CN114259470B - Sodium levofolinate particles with humidity stability and controllable release rate and preparation method thereof - Google Patents
Sodium levofolinate particles with humidity stability and controllable release rate and preparation method thereof Download PDFInfo
- Publication number
- CN114259470B CN114259470B CN202111612702.1A CN202111612702A CN114259470B CN 114259470 B CN114259470 B CN 114259470B CN 202111612702 A CN202111612702 A CN 202111612702A CN 114259470 B CN114259470 B CN 114259470B
- Authority
- CN
- China
- Prior art keywords
- sodium levofolinate
- levofolinate
- sodium
- particles
- ascorbic acid
- 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.)
- Active
Links
- FSDMNNPYPVJNAT-NJHZPMQHSA-L disodium;(2s)-2-[[4-[[(6s)-2-amino-5-formyl-4-oxo-1,6,7,8-tetrahydropteridin-6-yl]methylamino]benzoyl]amino]pentanedioate Chemical compound [Na+].[Na+].C([C@@H]1N(C=O)C=2C(=O)N=C(NC=2NC1)N)NC1=CC=C(C(=O)N[C@@H](CCC([O-])=O)C([O-])=O)C=C1 FSDMNNPYPVJNAT-NJHZPMQHSA-L 0.000 title claims abstract description 356
- 229940055346 sodium levofolinate Drugs 0.000 title claims abstract description 356
- 239000002245 particle Substances 0.000 title claims abstract description 228
- 238000002360 preparation method Methods 0.000 title claims abstract description 51
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims abstract description 156
- 235000010323 ascorbic acid Nutrition 0.000 claims abstract description 78
- 229960005070 ascorbic acid Drugs 0.000 claims abstract description 78
- 239000011668 ascorbic acid Substances 0.000 claims abstract description 78
- 239000008187 granular material Substances 0.000 claims abstract description 30
- 239000007787 solid Substances 0.000 claims abstract description 11
- 239000000725 suspension Substances 0.000 claims description 31
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 claims description 27
- FETSQPAGYOVAQU-UHFFFAOYSA-N glyceryl palmitostearate Chemical compound OCC(O)CO.CCCCCCCCCCCCCCCC(O)=O.CCCCCCCCCCCCCCCCCC(O)=O FETSQPAGYOVAQU-UHFFFAOYSA-N 0.000 claims description 27
- 229940046813 glyceryl palmitostearate Drugs 0.000 claims description 27
- 238000003756 stirring Methods 0.000 claims description 25
- 238000000034 method Methods 0.000 claims description 15
- 239000000203 mixture Substances 0.000 claims description 14
- 239000012768 molten material Substances 0.000 claims description 14
- 229940075507 glyceryl monostearate Drugs 0.000 claims description 13
- 238000002844 melting Methods 0.000 claims description 13
- 230000008018 melting Effects 0.000 claims description 13
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 claims description 13
- OKMWKBLSFKFYGZ-UHFFFAOYSA-N 1-behenoylglycerol Chemical compound CCCCCCCCCCCCCCCCCCCCCC(=O)OCC(O)CO OKMWKBLSFKFYGZ-UHFFFAOYSA-N 0.000 claims description 12
- 229940049654 glyceryl behenate Drugs 0.000 claims description 12
- 238000002156 mixing Methods 0.000 claims description 7
- 230000008569 process Effects 0.000 claims description 7
- 238000009472 formulation Methods 0.000 claims description 2
- 239000012535 impurity Substances 0.000 abstract description 19
- 238000006731 degradation reaction Methods 0.000 abstract description 10
- 238000010521 absorption reaction Methods 0.000 abstract description 8
- 230000015556 catabolic process Effects 0.000 abstract description 8
- 239000011248 coating agent Substances 0.000 abstract description 5
- 238000000576 coating method Methods 0.000 abstract description 5
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 230000002209 hydrophobic effect Effects 0.000 abstract description 3
- 230000007613 environmental effect Effects 0.000 abstract description 2
- 230000001105 regulatory effect Effects 0.000 abstract description 2
- 230000000052 comparative effect Effects 0.000 description 35
- 239000003814 drug Substances 0.000 description 20
- 238000012360 testing method Methods 0.000 description 16
- 229940079593 drug Drugs 0.000 description 15
- 239000002994 raw material Substances 0.000 description 14
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 12
- 230000000694 effects Effects 0.000 description 11
- 238000010438 heat treatment Methods 0.000 description 11
- 238000005259 measurement Methods 0.000 description 9
- KRWXDRXWUYUVJO-UHFFFAOYSA-N 2,3-dihydroxypropyl octadecanoate;hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O.CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO KRWXDRXWUYUVJO-UHFFFAOYSA-N 0.000 description 8
- 239000003795 chemical substances by application Substances 0.000 description 8
- 238000013270 controlled release Methods 0.000 description 7
- 238000004090 dissolution Methods 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- 230000004584 weight gain Effects 0.000 description 7
- 235000019786 weight gain Nutrition 0.000 description 7
- 238000000889 atomisation Methods 0.000 description 6
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 description 6
- 239000011780 sodium chloride Substances 0.000 description 6
- VVIAGPKUTFNRDU-UHFFFAOYSA-N 6S-folinic acid Natural products C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 VVIAGPKUTFNRDU-UHFFFAOYSA-N 0.000 description 5
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 5
- 239000002202 Polyethylene glycol Substances 0.000 description 5
- KVUAALJSMIVURS-ZEDZUCNESA-L calcium folinate Chemical compound [Ca+2].C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)N[C@@H](CCC([O-])=O)C([O-])=O)C=C1 KVUAALJSMIVURS-ZEDZUCNESA-L 0.000 description 5
- 239000012738 dissolution medium Substances 0.000 description 5
- 235000008191 folinic acid Nutrition 0.000 description 5
- 239000011672 folinic acid Substances 0.000 description 5
- 239000008103 glucose Substances 0.000 description 5
- 229960001691 leucovorin Drugs 0.000 description 5
- 229920001223 polyethylene glycol Polymers 0.000 description 5
- VVIAGPKUTFNRDU-STQMWFEESA-N (6S)-5-formyltetrahydrofolic acid Chemical compound C([C@H]1CNC=2N=C(NC(=O)C=2N1C=O)N)NC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 VVIAGPKUTFNRDU-STQMWFEESA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 230000009471 action Effects 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 239000004052 folic acid antagonist Substances 0.000 description 4
- 239000007789 gas Substances 0.000 description 4
- 239000011521 glass Substances 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- MSTNYGQPCMXVAQ-RYUDHWBXSA-N (6S)-5,6,7,8-tetrahydrofolic acid Chemical compound C([C@H]1CNC=2N=C(NC(=O)C=2N1)N)NC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 MSTNYGQPCMXVAQ-RYUDHWBXSA-N 0.000 description 3
- MPJKWIXIYCLVCU-UHFFFAOYSA-N Folinic acid Natural products NC1=NC2=C(N(C=O)C(CNc3ccc(cc3)C(=O)NC(CCC(=O)O)CC(=O)O)CN2)C(=O)N1 MPJKWIXIYCLVCU-UHFFFAOYSA-N 0.000 description 3
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 description 3
- 229960001921 calcium levofolinate Drugs 0.000 description 3
- KVUAALJSMIVURS-QNTKWALQSA-L calcium;(2s)-2-[[4-[[(6s)-2-amino-5-formyl-4-oxo-1,6,7,8-tetrahydropteridin-6-yl]methylamino]benzoyl]amino]pentanedioate Chemical compound [Ca+2].C([C@@H]1N(C=O)C=2C(=O)N=C(NC=2NC1)N)NC1=CC=C(C(=O)N[C@@H](CCC([O-])=O)C([O-])=O)C=C1 KVUAALJSMIVURS-QNTKWALQSA-L 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 238000009833 condensation Methods 0.000 description 3
- 230000005494 condensation Effects 0.000 description 3
- 230000007423 decrease Effects 0.000 description 3
- 235000019152 folic acid Nutrition 0.000 description 3
- 239000011724 folic acid Substances 0.000 description 3
- 229960000304 folic acid Drugs 0.000 description 3
- 238000000691 measurement method Methods 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 239000011148 porous material Substances 0.000 description 3
- 229940055334 sodium folinate Drugs 0.000 description 3
- UDDUKFYJPZYIPC-ZEDZUCNESA-M sodium folinate Chemical compound [Na+].C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)N[C@@H](CCC([O-])=O)C(O)=O)C=C1 UDDUKFYJPZYIPC-ZEDZUCNESA-M 0.000 description 3
- 235000008190 sodium folinate Nutrition 0.000 description 3
- 239000011673 sodium folinate Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- 239000012085 test solution Substances 0.000 description 3
- 239000005460 tetrahydrofolate Substances 0.000 description 3
- QYNUQALWYRSVHF-OLZOCXBDSA-N (6R)-5,10-methylenetetrahydrofolic acid Chemical compound C([C@H]1CNC=2N=C(NC(=O)C=2N1C1)N)N1C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 QYNUQALWYRSVHF-OLZOCXBDSA-N 0.000 description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 108010022394 Threonine synthase Proteins 0.000 description 2
- 230000003064 anti-oxidating effect Effects 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 230000001276 controlling effect Effects 0.000 description 2
- 230000001186 cumulative effect Effects 0.000 description 2
- 239000003405 delayed action preparation Substances 0.000 description 2
- 102000004419 dihydrofolate reductase Human genes 0.000 description 2
- 229960002949 fluorouracil Drugs 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 229940075961 levoleucovorin calcium pentahydrate Drugs 0.000 description 2
- 235000007635 levomefolic acid Nutrition 0.000 description 2
- 239000011578 levomefolic acid Substances 0.000 description 2
- ZNOVTXRBGFNYRX-ABLWVSNPSA-N levomefolic acid Chemical compound C1NC=2NC(N)=NC(=O)C=2N(C)C1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 ZNOVTXRBGFNYRX-ABLWVSNPSA-N 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000010358 mechanical oscillation Effects 0.000 description 2
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000000523 sample Substances 0.000 description 2
- 239000012488 sample solution Substances 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- VDZOOKBUILJEDG-UHFFFAOYSA-M tetrabutylammonium hydroxide Chemical compound [OH-].CCCC[N+](CCCC)(CCCC)CCCC VDZOOKBUILJEDG-UHFFFAOYSA-M 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- QHZLMUACJMDIAE-UHFFFAOYSA-N 1-monopalmitoylglycerol Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(O)CO QHZLMUACJMDIAE-UHFFFAOYSA-N 0.000 description 1
- FLPJVCMIKUWSDR-UHFFFAOYSA-N 2-(4-formylphenoxy)acetamide Chemical compound NC(=O)COC1=CC=C(C=O)C=C1 FLPJVCMIKUWSDR-UHFFFAOYSA-N 0.000 description 1
- RFVNOJDQRGSOEL-UHFFFAOYSA-N 2-hydroxyethyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCO RFVNOJDQRGSOEL-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 206010016880 Folate deficiency Diseases 0.000 description 1
- 208000010188 Folic Acid Deficiency Diseases 0.000 description 1
- 102000002667 Glycine hydroxymethyltransferase Human genes 0.000 description 1
- 108010043428 Glycine hydroxymethyltransferase Proteins 0.000 description 1
- 208000037147 Hypercalcaemia Diseases 0.000 description 1
- 102000005954 Methylenetetrahydrofolate Reductase (NADPH2) Human genes 0.000 description 1
- 108010030837 Methylenetetrahydrofolate Reductase (NADPH2) Proteins 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 239000008118 PEG 6000 Substances 0.000 description 1
- 229920002584 Polyethylene Glycol 6000 Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 239000000729 antidote Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 235000013871 bee wax Nutrition 0.000 description 1
- 239000012166 beeswax Substances 0.000 description 1
- 230000006399 behavior Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 239000004203 carnauba wax Substances 0.000 description 1
- 235000013869 carnauba wax Nutrition 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 229940074979 cetyl palmitate Drugs 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000005515 coenzyme Substances 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- OZRNSSUDZOLUSN-LBPRGKRZSA-N dihydrofolic acid Chemical compound N=1C=2C(=O)NC(N)=NC=2NCC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OZRNSSUDZOLUSN-LBPRGKRZSA-N 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
- 239000002552 dosage form Substances 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 229940096898 glyceryl palmitate Drugs 0.000 description 1
- 229940075529 glyceryl stearate Drugs 0.000 description 1
- PXDJXZJSCPSGGI-UHFFFAOYSA-N hexadecanoic acid hexadecyl ester Natural products CCCCCCCCCCCCCCCCOC(=O)CCCCCCCCCCCCCCC PXDJXZJSCPSGGI-UHFFFAOYSA-N 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000008172 hydrogenated vegetable oil Substances 0.000 description 1
- 230000000148 hypercalcaemia Effects 0.000 description 1
- 208000030915 hypercalcemia disease Diseases 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 238000006241 metabolic reaction Methods 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 239000004200 microcrystalline wax Substances 0.000 description 1
- 235000019808 microcrystalline wax Nutrition 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- GOQYKNQRPGWPLP-UHFFFAOYSA-N n-heptadecyl alcohol Natural products CCCCCCCCCCCCCCCCCO GOQYKNQRPGWPLP-UHFFFAOYSA-N 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 238000010525 oxidative degradation reaction Methods 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 235000019809 paraffin wax Nutrition 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 235000019271 petrolatum Nutrition 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 231100000572 poisoning Toxicity 0.000 description 1
- 230000000607 poisoning effect Effects 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 239000002213 purine nucleotide Substances 0.000 description 1
- WKSAUQYGYAYLPV-UHFFFAOYSA-N pyrimethamine Chemical compound CCC1=NC(N)=NC(N)=C1C1=CC=C(Cl)C=C1 WKSAUQYGYAYLPV-UHFFFAOYSA-N 0.000 description 1
- 229960000611 pyrimethamine Drugs 0.000 description 1
- 239000002719 pyrimidine nucleotide Substances 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 238000007711 solidification Methods 0.000 description 1
- 230000008023 solidification Effects 0.000 description 1
- 230000007480 spreading Effects 0.000 description 1
- 238000003892 spreading Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 238000009210 therapy by ultrasound Methods 0.000 description 1
- RWQNBRDOKXIBIV-UHFFFAOYSA-N thymine Chemical class CC1=CNC(=O)NC1=O RWQNBRDOKXIBIV-UHFFFAOYSA-N 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention relates to the technical field of pharmacy, and provides sodium levofolinate particles with controllable moisture stability and release rate and a preparation method thereof. The sodium levofolinate granule comprises 1 part by mass of sodium levofolinate, 5-20 parts by mass of retarder and 0.2-1 part by mass of ascorbic acid. The sodium levofolinate particles provided by the invention effectively solve the problem of moisture absorption and deliquescence which are very easy to occur in sodium levofolinate by adopting a hydrophobic retarder coating technology, improve the moisture stability of sodium levofolinate, and solve the problems of severe requirements on environmental humidity and high production cost in the preparation process of a sodium levofolinate solid preparation; meanwhile, the degradation of sodium levofolinate is effectively inhibited through the matched use of the retarder and the ascorbic acid, the impurity content in sodium levofolinate particles is reduced, and the property that the release rate of the sodium levofolinate particles can be regulated is endowed.
Description
Technical Field
The invention relates to the technical field of pharmacy, in particular to sodium levofolinate particles with stable humidity and controllable release rate and a preparation method thereof.
Background
Folic acid is a nutrient substance necessary for human body, and is converted into dihydrofolic acid in small intestine cells through catalysis of dihydrofolate reductase, so as to be further converted into tetrahydrofolate; under the action of serine hydroxymethyl transferase, tetrahydrofolate reacts to generate 5, 10-methylene tetrahydrofolate; under the action of methylene tetrahydrofolate reductase, 5, 10-methylene tetrahydrofolate is converted into 5-methyl tetrahydrofolate, and 5-methyl tetrahydrofolate can be used as coenzyme to participate in metabolic reaction of purine and pyrimidine nucleotide in vivo and biosynthesis reaction of certain amino acids. Folic acid antagonists such as methotrexate and pyrimethamine can be combined with dihydrofolate reductase to block conversion of folic acid into tetrahydrofolate, thereby affecting synthesis of thymine nucleotide, DNA, RNA and protein and further playing corresponding pharmacological actions. However, long-term or large-dose use of these folic acid antagonists causes toxic side effects due to folic acid deficiency.
Folinic acid is a formyl derivative of tetrahydrofolic acid, is an activated form of folic acid in vivo, is mainly used as an poisoning antidote of folic acid antagonist clinically, and is used for preventing serious toxic and side effects caused by excessive folic acid antagonist or large-dose treatment. In addition, folinic acid can be used as a biological regulator of 5-fluorouracil to enhance the cytotoxic effect of 5-fluorouracil and is widely used for treating tumors.
The leucovorin is raceme, and the leucovorin plays a pharmacological role, namely, the levofolinic acid. Left folinic acid is currently mainly applied clinically in the form of calcium left folinate and sodium left folinate. Calcium levofolinate was developed by the Hui corporation and marketed in the UK in 1994. Sodium levofolinate injection developed by the company MEDAC in 2008 was also successfully obtained. Compared with calcium levofolinate, sodium levofolinate has better water solubility; and calcium salts have the potential to cause hypercalcemia, while sodium salts do not present the above-mentioned risks. Therefore, compared with calcium levofolinate, sodium levofolinate has more formulation and safety advantages.
At present, the sodium levofolinate is only prepared into injection, the sodium levofolinate injection needs to be stored under the low-temperature condition to ensure the sufficient shelf life, and special medical staff is needed to infuse the sodium levofolinate during application, so that the pain in the infusion process is very easy to cause poor patient compliance. Compared with injection, the solid preparation which is administrated by the oral route has great advantages in aspects of transportation, carrying, use and patient compliance.
The prior art discloses some oral preparations of sodium levofolinate and a preparation method thereof. For example, chinese patent CN101862333 discloses an oral preparation of sodium levofolinate and a preparation method thereof, and specifically comprises the dosage forms and the preparation methods of tablets, capsules, granules, powder, oral solutions and the like of sodium levofolinate. However, in the process of reproducing the preparation methods of solid preparations such as tablets, capsules, granules and powder in the prior art, the phenomenon that sodium levofolinate is easy to absorb moisture and deliquesce is found, so that the serious moisture absorption phenomenon of the sodium levofolinate bulk drug can be avoided by strictly controlling the humidity of the environment in the preparation process, but the severe requirements on the environment humidity increase the manufacturing cost and the manufacturing difficulty of the corresponding solid preparation.
Therefore, a new sodium levofolinate granule and a preparation method thereof are needed to be developed to solve the technical problem that the sodium levofolinate bulk drug is very easy to generate moisture absorption and deliquescence.
Disclosure of Invention
The invention aims to provide a sodium levofolinate granule which is stable to humidity, so as to solve the technical problem that the sodium levofolinate bulk drug is easy to absorb moisture and deliquesce in the prior art.
In order to achieve the above purpose, the invention adopts the following technical scheme:
in a first aspect, the invention provides sodium levofolinate particles with controllable moisture stability and release rate, which comprise the following components in parts by weight:
sodium levofolinate 1;
5-20 parts of retarder;
ascorbic acid 0.2-1.
According to the sodium levofolinate granule provided by the invention, the retarder is used for coating the sodium levofolinate raw material by using the particle design principle, so that the problem of moisture absorption and deliquescence easily occurring in sodium levofolinate is effectively solved, and the moisture stability of sodium levofolinate is improved. The ascorbic acid is added as a pore-forming agent to be matched with a retarder for use, so that the sodium levofolinate particles have the property of adjustable release rate; simultaneously, the ascorbic acid can also effectively inhibit the degradation of sodium levofolinate and reduce the impurity content in sodium levofolinate particles.
The sodium levofolinate particles provided by the invention can be directly used for oral administration or further processed into other solid preparation forms for oral administration.
The retarder used in the invention can be selected from hydrophobic erodible skeleton materials commonly used in the field of pharmaceutics and used for preparing sustained and controlled release preparations, such as beeswax, carnauba wax, microcrystalline wax, paraffin wax, stearic acid, stearyl alcohol, hydrogenated vegetable oil, polyethylene glycol monostearate, glyceryl monostearate, cetyl palmitate, glyceryl behenate, glyceryl monostearate, glyceryl palmitate, glyceryl stearate and the like.
As a preferred embodiment of the sodium levofolinate granule provided by the invention, the particle diameter D90 of the sodium levofolinate is 3-110 mu m.
As a preferable mode of the sodium levofolinate particles provided by the invention, the particle diameter D90 of the ascorbic acid is 1-20 mu m.
As a preferable scheme of the sodium levofolinate granule provided by the invention, the retarder is at least one of glyceryl behenate, glyceryl monostearate and glyceryl palmitostearate.
Further preferably, the retarder is glyceryl palmitostearate.
As a preferable scheme of the sodium levofolinate granule, the mass fraction of the retarder is 10-20.
In a second aspect, the present invention also provides a method for preparing the sodium levofolinate particles, comprising:
melting the retarder to obtain a molten material;
adding ascorbic acid and sodium levofolinate into a molten material, and uniformly mixing to prepare a molten carrier suspension containing sodium levofolinate;
preparing a molten carrier suspension containing sodium levofolinate into fogdrops containing a molten mixture of sodium levofolinate by an atomizer;
condensing the fogdrops of the molten mixture containing sodium levofolinate to prepare sodium levofolinate particles.
In the preparation method of the sodium levofolinate particles, a common heating and melting method can be adopted for melting the retarder, and the heating behaviors of various heating devices prepared by utilizing heat transfer principles based on conduction, convection, radiation and the like are included. The target temperature to which the heating is applied may generally be selected to be any temperature value in the range of 0-15 c above the melting point temperature of the retarder material.
In the preparation method provided by the invention, the prepared molten carrier suspension containing sodium levofolinate, sodium levofolinate and ascorbic acid exist in a solid form, and the retarder exists in a liquid form.
The atomizer used in the preparation method provided by the invention can be selected from various devices which are prepared based on the principles of compression atomization, airflow impact atomization, ultrasonic atomization, high-speed centrifugal/vortex disk atomization, mechanical oscillation atomization, double-flow impact atomization and the like and can disperse liquid into liquid drops, such as a pressure atomizer, a compressed gas atomizer, an ultrasonic atomizer, a high-speed centrifugal atomizer, a mechanical oscillation atomizer and the like.
Condensation in the preparation process provided by the invention generally occurs by contacting droplets of a molten mixture containing sodium levofolinate with a gas or liquid having a temperature below the solidification temperature of the droplets. The condensation process is typically carried out in an enclosed space, and as the heat introduced by the droplets may cause an increase in the temperature of the accelerating gas or liquid in the enclosed space, the accelerating gas or liquid is typically circulated through the enclosed space to maintain a constant condensation temperature.
As a preferable scheme of the preparation method of the sodium levofolinate particles, the steps of adding ascorbic acid and sodium levofolinate into a molten material, uniformly mixing, and preparing a molten carrier suspension containing sodium levofolinate specifically comprise the following steps:
adding ascorbic acid into the molten material, and stirring at 8-12rpm for 3-8min; adding sodium levofolinate, and stirring at 8-12rpm for 5-15min to obtain molten carrier suspension containing sodium levofolinate.
Further preferably, the atomizer is a high-speed centrifugal atomizer, and the centrifugal disk rotation speed of the high-speed centrifugal atomizer is 4500-5500rpm.
In a third aspect, the invention also provides a sodium levofolinate solid oral preparation, comprising the sodium levofolinate particles or sodium levofolinate particles prepared by the preparation method of the sodium levofolinate particles.
The sodium levofolinate particles provided by the invention can be further processed into common oral solid preparations such as tablets, pills, capsules and the like by adopting a common solid preparation method so as to be used in an oral administration route.
The invention has the advantages that:
the invention provides sodium levofolinate particles with controllable release rate and humidity stability and a preparation method thereof. The sodium levofolinate particles effectively solve the problem of moisture absorption and deliquescence which are very easy to occur in sodium levofolinate by adopting a hydrophobic retarder coating technology, improve the moisture stability of sodium levofolinate, and solve the problems of severe requirements on environmental humidity and high production cost in the preparation process of the sodium levofolinate solid preparation; meanwhile, the degradation of sodium levofolinate is effectively inhibited through the matched use of the retarder and the ascorbic acid, the impurity content in sodium levofolinate particles is reduced, and the property that the release rate of the sodium levofolinate particles can be regulated is endowed.
Detailed Description
In order to make the technical problems, technical schemes and beneficial effects to be solved more clear, the invention is further described in detail below with reference to specific embodiments. It should be understood that the detailed description is presented herein only to illustrate the present patent and is not intended to limit the scope of the invention in any way.
The sodium levofolinate particles with controllable moisture stability and release rate provided by the invention comprise the following components in parts by weight:
sodium levofolinate 1;
5-20 parts of retarder;
ascorbic acid 0.2-1.
The particle diameter D90 of sodium levofolinate may be selected in the range of 3 to 110. Mu.m, for example, 3 μm,5 μm, 10 μm, 30 μm, 50 μm, 75 μm, 100 μm, 110 μm, etc. may be selected.
The particle diameter D90 of the ascorbic acid may be selected in the range of 1 to 20. Mu.m, for example, 1. Mu.m, 2. Mu.m, 4. Mu.m, 5. Mu.m, 8. Mu.m, 12. Mu.m, 15. Mu.m, 20. Mu.m, etc. may be selected.
The retarder can be at least one of glyceryl behenate, glyceryl monostearate and glyceryl palmitostearate.
The preparation method of the sodium levofolinate particles comprises the following steps:
melting the retarder to obtain a molten material;
adding ascorbic acid and sodium levofolinate into a molten material, and uniformly mixing to prepare a molten carrier suspension containing sodium levofolinate;
preparing a molten carrier suspension containing sodium levofolinate into fogdrops containing a molten mixture of sodium levofolinate by an atomizer;
condensing the fogdrops of the molten mixture containing sodium levofolinate to prepare sodium levofolinate particles.
Wherein, adding ascorbic acid and sodium levofolinate into the molten material, and uniformly mixing to prepare a molten carrier suspension containing sodium levofolinate, which comprises the following steps:
adding ascorbic acid into the molten material, and stirring at 8-12rpm for 3-8min; adding sodium levofolinate, and stirring at 8-12rpm for 5-15min to obtain molten carrier suspension containing sodium levofolinate.
The atomizer is preferably a high-speed centrifugal atomizer, and the centrifugal disk rotation speed of the high-speed centrifugal atomizer is 4500-5500rpm.
The invention is tested in a number of consecutive tests, and the invention will now be described in further detail with reference to a few tests, as will be described in detail with reference to the following specific examples:
unless defined otherwise, technical terms used in the following examples have the same meaning as commonly understood by one of ordinary skill in the art to which the present invention pertains. The reagents used in the following examples, unless otherwise specified, are all conventional biochemical reagents; the raw materials, instruments, equipment, etc. used in the following examples are all commercially available or available by existing methods; the reagent dosage is the reagent dosage in the conventional experimental operation if no special description exists; the experimental methods are conventional methods unless otherwise specified.
Example 1
A sodium levofolinate granule with adjustable moisture stability and release rate, which comprises the following components by mass:
sodium levofolinate 10g
Palmitic acid glyceryl stearate 100g
Ascorbic acid 5g;
wherein the particle diameter D90 of the sodium levofolinate is 30 mu m, and the particle diameter D90 of the ascorbic acid is 5 mu m (measured by a laser particle diameter instrument);
the preparation method of the sodium levofolinate particles comprises the following steps:
(1) Heating glyceryl palmitostearate to melt, and maintaining the temperature at 65deg.C;
(2) Adding ascorbic acid into melted glyceryl palmitostearate, and stirring at 10rpm for 5min to uniformly disperse; adding sodium levofolinate, stirring for 10min at the speed of 10rpm by using a stirring paddle to uniformly disperse the sodium levofolinate, and obtaining a molten carrier suspension containing sodium levofolinate;
(3) Conveying the molten carrier suspension containing sodium levofolinate into a high-speed centrifugal atomizer through a conveying pump and a temperature control pipeline to be atomized into fogdrops, wherein the rotating speed of a centrifugal disk of the high-speed centrifugal atomizer is 5000rpm, and the surface temperature is 65 ℃;
(4) The fogdrops are cooled and condensed in the presence of cold air in a collecting chamber to obtain sodium levofolinate particles.
Example 2
A sodium levofolinate granule with adjustable moisture stability and release rate, which comprises the following components by mass:
sodium levofolinate 10g
Glyceryl monostearate 100g
Ascorbic acid 5g;
wherein the particle diameter D90 of the sodium levofolinate is 30 mu m, and the particle diameter D90 of the ascorbic acid is 5 mu m (measured by a laser particle diameter instrument);
the preparation method of the sodium levofolinate particles comprises the following steps:
(1) Heating glyceryl monostearate to melt, and maintaining the temperature at 70deg.C;
(2) Adding ascorbic acid into melted glyceryl monostearate, and stirring at 10rpm for 5min to uniformly disperse; adding sodium levofolinate, stirring for 10min at the speed of 10rpm by using a stirring paddle to uniformly disperse the sodium levofolinate, and obtaining a molten carrier suspension containing sodium levofolinate;
(3) Conveying the molten carrier suspension containing sodium levofolinate into a high-speed centrifugal atomizer through a conveying pump and a temperature control pipeline to be atomized into fogdrops, wherein the rotating speed of a centrifugal disk of the high-speed centrifugal atomizer is 5000rpm, and the surface temperature is 70 ℃;
(4) The fogdrops are cooled and condensed in the presence of cold air in a collecting chamber to obtain sodium levofolinate particles.
Example 3
A sodium levofolinate granule with adjustable moisture stability and release rate, which comprises the following components by mass:
sodium levofolinate 10g
Glyceryl behenate 100g
Ascorbic acid 5g;
wherein the particle diameter D90 of the sodium levofolinate is 30 mu m, and the particle diameter D90 of the ascorbic acid is 5 mu m (measured by a laser particle diameter instrument);
the preparation method of the sodium levofolinate particles comprises the following steps:
(1) Heating glyceryl behenate to melt, and maintaining the temperature at 87 ℃;
(2) Adding ascorbic acid into melted glyceryl behenate, and stirring at 10rpm for 5min to uniformly disperse; adding sodium levofolinate, stirring for 10min at the speed of 10rpm by using a stirring paddle to uniformly disperse the sodium levofolinate, and obtaining a molten carrier suspension containing sodium levofolinate;
(3) Conveying the molten carrier suspension containing sodium levofolinate into a high-speed centrifugal atomizer through a conveying pump and a temperature control pipeline to be atomized into fogdrops, wherein the rotating speed of a centrifugal disk of the high-speed centrifugal atomizer is 5000rpm, and the surface temperature is 87 ℃;
(4) The fogdrops are cooled and condensed in the presence of cold air in a collecting chamber to obtain sodium levofolinate particles.
Example 4
A sodium levofolinate granule with adjustable moisture stability and release rate, which comprises the following components by mass:
sodium levofolinate 10g
Palmitic acid glyceryl stearate 100g
Ascorbic acid 2g;
wherein the particle size of sodium levofolinate, the particle size of ascorbic acid and the preparation method of sodium levofolinate particles are the same as in example 1.
Example 5
A sodium levofolinate granule with adjustable moisture stability and release rate, which comprises the following components by mass:
sodium levofolinate 10g
Palmitic acid glyceryl stearate 100g
10g of ascorbic acid;
wherein the particle size of sodium levofolinate, the particle size of ascorbic acid and the preparation method of sodium levofolinate particles are the same as in example 1.
Example 6
A sodium levofolinate granule with adjustable moisture stability and release rate, which comprises the following components by mass:
sodium levofolinate 10g
Palmitic acid glyceryl stearate 50g
Ascorbic acid 5g;
wherein the particle size of sodium levofolinate, the particle size of ascorbic acid and the preparation method of sodium levofolinate particles are the same as in example 1.
Example 7
A sodium levofolinate granule with adjustable moisture stability and release rate, which comprises the following components by mass:
sodium levofolinate 10g
Glyceryl palmitostearate 200g
Ascorbic acid 5g;
wherein the particle size of sodium levofolinate, the particle size of ascorbic acid and the preparation method of sodium levofolinate particles are the same as in example 1.
Example 8
Sodium levofolinate particles with a controlled release rate, which is moisture stable, differ from example 1 in that: the particle diameter D90 of sodium levofolinate was 3 μm (measured by a laser particle diameter meter).
Example 9
Sodium levofolinate particles with a controlled release rate, which is moisture stable, differ from example 1 in that: the particle diameter D90 of sodium levofolinate was 110. Mu.m (measured by a laser particle diameter meter).
Example 10
Sodium levofolinate particles with a controlled release rate, which is moisture stable, differ from example 1 in that: the particle diameter D90 of sodium levofolinate was 130 μm (measured by a laser particle diameter meter).
Example 11
Sodium levofolinate particles with a controlled release rate, which is moisture stable, differ from example 1 in that: the particle diameter D90 of the ascorbic acid was 1. Mu.m (measured by a laser particle diameter meter).
Example 12
Sodium levofolinate particles with a controlled release rate, which is moisture stable, differ from example 1 in that: the particle diameter D90 of the ascorbic acid was 10. Mu.m (measured by a laser particle diameter meter).
Example 13
Sodium levofolinate particles with a controlled release rate, which is moisture stable, differ from example 1 in that: the particle diameter D90 of the ascorbic acid was 20. Mu.m (measured by a laser particle diameter meter).
Example 14
Sodium levofolinate particles with a controlled release rate, which is moisture stable, differ from example 1 in that: the particle diameter D90 of the ascorbic acid was 100. Mu.m (measured by a laser particle diameter meter).
Comparative example 1
A sodium levofolinate granule with adjustable moisture stability and release rate, which comprises the following components by mass:
sodium levofolinate 10g
Palmitic acid glyceryl stearate 100g
Polyethylene glycol (PEG 6000) 5g;
wherein, the particle diameter D90 of the sodium levofolinate is 30 mu m (measured by a laser particle diameter instrument);
the preparation method of the sodium levofolinate particles comprises the following steps:
(1) Heating glyceryl palmitostearate to melt, and maintaining the temperature at 65deg.C;
(2) Adding polyethylene glycol into melted glyceryl palmitostearate, and stirring at 10rpm for 5min to uniformly disperse; adding sodium levofolinate, stirring for 10min at the speed of 10rpm by using a stirring paddle to uniformly disperse the sodium levofolinate, and obtaining a molten carrier suspension containing sodium levofolinate;
(3) Conveying the molten carrier suspension containing sodium levofolinate into a high-speed centrifugal atomizer through a conveying pump and a temperature control pipeline to be atomized into fogdrops, wherein the rotating speed of a centrifugal disk of the high-speed centrifugal atomizer is 5000rpm, and the surface temperature is 65 ℃;
(4) The fogdrops are cooled and condensed in the presence of cold air in a collecting chamber to obtain sodium levofolinate particles.
Comparative example 2
A sodium levofolinate granule with adjustable moisture stability and release rate, which comprises the following components by mass:
sodium levofolinate 10g
Palmitic acid glyceryl stearate 100g
Glucose 5g;
wherein the particle diameter D90 of the sodium levofolinate is 30 mu m, and the particle diameter D90 of the glucose is 5 mu m (measured by a laser particle diameter instrument);
the preparation method of the sodium levofolinate particles comprises the following steps:
(1) Heating glyceryl palmitostearate to melt, and maintaining the temperature at 65deg.C;
(2) Adding glucose into melted glyceryl palmitostearate, and stirring at 10rpm for 5min to uniformly disperse; adding sodium levofolinate, stirring for 10min at the speed of 10rpm by using a stirring paddle to uniformly disperse the sodium levofolinate, and obtaining a molten carrier suspension containing sodium levofolinate;
(3) Conveying the molten carrier suspension containing sodium levofolinate into a high-speed centrifugal atomizer through a conveying pump and a temperature control pipeline to be atomized into fogdrops, wherein the rotating speed of a centrifugal disk of the high-speed centrifugal atomizer is 5000rpm, and the surface temperature is 65 ℃;
(4) The fogdrops are cooled and condensed in the presence of cold air in a collecting chamber to obtain sodium levofolinate particles.
Comparative example 3
A sodium levofolinate granule with adjustable moisture stability and release rate, which comprises the following components by mass:
sodium levofolinate 10g
Palmitic acid glyceryl stearate 100g
5g of sodium chloride;
wherein the particle diameter D90 of the sodium levofolinate is 30 mu m; the particle diameter D90 of the sodium chloride is 2 μm (measured by a laser particle diameter meter);
the preparation method of the sodium levofolinate particles comprises the following steps:
(1) Heating glyceryl palmitostearate to melt, and maintaining the temperature at 65deg.C;
(2) Adding sodium chloride into the melted glyceryl palmitostearate, and stirring at 10rpm for 5min to uniformly disperse the sodium chloride; adding sodium levofolinate, stirring for 10min at the speed of 10rpm by using a stirring paddle to uniformly disperse the sodium levofolinate, and obtaining a molten carrier suspension containing sodium levofolinate;
(3) Conveying the molten carrier suspension containing sodium levofolinate into a high-speed centrifugal atomizer through a conveying pump and a temperature control pipeline to be atomized into fogdrops, wherein the rotating speed of a centrifugal disk of the high-speed centrifugal atomizer is 5000rpm, and the surface temperature is 65 ℃;
(4) The fogdrops are cooled and condensed in the presence of cold air in a collecting chamber to obtain sodium levofolinate particles.
Comparative example 4
A sodium levofolinate granule with adjustable moisture stability and release rate, which comprises the following components by mass:
sodium levofolinate 10g
100g of glyceryl palmitostearate;
wherein, the particle diameter D90 of the sodium levofolinate is 30 mu m (measured by a laser particle diameter instrument);
the preparation method of the sodium levofolinate particles comprises the following steps:
(1) Heating glyceryl palmitostearate to melt, and maintaining the temperature at 65deg.C;
(2) Adding sodium levofolinate into melted glyceryl palmitostearate, and stirring at a speed of 10rpm for 10min to uniformly disperse the sodium levofolinate to obtain a molten carrier suspension containing sodium levofolinate;
(3) Conveying the molten carrier suspension containing sodium levofolinate into a high-speed centrifugal atomizer through a conveying pump and a temperature control pipeline to be atomized into fogdrops, wherein the rotating speed of a centrifugal disk of the high-speed centrifugal atomizer is 5000rpm, and the surface temperature is 65 ℃;
(4) The fogdrops are cooled and condensed in the presence of cold air in a collecting chamber to obtain sodium levofolinate particles.
Comparative example 5
A sodium levofolinate granule with adjustable moisture stability and release rate, which comprises the following components by mass:
sodium levofolinate 10g
Palmitic acid glyceryl stearate 100g
15g of ascorbic acid;
wherein the particle size of sodium levofolinate, the particle size of ascorbic acid and the preparation method of sodium levofolinate particles are the same as in example 1.
Comparative example 6
A sodium levofolinate granule with adjustable moisture stability and release rate, which comprises the following components by mass:
sodium levofolinate 10g
Glyceryl palmitostearate 250g
Ascorbic acid 5g;
wherein the particle size of sodium levofolinate, the particle size of ascorbic acid and the preparation method of sodium levofolinate particles are the same as in example 1.
Evaluation of product Performance
1. Drug hygroscopicity test
Taking a dry glass dish, placing the glass dish at 25+/-1 ℃ and saturated for 24 hours in an environment with relative humidity of 80+/-2 percent, and precisely weighing (m 1 ) The method comprises the steps of carrying out a first treatment on the surface of the Sodium levofolinate raw material 1g, sodium levofolinate particles prepared in examples 1-3, examples 8-14 and comparative examples 1-3, 11.5g of sodium levofolinate particles prepared in example 4, 11.2g of sodium levofolinate particles prepared in example 5, 12g of sodium levofolinate particles prepared in example 6, 6.5g of sodium levofolinate particles prepared in example 7, 21.5g of sodium levofolinate particles prepared in example 7, 11g of sodium levofolinate particles prepared in comparative example 4, 12.5g of sodium levofolinate particles prepared in comparative example 5 and 26.5g of sodium levofolinate particles prepared in comparative example 6 are respectively weighed, spread in the above glass dishes, the spreading area is adjusted to make the thickness substantially uniform, and the weight (m 2 ) The method comprises the steps of carrying out a first treatment on the surface of the The glass plate was placed under an atmosphere of 25.+ -. 1 ℃ and 80.+ -. 2% relative humidity for 24 hours, and then precisely weighed (m 3 ). The percentage gain is calculated according to the formula:
the measurement results are shown in Table 1:
table 1 statistics of results of drug hygroscopicity tests
Sample of | Percentage of weight gain |
Sodium levofolinate raw material | 21% |
Example 1 | 0.9% |
Example 2 | 0.9% |
Example 3 | 0.7% |
Example 4 | 0.2% |
Example 5 | 1.8% |
Example 6 | 6.7% |
Example 7 | 0.3% |
Example 8 | 0.5% |
Example 9 | 1.0% |
Example 10 | 3.0% |
Example 11 | 0.7% |
Example 12 | 0.8% |
Example 13 | 1.0% |
Example 14 | 2.3% |
Comparative example 1 | 1.3% |
Comparative example 2 | 1.0% |
Comparative example 3 | 1.1% |
Comparative example 4 | 0.1% |
Comparative example 5 | 2.3% |
Comparative example 6 | 0.3% |
From the test results in table 1, it can be derived that:
the sodium levofolinate particles prepared in examples 1-14 and comparative examples 1-6 all have significantly reduced hygroscopicity compared with untreated sodium levofolinate bulk drug, indicating that the sodium levofolinate can be effectively improved in moisture stability after being coated with glyceryl palmitostearate, glyceryl monostearate and glyceryl behenate.
The percentage weight gain due to moisture absorption of the sodium levofolinate particles prepared in examples 1-3 is lower than 1%, which shows that the glyceryl palmitostearate, the glyceryl monostearate and the glyceryl behenate have good moisture-isolation effect.
The sodium levofolinate particles prepared in the example 1 and the comparative examples 1-3 are low in moisture absorption and weight gain percentage, which shows that good moisture isolation effect can be obtained by taking ascorbic acid, polyethylene glycol, glucose and sodium chloride as pore-forming agents.
The percentage weight gain data of the sodium levofolinate particles prepared in examples 1, 4-5 and comparative examples 4-5 demonstrate that reducing the amount of porogenic agent in the sodium levofolinate particles can increase the moisture stability of sodium levofolinate, and conversely, can decrease the moisture stability of sodium levofolinate.
The percentage weight gain data of sodium levofolinate particles prepared in examples 1, 6-7 and comparative example 6 demonstrate that increasing the amount of retarder in sodium levofolinate particles can increase the moisture stability of sodium levofolinate, and conversely, decrease the moisture stability of sodium levofolinate. However, when the mass ratio of the retarder to the sodium levofolinate is more than 20, the moisture-resistant effect of the sodium levofolinate particles is not further enhanced along with the increase of the dosage of the retarder.
The percentage weight gain data of sodium levofolinate particles prepared in examples 1 and 8-10 show that when the particle size (D90) of sodium levofolinate raw material is controlled within the range of 3-110 mu m, the influence of the particle size of the raw material on the hygroscopicity of the prepared sodium levofolinate particles is small; however, when the particle size (D90) of the levofolinic acid raw material was increased to 130. Mu.m, the hygroscopicity of the obtained sodium levofolinate particles was significantly increased. The reason for this is probably because the thickness of the coating of the retarder on the surface of the sodium levofolinate raw material is relatively reduced as the particle size of the sodium levofolinate raw material is increased; when the particle size (D90) of the sodium levofolinate raw material is larger than 110 mu m, the situation that the retarder cannot effectively coat the particle size of the sodium levofolinate raw material can easily occur, and the phenomenon of moisture absorption of the sodium levofolinate raw material which cannot be effectively coated or exposed outside the retarder can easily occur.
The percentage weight gain data of sodium levofolinate particles prepared in examples 1 and 11-14 show that the particle diameter D90 of the ascorbic acid is in the range of 1-20 μm, and the moisture permeability of the prepared sodium levofolinate particles is not obviously influenced; however, when the particle diameter (D90) of the ascorbic acid was further increased to 100. Mu.m, the hygroscopicity of the obtained sodium levofolinate particles was significantly increased. Thus, the moisture stability of the sodium levofolinate particles of the present invention can be enhanced by controlling the particle size of the ascorbic acid to 1-20 μm. This may occur because, during the preparation of sodium levofolinate particles, because the melting temperature of the retarder is much lower than the melting point of ascorbic acid, the ascorbic acid particles and sodium levofolinate particles are suspended together in the melted retarder to form a suspension, and when the molten mixture containing sodium levofolinate and ascorbic acid is formed into droplets and cooled, the ascorbic acid will squeeze the sodium levofolinate sites in the retarder to increase the likelihood of sodium levofolinate exposure, and reducing the particle size of the ascorbic acid will reduce the probability of squeezing the sodium levofolinate sites to increase the moisture stability of the sodium levofolinate particles.
2. Related substance measurement test
The test method is according to high performance liquid chromatography (China pharmacopoeia 2020 edition, four-part rule 0512).
Chromatographic conditions: octadecylsilane chemically bonded silica was used as a filler (4.6 mm. Times.250 mm,5 μm), and phosphate buffer (disodium hydrogen phosphate 2.2g plus 8mL of 10% tetrabutylammonium hydroxide, diluted with water to 780mL, and pH adjusted to 7.8 with 10% phosphoric acid solution): methanol (80:20) was the mobile phase, the flow rate was 1.0mL/min, the column temperature was 40℃and the detection wavelength was 286nm.
The sodium levofolinate raw materials of 0.1g, the sodium levofolinate particles prepared in examples 1-3, examples 8-14 and comparative examples 1-3 of 1.15g, the sodium levofolinate particles prepared in example 4 of 1.12g, the sodium levofolinate particles prepared in example 5 of 1.2g, the sodium levofolinate particles prepared in example 6 of 0.65g, the sodium levofolinate particles prepared in example 7 of 2.15g, the sodium levofolinate particles prepared in comparative example 4 of 1.1g, the sodium levofolinate particles prepared in comparative example 5 of 1.25g and the sodium levofolinate particles prepared in comparative example 6 of 2.65g are weighed respectively, added into a 100mL volumetric flask, added with a proper amount of mobile phase, subjected to ultrasonic treatment for 30min, diluted to a score line with the mobile phase, and shaken uniformly to obtain a test solution. And respectively precisely sucking 20 mu L of the test solution, injecting the test solution into a liquid chromatograph, recording a chromatogram, and calculating the total impurity amount according to an area normalization method.
The measurement results are shown in Table 2:
TABLE 2 statistics of measurement results of substances
/>
From the test results in table 2, it can be derived that:
the impurity content in the sodium levofolinate granules prepared in examples 1-14 and comparative examples 1-6 was increased to a different extent than that in untreated sodium levofolinate bulk drug. This is probably due to the fact that sodium levofolinate is unstable under oxidation and high temperature conditions and is susceptible to degradation reactions. Therefore, in the process of preparing sodium levofolinate particles by coating sodium levofolinate with a retarder, sodium levofolinate can be degraded to a certain extent under the action of oxygen and heat.
The impurity content in the sodium levofolinate granules prepared in examples 1-3 increases in sequence, which shows that the degradation degree of sodium levofolinate is different in the process of preparing the sodium levofolinate granules from glyceryl palmitostearate, glyceryl monostearate and glyceryl behenate respectively. Wherein, when the glyceryl palmitostearate is used as a retarder, the degradation impurities are least generated. The reason is probably because the melting point of the glyceryl palmitostearate is the lowest (52-55 ℃), and the melting points of the glyceryl monostearate and the glyceryl behenate are 55-60 ℃ and 65-77 ℃ respectively, so that the sodium levofolinate degradation reaction is more easily induced by higher temperature in the preparation process of the sodium levofolinate particles. Therefore, the sodium levofolinate particles provided by the invention select the glyceryl palmitostearate as the retarder, so that the impurity content in the sodium levofolinate particles can be minimized.
The impurity content of the sodium levofolinate particles prepared in comparative examples 1-3 is obviously higher than that of the sodium levofolinate particles prepared in example 1, which shows that the sodium levofolinate can be effectively prevented from being degraded in the preparation process of the sodium levofolinate particles when ascorbic acid is selected as a pore-forming agent. This is probably because ascorbic acid has a strong antioxidation effect, and can effectively inhibit the occurrence of oxidative degradation reaction of sodium levofolinate in a hot environment. Therefore, the sodium levofolinate particles provided by the invention select ascorbic acid as a pore-forming agent, so that the impurity content in the sodium levofolinate particles can be effectively reduced.
The measurement results of the impurity content in the sodium levofolinate particles prepared in the examples 1, 4-5 and comparative examples 4-5 show that the impurity content in the sodium levofolinate particles has an inverse correlation with the addition amount of ascorbic acid, which also shows that the use of ascorbic acid can effectively inhibit the degradation of sodium levofolinate in the preparation process of the sodium levofolinate particles. However, when the mass ratio of the ascorbic acid to the sodium levofolinate is more than 1, the impurity content in the sodium levofolinate particles is not further reduced with the increase of the dosage of the ascorbic acid.
The measurement results of the impurity content in the sodium levofolinate particles prepared in example 1, examples 6-7 and comparative example 6 show that: when the amount of the ascorbic acid is 0.5 times (mass ratio) of the sodium levofolinate, the change of the amount of the glyceryl palmitostearate within the range of 5-25 times (mass ratio) of the sodium levofolinate does not have obvious influence on the generation amount of impurities.
The measurement results of the impurity content in the sodium levofolinate particles prepared in the examples 1 and 8-10 show that the generation amount of impurities is not obviously influenced when the particle size D90 of the sodium levofolinate fluctuates within the range of 3-130 mu m.
The measurement results of the impurity content in the sodium levofolinate particles prepared in examples 1 and 11-14 show that the generation amount of the impurity in the sodium levofolinate particles has an inverse correlation with the particle size D90 of the ascorbic acid, namely the particle size of the ascorbic acid is increased, the effect of inhibiting the degradation of sodium levofolinate is weakened, the particle size of the ascorbic acid is reduced, and the effect of inhibiting the degradation of sodium levofolinate is enhanced. The reason for this is probably that as the particle diameter of ascorbic acid decreases, the specific surface area increases, and the contact area with the oxidizing substance increases, which is advantageous for the anti-oxidation effect of ascorbic acid.
3. In vitro Release test
11.5g of sodium levofolinate particles prepared in examples 1-3, 8-14 and comparative examples 1-3, 11.2g of sodium levofolinate particles prepared in example 4, 12g of sodium levofolinate particles prepared in example 5, 6.5g of sodium levofolinate particles prepared in example 6, 21.5g of sodium levofolinate particles prepared in example 7, 11g of sodium levofolinate particles prepared in comparative example 4, 12.5g of sodium levofolinate particles prepared in comparative example 5 and 26.5g of sodium levofolinate particles prepared in comparative example 6 are respectively taken, a release medium is taken according to a release rate measurement method (China pharmacopoeia 2020, fourth rule 0931, second rule) by taking 900mL of hydrochloric acid solution at 0.1mol/L, operating at 50rpm, 3mL of release medium is taken in a method, the same temperature and volume of release medium is immediately supplemented in each of 0.5, 1, 1.5, 3, 6, 9, 12, 15 and 18h, a sample solution obtained by taking a sample is filtered, a sample solution is taken, a high-performance liquid phase is calculated, and a sodium folinate content is discharged, and a high-efficiency sodium content measurement method is carried out by continuously taking a sodium folinate content measurement method.
Cumulative release rate (%) = { [ C n *V 1 +(C n-1 +····+C 2 +C 1 )*V 2 ]/Q}*100%
Wherein:
q: the total dosage of sodium levofolinate in the sodium levofolinate particles in the dissolution cup is added;
V 1 : volume of dissolution medium;
V 2 : fixing the sampling volume at each time point;
C n : the concentration of the solution was taken out at each time point.
The measurement results are shown in Table 3:
table 3 statistics of cumulative sodium folinate release (%) test results
From the test results in table 3, it can be derived that:
the release test results of the sodium levofolinate particles prepared in examples 1-3 show that the sodium levofolinate particles are prepared by taking glyceryl palmitostearate, glyceryl monostearate and glyceryl behenate as retarders, and the release speed of the medicament from the particles is sequentially increased. It is demonstrated that sodium levofolinate is relatively easier to release when glyceryl palmitostearate is used as a retarder.
The release test results of the sodium levofolinate particles prepared in the embodiment 1 and the comparative examples 1-3 show that when the anti-cyclosanguinic acid is used as a pore-forming agent, the drug release effect is equivalent to that when polyethylene glycol is used as the pore-forming agent, and the release rate of the drug is slightly faster than that when glucose or sodium chloride is used as the pore-forming agent.
The release degree test results of the sodium levofolinate particles prepared in the embodiment 1, the embodiment 4-5 and the comparative example 4-5 show that the reduction of the dosage of the anti-cyclic blood acid can reduce the probability that a dissolution medium enters the sodium levofolinate particles to form a permeation pore canal and delay the dissolution and release rates of the sodium levofolinate in the sodium levofolinate particles; conversely, the dissolution and release rates of sodium levofolinate in the sodium levofolinate particles are increased. Therefore, the sodium levofolinate particles provided by the invention can control the release speed of the medicine by adjusting the dosage of the anti-cyclosanguinic acid.
The release test results of the sodium levofolinate particles prepared in the examples 1, 6-7 and the comparative example 6 show that the use ratio of the retarder in the prescription is increased, the probability that a dissolution medium enters the sodium levofolinate particles to form a permeation pore canal can be reduced, and the dissolution and release speeds of sodium levofolinate in the sodium levofolinate particles are delayed; conversely, the dissolution and release rates of sodium levofolinate in the sodium levofolinate particles are increased. But when the mass ratio of retarder to sodium levofolinate is 25:1, there is a possibility that dissolution is incomplete. Therefore, the mass ratio of the sodium levofolinate to the retarder in the sodium levofolinate particles is controlled to be 1: (5-20) preferably. In the mass ratio range, the sodium levofolinate particles can control the release speed of the medicine by adjusting the dosage of the retarder.
The release test results of the sodium levofolinate particles prepared in examples 1 and 8-10 show that the particle size of the sodium levofolinate raw material can influence the release rate of sodium levofolinate in the sodium levofolinate particles. As the particle size of sodium levofolinate in the sodium levofolinate particles increases in sequence, the release rate also becomes faster in sequence. When the particle size of the sodium levofolinate is controlled to be 3-110 mu m, the sodium levofolinate particles can show good slow release effect. Sodium levofolinate particles showed a faster release rate when the sodium levofolinate particle size was 130 μm compared to 110 μm. The reason for this is probably that the sodium levofolinate bulk drug granules with larger particle size are not easily tightly wrapped by the retarder, so that the probability of dissolution and release of the sodium levofolinate bulk drug granules after exposure to the dissolution medium is increased. Therefore, the sodium levofolinate particles provided by the invention can control the release speed of the medicine by adjusting the particle size of the sodium levofolinate bulk drug.
The release degree test results of the sodium levofolinate particles prepared in the examples 1 and 11-14 show that the release rate of the drug in the sodium levofolinate particles is related to the particle size of the ascorbic acid, and the smaller the particle size (D90) of the ascorbic acid, the slower the release of the drug, the larger the particle size (D90) of the ascorbic acid and the faster the release of the drug. This is probably because, during the preparation of sodium levofolinate particles, because the melting temperature of the retarder is far lower than the melting point of ascorbic acid, the ascorbic acid and sodium levofolinate particles are suspended together in the melted retarder to form a suspension, and when the molten mixture containing sodium levofolinate and ascorbic acid is formed into fogdrops and cooled, the ascorbic acid can occupy the sites of sodium levofolinate in the retarder to increase the possibility of exposing sodium levofolinate, and when the sodium levofolinate particles are contacted with a release medium, sodium levofolinate and ascorbic acid exposed on the surface of the retarder are preferentially dissolved and released, and simultaneously the formed pore channels further promote the penetration of the dissolution medium into the sodium levofolinate particles, so that the release rate of sodium levofolinate from the particles is improved. Therefore, the sodium levofolinate particles provided by the invention can control the release speed of the medicine by adjusting the particle size of the ascorbic acid.
The foregoing description of the preferred embodiments of the invention is not intended to be limiting, but rather is intended to cover all modifications, equivalents, and alternatives falling within the spirit and principles of the invention.
Claims (7)
1. The sodium levofolinate granule with the controllable moisture stability and release rate is characterized by comprising the following components in parts by weight:
sodium levofolinate 1;
5-20 parts of retarder;
ascorbic acid 0.2-1;
the particle diameter D90 of the sodium levofolinate is 3-110 mu m;
the particle diameter D90 of the ascorbic acid is 1-20 mu m;
the retarder is at least one of glyceryl behenate, glyceryl monostearate and glyceryl palmitostearate;
the preparation method of the sodium levofolinate particles comprises the following steps:
melting the retarder to obtain a molten material;
adding ascorbic acid and sodium levofolinate into a molten material, and uniformly mixing to prepare a molten carrier suspension containing sodium levofolinate;
preparing a molten carrier suspension containing sodium levofolinate into fogdrops containing a molten mixture of sodium levofolinate by an atomizer;
condensing the fogdrops of the molten mixture containing sodium levofolinate to prepare sodium levofolinate particles.
2. Sodium levofolinate particles according to claim 1, wherein the retarder is glyceryl palmitostearate.
3. Sodium levofolinate granule according to claim 1, characterized in that the mass fraction of the retarder is 10-20.
4. A process for the preparation of the sodium levofolinate granule according to any one of claims 1 to 3, comprising:
melting the retarder to obtain a molten material;
adding ascorbic acid and sodium levofolinate into a molten material, and uniformly mixing to prepare a molten carrier suspension containing sodium levofolinate;
preparing a molten carrier suspension containing sodium levofolinate into fogdrops containing a molten mixture of sodium levofolinate by an atomizer;
condensing the fogdrops of the molten mixture containing sodium levofolinate to prepare sodium levofolinate particles.
5. The method of claim 4, wherein the step of adding ascorbic acid and sodium levofolinate to the molten material and mixing the mixture uniformly to obtain a molten carrier suspension containing sodium levofolinate comprises the following steps:
adding ascorbic acid into the molten material, and stirring at 8-12rpm for 3-8min; adding sodium levofolinate, and stirring at 8-12rpm for 5-15min to obtain molten carrier suspension containing sodium levofolinate.
6. The method according to claim 4 or 5, wherein the atomizer is a high-speed centrifugal atomizer having a centrifugal disk rotation speed of 4500-5500rpm.
7. A solid oral formulation of sodium levofolinate, comprising sodium levofolinate particles according to any one of claims 1 to 3 or sodium levofolinate particles according to any one of claims 1 to 3 as prepared by a process according to claim 4 or 5.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202111612702.1A CN114259470B (en) | 2021-12-27 | 2021-12-27 | Sodium levofolinate particles with humidity stability and controllable release rate and preparation method thereof |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202111612702.1A CN114259470B (en) | 2021-12-27 | 2021-12-27 | Sodium levofolinate particles with humidity stability and controllable release rate and preparation method thereof |
Publications (2)
Publication Number | Publication Date |
---|---|
CN114259470A CN114259470A (en) | 2022-04-01 |
CN114259470B true CN114259470B (en) | 2023-11-14 |
Family
ID=80830409
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202111612702.1A Active CN114259470B (en) | 2021-12-27 | 2021-12-27 | Sodium levofolinate particles with humidity stability and controllable release rate and preparation method thereof |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN114259470B (en) |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
BRPI0417348A (en) * | 2003-12-04 | 2007-03-13 | Pfizer Prod Inc | spray gelatinization process using an extruder for preparing multiparticulate crystalline drug compositions preferably containing a poloxamer and a glyceride |
CN101792444B (en) * | 2009-02-02 | 2011-10-12 | 天津康鸿医药科技发展有限公司 | Sodium levofolinate and preparation method and drug combination thereof |
CN101862333B (en) * | 2009-04-20 | 2013-07-24 | 天津药物研究院 | Stable sodium levofolinate oral preparation and preparation method thereof |
CN103169680B (en) * | 2012-12-07 | 2015-05-06 | 深圳市国源药业有限公司 | Diclofenac sodium sustained-release tablet and method for preparing same |
CN112972396A (en) * | 2019-12-17 | 2021-06-18 | 南京海辰药业股份有限公司 | Febuxostat controlled-release composition and preparation method thereof |
-
2021
- 2021-12-27 CN CN202111612702.1A patent/CN114259470B/en active Active
Also Published As
Publication number | Publication date |
---|---|
CN114259470A (en) | 2022-04-01 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US8895141B2 (en) | Excipient for compressed tablets comprising novel spherical mannitol | |
Houghton et al. | Elucidation of pathways of 5-fluorouracil metabolism in xenografts of human colorectal adenocarcinoma | |
EP0285682A1 (en) | Process for the manufacture of vitamin preparations | |
CN108478595A (en) | A kind of pharmaceutical composition containing calcium carbonate, vitamine D3, farnoquinone | |
KR20180039164A (en) | Intracellular ATP enhancer | |
EP4374857A1 (en) | Microcapsule powder stable in gastric acid, preparation method therefor and application thereof | |
CN114259470B (en) | Sodium levofolinate particles with humidity stability and controllable release rate and preparation method thereof | |
WO2014163132A1 (en) | Solid composition of amino carboxylate salt | |
CN101380327B (en) | Anti-cancer composite sustained-release composition and preparation method thereof | |
CN112999169A (en) | Regorafenib-coated nano porous hydroxyapatite sustained-release microsphere as well as preparation method and application thereof | |
Zins et al. | A dose‐ranging study of azathioprine pharmacokinetics after single‐dose administration of a delayed‐release oral formulation | |
CN105496967A (en) | Ranitidine hydrochloride releasing-controlling dry suspension and preparing method thereof | |
CN1196709C (en) | Troxerutin with high trihydroxy-ethyl-rutin content and method for preparing same | |
CN106619646B (en) | A kind of preparation method of tegafur, gimeracil and oteracil potassium composition | |
CN102824644B (en) | High-stability sustained-release tablet prepared by using hydroxy propyl cellulose | |
CN111617048B (en) | Erlotinib sustained release preparation for treating non-small cell lung cancer | |
CN111407744B (en) | Preparation method of tofacitinib citrate long-acting slow-release microspheres | |
CN1923171B (en) | Compound recipe anti-cancer drugs slow release agent comprising anticancer antibiotics and synergist thereof | |
CN104826120A (en) | Bosentan preparation | |
CN112618500B (en) | Folic acid preparation and preparation method thereof | |
CN101327185A (en) | Anticancer sustained-release implantation agent | |
Jain et al. | Development and evaluation of acyclovir loaded chitosan microspheres and cross linked with glutaraldehyde | |
CN106581001B (en) | A kind of preparation method of tegafur, gimeracil and oteracil potassium composition | |
CN108129652A (en) | A kind of polyethylene glycol lysine maleimide thioguanine conjugate | |
CN1435180A (en) | Gypenoside drip pill, and preparing process thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |