DK178242B1 - Farmaceutiske sammensætninger - Google Patents
Farmaceutiske sammensætninger Download PDFInfo
- Publication number
- DK178242B1 DK178242B1 DK200001171A DKPA200001171A DK178242B1 DK 178242 B1 DK178242 B1 DK 178242B1 DK 200001171 A DK200001171 A DK 200001171A DK PA200001171 A DKPA200001171 A DK PA200001171A DK 178242 B1 DK178242 B1 DK 178242B1
- Authority
- DK
- Denmark
- Prior art keywords
- pharmaceutical composition
- inorganic salt
- metasilicate
- cation
- multivalent
- Prior art date
Links
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 40
- 229910017053 inorganic salt Inorganic materials 0.000 claims abstract description 36
- 150000001768 cations Chemical class 0.000 claims abstract description 21
- 239000004480 active ingredient Substances 0.000 claims abstract description 9
- 150000003839 salts Chemical class 0.000 claims abstract description 8
- BPRHUIZQVSMCRT-VEUZHWNKSA-N rosuvastatin Chemical compound CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC(O)=O BPRHUIZQVSMCRT-VEUZHWNKSA-N 0.000 claims abstract description 6
- 239000000203 mixture Substances 0.000 claims description 37
- 239000011230 binding agent Substances 0.000 claims description 13
- 239000007884 disintegrant Substances 0.000 claims description 12
- 239000000945 filler Substances 0.000 claims description 12
- 235000019731 tricalcium phosphate Nutrition 0.000 claims description 12
- 239000000314 lubricant Substances 0.000 claims description 11
- BPQQTUXANYXVAA-UHFFFAOYSA-N Orthosilicate Chemical compound [O-][Si]([O-])([O-])[O-] BPQQTUXANYXVAA-UHFFFAOYSA-N 0.000 claims description 9
- GDVKFRBCXAPAQJ-UHFFFAOYSA-A dialuminum;hexamagnesium;carbonate;hexadecahydroxide Chemical group [OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Al+3].[Al+3].[O-]C([O-])=O GDVKFRBCXAPAQJ-UHFFFAOYSA-A 0.000 claims description 9
- SNAAJJQQZSMGQD-UHFFFAOYSA-N aluminum magnesium Chemical group [Mg].[Al] SNAAJJQQZSMGQD-UHFFFAOYSA-N 0.000 claims description 7
- 229910001701 hydrotalcite Inorganic materials 0.000 claims description 7
- 229960001545 hydrotalcite Drugs 0.000 claims description 7
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 6
- 150000001450 anions Chemical class 0.000 claims description 6
- 229910019142 PO4 Inorganic materials 0.000 claims description 5
- 238000000034 method Methods 0.000 claims description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 5
- 239000010452 phosphate Substances 0.000 claims description 5
- 239000004135 Bone phosphate Substances 0.000 claims description 4
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 4
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 4
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims description 4
- 229910052782 aluminium Inorganic materials 0.000 claims description 4
- 159000000007 calcium salts Chemical class 0.000 claims description 4
- 239000011777 magnesium Substances 0.000 claims description 4
- 229910052749 magnesium Inorganic materials 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 239000000843 powder Substances 0.000 claims description 4
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical group [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 3
- ILRRQNADMUWWFW-UHFFFAOYSA-K aluminium phosphate Chemical compound O1[Al]2OP1(=O)O2 ILRRQNADMUWWFW-UHFFFAOYSA-K 0.000 claims description 3
- 239000011575 calcium Substances 0.000 claims description 3
- 229910052791 calcium Inorganic materials 0.000 claims description 3
- 150000001875 compounds Chemical class 0.000 claims description 3
- GVALZJMUIHGIMD-UHFFFAOYSA-H magnesium phosphate Chemical compound [Mg+2].[Mg+2].[Mg+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O GVALZJMUIHGIMD-UHFFFAOYSA-H 0.000 claims description 3
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 2
- 229910052742 iron Inorganic materials 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- 239000011701 zinc Substances 0.000 claims description 2
- 229910052725 zinc Inorganic materials 0.000 claims description 2
- XYJRXVWERLGGKC-UHFFFAOYSA-D pentacalcium;hydroxide;triphosphate Chemical compound [OH-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O XYJRXVWERLGGKC-UHFFFAOYSA-D 0.000 claims 2
- 239000003795 chemical substances by application Substances 0.000 description 30
- 239000003826 tablet Substances 0.000 description 19
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 18
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 11
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- 239000008108 microcrystalline cellulose Substances 0.000 description 11
- 229940016286 microcrystalline cellulose Drugs 0.000 description 11
- 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 11
- 238000000576 coating method Methods 0.000 description 9
- 235000019359 magnesium stearate Nutrition 0.000 description 9
- HSHXDCVZWHOWCS-UHFFFAOYSA-N N'-hexadecylthiophene-2-carbohydrazide Chemical compound CCCCCCCCCCCCCCCCNNC(=O)c1cccs1 HSHXDCVZWHOWCS-UHFFFAOYSA-N 0.000 description 8
- 239000011248 coating agent Substances 0.000 description 8
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 8
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 8
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 8
- 229920003109 sodium starch glycolate Polymers 0.000 description 8
- 239000008109 sodium starch glycolate Substances 0.000 description 8
- 229940079832 sodium starch glycolate Drugs 0.000 description 8
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- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 description 7
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 7
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- UQSXHKLRYXJYBZ-UHFFFAOYSA-N iron oxide Inorganic materials [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 description 5
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- URAYPUMNDPQOKB-UHFFFAOYSA-N triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 description 4
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 3
- 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 3
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- 238000005507 spraying Methods 0.000 description 3
- 102000004286 Hydroxymethylglutaryl CoA Reductases Human genes 0.000 description 2
- 108090000895 Hydroxymethylglutaryl CoA Reductases Proteins 0.000 description 2
- 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 2
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- 230000015572 biosynthetic process Effects 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
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- 235000013773 glyceryl triacetate Nutrition 0.000 description 2
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- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 2
- 229910001411 inorganic cation Inorganic materials 0.000 description 2
- 235000013980 iron oxide Nutrition 0.000 description 2
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- NDLPOXTZKUMGOV-UHFFFAOYSA-N oxo(oxoferriooxy)iron hydrate Chemical compound O.O=[Fe]O[Fe]=O NDLPOXTZKUMGOV-UHFFFAOYSA-N 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
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- 239000003381 stabilizer Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
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- 239000001993 wax Substances 0.000 description 2
- 230000004584 weight gain Effects 0.000 description 2
- 235000019786 weight gain Nutrition 0.000 description 2
- 238000005550 wet granulation Methods 0.000 description 2
- -1 7-substituted 3,5-dihydroxy-6-heptenoic acid salts Chemical class 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
- 241000416162 Astragalus gummifer Species 0.000 description 1
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- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
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- 229920002907 Guar gum Polymers 0.000 description 1
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- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 description 1
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- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
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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
- A61K9/28—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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Abstract
Opfindelsen angår farmaceutiske sammensætninger og nærmere bestemt en farmaceutisk sammensætning indeholdende(E)-7 -[ 4-( 4-fluorphenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl]-(3R, 5S)-3,5-dihydroxyhept-6-ensyre eller et farmaceutisk acceptabelt salt deraf som den aktive bestanddel og et uorganisk salt, hvori kationen er multivalent.
Description
Den foreliggende opfindelse angår farmaceutiske sammensætninger og nærmere bestemt en farmaceutisk sammensætning indeholdende (E)-7-[4-(4-fluorphenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl]-(3R, 5S)-3,5-diliydroxyliept-6-ensyre eller et farmaceutisk acceptabelt salt deraf (og omtalt heri som "midlet"), især natrium-og calciumsaltene, og især calciumsaltet, bis[(E)-7-[4-(4-fluorphenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl]-(3R, 5S)-3,5-dihydroxyhept-6-ensyre], calciumsalt (med formlen I nedenfor).
Midlet beskrives som en inhibitor af 3-hydroxy-3-methylglutaryl-CoA-reduktase (HMG-CoA-reduktase) i den europæiske patentansøgning med publikationsnummeret0.521.471 og i Bioorganic and Medicinal Chemistry, (1997), 5(2), 437-444, og er nyttigt til behandling af hypercholesterolæmi, hyperlipidproteinæmi og atherosklerose.
Et problem, der forbundet med midlet, er, at det under visse betingelser er særligt følsomt over for nedbrydning. De vigtigste nedbrydningsprodukter, der dannes, er den tilsvarende (3R, 5S)-lacton (herefter omtalt som "lactonen") og et oxidationsprodukt (herefter omtalt som "B2"), hvori hydroxygruppen i nabostilling til carbon-carbon-dobbeltbindingen er oxideret til en ketonfunktionalitet. Potentialet for signifikant nedbrydning af midlet gør det vanskeligt at formulere og tilvejebringe en farmaceutisk sammensætning med acceptabel holdbarhed for et markedsført produkt.
Farmaceutiske formuleringer af visse 7-substituerede 3,5-dihydroxy-6-heptensyresalte, som er HMG-CoA-reduktaseinhibitorer, er beskrevet i britisk patent nr. 2.262.229, og at de er følsomme over for pH-nedbrydning. Disse formuleringer kræver nærvær af et alkalisk medium (såsom et carbonat eller bicarbonat), der er i stand til at bibringe en pH-værdi på mindst 8 til en vandig opløsning eller dispersion af sammensætningen.
Det har imidlertid vist sig, at det for midlet ikke er tilstrækkeligt at forbedre stabiliteten ved blot at styre pH-værdien i formuleringen. Det har vist sig, at med midlet forbedres stabiliteten ved udvælgelse af et uorganisk salt, som skal sættes til sammensætningen, og som indeholder én eller flere multivalente, uorganiske kationer. Selvom man ikke ønsker at være bundet til nogen teori, menes det, at den multivalente, uorganiske kation stabiliserer midlets struktur og gør det mindre tilbøjeligt til oxidation og/eller lactondan-nelse.
Der tilvejebringes som et træk ifølge opfindelsen (1) en farmaceutisk sammensætning omfattende midlet som en aktiv bestanddel og et uorganisk salt, hvori kationen er multivalent, (2) anvendelse af et uorganisk salt, hvori kationen er multivalent, som et stabiliseringsmiddel i en farmaceutisk sammensætning omfattende midlet.
Foretrukne træk ifølge opfindelsen er: (1) sådanne, hvori midlet er til stede i sammensætningen i en mængde på mere end 5 mg, fortrinsvis mere end 10 mg. Udelukkede sammensætninger er sådanne, hvori midlet er til stede med 1 mg, 2 mg, 5 mg og 10 mg. Foretrukne sammensætninger af sådanne, hvori mængden af midlet er 20 mg, 40 mg eller 80 mg, (2) hvori den stabiliserende forbindelse ikke er syntetisk hydrotalcit, (3) den dannede farmaceutiske sammensætning er en tablet eller et pulver.
Den farmaceutiske sammensætning ifølge opfindelsen er fortrinsvis en tablet.
Den multivalente kation, som findes i det uorganiske salt, kan vælges blandt følgende: calcium, magnesium, zink, aluminium og jern eller en blanding deraf. Foretrukne multivalente kationer er calcium, aluminium og magnesium eller en blanding deraf.
Særligt foretrukne multivalente kationer er aluminium og magnesium eller en blanding deraf.
Modanionen i det uorganiske salt kan vælges blandt et phosphat, et carbonat, et silicat, et oxid og et metasilicat. Foretrukne modanioner er valgt blandt et carbonat, et silicat, et oxid og et metasilicat. Særligt foretrukne modanioner er valgt blandt et silicat, et oxid eller et metasilicat.
Individuelle aspekter af opfindelsen omfatter et uorganisk salt omfattende en multivalent kation valgt blandt enhver af de ovenstående og en modamon også valgt blandt enhver af de ovenstående.
Foretrukne uorganiske salte til brug i den foreliggende opfindelse er: aluminiummagne-siummetacilicat (Neusolin™, Fuji Chemical Industry Limited), dibasisk eller tribasisk calciumphosphat, tribasisk magnesiumphosphat og tribasisk aluminiumphosphat. Alumi-niummagnesiummetasilicat og tribasisk calciumphosphat er særligt foretrukne.
Det foretrækkes ligeledes, at en sådan sammensætning har en god strømningshastighed for at lette bearbejdningen til enhedsdosisformer til oral administration, f.eks. til tabletter, og gode desintegrerings- og opløsningskarakteristika ved forarbejdning til tabletter til oral administration, hvilke tabletter kan være af forskellige dosisstyrker.
Forholdet mellem uorganisk salt og middel i den farmaceutiske sammensætning er f.eks. i området ffa 1:80 til 50:1 på vægtbasis, f.eks. 1:50 til 50:1 på vægtbasis, såsom 1:10 til 10:1 på vægtbasis og nærmere bestemt 1:5 til 10:1 på vægtbasis.
Den farmaceutiske sammensætning ifølge opfindelsen formuleres fortrinsvis til en oral dosisform, såsom en tablet. Et yderligere aspekt ved opfindelsen omfatter således en farmaceutisk sammensætning omfattende midlet, et uorganisk salt, hvori kationen er multivalent, samt et eller flere fyldstoffer, bindemidler, desintegreringsmidler eller smøremidler. Endnu et yderligere aspekt af opfindelsen angår en farmaceutisk sammensætning til oral administration omfattende midlet, et eller flere fyldstoffer, et eller flere bindemidler, et eller flere desmtegreringsmidler, et eller flere smøremidler og et uorganisk salt, hvori kationen er multivalent.
Egnede fyldstoffer omfatter f.eks. lactose, sukker, stivelser, modificerede stivelser, mannitol, sorbitol, uorganiske salte, cellulosederivater (f.eks. mikrokrystallinsk cellulose, cellulose), calciumsulfat, xylitol og lactitol.
Egnede bindemidler omfatter f.eks. polyvinylpyrrolidon, lactose, stivelser, modificerede stivelser, sukkerarter, akaciegummi, tragantgummi, guar gummi, pektin, voksbindemid-ler, mikrokrystallinsk cellulose, methylcellulose, carboxymethylcellulose, hydroxypro-pylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, copolyvidon, gelatine og natriumalginat.
Egnede desmtegreringsmidler omfatter f.eks. natrium-crosscarmellose, crospovidon, polyvinylpyrrolidon, natrium-stivelsesglycolat, majsstivelse, mikrokrystallinsk cellulose, hydroxypropylmethylcellulose og hydroxypropylcellulose.
Egnede smøremidler omfatter f.eks. magnesiumstearat, stearinsyre, palmitinsyre, cal-ciumstearat, talk, camaubavoks, hydrogenerede vegetabilske olier, mineralolie, poly-ethylenglycoler og natriumstearylfumarat.
Yderligere konventionelle excipienser, der kan tilsættes, omfatter konserveringsmidler, stabilisatorer, antioxidanter, sihcastrømningskonditionerende midler, anti-vedhæftnings-midler eller glidemidler.
Andre egnede fyldstoffer, bindemidler, desmtegreringsmidler, smørestoffer og yderligere excipienser, der kan anvendes, er beskrevet i Handbook of Pharmaceutical Excipients, 2. udgave, American Pharmaceutical Association; The Theory and Practice of Industrial Pharmacy, 2. udgave, Lachman, Leon, 1976; Pharmaceutical Dosage Forms: Tablets Volume 1, 2. udgave, Lieberman, Hebert A., et al., 1989; Modem Pharmaceutics, Banker, Gilbert and Rhodes, Christopher T, 1979, og Remington's Pharmaceutical Sciences, 15. udgave, 1975.
Midlet vil typisk være til stede i en mængde i området fra 1 til 50%, f.eks. 1 til 25%, såsom fra 1 til 20% og især 5 til 18% på vægtbasis.
Typisk vil det uorganiske salt, såsom tribasisk calciumphosphat, være til stede i en mængde i området fra 1 til 25%, f.eks. 1 til 20%, såsom 5 til 18% på vægtbasis.
Der vil typisk være et eller flere fyldstoffer til stede i en mængde fra 30 til 90 vægt%.
Der vil typisk være et eller flere bindemidler til sted i en mængde fra 2 til 90 vægt%.
Der vil typisk være et eller flere desintegreringsmidler til stede i en mængde fra 2 til 10, og især fra 4 til 6 vægt%.
Det vil forstås, at en bestemt excipiens kan virke både som et bindemiddel og et fyldstof eller som et bindemiddel, et fyldstof og et desintegreringsmiddel. Typisk udgør den kombinerede mængde fyldstof, bindemiddel og desintegreringsmiddel f.eks. 70 til 90 vægt% af sammensætningen.
Typisk vil et eller flere smøremidler være til stede i en mængde fra 0,5 til 3 og især 1 til 2 vægt%.
Den farmaceutiske sammensætning ifølge opfindelsen kan fremstilles under anvendelse af standardteknikker og fremstillingsprocesser, som er generelt kendte inden for området, f.eks. ved tørblanding af komponenterne. For eksempel sammenblandes midlet og et uorganisk salt, hvori kationen er multivalent, et eller flere fyldstoffer, et eller flere bindemidler og et eller flere desintegreringsmidler såvel som andre yderligere excipien-ser efter ønske. Blandingens komponenter forud for blanding eller selve blandingen kan føres gennem en sigte, f.eks. en sigte med en maskevidde på 400-700 μΐη. Et smøremiddel, som også kan være sigtet, sættes derefter til blandingen, og blanding fortsættes, indtil der opnås en homogen blanding. Blandingen komprimeres derefter til tabletter. Alternativt kan anvendes en vådgranuleringsteknik. For eksempel sammenblandes midlet og et uorganisk salt, hvori kationen er multivalent, et eller flere fyldstoffer, et eller flere bindemidler og en del af et desintegreringsmiddel såvel som andre yderligere excipienser efter ønske, f.eks. ved anvendelse af en granulator, og pulverblandingen granuleres med et lille volumen renset vand. Granulatet tørres og føres gennem en mølle. Resten af desintegreringsmidlet og et smøremiddel sættes til den formalede granulering, og efter blanding komprimeres den resulterende homogene blanding til tabletter. Det må forstås, at modifikationer af tørblandings- og vådgranuleringsteknikkeme, herunder rækkefølgen for tilsætning af komponenterne og deres sigtning og blanding forud for komprimering til tabletter, kan udføres i overensstemmelse med inden for fagområdet velkendte principper.
Der kan derefter påføres et tabletovertræk, f. eks. ved spray-coating, med en vandbaseret filmovertræksformulering. Overtrækket kan f.eks. omfatte lactose, hydroxypropylme-thylcellulose, triacetin, titandioxid ogjemoxider. Kombinationer af overtrækskomponenter er kommercielt tilgængelige, såsom de i de efterfølgende eksempler beskrevne. Overtrækket kan f.eks. udgøre 0,5 til 10 vægt% af tabletsammensætningen, især 1 til 6% og fortrinsvis 2 til 3 %. Overtræk indeholdende jemoxider er særligt foretrukne, da de reducerer dannelseshastigheden af fotonedbrydningsprodukter af midlet.
Som et træk ifølge opfindelsen tilvejebringes således en farmaceutisk sammensætning omfattende midlet, idet sammensætningen har et lysbeskyttende jemoxidovertræk.
Et yderligere aspekt af den foreliggende opfindelse omfatter en fremgangsmåde til fremstilling af en stabiliseret farmaceutisk sammensætning, som omfatter blanding af midlet med et uorganisk salt, hvori kationen er multivalent. Et yderligere aspekt af den foreliggende opfindelse omfatter en fremgangsmåde til fremstilling af en stabiliseret farmaceutisk sammensætning, som omfatter inkorporering af et uorganisk salt, hvor kationen er multivalent, i en farmaceutisk sammensætning indeholdende midlet.
Eksempel 1
Midlet 2,50 mg
Tribasisk calchunphosphat 20,0 mg
Mikrokrystallinsk cellulose 47,0 mg
Lactosemonohydrat 47,0 mg
Natriumstivelsesglycolat 3,00 mg
Butyleret hydroxytoluen 0,05 mg
Magnesiumstearat 1,00 mg
Midlet, mikrokrystallinsk cellulose, lactosemonohydrat, natriumstivelsesglycolat, tribasisk calciumphosphat og butyleret hydroxytoluen blev blandet sammen i 10 minutter. Magnesiumstearat blev sigtet gennem en #40 mesh (425 μτή) sigte og sat til blandingen, og blandingen blev fortsat i yderligere 3 minutter. Den resulterende homogene blanding blev komprimeret til tabletter.
Tabletterne blev opbevaret ved 70°C/80% relativ fugtighed i en uge. Efter en uge viste der sig kun at være dannet 0,11 vægt/vægt% af oxidationsproduktet B2 og kun 0,50 vægt/vægt% af lactonen.
Eksempel 2
Midlet 2,50 mg
Povidon 2,50 mg
Tribasisk calciumphosphat 20,0 mg
Mikrokrystallinsk cellulose 47,0 mg
Mannitol 47,0 mg
Natriumstivelsesglycolat 3,00 mg
Butyleret hydroxytoluen 0,05 mg
Magnesiumstearat 1,00 mg
Midlet, povidon, mannitol, mikrokrystallinsk cellulose, butyleret hydroxytoluen, triba-sisk calciumphosphat og natriumstivelsesglycolat (i de ovenfor angivne mængder) blev blandet i 5 til 60 minutter. Magnesiumstearat blev sigtet gennem en #40 mesh (425 μτα) sigte og sat til blandingen, og blandingen blev fortsat i yderligere 3 minutter. Den resulterende homogene blanding blev komprimeret til tabletter. De komprimerede tabletter blev overtrukket ved spray-coating med en blanding af hydroxypropylmethylcellulo-se, polyethylenglycol 400, titandioxid og ferrioxid (solgt som Spectrablend af Wamer-Jenkinson) og vand i en pande til overtræk. Vægtforøgelsen tilvejebragt af overtrækket var 1 til 6 vægt/vægt% og fortrinsvis fra 2 til 3 vægt/vægt%.
Tabletterne blev lagret ved 70°C/80% relativ fugtighed i en uge. Efter en uge viste der sig kun at være dannet 0,06 vægt/vægt% af oxidationsproduktet B2 og kun 2,22 vægt/vægt % af lactonen.
Eksempel 3
Midlet 2,60 mg
Crospovidon 3,75 mg
Tribasisk calciumphosphat 5,66 mg
Mikrokrystallinsk cellulose 15,5 mg
Lactosemonohydrat 46,5 mg
Magnesiumstearat 0,94 mg
Midlet og crospovidon blev blandet sammen i 5 minutter, og blandingen blev derefter ført gennem en 400-700 μιη sigte. En lille del af den mikrokrystallinske cellulose blev ført igennem sigten efterfølgende. Det sigtede materiale blev blandet med de andre bestanddele, bortset fra smøremidlet, i 10 minutter. Magnesiumstearat blev ført gennem en #40 mesh (425 μΐη) sigte og sat til blandingen, og blandingen blev blandet i yderligere 3 minutter. Den resulterende homogene blanding blev komprimeret til tabletter. De komprimerede tabletter blev overtrukket ved spray-coating med en blanding af lactose-monohydrat, hydroxypropylmethylcellulose, triacetin og ferrioxid (solgt som Opadry Π™ af Colorcon) og vand i en pande til overtræk. Vægtforøgelsen tilvejebragt af overtrækket var 1 til 6 vægt/vægt% og fortrinsvis 2 til 3 vægt/vægt%.
Tabletterne blev lagret ved 70°C/80% relativ fugtighed i en uge. Efter dette tidsrum var der kun dannet 0,19 vægt/vægt% af oxidationsproduktet B2 og kun 2,71 vægt/vægt% af lactonen.
Eksempel 4
Midlet 2,50 mg
Povidon 2,50 mg
Tribasisk calciumphosphat 20,0 mg
Mikrokrystallinsk cellulose 34,5 mg
Lactosemonohydrat 34,0 mg
Natriumstivelsesglycolat 6,00 mg
Magnesiumstearat 1,00 mg
Butyleret hydroxytoluen 0,05 mg
En del af det tribasiske calciumphosphat og butyleret hydroxytoluen blev blandet i 30 sekunder i en pose. Midlet, povidon, resten af det tribasiske calciumphosphat, mikrokrystallinsk cellulose, lactosemonohydrat, blandingen af tribasisk calciumphosphat og butyleret hydroxytoluen og en del af natriumstivelsesglycolatet blev blandet i en granula- tor i 30 sekunder. Pulverblandingen blev granuleret med renset vand i 1 minut med en tilsætningshastighed på 70 mg/tablet/minut. Granuleringen tørres i et tørreapparat med fluidiseret leje ved 50°C, indtil tørretabet er mindre end 2 vægt/vægt%. Den tørrede granulering føres gennem en mølle (f.eks. Comil™). Den formalede granulering og resten af natriumstivelsesglycolatet blev blandet i omkring 5 minutter. Magnesiumstearat blev sigtet gennem en #40 mesh (425 μΐη) sigte og sat til blandingen, og blandingen fortsatte i yderligere 3 minutter. Den resulterende homogene blanding blev komprimeret til tabletter.
Tabletterne blev lagret ved 70°C/80% relativ fugtighed i en uge. Efter dette tidsrum var der kun dannet 0,23 vægt/vægt% af oxidationsproduktet B2 og kun 0,28 vægt/vægt% af lactonen.
Formel I
Claims (28)
1. Farmaceutisk sammensætning omfattende (E)-7-[4-(4-fluorphenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl]-(3R, 5S)-3,5-dihydroxyhept-6-ensyre eller et farmaceutisk acceptabelt salt deraf som den aktive bestanddel og et uorganisk salt, hvori kationen er multivalent under forudsætningen af at det uorganiske salt ikke er hydrotalcit eller syntetisk hydrotalcit.
2. Farmaceutisk tablet omfattende (E)-7-[4-(4-fluorphenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl]-(3R, 5S)-3,5-dihydroxyhept-6-ensyre eller et farmaceutisk acceptabelt salt deraf som den aktive bestanddel og et uorganisk salt, hvori kationen er multivalent.
3. Farmaceutisk sammensætning ifølge krav 1 eller 2, hvori kationen af det uorganiske salt er valgt blandt calcium, magnesium, zink, aluminium og jern.
4. Farmaceutisk sammensætning ifølge ethvert af kravene 1-3, hvori modanionen i det uorganiske salt er valgt blandt et phosphat, et carbonat, et silicat, et oxid og et me-tasilicat.
5. Farmaceutisk sammensætning ifølge ethvert af kravene 1-3, hvori modanionen i det uorganiske salt er valgt blandt et silicat, et oxid eller et metasilicat.
6. Farmaceutisk sammensætning ifølge krav 1 eller 2, hvori det uorganiske salt er valgt blandt aluminiummagnesiummetasilicat, tribasisk calciumphosphat, tribasisk magnesiumphosphat og tribasisk aluminiumphosphat.
7. Farmaceutisk sammensætning ifølge krav 6, hvori det uorganiske salt er aluminiummagnesiummetasilicat.
8. Farmaceutisk sammensætning ifølge krav 1, som er en tablet eller et pulver.
9. Farmaceutisk sammensætning ifølge ethvert af kravene 1-8, hvori der er mere end 5 mg aktiv bestanddel til stede.
10. Farmaceutisk sammensætning ifølge ethvert af kravene 1- 9, hvori der er mere end 10 mg aktiv bestanddel til stede.
11. Farmaceutisk sammensætning ifølge ethvert af kravene 1-10, hvori forholdet mellem uorganisk salt og aktiv bestanddel er i området fra 1:80 til 50:1 på vægtbasis.
12. Farmaceutisk sammensætning ifølge ethvert af de foregående krav, som yderligere omfatter et eller flere fyldstoffer, bindemidler, desintegreringsmidler eller smøremidler.
13. Farmaceutisk sammensætning ifølge ethvert af kravene 1-9, hvori den aktive bestanddel er til stede i en mængde på 1 til 50 vægt% af sammensætningen.
14. Farmaceutisk sammensætning ifølge ethvert af kravene 1- 9, hvori det uorganiske salt er til stede i en mængde på 1 til 50 vægt% af sammensætningen.
15. Farmaceutisk sammensætning ifølge krav 12, hvori fyldstoffet er til stede i en mængde fra 30 til 90 vægt% af sammensætningen.
16. Farmaceutisk sammensætning ifølge krav 12 eller 15, hvori bindemidlet er til stede i en mængde fra 2 til 90 vægt% af sammensætningen.
17. Farmaceutisk sammensætning ifølge krav 12, 15 eller 16, hvori desintegreringsmidlet er til stedet i en mængde fra 2 til 10 vægt% af sammensætningen.
18. Farmaceutisk sammensætning ifølge krav 12, 15, 16 eller 17,, hvori smøremidlet er til stede i en mængde fra 0,5 til 3 vægt%.
19. Farmaceutisk sammensætning ifølge ethvert af de foregående krav, hvori den aktive bestanddel er calciumsaltet af (E)-7-[4-(4-fluorphenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl]-(3R, 5S)-3,5-dihydroxyhept-6-ensyre.
20. Anvendelse af et uorganisk salt, hvori kationen er multivalent, til stabilisering af forbindelsen (E)-7-[4-(4-fluorphenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyri-midin-5-yl]-(3R, 5S)-3,5-dihydroxyhept-6-ensyre eller et farmaceutisk acceptabelt salt deraf med den forudsætning at det uorganiske salt ikke er hydrotalcit eller syntetisk hy-drotalcit.
21. Anvendelse ifølge krav 20, hvori modanionen i det uorganiske salt er valgt blandt et phosphat, et carbonat, et silicat, et oxid og et metasilicat.
22. Anvendelse ifølge krav 20, hvori modanionen i det uorganiske salt er valgt blandt et silicat, et oxid eller et metasilicat.
23. Anvendelse ifølge krav 20, hvori det uorganiske salt, hvori kationen er multivalent, er valgt blandt aluminiummagnesiummetasilicat, tribasisk calciumphosphat, tribasisk magnesiumphosphat og tribasisk aluminiumphosphat.
24. Anvendelse ifølge krav 20, hvori det uorganiske salt, hvori kationen er multivalent, er aluminiummagnesiummetasilicat.
25. Fremgangsmåde til fremstilling af en stabiliseret farmaceutisk sammensætning, som omfatter inkorporering af et uorganisk salt, hvori kationen er multivalent, i en farmaceutisk sammensætning indeholdende forbindelsen (E)-7-[4-(4-fluorphenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl]-(3R, 5S)-3,5-dihydroxyhept-6-ensyre eller et farmaceutisk acceptabelt salt deraf med den forudsætning at det uorganiske salt ikke er hydrotalcit eller syntetisk hydrotalcit.
26. Fremgangsmåde ifølge krav 25, hvori modanionen i det uorganiske salt er valgt blandt et phosphat, et carbonat, et silicat, et oxid og et metasilicat.
27. Fremgangsmåde ifølge krav 25, hvori modanionen i det uorganiske salt er valgt blandt et silicat, et oxid eller et metasilicat.
28. Fremgangsmåde ifølge krav 25, hvori det uorganiske salt, hvori kationen er multivalent, er aluminiummagnesiummetasilicat.
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|---|---|---|---|
| GB0001621 | 2000-01-26 | ||
| GBGB0001621.2A GB0001621D0 (en) | 2000-01-26 | 2000-01-26 | Pharmaceutical compositions |
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| Publication Number | Publication Date |
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| DK200001171A DK200001171A (da) | 2001-07-27 |
| DK178242B1 true DK178242B1 (da) | 2015-09-28 |
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| DK200001170A DK200001170A (da) | 2000-01-26 | 2000-08-04 | Farmaceutiske sammensætninger |
| DK00953283T DK1223918T3 (da) | 2000-01-26 | 2000-08-04 | Farmaceutiske præparater omfattende en HMG-CoA-reductaseinhibitor |
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| DK200001170A DK200001170A (da) | 2000-01-26 | 2000-08-04 | Farmaceutiske sammensætninger |
| DK00953283T DK1223918T3 (da) | 2000-01-26 | 2000-08-04 | Farmaceutiske præparater omfattende en HMG-CoA-reductaseinhibitor |
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| PUP | Patent expired |
Expiry date: 20200804 |