CN105395493B - A kind of Lurasidone HCl piece - Google Patents
A kind of Lurasidone HCl piece Download PDFInfo
- Publication number
- CN105395493B CN105395493B CN201510827894.6A CN201510827894A CN105395493B CN 105395493 B CN105395493 B CN 105395493B CN 201510827894 A CN201510827894 A CN 201510827894A CN 105395493 B CN105395493 B CN 105395493B
- Authority
- CN
- China
- Prior art keywords
- lurasidone hcl
- lurasidone
- hcl
- piece
- sorbierite
- 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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- PQXKDMSYBGKCJA-CVTJIBDQSA-N lurasidone Chemical compound C1=CC=C2C(N3CCN(CC3)C[C@@H]3CCCC[C@H]3CN3C(=O)[C@@H]4[C@H]5CC[C@H](C5)[C@@H]4C3=O)=NSC2=C1 PQXKDMSYBGKCJA-CVTJIBDQSA-N 0.000 title claims abstract description 108
- 229960001432 lurasidone Drugs 0.000 title claims abstract description 107
- 238000002844 melting Methods 0.000 claims abstract description 20
- 230000008018 melting Effects 0.000 claims abstract description 20
- 239000001508 potassium citrate Substances 0.000 claims abstract description 20
- 229960002635 potassium citrate Drugs 0.000 claims abstract description 20
- QEEAPRPFLLJWCF-UHFFFAOYSA-K potassium citrate (anhydrous) Chemical compound [K+].[K+].[K+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O QEEAPRPFLLJWCF-UHFFFAOYSA-K 0.000 claims abstract description 20
- 235000011082 potassium citrates Nutrition 0.000 claims abstract description 20
- 238000002360 preparation method Methods 0.000 claims abstract description 20
- 239000012943 hotmelt Substances 0.000 claims abstract description 16
- 238000001125 extrusion Methods 0.000 claims abstract description 15
- 239000002245 particle Substances 0.000 claims abstract description 8
- 239000000463 material Substances 0.000 claims abstract description 6
- 239000007962 solid dispersion Substances 0.000 claims abstract description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 24
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 13
- 235000019359 magnesium stearate Nutrition 0.000 claims description 12
- 239000000843 powder Substances 0.000 claims description 12
- 239000000741 silica gel Substances 0.000 claims description 11
- 229910002027 silica gel Inorganic materials 0.000 claims description 11
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 claims description 10
- 235000019700 dicalcium phosphate Nutrition 0.000 claims description 10
- 238000004090 dissolution Methods 0.000 abstract description 21
- 238000000338 in vitro Methods 0.000 abstract description 10
- 239000003814 drug Substances 0.000 abstract description 7
- 238000004519 manufacturing process Methods 0.000 abstract description 6
- 230000001225 therapeutic effect Effects 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 22
- 239000000155 melt Substances 0.000 description 10
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 8
- 229920001353 Dextrin Polymers 0.000 description 6
- 239000004375 Dextrin Substances 0.000 description 6
- 239000007853 buffer solution Substances 0.000 description 6
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 6
- 235000019425 dextrin Nutrition 0.000 description 6
- 238000005516 engineering process Methods 0.000 description 5
- 230000007774 longterm Effects 0.000 description 5
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- 229920000858 Cyclodextrin Polymers 0.000 description 4
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 229930195725 Mannitol Natural products 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 239000000370 acceptor Substances 0.000 description 4
- 239000012738 dissolution medium Substances 0.000 description 4
- 239000000945 filler Substances 0.000 description 4
- 239000000594 mannitol Substances 0.000 description 4
- 235000010355 mannitol Nutrition 0.000 description 4
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- 235000021355 Stearic acid Nutrition 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000005557 antagonist Substances 0.000 description 3
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 235000013305 food Nutrition 0.000 description 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N lactose group Chemical group OC1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@@H](O)[C@H](O2)CO)[C@H](O1)CO GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical group CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 3
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 3
- 229960000502 poloxamer Drugs 0.000 description 3
- 229920001983 poloxamer Polymers 0.000 description 3
- 239000013558 reference substance Substances 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 239000008117 stearic acid Substances 0.000 description 3
- 239000004094 surface-active agent Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- DMBUODUULYCPAK-UHFFFAOYSA-N 1,3-bis(docosanoyloxy)propan-2-yl docosanoate Chemical compound CCCCCCCCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCCCCCCCC DMBUODUULYCPAK-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
- 229920000881 Modified starch Polymers 0.000 description 2
- VKVBDORNIIAKBR-SLIZCISESA-N OC1[C@@H]2CC[C@H]1[C@H]1[C@@H]2C(=O)N(C[C@@H]2CCCC[C@H]2CN2CCN(CC2)c2nsc3ccccc23)C1=O Chemical compound OC1[C@@H]2CC[C@H]1[C@H]1[C@@H]2C(=O)N(C[C@@H]2CCCC[C@H]2CN2CCN(CC2)c2nsc3ccccc23)C1=O VKVBDORNIIAKBR-SLIZCISESA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 description 2
- 235000011132 calcium sulphate Nutrition 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000001747 exhibiting effect Effects 0.000 description 2
- 238000011835 investigation Methods 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- 239000002207 metabolite Substances 0.000 description 2
- 239000008108 microcrystalline cellulose Substances 0.000 description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 108010050939 thrombocytin Proteins 0.000 description 2
- DCXXMTOCNZCJGO-UHFFFAOYSA-N tristearoylglycerol Chemical group CCCCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCCCC DCXXMTOCNZCJGO-UHFFFAOYSA-N 0.000 description 2
- 210000002700 urine Anatomy 0.000 description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical class CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- CSNIZNHTOVFARY-UHFFFAOYSA-N 1,2-benzothiazole Chemical compound C1=CC=C2C=NSC2=C1 CSNIZNHTOVFARY-UHFFFAOYSA-N 0.000 description 1
- 102100022738 5-hydroxytryptamine receptor 1A Human genes 0.000 description 1
- 101710138638 5-hydroxytryptamine receptor 1A Proteins 0.000 description 1
- 102100036321 5-hydroxytryptamine receptor 2A Human genes 0.000 description 1
- 101710138091 5-hydroxytryptamine receptor 2A Proteins 0.000 description 1
- 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 1
- 102000004506 Blood Proteins Human genes 0.000 description 1
- 108010017384 Blood Proteins Proteins 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 102000004328 Cytochrome P-450 CYP3A Human genes 0.000 description 1
- 108010081668 Cytochrome P-450 CYP3A Proteins 0.000 description 1
- 101150049660 DRD2 gene Proteins 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- UQOFGTXDASPNLL-XHNCKOQMSA-N Muscarine Chemical compound C[C@@H]1O[C@H](C[N+](C)(C)C)C[C@H]1O UQOFGTXDASPNLL-XHNCKOQMSA-N 0.000 description 1
- SNIXRMIHFOIVBB-UHFFFAOYSA-N N-Hydroxyl-tryptamine Chemical compound C1=CC=C2C(CCNO)=CNC2=C1 SNIXRMIHFOIVBB-UHFFFAOYSA-N 0.000 description 1
- 241000220324 Pyrus Species 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Substances CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 230000000561 anti-psychotic effect Effects 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 239000003693 atypical antipsychotic agent Substances 0.000 description 1
- 229940127236 atypical antipsychotics Drugs 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 230000036983 biotransformation Effects 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- MNNHAPBLZZVQHP-UHFFFAOYSA-N diammonium hydrogen phosphate Chemical class [NH4+].[NH4+].OP([O-])([O-])=O MNNHAPBLZZVQHP-UHFFFAOYSA-N 0.000 description 1
- 235000019838 diammonium phosphate Nutrition 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 238000011978 dissolution method Methods 0.000 description 1
- 238000007922 dissolution test Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 229960003638 dopamine Drugs 0.000 description 1
- 238000009506 drug dissolution testing Methods 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 230000008451 emotion Effects 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 230000009246 food effect Effects 0.000 description 1
- 235000021471 food effect Nutrition 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 235000012631 food intake Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 1
- 230000033444 hydroxylation Effects 0.000 description 1
- 238000005805 hydroxylation reaction Methods 0.000 description 1
- 239000012729 immediate-release (IR) formulation Substances 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 229940036674 latuda Drugs 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 238000005461 lubrication Methods 0.000 description 1
- NEKCRUIRPWNMLK-SCIYSFAVSA-N lurasidone hydrochloride Chemical compound Cl.C1=CC=C2C(N3CCN(CC3)C[C@@H]3CCCC[C@H]3CN3C(=O)[C@@H]4[C@H]5CC[C@H](C5)[C@@H]4C3=O)=NSC2=C1 NEKCRUIRPWNMLK-SCIYSFAVSA-N 0.000 description 1
- 229960002863 lurasidone hydrochloride Drugs 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- 239000004031 partial agonist Substances 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 235000021017 pears Nutrition 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- LTUDISCZKZHRMJ-UHFFFAOYSA-N potassium;hydrate Chemical compound O.[K] LTUDISCZKZHRMJ-UHFFFAOYSA-N 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 238000011125 single therapy Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000006104 solid solution Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000004577 thatch Substances 0.000 description 1
- 230000008673 vomiting Effects 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
- A61K9/20—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
-
- 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
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- 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
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Molecular Biology (AREA)
- Biophysics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The present invention relates to a kind of Lurasidone HCl piece, the invention belongs to medicine to manufacture new technical field, more particularly to Lurasidone HCl piece and its a kind of preparation method, the piece is using Lurasidone HCl as main component, is formed by Lurasidone HCl solid dispersion particles and auxiliary material direct tablet compressing；Described Lurasidone HCl solid dispersion particles are prepared as follows forming：Potassium citrate and sorbierite are heated to melting in hot-melt extruded machine, then Lurasidone HCl melting is added, by fused solution extrusion granulator, the weight ratio of Lurasidone HCl and potassium citrate is 1: 0.5 2, and the weight ratio of Lurasidone HCl and sorbierite is 1: 15.It is poor that the Lurasidone HCl piece of the present invention solves Lurasidone HCl In Vitro Dissolution, improves pharmaceutical effectiveness, has more preferably therapeutic effect.
Description
Technical field
The invention belongs to medicine to manufacture new technical field, and in particular to a kind of Lurasidone HCl piece and its one kind side of preparation
Method.
Background technology
Lurasidone HCl (Lurasidone Hydrochloride) is developed for big SUMITOMO CHEMICAL pharmacy, trade name
For LATUDA.2010 food and medicine Surveillance Authority of the U.S. on October 28, (FDA) ratify its listing, for schizophrenia and
The single therapy of the two-way disturbance of emotion associated depression breaking-out of I types shares auxiliary treatment with lithium, sodium vedproate.Draw hydrochloric acid Shandong
Western assimilation scientific name is (3aR, 4S, 7R, 7aS) -2- { (1R, 2R) -2- [4- (1,2- benzisothiazole -3- bases) piperazine -1- Ji Jia
Base] cyclohexyl methyl } hexahydro -1H-4,7- methyl iso-indoles -1,3- dione hydrochloride.Structural formula is as follows：
Lurasidone HCl is atypical antipsychotic, and it treats schizoid precise mechanism as other SARS
Type antipsychotic drug is similar, by the type dopamine (D of maincenter 22) and 2 type five hydroxytryptamine (5HT2A) acceptor joint antagonism and be situated between
Lead.Extracorporeal receptor binding is prompted, Lurasidone be d2 dopamine receptor (Ki=0.994nM) and serotonin (5-HT,
Thrombocytin) acceptor 5-HT2A (Ki=0.47nM) and 5-HT7 (Ki=0.495nM) the antagonist with high affinity；It is
The antagonist with moderate affinity of people's α 2c adrenocepters (Ki=10.8)；It is thrombocytin 5-HT1A (Ki=
6.38nM) the partial agonist of acceptor；And the antagonist of α 2A adrenocepters (Ki=40.7nM).Lurasidone is to group
Knit amine H1 and muscarine M1 acceptors show less affinity, or without affinity (IC50 distinguishes >=1,000nM and ＞ 1,
000nM).The activity of Lurasidone mostlys come from parent drug.In 20mg to 160mg daily total dose range, Lu La
The pharmacokinetics of western ketone and dosage are proportional.Lurasidone reached Css in 7 days.Single-dose Lurasidone 40mg
Afterwards, mean elimination half life (%CV) was 18 (7) hours.Lurasidone about reaches peak value blood after being absorbed after 1-3 hours
Starch concentration.The 9-19% of dosage is absorbed according to estimates.After Lurasidone 40mg is administered, average apparent volume of distribution (%CV)
For 6173 (17.2) L.Lurasidone combines with serum proteins height (~99%).In food effect research, when with food
Administration is compared with the level observed under fasting state together, the average C of LurasidonemaxAdd 3 times and 2 respectively with AUC
Times.Lurasidone exposure is unaffected, and should be food-intake to increase to 1000 calories and food fat content from 350 is not
Rely on.In the clinical research of the security and validity of clear and definite Lurasidone, patient is instructed to take at table daily
The medicine of dosage.Lurasidone is mainly metabolized by CYP3A4 enzymes.Main biotransformation pathway includes oxidation N- and takes off alkane
Baseization effect, the hydroxylation and S- oxidations of drop thatch alkane ring.Lurasidone is metabolized as two active metabolites
(ID-14283 and ID-14326) and two more nonactive metabolites (ID-20219 and ID-20220).Given in single
Give [14C] mark Lurasidone after, radioactive total excretion about 89% in urine and excrement, wherein about 80% from excrement
Recovery, 9% reclaims from urine.After Lurasidone 40mg is administered, average (18.0) mL/ of apparent clearance rate (%CV) 3902
min。
Lurasidone HCl is white to off-white powder；This product soluble,very slightly in water, acetone, it is slightly molten in methyl alcohol,
The slightly soluble in ethanol, dimethyl sulfoxide, dichloroethanes, it is almost insoluble in ethyl acetate, toluene.Lurasidone HCl is BCS II
Class compound, dissolubility difference are to influence the key factor of clinical efficacy difference.Prior art is directed to Lurasidone HCl dissolubility
The technology barrier of difference is solved using a variety of methods, but is failed in solution Lurasidone HCl 0 day or prolonged storage
Dissolution rate, fail solve Lurasidone HCl more than 85% can be discharged in 15min before the deadline.
CN103006661A discloses a kind of oral formulations, and it uses the technology of micronizing by Lurasidone HCl and disperseed
The average grain diameter of the micronized particle of carrier is controlled at 0.1-12 μm, and effective to increase Lurasidone HCl preparation molten at 0 day
Out-degree, but fail to solve to store the dissolution rate downward trend of middle Lurasidone HCl for a long time.
CN104248769A discloses a kind of lurasidone medicine composition, and it uses cyclodextrin to Lurasidone or its acid
The technology that addition salts are included adds dissolution rate of the Lurasidone HCl preparation at 0 day, but early stage dissolution is slow and fails
Solve the long-term dissolution rate downward trend for storing middle Lurasidone HCl, while cyclodextrin encapsulated yield is not high, further
Add production cost.
A kind of Lurasidone HCl immediate-release granules of CN104971046A, it uses micronizing that Lurasidone HCl is averaged grain
Footpath control is adding Lurasidone HCl preparation at 0 day less than 5 μm, and by adding exhibiting high surface agent poloxamer
Dissolution rate, but fail to prevent to store the dissolution rate downward trend of middle Lurasidone HCl for a long time, while exhibiting high surface activity
Gastrointestinal reaction during the addition increase oral hydrochloride Lurasidone tablet of agent poloxamer, heavy dose of poloxamer easily cause stomach and intestine
The reversion of road mucous membrane water oil environment, so as to cause vomiting of exerting one's utmost effort.
Therefore a kind of good In Vitro Dissolution, high income, the Lurasidone HCl piece of safety and stability is developed to be imminent.
The content of the invention：
In view of the deficiencies in the prior art, it is an object of the invention to studied by lot of experiments, there is provided a kind of production technology
Simply, In Vitro Dissolution is good, high income, safety and stability Lurasidone HCl piece and preparation method thereof.
Compared with prior art, the Lurasidone HCl piece of the present invention using hot-melt extruded have the following advantages that and
Marked improvement：(1) need to only take 1 time daily, blood concentration is steady；(2) simple production process, easy to operate, high income, Ke Yishi
The big production of existing industrialization；(3) Lurasidone HCl exists with carrier in a manner of solid solution, and dissolution in vitro is high, reaches and collapses
Solution is that dissolution is complete；(4) preparation release is affected by environment small, and In Vitro Dissolution curve is steady, and differences between batches are small；(5) it is long-term to place
Dissolution in vitro does not decline afterwards.
The purpose of the present invention is that following scheme is realized：
A kind of Lurasidone HCl piece is straight by Lurasidone HCl solid dispersion particles and pharmaceutically acceptable auxiliary material
Tabletting is connect to form；Described Lurasidone HCl solid dispersion particles are prepared as follows forming：By potassium citrate and mountain
Pears alcohol heats melting in hot-melt extruded machine, Lurasidone HCl melting is then added, by fused solution extrusion granulator.
Preferably, the weight ratio of above-mentioned Lurasidone HCl piece, wherein Lurasidone HCl and potassium citrate is 1:
0.5-2。
It is further preferred that the weight ratio of above-mentioned Lurasidone HCl piece, wherein Lurasidone HCl and potassium citrate
For 1: 0.8-1.2.
Preferably, the weight ratio of above-mentioned Lurasidone HCl piece, wherein Lurasidone HCl and sorbierite is 1: 1-5.
It is further preferred that the weight ratio of above-mentioned Lurasidone HCl piece, wherein Lurasidone HCl and sorbierite is 1
∶2-4。
Lurasidone HCl piece of the present invention, wherein described pharmaceutically acceptable accessory package contains filler and profit
Lubrication prescription.Described filler is selected from lactose, starch, microcrystalline cellulose, mannitol, dextrin, pregelatinized starch, calcium sulfate, phosphoric acid
One or more in hydrogen calcium and calcium carbonate；Described filler is preferably calcium monohydrogen phosphate.Described lubricant is stearic acid
One or more in magnesium, superfine silica gel powder, stearic acid, talcum powder, Compritol 888 ATO.Described lubricant is preferably tristearin
Sour magnesium.
The present invention provides a kind of preparation method of above-mentioned Lurasidone HCl piece, comprises the steps of：By potassium citrate and
Sorbierite heats melting in hot-melt extruded machine, Lurasidone HCl melting is then added, by fused solution extrusion granulator, with pharmacy
Upper acceptable auxiliary material direct tablet compressing forms.
Brief description of the drawings
Fig. 1 is embodiment 3, embodiment 4, Lurasidone HCl piece made of embodiment 5 and uses CN103006661A systems
Into Lurasidone HCl piece (micronizing), Lurasidone HCl piece (cyclodextrin encapsulated) made of CN104248769A,
0 day external stripping curve of Lurasidone HCl piece (adding surfactant) made of CN104971046A investigates figure (dissolution medium：
PH3.8 citrate-phosphate disodium hydrogens buffer solution).
Fig. 2 is embodiment 3, embodiment 4, Lurasidone HCl piece made of embodiment 5 and uses CN103006661A systems
Into Lurasidone HCl piece (micronizing), Lurasidone HCl piece (cyclodextrin encapsulated) made of CN104248769A,
The long-term In Vitro Dissolution curve in June of Lurasidone HCl piece (adding surfactant) made of CN104971046A investigates figure (dissolution
Medium：PH3.8 citrate-phosphate disodium hydrogens buffer solution).
Embodiment
The Lurasidone HCl piece that the present invention obtains has that method is simple, stability is good, and dissolution rate is high, spy evident in efficacy
Point.Implement the explanation present invention, but do not limit the invention in any way below.
Embodiment 1：
Prescription：
Preparation method：Potassium citrate and sorbierite are heated to melting in hot-melt extruded machine, Lurasidone HCl is then added and melts
Melt, fused solution extrusion granulator forms with calcium monohydrogen phosphate, superfine silica gel powder, magnesium stearate direct tablet compressing
Embodiment 2：
Prescription：
Preparation method：Potassium citrate and sorbierite are heated to melting in hot-melt extruded machine, Lurasidone HCl is then added and melts
Melt, fused solution extrusion granulator forms with calcium monohydrogen phosphate, superfine silica gel powder, magnesium stearate direct tablet compressing.
Embodiment 3：
Prescription：
Preparation method：Potassium citrate and sorbierite are heated to melting in hot-melt extruded machine, Lurasidone HCl is then added and melts
Melt, fused solution extrusion granulator forms with calcium monohydrogen phosphate, superfine silica gel powder, magnesium stearate direct tablet compressing.
Embodiment 4：
Prescription：
Preparation method：Potassium citrate and sorbierite are heated to melting in hot-melt extruded machine, Lurasidone HCl is then added and melts
Melt, fused solution extrusion granulator forms with calcium monohydrogen phosphate, superfine silica gel powder, magnesium stearate direct tablet compressing.
Embodiment 5：
Prescription：
Preparation method：Potassium citrate and sorbierite are heated to melting in hot-melt extruded machine, Lurasidone HCl is then added and melts
Melt, fused solution extrusion granulator forms with calcium monohydrogen phosphate, superfine silica gel powder, magnesium stearate direct tablet compressing.
Embodiment 6：
Prescription：
Preparation method：Potassium citrate and sorbierite are heated to melting in hot-melt extruded machine, Lurasidone HCl is then added and melts
Melt, fused solution extrusion granulator forms with mannitol, calcium sulfate, dextrin, Compritol 888 ATO, magnesium stearate direct tablet compressing.
Embodiment 7：
Prescription：
Preparation method：Potassium citrate and sorbierite are heated to melting in hot-melt extruded machine, Lurasidone HCl is then added and melts
Melt, fused solution extrusion granulator forms with lactose, calcium monohydrogen phosphate, dextrin, talcum powder, magnesium stearate direct tablet compressing.
Embodiment 8：
Prescription：
Preparation method：Potassium citrate and sorbierite are heated to melting in hot-melt extruded machine, Lurasidone HCl is then added and melts
Melt, fused solution extrusion granulator forms with microcrystalline cellulose, starch, dextrin, superfine silica gel powder, stearic acid direct tablet compressing.
Embodiment 9：
Prescription：
Preparation method：Potassium citrate and sorbierite are heated to melting in hot-melt extruded machine, Lurasidone HCl is then added and melts
Melt, fused solution extrusion granulator forms with mannitol, pregelatinized starch, calcium carbonate, talcum powder, magnesium stearate direct tablet compressing.
Embodiment 10：
Prescription：
Preparation method：Potassium citrate and sorbierite are heated to melting in hot-melt extruded machine, Lurasidone HCl is then added and melts
Melt, fused solution extrusion granulator forms with mannitol, calcium sulfate, dextrin, superfine silica gel powder, magnesium stearate direct tablet compressing.
Embodiment 11：
To using Lurasidone HCl piece made of embodiment 3, embodiment 4, embodiment 5 and real using CN103006661A
Apply Lurasidone HCl piece (micronizing) made of example 3, Lurasidone HCl piece (ring made of CN104248769A embodiments 2
Dextrin includes), Lurasidone HCl piece (adding surfactant) made of CN104971046A embodiments 2 carries out 0 day and long-term
In Vitro Dissolution curve in June is tested to investigate.
In Vitro Dissolution dissolution determination condition is as follows：
Dissolution testing conditions：
Dissolution medium：PH3.8 citrate-phosphate disodium hydrogens buffer solution (weighs the hydrations of monohydrate potassium 2.88g and 12
Disodium hydrogen phosphate 4.7g, water 1000ml is added to make dissolving)
Medium volume：900ml
Rotating speed：50rpm
Chromatographic condition and system suitability：
Chromatographic column：Octadecylsilane chemically bonded silica is filler (5 μm of particle diameter)
Column temperature：30℃
Mobile phase：0.02mol/L diammonium hydrogen phosphates buffer solution (adjusting pH value to 5.0 with phosphoric acid)-acetonitrile (40: 60)
Flow velocity：1.0ml/min
Detection wavelength：230nm
Sample size：10μl
Number of theoretical plate：It is not less than 5000 based on Lurasidone HCl peak
It is prepared by solution：
Reference substance solution：It is appropriate to weigh Lurasidone HCl reference substance, it is accurately weighed, add flowing phased soln and quantify dilution
It is made in every 1ml containing about 44 μ g solution；
Need testing solution：Dissolution test resulting solution is taken, is filtered, subsequent filtrate is as need testing solution.
Assay method：
This product 6 is taken, according to dissolution method (two the second methods of annex X C of Chinese Pharmacopoeia version in 2010) and efficient liquid phase
Chromatography (two annex V D of Chinese Pharmacopoeia version in 2010), precision measures reference substance solution and each 10 μ l of need testing solution, respectively
Liquid chromatograph is injected, records chromatogram, by external standard method with the stripping quantity of calculated by peak area every.Drawn according to every stripping quantity
Stripping curve table.Measurement result is shown in Table 1, table 2；Fig. 1, Fig. 2.
10 days external stripping curve investigation table (dissolution mediums of table：PH3.8 citrate-phosphate disodium hydrogens buffer solution)
| 5min | 15min | 20min | 30min | 45min | |
| Embodiment 3 | 93% | 97% | 97% | 98% | 98% |
| Embodiment 4 | 95% | 98% | 97% | 98% | 98% |
| Embodiment 5 | 96% | 99% | 99% | 98% | 96% |
| CN103006661A | 86% | 91% | 94% | 97% | 97% |
| CN104971046A | 84% | 95% | 95% | 97% | 97% |
| CN104971046A | 47% | 83% | 92% | 97% | 98% |
Long-term In Vitro Dissolution in the June curve investigation table (dissolution medium of table 2：PH3.8 citrate-phosphate disodium hydrogens buffer solution)
| 5min | 15min | 20min | 30min | 45min | |
| Embodiment 3 | 94% | 95% | 95% | 97% | 98% |
| Embodiment 4 | 95% | 95% | 96% | 97% | 99% |
| Embodiment 5 | 97% | 98% | 99% | 99% | 98% |
| CN103006661A | 42% | 51% | 64% | 72% | 72% |
| CN104971046A | 67% | 75% | 84% | 88% | 91% |
| CN104971046A | 31% | 43% | 55% | 78% | 87% |
Claims (6)
- A kind of 1. Lurasidone HCl piece, it is characterised in that：Directly pressed with auxiliary material by Lurasidone HCl solid dispersion particles Piece forms；Described Lurasidone HCl solid dispersion particles are prepared as follows forming：By potassium citrate and sorbierite Melting is heated in hot-melt extruded machine, Lurasidone HCl melting is then added, by fused solution extrusion granulator, Lurasidone HCl Weight ratio with potassium citrate is 1:The weight ratio of 0.5-2, Lurasidone HCl and sorbierite is 1:1-5；Described auxiliary material is Calcium monohydrogen phosphate, superfine silica gel powder and magnesium stearate, Lurasidone HCl and calcium monohydrogen phosphate, superfine silica gel powder, the weight ratio of magnesium stearate For 1:4.5-7.5:0.125-0.5:0.0375-0.075.
- 2. Lurasidone HCl piece according to claim 1, it is characterised in that：The weight of Lurasidone HCl and potassium citrate Amount is than being 1:0.8-1.2.
- 3. Lurasidone HCl piece according to claim 1, it is characterised in that：The weight of Lurasidone HCl and sorbierite Than for 1:2-4.
- 4. Lurasidone HCl piece according to claim 1, it is characterised in that：It is Lurasidone HCl and calcium monohydrogen phosphate, micro- The weight ratio preferably 1 of powder silica gel, magnesium stearate:5-6:0.2-0.4:0.04-0.06.
- 5. the preparation method of a kind of Lurasidone HCl piece according to claim any one of 1-4, it is characterised in that include Following steps：Potassium citrate and sorbierite are heated to melting in hot-melt extruded machine, then add Lurasidone HCl melting, will Fused solution extrusion granulator, formed with auxiliary material direct tablet compressing.
- 6. the Lurasidone HCl piece prepared by the preparation method of Lurasidone HCl piece according to claim 5.
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|---|---|---|---|
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| CN110114063B (en) * | 2017-01-06 | 2022-01-11 | 广东东阳光药业有限公司 | Lurasidone solid dispersion and preparation method thereof |
| CN107998093A (en) * | 2017-12-17 | 2018-05-08 | 佛山市弘泰药物研发有限公司 | A kind of Lurasidone HCl sustained release tablets and preparation method thereof |
| US20210251985A1 (en) * | 2017-12-26 | 2021-08-19 | Sunshine Lake Pharma Co., Ltd. | Lurasidone solid dispersion and preparation method thereof |
| US11103502B2 (en) | 2019-01-10 | 2021-08-31 | Slayback Pharma Llc | Pharmaceutical compositions of lurasidone |
| GB201904771D0 (en) * | 2019-04-04 | 2019-05-22 | Orexo Ab | New pharmaceutical compositions |
| CN110833532A (en) * | 2019-12-19 | 2020-02-25 | 赵洁 | Rapidly-released lurasidone hydrochloride tablet and preparation process thereof |
| CN112168794A (en) * | 2020-10-27 | 2021-01-05 | 浙江诺得药业有限公司 | Preparation method of brexpiprazole tablets |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102688189A (en) * | 2012-06-21 | 2012-09-26 | 李兴惠 | Lurasidone medicine composition and preparation method thereof |
| CN103536568A (en) * | 2012-07-12 | 2014-01-29 | 成都康弘药业集团股份有限公司 | Orally disintegrating tablets containing lurasidone and preparation method thereof |
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2015
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102688189A (en) * | 2012-06-21 | 2012-09-26 | 李兴惠 | Lurasidone medicine composition and preparation method thereof |
| CN103536568A (en) * | 2012-07-12 | 2014-01-29 | 成都康弘药业集团股份有限公司 | Orally disintegrating tablets containing lurasidone and preparation method thereof |
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Denomination of invention: A type of Lurasidone Hydrochloride Tablet Effective date of registration: 20231115 Granted publication date: 20180216 Pledgee: Nanjing Branch of Jiangsu Bank Co.,Ltd. Pledgor: NANJING ZENKOM PHARMACEUTICAL CO.,LTD. Registration number: Y2023980065250 |
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