NO171888B - PROCEDURE FOR THE PREPARATION OF A PHARMACEUTICAL PREPARATION CONTAINING MEDICINAL SUBSTANCES WHICH ARE SOLELY SOLUBLE OR USTABILE IN WATER - Google Patents
PROCEDURE FOR THE PREPARATION OF A PHARMACEUTICAL PREPARATION CONTAINING MEDICINAL SUBSTANCES WHICH ARE SOLELY SOLUBLE OR USTABILE IN WATER Download PDFInfo
- Publication number
- NO171888B NO171888B NO85853070A NO853070A NO171888B NO 171888 B NO171888 B NO 171888B NO 85853070 A NO85853070 A NO 85853070A NO 853070 A NO853070 A NO 853070A NO 171888 B NO171888 B NO 171888B
- Authority
- NO
- Norway
- Prior art keywords
- cyclodextrin
- water
- ether
- methyl
- groups
- Prior art date
Links
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 title claims description 27
- 238000000034 method Methods 0.000 title claims description 10
- 239000000126 substance Substances 0.000 title claims description 7
- 239000000825 pharmaceutical preparation Substances 0.000 title claims description 6
- 238000002360 preparation method Methods 0.000 title description 2
- 229920000858 Cyclodextrin Polymers 0.000 claims description 45
- 239000000243 solution Substances 0.000 claims description 29
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 claims description 26
- -1 hydroxypropyl Chemical group 0.000 claims description 20
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 16
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 12
- 238000006467 substitution reaction Methods 0.000 claims description 12
- 235000002639 sodium chloride Nutrition 0.000 claims description 10
- 239000011780 sodium chloride Substances 0.000 claims description 9
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 8
- GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 claims description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 125000001033 ether group Chemical group 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 239000007787 solid Substances 0.000 claims description 5
- 239000012907 medicinal substance Substances 0.000 claims description 4
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 3
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 3
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 3
- 229930195725 Mannitol Natural products 0.000 claims description 3
- 229910019142 PO4 Inorganic materials 0.000 claims description 3
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 claims description 3
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 3
- 239000008103 glucose Substances 0.000 claims description 3
- 235000001727 glucose Nutrition 0.000 claims description 3
- 239000000594 mannitol Substances 0.000 claims description 3
- 235000010355 mannitol Nutrition 0.000 claims description 3
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 claims description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- 239000000600 sorbitol Substances 0.000 claims description 3
- 235000010356 sorbitol Nutrition 0.000 claims description 3
- 239000000811 xylitol Substances 0.000 claims description 3
- 235000010447 xylitol Nutrition 0.000 claims description 3
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 claims description 3
- 229960002675 xylitol Drugs 0.000 claims description 3
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 2
- 239000007979 citrate buffer Substances 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 239000008363 phosphate buffer Substances 0.000 claims description 2
- HUKYUKIIXNZRBF-HZKYAONISA-N ε-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO HUKYUKIIXNZRBF-HZKYAONISA-N 0.000 claims 1
- 229940079593 drug Drugs 0.000 description 29
- 239000003814 drug Substances 0.000 description 29
- 150000001875 compounds Chemical class 0.000 description 11
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 10
- 239000007864 aqueous solution Substances 0.000 description 7
- 239000008055 phosphate buffer solution Substances 0.000 description 7
- 239000012528 membrane Substances 0.000 description 6
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 5
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 5
- 239000008139 complexing agent Substances 0.000 description 5
- 229960000905 indomethacin Drugs 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000000872 buffer Substances 0.000 description 4
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 4
- 150000002170 ethers Chemical class 0.000 description 4
- 230000002949 hemolytic effect Effects 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- 230000001988 toxicity Effects 0.000 description 4
- 231100000419 toxicity Toxicity 0.000 description 4
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 3
- 206010018910 Haemolysis Diseases 0.000 description 3
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 230000008588 hemolysis Effects 0.000 description 3
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 230000007794 irritation Effects 0.000 description 3
- XMAYWYJOQHXEEK-OZXSUGGESA-N (2R,4S)-ketoconazole Chemical compound C1CN(C(=O)C)CCN1C(C=C1)=CC=C1OC[C@@H]1O[C@@](CN2C=NC=C2)(C=2C(=CC(Cl)=CC=2)Cl)OC1 XMAYWYJOQHXEEK-OZXSUGGESA-N 0.000 description 2
- OGPIBXIQNMQSPY-FDDCHVKYSA-N (S,S)-tubulozole Chemical compound C1=CC(NC(=O)OCC)=CC=C1SC[C@H]1O[C@](CN2C=NC=C2)(C=2C(=CC(Cl)=CC=2)Cl)OC1 OGPIBXIQNMQSPY-FDDCHVKYSA-N 0.000 description 2
- VHVPQPYKVGDNFY-DFMJLFEVSA-N 2-[(2r)-butan-2-yl]-4-[4-[4-[4-[[(2r,4s)-2-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-1,2,4-triazol-3-one Chemical compound O=C1N([C@H](C)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@@H]3O[C@](CN4N=CN=C4)(OC3)C=3C(=CC(Cl)=CC=3)Cl)=CC=2)C=C1 VHVPQPYKVGDNFY-DFMJLFEVSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
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- 239000008186 active pharmaceutical agent Substances 0.000 description 2
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- 125000002947 alkylene group Chemical group 0.000 description 2
- GXDALQBWZGODGZ-UHFFFAOYSA-N astemizole Chemical compound C1=CC(OC)=CC=C1CCN1CCC(NC=2N(C3=CC=CC=C3N=2)CC=2C=CC(F)=CC=2)CC1 GXDALQBWZGODGZ-UHFFFAOYSA-N 0.000 description 2
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- AAOVKJBEBIDNHE-UHFFFAOYSA-N diazepam Chemical compound N=1CC(=O)N(C)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 AAOVKJBEBIDNHE-UHFFFAOYSA-N 0.000 description 2
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 238000006266 etherification reaction Methods 0.000 description 2
- NPUKDXXFDDZOKR-LLVKDONJSA-N etomidate Chemical compound CCOC(=O)C1=CN=CN1[C@H](C)C1=CC=CC=C1 NPUKDXXFDDZOKR-LLVKDONJSA-N 0.000 description 2
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- SMANXXCATUTDDT-QPJJXVBHSA-N flunarizine Chemical compound C1=CC(F)=CC=C1C(C=1C=CC(F)=CC=1)N1CCN(C\C=C\C=2C=CC=CC=2)CC1 SMANXXCATUTDDT-QPJJXVBHSA-N 0.000 description 2
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- 125000002791 glucosyl group Chemical group C1([C@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO)* 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
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- ZCGOMHNNNFPNMX-KYTRFIICSA-N levocabastine Chemical compound C1([C@@]2(C(O)=O)CCN(C[C@H]2C)[C@@H]2CC[C@@](CC2)(C#N)C=2C=CC(F)=CC=2)=CC=CC=C1 ZCGOMHNNNFPNMX-KYTRFIICSA-N 0.000 description 2
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
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- PSGAAPLEWMOORI-PEINSRQWSA-N medroxyprogesterone acetate Chemical compound C([C@@]12C)CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2CC[C@]2(C)[C@@](OC(C)=O)(C(C)=O)CC[C@H]21 PSGAAPLEWMOORI-PEINSRQWSA-N 0.000 description 2
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- PCWPQSDFNIFUPO-VDQKLNDWSA-N (1S,3R,5R,6S,8R,10R,11S,13R,15R,16S,18R,20R,21S,23R,25R,26S,28R,30R,31S,33R,35R,36R,37S,38R,39S,40R,41S,42R,43S,44R,45S,46R,47S,48R,49S)-37,39,41,43,45,47,49-heptakis(2-hydroxyethoxy)-5,10,15,20,25,30,35-heptakis(hydroxymethyl)-2,4,7,9,12,14,17,19,22,24,27,29,32,34-tetradecaoxaoctacyclo[31.2.2.23,6.28,11.213,16.218,21.223,26.228,31]nonatetracontane-36,38,40,42,44,46,48-heptol Chemical compound OCCO[C@H]1[C@H](O)[C@@H]2O[C@H]3O[C@H](CO)[C@@H](O[C@H]4O[C@H](CO)[C@@H](O[C@H]5O[C@H](CO)[C@@H](O[C@H]6O[C@H](CO)[C@@H](O[C@H]7O[C@H](CO)[C@@H](O[C@H]8O[C@H](CO)[C@@H](O[C@H]1O[C@@H]2CO)[C@@H](O)[C@@H]8OCCO)[C@@H](O)[C@@H]7OCCO)[C@@H](O)[C@@H]6OCCO)[C@@H](O)[C@@H]5OCCO)[C@@H](O)[C@@H]4OCCO)[C@@H](O)[C@@H]3OCCO PCWPQSDFNIFUPO-VDQKLNDWSA-N 0.000 description 1
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- DALSNPRWUFOYDT-UHFFFAOYSA-N 1-[(2-chlorophenyl)-(4-phenylphenyl)methyl]imidazole Chemical compound ClC1=CC=CC=C1C(N1C=NC=C1)C1=CC=C(C=2C=CC=CC=2)C=C1 DALSNPRWUFOYDT-UHFFFAOYSA-N 0.000 description 1
- AFNXATANNDIXLG-SFHVURJKSA-N 1-[(2r)-2-[(4-chlorophenyl)methylsulfanyl]-2-(2,4-dichlorophenyl)ethyl]imidazole Chemical compound C1=CC(Cl)=CC=C1CS[C@H](C=1C(=CC(Cl)=CC=1)Cl)CN1C=NC=C1 AFNXATANNDIXLG-SFHVURJKSA-N 0.000 description 1
- ZCJYUTQZBAIHBS-UHFFFAOYSA-N 1-[2-(2,4-dichlorophenyl)-2-{[4-(phenylsulfanyl)benzyl]oxy}ethyl]imidazole Chemical compound ClC1=CC(Cl)=CC=C1C(OCC=1C=CC(SC=2C=CC=CC=2)=CC=1)CN1C=NC=C1 ZCJYUTQZBAIHBS-UHFFFAOYSA-N 0.000 description 1
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- PZBPKYOVPCNPJY-UHFFFAOYSA-N 1-[2-(allyloxy)-2-(2,4-dichlorophenyl)ethyl]imidazole Chemical compound ClC1=CC(Cl)=CC=C1C(OCC=C)CN1C=NC=C1 PZBPKYOVPCNPJY-UHFFFAOYSA-N 0.000 description 1
- VWXFUOAKGNJSBI-UHFFFAOYSA-N 1-[4,4-bis(4-fluorophenyl)butyl]-4-[2-(2,6-dichloroanilino)-2-oxoethyl]piperazine-2-carboxamide Chemical compound C1CN(CCCC(C=2C=CC(F)=CC=2)C=2C=CC(F)=CC=2)C(C(=O)N)CN1CC(=O)NC1=C(Cl)C=CC=C1Cl VWXFUOAKGNJSBI-UHFFFAOYSA-N 0.000 description 1
- MDLAAYDRRZXJIF-UHFFFAOYSA-N 1-[4,4-bis(4-fluorophenyl)butyl]-4-[4-chloro-3-(trifluoromethyl)phenyl]-4-piperidinol Chemical compound C1CC(O)(C=2C=C(C(Cl)=CC=2)C(F)(F)F)CCN1CCCC(C=1C=CC(F)=CC=1)C1=CC=C(F)C=C1 MDLAAYDRRZXJIF-UHFFFAOYSA-N 0.000 description 1
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- BEJQXBXPRXFJDP-UHFFFAOYSA-N 3-(3,3-dihydroxypropoxy)propane-1,1-diol Chemical compound OC(O)CCOCCC(O)O BEJQXBXPRXFJDP-UHFFFAOYSA-N 0.000 description 1
- XHMWPVBQGARKQM-UHFFFAOYSA-N 3-ethoxy-1-propanol Chemical compound CCOCCCO XHMWPVBQGARKQM-UHFFFAOYSA-N 0.000 description 1
- JDFDHBSESGTDAL-UHFFFAOYSA-N 3-methoxypropan-1-ol Chemical compound COCCCO JDFDHBSESGTDAL-UHFFFAOYSA-N 0.000 description 1
- QOYHHIBFXOOADH-UHFFFAOYSA-N 8-[4,4-bis(4-fluorophenyl)butyl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one Chemical compound C1=CC(F)=CC=C1C(C=1C=CC(F)=CC=1)CCCN1CCC2(C(NCN2C=2C=CC=CC=2)=O)CC1 QOYHHIBFXOOADH-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 229910002016 Aerosil® 200 Inorganic materials 0.000 description 1
- 229920001450 Alpha-Cyclodextrin Polymers 0.000 description 1
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- 229940100050 virazole Drugs 0.000 description 1
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
Foreliggende oppfinnelse angår en fremgangsmåte for fremstilling av et farmasøytisk preparat av medisinske stoffer som er lite vannoppløselige eller er ustabile i vann. The present invention relates to a method for the production of a pharmaceutical preparation from medicinal substances that are poorly water-soluble or are unstable in water.
Nærmere bestemt angår oppfinnelsen en fremgangsmåte for fremstilling av et farmasøytisk preparat inneholdende inklusjonskomplekser av medisinske stoffer som er lite vannoppløselige eller er ustabile i vann, med et partielt foretret p<->cyklodekstrin idet etersubstituentene er hydroksyetyl-, hydroksypropyl- eller dihydroksypropylgrupper, der en del av etersubstituentene eventuelt kan være metyl- eller etylgrupper og g<->cyklodekstrineteren har en vannoppløselighet på mer enn 1,8 g/100 ml vann, hvori inklusjonskompleksene av retinoider med g<->cyklodekstrinetere er utelukket i den grad deres etersubstituenter er metyl-, etyl-og 2-hydroksyetylgrupper. More specifically, the invention relates to a method for the production of a pharmaceutical preparation containing inclusion complexes of medical substances that are poorly water-soluble or unstable in water, with a partially etherified p<->cyclodextrin, the ether substituents being hydroxyethyl, hydroxypropyl or dihydroxypropyl groups, where a part of the ether substituents may optionally be methyl or ethyl groups and the g<->cyclodextrin ether has a water solubility of more than 1.8 g/100 ml of water, in which the inclusion complexes of retinoids with g<->cyclodextrin ethers are excluded insofar as their ether substituents are methyl- , ethyl and 2-hydroxyethyl groups.
Et stort antall medikamenter er kun dårlig eller lite opp-løselige i vann slik at egnede inngivelsesformer som dråpe-oppløsninger eller injeksjonsoppløsninger fremstilles ved å bruke andre polare additiver som propylen glykol og så videre. Hvis medikamentmolekylet har basiske eller sure grupper foreligger det videre en mulighet for å øke vann-oppløseligheten ved saltdannelse. Som regel resulterer dette i redusert effektivitet eller forringet kjemisk stabilitet. På grunn av den skiftede fordelingslikevekt kan medikamentet kun langsomt trenge gjennom det lipofile membran i forhold til konsentrasjonen av den ikke-dissocierte fraksjon mens den ioniske fraksjon kan være gjenstand for en hurtig hydrolyttisk dekomponering. A large number of drugs are only poorly or slightly soluble in water so that suitable administration forms such as drop solutions or injection solutions are prepared by using other polar additives such as propylene glycol and so on. If the drug molecule has basic or acidic groups, there is also an opportunity to increase the water solubility by salt formation. As a rule, this results in reduced efficiency or impaired chemical stability. Due to the changed distribution equilibrium, the drug can only slowly penetrate the lipophilic membrane in relation to the concentration of the non-dissociated fraction, while the ionic fraction can be subject to rapid hydrolytic decomposition.
Ytterligere "vannlignende" oppløsningsmidler som lavmolekyl-vekts polyetylenglykoler eller 1,2-propylenglykol benyttes derfor ved fremstilling av vandige oppløsninger av lite vannoppløselige medikamenter, hvilke glykoler imidlertid ikke kan ansees som farmakologisk inerte, eller medikamentet er oppløseliggjort ved bruk av overflateaktive midler slik at medikamentmolekylene okkuleres i misceller. Denne oppløse-liggjøring har tallrike mangler. De overflateaktive molekyler som "benyttes har hyppig en sterkt hemolyttisk virkning og medikamentet må gå ut av miscellen ved diffusjon efter inngivelse. Dette resulterer i en forsinket virkning (se B.W Muller, "Gelbe Reihe", Vol. X,side 132ff (1983)). Additional "water-like" solvents such as low-molecular-weight polyethylene glycols or 1,2-propylene glycol are therefore used in the preparation of aqueous solutions of poorly water-soluble drugs, which glycols, however, cannot be considered pharmacologically inert, or the drug is solubilized using surface-active agents so that the drug molecules occluded in miscells. This dissolution equation has numerous shortcomings. The surface-active molecules that are "used often have a strong hemolytic effect and the drug must leave the micelle by diffusion after administration. This results in a delayed effect (see B.W Muller, "Gelbe Reihe", Vol. X, page 132ff (1983)) .
I henhold til dette kan det hevdes at det ikke foreligger noen tilfredsstillende og generelt anvendelig metode for oppløseliggjøring. According to this, it can be claimed that there is no satisfactory and generally applicable method for dissolution.
For faste medikamenter er det også viktig å bibeholde det snaut vannoppløselige medikament vannoppløselig fordi en god oppløselighet øker bioanvendeligheten av medikamentet. Det er beskrevet at inklusjonsforbindelse, for eksempel med urea eller komplekser av polyvinylpyrrolidon, kan forbedre oppløseligheten for en forbindelse, men i vandig oppløsning er de ikke stabile. Slike inklusjonsforbindelser er derfor best anvendelige for faste inngivelsesformer i forbindelse med medikamenter. For solid drugs, it is also important to keep the poorly water-soluble drug water-soluble because a good solubility increases the bioavailability of the drug. It has been described that inclusion compounds, for example with urea or complexes of polyvinylpyrrolidone, can improve the solubility of a compound, but in aqueous solution they are not stable. Such inclusion compounds are therefore best applicable for solid administration forms in connection with drugs.
Dette gjelder ikke når man benytter a-, P- og"y-cyklodextrin som kan binde et medikament i ringen også i vandig opp-løsning (W. Sanger, "Angewandte Chemie" 92, 343 (1980)). Imidlertid er det ufordelaktig at p-cyklodextrinet i seg selv kun er dårlig vannoppløselig (1,8 g/100 ml) slik at de terapeutisk nødvendige medikamentkonsentrasJoner ikke oppnås. This does not apply when using α-, β- and γ-cyclodextrin, which can bind a drug in the ring also in aqueous solution (W. Sanger, "Angewandte Chemie" 92, 343 (1980)). However, it is disadvantageous that the p-cyclodextrin itself is only poorly water soluble (1.8 g/100 ml) so that the therapeutically necessary drug concentrations are not achieved.
Hvis det dannes et derivat av cyklodextrin kan oppløselig-heten og derfor mengden oppløst medikament økes i betydelig grad. Således beskriver DE-OS 31 18 218 en oppløseliggjør-ingsmetode som benytter metylert g<->cyklodextrin som mono-metyl derivat med 7 metylgrupper og spesielt som dimetyl-derivat med 14 metylgrupper. Med 2,6-di-0-metyl-derivatet er det for eksempel mulig å øke vannoppløseligheten for indometacin 20,4 ganger og den til digitoxin 81,6 ganger. Imidlertid viser metylderivatene at p-cyklodextrin for terapeutiske anvendelse alvorlige mangler. På grunn av den økede lipofilitet har de en hemolyttisk virkning og de forårsaker videre irritasjoner av mucosa og øyne. If a derivative of cyclodextrin is formed, the solubility and therefore the amount of dissolved drug can be increased to a considerable extent. Thus, DE-OS 31 18 218 describes a solubilization method which uses methylated cyclodextrin as a mono-methyl derivative with 7 methyl groups and in particular as a dimethyl derivative with 14 methyl groups. With the 2,6-di-0-methyl derivative, it is for example possible to increase the water solubility of indomethacin 20.4 times and that of digitoxin 81.6 times. However, the methyl derivatives show that p-cyclodextrin for therapeutic applications is seriously lacking. Due to the increased lipophilicity, they have a hemolytic effect and they cause further irritations of the mucosa and eyes.
Den akutte intravenøse giftighet er ennu høyere enn den allerede betydelige giftighet for usubstituert p<->cyklo dextrin. Det er en ytterligere alvorlig mangel for den praktiske anvendelse at oppløseligheten for dimetyl p<->cyklodextrin og forbindelsens komplekser lider av en steil reduksjon ved høyere temperaturer slik at krystallinsk dextrin felles ut ved oppvarming. Dette fenomen gjør det meget vanskelig å sterilisere oppløsninger ved de vanlige The acute intravenous toxicity is even higher than the already significant toxicity of unsubstituted p<->cyclodextrin. It is a further serious shortcoming for the practical application that the solubility of dimethyl p<->cyclodextrin and the compound's complexes suffers from a steep reduction at higher temperatures so that crystalline dextrin precipitates on heating. This phenomenon makes it very difficult to sterilize solutions with the usual ones
temperaturer på 100 - 121°C. temperatures of 100 - 121°C.
Meget overraskende er det nu funnet at visse andre p-cyklo-dextrinderivater kan danne inklusjonsforbindelser som også betydelig øker vannoppløseligheten for nesten ikke vannopp-løselige og videre ustabile medikamenter uten å vise de ovenfor angitte mangler. Very surprisingly, it has now been found that certain other p-cyclodextrin derivatives can form inclusion compounds which also significantly increase the water solubility of almost water-insoluble and further unstable drugs without showing the above-mentioned shortcomings.
I henhold til det ovenfor anførte angår foreliggende oppfinnelse en fremgangsmåte av den innledningsvis nevnte art og denne karakteriseres ved at p<->cyklodekstrineteren oppløses I vann og at den tilsvarende medisinske substans tilsettes til et molforhold medisinsk substans:<p->cyklodekstrineter på 1:6 til 4:1, eventuelt ytterligere fysiologisk forenelige stoffer tilsettes til vannet, fortrinnsvis vanlig salt, glucose, mannitol, sorbitol, xylitol eller en fosfat- eller citratbuffer og eventuelt, den resulterende oppløsning av inneslutningskomplekset tørkes på i og for seg kjent måte, idet resten efter fjerning av oppløsningsmidlet pulveriseres og, eventuelt efter tilsetning av ytterligere hjelpestoffer, omdannes til en fast administreringsform. In accordance with the above, the present invention relates to a method of the nature mentioned at the outset and this is characterized by the p<->cyclodextrin ether being dissolved in water and the corresponding medicinal substance being added to a molar ratio of medicinal substance:<p->cyclodextrin ether of 1: 6 to 4:1, optionally further physiologically compatible substances are added to the water, preferably common salt, glucose, mannitol, sorbitol, xylitol or a phosphate or citrate buffer and optionally, the resulting solution of the inclusion complex is dried in a manner known per se, the residue after removal of the solvent is pulverized and, possibly after the addition of additional excipients, converted into a solid administration form.
Et partielt foretret p<->cyklodextrin med formel I benyttes fortrinnsvis idet resten R er en hydroksyetyl-, hydroksy propyl- eller dihydroksypropylgruppe. Eventuelle deler av restene R kan for eksempel være metyl- eller etylgrupper; bruken av partielt metylerte p<->cyklodextrinetere med fra 7 til 14 metylgrupper i p<->cyklodextrinmolekylet, slik de er kjent fra DE-OS 31 18 218, ligger ikke innenfor rammen av oppfinnelsen. Partielle etere av p<->cyklodextrin omfattende kun alkylgrupper, nemlig metyl eller etyl, kan være egnet i henhold til oppfinnelsen hvis de har en lav substitueringsgrad som definert nedenfor på 0,05 til 0,2. A partially etherified p<->cyclodextrin of formula I is preferably used where the residue R is a hydroxyethyl, hydroxypropyl or dihydroxypropyl group. Any parts of the residues R can be, for example, methyl or ethyl groups; the use of partially methylated p<->cyclodextrin ethers with from 7 to 14 methyl groups in the p<->cyclodextrin molecule, as they are known from DE-OS 31 18 218, is not within the scope of the invention. Partial ethers of p<->cyclodextrin comprising only alkyl groups, namely methyl or ethyl, may be suitable according to the invention if they have a low degree of substitution as defined below of 0.05 to 0.2.
p-cyklodextrin er en forbindelse med en ringstruktur som omfatter 7 hydroglucoseenheter; den kalles også cyklo-heptaamylose. Hver av de 7 glucoseringene inneholder i 2-, 3-og 6-stilling tre hydroksygrupper som kan være foretret. I de partielt foretrede p<->cyklodextrinderivater som benyttes er kun en del av disse hydroksygruppe foretret med hydroksyalkylgrupper og eventuelt ytterligere med alkylgrupper. Når foretringen med hydroksyalkylgrupper som kan gjennomføres ved en reaksjon med tilsvarende alkylenoksyder, er substitueringsgraden angitt som molekylær substituering, MS, det vil si i mol alkylenoksyd pr. anhydroglucoseenhet, se forøvrig US-PS 34 59 731, kolonne 4. I hydroksyalkyletere av p-cyklodextrin som benyttes ifølge oppfinnelsen er den molare substituering mellom 0,05 og 10, fortrinnsvis mellom 0,2 og 2. Spesielt foretrukket er en molar substituering på ca. 0,25 til ca. 1. β-Cyclodextrin is a compound with a ring structure comprising 7 hydroglucose units; it is also called cyclo-heptaamylose. Each of the 7 glucose rings contains in the 2-, 3- and 6-position three hydroxy groups which may be etherified. In the partially etherified p<->cyclodextrin derivatives that are used, only a part of these hydroxy groups are etherified with hydroxyalkyl groups and possibly further with alkyl groups. When the etherification with hydroxyalkyl groups which can be carried out by a reaction with corresponding alkylene oxides, the degree of substitution is indicated as molecular substitution, MS, that is in moles of alkylene oxide per anhydroglucose unit, see also US-PS 34 59 731, column 4. In hydroxyalkyl ethers of p-cyclodextrin used according to the invention, the molar substitution is between 0.05 and 10, preferably between 0.2 and 2. Particularly preferred is a molar substitution of about. 0.25 to approx. 1.
Foretringen med alkylgrupper kan angis direkte som substitueringsgrad, DS, pr. glucoseenhet, noe som, som angitt ovenfor, er 3 for total substituering. Partielt foretret p<->cyklodextrin benyttes innenfor oppfinnelsen og omfatter ved siden av hydroksyalkylgrupper også alkylgrupper, spesielt metyl- eller etylgrupper, opptil en substitueringsgrad på 0,05 til 2,0, fortrinnsvis 0,2 til 1,5. Aller helst er substitueringsgraden med alkylgruppene mellom ca. 0,5 og ca. 1,2. The etherification with alkyl groups can be stated directly as degree of substitution, DS, per glucose unit, which, as stated above, is 3 for total substitution. Partially etherified p<->cyclodextrin is used within the invention and comprises next to hydroxyalkyl groups also alkyl groups, especially methyl or ethyl groups, up to a degree of substitution of 0.05 to 2.0, preferably 0.2 to 1.5. Most preferably, the degree of substitution with the alkyl groups is between approx. 0.5 and approx. 1.2.
Molforholdet medikament:p-cyklodextrineter ligger innen området 1:6 til 4:1 og helst ca. 1:2 til 1:1. Som en regel er det foretrukket å benytte det kompleksdannende middel I et molart overskudd. The molar ratio drug:p-cyclodextrin ethers is within the range 1:6 to 4:1 and preferably approx. 1:2 to 1:1. As a rule, it is preferred to use the complexing agent in a molar excess.
Brukbare kompleksdannende midler er spesielt hydroksyetyl-, hydroksypropyl- og dihydroksypropyleter, disses tilsvarende blandede etere og videre blandede etere med metyl- eller etylgrupper som metyl-hydroksyetyl-, metyl-hydroksypropyl-, etyl-hydroksyetyl- og etyl-hydroksypropyleter av p-cyklodextrin. Useful complexing agents are in particular hydroxyethyl, hydroxypropyl and dihydroxypropyl ether, their corresponding mixed ethers and further mixed ethers with methyl or ethyl groups such as methyl hydroxyethyl, methyl hydroxypropyl, ethyl hydroxyethyl and ethyl hydroxypropyl ether of p-cyclodextrin.
Fremstillingen av hydroksyalkyleteren av p<->cyklodextrin kan gjennomføres ved å benytte metoden ifølge US-PS 34 59 731. Egnede fremtillingsmetoder for p-cyklodextrin kan videre finnes i J. Szejtli et al., "Staerke" 32, 165 (1980) og A.P. Croft og R.A. Bartsch, "Tetrahedron" 39, 1417 (1983). Blandede etere av p-cyklodextin kan fremstilles ved å omsette p<->cyklodextrin i et basisk reaksjonsmedium omfattende et alkalimetallhydroksyd, vann og eventuelt minst et organisk oppløsningsmiddel (for eksempel dimetoksyetan eller isopropanol) med minst to forskjellige hydroksyalkylerings-midler og eventuelt alkyleringsforetrende midler (for eksempel etylenoksyd, propylenoksyd, metyl- eller etyl-klorid). The production of the hydroxyalkyl ether of p<->cyclodextrin can be carried out by using the method according to US-PS 34 59 731. Suitable production methods for p-cyclodextrin can also be found in J. Szejtli et al., "Staerke" 32, 165 (1980) and A. P. Croft and R.A. Bartsch, "Tetrahedron" 39, 1417 (1983). Mixed ethers of p-cyclodextin can be prepared by reacting p<->cyclodextrin in a basic reaction medium comprising an alkali metal hydroxide, water and optionally at least one organic solvent (for example dimethoxyethane or isopropanol) with at least two different hydroxyalkylating agents and optionally alkylation-preferring agents ( for example ethylene oxide, propylene oxide, methyl or ethyl chloride).
Medikamenter som viser en betydelig øket vannoppløselighet og forbedret stabilitet efter henholdsvis å ha vært overført til inklusjonsforbindelser med de ovenfor nevnte p-cyklo-dextrinetere er de som har ønskede form og størrelse, for eksempel som passer inn i hulrommet i p<->cyklodextrinring-systemet. Dette inkluderer for eksempel ikke stereoide anti-reumatismemidler, steroider, kardialglykosider og derivater av benzodiazepin, benzimidazol, piperidin, piperazin, imidazol eller triazol. Medicines that show a significantly increased water solubility and improved stability after respectively having been transferred to inclusion compounds with the above-mentioned p-cyclodextrin ethers are those that have the desired shape and size, for example that fit into the cavity of the p<->cyclodextrin ring system . This does not include, for example, steroid anti-rheumatic drugs, steroids, cardiac glycosides and derivatives of benzodiazepine, benzimidazole, piperidine, piperazine, imidazole or triazole.
Brukbare benzimidazolderivater er tiabendazol, fuberidazol, oxibendazol, parbendazol, cambendazol, mebendazol, fenbenda-zol, flubendazol, albendazol, oxfendazol, nocodazol og astemisol. Egnede piperadin derivater er fluspirilen, plmozid, penfluridol, loperamid, astemizol, ketanserin, levocabastin, cisaprid, altanserin og ritanserin. Egnede piperazinderivater inkluderer lidoflazin, flunarizin, mianserin, oxatomid, mioflazin og cinnarizin. Eksempler på egnede imidazolderivater er metronidazol, ornidazol, ipronidazol, tinidazol, isoconazol, nimorazol, burimamid, metiamid, metomidat, enilconazol, etomidat, econazol, clotrimazol, carnidazol, cimetidin, docodazol, sulconazol, parconazol, orconazol, butoconazol, triadiminol, tioconazol, valconazol, fluotrimazol, ketoconazol, oxiconazol, lombazol, bifonazol, oxmetidin, fenticonazol og tubulazol. Som egnede triazolderivater skal nevnes virazol, itraconazol og terconazol. Useful benzimidazole derivatives are thiabendazole, fuberidazole, oxibendazole, parbendazole, cambendazole, mebendazole, fenbendazole, flubendazole, albendazole, oxfendazole, nocodazole and astemizole. Suitable piperadine derivatives are fluspirilene, plmozide, penfluridol, loperamide, astemizole, ketanserin, levocabastine, cisapride, altanserin and ritanserin. Suitable piperazine derivatives include lidoflazine, flunarizine, mianserin, oxatomide, mioflazine and cinnarizine. Examples of suitable imidazole derivatives are metronidazole, ornidazole, ipronidazole, tinidazole, isoconazole, nimorazole, burimamide, methiamide, metomidate, enilconazole, etomidate, econazole, clotrimazole, carnidazole, cimetidine, docodazole, sulconazole, parconazole, orconazole, butoconazole, triadiminol, tioconazole, valconazole , fluotrimazole, ketoconazole, oxiconazole, lombazole, bifonazole, oxmetidine, fenticonazole and tubulazole. Virazole, itraconazole and terconazole should be mentioned as suitable triazole derivatives.
Spesielt verdifulle farmasøytiske preparater oppnås ved omdanning av etomidat, ketoconazol, tubulazol, itraconazol, levocabastin eller flunarizin til vannoppløselig form ved bruk av de kompleksdannende midler ifølge oppfinnelsen. Particularly valuable pharmaceutical preparations are obtained by converting etomidate, ketoconazole, tubulazole, itraconazole, levocabastine or flunarizine into a water-soluble form using the complexing agents according to the invention.
Man kan som nevnt fremstille farmasøytiske preparater av snaut vannoppløselige eller vannustabile medikamenter ved å oppløse e-cyklodextrineteren i vann og dertil å tilsette det utvalgte moment såvel som eventuell tørking av oppløsningen av tildannet inklusjonsforbindelse ved bruk av fremgangsmåter som i og for seg er kjent, der oppløsningsdannelsen for eksempel kan skje ved temperaturer mellom 15 og 35°C. As mentioned, pharmaceutical preparations of sparingly water-soluble or water-unstable drugs can be prepared by dissolving the e-cyclodextrin ether in water and adding the selected component as well as possible drying of the solution of the inclusion compound formed using methods that are known in and of themselves, where the solution formation, for example, can take place at temperatures between 15 and 35°C.
Medikamentet tilsettes fortrinnsvis satsvis. Man kan videre omfatte fysiologisk forenelige forbindelser som natrium-klorid, kaliumnitrat, glucose, mannitol, sorbitol, xylitol eller buffere som fosfat, acetat eller citrat. The medication is preferably added in batches. One can further include physiologically compatible compounds such as sodium chloride, potassium nitrate, glucose, mannitol, sorbitol, xylitol or buffers such as phosphate, acetate or citrate.
Ved bruk ac p<->cyklodextrinetere ifølge oppfinnelsen er det mulig å fremstille anvendelsesformer for medikamenter for oral, parenteral, tropisk anvendelse, for eksempel infusering eller injisering, øyeoppløsninger (for eksempel de nye øyedråper eller nasaldråper), spray, aerosoler, siruper og andre medikale bad. By using ac p<->cyclodextrin ethers according to the invention, it is possible to prepare application forms for drugs for oral, parenteral, tropical use, for example infusion or injection, eye solutions (for example the new eye drops or nasal drops), sprays, aerosols, syrups and others medical baths.
De vandige oppløsninger kan videre omfatte egnede fysiologisk forenelige preserveringsmidler som en kvaternær ammoniumsepe eller klorbutanol. The aqueous solutions can further comprise suitable physiologically compatible preservatives such as a quaternary ammonium soap or chlorobutanol.
For fremstilling av faste formuleringer blir oppløsningene av inklusjonsforbindelsene tørket ved bruk av konvensjonelle metoder, således kan vannet fordampes i en rotasjonsfordamper ved bruk av lyofilisering. Resten pulveriseres og blir eventuelt efter tilsetning av ytterligere inert impreg-neringsmiddel omdannet til eventuelt belagte tabletter, suppositorier, kapsler, kremer eller lotioner. For the production of solid formulations, the solutions of the inclusion compounds are dried using conventional methods, thus the water can be evaporated in a rotary evaporator using lyophilization. The remainder is pulverized and, optionally after the addition of further inert impregnating agent, is converted into optionally coated tablets, suppositories, capsules, creams or lotions.
De følgende eksempler skal illustrere oppfinnelsen nærmere uten å gå utenfor dens ramme. The following examples shall illustrate the invention in more detail without going beyond its scope.
Fosfatbufferoppløsningen som nevnes i eksemplene hadde en pH-verdi på 6,6 og følgende sammensetning: The phosphate buffer solution mentioned in the examples had a pH value of 6.6 and the following composition:
Alle prosentandeler er på vektbasis. All percentages are by weight.
EKSEMPEL 1 EXAMPLE 1
Ut fra en 7#-ig masteroppløsning av hydroksyetyl p<->cyklodextrin (MS 0,43) i fosfatbufferoppløsning ble det fremstilt en fortynningsserie slik at den kompleksdannende middelkon-sentrasjon ble øket trinnvis til 1$. 3 ml av disse oppløs-ninger ble pipettert til en 5 ml sammensnøringsglass inneholdende medikamenter som skulle undersøkes. Efter rysting i 24 timer ved 25°C ble oppløsningen filtrert gjennom et membranfilter på 0,22 pm og det oppløste medika-mentinnhold ble bestemt spektrofotometrisk. Figurene 1, 3 og 4 viser økningen av medikamentkonsentrasjonen i oppløsningen i forhold til konsentrasjonen av kompleksdanningsmidlet for indometacin, fig. 1; piroxicam, fig. 2; og diazepam, fig. 4. From a 7% master solution of hydroxyethyl p<->cyclodextrin (MS 0.43) in phosphate buffer solution, a dilution series was prepared so that the complexing agent concentration was increased step by step to 1$. 3 ml of these solutions were pipetted into a 5 ml constriction glass containing drugs to be examined. After shaking for 24 hours at 25°C, the solution was filtered through a 0.22 µm membrane filter and the dissolved drug content was determined spectrophotometrically. Figures 1, 3 and 4 show the increase of the drug concentration in the solution in relation to the concentration of the complexing agent for indomethacin, fig. 1; piroxicam, fig. 2; and diazepam, fig. 4.
Maksimum medikamentkonsentrasjon avgrenses av den naturlige oppløselighet for cyklodextrinderivatet i bufferen som i tilfelle hydroksyetyl-p-cyklodextrinet med MS 0,43 oppnås ved 7,2 g/100 ml. The maximum drug concentration is delimited by the natural solubility of the cyclodextrin derivative in the buffer, which in the case of the hydroxyethyl-p-cyclodextrin with MS 0.43 is achieved at 7.2 g/100 ml.
Sammenligner man for eksempel resultatene som oppnås med indometacin med de som angis i DE-OS 31 18 218 for 2,6-di-0— metyle-cyklodextrin (fig. 2) vil man merke seg at hydroksy-etylderivatet har en betydelig høyere kompleksdannelses-konstant (sammenlilgnet med en forskjellig helling i figurene 1 og 2). If one compares, for example, the results obtained with indomethacin with those stated in DE-OS 31 18 218 for 2,6-di-O-methyl-cyclodextrin (fig. 2), one will notice that the hydroxy-ethyl derivative has a significantly higher complex formation -constant (compared to a different slope in figures 1 and 2).
EKSEMPEL 2 EXAMPLE 2
Metningsoppløseligheten ved 25°C for forskjellige medikamenter ble bestemt ved anvendelse av en 10$ hydroksypropyl-p<->cyklodextrin oppløsning med MS 0,35 i fosfatbufferoppløsnin-gen under de samme betingelser som i Eksempel 1. Metnings-oppløseligheten S^i fosfatbufferoppløsningen og S2i fosfatbufferoppløsning og 10$ tilsatt hydroksypropyl-3-cyklodextrin er angitt i Tabell 1. The saturation solubility at 25°C for various drugs was determined using a 10$ hydroxypropyl-p<->cyclodextrin solution with MS 0.35 in the phosphate buffer solution under the same conditions as in Example 1. The saturation solubility S^ in the phosphate buffer solution and S2i phosphate buffer solution and 10$ added hydroxypropyl-3-cyclodextrin are indicated in Table 1.
B. B.
Oppløsligeheten for medikamenter i en 4#-ig vandig oppløs-ning av hydroksypropyl-metyl-p<->cyklodextrin (DS 0,96; MS 0,43) ble bestemt på tilsvarende måte. De oppnådde resultater er oppsummert i den følgende Tabell 2 der forholdet R mellom mettet oppløselighet i vann eller ved den angitte pH-verdi, med og uten tilsetning av g<->cyklodextrin, er angitt for hvert medikament. Oppløsningen som ble fremstilt ifølge oppfinnelsen, ble videre funnet å være betydelig mere stabil, sammenlignet med vandige oppløsninger. The solubility of drugs in a 4% aqueous solution of hydroxypropyl-methyl-β-cyclodextrin (DS 0.96; MS 0.43) was determined in a similar manner. The results obtained are summarized in the following Table 2 where the ratio R between saturated solubility in water or at the specified pH value, with and without the addition of g<->cyclodextrin, is indicated for each drug. The solution produced according to the invention was further found to be significantly more stable, compared to aqueous solutions.
EKSEMPEL 3 EXAMPLE 3
I 10 ml fosfatbufferoppløsning ble 0,7 g hydroksyetyl-p--cyklodextrin (MS 0,43) oppløst sammen med 0,04 g Indometacin ved 25°C inntil det var dannet en klar oppløsning. Denne oppløsning ble filtrert gjennom et membranfilter, In 10 ml of phosphate buffer solution, 0.7 g of hydroxyethyl-p-cyclodextrin (MS 0.43) was dissolved together with 0.04 g of Indomethacin at 25°C until a clear solution was formed. This solution was filtered through a membrane filter,
0,22 pm, og fyl lt under laminær strøm i en på forhånd sterilisert injeksonsflaske som ble lagret ved 21°C (B). 0.22 pm, and fill lt under laminar flow into a pre-sterilized injection bottle that was stored at 21°C (B).
I en parallell prøve ble en mettet indometacinoppløsning i fosfatbufferoppløsning, 0,21 mg/ml, lagret under de samme betingelser (A). Medikamentkonsentrasjonene, bestemt ved høytrykks væskekromatografi, er angitt i Tabell 3. Den sterkt forbedrede stabilitet for forbindelsene ifølge oppfinnelsen er åpenbar. In a parallel sample, a saturated solution of indomethacin in phosphate buffer solution, 0.21 mg/ml, was stored under the same conditions (A). The drug concentrations, determined by high pressure liquid chromatography, are given in Table 3. The greatly improved stability of the compounds according to the invention is obvious.
EKSEMPEL 4 (injiserbar formulering) EXAMPLE 4 (injectable formulation)
0,35 g hydroksypropyl-P-cyklodextrin (MS 0,35) ble oppløst i en 5 ml fysiologisk natriumkloridoppløsning og oppvarmet til ca. 35"C hvorefter 3 mg diazepam ble tilsatt. Efter lagring i kort tid ble det oppnådd en klar oppløsning som ble fyllt på en ampulle efter filtrering gjennom et 0,45 pm membranfilter. 0.35 g of hydroxypropyl-β-cyclodextrin (MS 0.35) was dissolved in a 5 ml physiological sodium chloride solution and heated to approx. 35"C, after which 3 mg of diazepam was added. After storage for a short time, a clear solution was obtained which was filled into an ampoule after filtering through a 0.45 pm membrane filter.
EKSEMPEL 5 (Tablett) EXAMPLE 5 (Tablet)
I 100 ml vann ble 7 g hydroksyetyl-p<->cyklodextrin (MS 0,43) og 0,5 g medroxyprogesteronacetat oppløst. Vannet ble så fordampet i en rotasjonsfordamper. Resten på 75 mg ble pulverisert og efter tilsetning av 366 mg calciumhydrogen- fosfat.2H2O, 60 mg maisstivelse, 120 mg mikrokrystallinsk cellulosepulver, 4,2 mg meget dispergert silicium dioksyd av typen kommersielt tilgjengelig "Aerosil 200" og 4,8 mg magnesiumstearat, ble det fremstilt tabletter med en vekt på 630,0 mg omfattende 5 mg medikament/doseenhet. Oppløs-ningshastigheten for medroxyprogesteronacetat fra denne formulering er 21 ganger høyere sammenlignet med en tablett omfattende de samme inerte bestanddeler uten tilsetning av e-cyklodextrineter. In 100 ml of water, 7 g of hydroxyethyl β-cyclodextrin (MS 0.43) and 0.5 g of medroxyprogesterone acetate were dissolved. The water was then evaporated in a rotary evaporator. The remainder of 75 mg was pulverized and after adding 366 mg of calcium hydrogen phosphate.2H2O, 60 mg of corn starch, 120 mg of microcrystalline cellulose powder, 4.2 mg of highly dispersed silicon dioxide of the type commercially available "Aerosil 200" and 4.8 mg of magnesium stearate, tablets were produced with a weight of 630.0 mg comprising 5 mg of drug/dosage unit. The dissolution rate of medroxyprogesterone acetate from this formulation is 21 times higher compared to a tablet comprising the same inert ingredients without the addition of ε-cyclodextrins.
EKSEMPEL 6 EXAMPLE 6
5 g hydroksyetyl-p<->cyklodextrin (MS 0,43) og 14 mg vitamin A-acetat ble oppløst under omrøring i 100 ml vann eller sukkeroppløsning (5$ vandig oppløsning), i løpet av 2,5 timer under nitrogenatmosfære. Efter filtrering gjennom et membranfilter på 0,45 pm ble oppløsningen fyllt i ampuller og sterilisert eller fyllt i dryppflasker under tilsetning 5 g of hydroxyethyl p<->cyclodextrin (MS 0.43) and 14 mg of vitamin A acetate were dissolved with stirring in 100 ml of water or sugar solution (5% aqueous solution), during 2.5 hours under a nitrogen atmosphere. After filtration through a 0.45 µm membrane filter, the solution was filled into ampoules and sterilized or filled into dropper bottles while adding
av 0,4$ klorbutanol som preserveringsmiddel. of 0.4$ chlorobutanol as a preservative.
EKSEMPEL 7 EXAMPLE 7
5 eller 7,5 g hydroksyetyl-p-cyklodextrin (MS 0,43) og 0,5 eller 0,75 g Lidocain ble oppløst i 100 ml fysiologisk natriumkloridoppløsning ved 30°C (B). Injeksjonsoppløsninger, øyedråper og oppløsninger for topisk anvendelse ble fremstilt ut fra dette som beskrevet i Eksempel 6. 5 or 7.5 g of hydroxyethyl-p-cyclodextrin (MS 0.43) and 0.5 or 0.75 g of Lidocaine were dissolved in 100 ml of physiological sodium chloride solution at 30°C (B). Injection solutions, eye drops and solutions for topical use were prepared from this as described in Example 6.
Sammenligning av anestetisk virkning av disse oppløsninger i dyreprøver med en vandig lidocain-HCl-oppløsning (A) observerer man en utvidelse av virkningsvarigheten på 300$. Prøve: rotter, injisering av 0,1 ml i haleroten i nærheten av høyre eller venstre nervefilament og elektrisk irritering. Prøveresultatene er oppsummert i Tabell 4. Comparing the anesthetic effect of these solutions in animal tests with an aqueous lidocaine-HCl solution (A), an extension of the duration of action of 300$ is observed. Test: rats, injection of 0.1 ml into the root of the tail near the right or left nerve filament and electrical irritation. The test results are summarized in Table 4.
EKSEMPEL 8 EXAMPLE 8
6 mg dexametason og 100 mg hydroksyetyl-p<->cyklodextrin (MS 0,43) ble oppløst i 5 ml vann, steriliset ved filtrering gjennom 0,22 pm membranfilter og pakket i en aerosolbeholder som tillot å avgi 0,1 ml/dose. 6 mg of dexamethasone and 100 mg of hydroxyethyl-p<->cyclodextrin (MS 0.43) were dissolved in 5 ml of water, sterilized by filtration through a 0.22 µm membrane filter and packed in an aerosol container that allowed to release 0.1 ml/dose .
EKSEMPEL 9 EXAMPLE 9
Akutt intravenøs toksisitet for enkelte e-cyklodextriner ble prøvet på rotter med de følgende resultater. Det ble overraskende funnet at toksisiteten for derivatene som ble benyttet ifølge oppfinnelsen er en hel størrelsesorden lavere. Acute intravenous toxicity of some ε-cyclodextrins was tested on rats with the following results. It was surprisingly found that the toxicity of the derivatives used according to the invention is a whole order of magnitude lower.
Den hemolyttiske virkning av metyleteren ifølge DE-OS 31 18 218 ble sammenlignet med den til en eter benyttet ifølge oppfinnelsen. For dette formålet ble 100 pl av en fysiologisk natriumkloridoppløsning med et cyklodextrin-innhold på 10%, 800 pl av en buffer (400 mg MOPS,36 mg Na2HP04. 2 H20, 1,6 g NaCl i 200 ml H2O) og 100 pl av en suspensjon av human røde blodlegemer (vasket tre ganger med natriumklorid-oppløsning) blandet i 30 min. ved 37°C. Derefter ble blandingen sentrifugert og den optiske densitet bestemt ved 540 nm. The hemolytic effect of the methyl ether according to DE-OS 31 18 218 was compared with that of an ether used according to the invention. For this purpose, 100 µl of a physiological sodium chloride solution with a cyclodextrin content of 10%, 800 µl of a buffer (400 mg MOPS, 36 mg Na2HP04. 2 H2O, 1.6 g NaCl in 200 ml H2O) and 100 µl of a suspension of human red blood cells (washed three times with sodium chloride solution) mixed for 30 min. at 37°C. The mixture was then centrifuged and the optical density determined at 540 nm.
KONTROLLER: CHECK:
a) 100 pl natriumkloridoppløsning + buffer -* 0% hemolyse a) 100 pl sodium chloride solution + buffer -* 0% hemolysis
b) 900 pl vann -» 100$ hemolyse. b) 900 pl water -» 100$ hemolysis.
Resultatene som oppnås er oppsummert i den følgende tabell 6 The results obtained are summarized in the following table 6
der konsentrasjonene er angitt ved hvilken 50$ og 100% hemolyse opptrådte. where the concentrations are indicated at which 50% and 100% hemolysis occurred.
Resultatene viser at den hemolyttiske virkning av hydroksy-propylmetyleteren er ca. 5 til 8 ganger svakere enn den til dimetyleter ifølge kjent teknikk. Dyreprøver har vidre vist at hydroksyalkyleterene ikke forårsaker irritering av mucosa og øyne i motsetning til metyletrene. The results show that the haemolytic effect of the hydroxypropyl methyl ether is approx. 5 to 8 times weaker than that of dimethyl ether according to the prior art. Animal tests have also shown that the hydroxyalkyl ethers do not cause irritation of the mucosa and eyes, in contrast to the methyl ethers.
Claims (2)
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Application Number | Priority Date | Filing Date | Title |
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DE19833346123 DE3346123A1 (en) | 1983-12-21 | 1983-12-21 | PHARMACEUTICAL PREPARATIONS OF SUBSTANCES MEDICAL OR UNSTABLE IN WATER AND METHOD FOR THE PRODUCTION THEREOF |
PCT/EP1984/000417 WO1985002767A1 (en) | 1983-12-21 | 1984-12-20 | Pharmaceutical compositions containing drugs which are instable or sparingly soluble in water and methods for their preparation |
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NO853070L NO853070L (en) | 1985-08-02 |
NO171888B true NO171888B (en) | 1993-02-08 |
NO171888C NO171888C (en) | 1993-05-19 |
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NO853070A NO171888C (en) | 1983-12-21 | 1985-08-02 | PROCEDURE FOR THE PREPARATION OF A PHARMACEUTICAL PREPARATION CONTAINING MEDICINAL SUBSTANCES WHICH ARE SOLELY SOLUBLE OR USTABILE IN WATER |
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