WO2011055156A2 - Pharmaceutical compositions with enhanced stability - Google Patents
Pharmaceutical compositions with enhanced stability Download PDFInfo
- Publication number
- WO2011055156A2 WO2011055156A2 PCT/HU2010/000119 HU2010000119W WO2011055156A2 WO 2011055156 A2 WO2011055156 A2 WO 2011055156A2 HU 2010000119 W HU2010000119 W HU 2010000119W WO 2011055156 A2 WO2011055156 A2 WO 2011055156A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- gestagen
- eudragit
- estrogen
- type
- pharmaceutical compositions
- Prior art date
Links
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 30
- 239000000583 progesterone congener Substances 0.000 claims abstract description 24
- 229940011871 estrogen Drugs 0.000 claims abstract description 19
- 239000000262 estrogen Substances 0.000 claims abstract description 19
- 230000016087 ovulation Effects 0.000 claims abstract description 8
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 4
- 239000004480 active ingredient Substances 0.000 claims description 30
- 238000000034 method Methods 0.000 claims description 29
- 239000000203 mixture Substances 0.000 claims description 28
- NEDGUIRITORSKL-UHFFFAOYSA-N butyl 2-methylprop-2-enoate;2-(dimethylamino)ethyl 2-methylprop-2-enoate;methyl 2-methylprop-2-enoate Chemical compound COC(=O)C(C)=C.CCCCOC(=O)C(C)=C.CN(C)CCOC(=O)C(C)=C NEDGUIRITORSKL-UHFFFAOYSA-N 0.000 claims description 26
- 229960002568 ethinylestradiol Drugs 0.000 claims description 18
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 18
- 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 17
- BFPYWIDHMRZLRN-SLHNCBLASA-N Ethinyl estradiol Chemical group 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 16
- 238000005469 granulation Methods 0.000 claims description 16
- 230000003179 granulation Effects 0.000 claims description 16
- 229920003148 Eudragit® E polymer Polymers 0.000 claims description 11
- 150000001875 compounds Chemical class 0.000 claims description 7
- 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 6
- 229960004976 desogestrel Drugs 0.000 claims description 6
- RPLCPCMSCLEKRS-BPIQYHPVSA-N desogestrel Chemical compound C1CC[C@@H]2[C@H]3C(=C)C[C@](CC)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 RPLCPCMSCLEKRS-BPIQYHPVSA-N 0.000 claims description 6
- 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 6
- 229960003309 dienogest Drugs 0.000 claims description 6
- 239000008187 granular material Substances 0.000 claims description 6
- 229960004400 levonorgestrel Drugs 0.000 claims description 6
- 238000005507 spraying Methods 0.000 claims description 6
- 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 4
- -1 drospirenon Chemical compound 0.000 claims description 4
- 229960004766 estradiol valerate Drugs 0.000 claims description 4
- 239000012530 fluid Substances 0.000 claims description 4
- 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 4
- 229940053934 norethindrone Drugs 0.000 claims description 4
- 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 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 229960000417 norgestimate Drugs 0.000 claims description 3
- KIQQMECNKUGGKA-NMYWJIRASA-N norgestimate Chemical compound O/N=C/1CC[C@@H]2[C@H]3CC[C@](CC)([C@](CC4)(OC(C)=O)C#C)[C@@H]4[C@@H]3CCC2=C\1 KIQQMECNKUGGKA-NMYWJIRASA-N 0.000 claims description 3
- 229940124531 pharmaceutical excipient Drugs 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 12
- 239000000047 product Substances 0.000 description 25
- 239000000463 material Substances 0.000 description 15
- 230000008569 process Effects 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- 238000004090 dissolution Methods 0.000 description 12
- 229920003119 EUDRAGIT E PO Polymers 0.000 description 11
- 239000011248 coating agent Substances 0.000 description 9
- 238000000576 coating method Methods 0.000 description 9
- 239000011230 binding agent Substances 0.000 description 8
- 238000001035 drying Methods 0.000 description 8
- 239000007788 liquid Substances 0.000 description 8
- 238000000354 decomposition reaction Methods 0.000 description 7
- 238000002156 mixing Methods 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 241000124008 Mammalia Species 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- 229920002261 Corn starch Polymers 0.000 description 5
- 235000019759 Maize starch Nutrition 0.000 description 5
- 230000008859 change Effects 0.000 description 5
- 238000004040 coloring Methods 0.000 description 5
- 238000005516 engineering process Methods 0.000 description 5
- 238000005243 fluidization Methods 0.000 description 5
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 5
- 239000002245 particle Substances 0.000 description 5
- 229920001223 polyethylene glycol Polymers 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 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 4
- ZTHYODDOHIVTJV-UHFFFAOYSA-N Propyl gallate Chemical compound CCCOC(=O)C1=CC(O)=C(O)C(O)=C1 ZTHYODDOHIVTJV-UHFFFAOYSA-N 0.000 description 4
- 235000021355 Stearic acid Nutrition 0.000 description 4
- 238000007906 compression Methods 0.000 description 4
- 230000006835 compression Effects 0.000 description 4
- 238000009826 distribution Methods 0.000 description 4
- 239000007888 film coating Substances 0.000 description 4
- 238000009501 film coating Methods 0.000 description 4
- 229920000578 graft copolymer Polymers 0.000 description 4
- 229960001021 lactose monohydrate Drugs 0.000 description 4
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 4
- 239000008213 purified water Substances 0.000 description 4
- 239000008117 stearic acid Substances 0.000 description 4
- 229920003149 Eudragit® E 100 Polymers 0.000 description 3
- 238000010668 complexation reaction Methods 0.000 description 3
- 230000003247 decreasing effect Effects 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 238000005187 foaming Methods 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- 229940127234 oral contraceptive Drugs 0.000 description 3
- 239000003539 oral contraceptive agent Substances 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- 210000002784 stomach Anatomy 0.000 description 3
- DUZHXWCAIBMQPI-FYQPLNBISA-N (8s,13s,14s,17r)-17-ethynyl-13-methyl-7,8,12,14,15,16-hexahydro-6h-cyclopenta[a]phenanthrene-3,17-diol Chemical compound OC1=CC=C2C3=CC[C@](C)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 DUZHXWCAIBMQPI-FYQPLNBISA-N 0.000 description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 2
- 239000004141 Sodium laurylsulphate Substances 0.000 description 2
- 239000002518 antifoaming agent Substances 0.000 description 2
- 239000000084 colloidal system Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000002708 enhancing effect Effects 0.000 description 2
- 238000009478 high shear granulation Methods 0.000 description 2
- 238000000265 homogenisation Methods 0.000 description 2
- 229940088597 hormone Drugs 0.000 description 2
- 239000005556 hormone Substances 0.000 description 2
- 230000002209 hydrophobic effect Effects 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 239000000473 propyl gallate Substances 0.000 description 2
- 229940075579 propyl gallate Drugs 0.000 description 2
- 235000010388 propyl gallate Nutrition 0.000 description 2
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 150000003431 steroids Chemical class 0.000 description 2
- 238000009495 sugar coating Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- ORKBYCQJWQBPFG-WOMZHKBXSA-N (8r,9s,10r,13s,14s,17r)-13-ethyl-17-ethynyl-17-hydroxy-1,2,6,7,8,9,10,11,12,14,15,16-dodecahydrocyclopenta[a]phenanthren-3-one;(8r,9s,13s,14s,17r)-17-ethynyl-13-methyl-7,8,9,11,12,14,15,16-octahydro-6h-cyclopenta[a]phenanthrene-3,17-diol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1.O=C1CC[C@@H]2[C@H]3CC[C@](CC)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 ORKBYCQJWQBPFG-WOMZHKBXSA-N 0.000 description 1
- 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 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
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- 229920003134 Eudragit® polymer 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
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical class CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 description 1
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 229920000881 Modified starch Polymers 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 238000005054 agglomeration Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 239000000538 analytical sample Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 229940097362 cyclodextrins Drugs 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000007907 direct compression Methods 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000007922 dissolution test Methods 0.000 description 1
- SFNALCNOMXIBKG-UHFFFAOYSA-N ethylene glycol monododecyl ether Chemical compound CCCCCCCCCCCCOCCO SFNALCNOMXIBKG-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 229960005352 gestodene Drugs 0.000 description 1
- 239000003163 gonadal steroid hormone Substances 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 231100000546 inhibition of ovulation Toxicity 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 238000013021 overheating Methods 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229940057950 sodium laureth sulfate Drugs 0.000 description 1
- SXHLENDCVBIJFO-UHFFFAOYSA-M sodium;2-[2-(2-dodecoxyethoxy)ethoxy]ethyl sulfate Chemical compound [Na+].CCCCCCCCCCCCOCCOCCOCCOS([O-])(=O)=O SXHLENDCVBIJFO-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 229910021653 sulphate ion Inorganic materials 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
-
- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
- A61K31/567—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in position 17 alpha, e.g. mestranol, norethandrolone
-
- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
-
- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
- A61K31/585—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin containing lactone rings, e.g. oxandrolone, bufalin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/18—Feminine contraceptives
-
- 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
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
- A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
Definitions
- compositions with enhanced stability are provided.
- the present invention relates to ovulation inhibiting pharmaceutical compositions with enhanced stability containing an estrogen and a gestagen type component, and the manufacturing process thereof.
- Oral contraceptives including the combination of gestagen and estrogen components are used for decades, for example Yasmin, Yasminelle (ethinylestradiol-drospirenon; Bayer-Schering), Dienille (dienogest- ethinylestradiol; Ladee Pharma), Loette, Tri-Regol (levonorgestrel- ethinylestradiol; Wyeth, Gedeon Richter), Mercilon (desogestrel-ethinylestradiol; Organon), etc.
- Yasmin Yasminelle (ethinylestradiol-drospirenon; Bayer-Schering), Dienille (dienogest- ethinylestradiol; Ladee Pharma), Loette, Tri-Regol (levonorgestrel- ethinylestradiol; Wyeth, Gedeon Richter), Mercilon (desogestrel-ethinylestradio
- these pharmaceutical compositions contain natural or synthetic sex hormones in low dose, as the daily dose of these active ingredients is extremely low. This means amounts between 0.1 ⁇ g - 500 ⁇ g, which lead to serious technical challenges, such as to achieve technological reproducibility and the homogenous distribution of the active ingredients.
- the stability of the active ingredients causes problems, which influences the shelf life of the composition, and this may be related to the low dose of the active ingredient and to the interaction with the different excipients. This is a crucial parameter in the case of estrogen, particularly the ethinylestradiol containing oral contraceptives. There are numbers of attempts to improve the stability of estrogen, especially ethinylestradiol containing pharmaceutical compositions.
- the first step of the experiments to increase the stability of the compositions was to provide a stability enhancing coating for the active ingredient containing composition or to increase the thickness of the coating.
- the change of coating type had not brought adequate result, the thickness of the coating enhanced the stability in some cases, such as in the case of sugar coatings.
- this procedure caused a significant increase of the time of the manufacturing process, the analytical sample preparation, and it complicated the extraction of the active ingredient.
- the significance of the development of oral contraceptives with sugar coating is decreased owing to the long process time and the accessorial exacting processes (for example cleaning of devices) as well as the upcoming analytical problems.
- compositions of desogestrel and eihinylestradiol contained a-tocopherol as antioxidant in order to stabilize the system decreasing the decomposition of the active ingredients.
- the wet granulation plays a very important role in the industry.
- the fluidization and the high shear granulation which can be combined with vacuum microwave drying.
- both types of granulation liquid binder In both types of granulation liquid binder is applied, therefore the system is getting wet during the process, so this can have negative effect on the stability of the product.
- the most common binders in the pharmaceutical industry are the different types of polyvinylpyrrolidone, the different cellulose derivatives (such as HPMC, HPC, etc.).
- Kollicoat IR the copolymer of polyethylene glycol and polyvinyl alcohol.
- the application of these binders can be advantageous in the case of those active ingredients, which tend to decompose via oxidation, as their peroxide content is low.
- the "single pot technique" could not be applied in the case of older high shear granulation methods, since the wet mass had to be moved to a drying device.
- the modern high shear single pot techniques have their own disadvantages too.
- the process time of drying is long, in contrast to fluidization drying.
- the distribution of heat may be inhomogeneous, which results "hot spot", where the local overheating of the material can occur. Both effects may worsen the quality of the product consisting of thermo- sensitive drugs.
- the active ingredient is sprayed onto the powder blend as a solution or suspension.
- the spraying influences the dispersity rate of particles as a function of atomizing pressure under controlled conditions, nevertheless the chance that before these small drops meet with the powder blend, they are getting dried, and a part of them leave the system with the fluidizing air or stuck on the wall of the colonna in wet phase.
- These effects could cause loss of active ingredient and inhomogeneity in the product. Therefore it can be stated that atomizing can produce loss of active ingredient. The less the drug content of the system, the more this phenomenon is observed. Consequently this problem exists to a greater extent in the case of hormone-containing products. If the active ingredient is sprayed as suspension and not as solution the problem of inhomogeneity can occur.
- the low-dose steroid products can be stabilized with propyl gallate.
- propyl gallate is dissolved in the binder liquid and sprayed onto the powder blend by fluidization.
- the stability of product shows significant increase.
- the invention provides a pharmaceutical composition with enhanced stability comprising the combination of an estrogen and a gestagen type component, a type of Eudragit E and one ore more excipients, wherein the estrogen component can be ethinylestradiol or estradiol-valerate, and the gestagen type component is selected from the group gestoden, drospirenon, levonorgestrel, desogestrel, norethisteron, norgestimate, dienogest.
- Further object of the invention is the manufacturing process of the above mentioned pharmaceutical compositions, wherein the solution of a type of an Eudragit E is sprayed onto the mixture of granulated excipients usually employed in the pharmaceutical technology and the added gestagen type active ingredients, then the system is granulated, afterward the estrogen type component is added, followed by the homogenization and compression, and finally by coating.
- An additional object of the invention is a method to inhibit ovulation in mammals, especially in humans, wherein the ethinylestradiol and the gestagen type active ingredient is administered to the mentioned mammal in a pharmaceutically effective dose.
- the present invention provides a pharmaceutical composition with enhanced stability comprising the combination of an estrogen and a gestagen type component as active ingredients, a type of an Eudragit E and one ore more excipients.
- the estrogen type active ingredient of the present invention can be ethinylestradiol or estradiol-valerate.
- gestagen type active compound all active ingredients can be used, which possess gestagen effect.
- gestoden, drospirenon, levonorgestrel, desogestrel, norethisteron, norgestimate, dienogest can be used as gestagen type component, preferably drospirenon, levonorgestrel and dienogest.
- Eudragit E - Eudragit E PO, Eudragit E 100 and Eudragit E 12.5 % - are all derivatives of methacrylic acid. All members of the family are chemically the same, only their appearance is different: Eudragit E 12.5% is an organic dispersion, Eudragit E 100 is a powder suspended in organic solution, Eudragit E PO is a micronized powder. According to the present invention Eudragit E PO and Eudragit E 100 can favorably be used for producing pharmaceutical compositions. Considering the new referring guidelines, which increasingly restrict the use of organic solvents, and make the producing technology even difficult, the micronized form is preferable.
- Foaming of the system can be avoided with the use of another method of dissolution.
- the water solution of Eudragit E PO first the sodium lauryl sulphate is dissolved in the required amount of water, then the stearic acid and finally the micronized Eudragit E PO is added to the system. The so obtained mixture is stirred for 8-16 hours, preferably for 10-14 hours. This way the foaming of the system and the application of antifoaming agents can be avoided, a colloid solution is obtained, which is easy to handle, and the protecting layer on the particles is homogenous.
- the excipients of the intragranular phase are layered into the fluid granulator.
- lactose monohydrate, maize starch, potato starch, modified maize starch (Starch 1500), calcium phosphate and microcrystalline cellulose can be applied.
- the pre-granulation with water solution of PVA-PEG graft copolymer the granulates are dried, then the gestagen type active compound is added dropwise or by spraying into the system. In the case of dropwise addition this should be carried out at 50-80°C inlet air temperature, preferably at 60-75°C.
- the solvent is evaporated and the particles are coated with the solution of Eudragit E type excipient.
- This can be carried out by spraying of the solution of the excipient so that the temperature of the fluid bed is between 18-50°C, preferably between 22-40°C. 00119
- the further technological manufacturing of the coated particles with Eudragit E type material can be complicated, since the flowability of the obtained granules does not allow the exact dosing, which is very important in the case of hormones.
- the granulation can be made with the water solution of PVA-PEG graft copolymer.
- the so obtained granules containing gestagen type active ingredient are homogenized with the estrogen compound according to well-known procedures, then magnesium stearate and/or other lubricant is added to the system.
- the obtained material is then compressed into tablets; afterward the tablets are film-coated.
- films for film-coating well-known coating materials can be used, such as different types of Opadry, Eudragit or Sepic.
- the coating is carried out according to methods known from literature. During the process of coating it is important to apply the coloring material to the tablet cores very slowly at the beginning, to ensure the acquired adhesion of coloring material to the tablet cores.
- the present invention relates to the application of the above mentioned pharmaceutical composition to inhibit ovulation in mammals, especially in humans.
- the present invention relates to a method to inhibit ovulation in mammals, preferably in humans, wherein a pharmaceutically effective dose of the pharmaceutical composition of the present invention containing estrogen and gestagen type active ingredients is administered to the above mentioned mammal.
- a pharmaceutically effective dose on one hand the minimally effective dose has to be considered, which has still ovulation inhibiting effect, on the other hand the upper limit is the dose, at which the 10 000119
- interval of dose of active ingredients which is between 15-35 ⁇ g in the case of ethinylestradiol, between 500-4000 ⁇ g of estradiol-valerate, 50-100 ⁇ g of gestodene, 50-100 ⁇ g of drospirenon, 75-150 ⁇ g of levonorgestrel, 60-150 ⁇ g of desogestrel, 200-300 ⁇ g of norgestimat, 350-1000 ⁇ g of norethisteron, 500-4000 ⁇ g of dienogest.
- the dose and the correlated rate of all active compounds can be varied in the above mentioned interval.
- the following tables show the stability data of the composition of Example 8 with different types of binders. The differences between the compositions and manufacturing occur at accelerated stability tests, therefore this was applied practically.
- the experiments were carried out at 40°C and 75% relative humidity. Since the critical decomposition products of ethinylestradiol are 6-keto- efhinylestradiol and 9,11 - didehydro- ethinylestradiol, the comparison and the total amount of decomposition products are represented in the tables below.
- Table 2 Change of the amount of decomposition product 9,11-didehydro-ethinylestradiol
- Table 3 Change of the total amount of decomposition products of ethinylestradiol
- compositions according to the present invention compared to the compositions produced with previously known methods.
- the experiments were carried out at 40°C, so the restriction of temperature at storage is not necessary.
- compositions of the present invention applying a new composition and technology compared to well-known compositions influenced the stability advantageously, while further important parameters such as the dissolution profile remained intact.
- oral administration the product gets into the stomach, where the dissolution occurs.
- the pH interval of the stomach is between 1.3-5, the exact value depends on several factors, such as the fed or empty state of the stomach.
- Fig 1 Drospirenon dissolution profile of Yasminelle and DR+E products in water and 0.001 n HC1, at 37 °C, 50 rpm.
- Fig 2 Ethinylestradiol dissolution profile of Yasminelle and DR+E products in water and 0.001 n HC1, at 37 °C, 50 rpm.
- Example 1 Preparation of granulation liquid:
- Granulation liquid I 12.5 g of PVA-PEG graft copolymer is dissolved in 200.0 g of purified water by mixing for approximately 10 minutes at 300 ⁇ 50 rpm, then the mixing speed is reduced to 150 ⁇ 50 rpm and the liquid is mixed for 1 hour. The so obtained solution is used in pre-granulation.
- Granulation liquid II 12.5 g of PVA-PEG graft copolymer is dissolved in 240.0 g of purified water by mixing for approximately 10 minutes at 300 ⁇ 50 rpm, then the mixing speed is reduced to 150 ⁇ 50 rpm and the liquid is mixed for 1 hour. The so obtained solution is used in the second granulation.
- Example 2 Solution of active ingredient:
- Example 3 Colloid solution of Eudragit E PO:
- the spraying of ethanol solution of drospirenon, the granulation and the drying is performed in fluid granulation device (Glatt).
- the intragranular phase is put into the device by layers: firstly the half amount of lactose monohydrate (Flowlac 100), then maize starch, pregelatinized starch, then the second half of lactose monohydrate.
- After pre-granulation the granules are dried till 36°C product temperature, after this the ethanol solution of active compound is added dropwise onto the blend without spraying.
- the dropwise addition is carried out on higher inlet air temperature (70 ⁇ 10°C).
- the evaporation of the solvent is made till 36°C product temperature is reached.
- Example 5 Homogenization with ethinylestradiol and extragranular phase:
- the drospirenon granules produced by the method above is homogenized with micronized ethinylestradiol in several steps. At the end, magnesium stearate is added to the system.
- Example 6 Tablet compression on rotary tablet machine
- Example 8 Pharmaceutical composition of the invention 1.
- Example 9 Pharmaceutical composition of the invention 2. ingredients Amount(mg/tablet)
- Example 10 Pharmaceutical composition of the invention 3.
- Example 11 Pharmaceutical composition of the invention 4.
Abstract
The present invention relates to ovulation inhibiting pharmaceutical compositions with enhanced stability containing an estrogen and a gestagen type component, and the manufacturing process thereof.
Description
Pharmaceutical compositions with enhanced stability
The present invention relates to ovulation inhibiting pharmaceutical compositions with enhanced stability containing an estrogen and a gestagen type component, and the manufacturing process thereof.
Background of the invention
Oral contraceptives including the combination of gestagen and estrogen components are used for decades, for example Yasmin, Yasminelle (ethinylestradiol-drospirenon; Bayer-Schering), Dienille (dienogest- ethinylestradiol; Ladee Pharma), Loette, Tri-Regol (levonorgestrel- ethinylestradiol; Wyeth, Gedeon Richter), Mercilon (desogestrel-ethinylestradiol; Organon), etc.
Numbers of problems occur in connection with these preparations. On the one hand, these pharmaceutical compositions contain natural or synthetic sex hormones in low dose, as the daily dose of these active ingredients is extremely low. This means amounts between 0.1 μg - 500 μg, which lead to serious technical challenges, such as to achieve technological reproducibility and the homogenous distribution of the active ingredients. On the other hand, the stability of the active ingredients causes problems, which influences the shelf life of the composition, and this may be related to the low dose of the active ingredient and to the interaction with the different excipients. This is a crucial parameter in the case of estrogen, particularly the ethinylestradiol containing oral contraceptives. There are numbers of attempts to improve the stability of estrogen, especially ethinylestradiol containing pharmaceutical compositions.
The first step of the experiments to increase the stability of the compositions was to provide a stability enhancing coating for the active ingredient containing composition or to increase the thickness of the coating. Although, the change of coating type had not brought adequate result, the thickness of the coating enhanced the stability in some cases, such as in the case of sugar coatings. However this procedure caused a significant increase of the time of the manufacturing process, the analytical sample preparation, and it complicated the extraction of the active ingredient. The significance of the development of oral contraceptives with sugar
coating is decreased owing to the long process time and the accessorial exacting processes (for example cleaning of devices) as well as the upcoming analytical problems.
The efforts to make the active ingredient more stabile in the pharmaceutical composition proved to be more effective. Significant progress was for example that the active ingredient was not dissolved during the process, but it was applied in its micronized form. In the patent EP 0503521B1 the micronized estrogen (eihinylestradiol) and the gestagen component (desogestrel) are homogenized with excipients, which enable direct compression avoiding that the active ingredients meet with moisture. Nevertheless the decomposition of eihinylestradiol could not be decreased adequately; moreover, this technology is limited in terms of gestagen component. The dry blending technology is also risky, since the distribution of the active ingredient in the end-product is not always homogenous.
There were also efforts to put some stability enhancing excipients into the composition. According to the patent EP 0707848B1 the steroids were applied in dissolved, emulsified or suspended form in different oily excipients, receiving a system more hydrophobic, which could protect the active ingredient from moisture and the oxygen-content of air. The patent US 4378356 describes that the compositions of desogestrel and eihinylestradiol contained a-tocopherol as antioxidant in order to stabilize the system decreasing the decomposition of the active ingredients.
The wet granulation plays a very important role in the industry. In the pharmaceutical industry usually two different processes are applied: the fluidization and the high shear granulation, which can be combined with vacuum microwave drying. In both types of granulation liquid binder is applied, therefore the system is getting wet during the process, so this can have negative effect on the stability of the product. The most common binders in the pharmaceutical industry are the different types of polyvinylpyrrolidone, the different cellulose derivatives (such as HPMC, HPC, etc.). Nowadays even new binders are coming up, such as Kollicoat IR, the copolymer of polyethylene glycol and polyvinyl alcohol. The application of these binders can be advantageous in the case of those active ingredients, which tend to decompose via oxidation, as their peroxide content is low.
The "single pot technique" could not be applied in the case of older high shear granulation methods, since the wet mass had to be moved to a drying device. However the modern high shear single pot techniques have their own disadvantages too. On the one hand, the process time of drying is long, in contrast to fluidization drying. On the other hand, the distribution of
heat may be inhomogeneous, which results "hot spot", where the local overheating of the material can occur. Both effects may worsen the quality of the product consisting of thermo- sensitive drugs.
Further possibility to prepare the product is the fluidization and drying in the same device. In this case the active ingredient is sprayed onto the powder blend as a solution or suspension. The spraying influences the dispersity rate of particles as a function of atomizing pressure under controlled conditions, nevertheless the chance that before these small drops meet with the powder blend, they are getting dried, and a part of them leave the system with the fluidizing air or stuck on the wall of the colonna in wet phase. These effects could cause loss of active ingredient and inhomogeneity in the product. Therefore it can be stated that atomizing can produce loss of active ingredient. The less the drug content of the system, the more this phenomenon is observed. Consequently this problem exists to a greater extent in the case of hormone-containing products. If the active ingredient is sprayed as suspension and not as solution the problem of inhomogeneity can occur.
According to the patent US 6156341 the low-dose steroid products can be stabilized with propyl gallate. In this case propyl gallate is dissolved in the binder liquid and sprayed onto the powder blend by fluidization.
Further solution to enhance the stability of estrogens, especially that of ethinylestradiol, is the complexation with another material. Different types of cyclodextrins were used as complexation materials. These methods are described in the patents US 4727064 and EP 0579435.
Despite the achieved results there is a need for such products of estrogen-gestagen combinations, which possess enhanced stability, homogenous distribution, and are easy to manufacture. Therefore the aim of our invention was to produce a stable and homogeneous pharmaceutical composition of estrogen-gestagen combination.
Summary of the invention
Surprisingly it was found that applying a type of an Eudragit E as excipient, the stability of product shows significant increase. Thus the invention provides a pharmaceutical composition with enhanced stability comprising the combination of an estrogen and a gestagen type component, a type of Eudragit E and one ore more excipients, wherein the estrogen
component can be ethinylestradiol or estradiol-valerate, and the gestagen type component is selected from the group gestoden, drospirenon, levonorgestrel, desogestrel, norethisteron, norgestimate, dienogest.
Further object of the invention is the manufacturing process of the above mentioned pharmaceutical compositions, wherein the solution of a type of an Eudragit E is sprayed onto the mixture of granulated excipients usually employed in the pharmaceutical technology and the added gestagen type active ingredients, then the system is granulated, afterward the estrogen type component is added, followed by the homogenization and compression, and finally by coating.
Further object of the invention is the application of the above mentioned pharmaceutical compositions for inhibition of ovulation in mammals, especially in humans.
An additional object of the invention is a method to inhibit ovulation in mammals, especially in humans, wherein the ethinylestradiol and the gestagen type active ingredient is administered to the mentioned mammal in a pharmaceutically effective dose.
Detailed description of the invention
The present invention provides a pharmaceutical composition with enhanced stability comprising the combination of an estrogen and a gestagen type component as active ingredients, a type of an Eudragit E and one ore more excipients.
The estrogen type active ingredient of the present invention can be ethinylestradiol or estradiol-valerate. As gestagen type active compound all active ingredients can be used, which possess gestagen effect. According to the present invention gestoden, drospirenon, levonorgestrel, desogestrel, norethisteron, norgestimate, dienogest can be used as gestagen type component, preferably drospirenon, levonorgestrel and dienogest.
Surprisingly the use of an Eudragit E type excipient in pharmaceutical compositions resulted in the significant enhancement of the stability thereof, while all the other important properties of the compositions meet the relevant requirements - i.e. disintegration time, dissolution and hardness.
The members of product family of Eudragit E - Eudragit E PO, Eudragit E 100 and Eudragit E 12.5 % - are all derivatives of methacrylic acid. All members of the family are chemically the same, only their appearance is different: Eudragit E 12.5% is an organic dispersion,
Eudragit E 100 is a powder suspended in organic solution, Eudragit E PO is a micronized powder. According to the present invention Eudragit E PO and Eudragit E 100 can favorably be used for producing pharmaceutical compositions. Considering the new referring guidelines, which increasingly restrict the use of organic solvents, and make the producing technology even difficult, the micronized form is preferable.
Nevertheless, more problems come up during manufacturing with the application of Eudragit E PO. The use of its micronized form causes problems during tablet compression; therefore the application of the material in solution is more advantageous. However the solubility of Eudragit E PO in water is very low. According to recommendation of the manufacturer sodium lauryl sulphate and stearic acid are needed to add to solve this material in water, then the mixture has to be turraxed for 30-120 minutes, then magnesium stearate or talcum has to be added. During turraxing foaming of the system occurs, which can be inhibited with antifoaming agents, such as silicon, but the application of these materials may influence the quality of the product, therefore it is preferable to avoid it.
Foaming of the system can be avoided with the use of another method of dissolution. In order to prepare the water solution of Eudragit E PO first the sodium lauryl sulphate is dissolved in the required amount of water, then the stearic acid and finally the micronized Eudragit E PO is added to the system. The so obtained mixture is stirred for 8-16 hours, preferably for 10-14 hours. This way the foaming of the system and the application of antifoaming agents can be avoided, a colloid solution is obtained, which is easy to handle, and the protecting layer on the particles is homogenous.
During the manufacturing process of pharmaceutical compositions, first the excipients of the intragranular phase are layered into the fluid granulator. As excipients, lactose monohydrate, maize starch, potato starch, modified maize starch (Starch 1500), calcium phosphate and microcrystalline cellulose can be applied. After the pre-granulation with water solution of PVA-PEG graft copolymer the granulates are dried, then the gestagen type active compound is added dropwise or by spraying into the system. In the case of dropwise addition this should be carried out at 50-80°C inlet air temperature, preferably at 60-75°C.
According to the process of this invention after the addition of the solution of gestagen type active ingredient the solvent is evaporated and the particles are coated with the solution of Eudragit E type excipient. This can be carried out by spraying of the solution of the excipient so that the temperature of the fluid bed is between 18-50°C, preferably between 22-40°C.
00119
6
The further technological manufacturing of the coated particles with Eudragit E type material can be complicated, since the flowability of the obtained granules does not allow the exact dosing, which is very important in the case of hormones. Surprisingly it was found, that after a second granulation step with a binder a system with better properties was obtained, which is easy to treat and compress. The granulation can be made with the water solution of PVA-PEG graft copolymer. The so obtained granules containing gestagen type active ingredient are homogenized with the estrogen compound according to well-known procedures, then magnesium stearate and/or other lubricant is added to the system.
The obtained material is then compressed into tablets; afterward the tablets are film-coated. For film-coating well-known coating materials can be used, such as different types of Opadry, Eudragit or Sepic. The coating is carried out according to methods known from literature. During the process of coating it is important to apply the coloring material to the tablet cores very slowly at the beginning, to ensure the acquired adhesion of coloring material to the tablet cores.
The advantage of the above described technological process is, that low dose active ingredients can be homogenously manufactured in solid state or in solution by conventional methods. Although, during manufacturing the agglomeration occurs in the presence of usual moistening materials, the oxidation can be reduced significantly, which usually happen during fluidization granulation. Surprisingly it was found that using a binder in our pharmaceutical composition did not have any negative effect on the stability of estrogen component. However the particles of estrogen type component were not coated with hydrophobic layer or they were not isolated from the surrounding excipients through complexation. The composition formed this way and the manufacturing process is robust enough, easy to carry out technically, as well as the manufacturing is very economical.
In addition, the present invention relates to the application of the above mentioned pharmaceutical composition to inhibit ovulation in mammals, especially in humans.
Furthermore the present invention relates to a method to inhibit ovulation in mammals, preferably in humans, wherein a pharmaceutically effective dose of the pharmaceutical composition of the present invention containing estrogen and gestagen type active ingredients is administered to the above mentioned mammal. In order to determine the pharmaceutically effective dose on one hand the minimally effective dose has to be considered, which has still ovulation inhibiting effect, on the other hand the upper limit is the dose, at which the
10 000119
7
undesired adverse effects still not appear. Consequently there is an interval of dose of active ingredients, which is between 15-35 μg in the case of ethinylestradiol, between 500-4000 μg of estradiol-valerate, 50-100 μg of gestodene, 50-100 μg of drospirenon, 75-150 μg of levonorgestrel, 60-150 μg of desogestrel, 200-300 μg of norgestimat, 350-1000 μg of norethisteron, 500-4000 μg of dienogest. During the process the dose and the correlated rate of all active compounds can be varied in the above mentioned interval.
The stability of the pharmaceutical compositions of the related invention - as the tables show below - increased significantly. To illustrate the increased stability, the following tables show the stability data of the composition of Example 8 with different types of binders. The differences between the compositions and manufacturing occur at accelerated stability tests, therefore this was applied practically. The experiments were carried out at 40°C and 75% relative humidity. Since the critical decomposition products of ethinylestradiol are 6-keto- efhinylestradiol and 9,11 - didehydro- ethinylestradiol, the comparison and the total amount of decomposition products are represented in the tables below.
Explanation of tables:
Table 1 : Change of the amount of decomposition product 6-keto-ethinylestradiol
Table 2: Change of the amount of decomposition product 9,11-didehydro-ethinylestradiol Table 3 : Change of the total amount of decomposition products of ethinylestradiol
QL = 0,1%
Table 2.
QL = 0,1%
Table 3.
A significant increase in stability can be observed in the case of pharmaceutical compositions according to the present invention compared to the compositions produced with previously known methods. The experiments were carried out at 40°C, so the restriction of temperature at storage is not necessary.
In the case of pharmaceutical compositions of the present invention applying a new composition and technology compared to well-known compositions influenced the stability advantageously, while further important parameters such as the dissolution profile remained intact. By oral administration the product gets into the stomach, where the dissolution occurs. The pH interval of the stomach is between 1.3-5, the exact value depends on several factors, such as the fed or empty state of the stomach. The dissolution tests modeling the real conditions showed, that the dissolution profiles of the pharmaceutical compositions of the invention do not change under the pH=5 compared to the other compositions on the market. These are well illustrated by the dissolution profiles, which show the examination of the composition of Example 9 (DR+E) and a product from the market (Y asminelle) containing the same active ingredients in different media.
Explanation of figures:
Fig 1 : Drospirenon dissolution profile of Yasminelle and DR+E products in water and 0.001 n HC1, at 37 °C, 50 rpm.
Fig 2: Ethinylestradiol dissolution profile of Yasminelle and DR+E products in water and 0.001 n HC1, at 37 °C, 50 rpm.
Fig 3: Drospirenon dissolution profile of Yasminelle and DR+E products in medium pH=4.5, at 37 °C, 50 rpm.
Fig 4: Ethinylestradiol dissolution profile of Yasminelle and DR+E products in medium pH=4.5, at 37 °C, 50 rpm.
It is remarkable that with the application of Eudragit E the dissolution profiles changed above pH=5 (getting slower), but this did not affect the real conditions modeling dissolution data under pH=5.
The present invention is illustrated by the following not limiting examples.
Examples
Example 1.: Preparation of granulation liquid:
Granulation liquid I.: 12.5 g of PVA-PEG graft copolymer is dissolved in 200.0 g of purified water by mixing for approximately 10 minutes at 300 ± 50 rpm, then the mixing speed is reduced to 150 ± 50 rpm and the liquid is mixed for 1 hour. The so obtained solution is used in pre-granulation.
Granulation liquid II: 12.5 g of PVA-PEG graft copolymer is dissolved in 240.0 g of purified water by mixing for approximately 10 minutes at 300 ± 50 rpm, then the mixing speed is reduced to 150 ± 50 rpm and the liquid is mixed for 1 hour. The so obtained solution is used in the second granulation.
Example 2: Solution of active ingredient:
75.0 g of crystalline drospirenon is dissolved in a 2500.0g of 96% ethanol by mixing for approximately 20 - 25 minutes at 250 ± 50 rpm. Example 3.: Colloid solution of Eudragit E PO:
2.5 g of sodium laureth sulphate, then 3.75 g of stearic acid is dissolved in 240 g of purified water, then 25 g of micronized Eudragit E PO is added to the system. The system is mixed for 12 hours with a mixer. Example 4. Process of granulation:
The spraying of ethanol solution of drospirenon, the granulation and the drying is performed in fluid granulation device (Glatt). The intragranular phase is put into the device by layers: firstly the half amount of lactose monohydrate (Flowlac 100), then maize starch, pregelatinized starch, then the second half of lactose monohydrate. After pre-granulation the granules are dried till 36°C product temperature, after this the ethanol solution of active compound is added dropwise onto the blend without spraying. The dropwise addition is carried out on higher inlet air temperature (70 ± 10°C). The evaporation of the solvent is made till 36°C product temperature is reached. Afterwards the water solution of Eudragit E PO is sprayed onto the blend, so that the product temperature stays between 22 - 40°C. Then the whole amount of the granulation liquid II is sprayed onto the blend. The end point of the drying is 2.0 % loss on drying of the product. Regranulation is made in sieve 0.8 mm.
Example 5.: Homogenization with ethinylestradiol and extragranular phase:
The drospirenon granules produced by the method above is homogenized with micronized ethinylestradiol in several steps. At the end, magnesium stearate is added to the system.
Example 6.: Tablet compression on rotary tablet machine
Parameters of tableting: Set values
Main compression force 5 - 6 kN
Velocity of die table 40 rpm
Feeder speed („fill-o-matic") 30 rpm
Example 7.: Film-coating
26.0 g of Opadry II 85G18490 white coloring material is dispersed in 148.5 g of purified water at continuous mixing with paddle at 250 ± 50 rpm according to the instructions. At the process of coating it is important to carry up the coloring material to the tablet cores very slowly at the beginning, to ensure the acquired adhesion of coloring material to the tablet cores. The film-coating is sprayed onto the tablet cores in two steps:
Phase I. slow dosing rate, till the mass growth of tablets is 0.5%
Phase II. Faster dosing of film-coating agent till the end of process.
Example 8.: Pharmaceutical composition of the invention 1.
Example 9.: Pharmaceutical composition of the invention 2. ingredients Amount(mg/tablet)
Ethinylestradiol 0.030
Drospirenon, crystalline 3.000
Maize starch 20.400
Modified maize starch 4.500
Mg Stearate 0.800
Lactose monohydrate 48.520
Kollicoat IR 1.500
Eudragit E PO 1.000
Sodium laureth sulfate 0.100
Stearic acid 0.150
Total 80.000
10 000119
12
Example 10.: Pharmaceutical composition of the invention 3.
Example 11.: Pharmaceutical composition of the invention 4.
Claims
1. Pharmaceutical composition comprising an estrogen and a gestagen type active ingredient, a type of Eudragit E as excipient, PVA-PEG copolymer and one or more excipients.
2. The composition according to claim 1, wherein the gestagen component is selected from a group comprising gestoden, drospirenon, levonorgestrel, desogestrel, norethisteron, norgestimate, dienogest.
3. The composition according to claim 1 to 2 wherein the gestagen component is selected from a group comprising levonorgestrel, drospirenon, dienogest.
4. The composition according to claim 1 to 3 wherein the gestagen component is drospirenon.
5. The composition according to claim 1, wherein the estrogen component is ethinylestradiol or estradiol-valerate.
6. The method of preparation of pharmaceutical compositions according to claim 1 to 5, wherein the solution of type of Eudragit E is sprayed onto the mixture of well known pharmaceutical excipients and the added gestagen type active compound, and granulated with a well known granulation method, the granules are blended with estrogen type compound, and one or more excipients are added.
7. The method according to claim 6, wherein the temperature of the fluid bed at spraying is between 22-40°C.
8. The application of pharmaceutical compositions according to claim 1 to 5 to inhibit ovulation.
9. The method for inhibiting ovulation, wherein the pharmaceutical composition according to claim 1 to 5 is administered in therapeutically effective amount.
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Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4378356A (en) | 1980-03-18 | 1983-03-29 | Akzon N.V. | Multi-phase combination-type sequential preparation for oral contraception and method of oral contraception |
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 |
EP0579435A1 (en) | 1992-07-14 | 1994-01-19 | CYCLOPS h.f. | Cyclodextrin complexation |
EP0503521B1 (en) | 1991-03-12 | 1995-07-19 | Akzo Nobel N.V. | Low dose dry pharmaceutical preparations |
US6156341A (en) | 1994-07-04 | 2000-12-05 | Schering Aktiensgesellschaft | Low-dosed steroid tablets that contain gallic acid ester as an antioxidant, process for production, and use |
EP0707848B1 (en) | 1994-10-17 | 2002-01-09 | Akzo Nobel N.V. | Solid pharmaceutical composition comprising an excipient capable of binding water |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE19728516C2 (en) * | 1997-07-04 | 1999-11-11 | Sanol Arznei Schwarz Gmbh | TTS for administration of levonorgestrel and possibly estradiol |
WO2009100871A2 (en) * | 2008-02-13 | 2009-08-20 | Bayer Schering Pharma Aktiengesellschaft | Drug delivery system with stabilising effect |
TW201008569A (en) * | 2008-08-08 | 2010-03-01 | Bayer Schering Pharma Ag | Progestin-containing drug delivery system |
-
2009
- 2009-11-06 HU HU0900698A patent/HUP0900698A2/en unknown
-
2010
- 2010-11-05 WO PCT/HU2010/000119 patent/WO2011055156A2/en active Application Filing
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4378356A (en) | 1980-03-18 | 1983-03-29 | Akzon N.V. | Multi-phase combination-type sequential preparation for oral contraception and method of oral contraception |
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 |
EP0503521B1 (en) | 1991-03-12 | 1995-07-19 | Akzo Nobel N.V. | Low dose dry pharmaceutical preparations |
EP0579435A1 (en) | 1992-07-14 | 1994-01-19 | CYCLOPS h.f. | Cyclodextrin complexation |
US6156341A (en) | 1994-07-04 | 2000-12-05 | Schering Aktiensgesellschaft | Low-dosed steroid tablets that contain gallic acid ester as an antioxidant, process for production, and use |
EP0707848B1 (en) | 1994-10-17 | 2002-01-09 | Akzo Nobel N.V. | Solid pharmaceutical composition comprising an excipient capable of binding water |
Also Published As
Publication number | Publication date |
---|---|
HUP0900698A2 (en) | 2011-06-28 |
HU0900698D0 (en) | 2009-12-28 |
WO2011055156A3 (en) | 2011-07-07 |
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