JP2021510374A - エベロリムスを含む安定化した薬剤学的製剤 - Google Patents
エベロリムスを含む安定化した薬剤学的製剤 Download PDFInfo
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- JP2021510374A JP2021510374A JP2020538112A JP2020538112A JP2021510374A JP 2021510374 A JP2021510374 A JP 2021510374A JP 2020538112 A JP2020538112 A JP 2020538112A JP 2020538112 A JP2020538112 A JP 2020538112A JP 2021510374 A JP2021510374 A JP 2021510374A
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- granules
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- everolimus
- butylhydroxytoluene
- lubricant
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- HKVAMNSJSFKALM-GKUWKFKPSA-N Everolimus Chemical compound C1C[C@@H](OCCO)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 HKVAMNSJSFKALM-GKUWKFKPSA-N 0.000 title claims abstract description 38
- 229960005167 everolimus Drugs 0.000 title claims abstract description 38
- 239000008194 pharmaceutical composition Substances 0.000 title abstract description 9
- 239000008187 granular material Substances 0.000 claims abstract description 41
- 239000000825 pharmaceutical preparation Substances 0.000 claims abstract description 23
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 claims abstract description 22
- 239000000314 lubricant Substances 0.000 claims abstract description 21
- 239000000203 mixture Substances 0.000 claims abstract description 19
- 239000004480 active ingredient Substances 0.000 claims abstract description 16
- 230000003078 antioxidant effect Effects 0.000 claims abstract description 16
- 239000003963 antioxidant agent Substances 0.000 claims abstract description 15
- 239000011230 binding agent Substances 0.000 claims abstract description 12
- 238000004519 manufacturing process Methods 0.000 claims abstract description 12
- 239000008202 granule composition Substances 0.000 claims abstract description 5
- 238000000034 method Methods 0.000 claims description 10
- OKMWKBLSFKFYGZ-UHFFFAOYSA-N 1-behenoylglycerol Chemical compound CCCCCCCCCCCCCCCCCCCCCC(=O)OCC(O)CO OKMWKBLSFKFYGZ-UHFFFAOYSA-N 0.000 claims description 9
- 229940049654 glyceryl behenate Drugs 0.000 claims description 9
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 8
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 6
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 6
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 6
- 229960003943 hypromellose Drugs 0.000 claims description 6
- 210000000056 organ Anatomy 0.000 claims description 6
- 238000005550 wet granulation Methods 0.000 claims description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 4
- 229940075614 colloidal silicon dioxide Drugs 0.000 claims description 4
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 claims description 4
- 238000009472 formulation Methods 0.000 claims description 4
- 235000019359 magnesium stearate Nutrition 0.000 claims description 4
- 229940057948 magnesium stearate Drugs 0.000 claims description 4
- 229940045902 sodium stearyl fumarate Drugs 0.000 claims description 4
- 206010052779 Transplant rejections Diseases 0.000 claims description 3
- 239000002552 dosage form Substances 0.000 claims description 3
- 230000002265 prevention Effects 0.000 claims description 3
- 238000010586 diagram Methods 0.000 abstract 1
- 239000000126 substance Substances 0.000 description 17
- 238000002360 preparation method Methods 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 8
- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000003018 immunosuppressive agent Substances 0.000 description 6
- 239000012071 phase Substances 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 229960003444 immunosuppressant agent Drugs 0.000 description 5
- 239000007884 disintegrant Substances 0.000 description 4
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 description 3
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 3
- 229960000913 crospovidone Drugs 0.000 description 3
- -1 defololimus Chemical compound 0.000 description 3
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 3
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 description 3
- 229960002930 sirolimus Drugs 0.000 description 3
- 238000010998 test method Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
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- 229960004977 anhydrous lactose Drugs 0.000 description 2
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- MLDQJTXFUGDVEO-UHFFFAOYSA-N BAY-43-9006 Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=CC(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 MLDQJTXFUGDVEO-UHFFFAOYSA-N 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 206010009900 Colitis ulcerative Diseases 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 208000011231 Crohn disease Diseases 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 239000005511 L01XE05 - Sorafenib Substances 0.000 description 1
- 108010047230 Member 1 Subfamily B ATP Binding Cassette Transporter Proteins 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 208000006265 Renal cell carcinoma Diseases 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 102000013530 TOR Serine-Threonine Kinases Human genes 0.000 description 1
- 108010065917 TOR Serine-Threonine Kinases Proteins 0.000 description 1
- CBPNZQVSJQDFBE-FUXHJELOSA-N Temsirolimus Chemical compound C1C[C@@H](OC(=O)C(C)(CO)CO)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 CBPNZQVSJQDFBE-FUXHJELOSA-N 0.000 description 1
- 201000006704 Ulcerative Colitis Diseases 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 208000025302 chronic primary adrenal insufficiency Diseases 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 229960001681 croscarmellose sodium Drugs 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 235000019700 dicalcium phosphate Nutrition 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000007908 dry granulation Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- AKWHREAVLKZDDE-UHFFFAOYSA-N hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentone Chemical compound CCCCCCCC=CC=CC=CCCCC(=O)CCC=CCC(=O)CCCC(=O)CCCCCCC(=O)C(C)=O AKWHREAVLKZDDE-UHFFFAOYSA-N 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 230000001506 immunosuppresive effect Effects 0.000 description 1
- 230000001861 immunosuppressant effect Effects 0.000 description 1
- 229940124589 immunosuppressive drug Drugs 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 230000007721 medicinal effect Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000012466 permeate Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229960005330 pimecrolimus Drugs 0.000 description 1
- KASDHRXLYQOAKZ-ZPSXYTITSA-N pimecrolimus Chemical compound C/C([C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@]2(O)O[C@@H]([C@H](C[C@H]2C)OC)[C@@H](OC)C[C@@H](C)C/C(C)=C/[C@H](C(C[C@H](O)[C@H]1C)=O)CC)=C\[C@@H]1CC[C@@H](Cl)[C@H](OC)C1 KASDHRXLYQOAKZ-ZPSXYTITSA-N 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 229960003787 sorafenib Drugs 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000002626 targeted therapy Methods 0.000 description 1
- 229960000235 temsirolimus Drugs 0.000 description 1
- QFJCIRLUMZQUOT-UHFFFAOYSA-N temsirolimus Natural products C1CC(O)C(OC)CC1CC(C)C1OC(=O)C2CCCCN2C(=O)C(=O)C(O)(O2)C(C)CCC2CC(OC)C(C)=CC=CC=CC(C)CC(C)C(=O)C(OC)C(O)C(C)=CC(C)C(=O)C1 QFJCIRLUMZQUOT-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
Classifications
-
- 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
-
- F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
- F41—WEAPONS
- F41A—FUNCTIONAL FEATURES OR DETAILS COMMON TO BOTH SMALLARMS AND ORDNANCE, e.g. CANNONS; MOUNTINGS FOR SMALLARMS OR ORDNANCE
- F41A17/00—Safety arrangements, e.g. safeties
- F41A17/42—Safeties for locking the breech-block or bolt in a safety position
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
-
- 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
- A61K9/1629—Organic macromolecular compounds
- A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- 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
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
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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
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
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- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Immunology (AREA)
- Biophysics (AREA)
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- General Engineering & Computer Science (AREA)
- Transplantation (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Nutrition Science (AREA)
- Physiology (AREA)
Abstract
Description
有機溶媒にヒプロメロース、ブチルヒドロキシトルエン及びエベロリムスを入れ、結合液を製造した。乳糖水和物、クロスポビドン及びヒプロメロースの混合物に結合液を入れて煉り合わせた後に乾燥を行い、整粒機で整粒した。整粒物を乳糖水和物、無水乳糖及びクロスポビドンと混合した後、グリセリルベヘネートを入れ、最終混合を行ってエベロリムス顆粒混合物を製造した。最終混合物をもって打錠機で打錠して錠剤を製造した。製造された錠剤には、エベロリムス1.0mgが含まれている。
下記の表1の含有量に応じて、内部の総重量に基づくエベロリムス及びブチルヒドロキシトルエンの重量%をそれぞれ異ならせて、前記製造方法に従って実施例1〜5の錠剤を製造した。
実施例1〜5の類縁物質試験
下記の類縁物質試験の条件下で、実施例1〜5の錠剤に対する類縁物質実験を行うことで安定性を評価し、各製剤を過酷条件(温度60℃)で4週間保存し、液体クロマトグラフィ法で類縁物質の量を評価した。
1)検出器:紫外部吸光光度計(測定波長:276nm)
2)カラム:Zorbax SB−C18 4.6×250mm、5μm
3)注入量:50μL
4)流量:2.0mL/min
5)カラム温度:55℃近くの一定温度
6)サンプル温度:4℃近くの一定温度
7)分析時間:60分
8)移動相:
移動相A−水、アセトニトリル、メタノールの混液(30:20:50)
移動相B−アセトニトリル
滑沢剤の種類による安定性試験
滑沢剤とは、製剤に向上した流動特性を与える物質であって、この実験では、グリセリルベヘネート、ステアリン酸マグネシウム、ステアリルフマル酸ナトリウム及びコロイド性二酸化ケイ素を滑沢剤として、滑沢剤の種類による製剤の安定性を評価した。
1)検出器:紫外部吸光光度計(測定波長:276nm)
2)カラム:Zorbax SB−C18 4.6×250mm、5μm
3)注入量:50μL
4)流量:2.0mL/min
5)カラム温度:55℃近くの一定温度
6)サンプル温度:4℃近くの一定温度
7)分析時間:60分
8)移動相:
移動相A−水、アセトニトリル、メタノールの混液(30:20:50)
移動相B−アセトニトリル
Claims (13)
- 活性成分としてエベロリムスを含み、抗酸化剤としてブチルヒドロキシトルエンを含む顆粒を含む、薬剤学的製剤。
- 前記顆粒は、顆粒の総含有量に対して、0.5〜20重量%のエベロリムス、及び、0.05〜10重量%のブチルヒドロキシトルエンを含むことを特徴とする、請求項1に記載の薬剤学的製剤。
- 前記顆粒は、顆粒の総含有量に対して、1〜10重量%のエベロリムス、及び、0.1〜5重量%のブチルヒドロキシトルエンを含むことを特徴とする、請求項2に記載の薬剤学的製剤。
- 前記顆粒は、湿式造粒法により製造されることを特徴とする、請求項1に記載の薬剤学的製剤。
- 前記顆粒は、結合剤としてヒプロメロースをさらに含むことを特徴とする、請求項1に記載の薬剤学的製剤。
- 滑沢剤をさらに含むことを特徴とする、請求項1に記載の薬剤学的製剤。
- 滑沢剤は、グリセリルベヘネート、ステアリン酸マグネシウム、ステアリルフマル酸ナトリウム及びコロイド性二酸化ケイ素よりなる群から選ばれる少なくとも1種であることを特徴とする、請求項6に記載の薬剤学的製剤。
- 滑沢剤は、グリセリルベヘネートであることを特徴とする、請求項7に記載の薬剤学的製剤。
- 経口投与の形態に剤形化されることを特徴とする、請求項1に記載の薬剤学的製剤。
- 前記経口投与の形態は、錠剤であることを特徴とする、請求項9に記載の薬剤学的製剤。
- 臓器移植拒絶反応の予防または治療のためのものである、請求項1に記載の薬剤学的製剤。
- エベロリムス、ブチルヒドロキシトルエン及び結合剤を溶解させて混合物を製造するステップと、
前記混合物から顆粒を製造するステップと、
前記顆粒に滑沢剤を入れて顆粒混合物を製造するステップと、
を含む、活性成分としてエベロリムスを含み、抗酸化剤としてブチルヒドロキシトルエンを含む、薬剤学的製剤の製造方法。 - 結合剤はヒプロメロースであり、滑沢剤はグリセリルベヘネートであることを特徴とする、請求項12に記載の薬剤学的製剤の製造方法。
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