DE3304864A1 - Adsorbates of prostaglandins - Google Patents
Adsorbates of prostaglandinsInfo
- Publication number
- DE3304864A1 DE3304864A1 DE19833304864 DE3304864A DE3304864A1 DE 3304864 A1 DE3304864 A1 DE 3304864A1 DE 19833304864 DE19833304864 DE 19833304864 DE 3304864 A DE3304864 A DE 3304864A DE 3304864 A1 DE3304864 A1 DE 3304864A1
- Authority
- DE
- Germany
- Prior art keywords
- dextran
- prostaglandins
- formula
- drying
- bound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 150000003180 prostaglandins Chemical class 0.000 title claims abstract description 55
- 229940094443 oxytocics prostaglandins Drugs 0.000 title claims abstract description 43
- 239000002156 adsorbate Substances 0.000 title claims abstract description 28
- 229920002307 Dextran Polymers 0.000 claims abstract description 73
- 238000000034 method Methods 0.000 claims abstract description 21
- 239000003814 drug Substances 0.000 claims abstract description 9
- 239000004480 active ingredient Substances 0.000 claims description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- 239000002775 capsule Substances 0.000 claims description 13
- 238000001035 drying Methods 0.000 claims description 13
- 239000000203 mixture Substances 0.000 claims description 10
- 238000009472 formulation Methods 0.000 claims description 7
- 239000000463 material Substances 0.000 claims description 6
- 206010061459 Gastrointestinal ulcer Diseases 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 206010020772 Hypertension Diseases 0.000 claims description 4
- 241000124008 Mammalia Species 0.000 claims description 4
- 208000007536 Thrombosis Diseases 0.000 claims description 4
- 206010000210 abortion Diseases 0.000 claims description 4
- 231100000176 abortion Toxicity 0.000 claims description 4
- 208000006673 asthma Diseases 0.000 claims description 4
- 229920000159 gelatin Polymers 0.000 claims description 4
- 235000019322 gelatine Nutrition 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
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- 238000004108 freeze drying Methods 0.000 claims description 3
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- 201000010099 disease Diseases 0.000 claims 1
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- 239000008194 pharmaceutical composition Substances 0.000 abstract description 2
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- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 21
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 21
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 20
- 239000007963 capsule composition Substances 0.000 description 20
- GUBGYTABKSRVRQ-UHFFFAOYSA-N 2-(hydroxymethyl)-6-[4,5,6-trihydroxy-2-(hydroxymethyl)oxan-3-yl]oxyoxane-3,4,5-triol Chemical compound OCC1OC(OC2C(O)C(O)C(O)OC2CO)C(O)C(O)C1O GUBGYTABKSRVRQ-UHFFFAOYSA-N 0.000 description 18
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical class [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 17
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 17
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- 229960000711 alprostadil Drugs 0.000 description 12
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- 229960002986 dinoprostone Drugs 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- XEYBRNLFEZDVAW-ARSRFYASSA-N dinoprostone Chemical class CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1C\C=C/CCCC(O)=O XEYBRNLFEZDVAW-ARSRFYASSA-N 0.000 description 6
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 6
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- 230000000694 effects Effects 0.000 description 5
- -1 for example Chemical class 0.000 description 5
- 229940069328 povidone Drugs 0.000 description 5
- GMVPRGQOIOIIMI-UHFFFAOYSA-N (8R,11R,12R,13E,15S)-11,15-Dihydroxy-9-oxo-13-prostenoic acid Natural products CCCCCC(O)C=CC1C(O)CC(=O)C1CCCCCCC(O)=O GMVPRGQOIOIIMI-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 229930195725 Mannitol Natural products 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 4
- 239000006071 cream Substances 0.000 description 4
- 239000000594 mannitol Substances 0.000 description 4
- 235000010355 mannitol Nutrition 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- GMVPRGQOIOIIMI-DWKJAMRDSA-N prostaglandin E1 Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(O)=O GMVPRGQOIOIIMI-DWKJAMRDSA-N 0.000 description 4
- XEYBRNLFEZDVAW-UHFFFAOYSA-N prostaglandin E2 Natural products CCCCCC(O)C=CC1C(O)CC(=O)C1CC=CCCCC(O)=O XEYBRNLFEZDVAW-UHFFFAOYSA-N 0.000 description 4
- 239000008107 starch Substances 0.000 description 4
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- 150000004676 glycans Chemical class 0.000 description 3
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- 229920001282 polysaccharide Polymers 0.000 description 3
- 239000005017 polysaccharide Substances 0.000 description 3
- QAOBBBBDJSWHMU-WMBBNPMCSA-N 16,16-dimethylprostaglandin E2 Chemical compound CCCCC(C)(C)[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1C\C=C/CCCC(O)=O QAOBBBBDJSWHMU-WMBBNPMCSA-N 0.000 description 2
- 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 2
- 241001465754 Metazoa Species 0.000 description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 2
- 235000021355 Stearic acid Nutrition 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- YZXBAPSDXZZRGB-DOFZRALJSA-N arachidonic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 description 2
- 239000012876 carrier material Substances 0.000 description 2
- 235000012343 cottonseed oil Nutrition 0.000 description 2
- 239000002385 cottonseed oil Substances 0.000 description 2
- 229940041984 dextran 1 Drugs 0.000 description 2
- 239000003925 fat Substances 0.000 description 2
- 235000019197 fats Nutrition 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- 150000002430 hydrocarbons Chemical class 0.000 description 2
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 2
- 230000001939 inductive effect Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000008108 microcrystalline cellulose Substances 0.000 description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- 239000008117 stearic acid Substances 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 239000001993 wax Substances 0.000 description 2
- 239000003871 white petrolatum Substances 0.000 description 2
- KEJJEEMSWMJCHB-BDKFZLQASA-N (z)-7-[(1r,2r,3r)-3-hydroxy-2-[(e,3s,4s)-3-hydroxy-8-methoxy-4-methyloct-1-enyl]-5-oxocyclopentyl]hept-5-enoic acid Chemical compound COCCCC[C@H](C)[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1C\C=C/CCCC(O)=O KEJJEEMSWMJCHB-BDKFZLQASA-N 0.000 description 1
- LEACJMVNYZDSKR-UHFFFAOYSA-N 2-octyldodecan-1-ol Chemical compound CCCCCCCCCCC(CO)CCCCCCCC LEACJMVNYZDSKR-UHFFFAOYSA-N 0.000 description 1
- 229920000623 Cellulose acetate phthalate Polymers 0.000 description 1
- 241000283153 Cetacea Species 0.000 description 1
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- 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 description 1
- 229920000881 Modified starch Polymers 0.000 description 1
- 229920001214 Polysorbate 60 Polymers 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- HVUMOYIDDBPOLL-XWVZOOPGSA-N Sorbitan monostearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O HVUMOYIDDBPOLL-XWVZOOPGSA-N 0.000 description 1
- FPTFFTMXBKQFKC-JZKKULJYSA-N Tetranor-PGE1 Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1CCC(O)=O FPTFFTMXBKQFKC-JZKKULJYSA-N 0.000 description 1
- 150000001252 acrylic acid derivatives Chemical class 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 229940114079 arachidonic acid Drugs 0.000 description 1
- 235000021342 arachidonic acid Nutrition 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical group 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 229940081734 cellulose acetate phthalate Drugs 0.000 description 1
- 229940082500 cetostearyl alcohol Drugs 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
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- 238000006731 degradation reaction Methods 0.000 description 1
- 238000007598 dipping method Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000013583 drug formulation Substances 0.000 description 1
- 230000002183 duodenal effect Effects 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 239000011888 foil Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 125000002791 glucosyl group Chemical group C1([C@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO)* 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 description 1
- 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 description 1
- 239000004922 lacquer Substances 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000005445 natural material Substances 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920006254 polymer film Polymers 0.000 description 1
- QLPYHQHJKMTHED-UHFFFAOYSA-N prostaglandin E1 methyl ester Natural products CCCCCC(O)C=CC1C(O)CC(=O)C1CCCCCCC(=O)OC QLPYHQHJKMTHED-UHFFFAOYSA-N 0.000 description 1
- WGCXTGBZBFBQPP-UHFFFAOYSA-N prostaglandin E2 methyl ester Natural products CCCCCC(O)C=CC1C(O)CC(=O)C1CC=CCCCC(=O)OC WGCXTGBZBFBQPP-UHFFFAOYSA-N 0.000 description 1
- 239000008299 semisolid dosage form Substances 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000001587 sorbitan monostearate Substances 0.000 description 1
- 235000011076 sorbitan monostearate Nutrition 0.000 description 1
- 229940035048 sorbitan monostearate Drugs 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- OULAJFUGPPVRBK-UHFFFAOYSA-N tetratriacontyl alcohol Natural products CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO OULAJFUGPPVRBK-UHFFFAOYSA-N 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000009827 uniform distribution Methods 0.000 description 1
- 239000002966 varnish Substances 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- 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
- A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
-
- 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
- A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/56—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/58—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin
-
- 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
- A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/56—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/61—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule the organic macromolecular compound being a polysaccharide or a derivative thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
Adsorbate von ProstaglandinenAdsorbates of prostaglandins
Die vorliegende Erfindung betrifft Adsorbate von Prostaglandinen mit Dextranen ein Verfahren zur Herstellung dieser Adsorbate, ihre Verwendung in oder als Arzneimittel und Arzneimittel bzw. pharmazeutische Formulierungen enthaltend Adsorbate von Prostaglandinen an Dextranen.The present invention relates to adsorbates of prostaglandins with Dextrans a process for the production of these adsorbates, their use in or containing as medicaments and medicaments or pharmaceutical formulations Adsorbates of prostaglandins on dextrans.
Prostaglandine sind Naturstoffe, die über den Weg des Arachidonsäure-Stoffwechsels gebildet werden und sehr intensive und spezifische Wirkungen haben. Als natürliche Prostaglandine sind z.B. bekannt Prostaglandine der Typen: Die einzelnen natürlichen Verbindungen und deren synthetische Analoga unterscheiden sich durch unterschiedliche Substitutionen in den beiden Seitenketten an C-8 und C-12 des jeweiligen Fünfringes, z.B. durch OH-Gruppen, Doppelbindungen, aliphatische Substituenten, Carbonsäurereste und deren Ester.Prostaglandins are natural substances that are formed by the arachidonic acid metabolism and have very intense and specific effects. As natural prostaglandins, for example, prostaglandins of the types are known: The individual natural compounds and their synthetic analogues differ in the different substitutions in the two side chains at C-8 and C-12 of the respective five-membered ring, for example OH groups, double bonds, aliphatic substituents, carboxylic acid residues and their esters.
Wegen ihrer intensiven und spezifischen biologischen und pharmakologischen Aktivitäten erlangen die Prostaglandine zunehmendes Interesse. Diejenigen des E-Typs im weiteren PGE genannt - sind sehr gut zur Behandlung von Hypertension, Asthma bronchiale, Magen-Darm-Ulcera und Thrombosen sowie zur Einleitung von Wehen und Aborten bei Säugern, also Menschen und Tieren, geeignet.Because of their intense and specific biological and pharmacological The prostaglandins gain increasing interest in activities. Those of the E-type hereinafter referred to as PGE - are very good for treating hypertension and asthma bronchial, gastrointestinal ulcers and thromboses as well as for inducing labor and Abortions in mammals, i.e. humans and animals, are suitable.
Es ist jedoch bekannt, daß Prostaglandine, insbesondere Prostaglandin E-Derivate, relativ instabil sind. Diese Instabilität hat sich bisher als Hindernis für eine breite pharmazeutische Anwendung der PGE-Verbindungen erwiesen. Die Zersetzung der E-Derivate verläuft pH-abhängig unter Eliminierung von Wasser zu den entsprechenden PGA- bzw. PGB-Derivaten: Es hat daher nicht an Versuchen gefehlt, diese labilen Prostaglandin-Derivate zu stabilisieren.However, it is known that prostaglandins, especially prostaglandin E derivatives, are relatively unstable. This instability has heretofore proven to be an obstacle to widespread pharmaceutical application of the PGE compounds. The decomposition of the E-derivatives takes place depending on the pH with elimination of water to the corresponding PGA or PGB derivatives: There has therefore been no lack of attempts to stabilize these unstable prostaglandin derivatives.
Aus Eur. J. Phamacol. 4, 1968, S. 416-420 ist es bekannt, daß Lösungen von Prostaglandinen in Methanol in Abhängigkeit vom pH-Wert im Falle von PGE1 und PGE2 bis zu 40 Tagen bei Raumtemperatur stabil sind. Eine medizinische Verwendung ist jedoch schon wegen der Toxizität des Methanols ausgeschlossen.From Eur. J. Phamacol. 4, 1968, pp. 416-420 it is known that solutions of prostaglandins in methanol as a function of the pH in the case of PGE1 and PGE2 are stable for up to 40 days at room temperature. A medical use however, because of the toxicity of the methanol, this is excluded.
Nach einer Mitteilung in Lipids 8, 10, 1973, S. 592-594 verliert PGE2 in Ethanol bei einer Aufbewahrungstemperatur von 40C in einem Monat 5-12 % der Aktivität und zersetzt sich in Kochsalzlösung so rasch, daß nach 15 Tagen nur noch 58-62 % der ursprünglichen Aktivität vorhanden sind.According to a communication in Lipids 8, 10, 1973, pp. 592-594, PGE2 loses in ethanol at a storage temperature of 40C in one month 5-12% of the activity and decomposes so quickly in saline that after 15 days only 58-62% the original activity are present.
Uberraschenderweise wurde nun gefunden, daß durch Adsorption an Dextranen die Stabilität von Prostaglandinen wesentlich verbessert werden kann, so daß z.B. der breite Einsatz als Arzneimittel möglich ist.Surprisingly, it has now been found that by adsorption on dextrans the stability of prostaglandins can be significantly improved so that e.g. broad use as a medicinal product is possible.
Wenn weiterhin von Prostaglandinen die Rede ist, werden im Sinne der vorliegenden Erfindung nicht nur die natürlichen Prostaglandine, sondern insbesondere auch deren Derivate und Analoga verstanden. Unter den Derivaten und Analoga werden bevorzugt solche verstanden, die sich strukturell durch die Art, Anzahl und Position der funktionellen Gruppen und Substituenten und in ihrer Wirksamkeit insbesondere hinsichtlich der Selektivität, Spezifität und Stärke für einzelne medizinische Indikationen und Wirkorte von den natürlichen Prostaglandinen unterscheiden.If prostaglandins continue to be mentioned, in the sense of present invention not only the natural prostaglandins, but in particular also understood their derivatives and analogues. Among the derivatives and analogues are preferably those understood structurally by the type, number and position of the functional groups and substituents and in particular in their effectiveness in terms of selectivity, specificity and strength for individual medical indications and Differentiate sites of action from natural prostaglandins.
Gegenstand der vorliegenden Erfindung sind daher Adsorbate von Prostaglandinen an Dextrane.The present invention therefore relates to prostaglandin adsorbates of dextrans.
Ein weiterer Gegenstand der vorliegenden Erfindung ist ein Verfahren zur Herstellung stabiler Prostaglandin-Formulierungen, bei dem das Prostaglandin in gelöster Form auf Dextrane aufgebracht und anschließend getrocknet wird.Another object of the present invention is a method for the production of stable prostaglandin formulations in which the prostaglandin is applied in dissolved form to dextrans and then dried.
Ferner betrifft die vorliegende Erfindung Arzneimittel enthaltend an Dextrane Stärke adsorbierte Prostaglandine sowie die Verwendung von an Dextrane adsorbierter Prostaglandine bzw. deren Derivate in oder als Arzneimittel und zur Bekämpfung von Krankheiten, insbesondere zur Bekämpfung von Magen-Darm-Ulura, Hypertension, Asthmabronchiale, Thrombosen sowie zur Einleitung von Wehen und/oder Aborten bei Säugern.The present invention further relates to containing medicaments Prostaglandins adsorbed on dextrans starch and the use of dextrans adsorbed prostaglandins or their derivatives in or as drugs and for Combat diseases, in particular to combat gastrointestinal ulcers, hypertension, Asthma bronchial, thrombosis and induction of labor and / or abortion Mammals.
Unter Dextranen im Sinne der vorliegenden Erfindung werden aus Glukoseresten in 1,4- und 1,6-Bindung aufgebaute, kettenförmige, verzweigte Polysaccharide verstanden. Bevorzugt werden unter Dextranen solche Polysaccharide verstanden, die im wesentlichen aus durch 1,6-glukosidische Bindungen charakterisierte Anhydro-D-glucopyranose-Einheiten bestehen, die bei vollständiger Hydrolyse-D-Glucose liefern; bevorzugt weisen diese Polysaccharide ein Molekulargewicht zwischen da. 1000 bis ca. 20.000.000 auf, besonders bevorzugt zwischen ca. 10.000 bis ca. 1.000.000.For the purposes of the present invention, dextrans are derived from glucose residues Understood chain-like, branched polysaccharides built up in 1,4- and 1,6-bond. Dextrans are preferably understood to mean those polysaccharides which essentially composed of anhydro-D-glucopyranose units characterized by 1,6-glucosidic bonds exist which, when fully hydrolyzed, yield D-glucose; preferably show these Polysaccharides have a molecular weight between there. 1000 to about 20,000,000, especially preferably between about 10,000 to about 1,000,000.
Besonders bevorzugt werden Prstaglandine des E-Typs, insbesondere am C 16-Atom substituierte Prostaglandine im Sinne der vorliegenden Erfindung verstanden.E-type prstaglandins are particularly preferred, in particular Prostaglandins substituted on the C 16 atom are understood for the purposes of the present invention.
16-Methyl-1-11 , 16 RS-Trihydroxyprost- 13 E-en-9on der nachstehenden Formel I wird als ganz besonders bevorzugtes Prostaglandin im Sinne der vorliegenden Erfindung verstanden.16-methyl-1-11, 16 RS-trihydroxyprost-13 E-en-9one of formula I below is understood as a very particularly preferred prostaglandin in the context of the present invention.
Da die Prostaglandine pharmazeutisch extrem stark wirkende Substanzen darstellen und die Dosierungen unterhalb des Milligramm-Bereiches liegen können, ist das erfindungsgemäße Verfahren besonders gut geeignet, die Wirkstoffe in einfacher Weise auf große Mengen Trägerstoff aufzuziehen.Because the prostaglandins are pharmaceutically extremely powerful substances and the dosages can be below the milligram range, the method according to the invention is particularly well suited to simplifying the active ingredients Ways to be drawn up on large quantities of carrier material.
Bei sehr niedrigen Dosierungen ist eine große Menge Trägerstoff sogar wegen der einheitlichen Verteilung des Wirkstoffs pro Dosiseinheit (content uniformity) wünschenswert.At very low dosages, a large amount of vehicle is actually present because of the uniform distribution of the active ingredient per dose unit (content uniformity) desirable.
Bei den fertigen, nach der Trocknung erhaltenen Absorbaten von Prostaglandinen an Dextrane soll das Gewichtsverhältnis von Prostaglandinen, bevorzugt Prostaglandin E-Derivaten, zu Dextrane zwischen 1:1 bis 1:10 000 liegen, bevorzugt zwischen 1:10 und 1:1000 und ganz besonders bevorzugt zwischen 1:100 bis 1:500.In the finished absorbates of prostaglandins obtained after drying of dextrans should be the weight ratio of prostaglandins, preferably prostaglandins E derivatives for dextrans are between 1: 1 to 1:10 000, preferably between 1:10 and 1: 1000 and very particularly preferably between 1: 100 to 1: 500.
Bei dem erfindungsgemäßen Verfahren werden stabile Prostaglandin-Formulierungen erzielt, bei denen auch die vorstehend angegebenen Gewichtsverhältnisse bevorzugt sind. Bei dem erfindungsgemäßen Verfahren wird das entsprechende Prostaglandin mit der Dextran innig vermischt und von dieser gebunden.The method according to the invention produces stable prostaglandin formulations scored, where too the weight ratios given above are preferred. In the method according to the invention, the corresponding prostaglandin is used intimately mixed with the dextran and bound by this.
Dies kann z.B. dadurch geschehen, daß das Prostaglandin, vorzugsweise Prostaglandin E-Derivat, in einem organischen oder wäßrigen Lösungsmittel gelöst und Dextran gleichfalls in dieser Lösung entsprechend der oben angegebenen Gewichtsverhältnisse suspendiert wird.This can be done, for example, by removing the prostaglandin, preferably Prostaglandin E derivative, dissolved in an organic or aqueous solvent and dextran also in this solution in accordance with the weight ratios given above is suspended.
Aus dieser Suspension wird das Adsorbat durch schonendes Trocknen erhalten. Als erfindungsgemäße Trocknung kann z.B. eine Gefriertrocknung, Vakuumtrocknung, Vakuumwalzentrocknung, Wirbelschichttrocknung oder Sprühtrocknung durchgeführt werden. Diese Aufzählung ist jedoch nicht abschließend, sondern es können auch andere schonende Trocknungsverfahren angewendet werden.The adsorbate is made from this suspension by gentle drying obtain. As drying according to the invention, e.g. freeze drying, vacuum drying, Vacuum roller drying, fluidized bed drying or spray drying can be carried out. However, this list is not exhaustive; other gentle ones can also be used Drying methods are applied.
Eine andere Verfahrensvariante besteht darin, die gelösten Prostaglandine die das Dextran direkt auf zu tragen. Dies kann z.B. durch Aufsprühen der Wirkstofflösung auf das Trägermaterial durch Tauchen, Berieseln oder Wirbelschichtauftragung geschehen. Die Trocknung kann dann wieder nach einer der vorstehend erwähnten Methoden erfolgen.Another variant of the process consists in the dissolved prostaglandins which apply the dextran directly. This can be done, for example, by spraying the active ingredient solution done on the carrier material by dipping, sprinkling or fluidized bed application. The drying can then take place again by one of the methods mentioned above.
Das Verfahren mit anschließender Trocknung wird so durchgeführt, daß die erhaltenen Adsorbate einen bestimmten Restwassergehalt besitzen. Erfindungsgemäß und nach dem erfindungsgemäßen Verfahren hergestellte Adsorbate sollen einen Restwassergehalt, bezogen auf das Gesamtgewicht, zwischen 0,1 bis 15 Gew.-%, vorzugsweise zwischen 0,5 und 10 Gew.-% und ganz besonders bevorzugt zwischen 1 und 5 Gew.-% aufweisen. Es ist erfindungsgemäß nicht erwünscht, einen Restwassergehalt unter 0,1 Gew.-% zu erreichen. Die Restwassergehalte beziehen sich auf fertige Adsorbate, die nach der Bestimmungsmethode von Karl Fischer (Europäisches Arzneibuch, Bd.I, 1974, S. 107) analysiert werden.The process with subsequent drying is carried out so that the adsorbates obtained have a certain residual water content. According to the invention and adsorbates produced by the process according to the invention should have a residual water content, based on the total weight, between 0.1 to 15% by weight, preferably between 0.5 and 10% by weight and very particularly preferably between 1 and 5% by weight exhibit. According to the invention, it is not desirable to have a residual water content below To achieve 0.1 wt .-%. The residual water contents refer to finished adsorbates, according to the determination method of Karl Fischer (European Pharmacopoeia, Vol. I, 1974, p. 107).
Erfindungsgemäß weisen die Adsorbate nach ihrer Trocknung einen Prostaglandingehalt von 0,01-50 Gew.-%, vorzugsweise von 0,1-10 Gew.-%, besonders bevorzugt von 0,2-1 Gew.-% auf.According to the invention, the adsorbates have a prostaglandin content after they have been dried from 0.01-50% by weight, preferably from 0.1-10% by weight, particularly preferably from 0.2-1 % By weight.
Uberraschenderweise ist bei den erfindungsgemäßen Adsorbaten die Abbaugeschwindigkeit der Prostaglandine so weit reduziert, daß diese bei einer Lagertemperatur von etwa 300C über einen Zeitraum von mehr als einem Jahr deutlich weniger als 10 % Gehaltsabfall aufweisen.Surprisingly, the rate of degradation in the adsorbates according to the invention is the prostaglandins are reduced to such an extent that they are stored at a storage temperature of about 300C significantly less than 10% drop in salary over a period of more than a year exhibit.
Aufgrund der vorliegenden Untersuchungsergebnisse von Prostaglandinen der E-Reihe sind die erfindungsgemäßen Adsorbate über mehr als 2 Jahre stabil und weisen einen Gehaltsabfall an Wirkstoff unter 8 % auf.Based on the available test results of prostaglandins of the E series, the adsorbates according to the invention are stable for more than 2 years and show a drop in active substance content of less than 8%.
Die Adsorbate können alleine oder unter Zusatz von geeigneten Hilfsstoffen zu festen oder halbfesten und auch zu injizierbaren Arzneiformen wie auch zu Sprays oder Inhalaten verarbeitet werden. Als Hilfsstoffe kommen z.B.The adsorbates can be used alone or with the addition of suitable auxiliaries to solid or semi-solid and also to injectable dosage forms as well as sprays or inhalants are processed. As auxiliary materials, e.g.
Stärke, Cellulose, Zucker, Mannit, Polyvinylpyrrolidon, (PVP), Crosspovidone (quervernetztes PVP), Talkum, Stearinsäure und deren Salze, langkettige Aliphaten, wie z.B.Starch, cellulose, sugar, mannitol, polyvinylpyrrolidone, (PVP), crosspovidone (cross-linked PVP), talc, stearic acid and its salts, long-chain aliphatics, such as.
hydriertes Ricinus- oder Baumwollsaatöl, Wachse, Fette und flüssige, halbfeste und feste Kohlenwasserstoffe sowie Polyethylenglykole, Emulgatoren und andere pharmazeutische Hilfsstoffe, in Frage.hydrogenated castor or cottonseed oil, waxes, fats and liquid, semi-solid and solid hydrocarbons as well as polyethylene glycols, Emulsifiers and other pharmaceutical excipients.
Die Herstellung fester Arzneiformen wie Tabletten, Kapseln und Pulver, kann mittels einer Direkttablettierung bzw. Direktabfüllung der reinen Adsqrbate oder auch unter Zusatz weiterer Hilfsstoffe wie auch über die Zwischenstufe eines Granulations- und/oder Mischvorganges erfolgen. Als Hilfsstoffe zur Herstellung von Tabletten, Kapseln oder Pulver werden bevorzugt Stärke, Cellulose, Zucker, Mannit, Polyvinylpyrrolidon, Talkum, Stearinsäure und deren Salze wie auch langkettige Aliphaten, besonders bevorzugt getrocknete Stärke, mikrokristalline Cellulose oder Cellulosepulver und hydriertes Ricinus- oder Baumwollsaatöl eingesetzt.The manufacture of solid dosage forms such as tablets, capsules and powders, can by means of a direct tabletting or direct filling of the pure Adsqrbate or with the addition of further auxiliaries as well as via the intermediate stage Granulation and / or mixing process take place. As auxiliary materials for production of tablets, capsules or powder are preferred starch, cellulose, sugar, mannitol, Polyvinylpyrrolidone, talc, stearic acid and its salts as well as long-chain aliphatics, particularly preferably dried starch, microcrystalline cellulose or cellulose powder and hydrogenated castor or cottonseed oil are used.
Die Adsorbate lassen sich auch durch Dispergierung in Fetten, Wachsen, festen, halbfesten oder flüssigen Kohlenwasserstoffen, Polyethylenglykolen, Emulgatoren etc. zu Salben, Cremes, Gelen, Pasten, Suppositorien und anderen halbfesten Arzneiformen verarbeiten. Es ist ebenfalls möglich, Sprays, Inhalate, Tampons oder Pflaster auf der Basis dieser Adsorbate herzustellen.The adsorbates can also be dispersed in fats, waxes, solid, semi-solid or liquid hydrocarbons, polyethylene glycols, emulsifiers etc. for ointments, creams, gels, pastes, suppositories and other semi-solid dosage forms to process. It is also possible to use sprays, inhalants, tampons or plasters the basis of these adsorbates.
Derartige Präparate sind bei Raumtemperatur über Jahre stabil.Such preparations are stable for years at room temperature.
Die erfindungsgemäßen Arzneimittel enthalten an Dextrane adsorbierte Prostaglandine in Mengen von 0,001 bis 10 Gew.-%, vorzugsweise 0,01 bis 1 Gew.-%, besonders bevorzugt 0,03 bis 0,3 Gew.-%, gegebenenfalls neben den vorstehend aufgeführten Hilfsstoffen. Eine typische Arzneimittelformulierung weist folgende Zusammensetzung auf (Angaben in Gew.-%): Wirkstoff (Prostaglandin PGE): 0,01 - 1 Dextran 1 - 99,9 Wasser: 0,1 - 5 oder bei Verwendung von Hilfsstoffen: a. Tablette: bevorzugt besonders bevorzugt Wirkstoff 0,001-10 0,01- 3 0,03- 1 Dextran 1 -99 5 -90 10 -60 Cellulose 0 -50 1 -30 5 -20 Maisstärke 0 -50 1 -30 5 -20 hydriertes Ricinusöl 0 -5 0,1 -1 0,2 -0,5 Restwasser 0,5 -15 1 -10 2 -6 b. Kapsel bevorzugt besonders bevorzugt Wirkstoff 0,01-10 0,01- 3 0,03- 1 Dextran 1 -99 5 -90 10 -60 Restwasser 0,1 -15 0,5 -10 1 -5 Gelatine 10 -90 20 -80 30 -50 c. Pulver bevorzugt besonders bevorzugt Wirkstoff 0,001-10 0,01 - 3 0,03 - 1 Dextran 1 -99 5 -90 10 -60 mikrokristalline Cellulsoe 0 -50 1 -30 5 -20 vorverkleisterte Stärke 0 -50 1 -30 5 -20 Als vorzugsweise Formulierung werden Tabletten oder Kapseln im Sinne der vorliegenden Erfindung verwendet, die Prostaglandine und Dextran enthalten.The medicaments according to the invention contain adsorbed on dextrans Prostaglandins in amounts of 0.001 to 10% by weight, preferably 0.01 to 1% by weight, particularly preferably 0.03 to 0.3% by weight, optionally in addition to those listed above Auxiliary materials. A typical drug formulation has the following composition on (data in% by weight): Active ingredient (prostaglandin PGE): 0.01-1 dextran 1-99.9 Water: 0.1 - 5 or when using auxiliary materials: a. Tablet: preferred especially preferred active ingredient 0.001-10 0.01-3 0.03-1 dextran 1-99 5-90 10 -60 cellulose 0 -50 1 -30 5 -20 corn starch 0 -50 1 -30 5 -20 hydrogenated castor oil 0 -5 0.1 -1 0.2 -0.5 residual water 0.5 -15 1 -10 2 -6 b. Capsule preferably particularly preferably active ingredient 0.01-10 0.01- 3 0.03- 1 dextran 1 -99 5 -90 10 -60 residual water 0.1 -15 0.5 -10 1 -5 gelatin 10 -90 20 -80 30 -50 c. Powder is particularly preferred preferred active ingredient 0.001-10 0.01 - 3 0.03 - 1 dextran 1 -99 5 -90 10 -60 microcrystalline Cellulsoe 0 -50 1 -30 5 -20 pre-gelatinized starch 0 -50 1 -30 5 -20 As preferred In the formulation, tablets or capsules are used for the purposes of the present invention, which contain prostaglandins and dextran.
Bevorzugt hierbei werden Tabletten, die in den vorstehend genannten Zusammensetzungen verpreßt und bei Bedarf mit einer Hülle versehen werden. Vorzugsweise besteht die Kapselhülle aus Gelatine oder einem anderen, im Gastrointestinaltrakt löslichen Polymeren. Die Tabletten, wie auch die Kapseln, können zusätzlich mit einer weiteren Hülle oder auch einem Lack zur Verbesserung der Stabilität oder Handhabung oder auch zur Erzielung eines gewünschten Retardeffektes versehen werden. Damit die Anwendung des Mittels gezielt in Duodenal und Dünndarmbereich erfolgen kann, kann ein magensaftresistenter Lack aufgebracht werden. Als Filmbildner können Cellulose-Derivate (bevorzugt: Methyl-, Ethyl-, Hydroxypropyl-, Hydroxypropylmethyl-; Celluloseacetatphthalat oder Hydroxypropylmethylcellulosephthalat), polymere Acrylate oder deren Copolymerisate mit anderen Substanzen, zumeist unter Zusatz von Weichmachern, verwendet werden. Die Hüllen können bei Bedarf mit gefärbten oder farbgebenden Stoffen versehen sein. Auch weitere Hilfs- bzw. Geschmack- oder Wirkstoffe können sowohl in den Hüllen als auch in der Tablette bzw. Kapsel als auch in beiden vorhanden sein.Preference is given here to tablets in the above-mentioned Compositions are compressed and provided with a cover if necessary. Preferably If the capsule shell is made of gelatin or another, in the gastrointestinal tract soluble polymers. The tablets, like the capsules, can also be used with another cover or a lacquer to improve stability or handling or to achieve a desired retard effect. In order to the application of the agent can be targeted in the duodenal and small intestine area, an enteric varnish can be applied. Cellulose derivatives can be used as film formers (preferred: methyl, ethyl, hydroxypropyl, hydroxypropylmethyl; cellulose acetate phthalate or hydroxypropylmethyl cellulose phthalate), polymeric acrylates or their copolymers can be used with other substances, usually with the addition of plasticizers. the If necessary, covers can be made with colored or coloring substances be provided. Other auxiliaries or flavorings or active ingredients can also be used present in the shells as well as in the tablet or capsule as well as in both be.
Auch bei den Tabletten- bzw. Kapselformulierungen sind die vorstehend angegebenen Bereiche über Wirkstoff/Dextran-Verhältnis,' Wassergehalt, Wirkstoffgehalt bevorzugte Bereiche, auch in jeder beliebigen Kombination der angegebenen Bereiche miteinander.The above are also given for the tablet or capsule formulations specified areas about active ingredient / dextran ratio, water content, active ingredient content preferred ranges, also in any combination of the specified ranges together.
Erfindungsgemäß ist es auch möglich, mehrere Wirkstoffe von Prostaglandinen in dem gewünschten Verhältnis miteinander zu vermischen und der gewünschten Formulierung zuzuführen, wobei dann die Gew.-% sich auf den gesamten Wirkstoffgehalt beziehen und sich nicht additiv zusammenzusetzen.According to the invention it is also possible to use several active substances from prostaglandins to mix with each other in the desired ratio and the desired formulation to be added, the% by weight then being based on the total active ingredient content and not to put together additively.
Erfindungsgemäß besonders bevorzugt auch für die Tabletten-bzw. Kapselformulierung werden Prostaglandine der E-Reihe und hier besonders bevorzugt das bereits vorstehend beschriebene 16-Methyl-1-11 4 , 16 RS-Trihydroxyprost-13E-en-9on der Formel (I).According to the invention particularly preferably also for the tablet or. Capsule formulation E-series prostaglandins are particularly preferred here, and the above is particularly preferred 16-methyl-1-11 4, 16 RS-trihydroxyprost-13E-en-9one of the formula (I) described.
Ferner gelten als bevorzugt im Sinne der vorliegenden Erfindung folgende Prostaglandine: II 1 5-Deoxy- 1 6-hydroxy-1 7-cyclobutano-PGE1-methylester III PGE1 IV (17S)-17.20-Dimethyl-trans- A ²PGE1 V 198-Hydroxy-PGE1 VI (#)(16RS)-15-Deoxy-16-hydroxy-16-methyl-PGE1-methylester VII 16,16-Dimethyl-trans-#²-PGE1-methylester VIII 2-Decarboxy-2-hydroxy-methyl-PGE1 IX (+)-11 α, 16 α,ß-Dihydroxy-1,9-dioxo-1-(hydroxymethyl)-16-methyl-13-transprosiene X 4,5,6-Trinor-3,7-inter-m-phenylen-3-oxa-PGE1 XI PGE2 XII (15R)-15-Methyl-PGE2 XIII 16,16-Dimethyl-PGE2 XIV 1 6-Methyl-20-methoxy-PGE2 XV (#)(16RS)-15-Deoxy-16-hydroxy-16-methyl-PGE2-methylester XVI (+)-4,5-Didehydro-16-phenoxy-#-tetranor-PGE1 methylester XVII N-Methan-sulfonyl-10-phenoxy- # -tetranor-PGE-amid XVIII 9-Deoxo-9-methylen-1 6, 1 6-dimethyl-PGE2 Die erfindungsgemäßen an Dextrane gebundenen Prostaglandine, die nach dem erfindungsgemäßen Verfahren hergestellten Adsorbate, die Formulierungen und Tabletten und Kapseln werden als Arzneimittel eingesetzt. Bevorzugt werden die erfindungsgemäßen Adsorbate zur Bekämpfung von Magen-Darm-Ulcera, Hypertension Asthma bronchiale, Thrombosen sowie bei der Einleitung von Wehen oder Aborten bei Menschen und Tieren, insbesondere bei Säugern, eingesetzt. Bevorzugt ist die Verwendung bei der Bekämpfung von Magen-Darm-Ulcera und bevorzugt in Form von Tabletten, Kapseln sowie Suppositorien.The following prostaglandins are also considered to be preferred for the purposes of the present invention: II 1 5-Deoxy-1 6-hydroxy-1 7-cyclobutano-PGE1 methyl ester III PGE1 IV (17S) -17.20-dimethyl-trans- A²PGE1 V 198-Hydroxy-PGE1 VI (#) (16RS) -15-Deoxy-16-hydroxy-16-methyl-PGE1-methyl ester VII 16,16-dimethyl-trans- # ²-PGE1-methyl ester VIII 2-decarboxy-2-hydroxy-methyl-PGE1 IX (+) - 11α, 16α, β-Dihydroxy-1,9-dioxo-1- (hydroxymethyl) -16-methyl-13-transprosienes X 4,5,6-trinor-3,7-inter-m-phenylene-3-oxa-PGE1 XI PGE2 XII (15R) -15-methyl-PGE2 XIII 16,16-dimethyl-PGE2 XIV 1 6-methyl-20-methoxy-PGE2 XV (#) (16RS) -15-deoxy-16-hydroxy-16-methyl-PGE2-methyl ester XVI (+) - 4,5-didehydro-16-phenoxy - # - tetranor-PGE1 methyl ester XVII N-methanesulfonyl-10-phenoxy- # -tetranor-PGE-amide XVIII 9-Deoxo-9-methylene-16,16-dimethyl-PGE2 The prostaglandins according to the invention bound to dextrans, the adsorbates produced by the process according to the invention, the formulations and tablets and capsules are used as medicaments. The adsorbates according to the invention are preferably used for combating gastrointestinal ulcers, hypertension, bronchial asthma, thromboses and for inducing labor or abortions in humans and animals, in particular in mammals. Preference is given to use in combating gastrointestinal ulcers and preferably in the form of tablets, capsules and suppositories.
Die folgenden Beispiele sollen die vorliegende Erfindung noch weiter verdeutlichen: Beispiel 1 5,0 g Wirkstoff der Formel I werden in 150 ml Ethanol und 450 ml Wasser gelöst.The following examples are intended to further the present invention Make clear: Example 1 5.0 g of active ingredient of the formula I are in 150 ml of ethanol and 450 ml of water dissolved.
995,0 g Dextran werden in 5 1 Wasser suspendiert und mit der obigen Lösung intensiv verrührt, in Schalen gegossen und mittels Gefriertrocknung getrocknet. Das Lyophilisat wird durch ein Sieb von 0,5 mm Maschenweite-gesiebt und wie folgt weiterverarbeitet: A) Tabletten zu 0,5 mg Wirkstoff Formel I 200 g Lyophilisat 300 g Cross-Povidone 200 g Cellulose Pulver 95 g getrocknete Maisstärke 5 g hydriertes Ricinusöl werden gemischt und zu Tabletten von 80,0 mg Gewicht verpreßt.995.0 g of dextran are suspended in 5 l of water and with the above The solution is stirred intensively, poured into bowls and dried by freeze drying. The lyophilizate is sieved through a sieve of 0.5 mm mesh size and as follows further processed: A) tablets of 0.5 mg active ingredient formula I 200 g lyophilisate 300 g Cross-Povidone 200 g cellulose powder 95 g dried corn starch 5 g hydrogenated Castor oil are mixed and compressed into tablets weighing 80.0 mg.
B) Kapseln zu 0,1 mg Wirkstoff Formel I 200 g Lyophilisat 300 g Cross-Povidone werden gemischt und diese Mischung zu 50,0 mg in Hartgelatine-Kapseln der Größe 4 abgefüllt.B) Capsules of 0.1 mg active ingredient Formula I 200 g lyophilisate 300 g Cross-Povidone will mixed and this mixture filled to 50.0 mg in hard gelatine capsules of size 4.
C) Pulver zu 0,3 mg Wirkstoff Formel I 5000 g Maisstärke 3700 g mikrokristalline Cellulose 300 g vorverkleisterte Mais stärke werden gemischt und mit Wasser granuliert. Das Granulat wird getrocknet und durch ein Sieb mit 0,8 mm Maschenweite gesiebt.C) Powder containing 0.3 mg of active ingredient Formula I 5000 g of corn starch 3700 g of microcrystalline Cellulose 300 g pregelatinized corn starch are mixed and granulated with water. The granules are dried and sieved through a sieve with a mesh size of 0.8 mm.
600 g Lyophilisat 400 g Cross-Povidone 9000 g des obigen Granulates werden gemischt und zu 1,0 g in Beutel abgefüllt und diese verschlossen. Die Beutel können aus Papier, Aluminium-Folie oder einer indifferenten, für pharmazeutische Zwecke gegeigneten Polymer-Folie bestehen. Die Beutel können je nach Material, verklebt, verschweißt oder auf jede andere Methode, gegebenenfalls unter Luftauschluß und gegebenenfalls Inertbegasung verschlossen werden. Bei der Durchführung der Beispiele wurden Papierbeute, die verklebt wurden, verwendet. 600 g lyophilisate 400 g Cross-Povidone 9000 g of the above granules are mixed and filled to 1.0 g in bags and these are sealed. The bags can be made of paper, aluminum foil or an indifferent, for pharmaceutical Purposes of suitable polymer film exist. Depending on the material, the bags can be glued, welded or by any other method, possibly with the exclusion of air and if necessary, inert gassing can be closed. When performing the examples paper swabs that were glued were used.
D) Creme 100 g enthaltend 15 mg Wirkstoff Formel I Ein bl und eine Emulgatorphase bestehend aus: 2-Octyl-dodecanol 120 g Cetylstearylalkohol 100 g Walrat künstlich 20 g Sorbitanmonostearat 15 g Polyoxyethylen(20)-sorbitanmonostearat 10 g werden auf 60"C erwärmt und geschmolzen. Dann werden 705 g Wasser zugegeben und bis zur Bildung einer homogenen Creme intensiv gewährt.D) Cream 100 g containing 15 mg of active ingredient formula I one bl and one Emulsifier phase consisting of: 2-octyl-dodecanol 120 g of cetostearyl alcohol 100 g whale rat artificial 20 g sorbitan monostearate 15 g polyoxyethylene (20) sorbitan monostearate 10 g are heated to 60 ° C. and melted. 705 g water are then added and intensively granted until a homogeneous cream is formed.
Nach dem Abkühlen werden 30 g Lyophilisat zugegeben und intensiv verrührt. After cooling, 30 g of lyophilizate are added and intensively stirred.
Die fertige Creme wird zu 100 g in Tuben abgefüllt. The finished cream is filled into 100 g tubes.
E) Salbe 100 g enthaltend 15 mg Wirkstoff Formel I 30 g Lyophilisat werden mit 150 g weißer Vaseline verrieben, bis eine homogene Masse entstanden ist.E) Ointment 100 g containing 15 mg of active ingredient formula I 30 g of lyophilizate are rubbed with 150 g of white Vaseline until a homogeneous mass is formed.
Diese wird dann mit 820 g weißer Vaseline intensiv zu einer Salbe verrührt und z.B. zu 100 g in Tuben abgefüllt. This is then intensively turned into an ointment with 820 g of white petroleum jelly stirred and filled into tubes, e.g. 100 g.
F) Suppositorien zu 0,5 mg Wirkstoff Formel I 950 g Adeps.solidus als Suppositorienmasse werden auf ca. 42"C erwärmt, 50 g Lyophilisat darin homogen suspendiert und in Suppositorienformen zu 2 g gegossen. Beim Abkühlen erstarrt die Masse zu den fertigen Suppositorien.F) Suppositories of 0.5 mg active ingredient Formula I 950 g Adeps.solidus as a suppository mass are heated to approx. 42 ° C., 50 g of lyophilizate therein are homogeneous suspended and poured into suppository molds of 2 g. When it cools down, it solidifies Mass to the finished suppositories.
In der folgenden Tabelle 1 werden Tablettenformulierungen für Wirkstoff der Formel I, 16-Methyl-1-11 α , 16 RS-trihydroxyprost-13E-en-9-on als Adsorbat an Crosspovidone, mit diversen Hilfsstoffen in den erfindungsgemäß bevor zu ten Bereichen angegeben. Sämtliche Gewichtsangaben sind in mg.In the following table 1 are tablet formulations for active ingredient of formula I, 16-methyl-1-11 α, 16 RS-trihydroxyprost-13E-en-9-one as adsorbate to crosspovidone, with various auxiliaries in the inventions before to th Areas specified. All weights are in mg.
Tabelle 1 Beispiele für Tablettenformulierungen Nr. Formel 1 Dextran Cellulose- mikrokristall. Maisstärke Mannit Cross- hydriertes Magnesium-Pulver Cellulose povidone Ricinusöl stearat 1 0,01 1,0 50 - 28,79 - - 0,2 -2 0,01 2,0 - 50 27,79 - - - 0,2 3 0,01 5,0 - 50 19,79 - 5,0 - 0,2 4 0,01 2,0 60 - 27,69 30 - 0,3 -5 0,01 5,0 - 60 24,69 30 - - 0,3 6 0,03 3,0 50 - 26,77 - - 0,2 -7 0,03 6,0 50 - 18,77 - 5,0 0,2 -8 0,03 15,0 30 - 4,77 - 30,0 - 0,2 9 0,03 6,0 - 60 23,67 30 - - 0,3 10 0,03 15,0 - 60 24,67 - 30,0 - 0,3 11 0,05 5,0 50 - 19,75 - 5,0 0,2 -12 0,05 10,0 50 - 9,75 - 10,0 0,2 -13 0,05 25,0 - 20 24,65 - 50,0 - 0,3 14 0,05 10,0 50 - 29,65 20 10,0 0,3 -15 0,05 5,0 - 50 24,65 30 10,0 - 0,3 16 0,1 10,0 - 50 9,7 - 10,0 0,2 -17 0,1 20,0 40 - 19,6 40,0 - 0,3 18 0,1 50 60 - 39,5 - 150,0 - 0,4 19 0,1 10,0 60 - 39,6 - 10,0 0,3 -20 0,1 20,0 - 100 39,5 - 40,0 - 0,4 21 0,3 30,0 - 20 9,4 - 60,0 0,3 - Tabelle 1 Beispiele für Tablettenformulierungen Nr. Formel 1 Dextran Cellulose- mikrokristall. Maisstärke Mannit Cross- hydriertes Magnesium-Pulver Cellulose povidone Ricinusöl stearat 22 0,3 60,0 10 - 9,3 - 120 0,4 -23 0,3 150,0 - 100 48,7 - 300 - 1,0 24 0,3 30,0 100 - 9,3 - 60 0,4 -25 0,3 60,0 60 - 29,2 - 150 - 0,5 26 0,6 60,0 - 10 9,0 - 120 - 0,4 27 0,6 120,0 - 120 58,4 - 300 1,0 -28 0,6 60,0 60 - 28,9 - 150 0,3 -29 1,0 100,0 150 - 48,0 - 300 1,0 - In der folgenden Tabelle 2 werden Kapselformulierungen für Wirkstoff 16-Methyl-1,11 α-16RS-trihydroxyprost-13E-en-9on, Formel I, als Adsorbat an Crosspovidone gegebenenfalls unter Zusatz weiterer Hilfsstoffe, in mg angegeben.Table 1 Examples of tablet formulations No. Formula 1 Dextran Cellulose microcrystalline. Corn starch mannitol cross-hydrogenated magnesium powder cellulose povidone castor oil stearate 1 0.01 1.0 50 - 28.79 - - 0.2 -2 0.01 2.0 - 50 27.79 - - - 0.2 3 0.01 5.0 - 50 19.79 - 5.0 - 0.2 4 0.01 2.0 60 - 27.69 30 - 0.3 -5 0.01 5.0 - 60 24.69 30 - - 0.3 6 0.03 3.0 50 - 26.77 - - 0.2 -7 0.03 6.0 50 - 18.77 - 5.0 0.2 -8 0.03 15.0 30 - 4.77 - 30.0 - 0.2 9 0.03 6.0 - 60 23.67 30 - - 0.3 10 0.03 15.0 - 60 24.67 - 30.0 - 0.3 11 0.05 5.0 50 - 19.75 - 5.0 0.2 -12 0.05 10.0 50 - 9.75 - 10.0 0.2 -13 0.05 25.0 - 20 24.65 - 50.0 - 0.3 14 0.05 10.0 50 - 29.65 20 10.0 0.3 -15 0.05 5.0 - 50 24.65 30 10.0 - 0.3 16 0.1 10.0 - 50 9.7 - 10.0 0.2 -17 0.1 20.0 40 - 19.6 40.0 - 0.3 18 0.1 50 60 - 39.5 - 150.0 - 0.4 19 0.1 10.0 60 - 39.6 - 10.0 0.3 -20 0.1 20.0 - 100 39.5 - 40.0 - 0.4 21 0.3 30.0 - 20 9.4 - 60.0 0.3 - Table 1 Examples of tablet formulations No. Formula 1 dextran cellulose microcrystalline. Corn Starch Mannitol Cross-Hydrogenated Magnesium Powder Cellulose povidone castor oil stearate 22 0.3 60.0 10 - 9.3 - 120 0.4 -23 0.3 150.0 - 100 48.7 - 300 - 1.0 24 0.3 30.0 100 - 9.3 - 60 0.4 -25 0.3 60.0 60 - 29.2 - 150 - 0.5 26 0.6 60.0 - 10 9.0 - 120 - 0.4 27 0.6 120.0 - 120 58.4 - 300 1.0 -28 0.6 60.0 60 - 28.9 - 150 0.3 -29 1.0 100.0 150 - 48.0 - 300 1.0 - In Table 2 below lists capsule formulations for active ingredient 16-methyl-1,11 α-16RS-trihydroxyprost-13E-en-9on, formula I, as an adsorbate on crosspovidones optionally with the addition of further auxiliaries, given in mg.
Tabelle 2 Nr. Formel I Dextran Crosspovidon Cellulosepulver Maisstärke 1 0,01 1,0 20 10 8,99 2 0,01 2,0 20 10 7,99 3 0,01 5,0 20 10 4,99 4 0,01 2,0 20 - 17,99 5 0,01 5,0 20 - 14,99 6 0,03 3,0 20 10 6,97 7 0,03 6,0 20 10 3,97 8 0,03 15,0 20 - 4,97 9 0,03 6,0 20 - 13,97 10 0,03 15,0 30 20 4,97 11 0,05 5,0 20 10 4,95 12 0,05 10,0 20 - 9,95 13 0,05 25,0 45 14 0,05 10,0 30 20 9,95 15 0,05 25,0 50 20 4,95 16 0,1 10,0 20 - 9,9 17 0,1 20,0 40 - 9,9 18 0,1 50,0 100 19 0,1 10,0 . 30 20 9,9 20 0,1 20,0 60 10 9,9 21 0,3 30,0 60 - 9,7 22 0t3 60,0 120 23 0,3 150,0 300 24 0t3 30,0 80 20 19,7 25 0,3 60,0 150 20 19,7 In den folgenden Tabellen 3 bis 19 werden Tablettenformulierungen für verschiedene Wirkstoffe angegeben.Table 2 No. Formula I dextran crosspovidone cellulose powder corn starch 1 0.01 1.0 20 10 8.99 2 0.01 2.0 20 10 7.99 3 0.01 5.0 20 10 4.99 4 0.01 2.0 20 - 17.99 5 0.01 5.0 20 - 14.99 6 0.03 3.0 20 10 6.97 7 0.03 6.0 20 10 3.97 8 0.03 15.0 20 - 4.97 9 0.03 6.0 20 - 13.97 10 0.03 15.0 30 20 4.97 11 0.05 5.0 20 10 4.95 12 0.05 10.0 20 - 9.95 13 0.05 25.0 45 14 0.05 10.0 30 20 9.95 15 0.05 25.0 50 20 4.95 16 0.1 10.0 20 - 9.9 17 0.1 20.0 40 - 9.9 18 0.1 50.0 100 19 0.1 10.0. 30th 20 9.9 20 0.1 20.0 60 10 9.9 21 0.3 30.0 60 - 9.7 22 0t3 60.0 120 23 0.3 150.0 300 24 0t3 30.0 80 20 19.7 25 0.3 60.0 150 20 19.7 In the following Tables 3 to 19 give tablet formulations for various active ingredients.
Sämtliche Angaben in mg.All information in mg.
Als Wirkstoffe in den einzelnen Tabletten wurden folgende eingesetzt: Tabelle Name Formel 3 15-Deoxy-16-hydroxy-17-cyclobutano- II -PGE1-methylester 4 PGE1 III 5 (17S)-17,20-Dimethyl-trans-#² PGE1 IV 6 19ß-Hydroxy-PGE1 V 7 (#)(16RS)-15-Deoxy-16-hydroxy- VI 16methyl-PGE1-methylester 8 16,16-Dimethyl-trans-#²-PGE1- VII methylester 9 2-Decarboxy-2-hydroxy-methyl-PGE1 VIII 10 (+)-11α, 16 α, ß-Dihydroxy-1,9-dioxo- IX 1-(hydroxymethyl)-16-methyl-13-transprosiene 11 4,5,6-Trinor-3,7-inter-m-phenylen- X 3-oxa-PGE1 12 PGE2 XI 13 (15R)-15-methyl-PGE2 XII 14 16,16-Dimethyl-PGE2 XIII 15 16-Methyl-20-methoxy-PGE2 XIV 16 (#)(16RS)15-Deoxy-16-hydroxy-16- XV methyl-PGE2-methylester 17 (+)-4,5-Didehydro-16-phenoxy-#- XVI tetranor-PGE1-methylester 18 N-methan-sulfonyl-1 0-phenoxy- - XVII tetranor-PGE2-amid 19 9-Deoxo-9-methylen-16,16-dimethyl-PGE2 XVIII Tabelle 3 Beispiele für Tablettenformulierungen Nr. Formel II Dextran Cellulose- milkrokristall. Maisstärke Polyvinyl- hydriertes Magnesium Pulver Cellulose pyrrolidon Ricinusöl stearat 1 0,01 2,0 50 - 27,79 - - 0,2 2 0,03 6,0 50 - 18,77 5,0 - 0,2 3 0,1 20,0 - 40 19,6 40,0 0,3 -4 0,3 60,0 - 10 9,3 120,0 0,4 -5 1,0 100,0 150 - 48,0 300,0 - 1,0 Tabelle 4 Beispiele für Tablettenformulierungen Nr. Formel III Dextran Cellulose- mikrokristall. Maisstärke Polyvinyl- hydriertes Magnesium Pulver Cellulose pyrrolidon Ricinusöl stearat 1 0,01 2,0 50 - 27,79 - - 0,2 2 0,03 6,0 50 - 18,77 5,0 - 0,2 3 0,1 20,0 - 40 19,6 40,0 0,3 -4 0,3 60,0 - 10 9,3 120,0 0,4 -5 1,0 100,0 150 - 48,0 300,0 - 1,0 Tabelle 5 Beispiele für Tablettenformulierungen Nr. Formel IV Dextran Cellulose- mikrokristall. Maisstärke Polyvinyl- hydriertes Magnesium Pulver Cellulose pyrrolidon Ricinusöl stearat 1 0,01 2,0 50 - 27,79 - - 0,2 2 0,03 6,0 50 - 18,77 5,0 - 0,2 3 0,1 20,0 - 40 19,6 40,0 0,3 -4 0,3 60,0 - 10 9,3 120,0 0,4 -5 1,0 100,0 150 - 48,0 300,0 - 1,0 Tabelle 6 Beispiele für Tablettenformulierungen Nr. Formel V Dextran Cellulose- mikrokristall. Maisstärke Polyvinyl- hydriertes Magnesium Pulver Cellulose pyrrolidon Ricinusöl stearat 1 0,01 2,0 50 - 27,79 - - 0,2 2 0,03 6,0 50 - 18,77 5,0 - 0,2 3 0,1 20,0 - 40 19,6 40,0 0,3 -4 0,3 60,0 - 10 9,3 120,0 0,4 -5 1,0 100,0 150 - 48,0 300,0 - 1,0 Tabelle 7 Beispiele für Tablettenformulierungen Nr. Formel VI Dextran Cellulose- mikrokristall. Maisstärke Polyvinyl- hydriertes Magnesium Pulver Cellulose pyrrolidon Ricinusöl stearat 1 0,01 2,0 50 - 27,79 - - 0,2 2 0,03 6,0 50 - 18,77 5,0 - 0,2 3 0,1 20,0 - 40 19,6 40,0 0,3 -4 0,3 60,0 - 10 9,3 120,0 0,4 -5 1,0 100,0 150 - 48,0 300,0 - 1,0 Tabelle 8 Beispiele für Tablettenformulierungen Nr. Formel VII Dextran Cellulose- mikrokristall. Maisstärke Polyvinyl- hydriertes Magnesium Pulver Cellulose pyrrolidon Ricinusöl stearat 1 0,01 2,0 50 - 27,79 - - 0,2 2 0,03 6,0 50 - 18,77 5,0 - 0,2 3 0,1 20,0 - 40 19,6 40,0 0,3 -4 0,3 60,0 - 10 9,3 120,0 0,4 -5 1,0 100,0 150 - 48,0 300,0 - 1,0 Tabelle 9 Beispiele für Tablettenformulierungen Nr. Formel VIII Dextran Cellulose- mikrokristall. Maisstärke Polyvinyl- hydriertes Magnesium Pulver Cellulose pyrrolidon Ricinusöl stearat 1 0,01 2,0 50 - 27,79 - - 0,2 2 0,03 6,0 50 - 18,77 5,0 - 0,2 3 0,1 20,0 - 40 19,6 40,0 0,3 -4 0,3 60,0 - 10 9,3 120,0 0,4 -5 1,0 100,0 150 - 48,0 300,0 - 1,0 Tabelle 10 Beispiele für Tablettenformulierungen Nr. Formel IX Dextran Cellulose- mikrokristall. Maisstärke Polyvinyl- hydriertes Magnesium Pulver Cellulose pyrrolidon Ricinusöl stearat 1 0,01 2,0 50 - 27,79 - - 0,2 2 0,03 6,0 50 - 18,77 5,0 - 0,2 3 0,1 20,0 - 40 19,6 40,0 0,3 -4 0,3 60,0 - 10 9,3 120,0 0,4 -5 1,0 100,0 150 - 48,0 300,0 - 1,0 Tabelle 11 Beispiele für Tablettenformulierungen Nr. Formel X Dextran Cellulose- mikrokristall. Maisstärke Polyvinyl- hydriertes Magnesium Pulver Cellulose pyrrolidon Ricinusöl stearat 1 0,01 2,0 50 - 27,79 - - 0,2 2 0,03 6,0 50 - 18,77 5,0 - 0,2 3 0,1 20,0 - 40 19,6 40,0 0,3 -4 0,3 60,0 - 10 9,3 120,0 0,4 -5 1,0 100,0 150 - 48,0 300,0 - 1,0 Tabelle 12 Beispiele für Tablettenformulierungen Nr. Formel XI Dextran Cellulose- mikrokristall. Maisstärke Polyvinyl- hydriertes Magnesium Pulver Cellulose pyrrolidon Ricinusöl stearat 1 0,01 2,0 50 - 27,79 - - 0,2 2 0,03 6,0 50 - 18,77 5,0 - 0,2 3 0,1 20,0 - 40 19,6 40,0 0,3 -4 0,3 60,0 - 10 9,3 120,0 0,4 -5 1,0 100,0 150 - 48,0 300,0 - 1,0 Tabelle 13 Beispiele für Tablettenformulierungen Nr. Formel XII Dextran Cellulose- mikrokristall. Maisstärke Polyvinyl- hydriertes Magnesium Pulver Cellulose pyrrolidon Ricinusöl stearat 1 0,01 2,0 50 - 27,79 - - 0,2 2 0,03 6,0 50 - 18,77 5,0 - 0,2 3 0,1 20,0 - 40 19,6 40,0 0,3 -4 0,3 60,0 - 10 9,3 120,0 0,4 -5 1,0 100,0 150 - 48,0 300,0 - 1,0 Tabelle 14 Beispiele für Tablettenformulierungen Nr. Formel XII Dextran Cellulose- mikrokristall. Maisstärke Polyvinyl- hydriertes Magnesium Pulver Cellulose pyrrolidon Ricinusöl stearat 1 0,01 2,0 50 - 27,79 - - 0,2 2 0,03 6,0 50 - 18,77 5,0 - 0,2 3 0,1 20,0 - 40 19,6 40,0 0,3 -4 0,3 60,0 - 10 9,3 120,0 0,4 -5 1,0 100,0 150 - 48,0 300,0 - 1,0 Tabelle 15 Beispiele für Tablettenformulierungen Nr. Formel XIV Dextran Cellulose- mikrokristall. Maisstärke Polyvinyl- hydriertes Magnesium Pulver Cellulose pyrrolidon Ricinusöl stearat 1 0,01 2,0 50 - 27,79 - - 0,2 2 0,03 6,0 50 - 18,77 5,0 - 0,2 3 0,1 20,0 - 40 19,6 40,0 0,3 -4 0,3 60,0 - 10 9,3 120,0 0,4 -5 1,0 100,0 150 - 48,0 300,0 - 1,0 Tabelle 16 Beispiele für Tablettenformulierungen Nr. Formel XV Dextran Cellulose- mikrokristall. Maisstärke Polyvinyl- hydriertes Magnesium Pulver Cellulose pyrrolidon Ricinusöl stearat 1 0,01 2,0 50 - 27,79 - - 0,2 2 0,03 6,0 50 - 18,77 5,0 - 0,2 3 0,1 20,0 - 40 19,6 40,0 0,3 -4 0,3 60,0 - 10 9,3 120,0 0,4 -5 1,0 100,0 150 - 48,0 300,0 - 1,0 Tabelle 17 Beispiele für Tablettenformulierungen Nr. Formel XVI Dextran Cellulose- mikrokristall. Maisstärke Polyvinyl- hydriertes Magnesium Pulver Cellulose pyrrolidon Ricinusöl stearat 1 0,01 2,0 50 - 27,79 - - 0,2 2 0,03 6,0 50 - 18,77 5,0 - 0,2 3 0,1 20,0 - 40 19,6 40,0 0,3 -4 0,3 60,0 - 10 9,3 120,0 0,4 -5 1,0 100,0 150 - 48,0 300,0 - 1,0 Tabelle 18 Beispiele für Tablettenformulierungen Nr. Formel XVII Dextran Cellulose- mikrokristall. Maisstärke Polyvinyl- hydriertes Magnesium Pulver Cellulose pyrrolidon Ricinusöl stearat 1 0,01 2,0 50 - 27,79 - - 0,2 2 0,03 6,0 50 - 18,77 5,0 - 0,2 3 0,1 20,0 - 40 19,6 40,0 0,3 -4 0,3 60,0 - 10 9,3 120,0 0,4 -5 1,0 100,0 150 - 48,0 300,0 - 1,0 Tabelle 19 Beispiele für Tablettenformulierungen Nr. Formel XVIII Dextran Cellulose- mikrokristall. Maisstärke Polyvinyl- hydriertes Magnesium Pulver Cellulose pyrrolidon Ricinusöl stearat 1 0,01 2,0 50 - 27,79 - - 0,2 2 0,03 6,0 50 - 18,77 5,0 - 0,2 3 0,1 20,0 - 40 19,6 40,0 0,3 -4 0,3 60,0 - 10 9,3 120,0 0,4 -5 1,0 100,0 150 - 48,0 300,0 - 1,0 Tabelle 20 Beispiele für Kapselformulierungen Nr. Formel II Dextran Crosspovidone Cellulose-Pulver Maisstärke 1 0,01 2,0 20 10 7,99 2 0,3 6,0 20 10 3,97 3 0,05 10,0 20 - 9,95 4 0,1 20,0 40 - 9,9 5 0,3 60,00 120 - - Tabelle 21 Beispiele für Kapselformulierungen Nr. Formel III Dextran Crosspovidone Cellulose-Pulver Maisstärke 1 0,01 2,0 20 10 7,99 2 0,3 6,0 20 10 3,97 3 0,05 10,0 20 - 9,95 4 0,1 20,0 40 - 9,9 5 0,3 60,00 120 - - Tabelle 22 Beispiele für Kapselformulierungen Nr. Formel IV Dextran Crosspovidone Cellulose-Pulver Maisstärke 1 0,01 2,0 20 10 7,99 2 0,3 6,0 20 10 3,97 3 0,05 10,0 20 - 9,95 4 0,1 20,0 40 - 9,9 5 0,3 60,00 120 - - Tabelle 23 Beispiele für Kapselformulierungen Nr. Formel V Dextran Crosspovidone Cellulose-Pulver Maisstärke 1 0,01 2,0 20 10 7,99 2 0,3 6,0 20 10 3,97 3 0,05 10,0 20 - 9,95 4 0,1 20,0 40 - 9,9 5 0,3 60,00 120 - - Tabelle 24 Beispiele für Kapselformulierungen Nr. Formel VI Dextran Crosspovidone Cellulose-Pulver Maisstärke 1 0,01 2,0 20 10 7,99 2 0,3 6,0 20 10 3,97 3 0,05 10,0 20 - 9,95 4 0,1 20,0 40 - 9,9 5 0,3 60,00 120 - - Tabelle 25 Beispiele für Kapselformulierungen Nr. Formel VII Dextran Crosspovidone Cellulose-Pulver Maisstärke 1 0,01 2,0 20 10 7,99 2 0,3 6,0 20 10 3,97 3 0,05 10,0 20 - 9,95 4 0,1 20,0 40 - 9,9 5 0,3 60,00 120 - - Tabelle 26 Beispiele für Kapselformulierungen Nr. Formel VIII Dextran Crosspovidone Cellulose-Pulver Maisstärke 1 0,01 2,0 20 10 7,99 2 0,3 6,0 20 10 3,97 3 0,05 10,0 20 - 9,95 4 0,1 20,0 40 - 9,9 5 0,3 60,00 120 - - Tabelle 27 Beispiele für Kapselformulierungen Nr. Formel IX Dextran Crosspovidone Cellulose-Pulver Maisstärke 1 0,01 2,0 20 10 7,99 2 0,3 6,0 20 10 3,97 3 0,05 10,0 20 - 9,95 4 0,1 20,0 40 - 9,9 5 0,3 60,00 120 - - Tabelle 28 Beispiele für Kapselformulierungen Nr. Formel X Dextran Crosspovidone Cellulose-Pulver Maisstärke 1 0,01 2,0 20 10 7,99 2 0,3 6,0 20 10 3,97 3 0,05 10,0 20 - 9,95 4 0,1 20,0 40 - 9,9 5 0,3 60,00 120 - - Tabelle 29 Beispiele für Kapselformulierungen Nr. Formel XI Dextran Crosspovidone Cellulose-Pulver Maisstärke 1 0,01 2,0 20 10 7,99 2 0,3 6,0 20 10 3,97 3 0,05 10,0 20 - 9,95 4 0,1 20,0 40 - 9,9 5 0,3 60,00 120 - - Tabelle 30 Beispiele für Kapselformulierungen Nr. Formel XII Dextran Crosspovidone Cellulose-Pulver Maisstärke 1 0,01 2,0 20 10 7,99 2 0,3 6,0 20 10 3,97 3 0,05 10,0 20 - 9,95 4 0,1 20,0 40 - 9,9 5 0,3 60,00 120 - - Tabelle 31 Beispiele für Kapselformulierungen Nr. Formel XIII Dextran Crosspovidone Cellulose-Pulver Maisstärke 1 0,01 2,0 20 10 7,99 2 0,3 6,0 20 10 3,97 3 0,05 10,0 20 - 9,95 4 0,1 20,0 40 - 9,9 5 0,3 60,00 120 - - Tabelle 32 Beispiele für Kapselformulierungen Nr. Formel XIV Dextran Crosspovidone Cellulose-Pulver Maisstärke 1 0,01 2,0 20 10 7,99 2 0,3 6,0 20 10 3,97 3 0,05 10,0 20 - 9,95 4 0,1 20,0 40 - 9,9 5 0,3 60,00 120 - - Tabelle 33 Beispiele für Kapselformulierungen Nr. Formel XV Dextran Crosspovidone Cellulose-Pulver Maisstärke 1 0,01 2,0 20 10 7,99 2 0,3 6,0 20 10 3,97 3 0,05 10,0 20 - 9,95 4 0,1 20,0 40 - 9,9 5 0,3 60,00 120 - - Tabelle 34 Beispiele für Kapselformulierungen Nr. Formel XVI Dextran Crosspovidone Cellulose-Pulver Maisstärke 1 0,01 2,0 20 10 7,99 2 0,3 6,0 20 10 3,97 3 0,05 10,0 20 - 9,95 4 0,1 20,0 40 - 9,9 5 0,3 60,00 120 - - Tabelle 35 Beispiele für Kapselformulierungen Nr. Formel XVII Dextran Crosspovidone Cellulose-Pulver Maisstärke 1 0,01 2,0 20 10 7,99 2 0,3 6,0 20 10 3,97 3 0,05 10,0 20 - 9,95 4 0,1 20,0 40 - 9,9 5 0,3 60,00 120 - - Tabelle 36 Beispiele für Kapselformulierungen Nr. Formel XVIII Dextran Crosspovidone Cellulose-Pulver Maisstärke 1 0,01 2,0 20 10 7,99 2 0,3 6,0 20 10 3,97 3 0,05 10,0 20 - 9,95 4 0,1 20,0 40 - 9,9 5 0,3 60,00 120 - -The following were used as active ingredients in the individual tablets: Table Name Formula 3 15-Deoxy-16-hydroxy-17-cyclobutano- II -PGE1-methyl ester 4 PGE1 III 5 (17S) -17,20-dimethyl-trans- # ² PGE1 IV 6 19β-hydroxy-PGE1 V 7 (#) (16RS) -15-deoxy-16-hydroxy- VI 16methyl-PGE1 methyl ester 8 16,16-dimethyl-trans- # 2 -PGE1- VII methyl ester 9 2-decarboxy-2-hydroxymethyl-PGE1 VIII 10 (+) - 11α, 16α, β-dihydroxy-1,9-dioxo-IX 1- (hydroxymethyl) -16-methyl-13-transprosienes 11 4,5,6-trinor-3,7-inter-m-phenylene-X 3-oxa-PGE1 12 PGE2 XI 13 (15R) -15-methyl-PGE2 XII 14 16,16-dimethyl-PGE2 XIII 15 16-methyl-20-methoxy-PGE2 XIV 16 (#) (16RS) 15-deoxy-16-hydroxy-16- XV methyl PGE2 methyl ester 17 (+) - 4,5-didehydro-16-phenoxy - # - XVI tetranor PGE1 methyl ester 18 N-methanesulfonyl-10-phenoxy- - XVII tetranor-PGE2-amide 19 9-deoxo-9-methylene-16,16-dimethyl-PGE2 XVIII Table 3 Examples of tablet formulations No. Formula II dextran cellulose milkrocrystalline. Corn starch polyvinyl hydrogenated magnesium Powder cellulose pyrrolidone castor oil stearate 1 0.01 2.0 50 - 27.79 - - 0.2 2 0.03 6.0 50 - 18.77 5.0 - 0.2 3 0.1 20.0 - 40 19.6 40.0 0.3 -4 0.3 60.0 - 10 9.3 120.0 0.4 -5 1.0 100.0 150 - 48.0 300.0 - 1.0 Table 4 Examples of Tablet formulations No. Formula III Dextran Cellulose microcrystalline. Cornstarch Polyvinyl hydrogenated magnesium powder Cellulose pyrrolidone Castor oil stearate 1 0.01 2.0 50 - 27.79 - - 0.2 2 0.03 6.0 50 - 18.77 5.0 - 0.2 3 0.1 20.0 - 40 19.6 40.0 0.3 -4 0.3 60.0 - 10 9.3 120.0 0.4 -5 1.0 100.0 150 - 48.0 300.0 - 1.0 Tabel 5 examples of tablet formulations No. Formula IV dextran cellulose microcrystalline. Corn starch Polyvinyl hydrogenated magnesium powder Cellulose pyrrolidone Castor oil stearate 1 0.01 2.0 50 - 27.79 - - 0.2 2 0.03 6.0 50 - 18.77 5.0 - 0.2 3 0.1 20.0 - 40 19.6 40.0 0.3 -4 0.3 60.0 - 10 9.3 120.0 0.4 -5 1.0 100.0 150 - 48.0 300.0 - 1.0 Table 6 Examples of tablet formulations No. Formula V Dextran cellulose microcrystalline. Corn starch polyvinyl hydrogenated magnesium powder Cellulose pyrrolidone castor oil stearate 1 0.01 2.0 50 - 27.79 - - 0.2 2 0.03 6.0 50 - 18.77 5.0 - 0.2 3 0.1 20.0 - 40 19.6 40.0 0.3 -4 0.3 60.0 - 10 9.3 120.0 0.4 -5 1.0 100.0 150 - 48.0 300.0 - 1.0 Table 7 Examples of tablet formulations No. Formula VI dextran cellulose microcrystalline. Polyvinyl hydrogenated corn starch Magnesium powder Cellulose pyrrolidone Castor oil stearate 1 0.01 2.0 50 - 27.79 - - 0.2 2 0.03 6.0 50 - 18.77 5.0 - 0.2 3 0.1 20.0 - 40 19.6 40.0 0.3 -4 0.3 60.0 - 10 9.3 120.0 0.4 -5 1.0 100.0 150 - 48.0 300.0 - 1.0 Tabel 8 Examples of tablet formulations No. Formula VII Dextran Cellulose microcrystalline. Corn starch Polyvinyl hydrogenated magnesium powder Cellulose pyrrolidone Castor oil stearate 1 0.01 2.0 50 - 27.79 - - 0.2 2 0.03 6.0 50 - 18.77 5.0 - 0.2 3 0.1 20.0 - 40 19.6 40.0 0.3 -4 0.3 60.0 - 10 9.3 120.0 0.4 -5 1.0 100.0 150 - 48.0 300.0 - 1.0 Table 9 Examples of tablet formulations No. Formula VIII Dextran cellulose microcrystalline. Corn starch polyvinyl hydrogenated magnesium Powder cellulose pyrrolidone castor oil stearate 1 0.01 2.0 50 - 27.79 - - 0.2 2 0.03 6.0 50 - 18.77 5.0 - 0.2 3 0.1 20.0 - 40 19.6 40.0 0.3 -4 0.3 60.0 - 10 9.3 120.0 0.4 -5 1.0 100.0 150 - 48.0 300.0 - 1.0 Table 10 Examples of Tablet formulations No. Formula IX Dextran Cellulose microcrystalline. Cornstarch Polyvinyl hydrogenated magnesium powder Cellulose pyrrolidone Castor oil stearate 1 0.01 2.0 50 - 27.79 - - 0.2 2 0.03 6.0 50 - 18.77 5.0 - 0.2 3 0.1 20.0 - 40 19.6 40.0 0.3 -4 0.3 60.0 - 10 9.3 120.0 0.4 -5 1.0 100.0 150 - 48.0 300.0 - 1.0 Tabel 11 Examples of tablet formulations No. Formula X Dextran Cellulose microcrystalline. Corn starch Polyvinyl hydrogenated magnesium powder Cellulose pyrrolidone Castor oil stearate 1 0.01 2.0 50 - 27.79 - - 0.2 2 0.03 6.0 50 - 18.77 5.0 - 0.2 3 0.1 20.0 - 40 19.6 40.0 0.3 -4 0.3 60.0 - 10 9.3 120.0 0.4 -5 1.0 100.0 150 - 48.0 300.0 - 1.0 Table 12 Examples of tablet formulations No. Formula XI dextran cellulose microcrystalline. Corn starch polyvinyl hydrogenated magnesium Powder cellulose pyrrolidone castor oil stearate 1 0.01 2.0 50 - 27.79 - - 0.2 2 0.03 6.0 50 - 18.77 5.0 - 0.2 3 0.1 20.0 - 40 19.6 40.0 0.3 -4 0.3 60.0 - 10 9.3 120.0 0.4 -5 1.0 100.0 150 - 48.0 300.0 - 1.0 Table 13 Examples of Tablet formulations No. Formula XII Dextran Cellulose microcrystalline. Cornstarch Polyvinyl hydrogenated magnesium powder Cellulose pyrrolidone Castor oil stearate 1 0.01 2.0 50 - 27.79 - - 0.2 2 0.03 6.0 50 - 18.77 5.0 - 0.2 3 0.1 20.0 - 40 19.6 40.0 0.3 -4 0.3 60.0 - 10 9.3 120.0 0.4 -5 1.0 100.0 150 - 48.0 300.0 - 1.0 Tabel 14 Examples of tablet formulations No. Formula XII Dextran Cellulose microcrystalline. Corn starch Polyvinyl hydrogenated magnesium powder Cellulose pyrrolidone Castor oil stearate 1 0.01 2.0 50 - 27.79 - - 0.2 2 0.03 6.0 50 - 18.77 5.0 - 0.2 3 0.1 20.0 - 40 19.6 40.0 0.3 -4 0.3 60.0 - 10 9.3 120.0 0.4 -5 1.0 100.0 150 - 48.0 300.0 - 1.0 Table 15 Examples of tablet formulations No. Formula XIV dextran cellulose microcrystalline. Corn starch polyvinyl hydrogenated magnesium Powder cellulose pyrrolidone castor oil stearate 1 0.01 2.0 50 - 27.79 - - 0.2 2 0.03 6.0 50 - 18.77 5.0 - 0.2 3 0.1 20.0 - 40 19.6 40.0 0.3 -4 0.3 60.0 - 10 9.3 120.0 0.4 -5 1.0 100.0 150 - 48.0 300.0 - 1.0 Table 16 Examples of Tablet formulations No. Formula XV dextran cellulose microcrystalline. Cornstarch Polyvinyl hydrogenated magnesium powder Cellulose pyrrolidone Castor oil stearate 1 0.01 2.0 50 - 27.79 - - 0.2 2 0.03 6.0 50 - 18.77 5.0 - 0.2 3 0.1 20.0 - 40 19.6 40.0 0.3 -4 0.3 60.0 - 10 9.3 120.0 0.4 -5 1.0 100.0 150 - 48.0 300.0 - 1.0 Tabel 17 Examples of tablet formulations No. Formula XVI Dextran Cellulose microcrystalline. Corn starch Polyvinyl hydrogenated magnesium powder Cellulose pyrrolidone Castor oil stearate 1 0.01 2.0 50 - 27.79 - - 0.2 2 0.03 6.0 50 - 18.77 5.0 - 0.2 3 0.1 20.0 - 40 19.6 40.0 0.3 -4 0.3 60.0 - 10 9.3 120.0 0.4 -5 1.0 100.0 150 - 48.0 300.0 - 1.0 Table 18 Examples of tablet formulations No. Formula XVII dextran cellulose microcrystalline. Corn starch polyvinyl hydrogenated magnesium Powder cellulose pyrrolidone castor oil stearate 1 0.01 2.0 50 - 27.79 - - 0.2 2 0.03 6.0 50 - 18.77 5.0 - 0.2 3 0.1 20.0 - 40 19.6 40.0 0.3 -4 0.3 60.0 - 10 9.3 120.0 0.4 -5 1.0 100.0 150 - 48.0 300.0 - 1.0 Table 19 Examples of Tablet formulations No. Formula XVIII Dextran Cellulose microcrystalline. Cornstarch Polyvinyl hydrogenated magnesium powder Cellulose pyrrolidone Castor oil stearate 1 0.01 2.0 50 - 27.79 - - 0.2 2 0.03 6.0 50 - 18.77 5.0 - 0.2 3 0.1 20.0 - 40 19.6 40.0 0.3 -4 0.3 60.0 - 10 9.3 120.0 0.4 -5 1.0 100.0 150 - 48.0 300.0 - 1.0 Tabel 20 Examples of Capsule Formulations No. Formula II Dextran Crosspovidone Cellulose Powder Corn starch 1 0.01 2.0 20 10 7.99 2 0.3 6.0 20 10 3.97 3 0.05 10.0 20 - 9.95 4 0.1 20.0 40 - 9.9 5 0.3 60.00 120 - - Table 21 Examples of capsule formulations No. Formula III Dextran Crosspovidone Cellulose Powder Corn Starch 1 0.01 2.0 20 10 7.99 2 0.3 6.0 20 10 3.97 3 0.05 10.0 20 - 9.95 4 0.1 20.0 40 - 9.9 5 0.3 60.00 120 - - Table 22 Examples of Capsule Formulations No. Formula IV Dextran Crosspovidone Cellulose Powder Corn Starch 1 0.01 2.0 20 10 7.99 2 0.3 6.0 20 10 3.97 3 0.05 10.0 20 - 9.95 4 0.1 20.0 40 - 9.9 5 0.3 60.00 120 - - Tabel 23 Examples of capsule formulations No. Formula V Dextran Crosspovidone Cellulose powder Corn starch 1 0.01 2.0 20 10 7.99 2 0.3 6.0 20 10 3.97 3 0.05 10.0 20 - 9.95 4 0.1 20.0 40 - 9.9 5 0.3 60.00 120 - - Table 24 Examples of capsule formulations No. Formula VI Dextran Crosspovidone Cellulose Powder Corn Starch 1 0.01 2.0 20 10 7.99 2 0.3 6.0 20 10 3.97 3 0.05 10.0 20 - 9.95 4 0.1 20.0 40 - 9.9 5 0.3 60.00 120 - - Table 25 Examples of Capsule Formulations No. Formula VII Dextran Crosspovidone Cellulose Powder Corn Starch 1 0.01 2.0 20 10 7.99 2 0.3 6.0 20 10 3.97 3 0.05 10.0 20 - 9.95 4 0.1 20.0 40 - 9.9 5 0.3 60.00 120 - - Tabel 26 Examples of capsule formulations No. Formula VIII Dextran Crosspovidone Cellulose powder Corn starch 1 0.01 2.0 20 10 7.99 2 0.3 6.0 20 10 3.97 3 0.05 10.0 20 - 9.95 4 0.1 20.0 40 - 9.9 5 0.3 60.00 120 - - Table 27 Examples of capsule formulations No. Formula IX Dextran Crosspovidone Cellulose Powder Corn Starch 1 0.01 2.0 20 10 7.99 2 0.3 6.0 20 10 3.97 3 0.05 10.0 20 - 9.95 4 0.1 20.0 40 - 9.9 5 0.3 60.00 120 - - Table 28 Examples of Capsule Formulations No. Formula X Dextran Crosspovidone Cellulose Powder Corn Starch 1 0.01 2.0 20 10 7.99 2 0.3 6.0 20 10 3.97 3 0.05 10.0 20 - 9.95 4 0.1 20.0 40 - 9.9 5 0.3 60.00 120 - - Tabel 29 Examples of capsule formulations No. Formula XI Dextran Crosspovidone Cellulose Powder Corn starch 1 0.01 2.0 20 10 7.99 2 0.3 6.0 20 10 3.97 3 0.05 10.0 20 - 9.95 4 0.1 20.0 40 - 9.9 5 0.3 60.00 120 - - Table 30 Examples of capsule formulations No. Formula XII Dextran Crosspovidone Cellulose Powder Corn Starch 1 0.01 2.0 20 10 7.99 2 0.3 6.0 20 10 3.97 3 0.05 10.0 20 - 9.95 4 0.1 20.0 40 - 9.9 5 0.3 60.00 120 - - Table 31 Examples of Capsule Formulations No. Formula XIII Dextran Crosspovidone Cellulose Powder Corn Starch 1 0.01 2.0 20 10 7.99 2 0.3 6.0 20 10 3.97 3 0.05 10.0 20 - 9.95 4 0.1 20.0 40 - 9.9 5 0.3 60.00 120 - - Tabel 32 Examples of capsule formulations No. Formula XIV Dextran Crosspovidone Cellulose Powder Corn starch 1 0.01 2.0 20 10 7.99 2 0.3 6.0 20 10 3.97 3 0.05 10.0 20 - 9.95 4 0.1 20.0 40 - 9.9 5 0.3 60.00 120 - - Table 33 Examples of capsule formulations No. Formula XV Dextran Crosspovidone Cellulose Powder Corn Starch 1 0.01 2.0 20 10 7.99 2 0.3 6.0 20 10 3.97 3 0.05 10.0 20 - 9.95 4 0.1 20.0 40 - 9.9 5 0.3 60.00 120 - - Table 34 Examples of Capsule Formulations No. Formula XVI Dextran Crosspovidone Cellulose Powder Corn Starch 1 0.01 2.0 20 10 7.99 2 0.3 6.0 20 10 3.97 3 0.05 10.0 20 - 9.95 4 0.1 20.0 40 - 9.9 5 0.3 60.00 120 - - Tabel 35 Examples of Capsule Formulations No. Formula XVII Dextran Crosspovidone Cellulose Powder Corn starch 1 0.01 2.0 20 10 7.99 2 0.3 6.0 20 10 3.97 3 0.05 10.0 20 - 9.95 4 0.1 20.0 40 - 9.9 5 0.3 60.00 120 - - Table 36 Examples of capsule formulations No. Formula XVIII Dextran Crosspovidone Cellulose Powder Corn Starch 1 0.01 2.0 20 10 7.99 2 0.3 6.0 20 10 3.97 3 0.05 10.0 20 - 9.95 4 0.1 20.0 40 - 9.9 5 0.3 60.00 120 - -
Claims (17)
Priority Applications (17)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19833304864 DE3304864A1 (en) | 1983-02-12 | 1983-02-12 | Adsorbates of prostaglandins |
| US06/574,789 US4675182A (en) | 1983-02-12 | 1984-01-27 | Complexes of prostaglandins |
| PT78054A PT78054B (en) | 1983-02-12 | 1984-02-02 | Process for the preparation of stable complexes of prostaglandines and cross linked polyvinylpyrrolidones and stable pharma ceutical and veterinary compositions therewith |
| ES529483A ES8503512A1 (en) | 1983-02-12 | 1984-02-06 | Complexes of prostaglandins. |
| EP84101169A EP0116358B1 (en) | 1983-02-12 | 1984-02-06 | Complexes of prostaglandins |
| DE8484101169T DE3470663D1 (en) | 1983-02-12 | 1984-02-06 | Complexes of prostaglandins |
| AT84101169T ATE33761T1 (en) | 1983-02-12 | 1984-02-06 | COMPLEXES OF PROSTAGLANDINS. |
| AU24286/84A AU572115B2 (en) | 1983-02-12 | 1984-02-08 | Prostaglandin complexes |
| JP59020942A JPS59148760A (en) | 1983-02-12 | 1984-02-09 | Composite body of prostaglandin |
| IL70913A IL70913A (en) | 1983-02-12 | 1984-02-09 | Complexes of prostaglandins of the e type with crosspovidone,prepasted starch or dextrans,their preparation and pharmaceutical compositions containing them |
| PH30225A PH25606A (en) | 1983-02-12 | 1984-02-10 | Complexes of prostaglandins |
| CA000447149A CA1248524A (en) | 1983-02-12 | 1984-02-10 | Complexes of prostaglandins |
| IE313/84A IE56766B1 (en) | 1983-02-12 | 1984-02-10 | Complexes of prostaglandins |
| GR73782A GR79806B (en) | 1983-02-12 | 1984-02-10 | |
| HU84540A HU196127B (en) | 1983-02-12 | 1984-02-10 | Process for producing prostaglandin complexes and pharmaceutics comprising the same as active ingredient |
| DK61684A DK61684A (en) | 1983-02-12 | 1984-02-10 | COMPLEXES OF PROSTAGLANDINES WITH CROSSPOVIDONE, PREVIOUSLY ADDED STARCH OR DEXTRANES, THEIR PREPARATION AND USE |
| KR8400656A KR880002138B1 (en) | 1983-02-12 | 1984-02-11 | Process for preparing prostaglandin complexes |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19833304864 DE3304864A1 (en) | 1983-02-12 | 1983-02-12 | Adsorbates of prostaglandins |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DE3304864A1 true DE3304864A1 (en) | 1984-08-16 |
Family
ID=6190683
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE19833304864 Withdrawn DE3304864A1 (en) | 1983-02-12 | 1983-02-12 | Adsorbates of prostaglandins |
Country Status (2)
| Country | Link |
|---|---|
| JP (1) | JPS59148760A (en) |
| DE (1) | DE3304864A1 (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2005272458A (en) * | 2004-02-27 | 2005-10-06 | Ono Pharmaceut Co Ltd | Medical composition for oral administration |
| JP2005314413A (en) * | 2004-04-02 | 2005-11-10 | Ono Pharmaceut Co Ltd | Medicine composition for oral administration |
| US8455547B2 (en) * | 2008-02-05 | 2013-06-04 | Allergan, Inc. | Substituted cyclopentanes having prostaglandin activity |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5443570B2 (en) * | 1972-10-27 | 1979-12-20 | ||
| JPS5525602B2 (en) * | 1973-05-10 | 1980-07-07 | ||
| JPS6019740B2 (en) * | 1977-04-15 | 1985-05-17 | 東レ株式会社 | Prostaglandin heat-stabilized composition |
| JPS6054933B2 (en) * | 1978-01-27 | 1985-12-03 | 小野薬品工業株式会社 | Method for stabilizing prostaglandin and prostaglandin-like compound preparations |
| JPS57156460A (en) * | 1981-03-20 | 1982-09-27 | Ono Pharmaceut Co Ltd | Stabilized composition of prostaglandin and prostaglandin mimic compound, and its preparation |
| JPS5818357A (en) * | 1981-07-28 | 1983-02-02 | Ono Pharmaceut Co Ltd | Stabilized composition of 6,9-methano-pgi2 and 6,9- methano-pgi2 analogous compound and its preparation |
-
1983
- 1983-02-12 DE DE19833304864 patent/DE3304864A1/en not_active Withdrawn
-
1984
- 1984-02-09 JP JP59020942A patent/JPS59148760A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| JPS59148760A (en) | 1984-08-25 |
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