IE58340B1 - Etoposide oral dosage form - Google Patents
Etoposide oral dosage formInfo
- Publication number
- IE58340B1 IE58340B1 IE68685A IE68685A IE58340B1 IE 58340 B1 IE58340 B1 IE 58340B1 IE 68685 A IE68685 A IE 68685A IE 68685 A IE68685 A IE 68685A IE 58340 B1 IE58340 B1 IE 58340B1
- Authority
- IE
- Ireland
- Prior art keywords
- composition
- etoposide
- weight
- acid
- polyethylene glycol
- Prior art date
Links
- 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 title claims abstract description 45
- 229960005420 etoposide Drugs 0.000 title claims abstract description 44
- 239000006186 oral dosage form Substances 0.000 title 1
- 239000000203 mixture Substances 0.000 claims abstract description 50
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 40
- 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 abstract description 22
- 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 abstract description 22
- 239000002202 Polyethylene glycol Substances 0.000 claims abstract description 12
- 229920001223 polyethylene glycol Polymers 0.000 claims abstract description 12
- 239000002775 capsule Substances 0.000 claims abstract description 10
- 239000002253 acid Substances 0.000 claims abstract description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 35
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 30
- 239000007903 gelatin capsule Substances 0.000 claims description 8
- 239000004615 ingredient Substances 0.000 claims description 8
- 239000002552 dosage form Substances 0.000 claims description 7
- 239000007788 liquid Substances 0.000 claims description 7
- 229940068886 polyethylene glycol 300 Drugs 0.000 claims description 7
- 238000005538 encapsulation Methods 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 108010010803 Gelatin Proteins 0.000 claims description 3
- 230000018044 dehydration Effects 0.000 claims description 3
- 238000006297 dehydration reaction Methods 0.000 claims description 3
- 229920000159 gelatin Polymers 0.000 claims description 3
- 239000008273 gelatin Substances 0.000 claims description 3
- 235000019322 gelatine Nutrition 0.000 claims description 3
- 235000011852 gelatine desserts Nutrition 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
- 239000008203 oral pharmaceutical composition Substances 0.000 claims description 2
- 238000000034 method Methods 0.000 claims 2
- IMROMDMJAWUWLK-UHFFFAOYSA-N Ethenol Chemical compound OC=C IMROMDMJAWUWLK-UHFFFAOYSA-N 0.000 claims 1
- 229920000219 Ethylene vinyl alcohol Polymers 0.000 claims 1
- 229940079593 drug Drugs 0.000 abstract description 8
- 239000003814 drug Substances 0.000 abstract description 8
- 238000009472 formulation Methods 0.000 abstract description 5
- 238000010521 absorption reaction Methods 0.000 abstract description 3
- 239000008297 liquid dosage form Substances 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 39
- 230000015572 biosynthetic process Effects 0.000 description 11
- 235000015165 citric acid Nutrition 0.000 description 9
- 229960004106 citric acid Drugs 0.000 description 8
- 239000012895 dilution Substances 0.000 description 7
- 238000010790 dilution Methods 0.000 description 7
- 230000037406 food intake Effects 0.000 description 7
- 239000002244 precipitate Substances 0.000 description 7
- 238000001990 intravenous administration Methods 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 5
- 239000003613 bile acid Substances 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 230000002496 gastric effect Effects 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 229940068918 polyethylene glycol 400 Drugs 0.000 description 3
- 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 2
- 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
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000004480 active ingredient Substances 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
- 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
- 230000000694 effects Effects 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- 238000011835 investigation Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- DNXIKVLOVZVMQF-UHFFFAOYSA-N (3beta,16beta,17alpha,18beta,20alpha)-17-hydroxy-11-methoxy-18-[(3,4,5-trimethoxybenzoyl)oxy]-yohimban-16-carboxylic acid, methyl ester Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(C(=O)OC)C(O)C1OC(=O)C1=CC(OC)=C(OC)C(OC)=C1 DNXIKVLOVZVMQF-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
- 150000000996 L-ascorbic acids Chemical class 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
- LCQMZZCPPSWADO-UHFFFAOYSA-N Reserpilin Natural products COC(=O)C1COCC2CN3CCc4c([nH]c5cc(OC)c(OC)cc45)C3CC12 LCQMZZCPPSWADO-UHFFFAOYSA-N 0.000 description 1
- QEVHRUUCFGRFIF-SFWBKIHZSA-N Reserpine Natural products O=C(OC)[C@@H]1[C@H](OC)[C@H](OC(=O)c2cc(OC)c(OC)c(OC)c2)C[C@H]2[C@@H]1C[C@H]1N(C2)CCc2c3c([nH]c12)cc(OC)cc3 QEVHRUUCFGRFIF-SFWBKIHZSA-N 0.000 description 1
- 206010041067 Small cell lung cancer Diseases 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229940099352 cholate Drugs 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- BHQCQFFYRZLCQQ-OELDTZBJSA-N cholic 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)=O)C)[C@@]2(C)[C@@H](O)C1 BHQCQFFYRZLCQQ-OELDTZBJSA-N 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
- 239000006185 dispersion Substances 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
- 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
- 239000000706 filtrate Substances 0.000 description 1
- 239000012530 fluid Substances 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
- 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
- -1 hexesterol Chemical compound 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
- 239000012669 liquid formulation Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000001404 mediated effect Effects 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
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 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
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000001737 promoting effect Effects 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
- BJOIZNZVOZKDIG-MDEJGZGSSA-N reserpine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C([C]5C=CC(OC)=CC5=N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 BJOIZNZVOZKDIG-MDEJGZGSSA-N 0.000 description 1
- 229960003147 reserpine Drugs 0.000 description 1
- MDMGHDFNKNZPAU-UHFFFAOYSA-N roserpine Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(OC(C)=O)C(OC)C1OC(=O)C1=CC(OC)=C(OC)C(OC)=C1 MDMGHDFNKNZPAU-UHFFFAOYSA-N 0.000 description 1
- 150000003839 salts Chemical class 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
- 230000007928 solubilization Effects 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- 239000002904 solvent 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)
Abstract
A liquid dosage form suitable for oral administration of etoposide which is sufficiently concentrated to be administered in capsule form and which provides improved absorption of the drug relative to prior oral formulations, comprises etoposide, polyethylene glycol, taurocholic acid, ethanol and a water-soluble acid.
Description
. The present invention refers to a drug bio effecting and body treating composition having e, glyeosidic active ingredient.
Etoposide is a semi-synthetic product derived from podophyllotoxin. The material is identified by the chemical' name 4 '~demethylepipodophyl2otoxin~9~(4,6-0(?)-ethylidene-beta-D-glucopyranoside). It is referred to in the literature as vp-16-213, VePesid , Ethylidene-Lignan P, and B?EG. It has been evaluated . for use in treatment of cancer under the auspicious of The National Cancer Institute under the number NSC-131540. 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.
. In investigations conducted under the auspicious of the National Cancer Institute, the drug was supplied as a solution for injection having the following composition:· etoposide, 100 mg; citric acid, anhydrous 10 mg; benzyl alcohol, 150 mg; polysorbate 80, purified, 400 mg; polyethylene glycol 300, 3.25 g; alcohol, absolute qs 5.12 g. Each ampule of the foregoing composition consisted of 5 ml of solution which was diluted 20 to times with 0.9% sodium chloride or 5% dextrose for injection before administration by slow intravenous infusion.
When the foregoing intravenous composition was administered by ingestion rather than injection,, the 5 ml ampoule was either taken as a teaspoon dose form or-first diluted with water, it was found that the bioavailabilitv by the oral route was •approximately 90S that by the intravenous route (M.D’Incalci et al., Cancer Chemoterapy and Pharmacology (1982) 7:141-145). A similar dose taken by capsule in which 100 mg of active ingredient was contained in approximately 1.3 ml of encapsulated solution in which the vehicle consisted of polyethylene glycol 400, glycerine, water, and citric acid yielded only about one-half the bioavailability of the intravenous solution when taken by ingestion (M.D’Incalci et al., loc. cit.). The present invention addresses this problem of reduced bioavailability of the capsule dosage form, and provides a liquid formulation of sufficiently high concentration for encapsulation which affords bioavailability upon ingestion equal to the intravenous solution.
The present invention takes advantage of our discovery that taurocholic acid when included in a solution dosage composition with etoposide results in markedly improved absorption of the drug following ingestion of the composition. It is belxved that this is due to the formation of a micellar solution of etoposide on dilution thereof with the gastric contents.
In investigating this problem, we have found that the capsule formulation referred to above when mixed with water in the proportion of about 10 ml of water per 100 mg of etoposide results in the immediate formation of a heavy, milky white precipitate. When as little as an equal weight of taurocholic acid relative to the etoposide is included in the liquid capsule formulation, precipitate formation is delayed for over an hour on mixing the formulation with 10 ml of water. The following tabulation illustrates this effect of taurocholic acid and other bile acids.
V EFFECT OF ADDED BILE ON PRECIPITATE FORMATION Bile Acid or Amount of* Etoposide Amount of BiJe Acid/ Precipitate Formation Solution pH Experiment No, Salt- (mg) Salt (mg) Time (hr) 1 2 3 4 5 δ 7 Taurocholic Acid 200 200 100 100 100 100 100 1000 50 0 1000 500 200 100 10 1,5 1.0 21,0 5,0 2,0 1,5 Instantaneous 4.7 S Sodium 200 1000 >24 9 Cholate 200 500 1,0 10.9' 10 100 10· 00 >24 II 100 500 4,0 12 Sodium 200 1000 >24 13 Deoxychoiate 200 500 >24 11,0 '^'Supplied as a solution having the following composition: etoposide, micronized 100,0 mg, polyethylene glycol 400 1084,0 mg . glycerol 81.5 mg. water 77.6 mg, citric acid 2.0 mg.
Surface tension measurements on the aqueous dilutions of the bile acid formulations referred to in the foregoing table have confirmed that, indeed, micellar solutions of etoposide are produced. This is reflected in the failure for a further decrease in surface tension to occur as the concentration of taurocholic acid in the solution is increased. That concentration where no further decrease in surface tension occurs is referred to as critical micellar concentration.
The phenomenon of micellar solubilization of poorly water10 soluble drugs mediated by bile acids, including taurocholic acid, has been previously reported with respect to griseofulvin, hexesterol, glutethimide (Bates efc al., Journal of Pharmaceutical Sciences, 55, 191-199), reserpine, Malone et al., ibid. 55, 972-974 (1966), fatty acids, and cholesterol (Westergaard et al., Journal of Clinical Investigation, 58, 97-108 (1976)b According to the invention, there is provided an oral pharmaceutical composition in the form of a homogeneous liquid comprising etoposide, polyethylene glycol, taurocholic acid, ethanol, and a water soluble acid.
The pharmaceutical solution of etoposide of the present invention has the unique property of providing a stable apparent solution of the drug upon dilution thereof with from 1 to 100 volumes of water. The solution is stable and free of precipitate for a period of at least two hours sufficient to permit administration to and absorption by the mammalian organism. It has been found that the bioavailabilitv of etoposide following oral administration of the present dosage form is substantially equivalent to that achieved by intravenous administration of a solution of a drug. It is believed that ingestion of the present dosage form and resulting dilution thereof by the stomach contents results in the formation of a micellar solution of etoposide in the stomach which is readily absorbed by the gastrointestinal tract. Applicants do not wish to be bound, however, by any theoretical explanation of the mechanism by which the superior oral bioavailability of the present formulation is achieved.
Polyethylene glycol having a molecular weight of from 200 to 400 is preferred as the vehicle for the present composition. Polyethylene glycol has the necessary solvent capability for etoposide and exhibits acceptable viscosity and dispersibility in water to meet the requirements of the present invention. Polyethylene glycol having molecular weight of from 200 to 300 is more preferred because it is less viscous than polyethylene glycol 400. The lower viscosity facilitates manufacturing manipulations, and increases the dispersibility of the'composition on mixing with water or gastric contents. Other ingredients or the composition serve to improve dispersibility and to facilitate micelle formation on mixing thereof with water, or to improve compatibility of the solution with the oapsule shell when the material is encapsulated in preferred embodiment of the a soft gelatin invention. capsule according to a From 5 to 9 parts by weight of polyethylene glycol 300 per part by weight of etoposide is preferably employed. Within this range the rate of solution ox the etoposide is sufficient for manufacturing convenience, a sufficiently fluid mixture is obtained for convenient handling,, and the solution is sufficiently concentrated so that a unit dosage form may be contained in a sufficiently small volume of solution to permit encapsulation within a soft gelatin capsule. More dilute solutions may, of course, be prepared for dropper or teaspoon dosage use. Such is also contemplated by the present invention.
The etoposide is preferably micronized prior to formulation into the present composition, but this is primarily a convenience and not a necessity since a true solution of etoposide ·in the polyethylene glycol is formed. Ordinarily when etoposide is dissolved in a water soluble organic solvent, and the resulting soiution mixed with water, the etoposide precipitates because of its very low water solubility. According to the present invention, taurocholic acid is included in the composition and the presence of this ingredient results, presumably, in the formation of a micellar solution when the composition is mixed with water.
Other bile acids will similarly promote the formation of apparent micellar solutions on mixing of the polyethylene glycol solution with water, but they are unsuifced for use in the present compositions since the so-produced micellar solutions are unstable or do not form at acid pH. Sodium deoxycholate or sodium cholate form micellar solutions with etoposide, but the micellar solutions have pH values of pH 10.9 and pH 11.0 respectively. Upon acidification, the etoposide precipitates from such solutions. Such- are not therefor suitable for ingestion due to the acidic nature or the gastric contents. Furthermore, for encapsulation within a soft gelatin capsule shell an acidic pH is preferred because the gelatin shell is disrupted by fill-solutions. having pH values in excess of pH 8.0. It has been found by empirical experimentation that preferably about 3.5 parts by weight of taurocholic acid per part by weight of etoposide are desirable to provide a stable micellar solution on dilution of the composition with water. Smaller amounts such as 2,.0 parts-by weight, and larger amounts of taurocholic acid may be employed. No useful purpose is served by using more than about 10 parts by weight of taurocholic acid per part by weight of etoposide.
A water soluble acid Is included in the composition to assure that an acidic pH value is obtained upon dilution to form the micellar solution. For purposes of pharmaceutical elegance and ease of handling in a manufacturing operation, we prefer to use a solid water-soluble organic carboxylic acid, but other acids may be employed. We prefer maleic, tartaric, citric, gluconic, or ascorbic acids which are water-soluble, non-toxic and convenient to handle in a pharmaceutical manufacturing operation. Most ©referred is citric acid which we have found to be appropriate when used in from 0.1 to 0.5 parts by weight per part by weight of etoposide. The most preferred proportion is 0.2 parts by weight of citric acid per part by weight of etoposide Ethanol serves the important purpose in the composition of promoting rapid dispersion on mixing with water and facilitates 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 ingestion and, accordingly ethanol has been selected for this purpose. At least 5% by weight of the composition of ethanol is necessary for this purpose, but higher amounts up to 20% by weight may be used, particularly for purposes of a dropper or teaspoon dosage rorm.
For encapsulation within a soft gelatin capsule, a maximum of 10% by weight of ethanol in the composition may be used. Solutions having higher concentrations of ethanol than 10% by weight may cause dehydration of the gelatin capsule wall and hence may not be suitable for encapsulation with this type of a capsule.
Finally, for use of the present composition in a unit dose form contained within a soft gelatin capsule it is desirable to include up to about one part by weight of water per part by weight of etoposide to improve the compatibility of the composition with the soft gelatin capsule shell. The hydrophilic nature of polyethyleneglycol, ethanol, citric acid, and taurocholic acid causes the composition to abstract the water from the capsule shell and may cause it rupture on prolonged storage. Sufficient water is therefore included in the composition, preferably one part by weight of water per part by weight of etoposide, to render the composition compatible with the capsule shell and prevent dehydration thereof. It is desirable to select an amount of water which will confer stability for a storage period of two years at room temperature when the capsules are stored in a closed container.
The preferred embodiments of the present invention are stable, liquid compositions in the form of true solutions having the following composition: .1 ?ί Ingredient Parts by Weight polyethanol glycol 300 etoposide citric acid 5 to 9 1 0.1 to 0.5 5 taurocholic acid 2.0 to 10 ethanol 5 to 20% by weight of total solution weight The most preferred embodiment the following composition: of the present invention is 10 Ingredient Parts by Weight polyethylene glycol 300 6.8 etoposide, micronized 1.0 citric acid 0.2 ethanol 1.0 15 taurocholic acid 3.5 water 1.0 The following example constitutes a description of the preferred composition of the present invention.
Example 2o The following ingredients were weighed: Etoposide 25.Og Citric Acid, Anhydrous, USP 5'. Og Polyethylene glycol 300 170.Og Alcohol, USP 25.Og Taurocholic Acid 87.5g Purified Water, USP .Og The taurocholic acid is added portionwise to the polyethylene glycol 300 with stirring to form a suspension. The water is then added followed hy the alcohol and citric acid. A solution forms which is warmed to 65°C, allowed to cool to 35eC, and filtered (Millipore A? 25 29325). An atmosphere of nitrogen is maintained over the solution during those steps. The filtrate is kept at 30-35°C, and the etoposide is then dissolved therein. The solution is then assayed (found 71.3 mg/g of etoposide) and filled into soft gelatin capsules at 100 mg etoposide per tq capsule.
•The foregoing capsule-fill solution has the following characteristics, and stability.
CHARACTERISTICS 1. Color 2. pH 3. viscosity 4. Dispersibility . Shell Compatibility, Physical 6. Precipitation formation time on dilution with H^O to 1:1, 1:5, 1:10 and 1:100 Dark Brown 4.6 Satisfactory Easily dispersible Compatible >3 hours STABILITY Storage Temperature Storage Time (Days) % Remaining 4°C (Control) 8 100 70&C 5 102 70eC 8 102 56°C 8 102 37°C 8 105 25°C 8 99
Claims (14)
1. An oral pharmaceutical composition in the form of a homogeneous liquid comprising etoposide, polyethylene glycol, taurocholic acid, ethanol, and 5 a water soluble acid.
2. The composition of Claim 1 in the form of a dosage unit containing from 10 mg to 100 mg of etoposide.
3. The composition of claim 1 or 2 in dosage unit 10 form wherein said homogeneous liquid is contained within a soft gelatin capsule.
4. The composition of claim 3 wherein said homogeneous liquid also contains water in an amount sufficient to prevent dehydration of the capsule shell and to render 15 said shell stable during a storage period of at least 2 years at room temperature in a closed container.
5. The composition of any of claims 1 to 4 wherein the molecular weight of the polyethylene glycol is within the range of about 200 to 400. 20
6. The composition of claim 5 wherein the molecular weight of the polyethylene glycol is about 300.
7. The composition of any of claims 1 to 6 wherein the weight of' polyethylene glycol is from the weight of etoposide. 5 to 9 times 8. The composition of any of claims 1 to 7 wherein said wate r soluble acid is a non-toxic organic carboxylic acid • 9. The composition of any of claims 1 to 7 wherein said water soluble acid is citric acid. 10. The composition of any of claims 1 to 9 wherein from 2.0 to 10 parts by weight of taurocholic acid per 4 part by weight of etoposide is employed.
8. 11. The composition of claim 10 wherein about 3.5 10 parts by weight of taurocholic acid per part by weight of etoposide is employed.
9. 12. The composition of any of claims 1 to 11 wherein the amount of ethanol is from 5 to 20% by weight.
10. 13. A liquid pharmaceutical dosage form comprising a 15 solution of the following composition: Ingredient Parts by height polyethylene glycol 300 5 to 9 etoposide 1 citric acid 0.1 to 0.5 taurocholic acid 2.0 to 10 ethanol 5 to 20% by weight of the composition
11. 14. The composition of claim 13 comprising a solution adapted for encapsulation within a soft gelatin 25 shell and having the following composition: Ingredient Parts by Weight polyethylene glycol 300 · 6.8 etoposide, micronized 1.0 citric acid o.2 ethenol 1.0 taurocholic acid 3.5 wete r * 1.0
12. 15. A composition as claimed in claim 1, the ingredients of which are substantially as set forth in the foregoing 10 Example.
13. 16. A method for the production of dosage forms as claimed in claim 13, substantially as described in the foregoing Example.
14. 17. A dosage form produced by the method of claim 16.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US59114484A | 1984-03-19 | 1984-03-19 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IE850686L IE850686L (en) | 1985-09-19 |
| IE58340B1 true IE58340B1 (en) | 1993-09-08 |
Family
ID=24365235
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE68685A IE58340B1 (en) | 1984-03-19 | 1985-03-15 | Etoposide oral dosage form |
Country Status (28)
| Country | Link |
|---|---|
| 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) |
| MY (1) | MY101916A (en) |
| NL (1) | NL8500739A (en) |
| NO (1) | NO170569C (en) |
| NZ (1) | NZ211078A (en) |
| OA (1) | OA07968A (en) |
| PT (1) | PT80131B (en) |
| SE (1) | SE8501312L (en) |
| YU (1) | YU45243B (en) |
| ZA (1) | ZA851935B (en) |
Families Citing this family (7)
| 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 |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
-
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 NL NL8500739A patent/NL8500739A/en not_active Application Discontinuation
- 1985-03-14 ZA ZA851935A patent/ZA851935B/en unknown
- 1985-03-14 IT IT19897/85A patent/IT1187640B/en active
- 1985-03-15 IE IE68685A patent/IE58340B1/en not_active IP Right Cessation
- 1985-03-15 NO NO851022A patent/NO170569C/en unknown
- 1985-03-15 FI FI851040A patent/FI84023C/en not_active IP Right Cessation
- 1985-03-15 IL IL74615A patent/IL74615A/en unknown
- 1985-03-15 YU YU420/85A patent/YU45243B/en unknown
- 1985-03-16 EG EG164/85A patent/EG17521A/en active
- 1985-03-18 LU LU85812A patent/LU85812A1/en unknown
- 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 GB GB08506943A patent/GB2155789B/en not_active Expired
- 1985-03-18 BE BE0/214666A patent/BE901963A/en not_active IP Right Cessation
- 1985-03-18 KR KR1019850001736A patent/KR850006136A/en not_active Application Discontinuation
- 1985-03-18 PT PT80131A patent/PT80131B/en not_active IP Right Cessation
- 1985-03-18 DE DE19853509741 patent/DE3509741A1/en not_active Withdrawn
- 1985-03-18 CA CA000476750A patent/CA1238578A/en not_active Expired
- 1985-03-18 ES ES541370A patent/ES8702140A1/en not_active Expired
- 1985-03-18 SE SE8501312A patent/SE8501312L/en not_active Application Discontinuation
- 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 |
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| MM4A | Patent lapsed |