ZA200305532B - Compositions of estrogen-cyclodextrin complexes - Google Patents
Compositions of estrogen-cyclodextrin complexes Download PDFInfo
- Publication number
- ZA200305532B ZA200305532B ZA200305532A ZA200305532A ZA200305532B ZA 200305532 B ZA200305532 B ZA 200305532B ZA 200305532 A ZA200305532 A ZA 200305532A ZA 200305532 A ZA200305532 A ZA 200305532A ZA 200305532 B ZA200305532 B ZA 200305532B
- Authority
- ZA
- South Africa
- Prior art keywords
- cyclodextrin
- estrogen
- estradiol
- composition according
- composition
- Prior art date
Links
- 239000000203 mixture Substances 0.000 title claims description 204
- 239000000262 estrogen Substances 0.000 claims description 132
- 229940011871 estrogen Drugs 0.000 claims description 132
- 229920000858 Cyclodextrin Polymers 0.000 claims description 112
- 229960002568 ethinylestradiol Drugs 0.000 claims description 100
- BFPYWIDHMRZLRN-UHFFFAOYSA-N 17alpha-ethynyl estradiol Natural products OC1=CC=C2C3CCC(C)(C(CC4)(O)C#C)C4C3CCC2=C1 BFPYWIDHMRZLRN-UHFFFAOYSA-N 0.000 claims description 91
- BFPYWIDHMRZLRN-SLHNCBLASA-N Ethinyl estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 BFPYWIDHMRZLRN-SLHNCBLASA-N 0.000 claims description 90
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 claims description 74
- 238000009472 formulation Methods 0.000 claims description 59
- 238000000034 method Methods 0.000 claims description 49
- 238000002360 preparation method Methods 0.000 claims description 46
- 239000008187 granular material Substances 0.000 claims description 45
- METQSPRSQINEEU-UHFFFAOYSA-N dihydrospirorenone Natural products CC12CCC(C3(CCC(=O)C=C3C3CC33)C)C3C1C1CC1C21CCC(=O)O1 METQSPRSQINEEU-UHFFFAOYSA-N 0.000 claims description 38
- 229960004845 drospirenone Drugs 0.000 claims description 37
- METQSPRSQINEEU-HXCATZOESA-N drospirenone Chemical compound C([C@]12[C@H]3C[C@H]3[C@H]3[C@H]4[C@@H]([C@]5(CCC(=O)C=C5[C@@H]5C[C@@H]54)C)CC[C@@]31C)CC(=O)O2 METQSPRSQINEEU-HXCATZOESA-N 0.000 claims description 37
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 35
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 34
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 33
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 31
- VOXZDWNPVJITMN-ZBRFXRBCSA-N 17β-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 VOXZDWNPVJITMN-ZBRFXRBCSA-N 0.000 claims description 28
- 229960005309 estradiol Drugs 0.000 claims description 27
- 239000013543 active substance Substances 0.000 claims description 26
- 229930182833 estradiol Natural products 0.000 claims description 26
- 238000005469 granulation Methods 0.000 claims description 26
- 230000003179 granulation Effects 0.000 claims description 26
- 238000004519 manufacturing process Methods 0.000 claims description 23
- 238000003860 storage Methods 0.000 claims description 23
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 claims description 18
- 239000002552 dosage form Substances 0.000 claims description 17
- 239000003814 drug Substances 0.000 claims description 13
- UYIFTLBWAOGQBI-BZDYCCQFSA-N Benzhormovarine Chemical compound C([C@@H]1[C@@H](C2=CC=3)CC[C@]4([C@H]1CC[C@@H]4O)C)CC2=CC=3OC(=O)C1=CC=CC=C1 UYIFTLBWAOGQBI-BZDYCCQFSA-N 0.000 claims description 8
- GVBPNTAYETYXBE-WAJSLEGFSA-N S(N)(O)(=O)=O.[C@@H]12CCC(O)[C@@]1(C)CC[C@@H]1C3=C(CC[C@@H]21)C=C(O)C=C3 Chemical class S(N)(O)(=O)=O.[C@@H]12CCC(O)[C@@]1(C)CC[C@@H]1C3=C(CC[C@@H]21)C=C(O)C=C3 GVBPNTAYETYXBE-WAJSLEGFSA-N 0.000 claims description 8
- 229920002472 Starch Polymers 0.000 claims description 8
- 229950002007 estradiol benzoate Drugs 0.000 claims description 8
- 239000000583 progesterone congener Substances 0.000 claims description 8
- 239000008107 starch Substances 0.000 claims description 8
- 235000019698 starch Nutrition 0.000 claims description 8
- DNXHEGUUPJUMQT-UHFFFAOYSA-N (+)-estrone Natural products OC1=CC=C2C3CCC(C)(C(CC4)=O)C4C3CCC2=C1 DNXHEGUUPJUMQT-UHFFFAOYSA-N 0.000 claims description 7
- JKKFKPJIXZFSSB-UHFFFAOYSA-N 1,3,5(10)-estratrien-17-one 3-sulfate Natural products OS(=O)(=O)OC1=CC=C2C3CCC(C)(C(CC4)=O)C4C3CCC2=C1 JKKFKPJIXZFSSB-UHFFFAOYSA-N 0.000 claims description 7
- RSEPBGGWRJCQGY-RBRWEJTLSA-N Estradiol valerate Chemical compound C1CC2=CC(O)=CC=C2[C@@H]2[C@@H]1[C@@H]1CC[C@H](OC(=O)CCCC)[C@@]1(C)CC2 RSEPBGGWRJCQGY-RBRWEJTLSA-N 0.000 claims description 7
- DNXHEGUUPJUMQT-CBZIJGRNSA-N Estrone Chemical compound OC1=CC=C2[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1 DNXHEGUUPJUMQT-CBZIJGRNSA-N 0.000 claims description 7
- 229960004766 estradiol valerate Drugs 0.000 claims description 7
- 229960003399 estrone Drugs 0.000 claims description 7
- JKKFKPJIXZFSSB-CBZIJGRNSA-N estrone 3-sulfate Chemical compound OS(=O)(=O)OC1=CC=C2[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1 JKKFKPJIXZFSSB-CBZIJGRNSA-N 0.000 claims description 7
- 239000007788 liquid Substances 0.000 claims description 7
- 239000003963 antioxidant agent Substances 0.000 claims description 6
- 238000002156 mixing Methods 0.000 claims description 6
- 230000003078 antioxidant effect Effects 0.000 claims description 5
- 239000001913 cellulose Substances 0.000 claims description 5
- 229920002678 cellulose Polymers 0.000 claims description 5
- WWYNJERNGUHSAO-XUDSTZEESA-N (+)-Norgestrel Chemical compound O=C1CC[C@@H]2[C@H]3CC[C@](CC)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 WWYNJERNGUHSAO-XUDSTZEESA-N 0.000 claims description 4
- HFHDHCJBZVLPGP-RWMJIURBSA-N alpha-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO HFHDHCJBZVLPGP-RWMJIURBSA-N 0.000 claims description 4
- 239000002775 capsule Substances 0.000 claims description 4
- 238000002657 hormone replacement therapy Methods 0.000 claims description 4
- 229960004400 levonorgestrel Drugs 0.000 claims description 4
- 238000011068 loading method Methods 0.000 claims description 4
- 229920002774 Maltodextrin Polymers 0.000 claims description 2
- IMONTRJLAWHYGT-ZCPXKWAGSA-N Norethindrone Acetate Chemical compound C1CC2=CC(=O)CC[C@@H]2[C@@H]2[C@@H]1[C@@H]1CC[C@](C#C)(OC(=O)C)[C@@]1(C)CC2 IMONTRJLAWHYGT-ZCPXKWAGSA-N 0.000 claims description 2
- UWFYSQMTEOIJJG-FDTZYFLXSA-N cyproterone acetate Chemical compound C1=C(Cl)C2=CC(=O)[C@@H]3C[C@@H]3[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)C)[C@@]1(C)CC2 UWFYSQMTEOIJJG-FDTZYFLXSA-N 0.000 claims description 2
- 229960000978 cyproterone acetate Drugs 0.000 claims description 2
- 229960003309 dienogest Drugs 0.000 claims description 2
- AZFLJNIPTRTECV-FUMNGEBKSA-N dienogest Chemical compound C1CC(=O)C=C2CC[C@@H]([C@H]3[C@@](C)([C@](CC3)(O)CC#N)CC3)C3=C21 AZFLJNIPTRTECV-FUMNGEBKSA-N 0.000 claims description 2
- 229960005352 gestodene Drugs 0.000 claims description 2
- SIGSPDASOTUPFS-XUDSTZEESA-N gestodene Chemical compound O=C1CC[C@@H]2[C@H]3CC[C@](CC)([C@](C=C4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 SIGSPDASOTUPFS-XUDSTZEESA-N 0.000 claims description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 2
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims description 2
- 229940053934 norethindrone Drugs 0.000 claims description 2
- 229960001652 norethindrone acetate Drugs 0.000 claims description 2
- VIKNJXKGJWUCNN-XGXHKTLJSA-N norethisterone Chemical compound O=C1CC[C@@H]2[C@H]3CC[C@](C)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 VIKNJXKGJWUCNN-XGXHKTLJSA-N 0.000 claims description 2
- 239000005913 Maltodextrin Substances 0.000 claims 1
- 229940035034 maltodextrin Drugs 0.000 claims 1
- 239000000047 product Substances 0.000 description 23
- 239000003826 tablet Substances 0.000 description 19
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- 229940097362 cyclodextrins Drugs 0.000 description 11
- 239000007857 degradation product Substances 0.000 description 10
- 238000009477 fluid bed granulation Methods 0.000 description 10
- 150000001875 compounds Chemical class 0.000 description 9
- 239000008194 pharmaceutical composition Substances 0.000 description 9
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 7
- 239000004480 active ingredient Substances 0.000 description 7
- 230000015556 catabolic process Effects 0.000 description 7
- 238000010494 dissociation reaction Methods 0.000 description 7
- 230000005593 dissociations Effects 0.000 description 7
- 239000008101 lactose Substances 0.000 description 7
- 229960001375 lactose Drugs 0.000 description 7
- 239000000825 pharmaceutical preparation Substances 0.000 description 7
- 229940127557 pharmaceutical product Drugs 0.000 description 7
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 6
- 238000006731 degradation reaction Methods 0.000 description 6
- 229920002261 Corn starch Polymers 0.000 description 5
- 239000011230 binding agent Substances 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 229940007690 drospirenone and ethinylestradiol Drugs 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- QHTAUDUBRNENFJ-VCNAKFCDSA-N (8r,9s,13s,14s,17r)-17-ethynyl-3,17-dihydroxy-13-methyl-7,8,9,11,12,14,15,16-octahydrocyclopenta[a]phenanthren-6-one Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CC(=O)C2=C1 QHTAUDUBRNENFJ-VCNAKFCDSA-N 0.000 description 4
- 235000006708 antioxidants Nutrition 0.000 description 4
- KBPLFHHGFOOTCA-UHFFFAOYSA-N caprylic alcohol Natural products CCCCCCCCO KBPLFHHGFOOTCA-UHFFFAOYSA-N 0.000 description 4
- 235000010980 cellulose Nutrition 0.000 description 4
- 238000007907 direct compression Methods 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- 230000000670 limiting effect Effects 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 230000016087 ovulation Effects 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 230000006641 stabilisation Effects 0.000 description 4
- 230000003019 stabilising effect Effects 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 3
- 208000002874 Acne Vulgaris Diseases 0.000 description 3
- 235000019759 Maize starch Nutrition 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 206010000496 acne Diseases 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 230000000536 complexating effect Effects 0.000 description 3
- 238000010668 complexation reaction Methods 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 150000002678 macrocyclic compounds Chemical class 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 238000010525 oxidative degradation reaction Methods 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 238000012545 processing Methods 0.000 description 3
- -1 steroid compound Chemical class 0.000 description 3
- 150000003431 steroids Chemical class 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 239000001116 FEMA 4028 Substances 0.000 description 2
- 239000006057 Non-nutritive feed additive Substances 0.000 description 2
- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 description 2
- ZTHYODDOHIVTJV-UHFFFAOYSA-N Propyl gallate Chemical compound CCCOC(=O)C1=CC(O)=C(O)C(O)=C1 ZTHYODDOHIVTJV-UHFFFAOYSA-N 0.000 description 2
- MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testostosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- 230000006978 adaptation Effects 0.000 description 2
- 239000012736 aqueous medium Substances 0.000 description 2
- 235000011175 beta-cyclodextrine Nutrition 0.000 description 2
- 229960004853 betadex Drugs 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 238000007906 compression Methods 0.000 description 2
- 230000006835 compression Effects 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000004064 dysfunction Effects 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- PROQIPRRNZUXQM-ZXXIGWHRSA-N estriol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H]([C@H](O)C4)O)[C@@H]4[C@@H]3CCC2=C1 PROQIPRRNZUXQM-ZXXIGWHRSA-N 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 230000002175 menstrual effect Effects 0.000 description 2
- TVMXDCGIABBOFY-UHFFFAOYSA-N n-Octanol Natural products CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 2
- 238000005192 partition Methods 0.000 description 2
- 239000008188 pellet Substances 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 239000012429 reaction media Substances 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- PROQIPRRNZUXQM-UHFFFAOYSA-N (16alpha,17betaOH)-Estra-1,3,5(10)-triene-3,16,17-triol Natural products OC1=CC=C2C3CCC(C)(C(C(O)C4)O)C4C3CCC2=C1 PROQIPRRNZUXQM-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 description 1
- 241000283073 Equus caballus Species 0.000 description 1
- 239000001828 Gelatine Substances 0.000 description 1
- 101000605827 Homo sapiens Pinin Proteins 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- QAQJMLQRFWZOBN-LAUBAEHRSA-N L-ascorbyl-6-palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](O)[C@H]1OC(=O)C(O)=C1O QAQJMLQRFWZOBN-LAUBAEHRSA-N 0.000 description 1
- 235000000072 L-ascorbyl-6-palmitate Nutrition 0.000 description 1
- 239000011786 L-ascorbyl-6-palmitate Substances 0.000 description 1
- 206010027304 Menopausal symptoms Diseases 0.000 description 1
- 102100038374 Pinin Human genes 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- YJBYRYVLFAUXBJ-HFTRVMKXSA-N [(9s,13s,14s)-13-methyl-17-oxo-9,11,12,14,15,16-hexahydro-6h-cyclopenta[a]phenanthren-3-yl] hydrogen sulfate Chemical compound OS(=O)(=O)OC1=CC=C2[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4C3=CCC2=C1 YJBYRYVLFAUXBJ-HFTRVMKXSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 239000002170 aldosterone antagonist Substances 0.000 description 1
- 229940083712 aldosterone antagonist Drugs 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- 239000003098 androgen Substances 0.000 description 1
- 230000002280 anti-androgenic effect Effects 0.000 description 1
- 230000003466 anti-cipated effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- UHZZMRAGKVHANO-UHFFFAOYSA-M chlormequat chloride Chemical compound [Cl-].C[N+](C)(C)CCCl UHZZMRAGKVHANO-UHFFFAOYSA-M 0.000 description 1
- 238000000975 co-precipitation Methods 0.000 description 1
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 229940035811 conjugated estrogen Drugs 0.000 description 1
- 239000003433 contraceptive agent Substances 0.000 description 1
- 230000002254 contraceptive effect Effects 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- PDRGHUMCVRDZLQ-UHFFFAOYSA-N d-equilenin Natural products OC1=CC=C2C(CCC3(C4CCC3=O)C)=C4C=CC2=C1 PDRGHUMCVRDZLQ-UHFFFAOYSA-N 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 230000001882 diuretic effect Effects 0.000 description 1
- METQSPRSQINEEU-OLKMEILKSA-N drospirenone Chemical compound C([C@]12[C@H]3C[C@H]3C3C4[C@@H]([C@]5(CCC(=O)C=C5[C@@H]5C[C@@H]54)C)CC[C@@]31C)CC(=O)O2 METQSPRSQINEEU-OLKMEILKSA-N 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- PDRGHUMCVRDZLQ-WMZOPIPTSA-N equilenin Chemical compound OC1=CC=C2C(CC[C@]3([C@H]4CCC3=O)C)=C4C=CC2=C1 PDRGHUMCVRDZLQ-WMZOPIPTSA-N 0.000 description 1
- 229960001348 estriol Drugs 0.000 description 1
- 229960003836 estriol succinate Drugs 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000007941 film coated tablet Substances 0.000 description 1
- 239000007888 film coating Substances 0.000 description 1
- 238000009501 film coating Methods 0.000 description 1
- 239000013020 final formulation Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- LNTHITQWFMADLM-UHFFFAOYSA-N gallic acid Chemical compound OC(=O)C1=CC(O)=C(O)C(O)=C1 LNTHITQWFMADLM-UHFFFAOYSA-N 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 239000003163 gonadal steroid hormone Substances 0.000 description 1
- 125000001072 heteroaryl group Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N iron oxide Inorganic materials [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 description 1
- 229960001021 lactose monohydrate Drugs 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- NDLPOXTZKUMGOV-UHFFFAOYSA-N oxo(oxoferriooxy)iron hydrate Chemical compound O.O=[Fe]O[Fe]=O NDLPOXTZKUMGOV-UHFFFAOYSA-N 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 229960003387 progesterone Drugs 0.000 description 1
- 239000000186 progesterone Substances 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
- 230000002829 reductive effect Effects 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 125000003107 substituted aryl group Chemical group 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
- 238000010998 test method Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 229960003604 testosterone Drugs 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 229940070710 valerate Drugs 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
Description
COMPOSITIONS OF ESTROGEN-CYCLODEXTRIN COMPLEXES
The present invention relates to pharmaceutical compositions and formulations comprising . 5 a cyclodextrin-estrogen complex that confers very high chemical stability to the estrogen.
The invention allows for an improved physical stability of cyclodextrin-estrogen complexes and of the chemical stability of estrogens such ethinyl estradiol upon storage.
Degradation of estrogens, such as ethinyl estradiol, in conventional pharmaceutical products is one of the most critical issues with regard to product shelf life. Stabilisation of the estrogen may be achieved by either product packaging in hermetic containers or, more effectively, as in the present invention, by actual stabilisation of the pharmaceutical product.
Pharmaceutical products comprising naturally or synthetically derived sex hormones often consist of low dosages of these active ingredients. Given the small amounts of active ingredient required per single dosage, often ranging between 0.1 pg and 500 png, itis problematic to manufacture unit dosage formulations with reliably consistent amounts of active agent which do not fluctuate within one batch or between batches. Thus, the requirements of content uniformity as set forth by health authorities may not be met.
Moreover, degradation of these small amounts of active ingredient is a further contributor to the fluctuations of the active ingredient in low dosage formulations.
In general, these low dose formulations comprising unstable active agents are problematic in terms of their preparation, storage and use, and there is a need for providing means for stabilisation of such formulations.
Complexation of estrogens with cyclodextrins is widely used for improving stability, solubility or bioavailability. For example, EP 0 349 091 discloses compositions containing ) complexes between 17-B-estradiol and dimethyl-B-cyclodextrin for improving nasal administration, Fridriksdottir et al (Die Pharmazie, vol. 51, 1996, pages 39-42) describes : complexes between cyclodextrin and 17-B-estradiol for improving the solubility in aqueous solution so as to improve sublinqual application. Improved solubility is also the focus of
US 4,596,795, which relates to a complex between a-, B- and y-cyclodextrins and derivatives thereof with testosterone, progesterone, and estradiol. US 4,383,992 discloses
CONFIRMATION COPY a water soluble inclusion compound formed by complexing a steroid compound, such as an estrogen with beta-cyclodextrin.
Moreover, US 5,798, 338 discloses that the oxidative degradation of 17-a-ethinyl estradiol ’ is reduced upon forming clathrates (complexes) between B-cyclodextrin and 17-a~ethinyi estradiol. *
However, although complexation of estrogens with cyclodextrins may solve critical issues with regards to solubility, bioavailability and stability, there are still further problems to solve before complexes between active agents, such as estrogens, and cyclodextrins are suitable for use in pharmaceutical products. Namely, the complexes are prone to dissociation into the free estrogen and the cyclodextrin, particularly upon contact with water. The lack of physical stability of cyclodextrin-estrogen complexes results in significant amounts of free estrogen present in compositions due to, for instance, exposure to aqueous media during the manufacturing process, particularly during granulation. As a consequence, the lifetime of the composition may be decreased due to degradation of free estrogen.
Moreover, the intended improved bioavailability sought by complexing estrogen with cyclodextrin is not achieved due to the lack of physical stability of the cyclodextrin- estrogen complex and the chemical instability of the free estrogen.
Various attempts have been made in order to stabilise compositions comprising complexes between a cyclodextrin and an estrogen. For example, the composition may be stabilised by stabilising the complex itself. Thus, US 4, 727,064 attempts the stabilisation of complexes upon using amorphous forms of the complex. Alternatively, complexes may be stabilised and their solubility increased upon adding polymers to the reaction medium upon complexation , as disclosed by Loftsson et al. (Int. J. Pharmaceutics, Vol. 110, 1994, pp169-177). EP 0579435 also discloses complexes between estradiol and cyclodextrins wherein the addition of polymers to the reaction medium increases the stability constant of the complex.
The compositions may also be stabilised upon avoiding a granulation step in the manufacturing process of the composition, as disclosed in WO 00/21570. ‘
There is a need in the art for processes for preparing physically stable complexes of : cyclodextrin and estrogen and for compositions, which improve the stability of both the complex and the free estrogen. There is furthermore a need in the art for granulate formulations which allow for physically stable cyclodextrin-estrogen complexes.
: SUMMARY OF THE INVENTION . An object of the present invention is to provide a stable and homogenous pharmaceutical product comprising an estrogen, wherein the stability of the estrogen is significantly improved over that of conventional products, which have complexed estrogens or sensitive complexes between a cyclodextrin and an estrogen. Degradation of estrogens, such as ethinyl estradiol, in conventional products, is one of the most critical issues with regard to product shelf life.
It has surprisingly been found that products with improved stability of the estrogen are achieved by means of complexing estrogen with cyclodextrins, the judicious selection of excipients and/or proper adaptation of the manufacturing process. Consequently, the sheif-life of an estrogen-containing product is improved.
Thus, an important aspect of the invention relates to formulations and compositions comprising complexes between an estrogen and a cyclodextrin that are stable in spite of being manufactured by granulation. That is to say that the invention relates in a first aspect to a formulation comprising a complex between an estrogen and a cyclodextrin, wherein the formulation is a granulate preparation, said granulation preparation having a relative humidity of at most 60%, as determined at a temperature between 20°C and 40°C.
In a further aspect, the invention relates to compositions comprising i) a complex between an estrogen and a cyclodextrin; and ii) one or more excipient(s), the composition having a stability such that said estrogen is in amount of at least 85% w/w in relation to the initial content of the estrogen after storage for 12 months at 40°C and 75% relative humidity (RH). In a suitable embodiment thereof, the composition comprises a granulate preparation comprising said complex. In a further suitable embodiment, the composition is compressed directly into a tablet or equivalent unit dosage forms.
Thus, contrarily to previous findings, it is possible to obtain stable compositions comprising } an estrogen-cyclodextrin-complex in a granulate preparation.
Compositions of the present invention may be used as medicaments. Accordingly, the use of a composition described infra for the preparation of a medicament for female contraception, for hormone replacement therapy, or for treating acne or PMDD (pre- menstrual dysfunction disorders), is a further aspect of the present invention. ,
In a broad sense, the present invention relates to a method of improving the stability of an estrogen in a pharmaceutical composition that comprises an estrogen-cyclodextrin complex and one or more excipients in a granulate preparation, the method comprises the ’ steps of: i) forming an complex between said estrogen and a cyclodextrin; and . ii} mixing under granulation conditions the said complex with the one or mare excipients such that the relative humidity of the final granulate does not exceed 60%, as determined at a temperature between 20°C and 40°C.
Finally, the invention relates to a process for manufacturing a composition comprising a granulate preparation of a complex between an estrogen and a cyclodextrin, wherein the processing of the granulate preparation comprises the steps of i) loading the complex, one or more excipients and optionally one or more therapeutically active agent(s) into a granulator; ii) applying a liquid onto the loaded complex and the one or more excipients under granulation conditions so as to obtain granules having a relative humidity not exceeding 60%, as determined at a temperature between 20°C and 40°C.
The term "complex" is intended to mean a complex between an estrogen and a cyclodextrin, wherein a molecule of said estrogen is at least partially inserted into the cavity of one cyclodextrin molecule. Furthermore, the molecule of an estrogen may at least partially be inserted into the cavity of more cyclodextrin molecules, and two moieties of a single estrogen molecule may each be inserted into one cyclodextrin molecule to give 2:1 ratio between cyclodextrin and estrogen. Thus, the complex may be termed as an inclusion complex (clathrate) between an estrogen and a cyclodextrin. Similarly, the complex may comprise of more than one molecule of estrogen at least partially inserted into one or more cyclodextrin molecules, wherein for example 2 estrogen molecules are at least partially inserted into a single cyclodextrin molecule, to give a 1:2 ratio between cyclodextrin and estrogen. Complexes wherein one estrogen molecule is complexed with one or more cyclodextrin molecules are certainly anticipated such as 1 estrogen molecule . complexed with 2 cyclodextrin molecules or 3 cyclodextrin molecules. Typically, the ethinyl estradiol-p-cyclodextrin complex as prepared by the present invention is preferably a . complex between one molecule of ethinyl estradiol and two molecules of B-Cyclodextrin.
The term "ethinyl estradiol-p-Cyclodextrin complex” or "EE-8-CD" is intended to mean a complex, of any ratio, between ethinyl estradiol and B-cyclodextrin. ) The term "granulate preparation" relates to a preparation of a powder, wherein the particle 5 size of the powder is either increased upon processing with a liquid or by compression. The : liquid may be of any kind of aqueous or organic solvents, or mixtures thereof, optionally further comprising a binder such as a starch. Thus, a "granulate preparation” relates in a broad sense to granules, pellets and compressed powder or any particle formed by granulation, pelletation or compression of powder such that a mean particle size of at least about 100 um are formed.
The term "cyclodextrin" is intended to mean a cyclodextrin or a derivative thereof as well as mixtures of various cyclodextrins, mixtures of various derivatives of cyclodextrins and mixtures of various cyclodextrins and their derivatives. The cyclodextrin is further defined according to the invention.
The present inventors have developed products, wherein a remarkable improvement of the stability of an estrogen has been achieved by combined means. One such means is by the protection of the estrogen by forming a cyclodextrin complex. Another such means is by the judicious adaptation of the granulation process such that e.g. the dissociation of the complex into free estrogen and cyclodextrin is restricted during the manufacturing of the granulate preparation. The present inventors have provided data indicating that a complex between ethinyl estradiol and B-cyclodextrin is poorly stable when exposed to water.
Actually, in the event where the complex is dissolved in water, about 50% of the complex are dissociated into free ethinyl! estradiol and cyclodextrin within 3 minutes (see Example 6 herein). Thus, without being limited to a particular theory, the stability of the products is, at least in part, improved by limiting the dissociation of the complex into free estrogen during the manufacturing process, thereby limiting the content of free estrogen in the final product.
Therefore, in a first aspect the invention relates to a formulation comprising a complex between an estrogen and a cyclodextrin, wherein the formulation is a granulate preparation, said granulation preparation having a relative humidity of at most 60%, as : determined at a temperature between 20°C and 40°C. Preferably, the relative humidity is at most 55%, preferably of at most 45%, most preferably of at most 40%, as determined . at a temperature between 20°C and 40°C,
As stated, the present invention has lead to stable products comprising sensitive complexes between an estrogen and a cyclodextrin. Thus, in a second aspect, the invention relates to a composition comprising: i) a complex between an estrogen and a cyclodextrin; and } ii) one or more excipient(s), the composition having a stability such that said estrogen is in an amount of at least 85% w/w in relation to the initial content of the estrogen after - storage for 12 months at 40°C and 75% relative humidity (RH). The initial content of estrogen should be understood as the weighed quantity of estrogen included in the composition upon manufacturing the final formulation.
In one embodiment hereof, the composition is in a form of a tablet manufactured by direct compression of the composition. Preferably the composition comprises a restricted amount of polyvinylpyrrolidone as disclosed further herein.
In yet another embodiment, the complex between an estrogen and a cyclodextrin is formulated into the granulate preparation as defined herein.
In preferred embodiments, the composition has a stability such that said estrogen is in an amount of at least 90 % w/w, more preferably of at least 95% w/w, most preferably of at least 97% w/w such as of at least 98% in relation to the initial content of the estrogen after storage for 12 months at 40°C and 75% relative humidity (RH).
One further means for improving the stability of an estrogen in such formulations and compositions comprises the judicious selection of excipients such that the content of excipients capable of inducing degradation of ethiny! estradiol are minimised or excluded from the formulations. One such critical excipient is polyvinylpyrrolidone, which is typically used as a binding agent for fluid bed granulation. As disclosed herein, the ethinyl estradiol is sensitive to polyvinylpyrrolidone and significant quantities of ethinyl estradiol is degraded in formulations and compositions, nonetheless the ethinyl estradiol is protected in the form of a clathrate. For example, compositions comprising polyvinylpyrrolidone and prepared as disclosed in Example 3 of US 5,798,338, by fluid bed granulation have a poor stability with respect to ethinyl estradiol. The present inventors has found that in such a composition the content of ethinyl estradiol is decreased by 25% in relation to the initial content of the ethinyl estradiol after storage for 12 months at 40°C and 75 % relative ) humidity (See table 1.4, Example 1, Table A). Therefore, one aspect of the invention relates to compositions/ formulations low in the content of compounds with relatively high : } oxidising potential such as an oxidising potential greater than or similar to polyvinylpyrrolidone. For example, the compositions/formulations of the present invention preferably have less polyvinylpyrrolidone than the compositions of Example 3 of US
5,798,338. More preferably, suitable embodiments of the invention relate to compositions/ formulations comprising at most 2% w/w of polyvinylpyrrolidone, preferably at most 1% w/w, more preferably at most 0.5% w/w, most preferably at most 0.2% w/w of ’ polyvinylpyrrolidone. Moreover, particular interesting embodiments relate to compositions/ formulations essentially free of polyvinylpyrrolidone.
Individually, or acting in concert, the above mentioned means have resulted in compositions, wherein the estrogen is more stable than in conventional compositions comprising polyvinylpyrrolidone that are manufactured by direct compression or by an improper fluid bed granulation process. The thus provided stable compositions is characterised by having a content of said estrogen of at least 90% w/w in relation to the initial content of said estrogen after storage for 3 months at 40°C and 75% relative humidity (RH). Preferably, the content of said estrogen is least 92% w/w, more preferably at least 94 % w/w, even more preferably at least 96% w/w and most preferably at least 98% w/w in relation to the initial content of estrogen after storage for 3 months at 40°C and 75% relative humidity (RH).
Likewise, the compositions are also stable at higher temperatures, e.g. at 60°C and 75% relative humidity, wherein the stability is such that a content of estrogen, as determined after 3 months storage at 60°C and 75% relative humidity (RH), is 85% w/w in relation to the initial content of said estrogen, preferably at least 90% w/w, more preferably at least 92% w/w, even more preferably at feast 94% w/w, most preferably at least 96% w/w in relation to the initial content of said estrogen.
Importantly, the compositions according to the invention are more stable at ambient conditions in comparison to conventional compositions. Thus, the compositions as disclosed herein have improved stability upon storage for 12 months at 25°C and 60% relative humidity (RH), such that said estrogen is in an amount of at least 95% w/w in relation to the initial content of said estrogen. Preferably, the content of estrogen is at least 96% w/w, more preferably at least 97% w/w, most preferably at least 98% w/w in relation to the initial content of estrogen after storage for 12 months at 25°C and 60% relative humidity (RH). ’ As the person skilled in the art will appreciate, the estrogen may be selected from the group consisting of ethinyl estradiol (EE), estradiol, estradiol sulfamates, estradiol . valerate, estradiol benzoate, estrone, estriol, estriol succinate and conjugated estrogens, including conjugated equine estrogens such as estrone sulfate, 178-estradiol sulfate, 17q- estradiol sulfate, equilin sulfate, 17p-dihydroequilin sulfate, 17a-dihydroequilin sulfate, equilenin sulfate, 17p-dihydroequilenin sulfate and17«-dihydroequilenin sulfate or mixtures thereof. Particular interesting estrogens are selected from the group consisting of ethinyl estradiol (EE), estradiol sulfamates, estradiol valerate, estradiol benzoate, estrone, and estrone sulfate or mixtures thereof, notably ethinyl estradiol (EE), estradiol valerate, estradiol benzoate and estradiol sulfamates. Most preferred is ethinyl estradiol (EE). )
In the preferred embodiment wherein the estrogen is ethinyl estradiol (EE), some of the - degradation products are well known. Thus, unstable compositions, e.g. those comprising a sensitive complex between an ethinyl estradiol and a cyclodextrin that are manufactured by said conventional granulation methods, comprises degradation products of ethinyl estradiol, in particular following storage for a period of time. Moreover, since more ethiny! estradiol is degraded in said conventional compositions than in those developed by the present inventors (see Example 2, table 1.3), the conventional compositions may comprise higher quantities of these degradation products.
Accordingly, the stability according to one embodiment of the present invention is such that a molar sum product of known degradation products of ethiny! estradiol is at most 0.8% in relation to the initial content of ethiny! estradiol. Thus, wherein the estrogen is ethinyl estradiol, the molar sum product of 6-a-hydroxy-ethinyl estradiol, 6-p-hydroxy- ethinyl estradiol, 6-keto-ethinyl estradiol, A6,7-ethinyl estradiol and A-9,11-ethiny! estradiol totals at the most 0.8% in relation to the initial molar content of ethinyl estradioi as determined after storage for 12 months at 25°C and 60% relative humidity (RH).
Preferably, the molar sum product totals at the most 0.7% and more preferably at the most 0.6% at these storage conditions.
Furthermore, the stability is such that a molar sum product 6-a-hydroxy-ethinyi estradiol, 6-p-hydroxy-ethinyi estradiol, 6-keto-ethinyl estradiol, A6,7-ethinyl estradiol and A-9,11- ethinyl estradiol, totals at the most 3% in relation to the initial molar content of ethinyl estradiol as determined after storage for 12 months at 40°C and 75% relative humidity (RH). Preferably, the molar sum product totals at most 2% and more preferably at the most 0.6% at those storage conditions.
As stated, an object of the present invention is to provide a pharmaceutical composition/ pharmaceutical formulation comprising a complex between an estrogen and cyclodextrin, wherein the stability of said estrogen is significantly improved over that of conventional ) compositions/ formulations. Thus, for further improving the stability or ensuring the stability of embodiments according to the invention, the composition/ formulations further : } comprises an antioxidant. The antioxidant may either be included in the granulate preparation or added to the composition as a further excipient.
The cyclodextrin may be selected from a- cyclodextrin, p- cyclodextrin, y- cyclodextrin and derivatives thereof. The cyclodextrin may be modified such that some or all of the primary or secondary hydroxyls of the macrocycle, or both, may be alkylated or acylated. Methods of modifying these alcohols are well known to the person skilled in the art and many are commercially available. Thus, some or all of the hydroxyls of cyclodextrin may modified cyclodextrins have be substituted with an O-R group or an O-C(0)-R, wherein R is an optionally substituted C,_¢ alkyl, an optionally substituted C,.¢ alkenyl, an optionally substituted C,.¢ alkynyl, an optionally substituted aryl or heteroaryl group. Thus, R may be methyl, ethyl, propyl, butyl, pentyl, or hexyl group. Consequently, O-C(0)-R may be an acetate. Furthermore, with the commonly employed 2-hydroxyethy! group, or 2- hydroxypropy! group R may be used to derivatize cyclodextrin. Moreover, the cyclodextrin alcohols may be per-benzylated, per-benzoylated, or benzylated or benzoylated on just one face of the macrocycle, or wherein only 1, 2, 3, 4, 5, or 6 hydroxyls are benzylated or benzoylated. Naturally, the cyclodextrin alcohols may be per-alkylated or per-acylated such as per-methylated or per-acetylated, or alkylated or acylated, such as methylated or acetylated, on just one face of the macrocycle, or wherein only 1, 2, 3, 4, 5, or 6 hydroxyls are alkylated or acylated, such as methylated or acetylated.
The estrogen-cyclodextrin complex may be obtained by methods known to the person skilled in the art (e.g. US 5,798,338).
The ethinyl estradiol-p-cyclodextrin complex may also be obtained by co-precipitation as follows: Ethinyl estradiol is dissolved in ethanol; p-cyclodextrin is dissolved at 45°C in water; the ethinyl estradiol solution is added to the beta-cyclodextrin solution; the obtained suspension is stirred for some hours at 20 to 25°C and afterwards at 2°C; the crystallisation product is isolated and dried.
Alternatively, the ethinyl estradiol-B-cyclodextrin complex may be obtained as follows:
Ethinyl estradiol is dissolved in acetone; B-cyclodextrin is dissolved at 45°C in water; the ethinyl estradiol solution is added to the B-cyclodextrin solution; the obtained suspension is stirred for some hours at temperatures below 25°C; afterwards, the crystallisation product is isolated and dried.
Preferably, the complex between a cyclodextrin and an estrogen may have a given lipophilicity (hydrophobicity). Thus, suitable embodiments according to the invention relates to those, wherein the complex has a n-octanol/water partition coefficient of the complex at pH 7 ranging from about 2 to 5, preferably from about 3 to 4. Further interesting embodiments comprises the complex in crystalline form. Thus, in a limited aspect, the invention relates to crystalline complexes between an estrogen and a cyclodextrin. The term "crystalline" relates to various modifications of the physical structure of a compound, wherein a part of the compound can be in amorphous form.
Crystalline compounds may be characterised by being hydrated and containment of crystal water. Finally, the complexes may be defined by the examples provided herein such as those hydrated complexes disclosed in Example 12. Moreover, the crystalline complex may contain parts of free ethinyl estradiol and free cyclodextrin.
Preferably, the complex comprises of B-cyclodextrin or a derivative thereof, most preferably p-cyclodextrin. Thus, in a particularly preferred embodiment of the invention, which is a combination of preferred embodiments, the estrogen is ethinyl estradiol and the cyclodextrin is B-cyclodextrin.
In an alternative embodiment of the invention, the composition further comprises one or more therapeutically active agent. Thus, in this embodiment, the composition further comprises a progestogen. The progestogen may be selected from the group consisting of drospirenone, levonorgestrel, norgestrel, gestodene, dienogest, cyproterone acetate, norethisterone, norethisterone acetate, desorgestrel, 3-keto-desorgestrel. However, the preferred progestogen is drospirenone.
In the preferred embodiment wherein the therapeutically active substance is drospirenone, said drospirenone may optionally be micronised. In the preferred embodiment where the therapeutically active substance is drospirenone, all or substantially all of said drospirenone may be present as a complex with cyclodextrin. As the person skilled in the art will appreciate, the dissociation of the drospirenone cyclodextrin complex may result in a mixture of cyclodextrin-complexed drospirenone and uncomplexed (free) drospirenone.
As was the case for uncomplexed drospirenone, the complexed drospirenone may also be micronized.
Thus, a preferred embodiment of the invention relates to a composition/ formulation wherein the estrogen is ethinyl estradiol and the one or more therapeutically active agent(s) is drospirenone. A further interesting embodiment in connection hereto is where both the estrogen-cyclodextrin complex and the drospirenone are micronised.
As stated, the compositions and formulations comprises low doses of active agent, such that typical embodiments according to the invention comprises estrogen in an amount ) corresponding to a therapeutically equivalent amount of ethinyl! estradiol of from about 0.002 % w/w to 2 % w/w. oo In yet other typical embodiments, the composition/formulations comprises the estrogen, ethinyl estradiol, in an amount from about 0.002 % w/w to 2% w/w. Preferably, the amount is from about 0.004% w/w to 0.2% w/w, more preferably from about 0.008 % w/w to 0.1% w/w, most preferably from about 0.02% w/w to 0.05% w/w.
When taken the amount of the cyclodextrin into account such as in preferred embodiments wherein the estrogen is ethinyl estradiol and the cyclodextrin is f-cyclodextrin, the ethinyl : estradiol is in an amount relative to the ethinyl-estradiol-B-cyclodextrin complex of from about 5 % w/w to 20 % w/w, preferably from about 8% w/w to 15% w/w, most preferably from about 9 % w/w to 13% w/w.
Furthermore, according to the invention, the ratio between the estrogen and the cyclodextrin may be adjusted. Therefore, in suitable embodiments, the estrogen is in an amount relative to the cyclodextrin such that a molar ratio between the estrogen and the cyclodextrin is from about 2:1 to 1:10, preferably from about 1:1 to 1:5, most preferably from about 1:1 to 1:3, such as 1:1 and 1:2.
In embodiments wherein the composition further comprises a therapeutically active compound and that said compound is drospirenone, the drospirenone is in an amount from about 0.4 % to 20% w/w, preferably from about 0.8% w/w to 10% w/w, more preferably from about 1.5 % w/w to 5% w/w.
A further object of the invention is to provide a composition or a formulation as described herein further formulated as a unit dosage form, preferably such as a tablet, capsule or sachets.
A typical embodiment of the invention relates to a composition or a formulation in form of granules, pellets or dry compressed blends that may be filled into hard gelatine capsules or sachets, or compressed into tablet cores. In that event, the composition or formulation comprises (% wt/wt): i) Active agent:complex between ethinyl estradiol and pB-cyclodextrins; ii) 0-95% w/w of filling agents such as lactose, starch, cellulose and/or others; iii) 0-15% w/w of binding agents such as starch, cellulose, hydroxypropylcellulose hydroxypropylmethylcellulose, maltodextrine and/or others; iv) 0-5% w/w of glidants such as colloidal silicon dioxide and/or others; ’ v) 0-15% w/w of disintegrating agents such as starch, carmellose-calcium, crosscarmellose-sodium, carboxymethylstarch sodium and/or others; : vi) 0-5% w/w of stabilisers/antioxidants such as tocopherole acetate, propyl! gallate, ascorbic acid, ascorbic palmitate and/or others; and vii) 0-5 % w/w of lubricants such as magnesium stearate and/or others.
In the embodiment wherein the composition/formulation further comprises a therapeutically active compound, such as a progestogen, preferably drospirenone, a typical formulation may further comprise 0.1-15% w/w of drospirenone.
S A particular interesting embodiment relates to a unit dosage form comprising:
Drospirenone (micronised) 3.00 mg :
Ethiny! estradiol as p-cyclodextrin clathrate (micronised) 0.02 mg*
Lactose 48.18 mg**
Corn starch 28.00 mg
Magnesium stearate 0.8 mg
Water (processing aid) * 0.02 is the concentration of ethinyt estradiol (not taken B-cyclodextrin into consideration). The amount of ethinyl estradiol in the B-cyclodextrin clathrate is 9.5 to 12.5%. ** the amount of lactose is to be adjusted to the amount of B-cyclodextrin.
A further aspect of the invention relates to a method for improving the stability of an estrogen in a pharmaceutical composition that comprises an estrogen and one or more excipients in a granulate preparation, the method comprises the steps of: i) forming an complex between said estrogen and a cyclodextrin; and ii) mixing under granulation conditions the said complex with the one or more excipients such that the relative humidity of the final granulate does not exceed 60%, as determined at a temperature between 20°C and 40°C.
As described herein, this method of stabilising results in compositions that are more stable than reported for conventional compositions. The important features leading to the improved stability relates, at least in part, to the granulation process and to the proper choice of excipients. Thus, the method of improving the stability relates to the proper adjusting of the relative humidity of the granulate preparation. Most importantly, the relative humidity may not exceed 60% relative humidity, as determined at a temperature between 20°C and 40°C. Preferably, the relative humidity does not exceed 55%, more preferably does not exceed 45%, most preferably does not exceed 40%, as determined at a temperature between 20°C and 40°C.
In a further related aspect hereof, the invention relates to a method for improving the stability of an estrogen in a pharmaceutical composition that comprises an estrogen and ’ one or more excipients, the method comprises the steps of: i) forming an complex between said estrogen and a cyclodextrin; and ii) adding excipients in an amount so as to minimise the overall amount of excipients which have an oxidising potential greater than or similar to polyvinylpyrrolidone.
The aim is to restrict or minimise the amount of excipients, which have oxidising potentials greater than or similar to polyvinylpyrrolidone.
Thus, the method of stabilising also relates to limiting the content of excipients with an : oxidising potential greater than or similar to polyvinylpyrrolidone, including limiting the content of polyvinylpyrrolidone in the compositions/formulations. Thus, interesting embodiments of the invention relate to those wherein the one or more excipient(s) comprises polyvinylpyrrolidone in an amount of at most 2% w/w. Preferably, the amount is at most 1% w/w, more preferably at most 0.5% w/w, most preferably at most 0.2% w/w.
In a very preferred embodiment, the method of improving stability relates to excluding polyvinyipyrrolidone from the pharmaceutical composition. Thus, a method of stabilising an estrogen in a pharmaceutical composition relates to a composition/formulation essentially free of polyvinylpyrrolidone.
A still further object of the invention is to provide a process for preparing compositions and formulations that are stable and homogenous and as described supra. Suitable process conditions comprise the steps of preparing a granulation liquid, individually loading the active agents and the one or more excipient(s) into equipment suitable for granulation, granulating and drying. In a preferred embodiment hereof, the thus obtained granules have a relative humidity of at most 60%.
Thus, the invention relates to a process for manufacturing a granulate preparation comprising a complex between an estrogen and a cyclodextrin, wherein the processing of the granulate preparation comprises the steps of: i) loading the complex and one or more excipients into a granulator; ii) applying a liquid onto the loaded complex and the one or more excipients under granulation conditions so as to obtain granules having a relative humidity not exceeding 60 %, as determined at a temperature between 20°C and 40°C.
The process has lead to novel compositions comprising less degraded estrogen and iess degradation products in comparison to those compositions manufactured by conventional processes such as those granulation techniques using polyvinylpyrrolidone and/or techniques wherein the relative humidity are not properly adjusted.
Thus, in preferred embodiments according to the invention, the granulation conditions are even more restricted such as the relative humidity of the granulate preparation does not exceed 55%, preferably does not exceed 45%, most preferably does not exceed 40%, as determined at a temperature between 20°C and 40°C. Furthermore, the amount of polyvinylpyrrolidone is restricted.
As stated, the formulation comprises low doses of the active agents, in particularly of the ethinyl-estradiol-cyclodextrin complex. Consequently, it is critical to achieve homogenous formulations and to meet the requirements of content uniformity. Thus, an important issue : to consider, when manufacturing compositions/ formulations containing low doses of the active ingredient, is the homogeneity of the granulate preparation. Common practice applies to the use of pre-mixes of the active ingredient with an excipient, e.g. lactose when manufacturing low-dosages formulations. The pre-mix is normally made in a separate blending step. However, the present inventors have developed a process for manufacturing low-dosage formulations without using a step of pre-mixing the active agent with a suitable excipient.
Thus, an interesting embodiment of the invention relates to a method as described supra wherein the complex and the optionally further one or more therapeutically active agent(s) are provided as individual agent(s) without being pre-mixed with excipients. In a further embodiment related hereto, one or more therapeutically active agent(s), such as drospirenone, is further added to the granulator.
As stated, the properly adapted process of the invention has lead to the manufacturing of homogenous batches of the granulate preparation. In the event where the process further lead to unit dosage forms, such as a tablet, content uniformity is achieved. Thus, in very suitable embodiments of the invention, batches of final granulate and/or final unit dosage forms comply with the content uniformity so as to be within the range of 85% and 115%, preferably within the range of 90% and 110%, more preferably within 95% and 105%.
The content uniformity is determined by taking 10 random samples of the granulate preparation or by randomly taken 10 tablets from a batch of tablets, determining the quantitative content of estrogen in each sample or tablet, and finally calculating the coefficient of variation based on the individual quantities of estrogen.
The low doses referred to in this context relate to compositions/ formulations comprising the complex in an amount of from about 0.005 % w/w to 20% w/w, preferably from about 0.01 % w/w to 2% w/w, more preferably from about 0.05% w/w to 1% w/w, even more ) preferably from about 0.1% w/w to 0.7% w/w, most preferably from about 0.15% w/w to 0.5% w/w.
The granulation may be provided by any equipment that will provide a stable and homogenous granulate according to the invention. That is to say any equipment suitable for obtaining granules having a relative humidity of at most 60% at temperatures from 20°C to 40°C. However, in a preferred embodiment, the granulation conditions are provided by fluidised bed granulation.
A further object of the invention is related to the use of compositions described herein and ’ in the Examples in the preparation of a medicament for female contraception, for hormone replacement therapy, or for treating acne or PMDD (pre-menstrual dysfunction disorder).
The use of a compound of the present invention for hormone replacement therapy relates to treating menopausal, pre-menopausal, and/or post-menopausal symptoms in a female.
The medicament is suitably formulated according to general knowledge for a person skilled in the pharmaceutical art typically for oral administration.
In a preferred embodiment, the medicament is suitable for inhibiting ovulation in a female.
Apart from its ability to inhibit ovulation, the composition of the invention has been found to possess pronounced anti-androgenic properties and may therefore be used in the prevention or treatment of androgen-induced disorders, in particular acne. Such use may be independent from or concomitant with the use as a contraceptive disclosed above.
Furthermore, since drospirenone is an aldosterone antagonist, it has diuretic properties and is therefore suitable for counteracting the water-retentive properties of ethinyl estradiol.
As stated, the use of compositions for the preparation of a medicament for oral administration, preferably comprises the use of compositions comprising a complex between ethinyl estradiol and B-cyclodextrin and further comprising a therapeutically active agent. Most preferably, the agent is drospirenone. In a combination of preferred embodiments, the dose of ethinyl estradiol is from 0.015 mg to 0.04 mg, in particular from about 0.015 mg to 0.03 mg, and the dose of drospirenone is from about 2.5 mg to 3.5 mg, in particular about 3 mg for a daily dosage unit. More particularly, the compositions of the invention comprise an amount of drospirenone corresponding to a daily dosage of from about 3.0 to 3.5 mg and ethinyl estradiol in an amount corresponding to from about 0.015 to 0.03 mg.
The medicament for use in inhibiting ovulation may be an one-phase composition, i.e. a preparation wherein the amounts of either active agent remains constant for the entire at least 21-day period, or the amounts of either or both active agents may be varied over the at least 21-day period to generate a multiple-phase preparation, e.g. a two- or three- phase preparation, substantially as disclosed in, e.g., EP 148 724.
In an interesting embodiment of the present invention relating to the use of a medicament for inhibiting ovulation, the medicament is administered on each day of at least 21 consecutive days, a daily dosage unit comprising a combination of drospirenone in an amount of from about 2 mg to about 4 mg and ethinyl! estradiol in an amount from about 0.01 to about 0.05 mg, followed by administering, on each day of 7 or less consecutive days, a daily dosage unit containing no active agent, or alternatively, administering no . dosage units for 7 days or less.
In a further suitable embodiment, each of the daily dosage units comprising a combination of drospirenone and ethinyl estradiol are to be administered for 21, 22, 23 or 24 consecutive days, and each of the daily dosage units containing no active agent may be administered for 7, 6, 5 or 4 consecutive days, as appropriate. Furthermore, the daily dosage units comprising the combination of drospirenone and ethinyl estradiol may be administered for 28 consecutive days or 30 or 31 consecutive days. Suitably, the use of said medicament comprises administering, on each day of at least 21 consecutive days, a daily dosage unit comprising a combination of drospirenone in an amount of from about 2 mg to about 4 mg and ethinyl estradiol in an amount from about 0.01 to about 0.05 mg, followed by administering, on each day of 7 or less consecutive days, a daily dosage unit containing ethinyl estradiol alone in an amount of from about 0.01 mg to about 0.05 mg.
In this alternative method, the daily dosage units comprising the combination of drospirenone and ethinyl estradiol may suitably be administered for 21, 22, 23 or 24 consecutive days, and wherein the daily dosage units comprising ethinyl! estradiol alone may then be administered for 7, 6, 5 or 4 consecutive days, as appropriate. In a further embodiment of the method, the daily dosage units comprising the combination of drospirenone and ethinyl estradiol are administered for 2-4, preferably 2 or 3, times 28 consecutive days, followed by administration of the daily dosage units comprising the combination of drospirenone and ethinyl estradiol for 21 consecutive days and subsequently administration of the daily dosage units comprising ethinyl estradiol alone for 7 consecutive days.
The present invention is further defined by the Examples.
Example 1 discloses a pharmaceutical product according to some embodiments of the present invention along with pharmaceutical products known to the person skilled in the art. Table 1.3 illustrates the performance in terms of stability in comparison to known formulations after a fixed period of time under controlled environmental conditions. The data shows that direct compression of the powder blend resuits in good stability of ethinyl estradiol when provided in the form of a cyclodextrin complex (Product D). The product E ’ was prepared to be polyvinylpyrrolidone-free according to the present invention. This product also shows good stability of the ethinyl estradiol in spite of being manufactured by granulation. However, in the case where the product includes polyvinylpyrrolidone and is manufactured according to Example 3 in US 5,798,338 (Tablet A), the product is poorly stable.
Example 2 illustrates the stability of EE in Formulations D and E in comparison to other formulations in terms of the breakdown products isolated from samples upon storage after a fixed period of time under controlled environmental conditions.
Example 3 discloses the contents of one embodiment of the present invention, wherein the composition further comprises drospirenone.
Example 4 describes the morphology or some physical characteristics of a typical dosage form of a formulation according to the present invention.
Example 5 discloses a typical process for the preparation of a tablet.
Example 6 describes the method in which certain physical properties, namely the rate constant of the dissociation constant of the complex between EE and CD, was studied. The half-life of the 1:1 complex was determined to be 155.8 s and the dissociation constant was determined to be 4.45 x 103 s’!,
Example 7 describes the method in which the equilibrium stability constant (formation constant) of the complex between EE and CD was studied. The stability constant of the 1:1 complex was found to be 9.5 x 10™* M™'. The solubility of complexed ethiny! estradiol was found to improve in comparison to the free steroid.
Example 8 describes the method in which the equilibrium stability constant (formation constant) of the complex between EE and CD in acidic medium was studied. The stability constant of the 1:1 and 1:2 complex in acidic medium is disclosed. The solubility of complexed ethinyl! estradiol was found to improve in comparison to the free steroid in acidic medium.
Example 9 discloses the method in which the acid dissociation constant (pK,) of the EE-CD complex in aqueous media was determined to be approx. 10.51 in comparison to the pKa of approx. 10.25 of the free steroid. 9 Example 10 describes the method in which the n-octanol/water partition coefficient of the
EE-CD complex was determined and its dependence on pH. Its log P value ranges from 3.20 to 3.53.
Example 11 discussed whether the ethinyl estradiol-p-cyclodextrin complex can exist in multiple solid state forms and to provide test methods, which can detect and distinguish between such forms.
Example 12 describes typical preparations of an EE-CD complex.
Example 1.
Degradation of ethinyl estradiol in various formulations.
Comparative stability data of five tablet formulations comprising ethinyl estradiol has been investigated. The various formulations differ from each other with respect to the manufacturing process, use of ethinyl estradiol in the form of a cyclodextrin complex and use of polyvinylpyrrolidone 25.000 (PVP). Tablet A was prepared as disclosed in US 5,798, 338, Example 3, such as by fluid bed granulation based on pre-mixing of active ingredient with lactose and no adjusting of the relative humidity of the granules. Tablets, B, Cand E were prepared according to the manufacturing process disclosed herein.
Table 1.1
Summary of Parameters of Film-Coated Tablets
Cm Active agent Excipient ! [A fluid bed granulation* | EE-B-CD complex ER 5 [fluid bed granulation®* [EE [+ Pup
NN bed granulation** [EE CC]
D - | Direct compression EE-p-CD complex * Fluid bed granulation as disclosed in Example 3 of US 5,798, 338, ** fluid bed granulation as disclosed in example 5 herein, PVP = polyvinylipyrrolidone.
Table 1.2 [7 Composition of Test Formulations - TT Tablets
Composition: . —
B c > ee IE A - -]
EE-B-CD - - v Vv
DRSP HE oo 1 Cv v I lactose vv TTY maize starch v — v Lv v : micro cellulose - TC i - v = starch 1500 v eT PE
PVP 25.000 — v EEE IE
Results
The content of ethinyl estradiol was determined by HPLC just after manufacturing (start) and following storage at various conditions for 3 and 12 months. The content of ethinyl
S estradiol is expressed relatively to the initial content of ethinyl estradiol that was added to each formulation. :
Table 1.3 40°C, 75% 60°C, 75% 25°C, 60% 40°C, 75%
I ol il 100.1 95.8 86.1 100.1 92.1 101.5 98.8 96.4 101.4 99.9
P 102.7 101.8 100.0 103.3 102.0 96.6 101.8 99.3
Example 2,
Formation of oxidative degradation products of ethinyl! estradiol
The content of known oxidative degradation products of ethinyl estradiol was determined by HPLC following storage for 12 months at 25°C and 60 % relative humidity (RH) for 12 months. The molar content of each degradation products is expressed relatively to the initial molar content of ethinyl estradiol that was added to each formulation. Four formulations as well as the pure ethinyl estradiol and the ethinyl estradiol B-cyclodextrin complex were investigated.
Table 2.1. Stability results after 12 months, 25°C, 60% RH ~ Formation of degradation products (% of initial content of EE) 6-Keto-EE | A9,11-EE | total known 0.002 0.003 n.d 0.38 0.385
B 0.04 | 007 1 032 | 0.74 71.20 c 0.05 0.09 0.11 0.73 | 1.00 0.04 0.07 ! 0.08 0.70 0.91
NEE AE + : 0.01 0.01 n.d | 0.45 0.47 0.03 0.01 n.d 0.46 | 0.50
F 0.02 0.01 n.d oa0 | 0.43 n.d = not detectable; 6-a-OH-EE = 6-a-hydroxy-ethinyl estradiol; 6-B°OHEE = 6-p hydroxy-ethinyl estradiol; 6-Keto-EE = 6-keto- ethinyl estradiol; A9,11-EE = A9,11-ethinyl estradiol.
Table 2.2. Stability results after 12 months, 40°C, 75% RH
Formation of degradation products (% of initial content of EE)
Formulations | 6-0-OH-EE [ 6-B-OH-EE | 6-Keto-EE Sgt
EE 0.004 n.d 038 | 038 0.33 0.61 1.03 - mm
C 028 | 0.54 0.87 1.59 | 3.28 ] 0.03 0.09 0.10 | 0.79 1.01
D 0.03 0.10 0.09 0.79 0.98 . 0.08 0.19 0.30 0.93 | 150
E 0.08 0.19 0.41 0.89 | 1.58 n.d = not detectable; 6-a-OH-EE = 6-a-hydroxy-ethinyl estradiol; 6-B-OH-EE = 6-p- hydroxy-ethinyl estradiol; 6-Keto-EE = 6-keto- ethinyl estradiol; A9,11-EE = A9,11-ethinyl estradiol.
Example 3.
Typical compositions consisting of a tablet core is described. The tablet core may optionally be film-coated or sugar coated using the described ingredients. The specific ingredients are typical suitable ingredients according to the invention, but are not limited to those.
Table 3. etc |__|]
Active agent 1 estrogens in the form of an complex with a [ee a ES ES
Binder starch, cellulose, hydroxypropyicellulose, 0-15% mei
Disintegrant starch, carmellose-calcium, crosscarmeillose- | 0-15%
Stabiliser/antioxidant tocopherole acetate, Propyl gallate, ascorbic | 0-5%
I evr
Fimo
Film-binding agent hydroxypropylmethyicellulose, polyacrylic 20-100%
IR oe RA
Sorcontiog |__
Example 4.
Preferred compositions
A preferred composition consists of the components listed below. The batch size is 200,000 - 550,000 tablets (development site) and 2.5 Mio tablets up to 5 Mio tablets (production site), respectively. Water is used as a processing aid for the manufacture of the tablet mass (fluid bed granulation) and the film-coating. roredient One tablet Development Production (kg) (mg) (kg) . Drospirenone, micro15 | 30 1.650 | 7.500 =
Ethinyl estradiol-B- cyclodextrine complex, 0.020 * 0.011 * 0.050 * micro
Lactose monohydrate | 48.18 26.499 | 120.450
Corn starch 28.0 15.400 70.000 oe stearate 0.8 ** "tablet mass weight 80.0 mg 200.000 kg erepropyimetty | 1.5168 0.83424 3.792 talc 0.3036 | or 0.759 titanium dioxide 1.1748 0.64614 2.937 ferric oxide pigment, red | 0.0048 —— weight of film-coat | 3.0 mg 1.650 kg 7.500 kg total weight 83.0 mg 45.650 kg 207.500 kg * . quantities given state the amount of ethinyl estradiol. TT
Example 5.
Manufacturing Process
The manufacturing process comprises the following steps: eo Prepare the Suspend maize starch in purified water and add this granulation liquid: suspension to purified water while stirring. « Prepare the Introduce lactose, drospirenone micro 15, ethinyl estradiol-B- granules: cyclodextrine complex micro and maize starch (portion) into the fluid bed granulator. Activate a continuous fluid bed and
Claims (1)
1. A formulation comprising a complex between an estrogen and a cyclodextrin, wherein the formulation is a granulate preparation, said granulation preparation having a relative : humidity of at most 60%, as determined at a temperature between 20°C and 40°C.
2. The formulation according to claim 1, wherein the granulate preparation has a relative humidity of at most 55%, preferably of at most 45%, most preferably of at most 40%, as determined at a temperature between 20°C and 40°C.
3. The formulation according to any one of preceding claims, wherein the estrogen is selected from the group consisting of ethinyl estradiol (EE), estradiol, estradiol sulfamates, estradiol valerate, estradiol benzoate, estrone, and estrone sulfate or mixtures thereof.
4. The formulation according to any one of preceding claims, wherein the estrogen is selected from the group consisting of ethinyl estradiol (EE), estradiol sulfamates, estradiol valerate, estradiol benzoate, estrone, and estrone sulfate or mixtures thereof.
5. The formulation according to any one of preceding claims, wherein the estrogen is ethinyl estradiol.
6. The formulation according to any of preceding claims, wherein the cyclodextrin is selected from the group consisting of a-cyclodextrin, p-cyclodextrin, y-cyclodextrin and derivatives thereof.
7. The formulation according to claim 6, wherein the cyclodextrin is p-cyclodextrin or derivatives thereof.
8. The formulation according to any one of preceding claims comprising at most 2% w/w of polyvinylpyrrolidone, preferably at most 1% w/w, more preferably at most 0.5% w/w, most preferably at most 0.2% w/w of polyvinylpyrrolidone.
9. The formulation according to any one of preceding claims further comprising one or more therapeutically active agent(s). '
10. The formulation according to claim 9, wherein the one or more therapeutically active agent(s) is a progestogen.
PCT/IB01/02605 CLAIMS:
1. A composition comprising: i) a complex between an estrogen and a cyclodextrin in a granulate preparation, wherein when said granulate preparation comprises polyvinylpyrrolidone it is present in a concentration of at the most 2% w/w; and optionally ii} one or more excipient(s), the composition has a stability such that said estrogen is in amount of at least 85% w/w in relation to the initial content of said estrogen after storage for 12 months at 40°C and 75% relative humidity (RH).
2. The composition according to claim 1, wherein the estrogen is selected from the group consisting of ethinyl estradiol (EE), estradiol, estradiol sulfamates, estradiol valerate, estradiol benzoate, estrone, and estrone sulfate or mixtures thereof.
3. The composition according to claim 1 or 2, wherein the estrogen is selected from the group consisting of ethinyl estradiol (EE), estradiol sulfamates, estradiol valerate, estradiol benzoate, estrone, and estrone sulfate or mixtures thereof.
4. The composition according to claim 3, wherein the estrogen is ethinyl estradiol (EE).
5. The composition according to any of the preceding claims, wherein the cyclodextrin is selected from the group consisting of a-cyclodextrin, 3-cyclodextrin, y-cyclodextrin and derivatives thereof.
6. The composition according to claim 5, wherein the cyclodextrin is [3-cyclodextrin or derivatives thereof.
7. The composition according to any one of the preceding claims, wherein the estrogen is in an amount corresponding to a therapeutically equivalent amount of ethinyl estradiol of from about 0.002% w/w to 2% w/w.
8. The composition according to any of claims 1 to 6, wherein the estrogen is in an amount from about 0.002% w/w to 2% w/w. AMENDED SHEET
PCT/IB01/02605
9. The composition according to any of the preceding claims, wherein the estrogen is ethinyl estradiol and the cyclodextrin is -cyciodextrin, the ethinyl estradiol is in an amount relative to the ethinyl-estradiol-B-cyclodextrin complex of from about 5% w/w to 20% w/w.
10. The composition according to any of the preceding claims, wherein the estrogen is in an amount relative to the cyclodextrin such that a molar ratio between the estrogen and the cyclodextrin is from about 2:1 to 1:10.
11. The composition according to any of the preceding claims further comprising one or more therapeutically active agent(s).
12. The composition according to claim 11, wherein the one or more therapeutically active agent(s) is a progestogen.
13. The composition according to claim 12, wherein the progestogen is selected from the group consisting of drospirenone, levonorgestrel, norgestrel, gestodene, dienogest, cyproterone acetate, norethisterone, norethisterone acetate, desorgestrel, and 3-keto- desorgestrel.
14. The composition according to claim 13, wherein the progestogen is drospirenone.
15. The composition according to claim 14, wherein the drospirenone is micronised. :
16. The composition according to claim 14 or 15, wherein drospirenone is in an amount from about 0.4% to 20% w/w.
17. The composition according to any of the preceding claims, wherein the granulate preparation has a relative humidity of at the most 55% as determined at a temperature between 20°C and 40°C.
18. The composition according to any of the preceding claims comprising at the most 1% w/w polyvinylpyrrolidone. AMENDED SHEET
PCT/IB01/02605
19. The composition according to any of the preceding claims, wherein the one or more excipient(s) is selected from the group consisting of starch, cellulose, hydroxypropylceliulose, hydroxypropylmethylcellulose and maltodextrin.
20. The composition according to any of the preceding claims, wherein the complex is micronised.
21. The composition according to any of the preceding claims further comprising an antioxidant.
22. A unit dosage form comprising a composition according to any of claims 1-21.
23. The unit dosage form according to claim 22, wherein said unit dosage form is in the form of a tablet, a capsule or sachets.
24. A process for the manufacture of a composition comprising a complex between an estrogen and a cyclodextrin, the process comprising the steps of: i) obtaining a complex between an estrogen and a cyclodextrin; ii) loading the complex and one or more excipients into a granulator, ii) applying a liquid onto the loaded complex and the one or more excipients under granulation conditions so as to obtain granules having a relative humidity not exceeding 60%, as determined at a temperature between 20°C and 40°C, wherein when the one or more excipient(s) is polyvinyipyrrolidone it is present in the composition in a concentration of at most 2% w/w.
25. The process according to claim 24, wherein the relative humidity of the granulate preparation does not exceed 55% as determined at a temperature between 20°C and 40°C.
26. The process according to claim 24 or 25, wherein the estrogen is selected from the group consisting of ethinyl estradiol (EE), estradiol, estradiol sulfamates, estradiol valerate, estradiol benzoate, estrone, and estrone sulfate or mixtures thereof.
27. The process according to claim 26, wherein the estrogen is ethinyl estradiol (EE). AMENDED SHEET
PCT/IBO1/02605
28. The process according to any of claims 24 to 27 comprising at the most 1% w/w polyvinylpyrrolidone.
29. A composition obtainable by the process as defined in any of claims 24 to 28.
30. A method for improving the stability of an estrogen in a composition, the method comprising the steps of: i) forming a complex between said estrogen and a cyclodextrin; and ii) mixing under granulation conditions said complex with one or more excipients such that the relative humidity of the final granulate does not exceed 60%, as determined at a temperature between 20°C and 40°C, wherein when the one or more excipient(s) is polyvinylpyrrolidone it is present in the composition in a concentration of at the most 2% w/w.
31. The method according to claim 30 comprising at the most 1% w/w polyvinylpyrrolidone.
32. Use of a complex between an estrogen and a cyclodextrin for female contraception, said complex is in the form of a composition comprising a granulated preparation of said complex, wherein when said composition comprises polyvinylpyrrolidone it is present in a concentration of at the most 2% w/w, the composition has a stability such that said estrogen is in amount of at least 85% w/w in relation to the initial content of said estrogen after storage for 12 months at 40°C and 75% relative humidity (RH).
33. The use according to claim 32, wherein said composition is as defined in any of claims 2 to 21 or as defined in claim 29.
34. Use of a complex between an estrogen and a cyclodextrin for the preparation of a medicament for female hormone replacement therapy, said medicament comprises a composition comprising said complex in a granulate preparation, wherein when said granulate preparation comprises polyvinylpyrrolidone it is present in a concentration of at the most 2% w/w, AMENDED SHEET
PCT/IB01/02605 the medicament has a stability such that said estrogen is in amount of at least 85% w/w in relation to the initial content of said estrogen after storage for 12 months at 40°C and 75% relative humidity (RH).
35. The use according to claim 34, wherein said composition is as defined in any of claims 2 to 21 or as defined in claim 29.
36. A composition comprising: i) drospirenone and a complex between ethinyl estradiol and a cyclodextrin, wherein drospirenone is present in an amount of from 2 mg to 4 mg, and wherein ethinyl estradiol is present in an amount of from 0.01 mg to 0.05 mg; and ii) one or more excipient(s), the composition has a stability such that said ethinyl estradiol is in amount of at least 85% w/w in relation to the initial content of said ethinyl estradiol after storage for 12 months at 40°C and 75% relative humidity.
37. The composition according to claim 36, wherein ethinyl estradiol is present in an amount of from 0.015 mg to 0.04 mg.
38. The composition according to claim 37, wherein ethinyl estradiol is present in an amount of from 0.015 mg to 0.03 mg.
39. The composition according to any of claims 36-38, wherein drospirenone is present in an amount of from 2.5 mg to 3.5 mg.
40. The composition according to claim 39, wherein drospirenone is present in an amount of about 3 mg.
41. The composition according to any of claims 36-40, wherein the cyclodextrin is selected from the group consisting of a-cyclodextrin, B-cyclodextrin, y-cyclodextrin and derivatives thereof.
42. The composition according to claim 41, wherein the cyclodextrin is B-cyclodextrin or derivatives thereof. AMENDED SHEET
PCT/IB01/02605 43 The composition according to claim 42, wherein the cyclodextrin is B-cyclodextrin.
44. The composition according to any of claims 36-43, wherein drospirenone is micronised.
45. The composition according to any of claims 36-44, wherein the complex is micronised.
46. The composition according to any of claims 36-45, wherein said composition is in the form of a granulate preparation and wherein said granulation preparation has a relative humidity of at most 60%, as determined at a temperature between 20°C and 40°C.
47. The composition according to claim 46, wherein the granulate preparation has a relative humidity of at the most 55% as determined at a temperature between 20°C and 40°C.
48. The composition according to any of claims 36-47 comprising at the most 2% w/w polyvinylpyrrolidone.
49. The composition according to claim 48 comprising at the most 1% w/w polyvinyl- pyrrolidone.
50. The composition according to any of claims 36-49 further comprising an antioxidant.
51. A unit dosage form comprising a composition according to any of claims 36-50.
52. The unit dosage form according to claim 51, wherein said unit dosage form is formulated for oral administration.
53. The unit dosage form according to claim 51 or 52, wherein said unit dosage form is in the form of a tablet, a capsule or sachets.
54. The unit dosage form according to claim 53, wherein said unit dosage form is in the form of a tablet. AMENDED SHEET
PCT/IB01/02605
59. A composition according to claim 1, or claim 29, or claim 36, substantially as herein described with reference to and as illustrated in any of the examples.
56. A unit dosage form according to claim 22, or claim 51, substantially as herein described with reference to and as illustrated in any of the examples.
57. A process according to claim 24, substantially as herein described with reference to and as illustrated in any of the examples.
58. A method according to claim 30, substantially as herein described with reference to and as illustrated in any of the examples.
59. Use according to any one of claims 32 to 35, substantially as herein described with reference to and as illustrated in any of the examples. AMENDED SHEET
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP00610135A EP1216713A1 (en) | 2000-12-20 | 2000-12-20 | Compositions of estrogen-cyclodextrin complexes |
Publications (1)
Publication Number | Publication Date |
---|---|
ZA200305532B true ZA200305532B (en) | 2006-06-28 |
Family
ID=37516219
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
ZA200305532A ZA200305532B (en) | 2000-12-20 | 2003-07-17 | Compositions of estrogen-cyclodextrin complexes |
Country Status (7)
Country | Link |
---|---|
CN (1) | CN101116666B (en) |
AR (1) | AR032205A1 (en) |
ME (1) | ME00293B (en) |
PE (1) | PE20020709A1 (en) |
UA (1) | UA77626C2 (en) |
UY (1) | UY27088A1 (en) |
ZA (1) | ZA200305532B (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102512688A (en) * | 2011-12-29 | 2012-06-27 | 上海新华联制药有限公司 | Nilestriol-beta-cyclodextrin inclusion compound and preparation method thereof |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4727064A (en) * | 1984-04-25 | 1988-02-23 | The United States Of America As Represented By The Department Of Health And Human Services | Pharmaceutical preparations containing cyclodextrin derivatives |
NL8801670A (en) * | 1988-07-01 | 1990-02-01 | Walter Adrianus Josephus Johan | PHARMACEUTICAL PREPARATION. |
US5324718A (en) * | 1992-07-14 | 1994-06-28 | Thorsteinn Loftsson | Cyclodextrin/drug complexation |
DE19848303A1 (en) * | 1998-10-14 | 2000-04-20 | Schering Ag | Stable combination of 14,17-over-bridged steroid gestagen and cyclodextrin compound, useful for treating climacteric disorders or for contraception |
-
2001
- 2001-12-20 PE PE2001001280A patent/PE20020709A1/en active IP Right Grant
- 2001-12-20 CN CN200610092522.4A patent/CN101116666B/en not_active Expired - Lifetime
- 2001-12-20 AR ARP010105936 patent/AR032205A1/en not_active Application Discontinuation
- 2001-12-20 UY UY27088A patent/UY27088A1/en not_active IP Right Cessation
- 2001-12-20 ME MEP-2008-381A patent/ME00293B/en unknown
- 2001-12-20 UA UA2003076822A patent/UA77626C2/en unknown
-
2003
- 2003-07-17 ZA ZA200305532A patent/ZA200305532B/en unknown
Also Published As
Publication number | Publication date |
---|---|
PE20020709A1 (en) | 2002-08-23 |
UA77626C2 (en) | 2006-12-15 |
CN101116666A (en) | 2008-02-06 |
CN101116666B (en) | 2014-01-08 |
AR032205A1 (en) | 2003-10-29 |
UY27088A1 (en) | 2002-07-31 |
ME00293B (en) | 2011-05-10 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US7163931B2 (en) | Compositions of estrogen-cyclodextrin complexes | |
EP2040683B1 (en) | Pharmaceutical composition containing a tetrahydrofolic acid | |
ZA200305532B (en) | Compositions of estrogen-cyclodextrin complexes | |
AU2013202756B2 (en) | Pharmaceutical composition containing a tetrahydrofolic acid |