DK164535B - ETOPSIDE PREPARATION FOR ORAL ADMINISTRATION - Google Patents
ETOPSIDE PREPARATION FOR ORAL ADMINISTRATION Download PDFInfo
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- DK164535B DK164535B DK122285A DK122285A DK164535B DK 164535 B DK164535 B DK 164535B DK 122285 A DK122285 A DK 122285A DK 122285 A DK122285 A DK 122285A DK 164535 B DK164535 B DK 164535B
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- DK
- Denmark
- Prior art keywords
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- etoposide
- composition according
- acid
- water
- Prior art date
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- 238000002360 preparation method Methods 0.000 title description 9
- 239000000203 mixture Substances 0.000 claims description 47
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 41
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 claims description 39
- 229960005420 etoposide Drugs 0.000 claims description 38
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 33
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 26
- WBWWGRHZICKQGZ-UHFFFAOYSA-N Taurocholic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(=O)NCCS(O)(=O)=O)C)C1(C)C(O)C2 WBWWGRHZICKQGZ-UHFFFAOYSA-N 0.000 claims description 19
- WBWWGRHZICKQGZ-GIHLXUJPSA-N taurocholic acid Chemical compound C([C@@H]1C[C@H]2O)[C@@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@@H]([C@@H](CCC(=O)NCCS(O)(=O)=O)C)[C@@]2(C)[C@H](O)C1 WBWWGRHZICKQGZ-GIHLXUJPSA-N 0.000 claims description 19
- 239000002775 capsule Substances 0.000 claims description 11
- 239000002202 Polyethylene glycol Substances 0.000 claims description 10
- 239000007903 gelatin capsule Substances 0.000 claims description 10
- 229920001223 polyethylene glycol Polymers 0.000 claims description 10
- 229940068886 polyethylene glycol 300 Drugs 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 6
- 239000002552 dosage form Substances 0.000 claims description 6
- 239000007788 liquid Substances 0.000 claims description 6
- 238000005538 encapsulation Methods 0.000 claims description 5
- 230000018044 dehydration Effects 0.000 claims description 3
- 238000006297 dehydration reaction Methods 0.000 claims description 3
- 150000001735 carboxylic acids Chemical class 0.000 claims description 2
- 231100000252 nontoxic Toxicity 0.000 claims description 2
- 230000003000 nontoxic effect Effects 0.000 claims description 2
- 108010010803 Gelatin Proteins 0.000 claims 1
- 229920000159 gelatin Polymers 0.000 claims 1
- 239000008273 gelatin Substances 0.000 claims 1
- 235000019322 gelatine Nutrition 0.000 claims 1
- 235000011852 gelatine desserts Nutrition 0.000 claims 1
- 239000000243 solution Substances 0.000 description 37
- 230000015572 biosynthetic process Effects 0.000 description 8
- 235000015165 citric acid Nutrition 0.000 description 8
- 229960004106 citric acid Drugs 0.000 description 7
- 239000003814 drug Substances 0.000 description 7
- 238000010790 dilution Methods 0.000 description 6
- 239000012895 dilution Substances 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 238000009472 formulation Methods 0.000 description 6
- 238000001990 intravenous administration Methods 0.000 description 6
- 230000002378 acidificating effect Effects 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 239000003613 bile acid Substances 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 239000003708 ampul Substances 0.000 description 2
- 229960004543 anhydrous citric acid Drugs 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 239000007963 capsule composition Substances 0.000 description 2
- 230000001413 cellular effect Effects 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 230000037406 food intake Effects 0.000 description 2
- LNTHITQWFMADLM-UHFFFAOYSA-N gallic acid Chemical compound OC(=O)C1=CC(O)=C(O)C(O)=C1 LNTHITQWFMADLM-UHFFFAOYSA-N 0.000 description 2
- 230000002496 gastric effect Effects 0.000 description 2
- 229940068918 polyethylene glycol 400 Drugs 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- -1 taurocholic acid Chemical compound 0.000 description 2
- HSINOMROUCMIEA-FGVHQWLLSA-N (2s,4r)-4-[(3r,5s,6r,7r,8s,9s,10s,13r,14s,17r)-6-ethyl-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]-2-methylpentanoic acid Chemical compound C([C@@]12C)C[C@@H](O)C[C@H]1[C@@H](CC)[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)C[C@H](C)C(O)=O)CC[C@H]21 HSINOMROUCMIEA-FGVHQWLLSA-N 0.000 description 1
- HWAVCOACNKMYOH-UHFFFAOYSA-N 4-(morpholin-4-yldiselanyl)morpholine Chemical compound C1COCCN1[Se][Se]N1CCOCC1 HWAVCOACNKMYOH-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- IIUZTXTZRGLYTI-UHFFFAOYSA-N Dihydrogriseofulvin Natural products COC1CC(=O)CC(C)C11C(=O)C(C(OC)=CC(OC)=C2Cl)=C2O1 IIUZTXTZRGLYTI-UHFFFAOYSA-N 0.000 description 1
- 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
- JMBQKKAJIKAWKF-UHFFFAOYSA-N Glutethimide Chemical compound C=1C=CC=CC=1C1(CC)CCC(=O)NC1=O JMBQKKAJIKAWKF-UHFFFAOYSA-N 0.000 description 1
- UXWOXTQWVMFRSE-UHFFFAOYSA-N Griseoviridin Natural products O=C1OC(C)CC=C(C(NCC=CC=CC(O)CC(O)C2)=O)SCC1NC(=O)C1=COC2=N1 UXWOXTQWVMFRSE-UHFFFAOYSA-N 0.000 description 1
- 101001018064 Homo sapiens Lysosomal-trafficking regulator Proteins 0.000 description 1
- 150000000996 L-ascorbic acids Chemical class 0.000 description 1
- 102100033472 Lysosomal-trafficking regulator Human genes 0.000 description 1
- 244000038561 Modiola caroliniana Species 0.000 description 1
- 235000010703 Modiola caroliniana Nutrition 0.000 description 1
- DDUHZTYCFQRHIY-UHFFFAOYSA-N Negwer: 6874 Natural products COC1=CC(=O)CC(C)C11C(=O)C(C(OC)=CC(OC)=C2Cl)=C2O1 DDUHZTYCFQRHIY-UHFFFAOYSA-N 0.000 description 1
- RSPISYXLHRIGJD-UHFFFAOYSA-N OOOO Chemical compound OOOO RSPISYXLHRIGJD-UHFFFAOYSA-N 0.000 description 1
- JLNTWVDSQRNWFU-UHFFFAOYSA-N OOOOOOO Chemical compound OOOOOOO JLNTWVDSQRNWFU-UHFFFAOYSA-N 0.000 description 1
- 206010041067 Small cell lung cancer Diseases 0.000 description 1
- 244000269722 Thea sinensis Species 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 239000004927 clay Substances 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 229960003964 deoxycholic acid Drugs 0.000 description 1
- KXGVEGMKQFWNSR-LLQZFEROSA-N deoxycholic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 KXGVEGMKQFWNSR-LLQZFEROSA-N 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- YJGVMLPVUAXIQN-UHFFFAOYSA-N epipodophyllotoxin Natural products COC1=C(OC)C(OC)=CC(C2C3=CC=4OCOC=4C=C3C(O)C3C2C(OC3)=O)=C1 YJGVMLPVUAXIQN-UHFFFAOYSA-N 0.000 description 1
- 229940065639 etoposide 100 mg Drugs 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 229940074391 gallic acid Drugs 0.000 description 1
- 235000004515 gallic acid Nutrition 0.000 description 1
- 210000003736 gastrointestinal content Anatomy 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 229960002972 glutethimide Drugs 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- DDUHZTYCFQRHIY-RBHXEPJQSA-N griseofulvin Chemical compound COC1=CC(=O)C[C@@H](C)[C@@]11C(=O)C(C(OC)=CC(OC)=C2Cl)=C2O1 DDUHZTYCFQRHIY-RBHXEPJQSA-N 0.000 description 1
- 229960002867 griseofulvin Drugs 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 239000010985 leather Substances 0.000 description 1
- 239000012669 liquid formulation Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000000693 micelle Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 239000003186 pharmaceutical solution Substances 0.000 description 1
- YJGVMLPVUAXIQN-XVVDYKMHSA-N podophyllotoxin Chemical compound COC1=C(OC)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@H](O)[C@@H]3[C@@H]2C(OC3)=O)=C1 YJGVMLPVUAXIQN-XVVDYKMHSA-N 0.000 description 1
- 229960001237 podophyllotoxin Drugs 0.000 description 1
- YVCVYCSAAZQOJI-UHFFFAOYSA-N podophyllotoxin Natural products COC1=C(O)C(OC)=CC(C2C3=CC=4OCOC=4C=C3C(O)C3C2C(OC3)=O)=C1 YVCVYCSAAZQOJI-UHFFFAOYSA-N 0.000 description 1
- 239000003495 polar organic solvent Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 239000003001 serine protease inhibitor Substances 0.000 description 1
- 208000000587 small cell lung carcinoma Diseases 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- NRHMKIHPTBHXPF-TUJRSCDTSA-M sodium cholate Chemical group [Na+].C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC([O-])=O)C)[C@@]2(C)[C@@H](O)C1 NRHMKIHPTBHXPF-TUJRSCDTSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 201000001768 testis refractory cancer Diseases 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
-
- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/28—Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4858—Organic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Molecular Biology (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
Description
iin
DK 164535 BDK 164535 B
Den foreliggende opfindelse angår etetoposidpræparat til oral administrering, der er ejendommeligt ved <£t i krav l's kendetegnende del angivne.The present invention relates to ethetoposide composition for oral administration which is characterized by <1 in the characterizing portion of claim 1.
Etoposid er et semi-syntetisk proukt afledt af podophyllotoxin.Etoposide is a semi-synthetic product derived from podophyllotoxin.
5 Dette materiale har det kemiske navn ''-demethylepipodophyllotoxin-9-(4,6-0(R)-ethyliden-jS-D-glucopyranosd). Det omtales i litteraturen som VP-16-213, VePesidR, Ethyliden-Lignm P og EPEG. Det er blevet vurderet til anvendelse i behandlingen af caicer i The National Cancer ^ Institute's regi under nr. NSC-131‘40. Det er for nylig blevet godkendt 10 af Federal Food and Drug Administration til anvendelse i behandlingen af refraktær testi kulær cancer og er blevet foreslået til anvendelse i behandlingen af småcellet lungecancer.This material has the chemical name '' -demethylpipodophyllotoxin-9- (4.6-0 (R) -ethylidene-β-D-glucopyranoside). It is referred to in the literature as VP-16-213, VePesidR, Ethylidene-Lignm P and EPEG. It has been assessed for use in the treatment of caices under the auspices of The National Cancer ^ Institute under No. NSC-131'40. It has recently been approved by the Federal Food and Drug Administration for use in the treatment of refractory testicular cancer and has been proposed for use in the treatment of small cell lung cancer.
Ved undersøgelser udført i lational Cancer Institute's regi ti Iførtes lægemidlet som en opløsning til injektion med følgende sammensæt-15 ning: etoposid 100 mg, vandfri citronsyre 10 mg, benzyl al kohol 150 mg, renset polysorbat 80 400 mg, pclyethylenglycol 300 3,25 g og absolut alkohol op til 5,12 g. Hver ampul med ovennævnte sammensætning indeholdt 5 ml opløsning, der fortyndedes 20 til 50 gange med 0,9% natriumchlorid eller 5% dextrose til injektion før administrering ved langsom intrave-20 nøs infusion.In studies conducted under the auspices of the National Cancer Institute, the drug was administered as a solution for injection with the following composition: etoposide 100 mg, anhydrous citric acid 10 mg, benzyl alcohol 150 mg, purified polysorbate 80 400 mg, pclyethylene glycol 300 3.25 g and absolute alcohol up to 5.12 g. Each ampoule of the above composition contained 5 ml of solution diluted 20 to 50 times with 0.9% sodium chloride or 5% dextrose for injection before administration by slow intravenous infusion.
Når det ovennævnte intnvenøse præparat administreredes oralt frem for ved injektion, indtoges 5 ml ampullen enten som en teskefuld dosis eller fortyndedes først med vand, og det viste sig, at biotilgængeligheden via den orale vej var ca. 90% af biotilgængeligheden via den intra-25 venøse vej (M.D'Incalci et al., Cancer Chemoterapy and Pharmacology (1982) 7:141-145). En lignende dosis taget som kapsel, hvori 100 mg aktiv bestanddel var indeholdt i ca. 1,3 ml indkapslet opløsning, hvor vehiklet bestod af polyethylenglycol 400, glycerin, vand og citronsyre, gav kun ca. halvdelen af den intravenøse opløsnings biotilgængelighed, 30 når den indtoges oralt (M. D'Incalci et al., se ovenfor). Opfindelsen løser problemet med reduceret biotilgængelighed af kapsel dosisformen og tilvejebringer en flydende formulering med tilstrækkelig høj koncentration til indkapsling, hvilken formulering giver en biotilgængelighed ved oral indgift, som er lig med den intravenøse opløsnings biotilgængelig-35 hed.When the above-mentioned intravenous formulation was administered orally rather than by injection, the 5 ml ampoule was either taken as a teaspoonful of dose or diluted first with water, and it was found that bioavailability via the oral route was about 90% of bioavailability through the intravenous route (M.D.Incalci et al., Cancer Chemotherapy and Pharmacology (1982) 7: 141-145). A similar dose taken as a capsule containing 100 mg of active ingredient for approx. 1.3 ml of encapsulated solution, in which the vehicle consisted of polyethylene glycol 400, glycerine, water and citric acid, gave only approx. half of the bioavailability of the intravenous solution when taken orally (M. D'Incalci et al., supra). The invention solves the problem of reduced bioavailability of the capsule dosage form and provides a liquid formulation of sufficiently high concentration for encapsulation which provides a bioavailability by oral administration equal to the bioavailability of the intravenous solution.
Opfindelsen drager fordel af den opdagelse, at når taurocholsyre inkluderes i et opløsningsdosispræparat med etoposid, er resultatet en markant forbedret absorption af lægemidlet efter indtagelse af præpara- 2The invention benefits from the discovery that when taurocholic acid is included in a solution dose composition with etoposide, the result is a markedly improved absorption of the drug after ingestion of the preparation.
DK 164535 BDK 164535 B
tet. Det antages, at dette fyldes dannelsen af en micellær opløsning af etoposid ved fortynding deri med det gastriske indhold.ment. This is believed to fill the formation of a micellar solution of etoposide by dilution therein with the gastric content.
Ved undersøgelsen af de te problem har det vist sig, at den ovenfor omtalte kapsel formulering resulterer i umiddelbar dannelse af et tungt 5 mælkehvidt bundfald, når den bandes med vand i forholdet ca. 10 ml vand pr. 100 mg etoposid. Når så lict som en lige så stor vægtmængde tauro-cholsyre i forhold til etoposidinkluderes i den flydende kapsel formulering, forsinkes bundfaldsdannelsin i mere end en time ved blanding af formuleringen med 10 ml vand. Følgende tabel illustrerer denne virkning 10 af taurocholsyre og andre galdesyier.In investigating the tea problem, it has been found that the above-mentioned capsule formulation results in immediate formation of a heavy milky white precipitate when bound with water in the ratio of approx. 10 ml water per 100 mg etoposide. When as lict as an equal amount of weight of tauro-cholic acid relative to etoposide is included in the liquid capsule formulation, the precipitate formation is delayed for more than one hour by mixing the formulation with 10 ml of water. The following table illustrates this effect 10 of taurocholic acid and other bile acids.
33
DK 164535 BDK 164535 B
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Overfladespændingsmålinger på de vandige fortyndinger af alle gal-desyreformuleringerne omtalt i den foregående tabel har da også bekræf- . tet, at der dannes micellære opløsninger af etoposid. Dette afspejles af, at når koncentrationen af taurocholsyre i opløsningen forøges, 5 mindskes overfladespændingen indtil en vis grænse og derefter ikke yderligere. Den koncentration, hvor ingen yderligere formindskelse af overfladespændingen finder sted, omtales som den kritiske micellære koncentration.Surface tension measurements on the aqueous dilutions of all the gallic acid formulations discussed in the preceding table have also confirmed. micellar solutions of etoposide are formed. This is reflected in the fact that as the concentration of taurocholic acid in the solution is increased, the surface tension is reduced to a certain limit and then not further. The concentration at which no further reduction in surface tension occurs is referred to as the critical micellar concentration.
Fænomenet med micellær opløsning af lægemidler med ringe vandoplø-10 selighed fremkaldt af galdesyre, herunder taurocholsyre, er tidligere blevet omtalt med hensyn til griseofulvin, hexesterol, glutethimid (Bates et al., Journal of Pharmaceutical Sciences, 55, 191 - 199), re-serpin, Malone et al., ibid, 55, 972-974 (1966), fedtsyrer og cholesterol (Westergaard et al., Journal of Clinical Investigation, 58, 97-108 15 (1976))..The phenomenon of micellar dissolution of drugs with low water solubility induced by bile acid, including taurocholic acid, has been previously discussed with respect to griseofulvin, hexesterol, glutethimide (Bates et al., Journal of Pharmaceutical Sciences, 55, 191-199), re -serpin, Malone et al., ibid, 55, 972-974 (1966), fatty acids and cholesterol (Westergaard et al., Journal of Clinical Investigation, 58, 97-108 (1976)).
Den foreliggende opfindelse tilvejebringer en farmaceutisk opløsning af etoposid, der har den enestående egenskab at give en stabil "tilsyneladende opløsning" af lægemidlet ved fortynding deraf med fra 1 til 100 rumfang vand. Opløsningen er stabil og fri for bundfald i mindst 20 to timer, hvilket er tilstrækkeligt til administrering til og absorption i et pattedyrs organisme. Det har vist sig, at biotilgængeligheden af etoposid efter oral administrering af den omhandlede dosisform er i alt . væsentligt ækvivalent med den, som opnås ved intravenøs administrering af en opløsning af lægemidlet. Det antages, at indtagelsen af den om-25 handlede dosisform og den resulterende fortynding deraf med maveindhold-et resulterer i dannelsen af en micellær opløsning af etoposid i maven, der let absorberes i den gastrointestinale kanal. Ansøgerne ønsker imidlertid ikke at være bundet til nogen teoretisk forklaring på mekanismen, hvorved den enestående orale biotilgængelighed af den omhandlede formu-30 lering opnås.The present invention provides a pharmaceutical solution of etoposide having the unique property of providing a stable "apparent solution" of the drug by dilution thereof with from 1 to 100 volumes of water. The solution is stable and free from precipitation for at least 20 two hours, which is sufficient for administration to and absorption in a mammalian organism. It has been found that the bioavailability of etoposide after oral administration of the subject dosage form is total. substantially equivalent to that obtained by intravenous administration of a solution of the drug. It is believed that the ingestion of the subject dosage form and the resulting dilution thereof with the gastric contents results in the formation of a micellar solution of etoposide in the stomach which is readily absorbed in the gastrointestinal tract. However, the applicants do not wish to be bound by any theoretical explanation of the mechanism by which the unique oral bioavailability of the present formulation is achieved.
Polyethylenglykol med en molekylvægt på 200 til 400 er blevet valgt som vehikel for præparatet. Polyethylenglykol har den nødvendige opløsningskapacitet for etoposid og udviser acceptabel viskositet og disper-gerbarhed i vand til at opfylde kravene for opfindelsen. Polyethylengly-35 kol med molekylvægt på 200 til 300 foretrækkes, da det er mindre viskøst end polyethylenglykol 400. Den lavere viskositet letter fremstillingen og øger dispergerbarheden af præparatet ved blanding med vand eller ma-veindhold. Andre bestanddele i præparatet tjener til at forbedre disper- 5Polyethylene glycol having a molecular weight of 200 to 400 has been selected as the vehicle for the composition. Polyethylene glycol has the necessary dissolution capacity for etoposide and exhibits acceptable viscosity and dispersibility in water to meet the requirements of the invention. Polyethylene glycol carbon having a molecular weight of 200 to 300 is preferred since it is less viscous than polyethylene glycol 400. The lower viscosity facilitates the preparation and increases the dispersibility of the composition by admixture with water or mauve content. Other ingredients in the composition serve to improve dispersion
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gerbarheden og lette micelledannelsen ved blanding deraf med vand eller til at forbedre foreneligheden af opløsningen med kapsel skallen, når ma- . terialet indkapsles i en blød gelatinekapsel ifølge den foretrukne udførelsesform af opfindelsen.the agility and facilitate the micelle formation by mixing it with water or to improve the compatibility of the solution with the capsule shell when the terial is encapsulated in a soft gelatin capsule according to the preferred embodiment of the invention.
5 Der anvendes fortrinsvis fra 5 til 9 vægtdele polyethylenglykol 300 pr. vægtdel etoposid. Inden for dette område er etoposids opløsningshastighed tilstrækkelig til bekvem fremstilling, der opnås en tilstrækkeligt flydende blanding til bekvem håndtering, og opløsningen er tilstrækkeligt koncentreret til, at en enhedsdosisform kan indeholdes i et 10 tilstrækkeligt lille opløsningsvolumen til, at indkapsling i en blød gelatinekapsel muliggøres. Mere fortyndede opløsninger kan selvfølgelig fremstilles til dosering ved hjælp af pipette eller teske. Sådanne omfattes også af opfindelsen.Preferably from 5 to 9 parts by weight of polyethylene glycol 300 are used. part by weight of etoposide. Within this range, the dissolution rate of etoposide is sufficient for convenient preparation, a sufficient liquid mixture is obtained for convenient handling, and the solution is sufficiently concentrated to contain a unit dosage form in a sufficiently small solution volume to allow encapsulation in a soft gelatin capsule. Of course, more dilute solutions can be prepared for dosing by pipette or teaspoon. Such are also encompassed by the invention.
Etoposidet pulveriseres fortrinsvis fint før formulering til det 15 omhandlede præparat, men dette er fortrinsvis af bekvemmelighedsårsager og er ikke nødvendigt, da der dannes en sand opløsning af etoposid i polyethylenglykol . Når etoposid opløses i et vandopløseligt organisk opløsningsmiddel, og den resulterende opløsning blandes med vand, udfælder etoposidet almindeligvis på grund af dets meget lave vandopløselighed.The etoposide is preferably finely pulverized prior to formulation for the present composition, but this is preferably for convenience and is not necessary as a true solution of etoposide is formed in polyethylene glycol. When etoposide is dissolved in a water-soluble organic solvent and the resulting solution is mixed with water, the etoposide usually precipitates due to its very low water solubility.
20 Som anført indeholder præparatet taurocholsyre, og tilstedeværelsen af denne bestanddel resulterer antageligt i dannelsen af en micellær opløsning, når præparatet blandes med vand.As stated, the composition contains taurocholic acid, and the presence of this component presumably results in the formation of a micellar solution when the composition is mixed with water.
Andre galdesyrer vil ligeledes fremme dannelsen af tilsyneladende mi cell ære opløsninger ved blanding af polyethylenglykolopløsningen med 25 vand, men de er ikke egnede til anvendelse i de omhandlede præparater, da de således fremkomne micellære opløsninger er ustabile eller ikke dannes ved sure pH-værdier. Natriumdeoxycholat eller natriumcholat danner micellære opløsninger med etoposid, men de micellære opløsninger har pH-værdier på henholdsvis 10,9 og 11,0. Ved surgøring fælder etoposidet 30 ud fra sådanne opløsninger. Disse er derfor ikke egnede til oral indgift på grund af maveindholdets sure natur. Ydermere foretrækkes sure betingelser ved indkapsling i bløde gelatinekapsel skal ler, da gelatinekapslen ødelægges af ifyldte opløsninger med pH-værdier over 8,0. Ved empiriske forsøg har det vist sig, at ca. 3,5 vægtdele taurocholsyre pr. vægtdel 35 etoposid fortrinsvis er ønskværdige for tilvejebringelse af en stabil mi cel!ær opløsning ved fortynding af præparatet med vand. Mindre mængder, såsom 2,0 vægtdele, og større mængder taurocholsyre kan anvendes.Other bile acids will also promote the formation of apparent cellular solutions by mixing the polyethylene glycol solution with 25 water, but they are not suitable for use in the present compositions, since the resulting micellar solutions are unstable or not formed at acidic pH values. Sodium deoxycholate or sodium cholate forms micellar solutions with etoposide, but the micellar solutions have pH values of 10.9 and 11.0, respectively. Upon acidification, the etoposide 30 precipitates from such solutions. Therefore, these are not suitable for oral administration due to the acidic nature of the stomach contents. Furthermore, acidic conditions are preferred when encapsulated in soft gelatin capsule clay, as the gelatin capsule is destroyed by pre-filled solutions with pH values above 8.0. In empirical experiments it has been found that approx. 3.5 parts by weight of taurocholic acid per by weight of etoposide is preferably desirable to provide a stable cellular solution by diluting the composition with water. Smaller amounts such as 2.0 parts by weight and larger amounts of taurocholic acid may be used.
Det tjener intet nyttigt formål at anvende mere end ca. 10 vægtdele tau- 6It serves no useful purpose to use more than approx. 10 parts by weight of tau- 6
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rocholsyre pr. vægtdel etoposid.rocholic acid per part by weight of etoposide.
En vandopløselig syre inkluderes i præparatet for at sikre, at der . opnås en sur pH-værdi ved fortynding til dannelse af den micel lære opløsning. Af hensyn til farmaceutisk formfuldendthed og let håndtering 5 ved fremstillingen foretrækkes det at anvende en fast vandopløselig organisk carboxylsyre, men andre syrer kan anvendes. Malein-, vin-, citron-, glucon- eller ascorbinsyre, der er vandopløselige, ikke-toksiske og bekvemme at håndtere ved fremstilling af farmaceutica, foretrækkes.A water-soluble acid is included in the composition to ensure that. an acidic pH is obtained by dilution to form the micel leather solution. For pharmaceutical completeness and ease of handling in the preparation, it is preferred to use a solid water-soluble organic carboxylic acid, but other acids may be used. Maleic, tartaric, citric, gluconic or ascorbic acids which are water-soluble, non-toxic and convenient to handle in the preparation of pharmaceuticals are preferred.
Mest foretrukket er citronsyre, der har vist sig at være passende, når 10 den anvendes i mængder fra 0,1 til 0,5 vægtdele pr. vægtdel etoposid.Most preferred is citric acid which has been found to be suitable when used in amounts of 0.1 to 0.5 parts by weight per liter. part by weight of etoposide.
Det mest foretrukne forhold er 0,2 vægtdele citronsyre pr. vægtdel etoposid.The most preferred ratio is 0.2 parts by weight of citric acid per liter. part by weight of etoposide.
Ethanol tjener i præparatet det vigtige formål at tilvejebringe en hurtig dispersion ved blanding med vand og letter dannelsen af den mi-15 cellære opløsning. Andre vandopløselige, polære organiske opløsningsmidler, såsom methanol, propanol, acetone etc., der også er effektive, er ikke egnede til oral indgift, og i overensstemmelse hermed er ethanol blevet valgt til dette formål. Mindst 5 vægtprocent ethanol i præparatet er nødvendigt til dette formål, men højere mængder, op til 20 vægtpro-20 cent, kan anvendes, især i tilfælde af pipette- eller teskefulddoseringsformer. Til indkapsling i en blød gelatinekapsel kan der maksimalt anvendes 10 vægtprocent ethanol i præparatet. Opløsninger med højere koncentrationer af ethanol end 10 vægtprocent kan fremkalde dehydrering af gelatinekapsel væggen og er følgelig ikke egnede til indkapsling i 25 denne type kapsel.Ethanol in the composition serves the important purpose of providing a rapid dispersion by mixing with water and facilitates the formation of the micellar solution. Other water-soluble polar organic solvents such as methanol, propanol, acetone etc. which are also effective are not suitable for oral administration and accordingly ethanol has been selected for this purpose. At least 5% by weight of ethanol in the composition is necessary for this purpose, but higher amounts, up to 20% by weight, can be used, especially in the case of pipette or teaspoon dosage forms. For encapsulation in a soft gelatin capsule, a maximum of 10 weight percent ethanol can be used in the preparation. Solutions with ethanol concentrations higher than 10% by weight can cause dehydration of the gelatin capsule wall and are therefore not suitable for encapsulation in this type of capsule.
Til anvendelse af det omhandlede præparat i enhedsdosisform indeholdt i en blød gelatinekapsel er det sluttelig ønskværdigt at inkludere op til ca. en vægtdel vand pr. vægtdel etoposid for at forbedre foreneligheden af præparatet med den bløde gelatinekapsel skal. Den hydrofi-30 le natur af polyethylenglykol, ethanol, citronsyre og taurocholsyre gør, at præparatet uddrager vandet fra kapsel skallen, og kan bevirke, at denne ødelægges ved længere opbevaring. I præparatet inkluderes der derfor vand i tilstrækkelig mængde, fortrinsvis en vægtdel vand pr. vægtdel etoposid, til at gøre præparatet foreneligt med kapselskallen og fore-35 bygge dehydrering deraf. Det er ønskværdigt at vælge en mængde vand, der vil give stabilitet i en opbevaringsperiode på 2 år ved stuetemperatur, når kapslen opbevares i en lukket beholder.Finally, for use of the present unit dosage formulation contained in a soft gelatin capsule, it is desirable to include up to approx. one part by weight of water per part by weight etoposide to improve the compatibility of the composition with the soft gelatin capsule. The hydrophilic nature of polyethylene glycol, ethanol, citric acid and taurocholic acid causes the preparation to extract the water from the capsule shell, and can cause it to be destroyed by longer storage. Therefore, the composition includes water in sufficient quantity, preferably one part by weight of water per day. part by weight of etoposide to make the composition compatible with the capsule shell and prevent dehydration thereof. It is desirable to select an amount of water that will provide stability for a storage period of 2 years at room temperature when the capsule is stored in a sealed container.
De foretrukne udførelsesformer af præparatet ifølge opfindelsen er 7The preferred embodiments of the composition of the invention are 7
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stabile, flydende præparater i form af sande opløsninger med følgende sammensætning.stable, liquid preparations in the form of true solutions of the following composition.
Bestanddel Vægtdele 5 polyethylenglykol 300 5 til 9 etoposid 1 citronsyre 0,1 til 0,5 taurocholsyre 2,0 til 10Ingredient Weight parts 5 polyethylene glycol 300 5 to 9 etoposide 1 citric acid 0.1 to 0.5 taurocholic acid 2.0 to 10
Ethanol 5 til 20 vægtprocent af 10 opløsningens samlede vægtEthanol 5 to 20% by weight of the total weight of the solution
Den mest foretrukne udførelsesform af præparatet ifølge opfindelsen er følgende sammensætning: 15 Bestanddel Væqtdele polyethylenglykol 300 5,8 etoposid, fint pulveriseret 1,0 citronsyre 0,2 ethanol 1,0 20 taurocholsyre 3,5 vand 1,0The most preferred embodiment of the composition of the invention is the following composition: Component Weight parts polyethylene glycol 300 5.8 etoposide, finely powdered 1.0 citric acid 0.2 ethanol 1.0 20 taurocholic acid 3.5 water 1.0
Den foretrukne sammensætning ifølge opfindelsen belyses nærmere i det følgende eksempel.The preferred composition of the invention is elucidated in the following example.
2525
Eksempel Følgende bestanddele afvejedes: 30 etoposid 25,0 g citronsyre, vandfri, USP 5,0 g polyethylenglykol 300 170,0 g ethanol, USP 25,0 g taurocholsyre 87,5 g 35 renset vand, USP 25,0 gExample The following ingredients were weighed: etoposide 25.0 g citric acid, anhydrous, USP 5.0 g polyethylene glycol 300 170.0 g ethanol, USP 25.0 g taurocholic acid 87.5 g purified water, USP 25.0 g
Taurocholsyren sættes portionsvis til polyethylenglykol 300 under omrøring til dannelse af en suspension. Vandet tilsættes dernæst, efter-The taurocholic acid is added portionwise to polyethylene glycol 300 with stirring to form a suspension. The water is then added, after-
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8 fulgt af ethanolen og citronsyren. Der dannes en opløsning, som opvarmes til 65°C, tillades at afkøle til 35eC, og filtreres ("Mil 1ipore AP 25 29325"). En atmosfære af nitrogen opretholdes over opløsningen under disse trin. Filtratet holdes ved 30-35eC, og etoposidet opløses dernæst 5 deri. Opløsningen analyseres dernæst (fundet: 71,3 mg etoposid pr. g) og fyldes i bløde gelatinekapsler med 100 mg etoposid pr. kapsel.8 followed by the ethanol and citric acid. A solution is formed which is heated to 65 ° C, allowed to cool to 35 ° C, and filtered ("Mil 1ipore AP 25 29325"). An atmosphere of nitrogen is maintained over the solution during these steps. The filtrate is maintained at 30-35 ° C and the etoposide is then dissolved therein. The solution is then analyzed (found: 71.3 mg etoposide per g) and filled into soft gelatin capsules with 100 mg etoposide per g. capsule.
Den ovennævnte kapselfyldningsopløsning har følgende karakteristika og stabilitet:The above capsule filling solution has the following characteristics and stability:
10 KARAKTERISTIKA10 CHARACTERISTICS
1. Farve mørkebrun 2. pH 4,6 3. Viskositet tilfredsstillende 15 4. Dispergerbarhed let dispergerbar 5. Skal forenelighed, fysisk forenelig 6. Bundfaldsdannelsestid ved fortynding med Η£θ til 1:1, >3 timer 1:5, 1:10 og 1:100.1. Color dark brown 2. pH 4.6 3. Viscosity satisfactory 4. Dispersibility easily dispersible 5. Must be compatible, physically compatible 6. Precipitation time by dilution with Η £ θ to 1: 1,> 3 hours 1: 5, 1: 10 and 1: 100.
2020
StabilitetStability
Opbevaringstemperatur Opbevaringstid % tilbageværende (dage) 25 4eC (kontrol) 8 100 70°C 5 102 70eC 8 102 56eC 8 102 30 37eC 8 105 25°C 8 99Storage temperature Storage time% remaining (days) 25 4eC (control) 8 100 70 ° C 5 102 70eC 8 102 56eC 8 102 30 37eC 8 105 25 ° C 8 99
Claims (14)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US59114484A | 1984-03-19 | 1984-03-19 | |
| US59114484 | 1984-03-19 |
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| Publication Number | Publication Date |
|---|---|
| DK122285D0 DK122285D0 (en) | 1985-03-18 |
| DK122285A DK122285A (en) | 1985-09-20 |
| DK164535B true DK164535B (en) | 1992-07-13 |
| DK164535C DK164535C (en) | 1992-11-30 |
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| Application Number | Title | Priority Date | Filing Date |
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| DK122285A DK164535C (en) | 1984-03-19 | 1985-03-18 | ETOPSIDE PREPARATION FOR ORAL ADMINISTRATION |
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| JP (1) | JPS60209516A (en) |
| KR (1) | KR850006136A (en) |
| AT (1) | AT392904B (en) |
| AU (1) | AU571308B2 (en) |
| BE (1) | BE901963A (en) |
| CA (1) | CA1238578A (en) |
| CH (1) | CH662731A5 (en) |
| DE (1) | DE3509741A1 (en) |
| DK (1) | DK164535C (en) |
| EG (1) | EG17521A (en) |
| ES (1) | ES8702140A1 (en) |
| FI (1) | FI84023C (en) |
| FR (1) | FR2561104B1 (en) |
| GB (1) | GB2155789B (en) |
| GR (1) | GR850688B (en) |
| IE (1) | IE58340B1 (en) |
| IL (1) | IL74615A (en) |
| IT (1) | IT1187640B (en) |
| LU (1) | LU85812A1 (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS60239418A (en) * | 1984-05-15 | 1985-11-28 | Nippon Kayaku Co Ltd | Soft capsule containing etoposide |
| JPS61189230A (en) * | 1985-02-19 | 1986-08-22 | Nippon Kayaku Co Ltd | Etoposide preparation |
| DE3629386A1 (en) * | 1986-08-29 | 1988-03-03 | Scherer Gmbh R P | GELATINE CAPSULES AND METHOD FOR THEIR PRODUCTION |
| US4927638A (en) * | 1986-10-08 | 1990-05-22 | Bristol-Myers Company | Etoposide solutions |
| US5154930A (en) * | 1987-03-05 | 1992-10-13 | The Liposome Company, Inc. | Pharmacological agent-lipid solution preparation |
| US5376381A (en) * | 1988-02-25 | 1994-12-27 | The Liposome Company, Inc. | Integrity protected gelatin |
| JP2000247911A (en) * | 1999-02-26 | 2000-09-12 | Hisamitsu Pharmaceut Co Inc | Absorption promoter for large intestine |
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| CH580255A5 (en) * | 1974-06-04 | 1976-09-30 | Calinter Sa | |
| DE2452785A1 (en) * | 1974-11-07 | 1976-05-13 | Universal Oil Prod Co | Engine crankcase gases treatment - by catalytic reactor in heat exchange and partial mixture with exhaust gases |
| FR2358144A1 (en) * | 1976-07-13 | 1978-02-10 | Lipha | Compsn. for treating biliary lithiasis - contains hymecromone and chenodeoxy-cholic acid, with lower cost and better tolerance |
| JPS5940137B2 (en) * | 1976-10-14 | 1984-09-28 | 武田薬品工業株式会社 | Pharmaceutical composition for oral administration |
| FR2410504A1 (en) * | 1977-12-05 | 1979-06-29 | Air Liquide | Safety control in chemical reactor carrying out oxidations - comprises oxygen concn. monitoring in gaseous phase and nitrogen injections if set concn. is reached |
| DE2809543A1 (en) * | 1978-03-06 | 1979-09-13 | Werner Henke | Rendering oil or gas well gases harmless - by desulphurisation and oxidn. in catalytic reactors |
| JPS60239418A (en) * | 1984-05-15 | 1985-11-28 | Nippon Kayaku Co Ltd | Soft capsule containing etoposide |
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1985
- 1985-02-08 NZ NZ211078A patent/NZ211078A/en unknown
- 1985-02-20 AU AU38975/85A patent/AU571308B2/en not_active Ceased
- 1985-03-05 FR FR8503221A patent/FR2561104B1/en not_active Expired
- 1985-03-14 ZA ZA851935A patent/ZA851935B/en unknown
- 1985-03-14 NL NL8500739A patent/NL8500739A/en not_active Application Discontinuation
- 1985-03-14 IT IT19897/85A patent/IT1187640B/en active
- 1985-03-15 NO NO851022A patent/NO170569C/en unknown
- 1985-03-15 IE IE68685A patent/IE58340B1/en not_active IP Right Cessation
- 1985-03-15 YU YU420/85A patent/YU45243B/en unknown
- 1985-03-15 FI FI851040A patent/FI84023C/en not_active IP Right Cessation
- 1985-03-15 IL IL74615A patent/IL74615A/en unknown
- 1985-03-16 EG EG164/85A patent/EG17521A/en active
- 1985-03-18 KR KR1019850001736A patent/KR850006136A/en not_active Ceased
- 1985-03-18 JP JP60054088A patent/JPS60209516A/en active Pending
- 1985-03-18 DK DK122285A patent/DK164535C/en not_active IP Right Cessation
- 1985-03-18 CA CA000476750A patent/CA1238578A/en not_active Expired
- 1985-03-18 PT PT80131A patent/PT80131B/en not_active IP Right Cessation
- 1985-03-18 BE BE0/214666A patent/BE901963A/en not_active IP Right Cessation
- 1985-03-18 DE DE19853509741 patent/DE3509741A1/en not_active Withdrawn
- 1985-03-18 GB GB08506943A patent/GB2155789B/en not_active Expired
- 1985-03-18 SE SE8501312A patent/SE8501312L/en not_active Application Discontinuation
- 1985-03-18 ES ES541370A patent/ES8702140A1/en not_active Expired
- 1985-03-18 LU LU85812A patent/LU85812A1/en unknown
- 1985-03-19 OA OA58543A patent/OA07968A/en unknown
- 1985-03-19 AT AT819/85A patent/AT392904B/en not_active IP Right Cessation
- 1985-03-19 GR GR850688A patent/GR850688B/el unknown
- 1985-03-19 CH CH1223/85A patent/CH662731A5/en not_active IP Right Cessation
-
1987
- 1987-09-29 MY MYPI87002211A patent/MY101916A/en unknown
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PBP | Patent lapsed |