WO2013122135A1 - 経口用医薬組成物 - Google Patents
経口用医薬組成物 Download PDFInfo
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- WO2013122135A1 WO2013122135A1 PCT/JP2013/053514 JP2013053514W WO2013122135A1 WO 2013122135 A1 WO2013122135 A1 WO 2013122135A1 JP 2013053514 W JP2013053514 W JP 2013053514W WO 2013122135 A1 WO2013122135 A1 WO 2013122135A1
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- WIPO (PCT)
- Prior art keywords
- pharmaceutical composition
- oral pharmaceutical
- mass
- composition according
- metal salt
- Prior art date
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- 239000000203 mixture Substances 0.000 claims description 35
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- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 26
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- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 238000001125 extrusion Methods 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 239000007888 film coating Substances 0.000 description 1
- 238000009501 film coating Methods 0.000 description 1
- 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 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
- 239000000347 magnesium hydroxide Substances 0.000 description 1
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 1
- 239000000395 magnesium oxide Substances 0.000 description 1
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 1
- 239000000391 magnesium silicate Substances 0.000 description 1
- 229910052919 magnesium silicate Inorganic materials 0.000 description 1
- 235000019792 magnesium silicate Nutrition 0.000 description 1
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 description 1
- 235000016337 monopotassium tartrate Nutrition 0.000 description 1
- VRVKOZSIJXBAJG-TYYBGVCCSA-M monosodium fumarate Chemical compound [Na+].OC(=O)\C=C\C([O-])=O VRVKOZSIJXBAJG-TYYBGVCCSA-M 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229960003975 potassium Drugs 0.000 description 1
- KYKNRZGSIGMXFH-ZVGUSBNCSA-M potassium bitartrate Chemical compound [K+].OC(=O)[C@H](O)[C@@H](O)C([O-])=O KYKNRZGSIGMXFH-ZVGUSBNCSA-M 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 229960002816 potassium chloride Drugs 0.000 description 1
- 229940086065 potassium hydrogentartrate Drugs 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 235000010241 potassium sorbate Nutrition 0.000 description 1
- 239000004302 potassium sorbate Substances 0.000 description 1
- 229940069338 potassium sorbate Drugs 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 238000005096 rolling process Methods 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 235000010378 sodium ascorbate Nutrition 0.000 description 1
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 description 1
- 229960005055 sodium ascorbate Drugs 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 229960003885 sodium benzoate Drugs 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 229940080237 sodium caseinate Drugs 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- 235000019259 sodium dehydroacetate Nutrition 0.000 description 1
- 229940079839 sodium dehydroacetate Drugs 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 239000004320 sodium erythorbate Substances 0.000 description 1
- 235000010352 sodium erythorbate Nutrition 0.000 description 1
- 229940079827 sodium hydrogen sulfite Drugs 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 235000011121 sodium hydroxide Nutrition 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 239000001394 sodium malate Substances 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 235000019830 sodium polyphosphate Nutrition 0.000 description 1
- 229960004025 sodium salicylate Drugs 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 description 1
- DSOWAKKSGYUMTF-GZOLSCHFSA-M sodium;(1e)-1-(6-methyl-2,4-dioxopyran-3-ylidene)ethanolate Chemical compound [Na+].C\C([O-])=C1/C(=O)OC(C)=CC1=O DSOWAKKSGYUMTF-GZOLSCHFSA-M 0.000 description 1
- RBWSWDPRDBEWCR-RKJRWTFHSA-N sodium;(2r)-2-[(2r)-3,4-dihydroxy-5-oxo-2h-furan-2-yl]-2-hydroxyethanolate Chemical compound [Na+].[O-]C[C@@H](O)[C@H]1OC(=O)C(O)=C1O RBWSWDPRDBEWCR-RKJRWTFHSA-N 0.000 description 1
- WTWSHHITWMVLBX-DKWTVANSSA-M sodium;(2s)-2-aminobutanedioate;hydron Chemical compound [Na+].[O-]C(=O)[C@@H](N)CC(O)=O WTWSHHITWMVLBX-DKWTVANSSA-M 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 229940032147 starch Drugs 0.000 description 1
- 238000009495 sugar coating Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000013337 tricalcium citrate Nutrition 0.000 description 1
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 1
- UJMBCXLDXJUMFB-UHFFFAOYSA-K trisodium;5-oxo-1-(4-sulfonatophenyl)-4-[(4-sulfonatophenyl)diazenyl]-4h-pyrazole-3-carboxylate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)C1=NN(C=2C=CC(=CC=2)S([O-])(=O)=O)C(=O)C1N=NC1=CC=C(S([O-])(=O)=O)C=C1 UJMBCXLDXJUMFB-UHFFFAOYSA-K 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
Classifications
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- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
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- 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
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
- A61K31/7072—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
- A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
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- A61K9/20—Pills, tablets, discs, rods
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
Definitions
- the present invention relates to ⁇ , ⁇ , ⁇ -trifluorothymidine (FTD) and 5-chloro-6- (2-iminopyrrolidin-1-yl) methyl-2,4 (1H, 3H) -pyrimidinedione hydrochloride (TPI). ) Containing an oral pharmaceutical composition.
- TTD ⁇ , ⁇ , ⁇ -trifluorothymidine
- TPI 5-chloro-6- (2-iminopyrrolidin-1-yl) methyl-2,4 (1H, 3H) -pyrimidinedione hydrochloride
- the compounding agent suppresses the degradation of FTD in vivo by adding TPI having thymidine phosphorylase inhibitory activity to FTD that exhibits antitumor effect by inhibiting the synthesis of thymidylate and inhibiting DNA synthesis by incorporation into DNA. It is an antitumor agent with enhanced tumor effect (Patent Document 1).
- Non-patent Documents 1 and 2 an antitumor agent “TAS-102” containing FTD and TPI in a molar ratio of 1: 0.5 is under development as a preparation that can be administered orally.
- Non-patent Documents 1 and 2 tablets, granules, capsules and the like are known for TAS-102 preparations that can be administered orally.
- Patent Documents 1 and 2 the quality of the preparation, particularly the storage stability, has not been sufficiently studied.
- an object of the present invention is to provide an oral pharmaceutical composition containing FTD and TPI which can be administered orally with an active ingredient stable even under high humidity conditions.
- the present inventor has evaluated the storage stability of various additives added to FTD and TPI, and the amount of related substances increases when a composition using a metal salt as an additive is stored. It has been found that a stable oral pharmaceutical composition can be obtained if the metal salt is not substantially contained, and the present invention has been completed.
- the present invention provides an oral pharmaceutical composition containing FTD and TPI as active ingredients and substantially free of an additive comprising a metal salt.
- the present invention also provides an oral pharmaceutical preparation that is coated with the oral pharmaceutical composition.
- the stability of the preparation is ensured even under high temperature and / or high humidity conditions, a high-quality preparation can be provided to patients and medical staff.
- the active ingredients of the oral pharmaceutical composition of the present invention are FTD and TPI.
- the content molar ratio of FTD and TPI in the composition is preferably 1: 0.5.
- the FTD content per dosage unit of the oral pharmaceutical composition is preferably 5 to 35 mg, more preferably 15 to 20 mg.
- the contents of FTD and TPI, which are active ingredients in the oral pharmaceutical composition of the present invention vary depending on the dosage form, administration plan, etc., and are not particularly limited and may be selected as appropriate, both of which are active ingredients in the pharmaceutical composition The amount is preferably about 1 to 40% by mass.
- the oral pharmaceutical composition of the present invention is characterized in that it contains substantially no metal salt that increases the production of FTD and TPI related substances.
- metal salts include alkali metal salts and alkaline earth metal salts.
- alkali metal salts include sodium benzoate, sodium alginate, sodium ascorbate, sodium aspartate, sodium hydrogen carbonate, sodium hydrogen sulfite, sodium carbonate, sodium carboxymethyl starch, sodium caseinate, carmellose sodium, sodium chloride, sodium citrate, Anhydrous sodium citrate, copper chlorofin sodium, sodium dehydroacetate, sodium dihydrogen phosphate, sodium erythorbate, sodium hydroxide, sodium lauryl sulfate, DL-sodium malate, sodium pyrosulfite, sodium oleate, sodium polyphosphate, Natri such as sodium salicylate, monosodium fumarate, sodium sulfite, DL-sodium tartrate, L-sodium tartrate Unsalted; carmellose potassium, potassium carbonate, and potassium hydrogen tartrate, potassium carbonate, potassium chloride, potassium salts such as potassium sorbate.
- alkaline earth metals examples include calcium salts such as calcium acetate, calcium carbonate, calcium chloride, carmellose calcium, calcium citrate, calcium gluconate, calcium lactate, calcium monohydrogen phosphate, calcium silicate, calcium stearate, and calcium sulfate; Mention magnesium salts such as magnesium aluminate metasilicate, magnesium aluminate silicate, magnesium carbonate, magnesium chloride, magnesium hydroxide, magnesium magnesium hydroxide, magnesium oxide, magnesium silicate, magnesium aluminate silicate, magnesium stearate Can do.
- the natural product containing an alkali metal salt and / or an alkaline-earth metal salt like talc can be mentioned.
- metal salts it is preferable not to contain an alkaline earth metal salt from the viewpoint of the stability of the active ingredient, and it is more preferable not to include talc, carmellose calcium and magnesium stearate.
- substantially does not contain an additive comprising a metal salt means that the additive comprising a metal salt is not contained at all or is small in a range that does not impair the stability of FTD and TPI.
- the specific metal salt content is more preferably from 0 to 0.1 parts by weight, more preferably from 0 to 0.05 parts by weight, even more preferably from 0 to 0.01 parts by weight, based on 1 part by weight of FTD. 0 parts by mass is particularly preferred.
- the oral pharmaceutical composition of the present invention does not substantially contain an additive comprising a metal salt, and contains a specific sugar alcohol or disaccharide as an excipient, so that it can be stored under high humidity conditions. In addition, it can function sufficiently as an oral pharmaceutical composition while suppressing an increase in the production of FTD and TPI related substances.
- the sugar alcohol or disaccharide usable in the present invention is preferably lactose (including anhydrides and hydrates), purified sucrose, mannitol or erythritol, more preferably lactose, purified sucrose or mannitol, particularly lactose or mannitol. preferable.
- lactose including anhydrides and hydrates
- purified sucrose mannitol or erythritol
- more preferably lactose purified sucrose or mannitol, particularly lactose or mannitol. preferable.
- the content of the sugar alcohol or disaccharide in the oral pharmaceutical composition of the present invention is preferably 3.6 parts by mass or more per 1 part by mass of FTD from the viewpoint of the stability of FTD and TPI and the function as an excipient. 3.6 to 50 parts by mass is more preferable, 3.7 to 25 parts by mass is further preferable, and 3.7 to 10 parts by mass is further preferable.
- the proportion of the sugar alcohol or disaccharide in the oral pharmaceutical composition of the present invention is preferably 50 to 100% by mass of the total amount of additives from the viewpoint of the stability of the active ingredient, and preferably 70 to 100% by mass. The range is more preferable, and 70 to 98% by mass is particularly preferable.
- excipients other than sugar alcohols and disaccharides may be added to the pharmaceutical composition for oral administration of the present invention, but from the viewpoint of the stability of the active ingredients,
- the proportion of saccharides is preferably 50% by mass or more, more preferably 70% by mass or more, more preferably 90% by mass or more, and particularly preferably 100% by mass.
- a disintegrating agent can be added to the oral pharmaceutical composition of the present invention in addition to the above excipients in order to ensure good disintegration during oral administration.
- the disintegrant include low-substituted hydroxypropyl cellulose, corn starch, partially pregelatinized starch, carmellose, crospovidone, crystalline cellulose, and the like. From the viewpoint of stability of FTD and TPI, low-substituted hydroxypropyl cellulose. , Corn starch, partially pregelatinized starch or carmellose are preferred, and low-substituted hydroxypropylcellulose, corn starch or partially pregelatinized starch is particularly preferred. These may be used alone or in combination of two or more.
- the content of the disintegrant is preferably 2 to 16% by mass in the total amount of the oral pharmaceutical composition from the viewpoint of achieving both the uniformity of the drug content and the disintegration property of the tablet in the oral pharmaceutical composition of the present invention. More preferably, it is 3 to 13% by mass, still more preferably 3 to 10% by mass, and particularly preferably 3 to 7% by mass.
- the oral pharmaceutical composition of the present invention may further contain various commonly used additives as long as the effects of the present invention are not hindered.
- the additive is not particularly limited as long as it is generally used.
- the binder include hydroxypropyl cellulose, hypromellose and polyvinyl alcohol.
- the lubricant include hardened oil, stearic acid, sucrose fatty acid ester, etc., preferably hardened oil or stearic acid, more preferably stearic acid.
- the colorant include edible yellow No. 5 dye, edible blue No.
- the content of the binder is preferably 0.001 to 5% by mass, more preferably 0.01 to 3% by mass in the total composition.
- the content of the lubricant is preferably 0.001 to 3% by mass, more preferably 0.01 to 2% by mass in the total composition.
- Examples of the form of the oral pharmaceutical composition of the present invention include granulated products, compression-molded products (for example, uncoated tablets), and mixtures.
- the oral pharmaceutical composition of the present invention may be used as a pharmaceutical preparation as it is, but it can be further provided with a coating on its surface to form a stable and easy-to-use oral pharmaceutical preparation.
- the coating includes film coating and sugar coating.
- the coating base include hypromellose, ethyl cellulose, hydroxypropyl cellulose, polyvinyl alcohol, sucrose and the like.
- plasticizer examples include polyethylene glycol.
- colorant examples include edible tar dyes, edible tar dye lakes, iron sesquioxide, yellow iron sesquioxide, and titanium oxide.
- flavoring agents include various flavors of orange and lemon.
- corrigent examples include l-menthol, camphor and mint, and may be used alone or in combination of two or more.
- a lubricant containing a metal salt such as magnesium stearate, talc, and light anhydrous silicic acid to the surface.
- the total amount of the coating layer is preferably 1 to 5% by mass, more preferably 2 to 4% by mass in the total preparation.
- Examples of the oral pharmaceutical preparation of the present invention include tablets, granules, powders, fine granules and the like. Tablets include chewable tablets, troches, drops, and compositions that dissolve or disintegrate rapidly in the oral cavity and can be taken without water, and also include effervescent tablets that are dissolved during use. Granules, powders, and fine granules include dry syrups that are used upon dissolution, and powders that dissolve rapidly in the oral cavity and can be taken without water.
- the oral pharmaceutical composition and pharmaceutical preparation of the present invention can be produced by a known method for producing an orally administered preparation.
- granulation methods fluidized bed granulation method, stirring granulation method, rolling fluidized granulation method, extrusion granulation method, spray granulation method, crushing granulation method, etc. Can be manufactured.
- the granulation principle it is roughly divided into a dry granulation method and a wet granulation method, but the dry granulation method is preferable from the viewpoint of stability of FTD and TPI.
- the present invention there is a possibility that it may occur when an oral pharmaceutical composition and pharmaceutical preparation containing FTD and TPI as active ingredients are produced by substantially not including the additive comprising the metal salt. It is possible to suppress an increase in the production of related substances of active ingredients.
- the said related substance means things other than FTD, TPI, and an additive, and mainly refers to the structural related compound of the said 2 active ingredient.
- the metal salt is selected from an alkali metal salt and an alkaline earth metal salt.
- the metal salt is selected from a sodium salt, a potassium salt, a calcium salt, and a magnesium salt.
- the content of the metal salt is 0 to 0.1 parts by weight, preferably 0 to 0.05 parts by weight, more preferably 0 to 0.01 parts by weight, and still more preferably 0, relative to 1 part by weight of the FTD.
- the sugar alcohol or disaccharide contained as an excipient is one or more selected from lactose, purified white sugar, erythritol and mannitol, preferably one or two selected from lactose, purified white sugar and mannitol
- the content of sugar alcohol or disaccharide is 3.6 parts by mass or more, preferably 3.6 to 50 parts by mass, more preferably 3.7 to 25 parts by mass, further preferably 1 part by mass of FTD.
- an oral pharmaceutical composition according to [6] which is 3.7 to 10 parts by mass.
- the disintegrant one or more kinds selected from low-substituted hydroxypropylcellulose, carmellose, corn starch, partially pregelatinized starch and crospovidone, preferably low-substituted hydroxypropylcellulose, carmellose, cornstarch and Any one or two or more selected from partially pregelatinized starch, more preferably one or two selected from low-substituted hydroxypropylcellulose, corn starch and partially pregelatinized starch
- the content of the disintegrant is 2 to 16% by mass, preferably 3 to 13% by mass, more preferably 3 to 10% by mass, and particularly preferably 3 to 7% by mass in the total amount of the composition [8] ]
- the oral pharmaceutical composition of description one or more kinds selected from hardened oil, stearic acid and sucrose fatty acid ester, preferably one or two kinds of hardened oil and stearic acid, more preferably stearic acid.
- the oral pharmaceutical composition according to [10] wherein the content of the lubricant is 0.001 to 3% by mass, preferably 0.01 to 2% by mass, based on the total composition.
- the oral pharmaceutical composition according to any one of [1] to [11], containing FTD and TPI at a molar ratio of 1: 0.5.
- Example 1 1 g of FTD, 0.471 g of TPI, 3.779 g of lactose hydrate, 0.75 g of carmellose “NS-300” (manufactured by Gotoku Pharmaceutical) and 0.15 g of stearic acid were thoroughly mixed in a mortar, and 123 mg was weighed. Tablets were obtained by compression molding at 1 ton using a ⁇ 7 mm, R10 mm punch and a hydraulic press (manufactured by Riken Seiki) (see Table 1).
- Example 2 A tablet was obtained according to the same method as in Example 1 except that carmellose was not added. However, the tablet mass was set to 108 mg in order to obtain a mass corresponding to FTD 20 mg (see Table 1).
- Example 3 Tablets were obtained in the same manner as in Example 1 except that corn starch “Corn Starch W” (manufactured by Nippon Shokuhin Kako) was used instead of carmellose (see Table 1).
- Example 4 Tablets were obtained in the same manner as in Example 1 except that partially pregelatinized starch “PCS (PC-10)” (manufactured by Asahi Kasei Chemicals) was used instead of carmellose (see Table 1).
- Comparative Example 1 Tablets were obtained in the same manner as in Example 1 except that carmellose calcium “ECG-505” (manufactured by Gotoku Pharmaceutical) was used instead of carmellose (see Table 1).
- Comparative Example 2 Tablets were obtained in the same manner as in Example 1 except that croscarmellose sodium “Ac-Di-Sol” (manufactured by Asahi Kasei Kogyo) was used instead of carmellose (see Table 1).
- Test example 1 The tablets obtained in Examples 1 to 4 and Comparative Examples 1 and 2 were treated at 40 ° C./75% RP. H. And stored for 4 weeks. For comparison, a product stored at 5 ° C. (airtight container) was also prepared. The amount of the produced related substances was measured by the liquid chromatography method listed in the Japanese Pharmacopoeia General Test Method Physical Test Method. The results are shown in Table 1.
- the total amount of related substances refers to the sum of the amounts of related substances calculated based on the active ingredient area based on the areas other than FTD, TPI, and additives.
- Examples 1 to 4 which do not contain an additive composed of a metal salt, are 40 ° C./75% R.D. H. Even after storage under high-humidity conditions, the amount of increase in the total related substances was small compared with those stored at 5 ° C. in a cold place. On the other hand, in the comparative example, a significant increase in the total related substances was recognized as compared with the cold storage product. From the above, it was suggested that in the preparation containing FTD and TPI, the formulation containing a metal salt as an additive causes an increase in related substances.
- Example 5 30 g of FTD, 14.13 g of TPI, 270.87 g of lactose hydrate and 45 g of carmellose were charged into a stirring and mixing granulator (apparatus name “Vertical Granulator VG-05”, manufactured by POWREC), and purified water / ethanol (1: 1 ) The mixture was added and granulated. The granulated product was dried using a fluidized bed drying device (device name “Flow Coater MINI”, manufactured by Freund Corporation), and then sieved with a sieve having an opening of 600 ⁇ m to obtain a sized product.
- Example 6 A tablet was obtained in the same manner as in Example 5 except that stearic acid was not added. However, the tablet mass was 120 mg in order to obtain a mass corresponding to 10 mg FTD.
- Example 7 Tablets were obtained in the same manner as in Example 5 except that hydrogenated castor oil “Loveli wax-101” (Freund Sangyo) was used instead of stearic acid.
- Comparative Example 3 Tablets were obtained in the same manner as in Example 5 except that magnesium stearate (manufactured by Taihei Chemical Industry) was used instead of stearic acid.
- Test example 2 According to the method described in Test Example 1, the tablets obtained in Examples 5 to 7 and Comparative Example 3 were treated at 60 ° C./80% R.D. H. And stored for 8 days. The amount of the produced related substances was measured by the liquid chromatography method listed in the Japanese Pharmacopoeia General Test Method Physical Test Method. The results are shown in Table 2.
- Example 8 FTD400g, TPI188.4g, lactose hydrate 1511.6g, carmellose 300g and stearic acid 40g were mixed in a plastic bag, and this mixture was made into tablets with a diameter of 15 mm and a mass of 800 mg by a rotary tableting machine, and then by a crusher. Crushed and granulated products were obtained. Furthermore, 1 part of stearic acid was added to 122 parts of this granulated product, mixed in a plastic bag, and an uncoated tablet having a diameter of 7 mm and a mass of 123 mg was obtained using a rotary tableting machine (see Table 3).
- Example 9 1 g of a mixture of 1 part of FTD and 0.471 parts of TPI, 6 g of lactose hydrate, and 1 g of carmellose were mixed in a mortar, and this mixture was obtained by a hydraulic press to obtain an uncoated tablet having a mass of 235.36 mg (see Table 3).
- Example 10 1200 g of FTD, 565.2 g of TPI, 7258.8 g of lactose hydrate, 480 g of partially pregelatinized starch and 96 g of stearic acid were mixed in a plastic bag, and this mixture was obtained as a plain tablet having a diameter of 7 mm and a mass of 120 mg by a rotary tableting machine. (See Table 3).
- Example 11 According to the method described in Example 10, 100 g of FTD, 47.1 g of TPI, 371.9 g of lactose hydrate, 100 g of partially pregelatinized starch, and 6 g of stearic acid were mixed in a plastic bag, and this mixture was mixed with a rotary tableting machine. An uncoated tablet having a mass of 7 mm and a mass of 125 mg was obtained (see Table 4).
- Example 12 According to the method described in Example 10, 100 g of FTD, 47.1 g of TPI, 371.9 g of lactose hydrate, 25 g of partially pregelatinized starch, and 6 g of stearic acid were mixed in a plastic bag, and this mixture was mixed with a rotary tableting machine. An uncoated tablet having a mass of 7 mm and a mass of 110 mg was obtained (see Table 4).
- Example 13 According to the method described in Example 10, 100 g of FTD, 47.1 g of TPI, 371.9 g of lactose hydrate, 50 g of partially pregelatinized starch, and 6 g of stearic acid were mixed in a plastic bag, and this mixture was mixed with a rotary tableting machine. An uncoated tablet having a mass of 7 mm and a mass of 115 mg was obtained (see Table 4).
- Example 14 According to the method described in Example 10, 100 g of FTD, 47.1 g of TPI, 521.9 g of lactose hydrate, 75 g of partially pregelatinized starch and 6 g of stearic acid were mixed in a plastic bag, and this mixture was mixed with a rotary tableting machine. An uncoated tablet of 7 mm and a mass of 150 mg was obtained (see Table 4).
- Example 15 According to the method described in Example 10, 100 g of FTD, 47.1 g of TPI, 671.9 g of lactose hydrate, 75 g of partially pregelatinized starch, and 6 g of stearic acid were mixed in a plastic bag, and this mixture was mixed with a rotary tableting machine. An uncoated tablet of 7 mm and a mass of 150 mg was obtained (see Table 4).
- Example 16 According to the method described in Example 10, 50 g of FTD, 23.55 g of TPI, 226.45 g of lactose hydrate and 3 g of stearic acid were mixed in a plastic bag, and this mixture was mixed by a rotary tableting machine with a mass of 121.2 mg. Tablets were obtained (see Table 5).
- Example 17 According to the method described in Example 10, FTD 50 g, TPI 23.55 g, lactose hydrate 211.45 g, disintegrant (either corn starch, partially pregelatinized starch or low-substituted hydroxypropylcellulose) and stearic acid 3 g The mixture was mixed in a plastic bag, and the mixture was obtained with a rotary tableting machine to obtain an uncoated tablet having a mass of 121.2 mg (see Table 5).
- disintegrant either corn starch, partially pregelatinized starch or low-substituted hydroxypropylcellulose
- Example 18 According to the method described in Example 17, 50 g of FTD, 23.55 g of TPI, 196.45 g of lactose hydrate, 30 g of disintegrant (either corn starch, partially pregelatinized starch or low-substituted hydroxypropylcellulose) and 3 g of stearic acid The mixture was mixed in a plastic bag, and the mixture was obtained with a rotary tableting machine to obtain an uncoated tablet having a mass of 121.2 mg (see Table 5).
- disintegrant either corn starch, partially pregelatinized starch or low-substituted hydroxypropylcellulose
- Test example 3 According to the method described in Test Example 1, the tablets obtained in Examples 16, 17 and 18 were treated at 40 ° C./75% R.D. H. It was stored for 2 weeks in an open state, and the total amount of related substances was measured (see Table 5). As a result, no significant increase in related substances was observed in any of the tablets.
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Abstract
Description
現在、FTDとTPIをモル比1:0.5で配合した抗腫瘍剤「TAS-102」は経口投与可能な製剤として開発中である(非特許文献1及び2)。これまでに経口投与可能なTAS-102製剤に関しては錠剤、顆粒剤及びカプセル剤等が知られている(特許文献1及び2)。しかしながら、その製剤の品質、特に保存安定性に関しては十分に検討されていなかった。
従って、本発明の目的は、高湿度条件下でも有効成分が安定であり、経口投与可能なFTD及びTPI含有経口用医薬組成物を提供することにある。
本発明の経口用医薬組成物における有効成分であるFTD及びTPIの含有量は、剤形、投与計画等により変わり、特に限定されず適宜選択すればよいが、いずれも医薬組成物中の有効成分量を1~40質量%程度とするのが好ましい。
本発明の経口用医薬組成物における糖アルコールまたは二糖類が占める割合は、有効成分の安定性の観点から、全添加剤量の50~100質量%であるのが好ましく、70~100質量%の範囲がより好ましく、70~98質量%が特に好ましい。
また、本発明の経口投与用医薬組成物には糖アルコール及び二糖類以外の賦形剤を添加してもよいが、有効成分の安定性の観点から、全賦形剤中の糖アルコールまたは二糖類の占める割合は、50質量%以上が好ましく、70質量%以上がより好ましく、90質量%以上がより好ましく、100質量%が特に好ましい。
結合剤としてはヒドロキシプロピルセルロース、ヒプロメロース及びポリビニルアルコール等を挙げることができる。滑沢剤としては硬化油、ステアリン酸、ショ糖脂肪酸エステル等を挙げることができ、好ましくは硬化油又はステアリン酸であり、より好ましくはステアリン酸である。着色剤としては、食用黄色5号色素、食用青色2号色素、食用レーキ色素、三二酸化鉄、黄色三二酸化鉄及び酸化チタン等を挙げることができる。着香剤としては、オレンジ及びレモン各種香料等を挙げることができる。矯味剤としては、l-メントール、カンフル及びハッカ等が挙げられる。これらは、単独でまたは2種以上組み合わせて使用しても良い。
ここで結合剤の含有量は、全組成物中、0.001~5質量%が好ましく、0.01~3質量%がより好ましい。滑沢剤の含有量は、全組成物中、0.001~3質量%が好ましく、0.01~2質量%がより好ましい。
本発明の経口用医薬製剤としては、例えば錠剤、顆粒剤、散剤、細粒剤等が挙げられる。錠剤にはチュアブル錠、トローチ剤、ドロップ剤や口腔内で速やかに溶解または崩壊し、水なしでも服用できる組成物を含み、また用時溶解して用いる発泡錠も含む。顆粒剤、散剤及び細粒剤には、用時溶解して用いるドライシロップ剤を含み、また、口腔内で速やかに溶解し、水なしで服用できる粉粒状物を含む。
[2]金属塩が、アルカリ金属塩及びアルカリ土類金属塩から選択される[1]記載の経口用医薬組成物。
[3]金属塩が、ナトリウム塩、カリウム塩、カルシウム塩及びマグネシウム塩から選択される[1]又は[2]のいずれかに記載の経口用医薬組成物。
[4]金属塩の含有量が、FTD 1質量部に対して0~0.1質量部、好ましくは0~0.05質量部、より好ましくは0~0.01質量部、さらに好ましくは0質量部である[1]~[3]のいずれかに記載の経口用医薬組成物。
[5]金属塩からなる添加剤を実質的に含有せず、かつ賦形剤として糖アルコール又は二糖類を含有する[1]~[4]のいずれかに記載の経口用医薬組成物。
[6]賦形剤として含有する糖アルコール又は二糖類が、乳糖、精製白糖、エリスリトール及びマンニトールから選ばれる1種又は2種以上、好ましくは乳糖、精製白糖及びマンニトールから選ばれる1種又は2種以上である[5]記載の経口用医薬組成物。
[7]糖アルコール又は二糖類の含有量が、FTD 1質量部に対して3.6質量部以上、好ましくは3.6~50質量部、より好ましくは3.7~25質量部、さらに好ましくは3.7~10質量部である[6]記載の経口用医薬組成物。
[8]更に、崩壊剤として、低置換度ヒドロキシプロピルセルロース、カルメロース、コーンスターチ、部分アルファー化デンプン及びクロスポビドンから選ばれる1種又は2種以上、好ましくは低置換度ヒドロキシプロピルセルロース、カルメロース、コーンスターチ及び部分アルファー化デンプンから選ばれる1種又は2種以上、さらに好ましくは低置換度ヒドロキシプロピルセルロース、コーンスターチ及び部分アルファー化デンプンから選ばれる1種又は2種を含有する[1]~[7]のいずれかに記載の経口用医薬組成物。
[9]崩壊剤の含有量が、組成物全量中、2~16質量%、好ましくは3~13質量%、より好ましくは3~10質量%、特に好ましくは3~7質量%である[8]記載の経口用医薬組成物。
[10]更に、滑沢剤として、硬化油、ステアリン酸及びショ糖脂肪酸エステルから選ばれる1種又は2種以上、好ましくは硬化油及びステアリン酸を1種又は2種、より好ましくはステアリン酸を含有する[1]~[9]のいずれかに記載の経口用医薬組成物。
[11]滑沢剤の含有量が、全組成物中、0.001~3質量%、好ましくは0.01~2質量%である[10]記載の経口用医薬組成物。
[12]FTD及びTPIをモル比1:0.5で含有する[1]~[11]のいずれかに記載の経口用医薬組成物。
[13]FTD及びTPIを有効成分としてモル比1:0.5で含有し、金属塩からなる添加剤を実質的に含有せず、賦形剤として乳糖、精製白糖又はマンニトールから選ばれる1種又は2種以上(好ましくは乳糖)を含有し、崩壊剤として低置換度ヒドロキシプロピルセルロース、コーンスターチ、部分アルファー化デンプン及びカルメロースから選ばれる1種又は2種以上(好ましくはコーンスターチ及び部分アルファー化デンプンから選ばれる1種又は2種)を含有し、滑沢剤として硬化油及びステアリン酸を1種又は2種(好ましくはステアリン酸)含有する[1]~[12]のいずれかに記載の経口用医薬組成物。
[14]製剤形態が、造粒物、圧縮成形物又は混合物である[1]~[13]のいずれかに記載の経口用医薬組成物。
[15][1]~[14]のいずれかに記載の経口用組成物をコーティングしてなる経口用医薬製剤。
FTD 1g、TPI 0.471g、乳糖水和物 3.779g、カルメロース「NS-300」(五徳薬品製)0.75g及びステアリン酸0.15gを乳鉢中で充分混合後、123mgを秤取し、φ7mm、R10mmの杵及び油圧プレス(理研精機製)を用い、1トンで圧縮成型して錠剤を得た(表1参照)。
カルメロースを添加しないこと以外は、実施例1と同様の方法に従って錠剤を得た。ただし、錠剤質量はFTD 20mgに相当する質量とするために108mgとした(表1参照)。
カルメロースの代わりにコーンスターチ「コーンスターチW」(日本食品化工製)を用いた以外は、実施例1と同様の方法に従って錠剤を得た(表1参照)。
カルメロースの代わりに部分アルファー化デンプン「PCS(PC-10)」(旭化成ケミカルズ製)を用いた以外は、実施例1と同様の方法に従って錠剤を得た(表1参照)。
カルメロースの代わりにカルメロースカルシウム「E.C.G-505」(五徳薬品製)を用いた以外は、実施例1と同様の方法に従って錠剤を得た(表1参照)。
カルメロースの代わりにクロスカルメロースナトリウム「Ac-Di-Sol」(旭化成工業製)を用いた以外は、実施例1と同様の方法に従って錠剤を得た(表1参照)。
実施例1~4及び比較例1、2で得られた錠剤を40℃/75%R.H.で4週間保存した。また比較のために5℃(気密容器)保存品も調製した。
生成した類縁物質量を日本薬局方一般試験法物理学的試験法収載液体クロマトグラフィー法により測定した。結果を表1に示す。なお、総類縁物質量とはFTD、TPI及び添加剤以外のピークを類縁物質ピークとし、この面積から有効成分面積をもとに類縁物質量を算出した総和をいう。
FTD 30g、TPI 14.13g、乳糖水和物 270.87g及びカルメロース45gを撹拌混合造粒装置(装置名「バーチカルグラニュレーター VG-05」、パウレック製)に仕込み、精製水/エタノール(1:1)混液を添加して造粒を行った。造粒品を流動層乾燥装置(装置名「フローコーター MINI」、フロイント産業製)を用いて乾燥後、目開き600μmの篩で篩過し、整粒品を得た。
この整粒品2.4gと滑沢剤としてステアリン酸(日本油脂製)0.6gをポリ袋中で混合後、150mgを秤取し、φ7mm、R10mmの杵及び油圧プレスを用い、1トンで圧縮成型して錠剤を得た。
ステアリン酸を添加しないこと以外は、実施例5と同様の方法に従って錠剤を得た。ただし、錠剤質量はFTD 10mgに相当する質量とするために120mgとした。
ステアリン酸の代わりに硬化ヒマシ油「ラブリワックス-101」(フロイント産業製)を用いた以外は、実施例5と同様の方法に従って錠剤を得た。
ステアリン酸の代わりにステアリン酸マグネシウム(太平化学産業製)を用いた以外は、実施例5と同様の方法に従って錠剤を得た。
試験例1に記載の方法に準じて、実施例5~7及び比較例3で得られた錠剤を60℃/80%R.H.で8日間保存した。生成した類縁物質量を日本薬局方一般試験法物理学的試験法収載液体クロマトグラフィー法により測定した。結果を表2に示す。
FTD400g、TPI188.4g、乳糖水和物1511.6g、カルメロース300g及びステアリン酸40gをポリ袋内で混合し、この混合物をロータリー打錠機により径15mm、質量800mgの錠剤とした後、破砕機により破砕、造粒品を得た。更にこの造粒品122部に対しステアリン酸1部を添加、ポリ袋内で混合し、ロータリー打錠機を用いて径7mm、質量123mgの素錠を得た(表3参照)。
FTD1部とTPI0.471部の混合品1g、乳糖水和物6g及びカルメロース1gを乳鉢で混合し、この混合物を油圧プレスにより、質量235.36mgの素錠を得た(表3参照)。
FTD1200g、TPI565.2g、乳糖水和物7258.8g、部分アルファー化デンプン480g及びステアリン酸96gをポリ袋内で混合し、この混合物をロータリー打錠機により径7mm、質量120mgの素錠を得た(表3参照)。
実施例10に記載の方法に準じ、FTD100g、TPI47.1g、乳糖水和物371.9g、部分アルファー化デンプン100g及びステアリン酸6gをポリ袋内で混合し、この混合物をロータリー打錠機により径7mm、質量125mgの素錠を得た(表4参照)。
実施例10に記載の方法に準じ、FTD100g、TPI47.1g、乳糖水和物371.9g、部分アルファー化デンプン25g及びステアリン酸6gをポリ袋内で混合し、この混合物をロータリー打錠機により径7mm、質量110mgの素錠を得た(表4参照)。
実施例10に記載の方法に準じ、FTD100g、TPI47.1g、乳糖水和物371.9g、部分アルファー化デンプン50g及びステアリン酸6gをポリ袋内で混合し、この混合物をロータリー打錠機により径7mm、質量115mgの素錠を得た(表4参照)。
実施例10に記載の方法に準じ、FTD100g、TPI47.1g、乳糖水和物521.9g、部分アルファー化デンプン75g及びステアリン酸6gをポリ袋内で混合し、この混合物をロータリー打錠機により径7mm、質量150mgの素錠を得た(表4参照)。
実施例10に記載の方法に準じ、FTD100g、TPI47.1g、乳糖水和物671.9g、部分アルファー化デンプン75g及びステアリン酸6gをポリ袋内で混合し、この混合物をロータリー打錠機により径7mm、質量150mgの素錠を得た(表4参照)。
実施例10に記載の方法に準じ、FTD50g、TPI23.55g、乳糖水和物226.45g及びステアリン酸3gをポリ袋内で混合し、この混合物をロータリー打錠機により、質量121.2mgの素錠を得た(表5参照)。
実施例10に記載の方法に準じ、FTD50g、TPI23.55g、乳糖水和物211.45g、崩壊剤(コーンスターチ、部分アルファー化デンプンまたは低置換度ヒドロキシプロピルセルロースのいずれか)15g及びステアリン酸3gをポリ袋内で混合し、この混合物をロータリー打錠機により、質量121.2mgの素錠を得た(表5参照)。
実施例17に記載の方法に準じ、FTD50g、TPI23.55g、乳糖水和物196.45g、崩壊剤(コーンスターチ、部分アルファー化デンプンまたは低置換度ヒドロキシプロピルセルロースのいずれか)30g及びステアリン酸3gをポリ袋内で混合し、この混合物をロータリー打錠機により、質量121.2mgの素錠を得た(表5参照)。
試験例1に記載の方法に準じて、実施例16、17及び18で得られた錠剤を40℃/75%R.H.開放にて2週間保管し、総類縁物質量を測定した(表5参照)。
結果、いずれの錠剤においても著しい類縁物質増加は認められなかった。
Claims (15)
- α,α,α-トリフルオロチミジン及び5-クロロ-6-(2-イミノピロリジン-1-イル)メチル-2,4(1H,3H)-ピリミジンジオン塩酸塩を有効成分として含み、金属塩からなる添加剤を実質的に含有しない経口用医薬組成物。
- 金属塩が、アルカリ金属塩及びアルカリ土類金属塩から選択される請求項1記載の経口用医薬組成物。
- 金属塩が、ナトリウム塩、カリウム塩、カルシウム塩及びマグネシウム塩から選択される請求項1または2に記載の経口用医薬組成物。
- 金属塩の含有量が、α,α,α-トリフルオロチミジン1質量部に対して0~0.1質量部である請求項1~3のいずれかに記載の経口用医薬組成物。
- 金属塩からなる添加剤を実質的に含有せず、かつ賦形剤として糖アルコール又は二糖類を含有する請求項1~4のいずれかに記載の経口用医薬組成物。
- 賦形剤として含有する糖アルコール又は二糖類が、乳糖、精製白糖、エリスリトール及びマンニトールから選ばれる1種又は2種以上である請求項5記載の経口用医薬組成物。
- 糖アルコール又は二糖類の含有量が、α,α,α-トリフルオロチミジン1質量部に対して3.6質量部以上である請求項6記載の経口用医薬組成物。
- 更に、崩壊剤として、低置換度ヒドロキシプロピルセルロース、コーンスターチ、部分アルファー化デンプン、カルメロース及びクロスポビドンから選ばれる1種又は2種以上を含有する請求項1~7のいずれかに記載の経口用医薬組成物。
- 崩壊剤の含有量が、組成物全量中、2~16質量%である請求項8記載の経口用医薬組成物。
- 更に、滑沢剤として、硬化油、ステアリン酸及びショ糖脂肪酸エステルから選ばれる1種又は2種以上を含有する請求項1~9のいずれかに記載の経口用医薬組成物。
- 滑沢剤の含有量が、全組成物中、0.001~3質量%である請求項10記載の経口用医薬組成物。
- α,α,α-トリフルオロチミジン及び5-クロロ-6-(2-イミノピロリジン-1-イル)メチル-2,4(1H,3H)-ピリミジンジオン塩酸塩をモル比1:0.5で含有する請求項1~11のいずれかに記載の経口用医薬組成物。
- α,α,α-トリフルオロチミジン及び5-クロロ-6-(2-イミノピロリジン-1-イル)メチル-2,4(1H,3H)-ピリミジンジオン塩酸塩を有効成分としてモル比1:0.5で含有し、金属塩からなる添加剤を実質的に含有せず、賦形剤として乳糖、精製白糖又はマンニトールから選ばれる1種又は2種以上を含有し、崩壊剤として低置換度ヒドロキシプロピルセルロース、コーンスターチ、部分アルファー化デンプン及びカルメロースから選ばれる1種又は2種以上を含有し、滑沢剤として硬化油及びステアリン酸を1種又は2種含有する請求項1~12のいずれかに記載の経口用医薬組成物。
- 製剤形態が、造粒物、圧縮成形物又は混合物である請求項1~13のいずれかに記載の経口用医薬組成物。
- 請求項1~14のいずれかに記載の経口用組成物をコーティングしてなる経口用医薬製剤。
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AU2013219296A AU2013219296B2 (en) | 2012-02-15 | 2013-02-14 | Oral pharmaceutical composition |
KR1020147022338A KR101740105B1 (ko) | 2012-02-15 | 2013-02-14 | 경구용 의약 조성물 |
RS20200855A RS60552B1 (sr) | 2012-02-15 | 2013-02-14 | Oralna farmaceutska kompozicija |
SI201331757T SI2815752T1 (sl) | 2012-02-15 | 2013-02-14 | Oralni farmacevtski sestavek |
MX2014009834A MX365313B (es) | 2012-02-15 | 2013-02-14 | Composición farmacéutica oral que comprende a,a,a-trifluorotimidin a y clorhidrato de 5-cloro-6-(2-iminopirrolidina-1-il)metil-2,4(1h ,3h)-pirimidina diona. |
BR112014017633-7A BR112014017633B1 (pt) | 2012-02-15 | 2013-02-14 | Composição farmacêutica oral na forma de um comprimido não revestido compreendendo a-a-a -trifluorotimidina e cloridrato de 5-cloro-6-(2- iminopirrolidina-1-il)metil-2,4(1h,3h)-pirim idi nadiona como ingredientes ativos e formulação farmacêutica oral compreendendo dita composição |
EP13749905.9A EP2815752B1 (en) | 2012-02-15 | 2013-02-14 | Oral pharmaceutical composition |
PL13749905T PL2815752T3 (pl) | 2012-02-15 | 2013-02-14 | Doustna kompozycja farmaceutyczna |
CA2863018A CA2863018C (en) | 2012-02-15 | 2013-02-14 | A tablet comprising .alpha.,.alpha.,.alpha.-trifluorothymidine and 5-chloro-6-(2-iminopyrrolidine-1-yl)methyl-2,4(1h,3h)-pyrimidine dione hydrochloride |
CN201380008605.9A CN104105490A (zh) | 2012-02-15 | 2013-02-14 | 口服用医药组合物 |
DK13749905.9T DK2815752T3 (da) | 2012-02-15 | 2013-02-14 | Oral farmaceutisk sammensætning |
ES13749905T ES2804674T3 (es) | 2012-02-15 | 2013-02-14 | Composición farmacéutica oral |
SG11201403875VA SG11201403875VA (en) | 2012-02-15 | 2013-02-14 | Oral pharmaceutical composition |
LTEP13749905.9T LT2815752T (lt) | 2012-02-15 | 2013-02-14 | Peroralinė farmacinė kompozicija |
US14/373,449 US20140363512A1 (en) | 2012-02-15 | 2013-02-14 | Oral pharmaceutical composition |
JP2013558723A JP5798642B2 (ja) | 2012-02-15 | 2013-02-14 | 経口用医薬組成物 |
RU2014137158A RU2639473C2 (ru) | 2012-02-15 | 2013-02-14 | Пероральная фармацевтическая композиция |
HK15100293.7A HK1199821A1 (en) | 2012-02-15 | 2015-01-12 | Oral pharmaceutical composition |
US16/888,905 US20200289411A1 (en) | 2012-02-15 | 2020-06-01 | Oral pharmaceutical composition |
HRP20201140TT HRP20201140T1 (hr) | 2012-02-15 | 2020-07-21 | Oralna farmaceutska kompozicija |
CY20201100680T CY1123372T1 (el) | 2012-02-15 | 2020-07-23 | Απο toy στοματος φαρμακευτικη συνθεση |
US17/712,516 US20220218602A1 (en) | 2012-02-15 | 2022-04-04 | Oral pharmaceutical composition |
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EP (1) | EP2815752B1 (ja) |
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2019124544A1 (ja) | 2017-12-22 | 2019-06-27 | 大鵬薬品工業株式会社 | トリフルリジン及び/又はチピラシル由来の類縁物質の検出方法 |
WO2019135405A1 (ja) | 2018-01-05 | 2019-07-11 | 大鵬薬品工業株式会社 | トリフルリジン由来の類縁物質の検出方法 |
US10809237B2 (en) | 2018-01-05 | 2020-10-20 | Taiho Pharmaceutical Co., Ltd. | Method for detecting trifluridine-related substance by high-performance liquid chromatography |
US10866219B2 (en) | 2017-12-22 | 2020-12-15 | Taiho Pharmaceutical Co., Ltd. | Method for detecting trifluridine- and/or tipiracil-related substance |
Families Citing this family (7)
Publication number | Priority date | Publication date | Assignee | Title |
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TWI526210B (zh) | 2012-02-15 | 2016-03-21 | Taiho Pharmaceutical Co Ltd | Oral pharmaceutical composition |
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Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1996030346A1 (fr) | 1995-03-29 | 1996-10-03 | Taiho Pharmaceutical Co., Ltd. | Derives d'uracile, agents de potentialisation d'effet antitumoral et agent antitumoral renfermant ces derives |
JPH11322604A (ja) * | 1998-05-06 | 1999-11-24 | Pola Chem Ind Inc | ジフェニルピペラジン化合物を含有する製剤 |
JP2001131075A (ja) * | 1999-11-05 | 2001-05-15 | Taiho Yakuhin Kogyo Kk | 抗hiv剤 |
JP2005112744A (ja) * | 2003-10-06 | 2005-04-28 | Nagase Iyakuhin Kk | ユビデカレノン錠 |
JP2005314413A (ja) * | 2004-04-02 | 2005-11-10 | Ono Pharmaceut Co Ltd | 経口投与用医薬組成物 |
WO2006080327A1 (ja) | 2005-01-26 | 2006-08-03 | Taiho Pharmaceutical Co., Ltd. | α,α,α-トリフルオロチミジンとチミジンホスホリラーゼ阻害剤とを配合した抗癌剤 |
JP2007284390A (ja) * | 2006-04-18 | 2007-11-01 | Ohara Yakuhin Kogyo Kk | 塩酸イミダプリル含有錠剤 |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5232706A (en) * | 1990-12-31 | 1993-08-03 | Esteve Quimica, S.A. | Oral pharmaceutical preparation containing omeprazol |
US6316029B1 (en) * | 2000-05-18 | 2001-11-13 | Flak Pharma International, Ltd. | Rapidly disintegrating solid oral dosage form |
US7799783B2 (en) * | 2005-01-26 | 2010-09-21 | Taiho Pharmaceutical Co., Ltd. | Method of administrating an anticancer drug containing α, α, α-trifluorothymidine and thymidine phosphorylase inhibitor |
EP2036903B1 (en) * | 2006-06-30 | 2012-05-23 | Taiho Pharmaceutical Co., Ltd. | Potentiator of radiation therapy |
RU2346684C2 (ru) * | 2007-04-04 | 2009-02-20 | Закрытое акционерное общество "Биологические исследования и системы" | Фармацевтическая композиция на основе сигетина |
TWI526210B (zh) | 2012-02-15 | 2016-03-21 | Taiho Pharmaceutical Co Ltd | Oral pharmaceutical composition |
-
2013
- 2013-02-08 TW TW102105457A patent/TWI526210B/zh active
- 2013-02-14 HU HUE13749905A patent/HUE050840T2/hu unknown
- 2013-02-14 MX MX2014009834A patent/MX365313B/es active IP Right Grant
- 2013-02-14 US US14/373,449 patent/US20140363512A1/en not_active Abandoned
- 2013-02-14 RS RS20200855A patent/RS60552B1/sr unknown
- 2013-02-14 PL PL13749905T patent/PL2815752T3/pl unknown
- 2013-02-14 RU RU2014137158A patent/RU2639473C2/ru active
- 2013-02-14 SI SI201331757T patent/SI2815752T1/sl unknown
- 2013-02-14 SG SG11201403875VA patent/SG11201403875VA/en unknown
- 2013-02-14 WO PCT/JP2013/053514 patent/WO2013122135A1/ja active Application Filing
- 2013-02-14 EP EP13749905.9A patent/EP2815752B1/en active Active
- 2013-02-14 CN CN201380008605.9A patent/CN104105490A/zh active Pending
- 2013-02-14 KR KR1020147022338A patent/KR101740105B1/ko active IP Right Grant
- 2013-02-14 AU AU2013219296A patent/AU2013219296B2/en active Active
- 2013-02-14 PT PT137499059T patent/PT2815752T/pt unknown
- 2013-02-14 DK DK13749905.9T patent/DK2815752T3/da active
- 2013-02-14 JP JP2013558723A patent/JP5798642B2/ja active Active
- 2013-02-14 LT LTEP13749905.9T patent/LT2815752T/lt unknown
- 2013-02-14 ES ES13749905T patent/ES2804674T3/es active Active
- 2013-02-14 CA CA2863018A patent/CA2863018C/en active Active
- 2013-02-14 MY MYPI2014001998A patent/MY155938A/en unknown
-
2015
- 2015-01-12 HK HK15100293.7A patent/HK1199821A1/xx unknown
-
2020
- 2020-06-01 US US16/888,905 patent/US20200289411A1/en not_active Abandoned
- 2020-07-21 HR HRP20201140TT patent/HRP20201140T1/hr unknown
- 2020-07-23 CY CY20201100680T patent/CY1123372T1/el unknown
-
2022
- 2022-04-04 US US17/712,516 patent/US20220218602A1/en not_active Abandoned
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1996030346A1 (fr) | 1995-03-29 | 1996-10-03 | Taiho Pharmaceutical Co., Ltd. | Derives d'uracile, agents de potentialisation d'effet antitumoral et agent antitumoral renfermant ces derives |
JPH11322604A (ja) * | 1998-05-06 | 1999-11-24 | Pola Chem Ind Inc | ジフェニルピペラジン化合物を含有する製剤 |
JP2001131075A (ja) * | 1999-11-05 | 2001-05-15 | Taiho Yakuhin Kogyo Kk | 抗hiv剤 |
JP2005112744A (ja) * | 2003-10-06 | 2005-04-28 | Nagase Iyakuhin Kk | ユビデカレノン錠 |
JP2005314413A (ja) * | 2004-04-02 | 2005-11-10 | Ono Pharmaceut Co Ltd | 経口投与用医薬組成物 |
WO2006080327A1 (ja) | 2005-01-26 | 2006-08-03 | Taiho Pharmaceutical Co., Ltd. | α,α,α-トリフルオロチミジンとチミジンホスホリラーゼ阻害剤とを配合した抗癌剤 |
JP2007284390A (ja) * | 2006-04-18 | 2007-11-01 | Ohara Yakuhin Kogyo Kk | 塩酸イミダプリル含有錠剤 |
Non-Patent Citations (2)
Title |
---|
INTERNATIONAL JOURNAL OF ONCOLOGY, vol. 25, 2004, pages 571 - 578 |
INVEST NEW DRUGS, vol. 26, no. 5, October 2008 (2008-10-01), pages 445 - 54 |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2019124544A1 (ja) | 2017-12-22 | 2019-06-27 | 大鵬薬品工業株式会社 | トリフルリジン及び/又はチピラシル由来の類縁物質の検出方法 |
US10866219B2 (en) | 2017-12-22 | 2020-12-15 | Taiho Pharmaceutical Co., Ltd. | Method for detecting trifluridine- and/or tipiracil-related substance |
WO2019135405A1 (ja) | 2018-01-05 | 2019-07-11 | 大鵬薬品工業株式会社 | トリフルリジン由来の類縁物質の検出方法 |
US10809237B2 (en) | 2018-01-05 | 2020-10-20 | Taiho Pharmaceutical Co., Ltd. | Method for detecting trifluridine-related substance by high-performance liquid chromatography |
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