable by any one of the methods described above as either aspects or
- compositions as defined herein are compositions as defined herein.
- Various methods of loading the pharmaceutically active ingredient in a solvent into the composition are available, such as loading by placing the granulate or tablet in an excess amount of the pharmaceutically active ingredient in solution for a sufficient amount of time, or by loading under pressure, such as under reduced pressure or vacuum, or loading by spraying the pharmaceutically active ingredient in solution onto the granulate or tablet.
- pharmaceutically acceptable excipients are herein denoted “porous adsorbent material”.
- excipients may also be denoted "microporous adsorbents” or “porous adsorbent carrier material” or “porous carrier material”.
- porous adsorbent materials having suitable properties for providing a loadable composition, e.g. tablet, according to the invention.
- the porous adsorbent materials may be used alone or in combination provided that the desired porosity of the composition or tablet is obtained.
- the tablets are compressed into tablets by use of a certain compression force.
- the compression force may not be so low that the requirements with respect to hardness and friability of the tablets are compromised, i.e. these requirements ensure that the tablets are sufficiently robust.
- Suitable pharmaceutically acceptable excipients that can be used to obtain tablets having a porosity of 30% v/v or more are selected from the group consisting of metal oxides, metal silicates, metal carbonates, metal phosphates, metal sulfates, sugar alcohols, sugars and cellulose and cellulose derivatives.
- the metal is typically selected from the group consisting of sodium, potassium, magnesium, calcium, zinc, aluminium, titanium and silicon.
- a suitable metal oxide for use according to the invention may be selected from the group consisting of magnesium oxide, calcium oxide, zinc oxide, aluminium oxide, titanium dioxide including Tronox A-HP-328 and Tronox A-HP-100, silicon dioxides including Aerosil, Cab-O-Sil, Syloid, Aeroperl, Sunsil (silicon beads), Zeofree, Sipernat, and mixtures thereof.
- the metal oxide is a titanium dioxide or a silicon dioxide or mixtures thereof.
- the silicates can be divided in the following groups:
- Silicon dioxides are subdivided into porous and nonporous silicas
- Nonporous colloidal silicas e.g. Aerosil (fumed silicas)
- Porous silicas gels e.g. Syloid, Porasil, Lichrosorp
- a loadable tablet according to the invention may contain a metal oxide that is a non-porous silicate including fumed silicas of the Aerosil type, and/or a porous silicate including e.g. Syloid, Porasil and Lichrosorp.
- the pharmaceutically acceptable excipient for use according to the invention is a metal silicate selected from the group consisting of sodium silicate, potassium silicate, magnesium silicate, calcium silicate including synthetic calcium silicate such as, e.g., Hubersorp, microporous calcium silicate, such as Florite, zinc silicate, aluminum silicate, sodium aluminosilicate such as, e.g., Zeolex, magnesium aluminum silicate, magnesium aluminum metasilicate, aluminium metasilicate, Neusilin SG2 and Neusilin US2 and mixtures thereof.
- a metal silicate selected from the group consisting of sodium silicate, potassium silicate, magnesium silicate, calcium silicate including synthetic calcium silicate such as, e.g., Hubersorp, microporous calcium silicate, such as Florite, zinc silicate, aluminum silicate, sodium aluminosilicate such as, e.g., Zeolex, magnesium aluminum silicate, magnesium aluminum metasilicate, aluminium metasilicate, Neusilin
- the aluminum silicate is a highly porous material having a typical average pore size of 30 to 80, such as 50-60 angstrom and a surface area of from 250 to 400 m 2 /g, such as about 300 m 2 /g.
- the composition of the present invention typically has a porosity of 30 % v/v or more, which is necessary for absorption of a suitable amount of a pharmaceutically active ingredient.
- the porosity is 40 % v/v or more, 50 % v/v or more, 60 % v/v or more, 70 % v/v or more, 80 % v/v or more, or 90 % v/v or more.
- the porosity is measured on the aluminum silicate, such as Neusilin, and then it is calculated how much aluminum silicate and an optional pharmaceutically acceptable excipient, utilize of the porosity.
- the porosity of the granules or tablets before loading is calculated on basis of the density of the granule or tablet p t and the "true density" p s of the ingredients.
- the density of the granule or tablet is based on the ratio between weight and volume of the granule or tablet.
- the "true density" of the ingredients is based on the gas pycnometric density determined in helium using Micromeritics Accupyc 1330.
- the aluminum silicate is typically present in a concentration of about 20% w/w or more. It is apparent that the higher porosity desired the higher the concentration of the aluminum silicate, thus in further embodiments of the composition of the present invention the aluminum silicate is present in a concentration of about 25% w/w or more, about 30% w/w or more, about 35% w/w or more, about 40% w/w or more, about 45% w/w or more, about 50 w/w or more, about 60% w/w or more, about 70% or more, about 80% or more, about 90% or more, about 95% or more, or about 98% or more, in the unloaded composition.
- the aluminum silicate typically, has an average pore size of 30 to 80, such as 50- 60 angstrom and a surface area of from 250 to 400 m 2 /g, such as about 300 m 2 /g.
- the aluminum silicate is selected from magnesium aluminum metasilicate, magnesium aluminum silicate, and aluminium metasilicate, and mixtures thereof.
- Typical examples of aluminum silicates are Neusilin SG2, and Neusilin US2, and mixtures thereof, in particular A ⁇ Os.MgO.ySiC ⁇ . xH 2 0, wherein y is from 1.5-2, and x is 1 -10, preferred is magnesium aluminum metasilicate, e.g. Al 2 0 3- Mg0.2Si0 2 . 5H 2 0.
- a suitable pharmaceutically acceptable excipient may be a metal carbonate such as a carbonate selected from the group consisting of sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, calcium carbonate, magnesium carbonate, zinc carbonate and aluminum carbonate, and mixtures thereof.
- metal salt suitable for use according to the invention are metal phosphates selected from the group consisting of sodium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, calcium phosphate, magnesium phosphate, zinc phosphate and aluminum phosphate.
- the pharmaceutically acceptable excipient may be a calcium phosphate selected from the group consisting of dibasic anhydrous calcium phosphate, dibasic dihydrate calcium phosphate, and tribasic calcium phosphate.
- the dibasic anhydrous calcium phosphate is typically selected from the group consisting of A-Tab, calcium monohydrogen phosphate, calcium orthophosphate, Di- Cafos AN, dicalcium orthophosphate, E341 , Anhydrous Emcompress, Fujicalin, phosphoric acid calcium salt (1 :1 ), and secondary calcium phosphate, and mixtures thereof.
- the dibasic dihydrate calcium phosphate may be selected from the group consisting of Cafos, calcium hydrogen orthophosphate dihydrate, calcium
- tribasic calcium phosphates are e.g. hydroxyapatite, phosphoric acid calcium salt (2:3), precipitated calcium phosphate, tertiary calcium phosphate, Tri- Cafos, tricalcium diorthophosphate, tricalcium orthophosphate, tricalcium phosphate, TRI-CAL, WG, TRI-TAB.
- metal salts are metal sulfates such as, e.g, sodium sulfate, sodium hydrogen sulfate, potassium sulfate, potassium hydrogen sulfate, calcium sulfate, magnesium sulfate, zinc sulfate and/or aluminum sulfate.
- suitable calcium sulfates are e.g. calcium sulfate anhydrous including anhydrite, anhydrous gypsum, anhydrous sulfate of lime, Destab, Drêt, E516, karstenite, muriacite, and Snow White or calcium sulfate dihydrate including alabaster, Cal-Tab, Compactrol, Destab, E516, gypsum, light spar, mineral white, native calcium sulfate, precipitated calcium sulfate, satinite, satin spar, selenite, terra alba and USG Terra Alba.
- calcium sulfate anhydrous including anhydrite, anhydrous gypsum, anhydrous sulfate of lime, Destab, Drêt, E516, karstenite, muriacite, and Snow White or calcium sulfate dihydrate including alabaster, Cal-Tab, Compactrol, Destab, E516, gypsum, light spar, mineral white, native calcium s
- porous adsorbent materials are intended to be embodiments of the invention as long as they alone or in mixture provides a suitable porosity as described above.
- the below specified embodiments are not to be construed as limiting the invention in any way but are merely to highlight certain preferred embodiments.
- the porous abdsorbent material is selected from porous silicon dioxide, such as sodium silicate, potassium silicate, magnesium silicate, calcium silicate, including synthetic calcium silicate, microporous calcium silicate, zinc silicate, aluminum silicate, sodium aluminosilicate, hydrous aluminium silicates or alkaline earths, magnesium aluminum metasilicate, magnesium aluminum silicate, aluminium metasilicate, nonporous colloidal silicas, porous silicas gels, precipitated silicate, and mixtures thereof.
- the porous adsorbent material is selected from metal carbonates and metal phosphates.
- the porous adsorbent material is selected from magnesium aluminum metasilicate, precipitated silicate, and microporous calcium silicate.
- the present invention relates to a composition
- a composition comprising a porous adsorbent material and a pharmaceutically active ingredient classified according to the Biopharmaceutics Classification System as belonging to Class II and IV, wherein the pharmaceutically active ingredient is in essentially amorphous form.
- the pharmaceutically active ingredient to be loaded or compacted into the composition of the invention is a compound having low solubility, typically a small organic compound of less than 2000 Da.
- Such compounds with low solubility are classified, as described in Amidon et al, "A Theoretical Basis for a Biopharmaceutical Drug Classification: The correlation of in vitro Drug Product Dissolution and in vivo Bioavailability.” Pharmaceutical Reseach, vol. 12, no. 3, 1995. This classification system is known as the Biopharmaceutics Classification System (BCS).
- BCS Biopharmaceutics Classification System
- Biopharmaceutics Classification System is guidance for predicting the intestinal drug absorption provided by the U.S. Food and Drug Administration.
- the fundamental basis for the BCS was established by Dr. Gordon Amidon who was presented with a
- a pharmaceutically active ingredient to be loaded or compacted into the composition of the invention, or when referring to a composition comprising the pharmaceutically active ingredient as used herein, it is intended that it refers to the un-processed pharmaceutically active ingredient, thus, the pharmaceutically active ingredient before being processed according to the present invention.
- Solubility class boundaries It is based on the highest dose strength of an immediate release product. A drug is considered highly soluble when the highest dose strength is soluble in 250mL or less of aqueous media over the pH range of 1 to 7.5. The volume estimate of 250mL is derived from typical bioequivalence study protocols that prescribe administration of a drug product to fasting human volunteers with a glass of water.
- Permeability class boundaries It is based indirectly on the extent of absorption of a drug substance in humans and directly on the measurement of rates of mass transfer across human intestinal membrane.
- non-human systems capable of prediction the drug absorption systems capable of predicting the drug absorption in humans can be used (such as in-vitro culture methods).
- a drug substance is considered highly permeable when the extent of absorption in humans is determined to be 90 % or more of the administered dose based on a mass-balance determination or in comparison to and intravenous dose.
- Dissolution class boundaries An immediate release products is considered rapidly dissolving when no less than 85% of the labeled amount of the drug substance dissolve within 30 minutes using USP Dissolution Apparatus 1 at 100 RPM or
- Apparatus 2 at 50 RPM in a volume of 900ml or less in following media,) 0.1 N HCI or simulated gastric fluid or pH 4.5 buffer and pH 6.8 buffer or simulated intestinal fluid.
- the pharmaceutical active ingredient to be used in the composition of the invention is selected from compounds classified according to the Biopharmaceutics Classification System as belonging to Class II and IV, and such compounds are typically selected from atorvastatin, clopidogrel, esomeprazole, valsartan, olanzapine, risperidone, pioglitazone, quetiapine, lansoprazole, candesartan, imatinib, irbesartan, aripiprazole, ezetimibe, celecoxib, lamotrigine, telmisartan, olmesartan, tacrolimus, fenofibrate, fenofibric acid, ibuprofen, mycophenolate, bicalutamide, lopinavir, ritonavir, raloxifene, efavirenz, carvedilol, omeprazol, methylphenidate, cyclosporine, si
- a pharmaceutically active ingredient classified according to the Biopharmaceutics Classification System as belonging to Class II and IV are different forms of such compounds, such as the free forms, such as free acids, free bases, esters and salts thereof, or mixtures thereof. It is also important to understand that new chemical compounds which are developed and which can be classified according to BCS as belonging to Class II and IV is intended to be included in the term "a pharmaceutically active ingredient classified according to the Biopharmaceutics Classification System as belonging to Class II and IV".
- the pharmaceutically active ingredient is selected from class II.
- the pharmaceutically active ingredient has low water solubility.
- the pharmaceutically active ingredient has low water solubility and high permeability.
- suitable pharmaceutically active ingredients are selected from small organic molecules of less than 2000 Da, such as from 150 Da to 2000 Da.
- Biopharmaceutics Classification System as belonging to Class II and IV is provided in the composition of the present invention in amorphous form.
- a complete (i.e. 100%) conversion of the active ingredient into amorphous form is desirable, it will often not be technically possible or feasible to obtain a complete transformation.
- the terms "essentially” and “essentially all”, as used herein in connection with the content of active pharmaceutical ingredient(s) in the composition of the invention or the composition prepared by the method(s) of the invention denote compositions of the invention having at least 95% w/w of the pharmaceutically active ingredient is in amorphous form.
- at least 96% w/w of the pharmaceutically active ingredient is in amorphous form, such as from 97% w/w to 99.5% w/w.
- the composition of the present invention it may be necessary to heat the composition in order to produce the amorphous pharmaceutically active ingredient, or, alternatively, to subject the composition to evaporation.
- the heating may be done at a temperature below the melting point of the pharmaceutically active ingredient and this is typically done if the pharmaceutically active ingredient transforms to amorphous form below its melting point, or the heating may be done at a temperature above the melting point of the pharmaceutically active ingredient if needed to transform the pharmaceutically active ingredient to amorphous form.
- the pharmaceutically active ingredient has a melting point below 250°C, for instance below 200°C, such as below 180°C, e.g. below 100°C.
- heating of the granules or composition comprising the pharmaceutically active ingredient is done from about 5°C above to about 80°C above the melting point of the pharmaceutically active ingredient, thus, in a further embodiment the heating of the granules or composition is done from below 330°C, for instance below 250°C, such as below 180°C, e.g. below 100°C, such as from about 50°C to about 200°C.
- the pharmaceutically active ingredient is selected from atorvastatin, clopidogrel,
- lansoprazole candesartan, imatinib, irbesartan, aripiprazole, ezetimibe, celecoxib, lamotrigine, telmisartan, olmesartan, tacrolimus, fenofibrate, fenofibric acid, ibuprofen, mycophenolate, bicalutamide, lopinavir, ritonavir, raloxifene, efavirenz, carvedilol, omeprazol, methylphenidate, cyclosporine, simvastatin, ziprasidone, nifedipine, glimepiride, glipizide, glyburide, hydroxyzine, isotretinoin, loratadine,
- a salt is intended to indicate any such salt that a specific active ingredient may form upon contact with the relevant acid or base, and typically such salt is selected from a pharmaceutically acceptable salt, where the term "a pharmaceutically acceptable salt” is intended to indicate salts which are not harmful to the patient.
- Such salts include pharmaceutically acceptable acid addition salts, pharmaceutically acceptable metal salts, ammonium and alkylated ammonium salts.
- Acid addition salts include salts of inorganic acids as well as organic acids.
- suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, nitric acids and the like.
- suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, glycolic, lactic, maleic, malic, malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic, methanesulfonic, ethanesulfonic, tartaric, ascorbic, pamoic, bismethylene salicylic, ethanedisulfonic, gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, p-toluenesulfonic acids and the like.
- pharmaceutically acceptable inorganic include hydrochlor
- metal salts include lithium, sodium, potassium, magnesium salts and the like.
- ammonium and alkylated ammonium salts include ammonium, methylammonium, dimethylammonium, trimethylammonium, ethylammonium, hydroxyethylammonium, diethylammonium, butylammonium, tetramethylammonium salts and the like.
- the pharmaceutically active ingredient classified according to the Biopharmaceutics Classification System as belonging to Class II and IV may be dissolved in an organic solvent (essentially water free) or mixtures thereof, and loaded into the composition of the invention.
- an organic solvent essentially water free
- water is not suitable as a solvent it may be used as a co-solvent, and in an embodiment the organic solvent is mixed with water as co-solvent.
- the organic solvent may in principle be any organic solvent which can dissolve the pharmaceutically active ingredient as described above, however, many organic solvents are not suitable for pharmaceutical formulations, in particular for veterinary or humane medicines, and in this respect certain classes of solvent are preferred.
- Class 3 solvents According to The European Agency for the Evaluation of Medicinal Products guidelines for classification of solvents have been developed and described in VICH Topic GL18 (impurities solvents) and in this respect the solvents with low toxic potential are preferred. Such organic solvents are referred to herein as Class 3 solvents according to the EMEA guidelines. Although Class 3 solvents are preferred it may also be beneficial to use Class 2 solvents in some instances.
- the organic solvent to be used in the composition of the invention is typically, selected from solvents classified as Class 3 solvents according to the EMEA guidelines and such compounds are selected from formic acid, tetrahydrofuran, acetid acid, acetone, anisole, 1 -butanol, 2-butanol, butyl acetate, tert-butylmethyl ether, cumene, dimethylsulfoxide, ethanol, ethyl acetate, ethyl ether, ethyl formate, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1 -butanol, methylethyl ketone, methylisobutyl ketone, 2-methyl-1 -propanol, pentane, 1 -pentanol, 1 -propanol, 2-propanol, propyl acetate and mixtures thereof. It is also important to understand that new
- any one of the above organic solvents classified according to the EMEA guidelines as belonging to Class 3 solvent are intended to be embodiments of the invention. It should be understood that organic solvents that are un-classified, may later change classification into Class 3 solvent according to the EMEA guidelines, and are intended to be included in the term "a Class 3 solvent according to the EMEA guidelines".
- the below specified embodiments are not to be construed as limiting the invention in any way but are merely to highlight certain preferred embodiments.
- the organic solvent is classified as a Class 3 solvent according to the EMEA guidelines.
- the organic solvent is selected from formic acid, tetrahydrofuran, acetid acid, acetone, anisole, 1 -butanol, 2-butanol, butyl acetate, tert- butylmethyl ether, cumene, dimethylsulfoxide, ethanol, ethyl acetate, ethyl ether, ethyl formate, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1 - butanol, methylethyl ketone, methylisobutyl ketone, 2-methyl-1 -propanol, pentane, 1 - pentanol, 1 -propanol, 2-propanol, propyl acetate or mixtures thereof.
- the organic solvent is selected from ethanol or 2-propanol.
- the organic solvent to be used in the composition of the invention may be selected from solvents classified as Class 2 solvents according to the EMEA guidelines and such compounds are selected from acetonitrile, chlorobenzene, chloroform, cyclohexane, 1 ,2-dichloroethene, dichloromethane, 1 ,2-dimethoxyethane, N,N- dimethylacetamide, ⁇ , ⁇ -dimethylformamide, 1 ,4-dioxane, 2-ethoxyethanol, ethylene glycol, formamide, hexane, methanol, 2-methoxyethanol, methylbutylketone, methylcyclohexane, N-methylpyrrolidone, nitromethane, pyridine, sulfolane, tetraline, toluene, 1 ,1 ,2-thrchloroethene, or xylene, and mixtures thereof. It is also important to understand that new organic solvents which can be classified
- any one of the above organic solvents classified according to the EMEA guidelines as belonging to Class 2 solvent are intended to be embodiments of the invention. It should be understood that organic solvents that are un-classified, may later change classification into Class 2 solvent according to the EMEA guidelines, and are intended to be included in the term "a Class 2 solvent according to the EMEA guidelines".
- the below specified embodiments are not to be construed as limiting the invention in any way but are merely to highlight certain preferred embodiments.
- the organic solvent is classified as a Class 2 solvent according to the EMEA guidelines.
- the organic solvent is selected from acetonitrile, chlorobenzene, chloroform, cyclohexane, 1 ,2-dichloroethene, dichloromethane, 1 ,2- dimethoxyethane, N,N-dimethylacetamide, ⁇ , ⁇ -dimethylformamide, 1 ,4-dioxane, 2- ethoxyethanol, ethylene glycol, formamide, hexane, methanol, 2-methoxyethanol, methylbutylketone, methylcyclohexane, N-methylpyrrolidone, nitromethane, pyridine, sulfolane, tetraline, toluene, 1 ,1 ,2-thrchloroethene, or xylene or mixtures thereof.
- organic solvent Since it is intended to provide compositions which are dry, it is important that all, or essentially all, organic solvent can be removed from the composition; typically, the organic solvent has a boiling point of from 50°C to 140°C.
- composition such as tablet
- composition may of course also comprise or contain other and/or additional pharmaceutically acceptable excipients such as those normally employed in the manufacturing of tablets.
- the term "pharmaceutically acceptable excipient” is intended to denote any material, which is inert in the sense that it substantially does not have any therapeutic and/or prophylactic effect per se. Such an excipient may be added with the purpose of making it possible to obtain a pharmaceutical, cosmetic and/or foodstuff composition, which have acceptable technical properties.
- suitable excipients for use in a composition according to the invention include fillers, diluents, disintegrants, binders, lubricants etc. or mixture thereof.
- the choice of excipients is normally made taken such different uses into considerations.
- Other pharmaceutically acceptable excipients for suitable use are e.g.
- acidifying agents alkalizing agents, preservatives, antioxidants, buffering agents, chelating agents, coloring agents, complexing agents, emulsifying and/or solubilizing agents, flavors and perfumes, humectants, sweetening agents, wetting agents etc.
- suitable fillers, diluents and/or binders include lactose (e.g. spray- dried lactose, a-lactose, ⁇ -lactose, Tabletose®, various grades of Pharmatose®, Microtose® or Fast-Floe®), microcrystalline cellulose (various grades of Avicel®, Elcema®, Vivacel®, Ming Tai® or Solka-Floc®), hydroxypropylcellulose, L- hydroxypropylcellulose (low substituted), hydroxypropyl methylcellulose (HPMC) (e.g. Methocel E, F and K, Metolose SH of Shin-Etsu, Ltd, such as, e.g.
- methylcellulose polymers such as, e.g., Methocel A, Methocel A4C, Methocel A15C, Methocel A4M), hydroxyethylcellulose, sodium carboxymethylcellulose, carboxymethylene,
- carboxymethylhydroxyethylcellulose and other cellulose derivatives sucrose, agarose, sorbitol, mannitol, dextrins, maltodextrins, starches or modified starches (including potato starch, maize starch and rice starch), calcium phosphate (e.g. basic calcium phosphate, calcium hydrogen phosphate, dicalcium phosphate hydrate), calcium sulfate, calcium carbonate, sodium alginate, collagen etc.
- calcium phosphate e.g. basic calcium phosphate, calcium hydrogen phosphate, dicalcium phosphate hydrate
- calcium sulfate calcium carbonate
- sodium alginate collagen etc.
- diluents are e.g. calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, microcrystalline cellulose, powdered cellulose, dextrans, dextrin, dextrose, fructose, kaolin, lactose, mannitol, sorbitol, starch, pregelatinized starch, sucrose, sugar etc.
- binders are e.g. acacia, alginic acid, agar, calcium carrageenan, sodium carboxymethylcellulose, microcrystalline cellulose, dextrin, ethylcellulose, gelatin, liquid glucose, guar gum, hydroxypropyl methylcellulose, methylcellulose, pectin, PEG, povidone, pregelatinized starch etc.
- Glidants and lubricants may also be included in the tablet.
- examples include stearic acid, magnesium stearate, calcium stearate or other metallic stearate, colloidal silicondioxide (Aerosil) talc, waxes and glycerides, light mineral oil, PEG, glyceryl behenate, colloidal silica, hydrogenated vegetable oils, corn starch, sodium stearyl fumarate, polyethylene glycols, alkyl sulfates, sodium benzoate, sodium acetate etc.
- excipients which may be included in a loadable tablet of the invention are e.g. flavoring agents, coloring agents, taste-masking agents, pH-adjusting agents, buffering agents, preservatives, stabilizing agents, anti-oxidants, wetting agents, humidity-adjusting agents, surface-active agents, suspending agents, absorption enhancing agents, agents for modified release etc.
- additives in a composition or a solid dosage form according to the invention may be antioxidants like e.g. ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorous acid, monothioglycerol, potassium metabisulfite, propyl gallate, sodium formaldehylde sulfoxylate, sodium metabisulfite, sodium thiosulfate, sulfur dioxide, tocopherol, tocopherol acetate, tocopherol hemisuccinate, TPGS or other tocopherol derivatives, etc.
- the carrier composition may also contain e.g. stabilising agents.
- the concentration of an antioxidant and/or a stabilizing agent in the carrier composition is normally from about 0.1 % w/w to about 5% w/w.
- composition or solid dosage form according to the invention may also include one or more surfactants or substances having surface-active properties. It is contemplated that such substances are involved in the solubilization of the slightly soluble active substance and thus, contributes to improved solubility characteristics of the active substance.
- surfactant is intended to include one surfactant or a mixture of surfactants. In certain situations, such as to prevent recrystallization of the dissolved amorphous active ingredient in vivo, such as in the mammalian body, e.g. human body, it may be beneficial to add a surfactant to the composition and such surfactant is then mixed with the granulate before compacting the solid porous granulate into the composition.
- composition of the present invention may further comprise a disintegrant.
- disintegrants are e.g. croscarmellose sodium, alginic acid or alginates, microcrystalline cellulose, hydroxypropyl cellulose and other cellulose derivatives, crospovidone, polacrillin potassium, sodium starch glycolate, starch, pregelatinized starch, carboxymethyl stare and mixtures thereof (e.g. Primogel® and Explotab®) etc. Any one of these disintegrants is intended to be specific embodiments and may be combined with any one of the aspects and/or embodiments of the present invention.
- the concentration of disintegrant is from 1 %w/w to 20 %w/w, such as 1 %w/w to 10 %w/w, such as 2 %w/w to 15 %w/w, such as 2.5 %w/w to 8 %w/w (based on the total weight of the composition before loading).
- the final composition of the present invention may be formulated so as to provide immediate release, delayed or sustained release of the active ingredient.
- the composition of the present invention is formed as a tablet further comprising a disintegrant.
- the composition of the present invention comprising an aluminum silicate, and compressed into a tablet, is mixed with a disintegrant before making the tablet.
- the loadable solid porous composition of the present invention such as the tablet, comprises an aluminum silicate and a disintegrant.
- Such a disintegrant may be selected from croscarmellose sodium, alginic acid or alginates, microcrystalline cellulose, hydroxypropyl cellulose and other cellulose derivatives, crospovidone, polacrillin potassium, sodium starch glycolate, starch, pregelatinized starch, and carboxymethyl starch, typically croscarmellose sodium.
- the pharmaceutically active ingredient In order to provide a reliable pharmaceutical composition to be given to mammals, such has human subjects; the pharmaceutically active ingredient must be released, at least partly, from the loaded composition, and in particular must be released in a consistent and preferably high manner to ensure a therapeutically effective amount.
- the pharmaceutically active ingredient is released from the composition upon contact with an aqueous environment, such as administration to a mammal. Such release may be delayed or sustained and will depend on the tested active ingredient and the disease or disorder to be treated.
- the active ingredient contained in the porous composition e.g. tablet, may be released by erosion of the tablet depending on the additional excipients contained in the composition or may diffuse out of the composition into the aqueous environment, such as human bodily fluids.
- an immediate release is obtainable when a disintegrant is mixed together with the aluminum silicate to form a tablet of the present invention.
- any of the above described compositions such as tablets, capsules, granules or granulate, are for use as a medicine.
- the present invention relates to use of ibuprofen, posaconazole, celecoxib, or fenofibrate, or a salt or free acid form thereof for preparing the solid porous composition as described herein.
- a composition comprising a porous adsorbent material and a pharmaceutically active ingredient selected from the group consisting of active ingredients classified according to the Biopharmaceutics Classification System as belonging to Class II or Class IV, wherein essentially all pharmaceutically active ingredient is present in amorphous form.
- composition of embodiment 1 wherein the pharmaceutically active ingredient is belonging to Class II.
- composition of any one of embodiments 1 -7 wherein the pharmaceutically active ingredient is selected from the group consisting of atorvastatin, clopidogrel,
- lansoprazole candesartan, imatinib, irbesartan, ibuprofen, aripiprazole, ezetimibe, celecoxib, lamotrigine, telmisartan, olmesartan, tacrolimus, fenofibrate, fenofibric acid, mycophenolate, bicalutamide, lopinavir, ritonavir, raloxifene, efavirenz, carvedilol, omeprazol, methylphenidate, cyclosporine, simvastatin, ziprasidone, nifedipine, glimepiride, glipizide, glyburide, hydroxyzine, isotretinoin, loratadine,
- organic solvent essentially water free
- the organic solvent is classified as a Class 2 solvent or a Class 3 solvent according to the EMEA guidelines, preferably as a Class 3 solvent. 12.
- composition of embodiment 1 1 wherein the organic solvent is selected from formic acid, tetrahydrofuran, acetid acid, acetone, anisole, 1 -butanol, 2-butanol, butyl acetate, tert-butylmethyl ether, cumene, dimethylsulfoxide, ethanol, ethyl acetate, ethyl ether, ethyl formate, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3- methyl-1 -butanol, methylethyl ketone, methylisobutyl ketone, 2-methyl-1 -propanol, pentane, 1 -pentanol, 1 -propanol, 2-propanol, propyl acetate or mixtures thereof.
- the organic solvent is selected from formic acid, tetrahydrofuran, acetid acid, acetone,
- porous adsorbent material is selected from metal carbonates, metal phosphates, or porous silicon dioxide, such as sodium silicate, potassium silicate, magnesium silicate, calcium silicate, including synthetic calcium silicate, microporous calcium silicate, zinc silicate, aluminum silicate, sodium aluminosilicate, hydrous aluminium silicates or alkaline earths, magnesium aluminum metasilicate, magnesium aluminum silicate, aluminium metasilicate, nonporous colloidal silicas, porous silicas gels, precipitated silicate, and mixtures thereof.
- metal carbonates such as sodium silicate, potassium silicate, magnesium silicate, calcium silicate, including synthetic calcium silicate, microporous calcium silicate, zinc silicate, aluminum silicate, sodium aluminosilicate, hydrous aluminium silicates or alkaline earths, magnesium aluminum metasilicate, magnesium aluminum silicate, aluminium metasilicate, nonporous colloidal silicas, porous
- composition of any one of embodiments 1-16 wherein the composition is a tablet.
- composition of any one of the preceding embodiments further comprising a pharmaceutically acceptable excipient, such as a surfactant. 19.
- composition of any one of the preceding embodiments further comprising a pharmaceutically acceptable excipient, such as a disintegrant.
- a method for the preparation of a composition comprising a porous adsorbent material and a pharmaceutically active ingredient selected from the group consisting of active ingredients classified according to the Biopharmaceutics Classification System as belonging to Class II or ClasslV, where essentially all active ingredient is present in amorphous form, the method comprising the steps of:
- step iv) the temperature exceeding the melting point of the pharmaceutically active ingredient, such as exceeding the melting point with about 5°C to about 80°C, such as with about 10°C to about 70°C, such as with about 20°C to about 50°C.
- a method for the preparation of a composition comprising a porous adsorbent material and a pharmaceutically active ingredient selected from the group consisting of active ingredients classified according to the Biopharmaceutics Classification System as belonging to Class II or Class IV, where essentially all active ingredient is present in amorphous form, the method comprising the steps of:
- step v) comprising in step v) the temperature exceeding the melting point of the pharmaceutically active ingredient, such as exceeding the melting point with about 5°C to about 80°C, such as with about 10°C to about 70°C, such as with about 20°C to about 50°C. 26.
- a method for the preparation of a composition comprising a porous adsorbent material and a pharmaceutically active ingredient selected from the group consisting of active ingredients classified according to the Biopharmaceutics Classification System as belonging to Class II or Class IV, where essentially all active ingredient is present in amorphous form, the method comprising the steps of:
- iii) dissolving the pharmaceutically active ingredient in an organic solvent or a mixture thereof, iv) loading the pharmaceutically active ingredient in solution into the composition, until about 95 % of the loading capacity, such as about 90 %, about 80 %, about 70 %, preferably the solution is loaded from about 80 % of the loading capacity to 100 %, v) heating the composition at a temperature and for a sufficient time to a constant weight, to bring essentially all pharmaceutically active ingredient in amorphous form, to provide the composition.
- the loading capacity such as about 90 %, about 80 %, about 70 %
- step v) the temperature exceeding the melting point of the pharmaceutically active ingredient, such as exceeding the melting point with about 5°C to about 80°C, such as with about 10°C to about 70°C, such as with about 20°C to about 50°C.
- the method of embodiment 29 or 30, comprising heating the composition in step v) at a temperature from 50 to 200°C, such as 80°C to 1 10°C, to a constant weight.
- a method for the preparation of a composition comprising a porous adsorbent material and a pharmaceutically active ingredient selected from the group consisting of active ingredients classified according to the Biopharmaceutics Classification System as belonging to Class II or Class IV, where essentially all active ingredient is present in amorphous form, the method comprising the steps of:
- step vi) comprising in step vi) the temperature exceeding the melting point of the pharmaceutically active ingredient, such as exceeding the melting point with about 5°C to about 80°C, such as with about 10°C to about 70°C, such as with about 20°C to about 50°C.
- a method for the preparation of a composition comprising a porous adsorbent material and a pharmaceutically active ingredient selected from the group consisting of active ingredients classified according to the Biopharmaceutics Classification System as belonging to Class II or Class IV, where essentially all active ingredient is present in amorphous form, the method comprising the steps of:
- step iii) compacting, such as compressing or molding, the granulate into a composition, iv) heating the composition at a temperature and for a sufficient time to a constant weight, to bring essentially all pharmaceutically active ingredient in amorphous form, to provide the composition.
- step iv) comprising in step iv) the temperature exceeding the melting point of the pharmaceutically active ingredient, such as exceeding the melting point with about 5°C to about 80°C, such as with about 10°C to about 70°C, such as with about 20°C to about 50°C. 40.
- the method of embodiment 38 or 39, comprising heating the composition in step iv) at a temperature from 50 to 200°C, such as 80°C to 1 10°C, to a constant weight. 41.
- any one of embodiments 38-40 comprising heating the composition in step iv) for a time period of from 30 min to 24 hours, such as 3 to 20 hours.
- a method for the preparation of a composition comprising a porous adsorbent material and a pharmaceutically active ingredient selected from the group consisting of active ingredients classified according to the Biopharmaceutics Classification System as belonging to Class II or Class IV, where essentially all active ingredient is present in amorphous form, the method comprising the steps of:
- step vi) the temperature exceeding the melting point of the pharmaceutically active ingredient, such as exceeding the melting point with about 5°C to about 80°C, such as with about 10°C to about 70°C, such as with about 2 °C to about 50°C. 44.
- a composition comprising a porous adsorbent material and a pharmaceutically active ingredient selected from the group consisting of active ingredients classified according to the Biopharmaceutics Classification System as belonging to Class II or Class IV, wherein the pharmaceutically active ingredient is in essentially amorphous form obtainable by the method of any one of embodiments 20-47.
- composition of embodiment 48 wherein the composition is according to any one of embodiments 1 -19.
- composition of any one of embodiments 1-19 or 48-49 for use as a medicine is provided.
- composition is weighing from 1 mg to 2000 mg, such as from 1 mg to 10 mg, 10 mg to 100 mg, 100 mg to 1000 mg, or 60 mg to 1500 mg in dried form.
- the examples hereunder illustrate the invention disclosed herein by which a pharmaceutically active ingredient is converted into amorphous form.
- the loadable tablet or granule may be prepared as described in WO2006/000229A2.
- IPA isopropyl alcohol
- the tablet loading capacity is 0.764 mL as calculated based on the actual the tablet volume of 0.991 cm 3 and the tablet porosity of 84.1 % (pycnometric density of tablet excipients: 2.13 g/cm 3 ).
- the tablet was designed to load 0.727 mL corresponding to a loading capacity of 95%.
- the un-loaded tablets were heated to constant mass in an incubator (Memmert, model 100-800) at 1 10°C. 3.000 g fenofibrate were dissolved in 60 g of IPA. 25 g of dried tablets were transferred to the loading chamber with 54.3 mL IPA fenofibrate solution. The tablets were heated at 1 10°C to constant mass in the incubator. The tablet mass of the unloaded and the loaded tablets are shown in Table 1 . TABLE 1 Average tablet Rel. Std. Dev.
- the loaded granules and tablets were subjected to Differential Scanning Calorimetry (DSC) investigation (Perkin Elmer Diamond DSC, Pyris software) as were a physical mixture of the excipients with the same composition.
- the physical mixtures showed a melting peak at the melting point of fenofibrate as shown in Figure 1.
- the loaded granules and tablets showed no melting peak for fenofibrate, as shown for the tablets in Figure 2, demonstrating the presence of fenofibrate in amorphous form.
- DSC Differential Scanning Calorimetry
- the loaded tablets were crushed, using a morter and pestil, and subjected to DSC investigation (Mettler Toledo TGA DSC 1 , STAR 6 Software) including calculation of 1 .derivatine. No melting peaks for celecoxib were found, as shown for the heat treated loaded tablets in Figure 3. This shows that celecoxib is present in amorphous form.
- This example illustrates the process by which a pharmaceutically active ingredient is converted to essentially amorphous form by a dry method involving heat treatment above the melting point of the active pharmaceutical ingredient.
- posaconazole 200 mg was mixed manually with 1.6g of Neusilin US2 using sufficient agitation to render a homogeneous mixture.
- the mixture was heated to 190°C for 1 hour in an incubator (Memmert, model 100-800).
- Granules samples were subjected to DSC investigation (Mettler Toledo TGA DSC 1 , STAR 6 Software) including calculation of 1 .derivative. Melting peaks were found, at the melting point for the active ingredients in all un-treated granule samples but not after heat treatment. Results are listed in Table 3and shown for posaconazole samples in Figures 4 and 5. The absence of melting peaks shows that the active pharmaceutical ingredients (API's) are present in amorphous form. Table 3
- Solvent method where the API is dissolved within the porous granules and tablets
- This example illustrates the process by which a pharmaceutically active ingredient is converted to amorphous form by exposing a dry mixture to a solvent and subsequent evaporation of the solvent to render the API in amorphous form.
- the granule samples were subjected to DSC investigation (Mettler Toledo TGA DSC 1 , STAR 6 Software) including calculation of 1 .derivative. Melting endoterm was found at the melting point of celecoxib in un-treated granule sample but not after exposure to solvent and heat treatment, as listed in Table 4 and shown in Figure 6 and Figure 7. The absence of melting peaks shows that the celecoxib is present in amorphous form.
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Abstract
A composition or a tablet comprising a porous adsorbent material and a pharmaceutically active ingredient classified according to the Biopharmaceutics Classification System as belonging to any of the Classes II or IV, wherein essentially all pharmaceutically active ingredient is present in amorphous form, and a method for preparing the composition or tablet of the invention, for example using ibuprofen, posaconazole or celecoxib as active ingredient.
Description
COMPOSITION COMPRISING AN ACTIVE PRINCIPLE IN AN
AMORPHOUS FORM AND A POROUS ADSORBENT MATERIAL
The present invention relates to a composition comprising a porous adsorbent material and a pharmaceutically active ingredient, where essentially all active ingredient is present in amorphous form. The composition may typically be a tablet. The invention also provides methods for the preparation of the composition of the invention. One method of preparation is a dry method, whereas another method of preparation involves use of organic solvents for loading the pharmaceutically active ingredient into the composition and, typically, subsequent removal of the solvent. Typically, the composition is intended for oral administration to mammals such as human subjects.
BACKGROUND OF THE INVENTION
Many known and future drug substances may exhibit undesirable properties especially with respect to e.g. water solubility and oral bioavailability. Therefore, novel technologies, which enable especially therapeutically and/or prophylactically active substances to be delivered in vivo in a relatively easy manner and at the same time enables the desired therapeutic and/or prophylactic response, is highly needed.
Drugs or pharmaceutical compositions usually comprise one or more active substances and various excipients. One reason for preparing such pharmaceutical compositions is to manipulate the availability of the active compound in the body of the patient after ingestion of the pharmaceutical composition.
Pharmaceutical compositions for oral administration are conventionally provided as granules incorporating the active pharmaceutical ingredient or substance. Such granulate or granules may be compressed into tablets or filled into capsules.
One commonly used technique for granulation is a wet granulation, where a mixture of powders including the active compound is mixed with a liquid, usually an aqueous liquid, under mechanical influence for the preparation of granules. Usually the granules prepared by wet granulation are dried before use.
Other known techniques for the preparation of granules are melt agglomeration and controlled agglomeration.
WO2006/000229A2 discloses the preparation of a tablet solely containing inert pharmaceutically acceptable excipients (although in some cases it may be suitable also to incorporate an active substance therein). When this tablet is immersed in or contacted with a pharmaceutically acceptable liquid formulation e.g. containing the active pharmaceutically ingredient (substance), the tablet will due to its porosity -
absorb the liquid formulation (adsorbed to the walls of the inert tablet pores). This loading of an inert tablet takes place within a relatively short period of time and is reproducible, i.e. the same amount of liquid formulation is sorbed when the same type and size of tablet and liquid formulation is used. Typically, the pharmaceutically acceptable liquid formulation containing the active substance is described as an oil or an oily-like material, and it is intended that the oil or oily-like material containing the active substance remains in the tablet until administration to a mammal or human subject, and hereafter release occurs. SUMMARY OF THE INVENTION
The inventors of the present invention have found a method for providing a pharmaceutically active ingredient in amorphous form in a pharmaceutical composition, especially providing essentially all the active ingredient in amorphous form. Such a composition may be advantageous by providing the active ingredient in an improved, more soluble form.
In one aspect the present invention relates to a composition comprising a porous adsorbent material and a pharmaceutically active ingredient classified according to the Biopharmaceutics Classification System (BCS) as belonging to Class II and IV, wherein the pharmaceutically active ingredient is in amorphous form or essentially all the active pharmaceutical ingredient is in amorphous form.
The loadable composition may be prepared as described in WO2006/000229A2 using the porous adsorbent material as described herein. Such loadable composition or tablet may, after preparation, be loaded with a pharmaceutically active ingredient dissolved in an organic solvent, followed by removal of the solvent as described herein, thus providing the composition of the present invention. The composition of the present invention may also be provided by other methods, such methods being disclosed herein. Two main aspects of removing solvent in order to providing the amorphous ingredient preparation are contemplated, that is, 1 ) heating of composition, granulate or granules above melting point of a pharmaceutically active ingredient to evaporate solvent and to form amorphous active ingredient and 2) evaporation of solvent, e.g. under reduced pressure or by freeze drying, followed by heating the composition or granules at a temperature above the melting point of the pharmaceutically active ingredient to form the amorphous active ingredient.
Another aspect of the present invention is a method of dry formulation of the pharmaceutically active ingredient with the porous adsorbent material and heating to provide the amorphous form of the active ingredient.
DRAWINGS
Figure 1 : DSC chromatogram of physical mixture of fenofibrate, Neusilin US2 and magnesium stearate showing melting peak for fenofibrate.
Figure 2: DSC chromatogram of tablets loaded with fenofibrate solution showing no melting peak for fenofibrate.
Figure 3: DSC chromatogram of tablets loaded with celecoxib solution showing no melting peak for celecoxib.
Figure 4: DSC chromatogram of granule mixture of posaconazole before heat treatment, showing a melting peak for posaconazole. Figure 5: DSC chromatogram of granule mixture of posaconazole after heat treatment, showing no melting peak for posaconazole
Figure 6: DSC chromatogram of granule mixture of celecoxib after solvent treatment and evapoation, showing no melting peak for celecoxib.
Figure 7: DSC chromatogram of granule mixture of celecoxib after solvent treatment and evapoation, showing no melting peak for celecoxib.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a composition comprising a porous adsorbent material and a pharmaceutically active ingredient classified according to the
Biopharmaceutics Classification System as belonging to Class II and IV, wherein essentially all active ingredient is present in amorphous form.
It is important that the compositions of the present invention when in form of a tablet, such as compressed or molded tablet, are sufficiently robust to withstand the normal handling of tablets, i.e. they have a hardness of 20 N or more, typically, the tablet has a hardness of 25 N or more, about 30 N or more, about 35 N or more, about 40 N or more, about 45 N or more, about 50 N or more, about 60 N or more, about 70 N or more, about 90 N or more, about 100 N or more, about 150 N or more or about 200 N, typically from about 30 N to about 150 N, such as 30 N to 100 N.
The loaded tablets are sufficiently robust to withstand the normal handling of tablets during further processing (e.g. coating), packaging, storage etc., i.e. they fulfill the pharmacopoeial requirements with respect to hardness and friability. Furthermore, the tablets according to the invention have a friability of about 5% or less such as, e.g., about 4% or less, about 3% or less, about 2% or less such as about 1 % or less.
The composition of the present invention preferably has a porosity, which is sufficient to provide the amorphous active ingredient, and typically such composition has a porosity of 30 % v/v or more, such as 40 % v/v or more, 50 % v/v or more, 60 % v/v or more, 70 % v/v or more, 80 % v/v or more, or 90 % v/v or more. In order to obtain such porosity the porous adsorbent material is present in a concentration of about 20% w/w or more, about 25% w/w or more, about 30% w/w or more, about 35% w/w or more, about 40% w/w or more, about 45% w/w or more, about 50 w/w or more, about 60% w/w or more, about 70% or more, about 80% or more, about 90% or more, about 95% or more, or about 98% or more in the unloaded composition.
The composition of the present invention releases the pharmaceutically active ingredient from the composition upon contact with an aqueous environment, such as administration to a mammal.
Typically, the composition of the present invention is weighing from 1 mg to 2000 mg, such as from 1 mg to 10 mg, or from 200 mg to 1000 mg, or 60 mg to 1500 mg in dried form (unit dosage form).
The concentration of the pharmaceutically active ingredient in the composition will depend on the use as a medicine, whether in immediate release form or modified release form, and is typically about 1 % w/w or more, for instance, about 5% w/w or more such as, e.g., about 10% w/w or more, about 15% w/w or more, about 20% w/w or more, about 25% w/w or more, about 30% w/w or more, about 35% w/w or more, about 40% w/w or more, about 45% w/w or more, about 50 w/w or more, about 60% w/w or more or about 70% or more.
The composition of the present invention comprising a porous adsorbent material and a pharmaceutically active ingredient classified according to the
Biopharmaceutics Classification System as belonging to Class II and IV, wherein essentially all active ingredient is present in amorphous form, can be obtained by the methods as described herein after. Accordingly, a certain aspect of the present invention is such a composition obtainable by any one of the described methods.
Furthermore, any one of the herein described compositions either described as aspects or embodiments are to be seen as aspects or embodiments of the methods as described herein.
In a further aspect, the present invention relates to a method for the preparation of a composition comprising a porous adsorbent material and a pharmaceutically active ingredient classified according to the Biopharmaceutics Classification System as belonging to Class II and IV, where essentially all active ingredients are present in amorphous form, the method comprising the steps of:
i) preparing a granulate of the porous adsorbent material,
ii) dissolving the pharmaceutically active ingredient in an organic solvent or a mixture thereof,
iii) loading the pharmaceutically active ingredient in solution into the granules, until about 95 % of the loading capacity, such as about 90 %, about 80 %, about 70 %, preferably the solution is loaded from about 80 % of the loading capacity to 100 %, iv) heating the granules at a temperature and for a sufficient time to a constant weight, to bring the pharmaceutically active ingredient on essentially amorphous form, v) compacting, such as compressing or molding, the granulate into the composition.
In a further embodiment the temperature in step iv) is exceeding the melting point of the pharmaceutically active ingredient. If the pharmaceutically active ingredient becomes amorphous at a temperature lower than its melting point, then it will not be necessary to heat above melting point in such circumstances. Typically, heating of the granules or composition is done from about 5°C above to about 80°C above the melting point of the pharmaceutically active ingredient, such as from about 10°C above to about 70°C above the melting point of the pharmaceutically active ingredient, such as from about 20°C above to about 50°C above the melting point of the pharmaceutically active ingredient. This also applies to any one of the further aspects and embodiments described hereunder.
In a further embodiment the heating of the granules in step iv) is done at a temperature from 50 to 200°C, such as 80°C to 1 10°C, until constant weight is obtained. Such heating is carried out for as long as necessary, and typically for a time period of from 30 min to 24 hours, such as 3 to 20 hours.
In a further aspect the present invention relates to a method for the preparation of a composition comprising a porous adsorbent material and a pharmaceutically active ingredient classified according to the Biopharmaceutics Classification System as belonging to Class II and IV, where essentially all active ingredients are present in amorphous form, the method comprising the steps of:
i) preparing a granulate of the porous adsorbent material,
ii) dissolving the pharmaceutically active ingredient in an organic solvent or a mixture thereof,
iii) loading the pharmaceutically active ingredient in solution into the granules, until about 95 % of the loading capacity, such as about 90 %, about 80 %, about 70 %, preferably the solution is loaded from about 80 % of the loading capacity to 100 %, iv) removing the solvent form the granules by evaporation for a sufficient time, optionally, to a constant weight,
v) heating the granules at a temperature and for a sufficient time to a constant weight, to bring the pharmaceutically active ingredient on essentially amorphous form, vi) compacting, such as compressing or molding, the granulate into the composition.
In a further embodiment the temperature in step v) exceeds the melting point of the pharmaceutically active ingredient.
In a still further embodiment the solvent in step iv) is removed under reduced pressure or by freeze drying for a time period of from 30 min to 24 hours, such as 3 to 20 hours.
In a further embodiment the heating of the granules in step v) is done at a temperature from 50 to 200°C, such as 80°C to 1 10°C, to a constant weight. Typically, heating of the granules is done from about 5°C above to about 80°C above the melting point of the pharmaceutically active ingredient, such as from about 10°C above to about 70°C above the melting point of the pharmaceutically active ingredient, such as from about 20°C above to about 50°C above the melting point of the pharmaceutically active ingredient. Such heating is carried out for as long as necessary, and typically for a time period of from 30 min to 24 hours, such as 3 to 20 hours.
In yet a further aspect the present invention relates to a method for the preparation of a composition comprising a porous adsorbent material and a
pharmaceutically active ingredient classified according to the Biopharmaceutics Classification System as belonging to Class II and IV, where essentially all active ingredient is present in amorphous form, the method comprising the steps of:
i) preparing a granulate of the porous adsorbent material,
ii) compacting, such as compressing or molding, the granulate into a loadable composition,
iii) dissolving the pharmaceutically active ingredient in an organic solvent or a mixture thereof,
iv) loading the pharmaceutically active ingredient in solution into the composition, until about 95 % of the loading capacity, such as about 90 %, about 80 %, about 70 %, preferably the solution is loaded from about 80 % of the loading capacity to 100 %,
v) heating the composition at a temperature and for a sufficient time to a constant weight, to bring the pharmaceutically active ingredient on essentially amorphous form, to provide the composition.
In a further embodiment the temperature in step v) exceeds the melting point of the pharmaceutically active ingredient.
In a further embodiment the heating of the composition in step v) is done at a temperature from 50 to 200°C, such as 80°C to 1 10°C, to a constant weight. Typically, heating of the composition is done from about 5°C above to about 80°C above the melting point of the pharmaceutically active ingredient, such as from about 10°C above to about 70°C above the melting point of the pharmaceutically active ingredient, such as from about 20°C above to about 50°C above the melting point of the
pharmaceutically active ingredient. Such heating is carried out for as long as necessary, and typically for a time period of from 30 min to 24 hours, such as 3 to 20 hours.
In yet another aspect, the present invention relates to a method for the preparation of a composition comprising a porous adsorbent material and a
pharmaceutically active ingredient classified according to the Biopharmaceutics Classification System as belonging to Class II and IV, where essentially all active ingredient is present in amorphous form, the method comprising the steps of:
i) preparing a granulate of the porous adsorbent material,
ii) compacting, such as compressing or molding, the granulate into a loadable composition,
iii) dissolving the pharmaceutically active ingredient in an organic solvent or a mixture thereof,
iv) loading the pharmaceutically active ingredient in solution into the composition, until about 95 % of the loading capacity, such as about 90 %, about 80 %, about 70 %, preferably the solution is loaded from about 80 % of the loading capacity to 100 %, v) removing the solvent from the composition by evaporation for a sufficient time, optionally, to a constant weight,
vi) heating the composition at a temperature and for a sufficient time to a constant weight, to bring essentially all pharmaceutically active ingredient in amorphous form, to provide the composition.
This method may involve optionally treating a composition of the porous adsorbent material, by heating the empty composition before loading with a solvent. These comments also apply to any one of the further aspects and embodiments described hereunder.
In a further embodiment the temperature in step vi) exceeds the melting point of the pharmaceutically active ingredient.
In a still further embodiment the solvent in step v) is removed under reduced pressure or by freeze drying for a time period of from 30 min to 24 hours, such as 3 to 20 hours.
In a further embodiment the heating of the composition in step vi) is done at a temperature from 50 to 200°C, such as 80°C to 1 10°C, until constant weight is obtained. Typically, heating of the composition is done from about 5°C above to about 80°C above the melting point of the pharmaceutically active ingredient, such as from about 10°C above to about 70°C above the melting point of the pharmaceutically active ingredient, such as from about 20°C above to about 50°C above the melting point of the pharmaceutically active ingredient. Such heating is carried out for as long as necessary, and typically for a time period of from 30 min to 24 hours, such as 3 to 20 hours.
In yet another aspect, the present invention relates to a method for the preparation of a composition comprising a porous adsorbent material and a
pharmaceutically active ingredient classified according to the Biopharmaceutics Classification System as belonging to Class II and IV, where essentially all active ingredient is present in amorphous form, the method comprising the steps of:
i) preparing a granulate of the porous adsorbent material,
ii) mixing the pharmaceutically active ingredient with the granulate,
iii) compacting, such as compressing or molding, the granulate into a composition, iv) heating the composition at a temperature and for a sufficient time to a constant weight, to bring essentially all pharmaceutically active ingredient in amorphous form, to provide the composition.
In a further embodiment the temperature in step iv) exceeds the melting point of the pharmaceutically active ingredient.
In a further embodiment the heating of the composition in step iv) is carried out at a temperature from 50 to 200°C, such as 80°C to 1 10°C, until constant weight is obtained. Typically, heating of the composition is done from about 5°C above to about 80°C above the melting point of the pharmaceutically active ingredient, such as from about 10°C above to about 70°C above the melting point of the pharmaceutically active ingredient, such as from about 20°C above to about 50°C above the melting point of the pharmaceutically active ingredient. Such heating is carried out for as long as necessary, and typically for a time period of from 30 min to 24 hours, such as 3 to 20 hours.
In yet another aspect, the present invention relates to a method for the preparation of a composition comprising a porous adsorbent material and a
pharmaceutically active ingredient classified according to the Biopharmaceutics Classification System as belonging to Class II and IV, where essentially all active ingredient is present in amorphous form, the method comprising the steps of:
i) preparing a granulate of the porous adsorbent material,
ii) mixing the pharmaceutically active ingredient with the granulate,
iii) compacting, such as compressing or molding, the granulate into a composition, iv) loading an organic solvent or mixture thereof into the composition,
v) optionally, loading additional pharmaceutically active ingredient in solution into the composition,
vi) heating the composition at a temperature and for a sufficient time to a constant weight, to bring essentially all pharmaceutically active ingredient in amorphous form, to provide the composition.
In a further embodiment the temperature in step vi) exceeds the melting point of the pharmaceutically active ingredient.
In a further embodiment, the heating of the composition in step vi) is carried out at a temperature from 50 to 200°C, such as 80°C to 1 10°C, to a constant weight.
Typically, heating of the composition is done from about 5°C above to about 80°C above the melting point of the pharmaceutically active ingredient, such as from about 10°C above to about 70°C above the melting point of the pharmaceutically active ingredient, such as from about 20°C above to about 50°C above the melting point of the pharmaceutically active ingredient. Such heating is done for as long as necessary, and typically for a time period of from 30 min to 24 hours, such as 3 to 20 hours.
In certain situations, such as to prevent re-crystallization of the dissolved amorphous active ingredient in vivo, such as in the mammalian body, e.g. human body, it may be beneficial to add a surfactant to the composition and such surfactant is then mixed with the granulate before compacting the solid porous granulate into the composition.
In other situations, such as when an immediate release of the active ingredient is desired, then a disintegrant may be added to the granulate before compacting the solid porous granulate into the composition.
The present inventors have demonstrated that essentially all pharmaceutically active ingredient, when treated as described according to the above methods, and as illustrated by the examples given herein, will be present in the composition of the present invention in amorphous form. Thus, in a further aspect the present invention
relates to a composition comprising a porous adsorbent material and a pharmaceutically active ingredient classified according to the Biopharmaceutics Classification System as belonging to Class II and IV, wherein essentially all the pharmaceutically active ingredient is present amorphous form, this physical state being obtainable by any one of the methods described above as either aspects or
embodiments thereof.
In a further embodiment the composition is selected from any one of the
compositions as defined herein.
Various methods of loading the pharmaceutically active ingredient in a solvent into the composition are available, such as loading by placing the granulate or tablet in an excess amount of the pharmaceutically active ingredient in solution for a sufficient amount of time, or by loading under pressure, such as under reduced pressure or vacuum, or loading by spraying the pharmaceutically active ingredient in solution onto the granulate or tablet.
The composition, such as tablet, according to the invention comprises one or more pharmaceutically acceptable excipients. It is, however, of crucial importance that a least one pharmaceutically acceptable excipient are present in sufficient amounts and being capable of providing a tablet with a porosity of 30% v/v or more, such as 50% v/v or more, typically 70% v/v or more. Such pharmaceutically acceptable excipients are herein denoted "porous adsorbent material". Such excipients may also be denoted "microporous adsorbents" or "porous adsorbent carrier material" or "porous carrier material".
Below is provided a list of porous adsorbent materials having suitable properties for providing a loadable composition, e.g. tablet, according to the invention. The porous adsorbent materials may be used alone or in combination provided that the desired porosity of the composition or tablet is obtained.
To this end, it should be noted that the tablets are compressed into tablets by use of a certain compression force. However, the compression force may not be so low that the requirements with respect to hardness and friability of the tablets are compromised, i.e. these requirements ensure that the tablets are sufficiently robust.
Suitable pharmaceutically acceptable excipients that can be used to obtain tablets having a porosity of 30% v/v or more are selected from the group consisting of metal oxides, metal silicates, metal carbonates, metal phosphates, metal sulfates, sugar alcohols, sugars and cellulose and cellulose derivatives. The metal is typically selected from the group consisting of sodium, potassium, magnesium, calcium, zinc, aluminium, titanium and silicon.
A suitable metal oxide for use according to the invention may be selected from the group consisting of magnesium oxide, calcium oxide, zinc oxide, aluminium oxide, titanium dioxide including Tronox A-HP-328 and Tronox A-HP-100, silicon dioxides including Aerosil, Cab-O-Sil, Syloid, Aeroperl, Sunsil (silicon beads), Zeofree, Sipernat, and mixtures thereof.
In a specific embodiment, the metal oxide is a titanium dioxide or a silicon dioxide or mixtures thereof.
The silicates can be divided in the following groups:
• Hydrous aluminium silicates or alkaline earths. Neusilin belongs to this group and is based on synthetic polymerisation (magnesium aluminium metasilicate).
• Silicon dioxides are subdivided into porous and nonporous silicas
o Nonporous colloidal silicas e.g. Aerosil (fumed silicas)
o Porous silicas gels e.g. Syloid, Porasil, Lichrosorp
o Others e.g. Zeopharm S170, Zeopharm 6000, Aeroperl 300 Accordingly, a loadable tablet according to the invention may contain a metal oxide that is a non-porous silicate including fumed silicas of the Aerosil type, and/or a porous silicate including e.g. Syloid, Porasil and Lichrosorp.
In other embodiments, the pharmaceutically acceptable excipient for use according to the invention is a metal silicate selected from the group consisting of sodium silicate, potassium silicate, magnesium silicate, calcium silicate including synthetic calcium silicate such as, e.g., Hubersorp, microporous calcium silicate, such as Florite, zinc silicate, aluminum silicate, sodium aluminosilicate such as, e.g., Zeolex, magnesium aluminum silicate, magnesium aluminum metasilicate, aluminium metasilicate, Neusilin SG2 and Neusilin US2 and mixtures thereof.
The aluminum silicate is a highly porous material having a typical average pore size of 30 to 80, such as 50-60 angstrom and a surface area of from 250 to 400 m2/g, such as about 300 m2/g. The composition of the present invention typically has a porosity of 30 % v/v or more, which is necessary for absorption of a suitable amount of a pharmaceutically active ingredient. In further embodiments the porosity is 40 % v/v or more, 50 % v/v or more, 60 % v/v or more, 70 % v/v or more, 80 % v/v or more, or 90 % v/v or more. The porosity is measured on the aluminum silicate, such as Neusilin, and then it is calculated how much aluminum silicate and an optional pharmaceutically acceptable excipient, utilize of the porosity.
The porosity of the granules or tablets before loading is calculated on basis of the density of the granule or tablet pt and the "true density" ps of the ingredients. The porosity ε of the granule or tablet is calculated according to the Equation 1 .
ε = 1 -— Equation 1
P.
The density of the granule or tablet is based on the ratio between weight and volume of the granule or tablet. The "true density" of the ingredients is based on the gas pycnometric density determined in helium using Micromeritics Accupyc 1330.
In a further embodiment the composition of the present invention the aluminum silicate is typically present in a concentration of about 20% w/w or more. It is apparent that the higher porosity desired the higher the concentration of the aluminum silicate, thus in further embodiments of the composition of the present invention the aluminum silicate is present in a concentration of about 25% w/w or more, about 30% w/w or more, about 35% w/w or more, about 40% w/w or more, about 45% w/w or more, about 50 w/w or more, about 60% w/w or more, about 70% or more, about 80% or more, about 90% or more, about 95% or more, or about 98% or more, in the unloaded composition.
The aluminum silicate typically, has an average pore size of 30 to 80, such as 50- 60 angstrom and a surface area of from 250 to 400 m2/g, such as about 300 m2/g. In an embodiment the aluminum silicate is selected from magnesium aluminum metasilicate, magnesium aluminum silicate, and aluminium metasilicate, and mixtures thereof. Typical examples of aluminum silicates are Neusilin SG2, and Neusilin US2, and mixtures thereof, in particular A^Os.MgO.ySiC^. xH20, wherein y is from 1.5-2, and x is 1 -10, preferred is magnesium aluminum metasilicate, e.g. Al203-Mg0.2Si02. 5H20.
As mentioned above a suitable pharmaceutically acceptable excipient may be a metal carbonate such as a carbonate selected from the group consisting of sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, calcium carbonate, magnesium carbonate, zinc carbonate and aluminum carbonate, and mixtures thereof.
Other metal salt suitable for use according to the invention are metal phosphates selected from the group consisting of sodium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, calcium phosphate, magnesium phosphate, zinc phosphate and aluminum phosphate.
More specifically, the pharmaceutically acceptable excipient may be a calcium phosphate selected from the group consisting of dibasic anhydrous calcium phosphate, dibasic dihydrate calcium phosphate, and tribasic calcium phosphate.
The dibasic anhydrous calcium phosphate is typically selected from the group consisting of A-Tab, calcium monohydrogen phosphate, calcium orthophosphate, Di- Cafos AN, dicalcium orthophosphate, E341 , Anhydrous Emcompress, Fujicalin, phosphoric acid calcium salt (1 :1 ), and secondary calcium phosphate, and mixtures thereof. The dibasic dihydrate calcium phosphate may be selected from the group consisting of Cafos, calcium hydrogen orthophosphate dihydrate, calcium
monohydrogen phosphate dihydrate, Calipharm, Calstar, Di-Cafos, dicalcium orthophosphate, DI-TAB, Emcompress, phosphoric acid calcium salt (1 :1 ) dihydrate, secondary calcium phosphate, Fujiclin SG.
Examples of tribasic calcium phosphates are e.g. hydroxyapatite, phosphoric acid calcium salt (2:3), precipitated calcium phosphate, tertiary calcium phosphate, Tri- Cafos, tricalcium diorthophosphate, tricalcium orthophosphate, tricalcium phosphate, TRI-CAL, WG, TRI-TAB.
Other suitable metal salts are metal sulfates such as, e.g, sodium sulfate, sodium hydrogen sulfate, potassium sulfate, potassium hydrogen sulfate, calcium sulfate, magnesium sulfate, zinc sulfate and/or aluminum sulfate.
Examples of suitable calcium sulfates are e.g. calcium sulfate anhydrous including anhydrite, anhydrous gypsum, anhydrous sulfate of lime, Destab, Drierte, E516, karstenite, muriacite, and Snow White or calcium sulfate dihydrate including alabaster, Cal-Tab, Compactrol, Destab, E516, gypsum, light spar, mineral white, native calcium sulfate, precipitated calcium sulfate, satinite, satin spar, selenite, terra alba and USG Terra Alba.
Any one of the above porous adsorbent materials are intended to be embodiments of the invention as long as they alone or in mixture provides a suitable porosity as described above. The below specified embodiments are not to be construed as limiting the invention in any way but are merely to highlight certain preferred embodiments.
In a further embodiment, the porous abdsorbent material is selected from porous silicon dioxide, such as sodium silicate, potassium silicate, magnesium silicate, calcium silicate, including synthetic calcium silicate, microporous calcium silicate, zinc silicate, aluminum silicate, sodium aluminosilicate, hydrous aluminium silicates or alkaline earths, magnesium aluminum metasilicate, magnesium aluminum silicate, aluminium metasilicate, nonporous colloidal silicas, porous silicas gels, precipitated silicate, and mixtures thereof. In a further embodiment the porous adsorbent material is selected
from metal carbonates and metal phosphates. Typically, the porous adsorbent material is selected from magnesium aluminum metasilicate, precipitated silicate, and microporous calcium silicate.
As described above the present invention relates to a composition comprising a porous adsorbent material and a pharmaceutically active ingredient classified according to the Biopharmaceutics Classification System as belonging to Class II and IV, wherein the pharmaceutically active ingredient is in essentially amorphous form.
The pharmaceutically active ingredient to be loaded or compacted into the composition of the invention is a compound having low solubility, typically a small organic compound of less than 2000 Da. Such compounds with low solubility are classified, as described in Amidon et al, "A Theoretical Basis for a Biopharmaceutical Drug Classification: The correlation of in vitro Drug Product Dissolution and in vivo Bioavailability." Pharmaceutical Reseach, vol. 12, no. 3, 1995. This classification system is known as the Biopharmaceutics Classification System (BCS). The
Biopharmaceutics Classification System is guidance for predicting the intestinal drug absorption provided by the U.S. Food and Drug Administration. The fundamental basis for the BCS was established by Dr. Gordon Amidon who was presented with a
Distinguished Science Award at the August 2006 International Pharmaceutical Federation (FIP) congress in Salvador, Brazil. When referring to "a pharmaceutically active ingredient" to be loaded or compacted into the composition of the invention, or when referring to a composition comprising the pharmaceutically active ingredient as used herein, it is intended that it refers to the un-processed pharmaceutically active ingredient, thus, the pharmaceutically active ingredient before being processed according to the present invention.
According to the Biopharmaceutics Classification System, drug substances are classified as follows
• Class I - High Permeability, High Solubility
o Example: Metoprolol
o Those compounds are well absorbed and their absorption rate is usually higher than excretion.
• Class II - High Permeability, Low Solubility
o Example: Glibenclamide
o The bioavailability of those products is limited by their solvation rate. A correlation between the in vivo bioavailability and the in vitro solvation can be found.
• Class III - Low Permeability, High Solubility
o Example: Cimetidine
o The absorption is limited by the permeation rate but the drug is solvated very fast. If the formulation does not change the permeability or gastrointestinal duration time, then class I criteria can be applied.
• Class IV - Low Permeability, Low Solubility
o Example: Hydrochlorothiazide
o Those compounds have a poor bioavailability. Usually they are not well absorbed over the intestinal mucosa and a high variability is expected. The drugs are classified in BCS on the basis of following parameters: 1 . Solubility, 2.
Permeability, 3. Dissolution.
The class boundaries for these parameters arel . Solubility class boundaries: It is based on the highest dose strength of an immediate release product. A drug is considered highly soluble when the highest dose strength is soluble in 250mL or less of aqueous media over the pH range of 1 to 7.5. The volume estimate of 250mL is derived from typical bioequivalence study protocols that prescribe administration of a drug product to fasting human volunteers with a glass of water.
2. Permeability class boundaries: It is based indirectly on the extent of absorption of a drug substance in humans and directly on the measurement of rates of mass transfer across human intestinal membrane. Alternatively non-human systems capable of prediction the drug absorption systems capable of predicting the drug absorption in humans can be used (such as in-vitro culture methods). A drug substance is considered highly permeable when the extent of absorption in humans is determined to be 90 % or more of the administered dose based on a mass-balance determination or in comparison to and intravenous dose.
3. Dissolution class boundaries: An immediate release products is considered rapidly dissolving when no less than 85% of the labeled amount of the drug substance dissolve within 30 minutes using USP Dissolution Apparatus 1 at 100 RPM or
Apparatus 2 at 50 RPM in a volume of 900ml or less in following media,) 0.1 N HCI or simulated gastric fluid or pH 4.5 buffer and pH 6.8 buffer or simulated intestinal fluid.
The pharmaceutical active ingredient to be used in the composition of the invention is selected from compounds classified according to the Biopharmaceutics Classification System as belonging to Class II and IV, and such compounds are typically selected from atorvastatin, clopidogrel, esomeprazole, valsartan, olanzapine, risperidone, pioglitazone, quetiapine, lansoprazole, candesartan, imatinib, irbesartan,
aripiprazole, ezetimibe, celecoxib, lamotrigine, telmisartan, olmesartan, tacrolimus, fenofibrate, fenofibric acid, ibuprofen, mycophenolate, bicalutamide, lopinavir, ritonavir, raloxifene, efavirenz, carvedilol, omeprazol, methylphenidate, cyclosporine, simvastatin, ziprasidone, nifedipine, glimepiride, glipizide, glyburide, hydroxyzine, isotretinoin, loratadine, medroxyprogesterone, meloxicam, metaxalone, nelfinavir, rofecoxib, warfarin, cabergoline, carbamazepine, clozapine, cyproterone, itraconazole, nevirapine, orlistat, valproate, benidipine, cefditoren, ebastine, epalrestat, ethyl icosapentate, flurbiprofen, gefitinib, gliclazide, ketoprofen, cilostazol, diclofenac, manidipine, menatetrenone, mosapride, nicergoline, nilvadipine, pranlukast, rebamipide, tamoxifen, teprenone, ticlopidine, tocopherol, ursodeoxycholic acid, azithromycin, clarithromycin, valdecoxib, efavirenz, sirolimus, indinavir, amprenavir, aprepitant, eprosartan, lapatinib, posaconazole, tipranavir and mixtures thereof. Also included in the term "a pharmaceutically active ingredient classified according to the Biopharmaceutics Classification System as belonging to Class II and IV" are different forms of such compounds, such as the free forms, such as free acids, free bases, esters and salts thereof, or mixtures thereof. It is also important to understand that new chemical compounds which are developed and which can be classified according to BCS as belonging to Class II and IV is intended to be included in the term "a pharmaceutically active ingredient classified according to the Biopharmaceutics Classification System as belonging to Class II and IV".
Any one of the above pharmaceutically active ingredients classified according to the Biopharmaceutics Classification System as belonging to Class II and IV are intended to be embodiments of the invention. The below specified embodiments are not to be construed as limiting the invention in any way but are merely to highlight certain preferred embodiments. However, it is contemplated that, in general, also new and yet unknown chemical entities qualifying for classification in the BCS Classes II or IV will be embodiments of the invention.
In a particular embodiment the pharmaceutically active ingredient is selected from class II.
In a further embodiment the pharmaceutically active ingredient has low water solubility. Typically, the pharmaceutically active ingredient has low water solubility and high permeability.
As mentioned above suitable pharmaceutically active ingredients are selected from small organic molecules of less than 2000 Da, such as from 150 Da to 2000 Da.
Essentially all the pharmaceutically active ingredient classified according to the
Biopharmaceutics Classification System as belonging to Class II and IV is provided in
the composition of the present invention in amorphous form. Although a complete (i.e. 100%) conversion of the active ingredient into amorphous form is desirable, it will often not be technically possible or feasible to obtain a complete transformation. Accordingly, the terms "essentially" and "essentially all", as used herein in connection with the content of active pharmaceutical ingredient(s) in the composition of the invention or the composition prepared by the method(s) of the invention, denote compositions of the invention having at least 95% w/w of the pharmaceutically active ingredient is in amorphous form. Typically, at least 96% w/w of the pharmaceutically active ingredient is in amorphous form, such as from 97% w/w to 99.5% w/w.
During preparation of the composition of the present invention it may be necessary to heat the composition in order to produce the amorphous pharmaceutically active ingredient, or, alternatively, to subject the composition to evaporation. The heating may be done at a temperature below the melting point of the pharmaceutically active ingredient and this is typically done if the pharmaceutically active ingredient transforms to amorphous form below its melting point, or the heating may be done at a temperature above the melting point of the pharmaceutically active ingredient if needed to transform the pharmaceutically active ingredient to amorphous form. In further embodiments the pharmaceutically active ingredient has a melting point below 250°C, for instance below 200°C, such as below 180°C, e.g. below 100°C. Typically, heating of the granules or composition comprising the pharmaceutically active ingredient is done from about 5°C above to about 80°C above the melting point of the pharmaceutically active ingredient, thus, in a further embodiment the heating of the granules or composition is done from below 330°C, for instance below 250°C, such as below 180°C, e.g. below 100°C, such as from about 50°C to about 200°C.
In a further embodiment, the pharmaceutically active ingredient (or active pharmaceutical ingredient, API) is selected from atorvastatin, clopidogrel,
esomeprazole, valsartan, olanzapine, risperidone, pioglitazone, quetiapine,
lansoprazole, candesartan, imatinib, irbesartan, aripiprazole, ezetimibe, celecoxib, lamotrigine, telmisartan, olmesartan, tacrolimus, fenofibrate, fenofibric acid, ibuprofen, mycophenolate, bicalutamide, lopinavir, ritonavir, raloxifene, efavirenz, carvedilol, omeprazol, methylphenidate, cyclosporine, simvastatin, ziprasidone, nifedipine, glimepiride, glipizide, glyburide, hydroxyzine, isotretinoin, loratadine,
medroxyprogesterone, meloxicam, metaxalone, nelfinavir, rofecoxib, warfarin, cabergoline, carbamazepine, clozapine, cyproterone, itraconazole, nevirapine, orlistat, valproate, benidipine, cefditoren, ebastine, epalrestat, ethyl icosapentate, flurbiprofen, gefitinib, gliclazide, ketoprofen, cilostazol, diclofenac, manidipine, menatetrenone,
mosapride, nicergoline, nilvadipine, pranlukast, rebamipide, tamoxifen, teprenone, ticlopidine, tocopherol, ursodeoxycholic acid, azithromycin, clarithromycin, valdecoxib, efavirenz, sirolimus, indinavir, amprenavir, aprepitant, eprosartan, lapatinib, posaconazole, tipranavir, and free acids, bases, esters and salts thereof, or mixtures thereof. Typically, the pharmaceutically active ingredient is selected from
posaconazole, celecoxib, fenofibrate or ibuprofen.
In the present context, the term "a salt" is intended to indicate any such salt that a specific active ingredient may form upon contact with the relevant acid or base, and typically such salt is selected from a pharmaceutically acceptable salt, where the term "a pharmaceutically acceptable salt" is intended to indicate salts which are not harmful to the patient. Such salts include pharmaceutically acceptable acid addition salts, pharmaceutically acceptable metal salts, ammonium and alkylated ammonium salts. Acid addition salts include salts of inorganic acids as well as organic acids.
Representative examples of suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, nitric acids and the like. Representative examples of suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, glycolic, lactic, maleic, malic, malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic, methanesulfonic, ethanesulfonic, tartaric, ascorbic, pamoic, bismethylene salicylic, ethanedisulfonic, gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, p-toluenesulfonic acids and the like. Further examples of pharmaceutically acceptable inorganic or organic acid addition salts include the pharmaceutically acceptable salts listed in J. Pharm. Sci. 66, 2, (1977) which is incorporated herein by reference.
Examples of metal salts include lithium, sodium, potassium, magnesium salts and the like. Examples of ammonium and alkylated ammonium salts include ammonium, methylammonium, dimethylammonium, trimethylammonium, ethylammonium, hydroxyethylammonium, diethylammonium, butylammonium, tetramethylammonium salts and the like.
According to one aspect of the invention the pharmaceutically active ingredient classified according to the Biopharmaceutics Classification System as belonging to Class II and IV may be dissolved in an organic solvent (essentially water free) or mixtures thereof, and loaded into the composition of the invention. Although water is not suitable as a solvent it may be used as a co-solvent, and in an embodiment the organic solvent is mixed with water as co-solvent.
The organic solvent may in principle be any organic solvent which can dissolve the pharmaceutically active ingredient as described above, however, many organic
solvents are not suitable for pharmaceutical formulations, in particular for veterinary or humane medicines, and in this respect certain classes of solvent are preferred.
According to The European Agency for the Evaluation of Medicinal Products guidelines for classification of solvents have been developed and described in VICH Topic GL18 (impurities solvents) and in this respect the solvents with low toxic potential are preferred. Such organic solvents are referred to herein as Class 3 solvents according to the EMEA guidelines. Although Class 3 solvents are preferred it may also be beneficial to use Class 2 solvents in some instances. The organic solvent to be used in the composition of the invention is typically, selected from solvents classified as Class 3 solvents according to the EMEA guidelines and such compounds are selected from formic acid, tetrahydrofuran, acetid acid, acetone, anisole, 1 -butanol, 2-butanol, butyl acetate, tert-butylmethyl ether, cumene, dimethylsulfoxide, ethanol, ethyl acetate, ethyl ether, ethyl formate, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1 -butanol, methylethyl ketone, methylisobutyl ketone, 2-methyl-1 -propanol, pentane, 1 -pentanol, 1 -propanol, 2-propanol, propyl acetate and mixtures thereof. It is also important to understand that new organic solvents which can be classified according to the EMEA guidelines as belonging to Class 3 solvents is intended to be included in the term "a Class 3 solvent according to the EMEA guidelines".
Any one of the above organic solvents classified according to the EMEA guidelines as belonging to Class 3 solvent are intended to be embodiments of the invention. It should be understood that organic solvents that are un-classified, may later change classification into Class 3 solvent according to the EMEA guidelines, and are intended to be included in the term "a Class 3 solvent according to the EMEA guidelines". The below specified embodiments are not to be construed as limiting the invention in any way but are merely to highlight certain preferred embodiments.
In a further embodiment the organic solvent is classified as a Class 3 solvent according to the EMEA guidelines.
In a further embodiment the organic solvent is selected from formic acid, tetrahydrofuran, acetid acid, acetone, anisole, 1 -butanol, 2-butanol, butyl acetate, tert- butylmethyl ether, cumene, dimethylsulfoxide, ethanol, ethyl acetate, ethyl ether, ethyl formate, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1 - butanol, methylethyl ketone, methylisobutyl ketone, 2-methyl-1 -propanol, pentane, 1 - pentanol, 1 -propanol, 2-propanol, propyl acetate or mixtures thereof. Typically, the organic solvent is selected from ethanol or 2-propanol.
The organic solvent to be used in the composition of the invention may be selected from solvents classified as Class 2 solvents according to the EMEA guidelines
and such compounds are selected from acetonitrile, chlorobenzene, chloroform, cyclohexane, 1 ,2-dichloroethene, dichloromethane, 1 ,2-dimethoxyethane, N,N- dimethylacetamide, Ν,Ν-dimethylformamide, 1 ,4-dioxane, 2-ethoxyethanol, ethylene glycol, formamide, hexane, methanol, 2-methoxyethanol, methylbutylketone, methylcyclohexane, N-methylpyrrolidone, nitromethane, pyridine, sulfolane, tetraline, toluene, 1 ,1 ,2-thrchloroethene, or xylene, and mixtures thereof. It is also important to understand that new organic solvents which can be classified according to the EMEA guidelines as belonging to Class 2 solvents is intended to be included in the term "a Class 2 solvent according to the EMEA guidelines".
Any one of the above organic solvents classified according to the EMEA guidelines as belonging to Class 2 solvent are intended to be embodiments of the invention. It should be understood that organic solvents that are un-classified, may later change classification into Class 2 solvent according to the EMEA guidelines, and are intended to be included in the term "a Class 2 solvent according to the EMEA guidelines". The below specified embodiments are not to be construed as limiting the invention in any way but are merely to highlight certain preferred embodiments.
In a further embodiment the organic solvent is classified as a Class 2 solvent according to the EMEA guidelines.
In a further embodiment the organic solvent is selected from acetonitrile, chlorobenzene, chloroform, cyclohexane, 1 ,2-dichloroethene, dichloromethane, 1 ,2- dimethoxyethane, N,N-dimethylacetamide, Ν,Ν-dimethylformamide, 1 ,4-dioxane, 2- ethoxyethanol, ethylene glycol, formamide, hexane, methanol, 2-methoxyethanol, methylbutylketone, methylcyclohexane, N-methylpyrrolidone, nitromethane, pyridine, sulfolane, tetraline, toluene, 1 ,1 ,2-thrchloroethene, or xylene or mixtures thereof.
Since it is intended to provide compositions which are dry, it is important that all, or essentially all, organic solvent can be removed from the composition; typically, the organic solvent has a boiling point of from 50°C to 140°C.
The composition, such as tablet, may of course also comprise or contain other and/or additional pharmaceutically acceptable excipients such as those normally employed in the manufacturing of tablets.
In the present context, the term "pharmaceutically acceptable excipient" is intended to denote any material, which is inert in the sense that it substantially does not have any therapeutic and/or prophylactic effect per se. Such an excipient may be added with the purpose of making it possible to obtain a pharmaceutical, cosmetic and/or foodstuff composition, which have acceptable technical properties.
Examples of suitable excipients for use in a composition according to the invention include fillers, diluents, disintegrants, binders, lubricants etc. or mixture thereof. As the composition or solid dosage form according to the invention may be used for different purposes, the choice of excipients is normally made taken such different uses into considerations. Other pharmaceutically acceptable excipients for suitable use are e.g. acidifying agents, alkalizing agents, preservatives, antioxidants, buffering agents, chelating agents, coloring agents, complexing agents, emulsifying and/or solubilizing agents, flavors and perfumes, humectants, sweetening agents, wetting agents etc.
Examples of suitable fillers, diluents and/or binders include lactose (e.g. spray- dried lactose, a-lactose, β-lactose, Tabletose®, various grades of Pharmatose®, Microtose® or Fast-Floe®), microcrystalline cellulose (various grades of Avicel®, Elcema®, Vivacel®, Ming Tai® or Solka-Floc®), hydroxypropylcellulose, L- hydroxypropylcellulose (low substituted), hydroxypropyl methylcellulose (HPMC) (e.g. Methocel E, F and K, Metolose SH of Shin-Etsu, Ltd, such as, e.g. the 4,000 cps grades of Methocel E and Metolose 60 SH, the 4,000 cps grades of Methocel F and Metolose 65 SH, the 4,000, 15,000 and 100,000 cps grades of Methocel K; and the 4,000, 15,000, 39,000 and 100,000 grades of Metolose 90 SH), methylcellulose polymers (such as, e.g., Methocel A, Methocel A4C, Methocel A15C, Methocel A4M), hydroxyethylcellulose, sodium carboxymethylcellulose, carboxymethylene,
carboxymethylhydroxyethylcellulose and other cellulose derivatives, sucrose, agarose, sorbitol, mannitol, dextrins, maltodextrins, starches or modified starches (including potato starch, maize starch and rice starch), calcium phosphate (e.g. basic calcium phosphate, calcium hydrogen phosphate, dicalcium phosphate hydrate), calcium sulfate, calcium carbonate, sodium alginate, collagen etc.
Specific examples of diluents are e.g. calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, microcrystalline cellulose, powdered cellulose, dextrans, dextrin, dextrose, fructose, kaolin, lactose, mannitol, sorbitol, starch, pregelatinized starch, sucrose, sugar etc.
Specific examples of useful binders are e.g. acacia, alginic acid, agar, calcium carrageenan, sodium carboxymethylcellulose, microcrystalline cellulose, dextrin, ethylcellulose, gelatin, liquid glucose, guar gum, hydroxypropyl methylcellulose, methylcellulose, pectin, PEG, povidone, pregelatinized starch etc.
Glidants and lubricants may also be included in the tablet. Examples include stearic acid, magnesium stearate, calcium stearate or other metallic stearate, colloidal silicondioxide (Aerosil) talc, waxes and glycerides, light mineral oil, PEG, glyceryl
behenate, colloidal silica, hydrogenated vegetable oils, corn starch, sodium stearyl fumarate, polyethylene glycols, alkyl sulfates, sodium benzoate, sodium acetate etc.
Other excipients which may be included in a loadable tablet of the invention are e.g. flavoring agents, coloring agents, taste-masking agents, pH-adjusting agents, buffering agents, preservatives, stabilizing agents, anti-oxidants, wetting agents, humidity-adjusting agents, surface-active agents, suspending agents, absorption enhancing agents, agents for modified release etc.
Other additives in a composition or a solid dosage form according to the invention may be antioxidants like e.g. ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorous acid, monothioglycerol, potassium metabisulfite, propyl gallate, sodium formaldehylde sulfoxylate, sodium metabisulfite, sodium thiosulfate, sulfur dioxide, tocopherol, tocopherol acetate, tocopherol hemisuccinate, TPGS or other tocopherol derivatives, etc. The carrier composition may also contain e.g. stabilising agents. The concentration of an antioxidant and/or a stabilizing agent in the carrier composition is normally from about 0.1 % w/w to about 5% w/w.
The composition or solid dosage form according to the invention may also include one or more surfactants or substances having surface-active properties. It is contemplated that such substances are involved in the solubilization of the slightly soluble active substance and thus, contributes to improved solubility characteristics of the active substance. As used herein the term "surfactant" is intended to include one surfactant or a mixture of surfactants. In certain situations, such as to prevent recrystallization of the dissolved amorphous active ingredient in vivo, such as in the mammalian body, e.g. human body, it may be beneficial to add a surfactant to the composition and such surfactant is then mixed with the granulate before compacting the solid porous granulate into the composition.
Examples of useful surfactants are:
Cremophor RH40 Polyoxyl 40 hydrogenated castor oil
Cremophore ELP Polyoxyl 35 castor oil
Polysorbate 20, Tween 20, Polyoxyethylene Sorbitan
Montanox 20 PHA Fatty Acid Ester based on Laurie acid
Polysorbate 80, Tween 80, Polyoxyethylene Sorbitan
Montanox 80 VG PHA Fatty Acid Ester based on Oleic acid
Labrafil M 1944 CS Oleoyl macrogol-6-glycerides
Labrafil M 2125 CS Lauroyl Macrogol-6 glycerides
Labrasol Caprylocaproyl macrogolglycerides
Lutrol F127 Poloxamer 407
Lutrol F68 Poloxamer 188
Montane 20 PHA Sorbitan monolaurate, Span 20
Span 60 pharma Sorbitan monostearate
Montane 80 VG PHA Sorbitan monooleate, Span 80
Soluplus Polyvinyl-caprolactam-polyvinyl acetate
Solutol HS 15 Polyoxyl 15 Hydroxystearate
Speziol TPGS Pharma Vitamin E TPGS
Transcutol HP Diethylene glycol monoethyl ether
Any one of these surfactants is intended to be specific embodiments and may be combined with any one of the aspects and/or embodiments of the present invention.
The composition of the present invention may further comprise a disintegrant. Specific examples of disintegrants are e.g. croscarmellose sodium, alginic acid or alginates, microcrystalline cellulose, hydroxypropyl cellulose and other cellulose derivatives, crospovidone, polacrillin potassium, sodium starch glycolate, starch, pregelatinized starch, carboxymethyl stare and mixtures thereof (e.g. Primogel® and Explotab®) etc. Any one of these disintegrants is intended to be specific embodiments and may be combined with any one of the aspects and/or embodiments of the present invention.
Typically, the concentration of disintegrant is from 1 %w/w to 20 %w/w, such as 1 %w/w to 10 %w/w, such as 2 %w/w to 15 %w/w, such as 2.5 %w/w to 8 %w/w (based on the total weight of the composition before loading).
The final composition of the present invention may be formulated so as to provide immediate release, delayed or sustained release of the active ingredient. When immediate release is desired the composition of the present invention is formed as a tablet further comprising a disintegrant. To optimize disintegration the composition of the present invention comprising an aluminum silicate, and compressed into a tablet, is mixed with a disintegrant before making the tablet. Thus, in an embodiment the loadable solid porous composition of the present invention, such as the tablet, comprises an aluminum silicate and a disintegrant. Such a disintegrant may be selected from croscarmellose sodium, alginic acid or alginates, microcrystalline cellulose, hydroxypropyl cellulose and other cellulose derivatives, crospovidone,
polacrillin potassium, sodium starch glycolate, starch, pregelatinized starch, and carboxymethyl starch, typically croscarmellose sodium.
In order to provide a reliable pharmaceutical composition to be given to mammals, such has human subjects; the pharmaceutically active ingredient must be released, at least partly, from the loaded composition, and in particular must be released in a consistent and preferably high manner to ensure a therapeutically effective amount. The pharmaceutically active ingredient is released from the composition upon contact with an aqueous environment, such as administration to a mammal. Such release may be delayed or sustained and will depend on the tested active ingredient and the disease or disorder to be treated. The active ingredient contained in the porous composition, e.g. tablet, may be released by erosion of the tablet depending on the additional excipients contained in the composition or may diffuse out of the composition into the aqueous environment, such as human bodily fluids. As explained above an immediate release is obtainable when a disintegrant is mixed together with the aluminum silicate to form a tablet of the present invention.
In a further aspect of the present invention, any of the above described compositions, such as tablets, capsules, granules or granulate, are for use as a medicine. In particular, the present invention relates to use of ibuprofen, posaconazole, celecoxib, or fenofibrate, or a salt or free acid form thereof for preparing the solid porous composition as described herein.
List of embodiments
1 . A composition comprising a porous adsorbent material and a pharmaceutically active ingredient selected from the group consisting of active ingredients classified according to the Biopharmaceutics Classification System as belonging to Class II or Class IV, wherein essentially all pharmaceutically active ingredient is present in amorphous form.
2. The composition of embodiment 1 wherein the pharmaceutically active ingredient is belonging to Class II.
3. The composition of any one of embodiments 1 -2 wherein the pharmaceutically active ingredient has low water solubility.
4. The composition of any one of embodiments 1 -3 wherein the pharmaceutically active ingredient has low water solubility and high permeability.
5. The composition of any one of embodiments 1 -4 wherein the pharmaceutically active ingredient is a small organic molecule of from 150 Da to 2000 Da. 6. The composition of any one of embodiments 1 -5 wherein at least 95% (w/w) of the pharmaceutically active ingredient is present in amorphous form, such as 96% to 99%.
7. The composition of any one of embodiments 1 -6 wherein the pharmaceutically active ingredient has a melting point below 250°C, for instance below 200°C, such as below 180°C, e.g. below 100°C.
8. The composition of any one of embodiments 1 -7 wherein the pharmaceutically active ingredient is selected from the group consisting of atorvastatin, clopidogrel,
esomeprazole, valsartan, olanzapine, risperidone, pioglitazone, quetiapine,
lansoprazole, candesartan, imatinib, irbesartan, ibuprofen, aripiprazole, ezetimibe, celecoxib, lamotrigine, telmisartan, olmesartan, tacrolimus, fenofibrate, fenofibric acid, mycophenolate, bicalutamide, lopinavir, ritonavir, raloxifene, efavirenz, carvedilol, omeprazol, methylphenidate, cyclosporine, simvastatin, ziprasidone, nifedipine, glimepiride, glipizide, glyburide, hydroxyzine, isotretinoin, loratadine,
medroxyprogesterone, meloxicam, metaxalone, nelfinavir, rofecoxib, warfarin, cabergoline, carbamazepine, clozapine, cyproterone, itraconazole, nevirapine, orlistat, valproate, benidipine, cefditoren, ebastine, epalrestat, ethyl icosapentate, flurbiprofen, gefitinib, gliclazide, ketoprofen, cilostazol, diclofenac, manidipine, menatetrenone, mosapride, nicergoline, nilvadipine, posaconazole, pranlukast, rebamipide, tamoxifen, teprenone, ticlopidine, tocopherol, ursodeoxycholic acid, azithromycin, clarithromycin, valdecoxib, efavirenz, sirolimus, indinavir, amprenavir, aprepitant, eprosartan, lapatinib, posaconazole, tipranavir, and free acids, bases, esters and salts thereof; and from mixtures thereof. 9. The composition of any one of embodiments 1 -8 wherein the pharmaceutically active ingredient is posaconazole, celecoxib, fenofibrate, or ibuprofen.
10. The composition of any one of embodiments 1-9 wherein the pharmaceutically active ingredient is dissolved in an organic solvent (essentially water free) or mixtures thereof, and loaded into the composition.
1 1. The composition of embodiment 10 wherein the organic solvent is classified as a Class 2 solvent or a Class 3 solvent according to the EMEA guidelines, preferably as a Class 3 solvent. 12. The composition of embodiment 1 1 wherein the organic solvent is selected from formic acid, tetrahydrofuran, acetid acid, acetone, anisole, 1 -butanol, 2-butanol, butyl acetate, tert-butylmethyl ether, cumene, dimethylsulfoxide, ethanol, ethyl acetate, ethyl ether, ethyl formate, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3- methyl-1 -butanol, methylethyl ketone, methylisobutyl ketone, 2-methyl-1 -propanol, pentane, 1 -pentanol, 1 -propanol, 2-propanol, propyl acetate or mixtures thereof.
13. The composition of embodiment 1 1 or 12 wherein the organic solvent has a boiling point of from 50°C to 140°C. 14. The composition of any one of embodiments 10-13, wherein the solvent is removed from the composition and the composition is free of solvent.
15. The composition of any one of embodiments 1-14. wherein the composition is dry. 16. The composition of any one of embodiments 1-15 wherein the porous adsorbent material is selected from metal carbonates, metal phosphates, or porous silicon dioxide, such as sodium silicate, potassium silicate, magnesium silicate, calcium silicate, including synthetic calcium silicate, microporous calcium silicate, zinc silicate, aluminum silicate, sodium aluminosilicate, hydrous aluminium silicates or alkaline earths, magnesium aluminum metasilicate, magnesium aluminum silicate, aluminium metasilicate, nonporous colloidal silicas, porous silicas gels, precipitated silicate, and mixtures thereof.
17. The composition of any one of embodiments 1-16 wherein the composition is a tablet.
18. The composition of any one of the preceding embodiments further comprising a pharmaceutically acceptable excipient, such as a surfactant. 19. The composition of any one of the preceding embodiments further comprising a pharmaceutically acceptable excipient, such as a disintegrant.
20. A method for the preparation of a composition comprising a porous adsorbent material and a pharmaceutically active ingredient selected from the group consisting of active ingredients classified according to the Biopharmaceutics Classification System as belonging to Class II or ClasslV, where essentially all active ingredient is present in amorphous form, the method comprising the steps of:
i) preparing a granulate of the porous adsorbent material,
ii) dissolving the pharmaceutically active ingredient in an organic solvent or a mixture thereof,
iii) loading the pharmaceutically active ingredient in solution into the granules, until about 95 % of the loading capacity, such as about 90 %, about 80 %, about 70 %, preferably the solution is loaded from about 80 % of the loading capacity to 100 %, iv) heating the granules at a temperature and for a sufficient time to obtain constant weight, to bring essentially all pharmaceutically active ingredient in amorphous form, v) compacting, such as compressing or molding, the granulate into the composition.
21. The method of embodiment 20, comprising in step iv) the temperature exceeding the melting point of the pharmaceutically active ingredient, such as exceeding the melting point with about 5°C to about 80°C, such as with about 10°C to about 70°C, such as with about 20°C to about 50°C.
22. The method of embodiments 20 or 21 , comprising heating the granules in step iv) at a temperature from 50 to 200°C, such as 80°C to 1 10°C, to a constant weight. 23. The method of any one of embodiments 20-22, comprising heating the granules in step iv) for a time period of from 30 min to 24 hours, such as 3 to 20 hours.
24. A method for the preparation of a composition comprising a porous adsorbent material and a pharmaceutically active ingredient selected from the group consisting of active ingredients classified according to the Biopharmaceutics Classification System as belonging to Class II or Class IV, where essentially all active ingredient is present in amorphous form, the method comprising the steps of:
i) preparing a granulate of the porous adsorbent material,
ii) dissolving the pharmaceutically active ingredient in an organic solvent or a mixture thereof,
iii) loading the pharmaceutically active ingredient in solution into the granules, until about 95 % of the loading capacity, such as about 90 %, about 80 %, about 70 %, preferably the solution is loaded from about 80 % of the loading capacity to 100 %, iv) removing the solvent form the granules by evaporation for a sufficient time, optionally, to a constant weight,
v) heating the granules at a temperature and for a sufficient time to a constant weight, to bring essentially all pharmaceutically active ingredient in amorphous form, vi) compacting, such as compressing or molding, the granulate into the composition. 25. The method of embodiment 24, comprising in step v) the temperature exceeding the melting point of the pharmaceutically active ingredient, such as exceeding the melting point with about 5°C to about 80°C, such as with about 10°C to about 70°C, such as with about 20°C to about 50°C. 26. The method of embodiment 24 or 25, comprising removing the solvent in step iv) under reduced pressure or by freeze drying for a time period of from 30 min to 24 hours, such as 3 to 20 hours.
27. The method of any one of embodiments 24-26, comprising heating the granules in step v) at a temperature from 50 to 200°C, such as 80°C to 1 10°C, to a constant weight.
28. The method of any one of embodiments 24-27, comprising heating the granules in step v) for a time period of from 30 min to 24 hours, such as 3 to 20 hours.
29. A method for the preparation of a composition comprising a porous adsorbent material and a pharmaceutically active ingredient selected from the group consisting of active ingredients classified according to the Biopharmaceutics Classification System as belonging to Class II or Class IV, where essentially all active ingredient is present in amorphous form, the method comprising the steps of:
i) preparing a granulate of the porous adsorbent material,
ii) compacting, such as compressing or molding, the granulate into a loadable composition,
iii) dissolving the pharmaceutically active ingredient in an organic solvent or a mixture thereof,
iv) loading the pharmaceutically active ingredient in solution into the composition, until about 95 % of the loading capacity, such as about 90 %, about 80 %, about 70 %, preferably the solution is loaded from about 80 % of the loading capacity to 100 %, v) heating the composition at a temperature and for a sufficient time to a constant weight, to bring essentially all pharmaceutically active ingredient in amorphous form, to provide the composition.
30. The method of embodiment 29, comprising in step v) the temperature exceeding the melting point of the pharmaceutically active ingredient, such as exceeding the melting point with about 5°C to about 80°C, such as with about 10°C to about 70°C, such as with about 20°C to about 50°C.
31. The method of embodiment 29 or 30, comprising heating the composition in step v) at a temperature from 50 to 200°C, such as 80°C to 1 10°C, to a constant weight.
32. The method of any one of embodiments 29-31 , comprising heating the composition in step v) for a time period of from 30 min to 24 hours, such as 3 to 20 hours.
33. A method for the preparation of a composition comprising a porous adsorbent material and a pharmaceutically active ingredient selected from the group consisting of active ingredients classified according to the Biopharmaceutics Classification System as belonging to Class II or Class IV, where essentially all active ingredient is present in amorphous form, the method comprising the steps of:
i) preparing a granulate of the porous adsorbent material,
ii) compacting, such as compressing or molding, the granulate into a loadable composition,
iii) dissolving the pharmaceutically active ingredient in an organic solvent or a mixture thereof,
iv) loading the pharmaceutically active ingredient in solution into the composition, until about 95 % of the loading capacity, such as about 90 %, about 80 %, about 70 %, preferably the solution is loaded from about 80 % of the loading capacity to 100 %, v) removing the solvent form the composition by evaporation for a sufficient time, optionally, to a constant weight,
vi) heating the composition at a temperature and for a sufficient time to a constant weight, to bring essentially all pharmaceutically active ingredient in amorphous form, to provide the composition.
34. The method of embodiment 33, comprising in step vi) the temperature exceeding the melting point of the pharmaceutically active ingredient, such as exceeding the melting point with about 5°C to about 80°C, such as with about 10°C to about 70°C, such as with about 20°C to about 50°C.
35. The method of embodiment 33 or 34, comprising removing the solvent in step v) under reduced pressure or by freeze drying for a time period of from 30 min to 24 hours, such as 3 to 20 hours.
36. The method of any one of embodiments 33-35, comprising heating the composition in step vi) at a temperature from 50 to 200°C, such as 80°C to 1 10°C, to a constant weight. 37. The method of any one of embodiments 33-36, comprising heating the composition in step vi) for a time period of from 30 min to 24 hours, such as 3 to 20 hours.
38. A method for the preparation of a composition comprising a porous adsorbent material and a pharmaceutically active ingredient selected from the group consisting of active ingredients classified according to the Biopharmaceutics Classification System as belonging to Class II or Class IV, where essentially all active ingredient is present in amorphous form, the method comprising the steps of:
i) preparing a granulate of the porous adsorbent material,
ii) mixing the pharmaceutically active ingredient with the granulate,
iii) compacting, such as compressing or molding, the granulate into a composition, iv) heating the composition at a temperature and for a sufficient time to a constant weight, to bring essentially all pharmaceutically active ingredient in amorphous form, to provide the composition. 39. The method of embodiment 38, comprising in step iv) the temperature exceeding the melting point of the pharmaceutically active ingredient, such as exceeding the melting point with about 5°C to about 80°C, such as with about 10°C to about 70°C, such as with about 20°C to about 50°C. 40. The method of embodiment 38 or 39, comprising heating the composition in step iv) at a temperature from 50 to 200°C, such as 80°C to 1 10°C, to a constant weight.
41. The method of any one of embodiments 38-40, comprising heating the composition in step iv) for a time period of from 30 min to 24 hours, such as 3 to 20 hours. 42. A method for the preparation of a composition comprising a porous adsorbent material and a pharmaceutically active ingredient selected from the group consisting of active ingredients classified according to the Biopharmaceutics Classification System as belonging to Class II or Class IV, where essentially all active ingredient is present in amorphous form, the method comprising the steps of:
i) preparing a granulate of the porous adsorbent material,
ii) mixing the pharmaceutically active ingredient with the granulate,
iii) compacting, such as compressing or molding, the granulate into a composition, iv) loading an organic solvent or mixture thereof into the composition,
v) optionally, loading additional pharmaceutically active ingredient in solution into the composition,
vi) heating the composition at a temperature and for a sufficient time to a constant weight, to bring essentially all pharmaceutically active ingredient in amorphous form, to provide the composition. 43. The method of embodiment 42, comprising in step vi) the temperature exceeding the melting point of the pharmaceutically active ingredient, such as exceeding the melting point with about 5°C to about 80°C, such as with about 10°C to about 70°C, such as with about 2 °C to about 50°C. 44. The method of embodiment 42 or 43, comprising heating the composition in step vi) at a temperature from 50 to 200°C, such as 80°C to 1 10°C, to obtain constant weight.
45. The method of any one of embodiments 42-44, comprising heating the composition in step vi) for a time period of from 30 min to 24 hours, such as 3 to 20 hours.
46. The method of any one of embodiments 20-45, comprising adding a surfactant to the granules or granulate before compacting the solid porous granulate into the composition.
47. The method of any one of embodiments 20-46, comprising adding a disintegrant to the granules or granulate before compacting the solid porous granulate into the composition. 48. A composition comprising a porous adsorbent material and a pharmaceutically active ingredient selected from the group consisting of active ingredients classified according to the Biopharmaceutics Classification System as belonging to Class II or Class IV, wherein the pharmaceutically active ingredient is in essentially amorphous form obtainable by the method of any one of embodiments 20-47.
49. The composition of embodiment 48 wherein the composition is according to any one of embodiments 1 -19.
50. The method of embodiment 20-49 wherein the loading is performed by placing the granules, granulate or tablet in an excess amount of the pharmaceutically active ingredient in solution for a sufficient amount of time.
51 . The method of embodiment 20-50 wherein the loading is performed under pressure, such as under reduced pressure or vacuum or by freeze drying.
52. The method of embodiment 20-51 wherein the loading is performed by spraying the pharmaceutically active ingredient in solution onto the granules, granulate or tablet.
53. The composition of any one of embodiments 1-19 or 48-49 for use as a medicine.
54. The method, composition, or use of any one of the preceding embodiments, wherein the composition is weighing from 1 mg to 2000 mg, such as from 1 mg to 10 mg, 10 mg to 100 mg, 100 mg to 1000 mg, or 60 mg to 1500 mg in dried form.
The examples hereunder illustrate the invention disclosed herein by which a pharmaceutically active ingredient is converted into amorphous form. The loadable tablet or granule may be prepared as described in WO2006/000229A2.
Materials:
Ibuprofen (Marsing og Co, lot 248082005),
Posaconazole (Ind-Swift Laboratories Limited, lot DJ/POS/257/020),
Celecoxib (Euroasia, lot CBX/303013)
Fenofibrate (ChemAgis ltd., lot 3FNFTN0G726),
Neusilin US2 (Fuji Chemical Industry, lot 81 1025),
Magnesium stearate (Mallinckrodt Chemicals Ltd., lot J001 19),
Ethanol (Kemetyl A/S),
Isopropyl alcohol (Ceasar & Loretz, lot 40412).
EXAMPLE 1
Loading of a solution of fenofibrate in isopropyl alcohol (IPA) into loadable granules and tablets
A solution of fenofibrate in isopropyl alcohol (IPA) was loaded into a loadable tablet or granule, and subsequently the IPA was evaporated by heating the loaded tablet above the boiling point of IPA (82.4°C). The melting point of fenofibrate is 79-82 (79.8) °C.
Loading of Fenofibrate/IPA solution into granules
3.000 g of fenofibrate was dissolved in 60 g IPA. 21 .70mL of the solution was added to a vessel containing 10.00 g of Neusilin US2, which had been dried to constant weight at 1 10°C immediately prior to use. The loaded granules are heated at 1 10°C in an incubator (Memmert, model 100-800) to constant mass.
Loading of Fenofibrate/IPA solution to tablets
Empty, i.e. un-loaded, tablets were prepared as described in WO 2006/000229A2.A mixture of 99% w/w of Neusilin US2 and 1 % w/w of magnesium stearate were compressed into 14 mm round tablets with a tablet weight of 335 mg and a tablet height of 7.58 mm on a single punch tablet press (Diaf, Denmark).
The tablet loading capacity is 0.764 mL as calculated based on the actual the tablet volume of 0.991 cm3 and the tablet porosity of 84.1 % (pycnometric density of tablet excipients: 2.13 g/cm3). The tablet was designed to load 0.727 mL corresponding to a loading capacity of 95%.
The un-loaded tablets were heated to constant mass in an incubator (Memmert, model 100-800) at 1 10°C. 3.000 g fenofibrate were dissolved in 60 g of IPA. 25 g of dried tablets were transferred to the loading chamber with 54.3 mL IPA fenofibrate solution. The tablets were heated at 1 10°C to constant mass in the incubator. The tablet mass of the unloaded and the loaded tablets are shown in Table 1 .
TABLE 1 Average tablet Rel. Std. Dev.
mass, [mg] [% rel]
A: Dried unloaded tablets 320.0 0.86
B: Loaded and dried tablets 340.5 0.82
Results
The loaded granules and tablets were subjected to Differential Scanning Calorimetry (DSC) investigation (Perkin Elmer Diamond DSC, Pyris software) as were a physical mixture of the excipients with the same composition. The physical mixtures showed a melting peak at the melting point of fenofibrate as shown in Figure 1. The loaded granules and tablets showed no melting peak for fenofibrate, as shown for the tablets in Figure 2, demonstrating the presence of fenofibrate in amorphous form. EXAMPLE 2
Loading of celecoxib solution into loadable tablets
A 10% w/w solution of celecoxib in ethanol (EtOH) was loaded into loadable tablets. Subsequently the ethanol was evapoated by heating above its boiling point (72.6°C). Celecoxib's melting point is 157°C. Further, dried tablets loaded with celecoxib were heated above the melting point of celecoxib.
Loading of Celecoxib/Ethanol solution into loadable tablets
Empty, i.e. unloaded, tablets were prepared as described in Example 1 . The un-loaded tablets were heated at 1 10°C to constant weight in an incubator (Memmert, model 100- 800). 3.00 g of celecoxib was dissolved in 27.0 g of ethanol to produce a 10 % w/w solution. 6 g of dried tablets were transferred to the loading chamber and mixed with 1 1.9 g of the celecoxib solution for 30min. The loaded tablets were heated at 1 10°C to constant weight in an incubator (Memmert, model 100-800).
Heat treatment of loaded tablets
3.45 g of loaded and dried tablets were heated to 190°C for 2 hours in an incubator (Memmert, model 100-800). The mass of the prepared tablets are listed in Table 2:
Tablet ID and description Average Relative standard
tablet mass deviation of tablet mass
[mg] [%rel]
A: Dried unloaded tablets 321 .1 0.67
B: Loaded and dried tablets 382.8 1 .10
C Loaded, dried and heat treated tablets 382.6 1 .00
Results
The loaded tablets were crushed, using a morter and pestil, and subjected to DSC investigation (Mettler Toledo TGA DSC 1 , STAR6 Software) including calculation of 1 .derivatine. No melting peaks for celecoxib were found, as shown for the heat treated loaded tablets in Figure 3. This shows that celecoxib is present in amorphous form.
EXAMPLE 3
Solvent free preparation method using fenofibrate, ibuprofen, posaconazole and celecoxib
This example illustrates the process by which a pharmaceutically active ingredient is converted to essentially amorphous form by a dry method involving heat treatment above the melting point of the active pharmaceutical ingredient. Mixing and heat treatment of excipients using fenofibrate and ibuprofen
300 mg of either fenofibrate or ibuprofen was mixed manually with 2.4 g of Neusilin US2 using sufficient agitation to render a homogeneous mixture. The mixture is heated to 1 10°C for 1 hour in an incubator (Memmert, model 100-800).
Mixing and heat treatment of excipients using posaconazole and celecoxib
200 mg of posaconazole was mixed manually with 1.6g of Neusilin US2 using sufficient agitation to render a homogeneous mixture. The mixture was heated to 190°C for 1 hour in an incubator (Memmert, model 100-800).
Results
Granules samples were subjected to DSC investigation (Mettler Toledo TGA DSC 1 , STAR6 Software) including calculation of 1 .derivative. Melting peaks were found, at the melting point for the active ingredients in all un-treated granule samples but not after heat treatment. Results are listed in Table 3and shown for posaconazole samples in Figures 4 and 5. The absence of melting peaks shows that the active pharmaceutical ingredients (API's) are present in amorphous form.
Table 3
EXAMPLE 4
Solvent method where the API is dissolved within the porous granules and tablets This example illustrates the process by which a pharmaceutically active ingredient is converted to amorphous form by exposing a dry mixture to a solvent and subsequent evaporation of the solvent to render the API in amorphous form.
Mixing, solvent exposure and evaporation
200 mg of celecoxib was mixed manually with 1 .6 g neusillin US2, using sufficient agitation to render a homogeneous mixture. 1 g of the powder mixture was added to a vessel containing 1 g ethanol and the vessel was closed. After two hours the vessel was opened and heated to 1 10°C to constant mass in an incubator (Memmert, Model 100-800). Results
The granule samples were subjected to DSC investigation (Mettler Toledo TGA DSC 1 , STAR6 Software) including calculation of 1 .derivative. Melting endoterm was found at
the melting point of celecoxib in un-treated granule sample but not after exposure to solvent and heat treatment, as listed in Table 4 and shown in Figure 6 and Figure 7. The absence of melting peaks shows that the celecoxib is present in amorphous form.
Table 4
Sample Peak Integral Peak, 1. Integra, 1.
[°C] [mJ] derivative derivative
[°C] [mW]
Celecoxib granules before 162.4 1 .58 161 .1 0.28 solvent exposure and heat
treatment
Celecoxib granules after Not Not Not Not solvent exposure and heat detected detected detected detected treatment, 1 10°C
Claims
1 . A composition, obtainable by the method of any one of claims 5-15, comprising a porous adsorbent material and a pharmaceutically active ingredient selected from the group consisting of active ingredients classified according to the Biopharmaceutics Classification System as belonging to Class II or Class IV, wherein essentially all pharmaceutically active ingredient is present in amorphous form.
2. The composition of claim 1 wherein the pharmaceutically active ingredient has low water solubility.
3. The composition of any one of claims 1 -2 wherein the porous adsorbent material is selected from metal carbonates, metal phosphates, or porous silicon dioxide, such as sodium silicate, potassium silicate, magnesium silicate, calcium silicate, including synthetic calcium silicate, microporous calcium silicate, zinc silicate, aluminum silicate, sodium aluminosilicate, hydrous aluminium silicates or alkaline earths, magnesium aluminum metasilicate, magnesium aluminum silicate, aluminium metasilicate, nonporous colloidal silicas, porous silicas gels, precipitated silicate, and mixtures thereof.
4. The composition of any one of claims 1 -3 wherein at least 95% (w/w), preferably at least 75% (w/w), of the pharmaceutically active ingredient is in amorphous form.
5. A method for the preparation of a composition comprising a porous adsorbent material and a pharmaceutically active ingredient selected from the group consisting of active ingredients classified according to the Biopharmaceutics Classification System as belonging to Class II or Class IV, wherein essentially all pharmaceutically active ingredient is present in amorphous form, the method comprising the steps of:
i) preparing a granulate of the porous adsorbent material,
ii) dissolving the pharmaceutically active ingredient in an organic solvent or a mixture thereof,
iii) loading the pharmaceutically active ingredient in solution into the granules, iv) heating the granules at a temperature and for a sufficient time to a constant weight, to bring essentially all pharmaceutically active ingredient in amorphous form, v) compacting, such as compressing or molding, the granulate into the composition.
6. The method of claim 5, comprising in step iv) heating at a temperature above the melting point of the pharmaceutically active ingredient, preferably at at temperature not exceeding said melting point with more than about 80°C.
7. A method for the preparation of a composition comprising a porous adsorbent material and a pharmaceutically active ingredient selected from the group consisting of active ingredients classified according to the Biopharmaceutics Classification System as belonging to Class II or Class IV, wherein essentially all pharmaceutically active ingredient is present in amorphous form, the method comprising the steps of:
i) preparing a granulate of the porous adsorbent material,
ii) dissolving the pharmaceutically active ingredient in an organic solvent or a mixture thereof,
iii) loading the pharmaceutically active ingredient in solution into the granules, iv) removing the solvent form the granules by evaporation for a sufficient time, optionally, to a constant weight,
v) heating the granules at a temperature and for a sufficient time to a constant weight, to bring essentially all pharmaceutically active ingredient in amorphous form, vi) compacting, such as compressing or molding, the granulate into the composition.
8. The method of claim 7, comprising in step v) heating at a temperature above the melting point of the pharmaceutically active ingredient, preferably at at temperature not exceeding said melting point with more than about 80°C.
9. A method for the preparation of a composition comprising a porous adsorbent material and a pharmaceutically active ingredient selected from the group consisting of active ingredients classified according to the Biopharmaceutics Classification System as belonging to Class II or Class IV, wherein essentially all pharmaceutically active ingredient is present in amorphous form, the method comprising the steps of:
i) preparing a granulate of the porous adsorbent material,
ii) compacting, such as compressing or molding, the granulate into a loadable composition,
ii) dissolving the pharmaceutically active ingredient in an organic solvent or a mixture thereof,
iv) loading the pharmaceutically active ingredient in solution into the composition, v) heating the composition at a temperature and for a sufficient time to a constant weight, to bring essentially all pharmaceutically active ingredient in amorphous form, to provide the composition.
10. The method of claim 9, comprising in step v) heating at a temperature above the melting point of the pharmaceutically active ingredient, preferably at at temperature not exceeding said melting point with more than about 80°C.
1 1. A method for the preparation of a composition comprising a porous adsorbent material and a pharmaceutically active ingredient selected from the group consisting of active ingredients classified according to the Biopharmaceutics Classification System as belonging to Class II or Class IV, wherein essentially all pharmaceutically active ingredient is present in amorphous form, the method comprising the steps of:
i) preparing a granulate of the porous adsorbent material,
ii) compacting, such as compressing or molding, the granulate into a loadable composition,
iii) dissolving the pharmaceutically active ingredient in an organic solvent or a mixture thereof,
iv) loading the pharmaceutically active ingredient in solution into the composition, v) removing the solvent form the composition by evaporation for a sufficient time, optionally, to a constant weight,
vi) heating the composition at a temperature and for a sufficient time to a constant weight, to bring essentially all pharmaceutically active ingredient in amorphous form, to provide the composition.
12. The method of claim 1 1 , comprising in step vi) heating at a temperature above the melting point of the pharmaceutically active ingredient, preferably at at temperature not exceeding said melting point with more than about 80°C.
13. A method for the preparation of a composition comprising a porous adsorbent material and a pharmaceutically active ingredient selected from the group consisting of active ingredients classified according to the Biopharmaceutics Classification System as belonging to Class II or Class IV, wherein essentially all pharmaceutically active ingredient is present in amorphous form, the method comprising the steps of:
i) preparing a granulate of the porous adsorbent material,
ii) mixing the pharmaceutically active ingredient with the granulate, iii) compacting, such as compressing or molding, the granulate into a composition, iv) heating the composition at a temperature and for a sufficient time to a constant weight, to bring essentially all pharmaceutically active ingredient in amorphous form, to provide the composition.
14. The method of claim 13, comprising in step iv) heating at a temperature above the melting point of the pharmaceutically active ingredient, preferably at at temperature not exceeding said melting point with more than about 80°C.
15. The method of any one of claims 5-14 wherein the organic solvent is selected from formic acid, tetrahydrofuran, acetid acid, acetone, anisole, 1 -butanol, 2-butanol, butyl acetate, tert-butylmethyl ether, cumene, dimethylsulfoxide, ethanol, ethyl acetate, ethyl ether, ethyl formate, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3- methyl-1 -butanol, methylethyl ketone, methylisobutyl ketone, 2-methyl-1 -propanol, pentane, 1 -pentanol, 1 -propanol, 2-propanol, propyl acetate or mixtures thereof.
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WO2016097030A1 (en) * | 2014-12-19 | 2016-06-23 | Synthon B.V. | Pharmaceutical composition comprising amorphous lenalidomide |
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WO2016128727A1 (en) * | 2015-02-09 | 2016-08-18 | Cubic Pharmaceuticals Ltd. | Method of preparing an extruded composition |
WO2017221144A1 (en) * | 2016-06-20 | 2017-12-28 | Dr. Reddy's Laboratories Limited | Process for the preparation of elagolix sodium and its polymorph |
US10835495B2 (en) | 2012-11-14 | 2020-11-17 | W. R. Grace & Co.-Conn. | Compositions containing a biologically active material and a non-ordered inorganic oxide material and methods of making and using the same |
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US10835495B2 (en) | 2012-11-14 | 2020-11-17 | W. R. Grace & Co.-Conn. | Compositions containing a biologically active material and a non-ordered inorganic oxide material and methods of making and using the same |
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