CN103479667B - One kind of multiple micro-element injections (II) pharmaceutical composition and preparation method thereof - Google Patents
One kind of multiple micro-element injections (II) pharmaceutical composition and preparation method thereof Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 27
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 16
- 238000002347 injection Methods 0.000 title claims description 29
- 239000007924 injection Substances 0.000 title claims description 29
- 229910000397 disodium phosphate Inorganic materials 0.000 claims abstract description 9
- 239000006166 lysate Substances 0.000 claims description 29
- 238000003756 stirring Methods 0.000 claims description 21
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 16
- 239000000203 mixture Substances 0.000 claims description 16
- XOAAWQZATWQOTB-UHFFFAOYSA-N taurine Chemical compound NCCS(O)(=O)=O XOAAWQZATWQOTB-UHFFFAOYSA-N 0.000 claims description 16
- 239000000243 solution Substances 0.000 claims description 15
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 14
- 230000003139 buffering effect Effects 0.000 claims description 13
- 239000007788 liquid Substances 0.000 claims description 13
- 239000003610 charcoal Substances 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 11
- 239000004471 Glycine Substances 0.000 claims description 8
- 229910021380 Manganese Chloride Inorganic materials 0.000 claims description 8
- GLFNIEUTAYBVOC-UHFFFAOYSA-L Manganese chloride Chemical compound Cl[Mn]Cl GLFNIEUTAYBVOC-UHFFFAOYSA-L 0.000 claims description 8
- QSWDMMVNRMROPK-UHFFFAOYSA-K chromium(3+) trichloride Chemical compound [Cl-].[Cl-].[Cl-].[Cr+3] QSWDMMVNRMROPK-UHFFFAOYSA-K 0.000 claims description 8
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 claims description 8
- 239000011565 manganese chloride Substances 0.000 claims description 8
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Substances [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 8
- 239000011684 sodium molybdate Substances 0.000 claims description 8
- TVXXNOYZHKPKGW-UHFFFAOYSA-N sodium molybdate (anhydrous) Chemical compound [Na+].[Na+].[O-][Mo]([O-])(=O)=O TVXXNOYZHKPKGW-UHFFFAOYSA-N 0.000 claims description 8
- 239000011781 sodium selenite Substances 0.000 claims description 8
- 229960003080 taurine Drugs 0.000 claims description 8
- 239000011592 zinc chloride Substances 0.000 claims description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 7
- 229910052799 carbon Inorganic materials 0.000 claims description 7
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims description 7
- 238000001914 filtration Methods 0.000 claims description 6
- 239000012467 final product Substances 0.000 claims description 6
- XLYOFNOQVPJJNP-ZSJDYOACSA-N heavy water Substances [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 claims description 6
- 239000011775 sodium fluoride Substances 0.000 claims description 6
- 239000008215 water for injection Substances 0.000 claims description 6
- 229910021556 Chromium(III) chloride Inorganic materials 0.000 claims description 3
- 229910021592 Copper(II) chloride Inorganic materials 0.000 claims description 3
- 229910021578 Iron(III) chloride Inorganic materials 0.000 claims description 3
- 229910004619 Na2MoO4 Inorganic materials 0.000 claims description 3
- 229910003424 Na2SeO3 Inorganic materials 0.000 claims description 3
- 239000011636 chromium(III) chloride Substances 0.000 claims description 3
- 238000009472 formulation Methods 0.000 claims description 3
- 230000001954 sterilising effect Effects 0.000 claims description 3
- 239000000463 material Substances 0.000 claims description 2
- YASYEJJMZJALEJ-UHFFFAOYSA-N Citric acid monohydrate Chemical compound O.OC(=O)CC(O)(C(O)=O)CC(O)=O YASYEJJMZJALEJ-UHFFFAOYSA-N 0.000 claims 2
- 229960002303 citric acid monohydrate Drugs 0.000 claims 2
- 239000011573 trace mineral Substances 0.000 abstract description 12
- 235000013619 trace mineral Nutrition 0.000 abstract description 12
- 239000003814 drug Substances 0.000 abstract description 11
- 239000003182 parenteral nutrition solution Substances 0.000 abstract description 7
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 abstract description 6
- 229940079593 drug Drugs 0.000 abstract description 5
- 238000001556 precipitation Methods 0.000 abstract description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 abstract description 2
- 230000003993 interaction Effects 0.000 abstract 1
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 30
- 238000012360 testing method Methods 0.000 description 16
- 229910052742 iron Inorganic materials 0.000 description 15
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 11
- 239000011701 zinc Substances 0.000 description 11
- 229910052725 zinc Inorganic materials 0.000 description 11
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 10
- BUGBHKTXTAQXES-UHFFFAOYSA-N Selenium Chemical compound [Se] BUGBHKTXTAQXES-UHFFFAOYSA-N 0.000 description 10
- 229910052802 copper Inorganic materials 0.000 description 10
- 239000010949 copper Substances 0.000 description 10
- 229910052711 selenium Inorganic materials 0.000 description 10
- 239000011669 selenium Substances 0.000 description 10
- VYZAMTAEIAYCRO-UHFFFAOYSA-N Chromium Chemical compound [Cr] VYZAMTAEIAYCRO-UHFFFAOYSA-N 0.000 description 9
- ZOKXTWBITQBERF-UHFFFAOYSA-N Molybdenum Chemical compound [Mo] ZOKXTWBITQBERF-UHFFFAOYSA-N 0.000 description 9
- 229910052804 chromium Inorganic materials 0.000 description 9
- 239000011651 chromium Substances 0.000 description 9
- 229910052750 molybdenum Inorganic materials 0.000 description 9
- 239000011733 molybdenum Substances 0.000 description 9
- 229940091258 selenium supplement Drugs 0.000 description 9
- PUZPDOWCWNUUKD-UHFFFAOYSA-M sodium fluoride Chemical compound [F-].[Na+] PUZPDOWCWNUUKD-UHFFFAOYSA-M 0.000 description 9
- 239000011734 sodium Substances 0.000 description 8
- 229910001868 water Inorganic materials 0.000 description 7
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 6
- WPBNNNQJVZRUHP-UHFFFAOYSA-L manganese(2+);methyl n-[[2-(methoxycarbonylcarbamothioylamino)phenyl]carbamothioyl]carbamate;n-[2-(sulfidocarbothioylamino)ethyl]carbamodithioate Chemical compound [Mn+2].[S-]C(=S)NCCNC([S-])=S.COC(=O)NC(=S)NC1=CC=CC=C1NC(=S)NC(=O)OC WPBNNNQJVZRUHP-UHFFFAOYSA-L 0.000 description 6
- 239000011591 potassium Substances 0.000 description 6
- 229910052700 potassium Inorganic materials 0.000 description 6
- 229910021555 Chromium Chloride Inorganic materials 0.000 description 5
- 201000010099 disease Diseases 0.000 description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 5
- BVTBRVFYZUCAKH-UHFFFAOYSA-L disodium selenite Chemical compound [Na+].[Na+].[O-][Se]([O-])=O BVTBRVFYZUCAKH-UHFFFAOYSA-L 0.000 description 5
- 235000002867 manganese chloride Nutrition 0.000 description 5
- 229940099607 manganese chloride Drugs 0.000 description 5
- 235000015393 sodium molybdate Nutrition 0.000 description 5
- 229960001471 sodium selenite Drugs 0.000 description 5
- 235000015921 sodium selenite Nutrition 0.000 description 5
- 235000005074 zinc chloride Nutrition 0.000 description 5
- 102000004190 Enzymes Human genes 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 229940088598 enzyme Drugs 0.000 description 4
- 238000005259 measurement Methods 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 235000013024 sodium fluoride Nutrition 0.000 description 4
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 description 3
- 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 3
- PWHULOQIROXLJO-UHFFFAOYSA-N Manganese Chemical compound [Mn] PWHULOQIROXLJO-UHFFFAOYSA-N 0.000 description 3
- 229930003268 Vitamin C Natural products 0.000 description 3
- 230000007812 deficiency Effects 0.000 description 3
- 230000036541 health Effects 0.000 description 3
- 229910052748 manganese Inorganic materials 0.000 description 3
- 239000011572 manganese Substances 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 235000019154 vitamin C Nutrition 0.000 description 3
- 239000011718 vitamin C Substances 0.000 description 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- NCFTXMQPRQZFMZ-WERGMSTESA-M Cefoperazone sodium Chemical compound [Na+].O=C1C(=O)N(CC)CCN1C(=O)N[C@H](C=1C=CC(O)=CC=1)C(=O)N[C@@H]1C(=O)N2C(C([O-])=O)=C(CSC=3N(N=NN=3)C)CS[C@@H]21 NCFTXMQPRQZFMZ-WERGMSTESA-M 0.000 description 2
- 102000018832 Cytochromes Human genes 0.000 description 2
- 108010052832 Cytochromes Proteins 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 2
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 229960002417 cefoperazone sodium Drugs 0.000 description 2
- 229960000479 ceftriaxone sodium Drugs 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- FDRNWTJTHBSPMW-GNXCPKRQSA-L disodium;(6r,7r)-7-[[(2e)-2-(2-amino-1,3-thiazol-4-yl)-2-methoxyiminoacetyl]amino]-3-[(2-methyl-6-oxido-5-oxo-1,2,4-triazin-3-yl)sulfanylmethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound [Na+].[Na+].S([C@@H]1[C@@H](C(N1C=1C([O-])=O)=O)NC(=O)/C(=N/OC)C=2N=C(N)SC=2)CC=1CSC1=NC(=O)C([O-])=NN1C FDRNWTJTHBSPMW-GNXCPKRQSA-L 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 229910021645 metal ion Inorganic materials 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 229910017604 nitric acid Inorganic materials 0.000 description 2
- 230000035790 physiological processes and functions Effects 0.000 description 2
- -1 sorbierite Chemical compound 0.000 description 2
- 239000012086 standard solution Substances 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- ZKHQWZAMYRWXGA-UHFFFAOYSA-N Adenosine triphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(=O)OP(O)(O)=O)C(O)C1O ZKHQWZAMYRWXGA-UHFFFAOYSA-N 0.000 description 1
- 239000002126 C01EB10 - Adenosine Substances 0.000 description 1
- 201000004624 Dermatitis Diseases 0.000 description 1
- 206010015150 Erythema Diseases 0.000 description 1
- CWYNVVGOOAEACU-UHFFFAOYSA-N Fe2+ Chemical compound [Fe+2] CWYNVVGOOAEACU-UHFFFAOYSA-N 0.000 description 1
- 206010022971 Iron Deficiencies Diseases 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 241000669618 Nothes Species 0.000 description 1
- 206010033733 Papule Diseases 0.000 description 1
- 229910000831 Steel Inorganic materials 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- AUYYCJSJGJYCDS-LBPRGKRZSA-N Thyrolar Chemical class IC1=CC(C[C@H](N)C(O)=O)=CC(I)=C1OC1=CC=C(O)C(I)=C1 AUYYCJSJGJYCDS-LBPRGKRZSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 229960005305 adenosine Drugs 0.000 description 1
- LFVGISIMTYGQHF-UHFFFAOYSA-N ammonium dihydrogen phosphate Chemical compound [NH4+].OP(O)([O-])=O LFVGISIMTYGQHF-UHFFFAOYSA-N 0.000 description 1
- 208000007502 anemia Diseases 0.000 description 1
- 210000000436 anus Anatomy 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 238000005842 biochemical reaction Methods 0.000 description 1
- 239000012490 blank solution Substances 0.000 description 1
- 238000011088 calibration curve Methods 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- CCGSUNCLSOWKJO-UHFFFAOYSA-N cimetidine Chemical compound N#CNC(=N/C)\NCCSCC1=NC=N[C]1C CCGSUNCLSOWKJO-UHFFFAOYSA-N 0.000 description 1
- 229960001380 cimetidine Drugs 0.000 description 1
- 239000010941 cobalt Substances 0.000 description 1
- 229910017052 cobalt Inorganic materials 0.000 description 1
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 150000004696 coordination complex Chemical class 0.000 description 1
- 230000002354 daily effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 210000001508 eye Anatomy 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229940088597 hormone Drugs 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
- 230000007233 immunological mechanism Effects 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 238000002354 inductively-coupled plasma atomic emission spectroscopy Methods 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- FBAFATDZDUQKNH-UHFFFAOYSA-M iron chloride Chemical compound [Cl-].[Fe] FBAFATDZDUQKNH-UHFFFAOYSA-M 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000008155 medical solution Substances 0.000 description 1
- 229910000000 metal hydroxide Inorganic materials 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229960004048 pantoprazole sodium Drugs 0.000 description 1
- YNWDKZIIWCEDEE-UHFFFAOYSA-N pantoprazole sodium Chemical compound [Na+].COC1=CC=NC(CS(=O)C=2[N-]C3=CC=C(OC(F)F)C=C3N=2)=C1OC YNWDKZIIWCEDEE-UHFFFAOYSA-N 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000010959 steel Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- 230000005619 thermoelectricity Effects 0.000 description 1
- 239000005495 thyroid hormone Substances 0.000 description 1
- 229940036555 thyroid hormone Drugs 0.000 description 1
- 229910021642 ultra pure water Inorganic materials 0.000 description 1
- 239000012498 ultrapure water Substances 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
- 210000003905 vulva Anatomy 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The present invention relates to a kind of multi-microelement injecta that improves compatibility stability (II) pharmaceutical composition and preparation method thereof. The present invention utilizes citric acid-Na2HPO4Cushion right strong buffer capacity and citric acid and micro-chelation, make multi-microelement injecta (II) pharmaceutical composition prepared by the present invention in the time using with other parenteral solution compatibility, still can keep stable pH degree, avoid making trace element form precipitation of hydroxide because pH after compatibility changes, also sheltered the interaction of trace element with other medicines simultaneously, greatly improve the security of medication, improved the compliance of patient to medicine.
Description
Technical field
The present invention belongs to field of pharmaceutical preparations, be specifically related to one kind of multiple micro-element injections (II) pharmaceutical composition andIts preparation method.
Background technology
Human body is made up of 50 multiple elements, and the content difference according to element in human body, can be divided into macroelement and micro-The large class of secondary element two. Every human total weight's ten thousand/above element that accounts for, as carbon, hydrogen, oxygen, nitrogen phosphate and sulfur,Calcium, magnesium, sodium etc., be called macroelement; Every human total weight's ten thousand/following element that accounts for, as iron, zinc, copper,Manganese, chromium, selenium, molybdenum, cobalt, fluorine etc., be called trace element (iron claims again semimicro element). Trace element is in the human bodyContent is really very little, and as zinc only accounts for human total weight's 1,000,000/33, iron also only has 60/1000000ths.
Trace element mainly exists with two kinds of forms in human body: one is and protein, nucleic acid (RNA) and Adenosine triphosphateGlycosides (ATP) etc. form metal complex; Another kind is to be combined with the active site of enzyme to form various enzymes, hormone or vitamin,As hundreds of enzymes of iron content, copper, zinc, manganese and selenium, containing the thyroid hormone of iodine, the cytochromes of iron content etc., can make metalBiological action, physiological function and the biochemical reaction of the various uniqueness of-organic composite deposits yields, produce human life activityTremendous influence. Sugar and fatty oxidation, the generation of water in vital movement, all urging at the cytochromes of enzyme and iron content or copperUnder change, complete.
Each trace element has its special function, lacks or exceed limitation all unfavorable to health. Therefore trace unitElement is closely bound up with people's existence and health, and people's life is played to vital effect. Their excess intake, deficiency,Uneven or shortage all can cause to some extent the abnormal of Human Physiology or disease, even threat to life occur.
Approximately 30% disease is directly due to microelement deficiencies or imbalance, can cause mouthful, eye, anus or vulva as lacked zincPortion's redness, papule, eczema, iron deficiency can cause hypoferric anemia. Abroad studies have reported that, iron content in body, copper, zinc are totalAmount reduces, and all can weaken immunologic mechanism, reduces the ability of resist the disease. Trace element disease-resistant, give protection against cancer, promote longevity etc.Aspect all also plays very important effect. Healthy People can absorb every day from food, if but patient at disease shapeState or for a long time can only be using intravenous hyperalimentation as energy nutrient time, will cause micro-shortage and affect human body health andNormal physiological function. Therefore, micro-element injection is widely used clinically. Multi-microelement injecta (I)Supplement the daily need of adult to trace element chromium, iron, molybdenum, zinc, copper, manganese, selenium for PN solution, multiple micro-It is medium to the fundamental sum of chromium, copper, iron, manganese, molybdenum, selenium, zinc, fluorine and iodine that secondary element parenteral solution (II) can meet per day for adultsNeed, be also applicable to gravid woman's microelement-supplementing.
Micro-element injection is micro-concentrate, containing various trace elements metal ion, complicated component, therefore works asWhile use as the compatibility such as amino acid, vitamin C with other parenteral solution medicine, there will be the phenomenon such as muddiness, variable color. There is literary compositionChapter report (Zhao Weili, multi-microelement injecta and pharmaceutical incompatibility analysis, Chinese journals of practical medicine, 2012,29 (8):711-712) multi-microelement injecta with cefoperazone sodium, Ceftriaxone Sodium, fleraxacin, Furbenicillin sodium, westMiaow is for fourth, Pantoprazole Sodium, Cobastab6, occur when the parenteral solution compatibility of drugs such as amino acid, vitamin C cotton-shaped heavy, therefore there is incompatibility in the phenomenons such as shallow lake, muddiness, variable color and intensification. This is mainly that pH occurs their systems in the time of compatibilityChange and make some metal ions in trace element form that precipitation of hydroxide and oxidation cause. This incompatibility pairThe security that multi-microelement injecta uses has produced very large impact, is therefore badly in need of clinically now a kind of stable, noThe multi-microelement injecta product that affected by compatibility, exploitation does not have the multi-microelement injecta product one of incompatibilityIt is directly difficult problem urgently to be resolved hurrily of the art.
Summary of the invention
For the technical problem existing in above-mentioned prior art, inventor has carried out system research, repetition test, finally pleasantly surprisedGround is found, is introduced citric acid-Na in composition2HPO4Buffering can solve above-mentioned various trace elements injection well to systemLiquid incompatibility problem. Therefore the technical problem to be solved in the present invention is: be directed to the deficiencies in the prior art, provide one manyKind of micro-element injection composition and method of making the same, thus this prepared injecta composition product with other injectionLiquid compatibility still can keep stable pH degree while use, nondiscolouring, does not produce precipitation, thereby can greatly improve the safety of medicationProperty, improve the compliance of patient to medicine.
Technical scheme of the present invention is as follows:
Multi-microelement injecta provided by the invention (II) pharmaceutical composition comprises chromium chloride (CrCl3·6H2O）、Copper chloride (CuCl2·2H2O), iron chloride (FeCl3·6H2O), manganese chloride (MnCl2·4H2O), sodium molybdate（Na2MoO4·2H2O), sodium selenite (Na2SeO3·5H2O), zinc chloride (ZnCl2), KI (KI),Sodium fluoride (NaF), sorbierite, taurine and glycine.
It is right that said composition also comprises pH buffering.
Above-mentioned pH cushions being citric acid-Na2HPO4。
In the every 2mL unit formulation of said composition, each supplementary material and consumption are as follows:
Further, in the every 2mL unit formulation of said composition, each supplementary material and consumption are as follows:
The present invention also provides the preparation method of this multi-microelement injecta (II) pharmaceutical composition, and it comprises the following steps:
(1) prepare the citric acid-Na of pH2.0～2.4 with water for injection2HPO4Buffering to lysate, wherein every 1 liter moltenSeparate citric acid (C in liquid6H8O7·H2O) consumption is 19.698～20.895g, Na2HPO4Consumption is 0.142～1.7608g；
(2) get recipe quantity chromium chloride, copper chloride, manganese chloride, zinc chloride, sodium fluoride with cushioning lysate is dissolved in right amount;
(3) sorbierite, taurine, the glycine of getting recipe quantity are used and are cushioned after lysate stirring and dissolving in right amount, add stepSuddenly in the solution that (2) make, mix;
(4) add 0.02% active carbon (W/V) of step (3) gained liquor capacity, stirring and adsorbing 10～15min, followsThe de-charcoal 10～20min of ring;
(5) get recipe quantity ferric trichloride, sodium selenite, KI, sodium molybdate, molten to lysate by appropriate buffering respectivelyXie Hou, adds after the de-charcoal of step (4) in solution successively, stir add after 10～15min buffering to lysate to full dose,Stir and circulating filtration;
(6) after visible foreign matters and pH value passed examination, 0.22 μ m filter essence filter, embedding, sterilizing, to obtain final product.
Iron, zinc, manganese, copper, selenium, molybdenum, chromium, potassium in multi-microelement injecta of the present invention (II) pharmaceutical compositionAssay adopt ICP-AES method to carry out as follows:
(1) instrument and reagent
IRISAdvantageER/S type high-resolution Induction Couple Plasma (U.S.'s thermoelectricity public affairsDepartment), the concentric spray chamber of glass, echelle grating, two-dimension chromatic dispersion system, CID charge injection formula solid-state detector, wavelength modelEnclose 170-900nm. Testing pure water used is the UPW-3-90Z type ultra-pure water mechanism that Chengdu Ultra Pure Science & Technology Co., Ltd producesStandby, pure resistivity of water is 18.23M Ω CM. Hydrochloric acid (A.R level), nitric acid (A.R level), micro-element injection(injection stage).
(2) running parameter of instrument
Radio-frequency signal generator power output is the wherein measurement employing 750W of potassium of 1150W(), frequency is 27.12MHz; AtomizationPressure 192.9KPa, the time of integration: shortwave and long wave are respectively 20s and 10s, sample size is 1.85mLmin-1。
(3) preparation of standard liquid
Standard reserving solution: iron, zinc, manganese, copper, selenium, molybdenum, chromium, the standard liquid of potassium is 1000mgL-1. CountryThe Iron and Steel Research Geueral Inst preparation of ferrous materials test center.
Mixed standard solution: by 1% nitric acid or 1% hydrochloric acid stepwise dilution for standard reserving solution, be first mixed with 100mgL-1，Be made into respectively the more mixed mark of high, medium and low three kinds of series.
Mixed mark (1) high standard liquid: manganese 10.0mgL-1, copper 10.0mgL-1, iron 10.0mgL-1, zinc 10.0mgL-1；
Mixed mark (1) low mark liquid: manganese 1.0mgL-1, copper 1.0mgL-1, iron 1.0mgL-1, zinc 1.0mgL-1；
Mixed mark (2) high standard liquid: potassium 5.0mgL-1；
Mixed mark (2) low mark liquid: potassium 0.5mgL-1；
Mixed mark (3) high standard liquid: chromium 1.0mgL-1, molybdenum 1.0mgL-1, selenium 1.0mgL-1；
Mixed mark (3) acceptance of the bid liquid: chromium 0.5mgL-1, molybdenum 0.5mgL-1Selenium 0.5mgL-1；
Mixed mark (3) low mark liquid: chromium 0.1mgL-1, molybdenum 0.1mgL-1, selenium 0.1mgL-1。
(4) sample preparation
Multi-microelement injecta matrix is the aqueous solution, do not need to clear up, and directly to measure after 1% hydrochloric acid dilution, dilutionMultiple be respectively and survey 12.5 times, manganese, each 50 times of copper and iron. 10 times of chromium, molybdenum, potassium, each 5 times of selenium, 333 times, zinc. OnlyHave within test solution concentration is controlled at the optimum measurement scope of instrument, the degree of accuracy of measurement and precision could improve.
(5) sample in measurement
According to the test job condition of instrument, first suck high standard solution, carry out surveyed element standard spectral line automatic calibration; Treat eachSpectral line that element is surveyed has carried out after calibration, then carries out the setting of background deduction point. Setting completed for best background dot, tests each unitThe calibration curve of element, test sample concentration and blank solution under same test parameter condition.
Multi-microelement injecta provided by the invention (II) pharmaceutical composition and preparation method thereof has the following advantages:
(1) solved current multi-microelement injecta (II) in the time using with other parenteral solution compatibility because pH changes shapeBecome micro-metal hydroxides and occur the phenomenons such as flocculent deposit, muddiness, variable color and intensification and the incompatibility that produces is askedTopic, has improved security and the compliance of patient to medicine of clinical application.
(2) increasing on the basis of glycine, taurine, newly introduce citric acid-Na2HPO4It is right to cushion, in enhancing systemWhen oxidation resistance, improve the stable of system pH degree, thereby make each trace element in product possess better stability.
(3) multi-microelement injecta provided by the invention (II) pharmaceutical composition preparation method is easy, is easy to realizeIndustrialization.
Detailed description of the invention
Below will by embodiment, the invention will be further described, these descriptions are not that content of the present invention is done furtherRestriction. One skilled in the art will understand that the replacement that is equal to that content of the present invention is done, or improve accordingly, still belong toWithin protection scope of the present invention.
The preparation of embodiment 1 multi-microelement injecta (II) pharmaceutical composition
Prescription:
Preparation method, as follows preparation:
(1) with citric acid-Na of water for injection preparation pH2.42HPO4Buffering is to lysate, wherein in every 1 liter of lysateCitric acid (C6H8O7·H2O) consumption is 19.698g, Na2HPO4Consumption is 1.7608g;
(2) get recipe quantity chromium chloride, copper chloride, manganese chloride, zinc chloride, sodium fluoride with cushioning lysate is dissolved in right amount;
(3) sorbierite, taurine, the glycine of getting recipe quantity are used and are cushioned after lysate stirring and dissolving in right amount, add stepSuddenly in the solution that (2) make, mix;
(4) add 0.02% active carbon (W/V) of step (3) gained liquor capacity, stirring and adsorbing 15min, the de-charcoal of circulation20min；
(5) get recipe quantity ferric trichloride, sodium selenite, KI, sodium molybdate, molten to lysate by appropriate buffering respectivelyXie Hou, adds after the de-charcoal of step (4) in solution successively, stir add after 15min buffering to lysate to full dose, stirEven also circulating filtration 15min;
(6) after visible foreign matters and pH value passed examination, 0.22 μ m filter essence filter, 2mL/ props up embedding, 121 DEG C of 15minSterilizing, to obtain final product.
The preparation of embodiment 2 multi-microelement injectas (II) pharmaceutical composition
Prescription:
Preparation method, as follows preparation:
(1) with citric acid-Na of water for injection preparation pH2.22HPO4Buffering is to lysate, wherein in every 1 liter of lysateCitric acid (C6H8O7·H2O) consumption is 20.58g, Na2HPO4Consumption is 0.568g;
(2) get recipe quantity chromium chloride, copper chloride, manganese chloride, zinc chloride, sodium fluoride with cushioning lysate is dissolved in right amount;
(3) sorbierite, taurine, the glycine of getting recipe quantity are used and are cushioned after lysate stirring and dissolving in right amount, add stepSuddenly in the solution that (2) make, mix;
(4) add 0.02% active carbon (W/V) of step (3) gained liquor capacity, stirring and adsorbing 10min, the de-charcoal of circulation10min；
(5) get recipe quantity ferric trichloride, sodium selenite, KI, sodium molybdate, molten to lysate by appropriate buffering respectivelyXie Hou, adds after the de-charcoal of step (4) in solution successively, stir add after 10min buffering to lysate to full dose, stirEven also circulating filtration 10min;
(6) after visible foreign matters and pH value passed examination, 0.22 μ m filter essence filter, 2mL/ props up embedding, 121 DEG C of 10minSterilizing, to obtain final product.
The preparation of embodiment 3 multi-microelement injectas (II) pharmaceutical composition
Prescription:
Preparation method, as follows preparation:
(1) with citric acid-Na of water for injection preparation pH2.02HPO4Buffering is to lysate, wherein in every 1 liter of lysateCitric acid (C6H8O7·H2O) consumption is 20.895g, Na2HPO4Consumption is 0.142g;
(2) get recipe quantity chromium chloride, copper chloride, manganese chloride, zinc chloride, sodium fluoride with cushioning lysate is dissolved in right amount;
(3) sorbierite, taurine, the glycine of getting recipe quantity are used and are cushioned after lysate stirring and dissolving in right amount, add stepSuddenly in the solution that (2) make, mix;
(4) add 0.02% active carbon (W/V) of step (3) gained liquor capacity, stirring and adsorbing 20min, the de-charcoal of circulation15min；
(5) get recipe quantity ferric trichloride, sodium selenite, KI, sodium molybdate, molten to lysate by appropriate buffering respectivelyXie Hou, adds after the de-charcoal of step (4) in solution successively, stir add after 15min buffering to lysate to full dose, stirEven also circulating filtration 20min;
(6) after visible foreign matters and pH value passed examination, 0.22 μ m filter essence filter, 2mL/ props up embedding, 115 DEG C of 30minSterilizing, to obtain final product.
Test example 1---compatibility test
Get the sample of embodiment 1～3 preparation, with 10% calcium gluconae, vitamin C, Cobastab6, compound aminoThe parenteral solution medicines such as acid, cefoperazone sodium, Ceftriaxone Sodium, Furbenicillin sodium, Cimetidine respectively compatibility (are pressed each 2mLSuction 30mL syringe leaves standstill 5min), all do not occur producing the incompatibility phenomenons such as precipitation, muddiness, variable color, after compatibilityAdmixing medical solutions place after 24 hours and still keep good clarity. And with commercially available multi-microelement injecta (II)Replace the sample of embodiment 1～3 preparation to carry out compatibility test by above-mentioned same operation, and result and document (Zhao Weili, manyKind of micro-element injection and pharmaceutical incompatibility analysis, Chinese journals of practical medicine, 2012,29 (8): 711-712) report oneCause, all occurred the incompatibility phenomenons such as precipitation in various degree, muddiness, variable color. This illustrates the embodiment of the present invention 1～3The sample of preparation there will not be the problem of incompatibility in the time using with other parenteral solution compatibility of drugs.
Test example 2(study on the stability)---accelerated test
The sample of getting embodiment 1～3 preparation detects by preceding method and the countries concerned's standard, and indices meets ruleFixed, each sample is placed under 30 DEG C ± 2 DEG C of temperature, relative humidity 65% ± 5% condition, to place after 12 months and rechecks, everyIndex testing result sees the following form 1:
Table 1 multi-microelement injecta of the present invention (II) pharmaceutical composition accelerated test testing result
Accelerated test investigate result show: multi-microelement injecta of the present invention (II) pharmaceutical composition after accelerated test,Every detection index, without significant change, all meets quality standard requirement, shows that composition stable is good.
Claims (2)
1. one kind of multiple micro-element injections (II) pharmaceutical composition, is characterized in that: each former in its 2mL unit formulationAuxiliary material and consumption are as follows:
Prepare by comprising the following steps:
(1) prepare the citric acid-Na of pH2.0～2.4 with water for injection2HPO4Cushion to lysate wherein every 1 liter of dissolvingIn liquid, Citric Acid Monohydrate consumption is 19.698～20.895g, Na2HPO4Consumption is 0.142～1.7608g;
(2) get recipe quantity CrCl3·6H2O、CuCl2·2H2O、MnCl2·4H2O、ZnCl2, NaF is with cushioning molten in right amountSolution liquid dissolves;
(3) sorbierite, taurine, the glycine of getting recipe quantity are used and are cushioned after lysate stirring and dissolving in right amount, add step (2)In the solution making, mix;
(4) add 0.02% active carbon (W/V) of step (3) gained liquor capacity, stirring and adsorbing 10～15min, circulationDe-charcoal 10～20min;
(5) get recipe quantity FeCl3·6H2O、Na2SeO3·5H2O、KI、Na2MoO4·2H2O is right by appropriate buffering respectivelyAfter lysate dissolves, add successively after the de-charcoal of step (4) in solution, add buffering to lysate extremely after stirring 10～15minFull dose, stirs and circulating filtration;
(6) after visible foreign matters and pH value passed examination, 0.22 μ m filter essence filter, embedding, sterilizing, to obtain final product.
2. pharmaceutical composition as claimed in claim 1, it is characterized in that in its 2mL unit formulation each supplementary material and consumption asUnder:
Prepare by comprising the following steps:
(1) with citric acid-Na of water for injection preparation pH2.42HPO4Buffering is to lysate, wherein in every 1 liter of lysate,Citric Acid Monohydrate consumption is 19.698g, Na2HPO4Consumption is 1.7608g;
(2) get recipe quantity CrCl3·6H2O、CuCl2·2H2O、MnCl2·4H2O、ZnCl2, NaF is with cushioning molten in right amountSolution liquid dissolves;
(3) sorbierite, taurine, the glycine of getting recipe quantity are used and are cushioned after lysate stirring and dissolving in right amount, add step (2)In the solution making, mix;
(4) add 0.02% active carbon (W/V) of step (3) gained liquor capacity, stirring and adsorbing 10～15min, circulationDe-charcoal 10～20min;
(5) get recipe quantity FeCl3·6H2O、Na2SeO3·5H2O、KI、Na2MoO4·2H2O is right by appropriate buffering respectivelyAfter lysate dissolves, add successively after the de-charcoal of step (4) in solution, add buffering to lysate extremely after stirring 10～15minFull dose, stirs and circulating filtration;
(6) after visible foreign matters and pH value passed examination, 0.22 μ m filter essence filter, embedding, sterilizing, to obtain final product.
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