JP5557999B2 - 一体型医薬投薬形態 - Google Patents
一体型医薬投薬形態 Download PDFInfo
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- JP5557999B2 JP5557999B2 JP2008517084A JP2008517084A JP5557999B2 JP 5557999 B2 JP5557999 B2 JP 5557999B2 JP 2008517084 A JP2008517084 A JP 2008517084A JP 2008517084 A JP2008517084 A JP 2008517084A JP 5557999 B2 JP5557999 B2 JP 5557999B2
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- JP
- Japan
- Prior art keywords
- composition
- tenofovir
- component
- efavirenz
- emtricitabine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 239000002552 dosage form Substances 0.000 title claims description 27
- 239000000203 mixture Substances 0.000 claims description 85
- VCMJCVGFSROFHV-WZGZYPNHSA-N tenofovir disoproxil fumarate Chemical compound OC(=O)\C=C\C(O)=O.N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N VCMJCVGFSROFHV-WZGZYPNHSA-N 0.000 claims description 85
- XPOQHMRABVBWPR-ZDUSSCGKSA-N efavirenz Chemical compound C([C@]1(C2=CC(Cl)=CC=C2NC(=O)O1)C(F)(F)F)#CC1CC1 XPOQHMRABVBWPR-ZDUSSCGKSA-N 0.000 claims description 61
- XPOQHMRABVBWPR-UHFFFAOYSA-N Efavirenz Natural products O1C(=O)NC2=CC=C(Cl)C=C2C1(C(F)(F)F)C#CC1CC1 XPOQHMRABVBWPR-UHFFFAOYSA-N 0.000 claims description 52
- 229960003804 efavirenz Drugs 0.000 claims description 52
- XQSPYNMVSIKCOC-NTSWFWBYSA-N Emtricitabine Chemical compound C1=C(F)C(N)=NC(=O)N1[C@H]1O[C@@H](CO)SC1 XQSPYNMVSIKCOC-NTSWFWBYSA-N 0.000 claims description 38
- 229960000366 emtricitabine Drugs 0.000 claims description 29
- 239000004094 surface-active agent Substances 0.000 claims description 25
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 20
- 238000007908 dry granulation Methods 0.000 claims description 19
- 239000000539 dimer Substances 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 12
- 235000019359 magnesium stearate Nutrition 0.000 claims description 10
- 229940054565 sustiva Drugs 0.000 claims description 9
- 239000004615 ingredient Substances 0.000 claims description 7
- 229940008349 truvada Drugs 0.000 claims description 7
- 238000005550 wet granulation Methods 0.000 claims description 6
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 5
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 5
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical group [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 5
- 230000000368 destabilizing effect Effects 0.000 claims description 5
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 5
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- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 5
- 235000019333 sodium laurylsulphate Nutrition 0.000 claims description 5
- 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 claims description 4
- 229960001681 croscarmellose sodium Drugs 0.000 claims description 4
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 4
- 239000007888 film coating Substances 0.000 claims description 4
- 238000009501 film coating Methods 0.000 claims description 4
- 238000003860 storage Methods 0.000 claims description 4
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 3
- 230000000840 anti-viral effect Effects 0.000 claims description 3
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 3
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 3
- 239000002274 desiccant Substances 0.000 claims description 2
- 229940057948 magnesium stearate Drugs 0.000 claims 2
- 239000003826 tablet Substances 0.000 claims 2
- 230000036436 anti-hiv Effects 0.000 claims 1
- 239000007942 layered tablet Substances 0.000 claims 1
- 239000007857 degradation product Substances 0.000 description 45
- 239000000047 product Substances 0.000 description 25
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 23
- VERWQPYQDXWOGT-LVJNJWHOSA-N 4-amino-5-fluoro-1-[(2r,5s)-2-(hydroxymethyl)-1,3-oxathiolan-5-yl]pyrimidin-2-one;[[(2r)-1-(6-aminopurin-9-yl)propan-2-yl]oxymethyl-(propan-2-yloxycarbonyloxymethoxy)phosphoryl]oxymethyl propan-2-yl carbonate;(e)-but-2-enedioic acid Chemical compound OC(=O)\C=C\C(O)=O.C1=C(F)C(N)=NC(=O)N1[C@H]1O[C@@H](CO)SC1.N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N VERWQPYQDXWOGT-LVJNJWHOSA-N 0.000 description 21
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 239000000523 sample Substances 0.000 description 16
- 238000005469 granulation Methods 0.000 description 15
- 230000003179 granulation Effects 0.000 description 15
- 239000008187 granular material Substances 0.000 description 14
- 239000008186 active pharmaceutical agent Substances 0.000 description 13
- 238000002347 injection Methods 0.000 description 12
- 239000007924 injection Substances 0.000 description 12
- 239000000546 pharmaceutical excipient Substances 0.000 description 12
- 230000035945 sensitivity Effects 0.000 description 12
- 239000012086 standard solution Substances 0.000 description 12
- 238000009472 formulation Methods 0.000 description 11
- 239000002904 solvent Substances 0.000 description 11
- 239000002245 particle Substances 0.000 description 10
- 239000000843 powder Substances 0.000 description 9
- 239000012488 sample solution Substances 0.000 description 9
- 239000012535 impurity Substances 0.000 description 8
- 238000004519 manufacturing process Methods 0.000 description 8
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 7
- 238000000354 decomposition reaction Methods 0.000 description 7
- 229940079593 drug Drugs 0.000 description 7
- 239000003814 drug Substances 0.000 description 7
- LLYJISDUHFXOHK-GOCONZMPSA-N ferroptocide Chemical compound C[C@@H]1CC[C@@]23C[C@@H](C(=O)[C@]2([C@@]1([C@@H](C[C@H]([C@@H]3C)C4=CCN5C(=O)N(C(=O)N5C4)C6=CC=CC=C6)OC(=O)CCl)C)O)O LLYJISDUHFXOHK-GOCONZMPSA-N 0.000 description 7
- 239000010410 layer Substances 0.000 description 7
- 230000014759 maintenance of location Effects 0.000 description 7
- 230000015556 catabolic process Effects 0.000 description 6
- 238000006731 degradation reaction Methods 0.000 description 6
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- 238000000576 coating method Methods 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 238000007873 sieving Methods 0.000 description 5
- 238000013459 approach Methods 0.000 description 4
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- 239000011248 coating agent Substances 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 239000000374 eutectic mixture Substances 0.000 description 4
- 238000005259 measurement Methods 0.000 description 4
- 239000008363 phosphate buffer Substances 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 230000004044 response Effects 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 238000012546 transfer Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 241000237858 Gastropoda Species 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 238000005056 compaction Methods 0.000 description 3
- 238000009826 distribution Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
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- 230000000087 stabilizing effect Effects 0.000 description 3
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- 238000012360 testing method Methods 0.000 description 3
- 238000010268 HPLC based assay Methods 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 230000004888 barrier function Effects 0.000 description 2
- 239000013066 combination product Substances 0.000 description 2
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- 238000010790 dilution Methods 0.000 description 2
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- 238000001035 drying Methods 0.000 description 2
- 229940001018 emtriva Drugs 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
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- 229960004693 tenofovir disoproxil fumarate Drugs 0.000 description 2
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 208000031886 HIV Infections Diseases 0.000 description 1
- 208000037357 HIV infectious disease Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- VJHCJDRQFCCTHL-UHFFFAOYSA-N acetic acid 2,3,4,5,6-pentahydroxyhexanal Chemical compound CC(O)=O.OCC(O)C(O)C(O)C(O)C=O VJHCJDRQFCCTHL-UHFFFAOYSA-N 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000012566 active pharmaceutical ingredient starting material Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- -1 cachets Substances 0.000 description 1
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- 150000001875 compounds Chemical class 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
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- 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 description 1
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- 230000010354 integration Effects 0.000 description 1
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- 239000011159 matrix material Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
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- 229940111688 monobasic potassium phosphate Drugs 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
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- 230000008520 organization Effects 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
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- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 1
- 239000011241 protective layer Substances 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
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- 230000002195 synergetic effect Effects 0.000 description 1
- 239000012489 system suitability test solution Substances 0.000 description 1
- 229960004556 tenofovir Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 230000004584 weight gain Effects 0.000 description 1
- 235000019786 weight gain Nutrition 0.000 description 1
Classifications
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
-
- 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
- A61K31/495—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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- 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
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
- A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
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- A—HUMAN NECESSITIES
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/536—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines ortho- or peri-condensed with carbocyclic ring systems
-
- A—HUMAN NECESSITIES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
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- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
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- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
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- A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
- A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
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- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Virology (AREA)
- Organic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Molecular Biology (AREA)
- Tropical Medicine & Parasitology (AREA)
- AIDS & HIV (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
本出願は、知られている抗ウイルス性化合物エファビレンツ(efavirenz)(商標名Sustiva、EFVとしても知られる)、エムトリシタビン(emtricitabine)(商標名Emtriva、FTCとしても知られる)、およびテノホビル(tenofovir)DF(フマル酸ジソプロキシル(disoproxil fumarate)、TDFとしても知られる)(商標名Viread;エムトリシタビンと組み合わせて、商標名Truvadaのもとに販売される)を使用した、ウイルス感染症、特にHIV感染症を治療するための製品に関する。
約3%以下、通例約1.5%のモノ−POC PMPA、
約1%以下、通例約0.5%の二量体、
約0.5%以下、通例約0.25%の混合型二量体。
約10%以下、通例約5%のモノ−POC PMPA、
約2%以下、通例約1%の二量体、
約2%以下、通例約1%の混合型二量体。
約2%以下、通例約0.5%のモノ−POC PMPA、
約0.6%以下、通例約0.1%の二量体、
約0.3%以下、通例約0.05%の混合型二量体。
約9%以下、通例約4%のモノ−POC PMPA、
約1.6%以下、通例約0.6%の二量体、
約1.8%以下、通例約0.8%の混合型二量体。
エファビレンツ粉末ブレンド、FTC/TDF粉末ブレンド、およびフィルムコーティング二層型EFV/FTC/TDF錠剤の定量的組成を、それぞれ表1、表2、および表3に掲げる。それぞれの造粒物において、医薬含量ファクター(DCF)についての値が0.99未満である場合、微結晶セルロースの量に対して付随的薬剤を減量することにより、エファビレンツ、エムトリシタビン、およびテノホビルDFの量を調節した。
エファビレンツは、Nitro−Fielder PMA−400設備列を使用して湿式造粒した。エファビレンツ、微結晶セルロース、およびラウリル硫酸ナトリウム(表1)をPMA−400に加え、3分間ブレンドした。クロスカルメロースナトリウムおよびヒドロキシプロピルセルロース(表1)をプレミックスに添加し、さらに2分間ブレンドした。精製水を添加して、適切な造粒状態を形成し、続いて水添加後さらに湿った塊とした。表4は、2つの代表的なロットおよび副部分(sub part)について使用した造粒パラメータを要約したものを掲げる。全ての副部分は、水:エファビレンツ比1.25を使用したAB509のミックスCを除いて、水:エファビレンツ比1.30を使用した。
Gallayブレンダーを使用し、650L運搬用ビン内でエムトリシタビン、微結晶セルロース、テノホビルDF、およびクロスカルメロース(表2)を10分間ブレンドした。ステアリン酸マグネシウム(表2)を添加し、さらに5分間ブレンドした。次いでこのプレブレンドを、ローラー圧密ホッパー中への物質移動を助けるコーンバルブ排出装置を取り付けた320−L Matconビンに移した。
エファビレンツ造粒物および顆粒外ステアリン酸マグネシウムの質量は、エムトリシタビン/テノホビルDF乾式造粒物の収量に基づいて適正に調整した。エファビレンツ造粒物、およびエムトリシタビン/テノホビルDF乾式造粒物を、3立方フィートV−ブレンダーで10分間ブレンドした。ステアリン酸マグネシウムを添加し、さらに5分間ブレンドした。ブレンディング後、最終粉末ブレンド試料を10カ所の異なる位置から採取し、ブレンド均一性について分析した。エファビレンツおよびエムトリシタビン/テノホビルDF最終粉末ブレンドは、全ての3種の活性成分について許容できるブレンド均一性および均質性を示し、エムトリシタビン/テノホビルDF乾式造粒物およびエファビレンツ造粒物の粒径またはかさ密度にかかわらない、製剤の頑強さを示している。これらの造粒物、およびブレンディング手順は、より大規模な製剤向けに満足の行くものであろう。
Stokes Genesis Model 757の、平面形上面/エンボス形「123」底面、カプセル形状(20.0mm×10.4mm)パンチを備えた41ステーション二層型錠剤プレスを使用して、エファビレンツ/エムトリシタビン/テノホビルDF最終粉末ブレンドを圧縮して錠剤芯部とした。錠剤芯部の目標質量は1550mgであった。圧縮操作の間に最小限20カ所の等間隔位置から錠剤芯部の試料を採取し、含量の均一性について分析した。全体として、全ての粉末ブレンドが、錠剤の硬さ、脆さ、錠剤の厚さ、錠剤の外観、および錠剤の重量変動に関して、この回転型錠剤プレスで満足の行くように圧縮された。満足の行く錠剤重量の均一性をもたらすため、圧縮操作は、およそ錠剤500個/分(プレス速度12rpm)またはおよそ0.8kg/分の速さで行われた。
適切なフィルムコーティングは、商業的に使用できる製剤を日常的に選別することにより、選択される。この活動は、十分に当業者の熟練の範囲内にある。錠剤芯部の各ロットを、2つのコーティング用サブロットに分割し、48−インチThomas Engineering社COMPU−LABコーティングパンにおいて2ノズル噴霧システムを使用してフィルムコーティングした。製剤の24時間以内に使用する15重量/重量%水性コーティング懸濁液Opadry II Pinkを用い、全ての錠剤芯部をフィルムコーティングした。全ての錠剤芯部は、目標噴霧速度180g/分を用い目標重量増3.0%までコーティングし、これは標準化した噴霧速度1.5〜2.3g/分/kg錠剤に相当する。
HPLCによりエファビレンツ/エムトリシタビン/テノホビルDF錠剤(EFV/FTC/TDF錠剤)のEFV、FTC、およびTDFについて、外部対照標準を使用して検定する。適正なものへの、相対的応答係数の適用による面積の標準化によりEFV、FTC、およびTDFの分解生成物を測定する。EFV、FTC、およびTDFの同一性を、それらの保持時間を対照標準のそれと比較することにより確認する。
標準および試料溶媒
25mMリン酸塩緩衝液、pH 3
3.4gの無水一塩基性リン酸カリウムの重量をはかり、1Lメスフラスコに移し入れる。約800mLの水を添加し、溶解するまで混合する。リン酸でpHを3.0±0.1に調節し、次いで水で体積に合わせて希釈する。
400mLの25mMリン酸塩緩衝液、pH 3と、300mLのアセトニトリルと、300mLのメタノールとを合わせて、混合する。周囲温度まで平衡化させる。
500mLのアセトニトリルと、500mLのメタノールとを合わせて、混合する。周囲温度まで平衡化させる。
およそ60mgのEFV対照標準と、20mgのFTC対照標準と、30mgのTDF対照標準とを、正確に重量をはかり、100mLメスフラスコに移し入れる。およそ80mLの試料溶媒(40:30:30)をこのフラスコに添加し、溶解するまで混合し、または超音波処理する。試料溶媒(40:30:30)で体積に合わせて希釈し、十分に混合する。各成分の最終濃度は、およそ0.6mg/mLのEFV、0.2mg/mLのFTC、および0.3mg/mLのTDFである。
感度チェック標準
およそ10mgのFTU基準物質を、正確に重量をはかり出し100mLメスフラスコに入れることにより、10μg/mL FTU貯蔵溶液を調製する。試料溶媒(40:30:30)を体積のおよそ80%まで添加し、溶解するまで混合または超音波処理する。試料溶媒(40:30:30)で体積に合わせて希釈し、十分に混合する。10mLのこの溶液を100mLメスフラスコにピペットで入れる。試料溶媒(40:30:30)で体積に合わせて希釈し、十分に混合する。
EFV/FTC/TDF錠剤の強度および分解生成物含量を、錠剤10個から調製した複合溶液の分析により測定する。試料溶液中の各成分の最終濃度は、およそ0.6mg/mLのEFV、0.2mg/mLのFTC、および0.3mg/mLのTDFである。
1.UV検出器および電子的データ収集系を備えたHPLCを使用している。
カラムが平衡していることを確認し、また何らかの可能性のあるアーチファクトピークを特定するため、ブランクとして試料溶媒を少なくとも2回注入する。
理論的プレートおよびテーリング係数
標準溶液クロマトグラムから、EFV、FTC、およびTDFピークについての理論的プレート係数(N)およびテーリング係数(T)の数字を計算する。NおよびT測定のための式は、現在の米国薬局方において定義されている。これらのパラメータの値は、判定基準:N≦40,000、および0.8≦T≧2.0に適合しなければならない。
感度チェックには、感度チェック標準におよそ0.10%存在するFTUピークを利用する。個々の分解生成物パーセントの計算を使用して、適正なRRF(表2に掲げている)を感度チェック標準に適用することにより、FTUピークの面積パーセントを計算する。この結果を、下記のように感度チェック標準についてのFTUの理論パーセントと比較する:
分解生成物の同定
0.05%以下で存在するピークの検出を可能にするため、適正な検出パラメータ(ピーク閾値、最小ピーク面積など)を用いる。試料溶液注入物のクロマトグラム中に存在するEFV、FTC、およびTDFの不純物および分解生成物を、観察された二次ピークの相対的保持時間(RRT)を求めること、試料に関連のないどんなピークも考慮に入れないことにより同定する。分解生成物だけが定量される。全ての試料溶液注入物からの結果の平均を0.01%に最も近付くまで計算する。1回の注入および/または試料において、分解生成物が検出されないまたは積分の閾値未満である場合、定量された結果だけを計算に使用する(すなわち、ゼロ値として処理しない)。
FTC分解生成物の定量
下記の式を使用して、試料溶液注入物のクロマトグラムにおいて観察されるFTCの各分解生成物のレベルを測定する:
下記の式を使用して、試料溶液注入物のクロマトグラムにおいて観察されるTDFの各分解生成物のレベルを測定する:
I=分解生成物ピークまたは未帰属ピークの面積、
TPA=RRFにより補正した合計ピーク面積(不純物およびアーチファクトを除く、TDF主ピーク、全ての関連分解生成物ピーク、および未特定ピークの面積)、
RRF=TDFに関する相対的応答係数。
分解生成物含量
観察された各分解生成物についての結果の平均を、0.01%に最も近付くまで個別に報告する。EFV、FTC、およびTDFの全分解生成物含量を、観察された全ての分解生成物ピークの平均レベルの合計としてそれぞれ、0.1%に最も近付くまで報告する。0.05%未満のレベルで見出された分解生成物については、痕跡量としてそれらのレベルを報告し、全分解生成物含量の計算にはそれらのレベルを含めない。
Claims (23)
- エファビレンツと、テノホビルDFと、エムトリシタビンと、界面活性剤とを含む組成物であって、該界面活性剤が、テノホビルDFとの安定化している配置にあり、該テノホビルDFが該界面活性剤から分離されている組成物であって、該組成物は、一体型投薬形態であり、該テノホビルDFおよび該エムトリシタビンが第1の成分中にあり、該エファビレンツおよび該界面活性剤が第2の成分中にあり、該第1の成分と該第2の成分とが、物理的に分離しているが、互いに接触しており、該成分が層である、組成物。
- 経口投与に適している、請求項1に記載の組成物。
- 2.5グラム未満の重さの二層型錠剤である、請求項1に記載の組成物。
- 成分2が高せん断力湿式造粒により製造される、請求項1に記載の組成物。
- 前記界面活性剤がラウリル硫酸ナトリウムである、請求項1に記載の組成物。
- 成分1が乾式造粒により製造される、請求項1に記載の組成物。
- エファビレンツ、エムトリシタビン、およびテノホビルDFの合計量が前記組成物の60重量%を超える、請求項1に記載の組成物。
- ステアリン酸マグネシウム、クロスカルメロースナトリウム、微結晶セルロース、およびヒドロキシプロピルセルロースをさらに含む、請求項1に記載の組成物。
- エファビレンツ、テノホビルDF、エムトリシタビン、ステアリン酸マグネシウム、クロスカルメロースナトリウム、微結晶セルロース、ラウリル硫酸ナトリウム、およびヒドロキシプロピルセルロースのおよその重量百分率が、それぞれ39、19、13、2、7、17、1、および2である、請求項8に記載の組成物。
- エファビレンツ、エムトリシタビン、およびテノホビルDFが、FDA認証製品TruvadaおよびSustivaと同一のAUCおよびCmaxで経口投与により患者に提供されることを特徴とし、該TruvadaはテノホビルDFおよびエムトリシタビンを含み、かつ、該Sustivaはエファビレンツを含む、請求項1に記載の組成物。
- 1200mgから2300mgの重さがある(必要に応じて存在する任意のフィルムコーティングを含む)、請求項3に記載の組成物。
- 前記層が、前記錠剤の軸に沿って水平に配向されている、請求項3に記載の組成物。
- 請求項1に記載の組成物と、乾燥剤とを含む、容器。
- テノホビルDFおよびエムトリシタビンを含む成分1を提供するステップと、エファビレンツおよび界面活性剤を含む成分2を提供するステップと、両成分を互いに安定化している配置にするステップとを含む、テノホビルDFと、エファビレンツと、界面活性剤とを含む組成物を調製するための方法であって、ここで、該テノホビルDFが該界面活性剤から分離されている、方法であって、該組成物は、一体型投薬形態であり、該成分1と該第成分2とが、物理的に分離しているが、互いに接触しており、該成分が層である、方法。
- 成分1が乾式造粒により製造され、成分2が湿式造粒により製造される、請求項14に記載の方法。
- 乾式造粒されたテノホビルDFおよびエムトリシタビンをステアリン酸マグネシウムと組み合わせ、湿式造粒されたエファビレンツをステアリン酸マグネシウムと組み合わせ、かつこれらの2つのステアリン酸マグネシウム組成物を圧縮して二層型錠剤とする、請求項15に記載の方法。
- 経口投与されることを特徴とする請求項1に記載の組成物を含む、抗ウイルス治療のための組成物。
- 前記組成物が、1日1回のみ投与されることを特徴とする、請求項17に記載の組成物。
- 前記抗ウイルス治療が抗HIV治療である、請求項18に記載の組成物。
- エムトリシタビン、テノホビルDFおよびエファビレンツと、界面活性剤とを含む製品であって、該界面活性剤とテノホビルDF間における不安定化する接触を防止するために空間的構成が使用され、該テノホビルDFが該界面活性剤から分離されており、該テノホビルDFおよび該エムトリシタビンが第1の成分中にあり、該エファビレンツおよび該界面活性剤が第2の成分中にあり、該第1の成分と該第2の成分とが、物理的に分離しているが、互いに接触しており、該成分が層である、製品。
- 請求項2〜12のいずれか1項に記載の組成物であって、医薬的に許容できない濃度の、FTU、モノ−POC PMPA、二量体、および混合型二量体を含まない、組成物。
- FTU、モノ−POC PMPA、二量体、および混合型二量体の前記濃度が、それぞれ3.9重量%、9重量%、1.6重量%、および1.8重量%である、請求項21に記載の組成物。
- 前記濃度が、25℃/60%相対湿度で24カ月間の前記組成物の貯蔵後に測定される、請求項22に記載の組成物。
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WO2012003413A1 (en) | 2010-06-30 | 2012-01-05 | The Broad Institute, Inc. | Novel solid forms of tacedinaline |
BR112013012245B1 (pt) | 2010-11-19 | 2022-09-27 | Janssen Sciences Ireland Uc | Comprimido compreendendo hcl de rilpivirina e fumarato de tenofovir disoproxila seu uso no tratamento profilático ou terapêutico de uma infecção por hiv |
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